Comparison of Clinical Outcomes and Adverse Events Associated with Glucose-Lowering Drugs in Patients with Type 2 Diabetes: a Meta-Analysis

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Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. doi:10.1001/jama.2016.9400.

eMethods. Summary of Statistical Analysis eTable 1. Search Strategies eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 4. Description of Included Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin Plus Sulfonylurea eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 7. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin plus Sulfonylurea eTable 8. Estimated Global Inconsistency in Networks of Outcomes eTable 9. Estimated Heterogeneity in Networks eTable 10. Definitions of Treatment Failure Outcome eTable 11. Contributions of Direct Evidence to the Networks of Treatments eTable 12. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes Given as Monotherapy eTable 13. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes When Used in Dual Therapy (in Addition to Metformin) eTable 14. Network Meta-analysis Estimates of Comparative Treatment Effects for Drug Classes Given as Triple Therapy eTable 15. Meta-regression Analyses for Drug Classes Given as Monotherapy (Compared With Metformin) eTable 16. Subgroup Analyses of Individual Sulfonylurea Drugs (as Monotherapy) on Hypoglycemia eTable 17. Sensitivity Analysis—Summary Treatment Estimates of Glucose-Lowering Interventions Restricted to Clinical Trials at Low Risk of Bias From Allocation Concealment Methods eFigure 1. Summary Study-Level Characteristics According to Drug Class eFigure 2. Networks of Secondary Outcomes eFigure 3. Evaluation of Loop Specific Consistency in Effect Estimates in Triangular and Quadratic Treatment Loops Within Each Network for Drug Classes Given as Monotherapy eFigure 4. Evaluation of Loop Specific Consistency in Effect Estimates in Triangular and Quadratic Treatment Loops Within Each Network for Drug Classes Given as Dual Therapy in Addition to Metformin eFigure 5. Evaluation of Loop Specific Consistency in Effect Estimates in Triangular and Quadratic Treatment Loops Within Each Network of Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea eFigure 6. Direct (Pairwise) and Network Estimates of Treatment Effects for Drug Classes Given as Monotherapy

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 7. Direct (Pairwise) and Network Estimates of Treatment Effects for Drug Classes Given as Dual Therapy in Addition to Metformin eFigure 8. Direct (Pairwise) and Network Estimates of Treatment Effects for Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea eFigure 9. Rankograms for Odds of Hypoglycemia Associated With Individual Sulfonylurea Drugs Given as Monotherapy eReferences

This supplementary material has been provided by the authors to give readers additional information about their

work.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eMethods. Summary of Statistical Analysis

The statistical analyses are presented in detail in the pre-specified protocol which is available at http://tinyurl.com/onjketx.

First, pairwise random-effects meta-analysis was conducted by synthesizing data from trials comparing two different drug classes. Using a random-effects model, different studies were assumed to assess different yet related treatment effects. The relative treatment effects of the competing interventions were estimated using standardized mean differences (SMD) for continuous outcomes (glycated hemoglobin (HbA1C) and body weight) and odds ratios for the dichotomous outcomes (cardiovascular mortality, all-cause mortality, treatment failure, hypoglycemia, and serious adverse events). An SMD equal to zero meant that the compared treatment strategies had equivalent effects. For both HbA1C and body weight, an improvement was assumed to be associated with lower values on the continuous outcomes of interest. Therefore, an SMD below zero indicated the degree to which the intervention was associated with lower HbA1C than the comparator and an SMD above zero indicated the degree to which the intervention was associated with a higher HbA1C than the comparator.

An odds ratio below 1 indicated that the treatment was associated with a lower odds of the outcome (all-cause mortality, cardiovascular mortality, hypoglycemia, serious adverse events) than the comparator while an odds ratio above 1 indicated that the treatment was associated with a greater odds of the outcome than the comparator. Risk differences were also estimated for all binary outcomes (all-cause mortality, cardiovascular mortality, serious adverse events, hypoglycemia) where they are reported in the text.

For indirect and mixed treatment estimates, network meta-analysis was conducted to compare different glucose- lowering drug classes. Network meta-analysis synthesized both direct evidence (from head to head trial comparisons) and indirect evidence (estimating the relative effectiveness between pairs of interventions even if these have never been compared directly in trials).2-4 Network analysis was then used to rank interventions.

A key assumption of network analysis was that of consistency; that one can learn about the relative effectiveness between the two interventions indirectly. Consistency implied that the distribution of effect modifiers was the same across treatment comparisons.5 For example, potential effect modifiers were similar across all included trials. The variables of age, baseline glycemic control, body weight, duration of diagnoses type 2 diabetes, and duration of treatment were all considered when assessing this assumption. Consistency implied that the studies comparing different drugs (for example metformin versus basal insulin or metformin versus placebo) were similar in terms of these patient and study characteristics. To maximize consistency, trials were stratified according to the intensity of drug treatment, assuming that people receiving three drugs for glucose control were likely to be different from those receiving only one- or two-drugs for glucose control. Networks of drug treatments were generated separately according to whether patients were receiving no, one (metformin), or two (metformin plus sulfonylurea) other drugs as glucose-lowering medication.

Frequentist random-effects network meta-analysis was performed in Stata using the mvmeta and network commands and self-programmed Stata routines available at http://www.mtm.uoi.gr/index.php/stata-routines-for-network-meta- analysis.6,7 The ranking probabilities for all treatments being at each possible rank for each intervention were estimated.8 The treatment hierarchy of the competing interventions was obtained by using rankograms, the surface under the cumulative ranking curve (SUCRA), and mean ranks.6,9 SUCRA expressed as a percentage the efficacy or safety of each intervention relative to an imaginary intervention that was always the best without uncertainty. A SUCRA of 80% meant that the intervention of interest was associated with 80% of the effectiveness of this imaginary intervention. The larger the SUCRA value for an intervention, the larger the association with treatment effect the intervention had.

In network meta-analysis, heterogeneity was assumed to be the same for all treatment comparisons within a single network. The restricted maximum likelihood (REML) method was used to estimate heterogeneity assuming a common estimate for the heterogeneity variance across the different drug classes. The assessment of heterogeneity

Downloaded From: https://jamanetwork.com/ on 10/02/2021 in the entire network was based on the magnitude of the heterogeneity variance parameter estimated from the network meta-analysis models. The heterogeneity variance was compared with the empirical distribution derived by Spiegelhalter et al.10

Disagreement between direct and indirect evidence challenges the consistency assumption. To evaluate for the presence of inconsistency, the loop-specific approach was used to evaluate the difference between direct and indirect estimates for a specific comparison in the loop (consistency factor). A common heterogeneity estimate within each loop was assumed. The results of this approach were also presented graphically in a forest plot in which the ratio of odds ratios between the direct and indirect evidence was plotted. A ratio with a 95% confidence interval excluding 1 indicated evidence of statistical inconsistency between a direct treatment estimate and an indirect treatment estimate derived from treatments within the same triangular or quadratic loop of evidence.11,12 To check the assumption of consistency in the entire network, the ‘design-by-treatment’ model was used as has been described by Higgins and colleagues.13 This method accounted for different potential sources of inconsistency that can occur when studies with different designs (two-arm trials versus three arm trials) gave different results as well as differences between direct and indirect evidence. Using this method, the presence of any inconsistency from sources in the entire network was inferred based on a chi-square test.

Finally, meta-regression analyses were conducted for the outcomes of HbA1C, hypoglycemia and body weight. Potential effect modifiers were assessed including baseline age, hbA1C, body weight, duration of diagnosed diabetes, and duration of treatment.

The systematic review was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement incorporating network meta-analyses of health care interventions.14

Differences between protocol and final review

The following changes to the review were made before data analyses were done:

1. Treatments were stratified according to monotherapy, added to metformin (dual therapy) and added to metformin and sulfonylurea (triple therapy) 2. Analyses were limited to the following drug classes: metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT-2 inhibitors, basal insulin, alpha glucosidase inhibitors, meglitinides and placebo. 3. Outcomes in this report were limited to mortality, serious adverse events, HbA1C, hypoglycemia, and body weight 4. Additional subgroup analyses were conducted to examine to any differences in risks of hypoglycemia with individual sulfonylurea drugs

The following additional analyses were conducted during revision of the manuscript:

5. Sensitivity analyses were conducted restricted to clinical trials at low risk of bias (low risk allocation concealment). 6. Myocardial infarction and stroke were added as additional individual endpoints

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 1. Search Strategies

Database Search items EMBASE: 1. diabetes mellitus/ 1974 to 2. non insulin dependent diabetes mellitus/ Week 12, 3. ((diabetes or diabetes mellitus or diabetic*) adj1 (type 2 or type II or type ii or non- 2016 insulin dependent or noninsulin dependent or adult onset or mature onset or late onset)).tw. 4. NIDDM.tw. 5. Diabetic Nephropathy/ 6. (diabetic nephropath* or diabetic kidney disease).tw. 7. or/1-6 8. long acting insulin/ 9. ((long acting or longer acting or intermediate acting) adj insulin*).tw. 10. insulin degludec/ 11. (insulin adj1 degludec).tw. 12. insulin detemir/ 13. (insulin adj1 detemir).tw. 14. insulin glargine/ 15. (insulin adj1 glargine).tw. 16. insulin zinc suspension/ 17. (insulin adj1 zinc).tw. 18. insulin aspart/ 19. (insulin adj1 aspart).tw. 20. insulin lispro/ 21. (insulin adj1 lispro).tw. 22. isophane insulin/ 23. (insulin adj1 isophane).tw. 24. (insulin adj1 lente).tw. 25. (insulin adj1 ultralente).tw. 26. meglitinide/ 27. meglitinide*.tw. 28. mitiglinide/ 29. mitiglinide.tw. 30. nateglinide/ 31. nateglinide.tw. 32. repaglinide/ 33. repaglinide.tw. 34. amylin derivative/ 35. (amylin analogue* or amylin derivative*).tw. 36. pramlintide/ 37. pramlintide.tw. 38. biguanide derivative/ 39. biguanide*.tw. 40. metformin.tw,sh. 41. sulphonylurea derivative/ 42. sulphonylurea*.tw. 43. acetohexamide/ 44. carbutamide/ 45. chlorpropamide/ 46. glibenclamide/ 47. glibornuride/ 48. gliclazide/ 49. glimepiride.sh,tw. 50. glipizide/ 51. gliquidone/ 52. tolazamide/

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Database Search items 53. acetohexamide.tw. 54. carbutamide.tw. 55. chlorpropamide.tw. 56. glibenclamide.tw. 57. gliclazide.tw. 58. glimepiride.tw. 59. glibornuride.tw. 60. glipizide.tw. 61. gliquidone.tw. 62. glyburide.tw. 63. glycopyramide.tw. 64. tolazamide.tw. 65. alpha glucosidase inhibitor/ 66. alpha glucosidase inhibitor*.tw. 67. acarbose/ 68. miglitol/ 69. voglibose/ 70. acarbose.tw. 71. miglitol.tw. 72. voglibose.tw. 73. glitazone derivative/ 74. (glitazone adj1 (derivative* or analogue*)).tw. 75. thiazolidinedione*.tw. 76. pioglitazone/ 77. rivoglitazone/ 78. rosiglitazone/ 79. pioglitazone.tw. 80. rivoglitazone.tw. 81. rosiglitazone.tw. 82. glucagon like peptide 1 receptor agonist/ 83. (glucagon-like peptide 1 receptor inhibitor* or glucagon-like peptide 1 receptor agonist* or glucagon-like peptide 1 inhibitor* or glucagon-like peptide 1 agonist* or GLP-1 receptor inhibitor* or GLP-1 receptor agonist* or GLP-1 inhibitor* or GLP-1 agonist*).tw. 84. albiglutide/ 85. dulaglutide/ 86. exendin 4/ 87. liraglutide/ 88. lixisenatide/ 89. semaglutide/ 90. taspoglutide/ 91. albiglutide.tw. 92. dulaglutide.tw. 93. (exenatide or exendin 4).tw. 94. liraglutide.tw. 95. lixisenatide.tw. 96. semaglutide.tw. 97. taspoglutide.tw. 98. dipeptidyl peptidase IV inhibitor/ 99. (dipeptidyl-peptidase IV Inhibitor* or dipeptidyl-peptidase 4 Inhibitor* or ((DPP4 or DPP 4 or DPP IV) adj inhibitor*)).tw. 100. alogliptin/ 101. anagliptin/ 102. gemigliptin/ 103. linagliptin/ 104. omarigliptin/

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Database Search items 105. saxagliptin/ 106. sitagliptin/ 107. teneligliptin/ 108. vildagliptin/ 109. alogliptin.tw. 110. anagliptin.tw. 111. gemigliptin.tw. 112. linagliptin.tw. 113. omarigliptin.tw. 114. saxagliptin.tw. 115. sitagliptin.tw. 116. teneligliptin.tw. 117. vildagliptin.tw. 118. sodium glucose cotransporter 2 inhibitor/ 119. (sodium glucose transporter 2 inhibitor* or sodium glucose transporter ii inhibitor* or SGLT 2 inhibitor*).tw. 120. (sodium glucose cotransporter adj3 inhibitor*).tw. 121. (sodium glucose co transporter adj3 inhibitor*).tw. 122. canagliflozin/ 123. dapagliflozin.tw. 124. empagliflozin/ 125. ertugliflozin/ 126. tofogliflozin/ 127. canagliflozin.tw. 128. dapagliflozin.tw. 129. empagliflozin.tw. 130. ertugliflozin.tw. 131. tofogliflozin.tw. 132. antidiabetic agent/ 133. oral antidiabetic agent/ 134. or/8-133 135. and/7,134 136. randomized controlled trial/ 137. double-blind procedure/ 138. single-blind procedure/ 139. random$.tw. 140. factorial$.tw. 141. placebo$.tw. 142. (double$ adj blind$).tw. 143. (singl$ adj blind$).tw. 144. assign$.tw. 145. allocat$.tw. 146. or/136-145 147. and/135,146 148. MEDLINE.cr. 149. 147 not 148 150. (mouse or mice or murine or rat or rats or dog or dogs or animal*).ti. 151. 149 not 150 152. (2013* or 2014*).em. 153. and/151-152 MEDLINE: 1. exp Diabetes Mellitus Type 2/ 1946 to 2. Diabetes Mellitus/ March 3. ((diabetes or diabetes mellitus or diabetic*) adj1 (type 2 or type II or type ii or non- week 2, insulin dependent or noninsulin 2016 dependent or adult onset or mature onset or late onset)).tw.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Database Search items 4. NIDDM.tw. 5. Diabetic Nephropathies/ 6. (diabetic nephropath* or diabetic kidney disease).tw. 7. or/1-6 8. exp Insulin, Long Acting/ 9. ((long acting or longer acting or intermediate acting) adj insulin*).tw. 10. (insulin adj1 degludec).tw. 11. (insulin adj1 glargine).tw. 12. (insulin adj1 detemir).tw. 13. (insulin adj1 zinc).tw. 14. (insulin adj1 isophane).tw. 15. (insulin adj1 aspart).tw. 16. (insulin adj1 lispro).tw. 17. (insulin adj1 lente).tw. 18. (insulin adj1 ultralente).tw. 19. Sulfonylurea Compounds/ 20. Acetohexamide/ 21. Carbutamide/ 22. Chlorpropamide/ 23. Gliclazide/ 24. Glipizide/ 25. Glyburide/ 26. Tolazamide/ 27. (sulphonylurea or sulphonylureas).tw. 28. acetohexamide.tw. 29. carbutamide.tw. 30. chlorpropamide.tw. 31. glibenclamide.tw. 32. gliclazide.tw. 33. glimepiride.tw. 34. glibornuride.tw. 35. glipizide.tw. 36. gliquidone.tw. 37. glyburide.tw. 38. glycopyramide.tw. 39. tolazamide.tw. 40. Biguanides/ 41. biguanides.tw. 42. Metformin/ 43. metformin.tw. 44. alpha-Glucosidases/ai [Antagonists & Inhibitors] 45. alpha glucosidase inhibitor*.tw. 46. Acarbose/ 47. acarbose.tw. 48. miglitol.tw. 49. voglibose.tw. 50. Thiazolidinediones/ 51. thiazolidinedione*.tw. 52. pioglitazone.tw. 53. rivoglitazone.tw. 54. rosiglitazone.tw. 55. meglitinide*.tw. 56. repaglinide.tw. 57. nateglinide.tw. 58. mitiglinide.tw. 59. Receptors, Glucagon/ag

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Database Search items 60. Glucagon-like Peptide 1/ag 61. (glucagon-like peptide 1 receptor inhibitor* or glucagon-like peptide 1 receptor agonist* or glucagon-like peptide 1 inhibitor* or glucagon-like peptide 1 agonist* or GLP-1 receptor inhibitor* or GLP-1 receptor agonist* or GLP-1 inhibitor* or GLP-1 agonist*).tw. 62. dulaglutide.tw. 63. (exenatide or exendin 4).tw. 64. liraglutide.tw. 65. semaglutide.tw. 66. taspoglutide.tw. 67. lixisenatide.tw. 68. albiglutide.tw. 69. Dipeptidyl-peptidase IV Inhibitors/ 70. (dipeptidyl-peptidase IV Inhibitor* or dipeptidyl-peptidase 4 Inhibitor* or ((DPP4 or DPP 4 or DPP IV) adj inhibitor*)).tw. 71. omarigliptin.tw. 72. vildagliptin.tw. 73. sitagliptin.tw. 74. saxagliptin.tw. 75. linagliptin.tw. 76. alogliptin.tw. 77. septagliptin.tw. 78. gemigliptin.tw. 79. anagliptin.tw. 80. teneligliptin.tw. 81. Sodium-Glucose Transporter 2/ai 82. (sodium glucose transporter 2 inhibitor* or sodium glucose transporter ii inhibitor* or SGLT 2 inhibitor*).tw. 83. (sodium glucose cotransporter adj3 inhibitor*).tw. 84. (sodium glucose co transporter adj3 inhibitor*).tw. 85. canagliflozin.tw. 86. dapagliflozin.tw. 87. empagliflozin.tw. 88. ertugliflozin.tw. 89. tofogliflozin.tw. 90. (amylin adj1 (analogue* or derivative*)).tw. 91. pramlintide.tw. 92. Insulins/ 93. Hypoglycemic Agents/ 94. or/8-93 95. and/7,94 96. randomized controlled trial.pt. 97. controlled clinical trial.pt. 98. pragmatic clinical trial.pt. 99. randomized.ab. 100. placebo.ab. 101. clinical trials as topic/ 102. randomly.ab. 103. trial.ti. 104. or/96-103 105. animals/ not (humans/ and animals/) 106. 104 not 105 107. and/95,106 CENTRAL: 1. MeSH descriptor: [Diabetes Mellitus] this term only issue 2 of 2. ((diabetes or diabetic* or "diabetes mellitus") near/1 ("type 2" or "type ii" or "non-insulin 12, 2016 dependent" or "non insulin dependent" or "noninsulin dependent" or "adult onset" or

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Database Search items "mature onset" or "late onset")):ti,ab,kw 3. ("diabetes mellitus" not "insulin dependent diabetes mellitus"):kw 4. #3 and EMBASE 5. NIDDM:ti,ab,kw 6. ((diabetic next nephropath*) or "diabetic kidney disease"):ti,ab,kw 7. or #1-#2, #4-#6 8. ((long acting or longer acting or intermediate acting) near/1 insulin*):ti,ab,kw 9. insulin near/1 degludec:ti,ab,kw 10. insulin near/1 detemir:ti,ab,kw 11. insulin near/1 glargine:ti,ab,kw 12. insulin near/1 zinc 13. insulin near/1 aspart:ti,ab,kw 14. insulin near/1 lispro:ti,ab,kw 15. insulin near/1 isophane:ti,ab,kw 16. insulin near/1 ultralente:ti,ab,kw 17. insulin near/1 lente 18. meglitinide*:ti,ab,kw 19. mitiglinide:ti,ab,kw 20. nateglinide:ti,ab,kw 21. repaglinide:ti,ab,kw 22. (amylin next analogue* or amylin next derivative*):ti,ab,kw 23. pramlintide:ti,ab,kw 24. biguanide*:ti,ab,kw 25. metformin:ti,ab,kw 26. (sulfonylurea* or sulphonylurea*):ti,ab,kw 27. acetohexamide:ti,ab,kw 28. carbutamide:ti,ab,kw 29. chlorpropamide:ti,ab,kw 30. glibenclamide:ti,ab,kw 31. gliclazide:ti,ab,kw 32. glimepiride:ti,ab,kw 33. glibornuride:ti,ab,kw 34. glipizide:ti,ab,kw 35. gliquidone:ti,ab,kw 36. glyburide:ti,ab,kw 37. glycopyramide:ti,ab,kw 38. tolazamide:ti,ab,kw 39. MeSH descriptor: [alpha-Glucosidases] this term only and with qualifier(s): [Antagonists & inhibitors – Al] 40. alpha next glucosidase next inhibitor*:ti,ab,kw 41. acarbose:ti,ab,kw 42. miglitol:ti,ab,kw 43. voglibose:ti,ab,kw 44. (glitazone near/1 (derivative* or analogue*)):ti,ab,kw 45. thiazolidinedione*:ti,ab,kw 46. pioglitazone:ti,ab,kw 47. rivoglitazone:ti,ab,kw 48. rosiglitazone:ti,ab,kw 49. MeSH descriptor: [Receptors, Glucagon] explode all trees and with qualifier(s): [Agonists - AG] 50. MeSH descriptor: [Glucagon-Like Peptide 1] explode all trees and with qualifier(s): Antagonists & inhibitors – Al] 51. ("glucagon-like peptide 1 receptor inhibitor" or "glucagon-like peptide 1 receptor agonist" or "glucagon-like peptide 1 inhibitor" or "glucagon-like peptide 1 agonist" or "GLP-1 receptor inhibitor" or "GLP-1 receptor agonist" or "GLP-1 inhibitor" or "GLP-1 agonist"):ti,ab,kw

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Database Search items 52. ("glucagon-like peptide 1 receptor inhibitors" or "glucagon-like peptide 1 receptor agonists" or "glucagon-like peptide 1 inhibitors" or "glucagon-like peptide 1 agonists" or "GLP-1 receptor inhibitors" or "GLP-1 receptor agonists" or "GLP-1 inhibitors" or "GLP- 1 agonists"):ti,ab,kw 53. albiglutide:ti,ab,kw 54. dulaglutide:ti,ab,kw 55. (exenatide or "exendin 4"):ti,ab,kw 56. liraglutide:ti,ab,kw 57. lixisenatide:ti,ab,kw 58. semaglutide:ti,ab,kw 59. taspoglutide:ti,ab,kw 60. "dipeptidyl-peptidase IV Inhibitor" or "dipeptidyl-peptidase 4 Inhibitor" or "dipeptidyl- peptidase IV Inhibitors" or "dipeptidyl-peptidase 4 Inhibitors"):ti,ab,kw 61. ((DPP4 or DPP 4 or DPP IV) next inhibitor*):ti,ab,kw 62. alogliptin:ti,ab,kw 63. anagliptin:ti,ab,kw 64. gemigliptin:ti,ab,kw 65. linagliptin:ti,ab,kw 66. omarigliptin:ti,ab,kw 67. saxagliptin:ti,ab,kw 68. sitagliptin:ti,ab,kw 69. teneligliptin:ti,ab,kw 70. vildagliptin:ti,ab,kw 71. MeSH descriptor: [Sodium-Glucose Transporter 2] explode all trees and with qualifier(s): [Antagonists & inhibitors - AI] 72. ("sodium glucose transporter 2 inhibitor" or "sodium glucose transporter ii inhibitor" or "SGLT 2 inhibitor" or "sodium glucose transporter 2 inhibitors" or "sodium glucose transporter ii inhibitors" or "SGLT 2 inhibitors"):ti,ab,kw 73. ("sodium glucose cotransporter" near/3 inhibitor*):ti,ab,kw 74. ("sodium glucose co-transporter" near/3 inhibitor*):ti,ab,kw 75. canagliflozin:ti,ab,kw 76. dapagliflozin:ti,ab,kw 77. empagliflozin:ti,ab,kw 78. ertugliflozin:ti,ab,kw 79. tofogliflozin:ti,ab,kw 80. MeSH descriptor: [Insulins] this term only 81. MeSH descriptor: [Hypoglycemic Agents] this term only 82. (antidiabetic next agent*):kw 83. (oral next antidiabetic next agent*):kw 84. or #8-#83 85. and #7, #84

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 2000 mg Metformin 111 4.08 52.6 56.6 8.39 81.79 6 daily 1000 mg MET v Metformin 114 3.78 54.6 53.6 8.5 81.69 6 Pratley NCT01 daily 22 DPP-4-i 2014 023581 v PCO Alogliptin 25 mg daily 112 3.65 52.6 53.8 8.3 81.82 6 Alogliptin 25 mg daily 113 3.97 53.7 71.2 8.44 82.83 6 Placebo 109 4.25 53.1 60 8.49 86.92 6 2000 mg Metformin 182 4.4 53.2 45.1 8.7 5.5 daily MET v 1000 mg Sitaglipti NCT00 Metformin 182 4.5 53.4 48.9 8.9 5.5 23 DPP-4-i n 036 103857 daily v PCO Sitagliptin 100 mg daily 179 4.4 53.3 52 8.9 5.5 Placebo 176 4.6 53.6 52.8 8.7 5.5 1500 mg Metformin 62 7.3 58.7 72.6 8.2 8.3 MET v daily Wolever 24 NA AGI v 75-300 mg 2000 Miglitol 45 4.7 56.8 86.7 7.9 8.3 PCO daily Placebo 45 4.5 58.5 60 7.8 8.3 1500 mg MET v Metformin 178 4.5 56.8 68 8.4 5.5 Horton GLITINI daily 25 NA 2000 DE v Nateglinide 360 mg daily 179 4.7 58.6 61.5 8.3 5.5 PCO Placebo 172 4.6 59.6 60.5 8.3 5.5 0.625-2.5 mg Banerji SU v Glipizide 10 90 4.7 36 26 NA daily 1995 PCO Placebo 10 30 4.7 36 2.5-15 mg Glipizide 15 15 daily Birkelan SU v 1.75-10.5 mg 27 NA Glyburide 15 15 d 1994 PCO daily Placebo 16 15 Camerin 20-40 mg Glipizide 46 4.8 46.8 12.7 24 i- SU v daily NA Davalos PCO 28 Placebo 31 5.6 47.1 12.9 24 1988 4.3 mg daily SU v Glibenclamide 27 1.5 59.5 48 8.3 5.5 Essen (mean) 29 NA AGI v 1994 Acarbose 300 mg daily 28 1.1 58.8 46 8.29 5.5 PCO Placebo 30 1 56.9 40 8.29 5.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 1.25-20 mg Glyburide 92 7.2 67.7 64.1 8.4 12 daily SU v Johnsto Miglitol 150 mg daily 85 6.8 67.8 71.8 8.4 12 30 NA AGI v n 1998 PCO Miglitol 75 mg daily 95 7.5 67.2 63.2 8.3 12 Placebo 92 7 68.5 71.7 8.4 12 3.5-7 mg Glibenclamide 69 56 62.2 7.96 6 SU v daily Segal 31 NA AGI v 150-300 mg 1997 Miglitol 67 61 55 7.95 6 PCO daily Placebo 65 59 57.1 8.25 6 Rivoglitazone 1.5 mg daily 750 4.3 55.1 50.9 7.7 80.6 6 Chou NCT00 TZD v Rivoglitazone 1 mg daily 274 5 55 48.2 7.7 80.5 6 32 2012 484198 PCO Pioglitazone 45 mg daily 751 4.4 55 53 7.7 81.6 6 Placebo 137 4.9 55.4 48.9 7.7 82 6 Not Hong TZD v Pioglitazone Not reported 25 6 33 provide 2013 PCO d Placebo 25 6 Not Hu TZD v Rosiglitazone 4 mg daily 40 62 55 8.6 6 34 provide 2007 PCO d Placebo 38 62 52 8.5 6 Rosiglitazone 4 mg daily 159 5 55 62.9 8.9 7 Kikuchi NCT00 TZD v 35 Pioglitazone 30 mg daily 159 4.2 56 62.3 8.8 7 2012 297063 PCO Placebo 54 4.2 53.9 61.1 9 7 Kim NCT01 TZD v Lobeglitazone 0.5 mg daily 115 4.31 56.36 57.39 7.95 66.45 5.5 36 2014 001611 PCO Placebo 58 4.9 54.72 55.17 8.05 95.93 5.5 Rosiglitazone 8 mg daily 169 5.4 61 66.9 8.8 6 Lebovitz TZD v 37 NA Rosiglitazone 4 mg daily 166 4.8 60 64.5 9 6 2001 PCO Placebo 158 4.6 59 65.8 9 6 Pioglitazone 45 mg daily 11 55 45.5 9.1 86 6 Pioglitazone 30 mg daily 11 51 72.7 8.5 97 6 Miyazaki TZD v 38 NA Pioglitazone 15 mg daily 12 57 66.7 8 93 6 2002 PCO Pioglitazone 7.5 mg daily 13 51 76.9 8.9 93 6 Placebo 11 58 27.3 8.6 90 6

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years Rosiglitazone 8 mg daily 181 6.1 58.9 65.7 8.9 6 Rosiglitazone 8 mg daily 187 5.9 56.5 65.2 9 6 Phillips TZD v 39 NA Rosiglitazone 4 mg daily 181 5.4 57.5 58.6 8.9 6 2001 PCO Rosiglitazone 4 mg daily 186 5.5 56.8 59.1 8.9 6 Placebo 173 6.6 57.7 68.8 8.9 6 Pioglitazone 45 mg daily 76 10.3 90.8 6 Pioglitaz Pioglitazone 30 mg daily 85 10.2 90.3 6 TZD v one NA Pioglitazone 15 mg daily 79 10.2 91.2 6 40 PCO 001 Pioglitazone 7.5 mg daily 80 10 93.5 6 Placebo 79 10.4 90.4 6 Rahman NCT00 TZD v Rosiglitazone 4 mg daily 11 7.5 12 41 2010 489229 PCO Placebo 11 8.3 12 Scherba Pioglitazone 30 mg daily 78 4.6 59.6 41 9.06 82 6 TZD v um NA Pioglitazone 15 mg daily 89 5.4 58 62.9 9.33 87.2 6 42 PCO 2002 Placebo 84 5.6 59.1 55.9 8.75 84.8 6 Pioglitazone 45 mg daily 91 6.6 56.6 58.2 7.98 94.9 6 Rivoglitazone 3 mg daily 86 6.7 56.4 52.3 8.23 95.8 6 Truitt NCT00 TZD v 43 Rivoglitazone 2 mg daily 85 5.2 55 56.5 8.05 96.3 6 2010 143520 PCO Rivoglitazone 1 mg daily 87 6.2 55.4 52.9 8 93.3 6 Placebo 92 6.7 55.3 51.1 8.21 92.9 6 Not 15-45 mg Wajcber TZD v Pioglitazone 16 7.1 51 43.8 8.1 87 5.5 44 provide daily g 2007 PCO d Placebo 15 6.9 49 46.7 7.9 87 5.5 Yee NCT00 TZD v Rosiglitazone 4-8 mg daily 28 7.5 62.6 78.6 7.65 79.6 12 45 2010 231387 PCO Placebo 29 10 66.1 79.3 7.55 81.8 12 Alogliptin 25 mg daily 131 6 Aloglipti NCT00 DPP-4-i 12.5 mg n Study Alogliptin 133 6 46 286455 v PCO daily 010 Placebo 64 6 50-100 mg Sitagliptin 102 7.2 71.6 47 7.8 85.6 5.5 Barzilai NCT00 DPP-4-i daily 201147 305604 v PCO Placebo 104 7 72.1 47 7.8 85.8 5.5 Chen NCT01 DPP-4-i Linagliptin 5 mg daily 200 54.6 58 7.95 69 5.5 48 2015 214239 v PCO Placebo 99 54.1 59.6 8.09 68.2 5.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years Saxagliptin 10 mg daily 98 2.3 52.72 45.9 7.8 89.3 6 CV181- NCT00 DPP-4-i Saxagliptin 5 mg daily 106 2.5 53.91 50.9 8 90.9 6 49 011 121641 v PCO Saxagliptin 2.5 mg daily 102 3.1 53.27 56.9 7.9 92.1 6 Placebo 95 2.3 53.91 49.5 7.9 86.56 6 Vildagliptin 100 mg daily 157 2.4 53.6 53.3 8.4 5.5 Dejager NCT00 DPP-4-i Vildagliptin 50 mg daily 163 2.1 55.3 41.3 8.2 5.5 50 2007 099905 v PCO Vildagliptin 100 mg daily 152 2.1 52.8 46.7 8.6 5.5 Placebo 160 1.6 52.2 47.9 8.4 5.5 Del NCT00 DPP-4-i Linagliptin 5 mg daily 336 56.4 48.8 8 78.53 5.5 Prato 51 621140 v PCO 2011 Placebo 167 54.4 47.3 8 79.21 5.5 Foley NCT00 DPP-4-i Vildagliptin 100 mg daily 29 1.4 57.4 58.6 6 90.2 12 52 2011 260156 v PCO Placebo 30 0.6 57 60 6 87.6 12 Saxagliptin 5 mg daily 74 1.7 54.7 51.4 8 86.5 5.5 Saxagliptin 5 mg daily 72 2 55.1 45.8 7.9 83.3 5.5 Frederic NCT00 DPP-4-i Saxagliptin 2.5 mg daily 74 1.2 55.2 33.8 8 83.8 5.5 53 h 2012 316082 v PCO 2.5-5 mg Saxagliptin 71 2 54.3 52.1 8 85.4 5.5 daily Placebo 74 1.7 55.6 47.3 7.8 85.4 5.5 100 mg Trelagliptin 102 6.25 58 72 7.73 69.23 5.5 Inagaki NCT01 DPP-4-i weekly 201554 632007 v PCO Alogliptin 25 mg daily 92 7.1 60 75 7.87 67.37 5.5 Placebo 51 7.54 62 86 7.72 67.2 5.5 Mari NCT00 DPP-4-i Vildagliptin 50 mg daily 156 2.5 63.3 59.6 6.7 12 55 2008 101712 v PCO Placebo 150 2.7 62.8 59.3 6.8 12 Pan NCT00 DPP-4-i Saxagliptin 5 mg daily 284 0.8 51.2 56.3 8.1 69.2 5.5 56 2012a 698932 v PCO Placebo 284 1.2 51.6 54.6 8.2 69.2 5.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years Vildagliptin 100 mg daily 91 2.1 52 53.8 8.3 90.8 6 Pi- NCT00 DPP-4-i Vildagliptin 100 mg daily 83 2.4 50.2 56.6 8.4 89.9 6 Sunyer 102053 57 v PCO 2007 6 Vildagliptin 50 mg daily 88 1.8 50.6 55.7 8.4 90.5 6 Placebo 92 2.5 52 54.3 8.5 93 6 Scherba NCT00 DPP-4-i Vildagliptin 50 mg daily 156 2.5 63.3 59.6 6.7 86 12 um 58 101712 v PCO 2008 Placebo 150 2.7 62.8 59.3 6.8 85 12 Sitagliptin 200 mg daily 238 4.3 54.9 46.8 8.1 83.7 5.5 Sitaglipti NCT00 DPP-4-i 59 Sitagliptin 100 mg daily 229 4.3 53.4 57.1 8 85 5.5 n 021 087516 v PCO Placebo 244 4.6 54.3 51.4 8 85 5.5 Thrashe NCT01 DPP-4-i Linagliptin 5 mg daily 106 53.7 56.6 8.68 95.8 5.5 60 r 2014 194830 v PCO Placebo 120 54.1 50.8 8.78 99 5.5 Not Wu DPP-4-i Linagliptin 5 mg daily 34 52.5 65.7 7.97 67.05 5.5 61 provide 2015 v PCO d Placebo 23 51.2 50 8 65.24 5.5 Not Yang DPP-4-i Gemigliptin 50 mg daily 90 3.24 65.5 8.2 5.5 62 provide 2013 v PCO d Placebo 92 2.86 50.6 8.3 5.5 Sitagliptin 100 mg daily 223 55.1 63 7.85 79.3 5.5 DPP-4-i EMPA- NCT01 v SGLT- Empagliflozin 25 mg daily 224 53.8 65 7.86 77.8 5.5 REG 63 177813 2-i v MONO Empagliflozin 10 mg daily 224 56.2 63 7.87 78.4 5.5 PCO Placebo 228 54.9 54 7.91 78.2 5.5 Gastald GLP- Exenatide 20 mcg daily 37 59 37.9 7.73 87.1 5.5 NCT00 elli 1RA v Exenatide 10 mcg daily 33 57 38.5 7.78 87.4 5.5 64 381342 2014 PCO Placebo 34 54 50 7.77 91.9 5.5 GLP- Albiglutide 50 mg daily 102 4.2 52.8 50.5 8.2 97.1 5.5 HARMO NCT00 65 1RA v Albiglutide 30 mg daily 102 3.4 53.6 57.4 8 95.8 5.5 NY 2 849017 PCO Placebo 105 4.3 53.1 57.4 8 95.4 5.5 0.75 mg Miyaga GLP- Dulaglutide 281 6.8 57.2 81 8.15 71.3 5.5 NCT01 weekly wa 1RA v 66 558271 Liraglutide 0.9 mg daily 141 6.3 57.9 83 8.08 70.2 5.5 2015 PCO Placebo 70 6.3 57.7 79 8.2 69.3 5.5 GLP- Exenatide 20 mcg daily 78 2 55 61.5 7.8 86 5.5 Moretto NCT00 67 1RA v Exenatide 10 mcg daily 77 2 54 51.9 7.9 85 5.5 2008 381342 PCO Placebo 78 1 53 54.5 7.8 86 5.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years T- GLP- Taspoglutide 20 mg daily 131 2.1 55 36 7.7 85 6 NCT00 Emerge 1RA v Taspoglutide 10 mg daily 118 2.8 53.4 37 7.5 88.4 6 68 744926 1 PCO Placebo 124 2.3 55.8 37 7.6 87.4 6 Dapagliflozin 5 mg daily 69 1.4 51.3 47.1 7.9 85.4 5.5 Not Bailey SGLT-2- Dapagliflozin 2.5 mg daily 74 1.5 53.5 45.9 8.1 84.3 5.5 69 provide 2012 i v PCO d Dapagliflozin 1 mg daily 72 1.6 53.7 52.8 7.8 88.2 5.5 Placebo 68 1.1 53.5 54.4 7.8 90 5.5 Canagliflozin 300 mg daily 197 4.3 55.3 45.2 8 86.9 6 CANTA NCT01 SGLT-2- 70 Canagliflozin 100 mg daily 195 4.5 55.1 41.5 8.1 85.8 6 TA-M 081834 i v PCO Placebo 192 4.2 55.7 45.8 8 87.6 6 Dapagliflozin 10 mg daily 70 50.6 48.6 8.01 94.2 5.5 Ferranni NCT00 SGLT-2- Dapagliflozin 5 mg daily 64 52.6 48.4 7.86 87.6 5.5 ni 71 528372 i v PCO 2010 Dapagliflozin 2.5 mg daily 65 53 55.4 7.92 90.8 5.5 Placebo 75 52.7 41.3 7.84 88.8 5.5 Canagliflozin 200 mg daily 89 5.88 57.4 81.8 8.04 69.88 5.5 Inagaki NCT01 SGLT-2- 72 Canagliflozin 100 mg daily 90 4.72 58.4 65.6 7.98 69.1 5.5 2014 413204 i v PCO Placebo 93 5.63 58.2 64.5 8.04 68.57 5.5 Dapagliflozin 10 mg daily 133 1.67 51.2 64.7 8.28 70.92 5.5 Ji NCT01 SGLT-2- 73 Dapagliflozin 5 mg daily 128 1.15 53 65.6 8.14 68.89 5.5 2014 095653 i v PCO Placebo 132 1.3 49.9 65.9 8.35 72.18 5.5 Tofogliflozin 40 mg daily 59 6.7 57 67.2 8.37 68.72 5.5 Japic Kaku SGLT-2- Tofogliflozin 20 mg daily 60 6.4 56.6 67.2 8.34 68.06 5.5 74 CTI- 2014 i v PCO 101349 Tofogliflozin 10 mg daily 59 6.3 58.6 66.7 8.45 67.26 5.5 Placebo 57 6 56.8 66.1 8.41 71.2 5.5 Not Dapagliflozin 10 mg daily 88 4.93 57.5 60.2 7.46 69.7 5.5 Kaku SGLT-2- 75 provide Dapagliflozin 5 mg daily 86 4.59 58.6 58.1 7.5 65.81 5.5 2014a i v PCO d Placebo 87 5.29 60.4 59.8 7.5 65.96 5.5 Asian 150-300 mg Acarbose 63 2.7 52.8 50.8 8.2 64.1 5.5 Acarbos AGI v daily NA e PCO 76 Placebo 63 2.1 54 50.8 8.6 65.4 5.5 Study 150-300 mg Braun AGI v Acarbose 80 1.3 60 61.9 10 76.3 6 77 NA daily 1996 PCO Placebo 72 1.4 61 54.5 9.9 76 6

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 150-600 mg Chiasso AGI v Acarbose 38 12 78 NA daily n 1994 PCO Placebo 39 62.3 12 75-300 mg Chiasso AGI v Miglitol 82 5.2 57.3 78 8.2 91 8.3 79 NA daily n 2001 PCO Placebo 83 5.1 57.7 67.5 8.1 88.6 8.3 150-900 mg Coniff AGI v Acarbose 105 56 45 6.78 93.4 5.5 80 NA daily 1994 PCO Placebo 107 55.6 54 6.65 94.5 5.5 Coniff AGI v Acarbose 600 mg daily 76 5.1 56.2 39 6.88 81.6 5.5 81 NA 1995 PCO Placebo 72 5.5 56.3 52 7.1 85.8 5.5 Not 150-300 mg Derosa AGI v Acarbose 96 49 6.8 75.1 7 82 provide daily 2011 PCO d Placebo 92 48.9 6.7 76.5 7 Miglitol 600 mg daily 93 64 63.8 8.1 79 5.5 Miglitol 300 mg daily 94 63 52.1 8 82 5.5 Drent AGI v 83 NA Miglitol 150 mg daily 93 63 56 8.09 79 5.5 2002 PCO Miglitol 75 mg daily 92 64 48.8 8.14 79 5.5 Placebo 93 63 56.3 7.94 79 5.5 Acarbose 600 mg daily 98 1.8 59.4 51 7.51 5.5 Acarbose 300 mg daily 99 1.4 56.8 59 7.43 5.5 Fischer AGI v 84 NA Acarbose 150 mg daily 99 1.7 55.5 49 7.52 5.5 1998 PCO Acarbose 75 mg daily 102 2.2 58.5 53 7.42 5.5 Placebo 97 2 52.7 53 7.26 5.5 Hanefel AGI v Acarbose 300 mg daily 50 5.8 60 49 9.2 76.2 5.5 85 NA d 1991 PCO Placebo 50 4.1 59 53 9.5 78.2 5.5 100-600 mg Hasche AGI v Acarbose 36 63.8 47.2 8.5 74.3 24 86 NA daily 1999 PCO Placebo 38 63.1 50 8.3 75.5 24 Hegele AGI v Acarbose Not reported 70 53.7 48.6 12.2 12 87 NA 1995 PCO Placebo 71 55.5 46.5 12.4 12 Hotta AGI v Acarbose 300 mg daily 20 4.6 49.8 73.7 11.1 60.7 5.5 88 NA 1993 PCO Placebo 20 4.8 47.9 77.8 10.4 60.8 5.5 50-300 mg Josse AGI v Acarbose 93 5.8 69.7 69.9 7.4 79.4 12 89 NA daily 2003 PCO Placebo 99 4.8 70.3 60.6 7.3 81.3 12

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years Leonhar AGI v Acarbose 300 mg daily 47 5.5 dt NA 90 PCO 1991 Placebo 47 5.5 150-300 mg Meneilly AGI v Acarbose 22 68 7.3 12 91 NA daily 2000 PCO Placebo 23 70 7 12 Mitrakou AGI v Miglitol 300 mg daily 60 8.48 57.4 48.3 9.9 67.3 5.5 92 NA 1998 PCO Placebo 60 7.87 57.4 61.7 9.9 68.9 5.5 Patel NCT01 AGI v Acarbose 300 mg daily 109 53.6 36 6.13 96.9 12 93 2013 470937 PCO Placebo 110 53.6 38 6.12 97.7 12 Jovanov GLITINI Repaglinide 12 mg daily 146 6.3 57.6 60 8.7 5.5 ic NA DE v Repaglinide 3 mg daily 140 6.6 57.9 69 8.9 5.5 94 2000 PCO Placebo 75 6.8 58.5 65 8.6 5.5 Nateglinide 360 mg daily 171 3.7 59.6 65.5 6.57 5.5 GLITINI Salorant Nateglinide 180 mg daily 175 3.6 61.1 61.1 6.53 5.5 95 NA DE v a 2002 PCO Nateglinide 90 mg daily 166 3.8 61 63.3 6.55 5.5 Placebo 163 3.2 59.1 60.1 6.45 5.5 ChiCTR 500-1500 mg Metformin 80 55.6 8 68.6 5.5 Bi -TRC- MET v daily 201396 100009 SU 5-15 mg Glipizide 80 54.5 8.1 67.2 5.5 41 daily 1000-3000 Metformin 24 2.3 57 33.3 11.5 78.2 12 Campbe MET v mg daily 97 NA ll 1994 SU 5-30 mg Glipizide 24 2.8 57 33.3 11.8 82.2 12 daily 1500 mg Metformin 18 52.5 12 Dalzell MET v daily 98 NA 1986 SU 1500 mg Tolbutamide 15 54.1 12 daily 1000-3000 Derosa MET v Metformin 83 58 50.6 8.4 12 99 NA mg daily 2004a SU Glimepiride 1-4 mg daily 81 56 46.9 8.5 12 Not 500-2000 mg Rahman MET v Metformin 102 51.9 48 10.5 78.1 12 100 provide daily 2011 SU d Glimepiride 2-8 mg daily 102 52 47 10.6 77.6 12 SPREA 750-1500 mg Metformin 156 5.6 62.8 78.2 7.6 69.6 36 D- NCT00 MET v daily DIMCA 513630 SU 15-30 mg 101 Glipizide 148 5.6 63.8 77 7.6 68.7 36 D daily

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 500-2000 mg Metformin 1455 57.9 59.4 7.36 91.6 48 1 MET v daily ADOPT NCT00 02 SU v 2.5-15 mg 279045 Glyburide 1447 56.4 58 7.35 92 48 TZD daily Rosiglitazone 4-8 mg daily 1458 56.3 55.7 7.36 91.5 48 500-2000 mg Metformin 20 52.2 31.6 7.62 87.47 12 daily Not MET v Erem 30-120 mg 103 provide SU v Gliclazide 20 55 36.8 8.26 90.06 12 2014 daily d TZD 15-45 mg Pioglitazone 20 52.5 26.3 8.03 81.93 12 daily 1000-3000 Metformin 21 59.5 60 8.04 6 mg daily Lawrenc MET v 80-160 mg e NA SU v Gliclazide 22 63.5 65 7.95 6 104 daily 2004 TZD 30-45 mg Pioglitazone 21 60.4 70 7.43 6 daily Metformin 750 mg daily 39 3 54.7 51.3 9.9 12 Yamano MET v uchi NA SU v Glimepiride 1-2 mg daily 37 3.3 55.6 51.4 9.8 12 105 30-45 mg 2005 TZD Pioglitazone 38 3.2 55.2 47.4 10.2 12 daily 1700 mg Not MET v Metformin 29 0 54 62.1 8.07 71.6 6 Wang daily 106 provide SU v 2013 Gliclazide 120 mg daily 30 0 55.89 70 8.4 70.4 6 d AGI Acarbose 300 mg daily 27 0 54.7 66.7 8.06 70.4 6 Bilezikia 1000-2000 NCT00 MET v Metformin 111 3.3 64 0 6.8 76.9 12 n mg daily 107 679939 TZD 2013 Rosiglitazone 4-8 mg daily 114 3.9 63.6 0 6.8 76.9 12 1000-3000 Not Metformin 67 55 50.7 9.1 77.7 15 Derosa MET v mg daily 108 provide 2009a TZD 15-45 mg d Pioglitazone 69 54 46.4 9.2 76.7 15 daily 1000-2000 Not Metformin 55 54.9 50.9 8.1 83.5 5.5 Esposito MET v mg daily 109 provide 2011 TZD 15-45 mg d Pioglitazone 55 54.2 54.5 8 84.5 5.5 daily Not 1500 mg Ma MET v Metformin 30 53.8 53.3 7.82 12 110 provide daily 2015 TZD d Pioglitazone 15 mg daily 30 55.3 60 8.13 12 850-2250 mg Metformin 100 0.5 55.8 56 8.6 88.9 6 Pavo MET v daily 111 NA 2003 TZD 30-45mg Pioglitazone 105 0.5 54.2 43.8 8.6 86.6 6 daily

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 2250 mg QUART MET v Metformin 597 3.1 56 57.8 8.7 89.7 12 112 NA daily ER TZD Pioglitazone 45 mg daily 597 3.4 57 52.6 8.7 88.2 12 Rosenst Not 500-2000 mg MET v Metformin 154 2.9 51.5 56 8.8 7.4 ock provide daily 113 TZD 2006 d Rosiglitazone 4-8 mg daily 159 2.7 50.6 58 8.8 7.4 Not 2000 mg Sohn MET v Metformin 8 1.05 52 50 8.96 59.9 8 114 provide daily 2008 TZD d Rosiglitazone 8 mg daily 11 1.81 48.1 63.6 8.78 65.8 8 Not 1500 mg Wu MET v Metformin 47 60.1 7.2 12 115 provide daily 2014 TZD d Pioglitazone 15 mg daily 46 60.3 7.1 12 2000 mg MET v Metformin 246 2.6 54 62.6 8.6 85.9 6 TZD v daily DURATI NCT00 DPP-4-i Pioglitazone 45 mg daily 163 2.7 55 59.5 8.5 86.1 6 116 ON-4 676338 v Sitagliptin 100 mg daily 163 2.7 52 57.7 8.5 88.7 6 GLP- 2.0 mg Exenatide 248 2.7 54 56 8.5 87.5 6 1RA weekly Not MET v Metformin 850 mg daily 16 52.4 6.7 12 Kiyici 117 provide TZD v Rosiglitazone 4mg daily 19 50.7 7.1 12 2009 d CON Control 15 52.1 6.4 12 1700 mg Metformin 16 1.5 56.8 25 6.3 80 6 Turkme Not MET v daily n Kemal provide TZD v Rosiglitazone 8 mg daily 13 2.75 55.92 23.1 6.2 75 6 2007118 d CON Control 17 1.2 54.59 23.5 5.7 78.1 6 500-2000 mg Metformin 328 1.7 51.8 49.7 9.4 83.1 18 CV181- NCT00 MET v daily 039119 327015 DPP-4-i Saxagliptin 10 mg 335 1.7 52.1 50.4 9.6 82.8 18 Schweiz 2000 mg NCT00 MET v Metformin 254 53.6 57.5 8.7 12 er daily 120 099866 DPP-4-i 2007 Vildagliptin 100 mg daily 526 52.8 52.9 8.7 91.4 12 Schweiz NCT20 500-1500 mg MET v Metformin 166 3 70.2 53 7.7 5.5 er 0600 daily 121 DPP-4-i 2009 246619 Vildagliptin 100 mg daily 169 2.9 71.6 44.4 7.8 5.5 2000 mg Metformin 522 2.1 55.7 44 7.2 6 Sitaglipti NCT00 MET v daily n 049122 449930 DPP-4-i Sitagliptin 100 mg daily 528 2.6 56.3 48 7.2 6

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 2000 mg Metformin daily 268 3 55 45 7.6 92 12 MET v (maximum) AWARD NCT01 123 GLP- 1.5 mg -3 126580 Dulaglutide 269 3 56 42 7.6 93 12 1RA weekly 0.75 mg Dulaglutide 270 3 56 44 7.6 92 12 weekly UMIN0 MET v 2250 mg Tanaka Metformin 24 4.7 51 66.7 8 78.9 5.5 124 000042 GLP- daily 2015 43 1RA Liraglutide 0.9 mg daily 23 5.6 51 59 7.7 76.2 5.5 1000-2000 Not MET v Metformin 26 56.8 46.2 8.11 83.7 6 Yuan mg daily 125 provide GLP- 2012 10-20 mcg d 1RA Exenatide 33 58.5 51.5 8.27 82.2 6 daily 500-2000 mg Metformin 201 1.6 51.8 47.3 9.2 85.6 5.5 daily MET v Henry NCT00 Dapagliflozin 5 mg daily 203 1.6 52.3 45.3 9.1 86.2 5.5 126 SGLT-2- 2012 643851 500-2000 mg i Metformin 208 1.9 52.7 46.6 9.1 87.2 5.5 daily Dapagliflozin 10 mg daily 219 2.1 51.1 47.9 9.1 88.5 5.5 2500-5000 Metformin 46 59.4 0 10.4 12 Onuchin MET v mg daily 127 None 2010 BASAL Insulin Titrated 45 61.1 0 11.03 12 protophane 2000 mg Pistrosc Metformin 36 2.6 62.03 50 6.9 87.6 9 NCT00 MET v daily h 128 857870 BASAL Insulin 2013 Titrated 39 2.8 60 33.3 7.2 87.6 9 glargine ChiCTR 500-1500 mg Metformin 395 0.26 50.2 60 7.59 70.7 11 Yang -TRC- MET v daily 2014129 080002 AGI Acarbose 300 mg daily 393 0.22 50.6 61 7.49 70.1 11 31 1500-2500 Derosa MET v Metformin 56 52 48.2 7.4 72.3 12 130 NA mg daily 2003a GLIN Repaglinide 2-4 mg daily 56 55 51.8 7.6 70.2 12 Not 850-1700 mg Nar MET v Metformin 19 0 49.4 21.1 6.9 6 131 provide daily 2009 CON d Control 15 0 44.5 33.3 6.1 6 1700 mg Teupe MET v Metformin daily 50 8.1 51.5 40 9 87.7 24 132 NA 1991 CON (maximum) Control 50 6.4 56 40 8.7 83.1 24 APPRO NCT00 SU v 5-15 mg 133 Glipizide 339 60.2 65.8 7.2 83.3 18 ACH 116831 TZD daily

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years Rosiglitazone 4-8 mg daily 333 61.8 70 7.1 82 18 10 mg daily Bakris SU v Glyburide 99 56.1 71 9.5 6.4 134 NA (median) 2003 TZD Rosiglitazone 8 mg daily 104 55.1 75 9.1 6.4 SB- Chou SU v Glimepiride 1-4 mg daily 225 53 57.7 9 91.6 6.4 135 797620/ 2008 TZD 004 Rosiglitazone 4-8 mg daily 232 53.6 60 9.1 88.9 6.4 1.75-10.5 mg Glibenclamide 109 5.2 57.9 73 8.5 89 12 GLAC SU v day 136 NA study TZD 30-45 mg Pioglitazone 91 4.8 60 62 8.4 88.4 12 daily 80-320 mg Gliclazide 297 2.9 56 61.3 89.2 24 GLAL SU v daily 137 NA study TZD 15-45 mg Pioglitazone 270 2.7 57 63.3 91.7 24 daily 2.5-15 mg Hanefel Not Glibenclamide 207 6.4 60.1 70.4 8.2 12 SU v daily d provide 138 TZD Rosiglitazone 8 mg daily 191 6 60.6 57.7 8.2 12 2007 d Rosiglitazone 4 mg daily 200 5.9 60.4 68.2 8.1 12 1.75-10.5 mg Heliövaa Not Glibenclamide 30 57.2 73.3 8.35 12 SU v daily ra provide 139 TZD 30-45 mg 2007 d Pioglitazone 29 57.4 58.6 8.18 12 daily 5-15 mg Not Glyburide 251 0.78 52.1 56.2 9.2 94.3 12.9 Jain SU v daily 140 provide 2006 TZD 15-45 mg d Pioglitazone 251 0.80 52.1 53 9.2 93.9 12.9 daily Glimepiride 1-4 mg daily 273 59.7 65.9 7.4 92.8 18 PERISC NCT00 SU v 141 15-45 mg OPE 225277 TZD Pioglitazone 274 60 68.9 7.4 94.2 18 daily Pop- NCT00 SU v Glyburide 10 mg daily 13 76.9 7.5 6 Busui 142 549874 TZD 2009 Rosiglitazone 8 mg daily 14 28.6 6.5 6 St. John SU v Glyburide 20 mg daily 99 6.2 56.1 72 9.5 85.1 12 Sutton NA 143 TZD 2002 Rosiglitazone 8 mg daily 104 5.3 55.1 72.1 9.1 86.2 12 Sun SU v Glipizide 5 mg daily 30 8.9 6 144 None 2006 TZD Pioglitazone 30 mg daily 30 8.8 6 1.25-2.5 mg Teramot Not Glibenclamide 46 56.4 76.1 8.36 67.7 5.5 SU v daily o provide 145 TZD 15-30 mg 2007 d Pioglitazone 46 57 71.7 8.01 64.8 5.5 daily

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 15-45 mg Pioglitazone 1063 6 57.2 9.5 36 Tolman NCT00 SU v daily 2009146 494312 TZD 5-15 mg Glibenclamide 1057 6 55.5 9.5 36 daily Wantan 1.25-2.5 mg SU v Glibenclamide 14 65.1 85.7 7.2 6 abe NA daily 147 TZD 2005 Pioglitazone 15 mg daily 13 62.9 84.6 6.9 6 5-20 mg Glibenclamide 15 17 55 53.3 7.9 12 Nakamu SU v daily ra NA TZD v Pioglitazone 30 mg daily 15 17.5 56.5 60 7.9 12 2004148 AGI Voglibose 0.6 mg daily 15 16.8 55 53.3 8.1 12 SU v Nateglinide 270 mg daily 16 16.6 53.5 56.25 7.7 12 5-20 mg Nakamu Not TZD v Glibenclamide 18 16.5 53.5 55.6 7.8 12 ra provide AGI v daily 2006149 d GLITINI Pioglitazone 30 mg daily 17 16 56 52.9 8 12 DE Voglibose 0.6 mg daily 17 16.2 55 58.8 7.6 12 Arjona 2.5-20 mg NCT00 SU v Glipizide 65 58.5 56.9 7.8 12.4 Ferreira daily 150 509236 DPP-4-i 2013 Sitagliptin 25 mg daily 64 60.5 62.5 7.9 12.4 2.5-20 mg Arjona Glipizide 212 10.1 64.3 54.9 7.8 70.2 12.4 NCT00 SU v daily Ferreira 151 509262 DPP-4-i 25-50 mg 2013a Sitagliptin 211 10.7 64.8 59.3 7.8 68 12.4 daily 80-320 mg Gliclazide 546 1.9 54.3 52.7 8.69 84.3 24 Foley NCT00 SU v daily 2009152 102388 DPP-4-i 50 mg twice Vildagliptin 546 2.4 55.2 58.8 8.6 84.2 24 daily Glimepiride 1-6 mg daily 239 9.4 70.8 40.3 7.8 75.3 7 Hartley NCT01 SU v 153 50-100 mg 2015 189890 DPP-4-i Sitagliptin 241 8 70.6 47.2 7.8 76.9 7 daily 0.25-1.0 mg UMIN0 Glimepiride 68 6 5.1 72.1 7.5 12 Kondo SU v daily 154 000479 2016 DPP-4-i 25-100 mg 1 Sitagliptin 65 6.2 6 75.4 7.4 12 daily Rosenst 5-10 mg NCT00 SU v Glipizide 219 5.94 69.8 43.8 7.45 12 ock daily 155 707993 DPP-4-i 2013 Alogliptin 25 mg daily 222 6.25 70.1 45.9 7.5 12

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 0.5-4 mg SU v Glimepiride 17 3.4 52 57 6.7 6 Gudipat daily NCT00 DPP-4-i y Sitagliptin 100 mg daily 13 5.3 57 64 6.5 6 156 775684 v GLP- 2014 10-20 mcg 1RA Exenatide 17 3.3 57 67 6.4 6 daily 1.25-2.5 mg SU v Glibenclamide 132 8.5 58.5 65.2 9.18 65.4 12 Kaku NCT00 daily 157 GLP- 2011 393718 0.3-0.9 mg 1RA Liraglutide 268 8.1 58.2 68.3 9.32 66.2 12 daily SU v Glimepiride 8 mg daily 248 5.6 53.4 54 8.4 93.4 12 LEAD-3 NCT00 158 GLP- Liraglutide 1.8 mg daily 246 5.3 52 49 8.3 92.8 12 Mono 294723 1RA Liraglutide 1.2 mg daily 251 5.2 53.7 47 8.3 92.5 12 Birkelan 1.75-10.5 mg SU v Glibenclamide 16 81.3 8.6 77.1 12 d NA daily 159 BASAL 1994a Insulin NOS Titrated 18 44.4 8.8 75.3 12 2.5-20 mg Nathan SU v Glyburide 16 5.9 50.3 56.3 10.5 89.3 9 160 NA daily 1988 BASAL NPH Insulin Titrated 15 3.7 53.5 53.3 10.3 80.6 9 1.75-3.5 mg Alvarsso SU v Glibenclamide 28 55.6 71.4 6.9 12 daily n NA BASAL- 161 Mixtard 30/70 2003 BOLUS Titrated 23 51.1 61.1 7.3 12 insulin SU v 3.5-10.5 mg Forst Glibenclamide 68 4.3 56.6 57.4 7.7 84.1 6 162 NA PRANDI daily 2003 AL Insulin lispro Titrated 75 4.4 58.7 68 7.5 87.2 6 5-10 mg Glibenclamide 10 7 64 60 7.8 71.6 5.5 Marena SU v daily 163 NA 1993 AGI 150-300 mg Miglitol 10 5 57 70 8.2 72.5 5.5 daily 5-10 mg Glibenclamide 47 7 59 51.1 7.8 71.6 5.5 Pagano SU v daily 164 NA 1995 AGI 150-300 mg Miglitol 49 5 57 67.4 8.2 72.5 5.5 daily 1.75-10.5 mg Rosenth Glibenclamide 37 2.5 57.7 7.2 82.8 6 SU v daily al NA 165 AGI 150-300 mg 2002 Acarbose 39 1.7 57.4 7 84.7 6 daily

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years 80-160 mg Gliclazide 30 4.7 56.1 53.3 8.7 5.5 Salman SU v daily 166 NA 2001 AGI 150-300 mg Acarbose 27 4.2 52.6 63 8.9 5.5 daily 3.5-10.5 mg Spengle Glibenclamide 29 60 38 11 6 SU v daily r NA 167 AGI 150-300 mg 1989 Acarbose 26 59 42 10.8 6 daily SU v Derosa Glimepiride 1 mg daily 62 54 48.4 7.8 77.1 12 168 NA GLITINI 2003 DE Repaglinide 1 mg daily 62 56 50 8 76.4 12 5-10 mg SU v Glyburide 87 51.3 52.9 7.4 12 Esposito daily 169 NA GLITINI 2004 1.5-12 mg DE Repaglinide 88 52 53.4 7.5 12 daily 5-15 mg Not SU v Glibenclamide 50 45.8 20 10.2 65.8 12 Jibran daily 170 provide GLITINI 2006 1.5-6 mg d DE Repaglinide 50 46.6 32 9.9 72.7 12 daily 5-15 mg Madsba SU v Glipizide 81 7 62 64.2 7.2 83.6 12 daily d NA GLITINI 171 1.5-12 mg 2001 DE Repaglinide 175 8.1 60.2 61.1 7.3 82.9 12 daily 2.5-15 mg SU v Glyburide 193 8.3 58.7 66 8.9 12 Marbury daily 172 NA GLITINI 1999 1.5-12 mg DE Repaglinide 383 7.2 58.3 67 8.7 12 daily 8.8 mg daily Not SU v Glibenclamide 50 45.8 20 10.2 65.8 12 Saleem (mean) 173 provide GLITINI 2011 4.27 mg d DE Repaglinide 50 46.6 32 9.9 72.7 12 daily (mean) 5-15 mg Not SU v Glibenclamide 100 0 45.2 31 64.8 12 Shah daily 174 provide GLITINI 2011 1.5-6 mg d DE Repaglinide 100 0 46 20 71.6 12 daily 1.75-7.0 mg Wolffen SU v Glyburide 139 61 68 7 81.3 12 daily buttel NA GLITINI 175 1.5-6 mg 1999 DE Repaglinide 286 61 62 7.1 81.5 12 daily

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy Durati on of Propo Duratio Mean Trial Drug diagn Mean rtion Mean n of body Study registr compar Drug Dose N osed age, of HbA1C, treatme weight, ation ison(s) diabe years men, % nt, kg tes, % months years Pioglitazone 45 mg daily 188 3.7 52.5 50.5 8.7 88.5 12 Henry NCT00 TZD v Pioglitazone 30 mg daily 194 3.9 51.8 54.1 8.9 83.4 12 176 2014 722371 DPP-4-i Pioglitazone 15 mg daily 183 3.7 50.3 65 8.8 90.4 12 Sitagliptin 100 mg daily 186 4.5 51 60.2 8.6 88.1 12 Rosenst NCT00 TZD v Rosiglitazone 8 mg daily 267 2.7 54.2 57.6 8.7 93.1 5.5 ock 177 099918 DPP-4-i 2007 Vildagliptin 100 mg daily 519 2.3 54.5 57.5 8.7 91.2 5.5 Rosenst NCT00 TZD v Pioglitazone 30 mg daily 161 2.2 52.4 64 8.7 81 5.5 ock 178 101803 DPP-4-i 2007a Vildagliptin 100 mg daily 154 1.9 51.4 63.6 8.6 82 5.5 30-45 mg TZD v Pioglitazone 136 50 61 8 71.2 11 daily GLP- CONFID NCT01 10-20 mcg 179 1RA v Exenatide 142 50 69 8 72.6 11 ENCE 147627 daily BASAL- Lispro BOLUS Titrated 138 51 61.6 8.1 70.3 11 Premix25 Pioglitazone 45 mg daily 129 4.8 58.9 53.5 8.98 6 Goke TZD v 180 NA 50-300 mg 2002 AGI Acarbose 136 4.9 58.8 54.5 9.03 6 daily Not Takase TZD v Pioglitazone 15 mg daily 20 67.8 55 7 6 181 provide 2007 AGI d Voglibose 0.6 mg daily 19 68.2 63.2 6.9 6 Jovanov TZD v Pioglitazone 30 mg daily 62 6.1 56.2 50 9.1 5.5 ic NA GLITINI 1.5-12 mg 182 Repaglinide 61 6.9 57.8 59 9 5.5 2004 DE daily TZD v Rosiglitazone 4-8 mg daily 62 7.4 56.6 38.7 8.5 5.5 Raskin 183 NA GLITINI 1.5-12 mg 2004 Repaglinide 63 7.2 58.5 61.9 9.1 5.5 DE daily Berbero Not TZD v Rosiglitazone 4 mg daily 26 60.7 0 6.3 24 glu provide 184 CON 2010 d Control 23 59.8 0 6 24 NCT Coletta TZD v Pioglitazone 45 mg daily 14 7.1 51 64 8.3 89 6 185 008162 2009 CON 18 Control 12 6.9 50 75 8.1 84.4 6 Not Stewart TZD v Rosiglitazone 4-8 mg daily 254 3.7 58.9 55 7.2 88.1 7.4 186 provide 2006 CON d Control 272 3.7 59 56 7.2 87.2 7.4 Not DPP-4-i Suzuki Sitagliptin 50 mg daily 16 1.9 56.1 56.25 9.1 81.7 6 187 provide v GLP- 2014 d 1RA Liraglutide 0.9 mg daily 24 2.4 58.6 41.6 9.8 82.3 6 Lewin NCT01 DPP-4-i Linagliptin 5 mg daily 133 53.8 56.4 8.05 89.5 5.5 188 2015 422876 v SGLT- Empagliflozin 25 mg daily 133 56 57.9 7.99 86.7 5.5

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP- 1RA = glucagon-like peptide-1 receptor agonist; HbA1C = glycated hemoglobin; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium-glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione. Data for age, HbA1C, and body weight are reported as the mean or median values of the corresponding treatment group within the trial.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years Pioglitazone 30 mg daily 129 7.6 56.1 48.8 8.5 85.9 6 Pioglitazone 15 mg daily 130 5.7 54.1 46.9 8.5 84.7 6 TZD v DeFronzo NCT003 Pioglitazone 45 mg daily 129 5.7 54.5 41.1 8.5 82.1 6 199 DPP-4-i 2012 28627 v PCO Alogliptin 25 mg daily 129 5.6 53.7 38.8 8.6 83.3 6 Alogliptin 12.5 mg daily 128 6.2 53.1 52.3 8.6 84.6 6 Placebo 129 6 55.2 47.3 8.5 83.4 6 Ahrén DPP-4-i Vildagliptin 50 mg daily 42 5.8 58.4 61.9 7.6 12 200 NA 2004 v PCO Placebo 29 4.6 54.3 75.9 7.8 12 Vildagliptin 100 mg daily 185 5.8 53.9 61.5 8.4 95.3 5.5 Bosi NCT000 DPP-4-i 201 Vildagliptin 50 mg daily 177 6.8 54.3 57.3 8.4 92.5 5.5 2007 99892 v PCO Placebo 182 6.2 54.5 53.1 8.3 94.8 5.5 Derosa DPP-4-i Sitagliptin 100 mg daily 91 0.48 55.9 46.2 8.1 78.4 5.5 202 None 2012 v PCO Placebo 87 0.45 54.8 50.6 8 78.6 5.5 Derosa Not DPP-4-i Vildagliptin 100 mg daily 84 6.1 54.2 50 8.1 76.9 12 203 2012a provided v PCO Placebo 83 6.3 52.4 51.8 8.2 78.5 12 Goodman Not DPP-4-i Vildagliptin 100 mg daily 248 54.9 52.8 8.5 5.5 204 2009 provided v PCO Placebo 122 54.5 67.2 8.7 5.5 Alogliptin 25 mg daily 210 6 54 54.3 7.9 6 Nauck NCT002 DPP-4-i 205 Alogliptin 12.5mg daily 213 6 55 47.4 7.9 6 2009 86442 v PCO Placebo 104 6 56 48 8 6 Vildagliptin 100 mg daily 146 4.92 54.2 50 8.09 71.58 5.5 Pan Not DPP-4-i 206 Vildagliptin 100 mg daily 148 5.02 53.7 44.6 8.05 68.36 5.5 2012 provided v PCO Placebo 144 5.15 54.5 45.8 8.01 69.83 5.5 Raz NCT003 DPP-4-i Sitagliptin 100 mg daily 96 8.4 53.6 51 9.3 81.5 6.9 207 2008 37610 v PCO Placebo 94 7.3 56.1 41.5 9.1 81.2 6.9 Saxagliptin 10 mg daily 181 6.4 54.2 52.5 8 87.8 5.5 Saxaglipti NCT001 DPP-4-i Saxagliptin 5 mg daily 191 6.4 54.7 53.9 8.1 87.3 5.5 208 n 014 21667 v PCO Saxagliptin 2.5 mg daily 192 6.7 54.7 42.2 8.1 86 5.5 Placebo 179 6.7 54.8 53.6 8.1 87.1 5.5 Sitagliptin NCT008 DPP-4-i Sitagliptin 100 mg daily 464 6 54.4 55.8 8 86.7 5.5 209 020 6515 v PCO Placebo 237 6.6 54.7 59.5 8 89.6 5.5 Taskinen NCT006 DPP-4-i Linagliptin 5 mg daily 523 56.5 53 8.09 82.2 5.5 210 2011 01250 v PCO Placebo 177 56.6 57 8.02 83.3 5.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years Wang NCT012 DPP-4-i Linagliptin 5 mg daily 205 55.1 49.8 7.99 68.1 5.5 211 2016 15097 v PCO Placebo 101 56.5 50 8 68.5 5.5 Yang NCT006 DPP-4-i Saxagliptin 5 mg daily 283 5.1 53.8 48.1 7.9 68.9 5.5 212 2011 61362 v PCO Placebo 287 5.1 54.4 48.4 7.9 69 5.5 Yang NCT008 DPP-4-i Sitagliptin 100 mg daily 197 6.4 54.1 47 8.5 67.9 5.5 213 2012 13995 v PCO Placebo 198 7.3 55.1 55 8.5 68.9 5.5 Sitagliptin 100 mg daily 315 7 54 48 8.1 86 6 DPP-4-i 1.5 mg Dulaglutide 304 7 54 48 8.1 87 6 AWARD- NCT007 v GLP- weekly 5214 34474 1RA v 0.75 mg Dulaglutide 302 7 54 44 8.2 86 6 PCO weekly Placebo 177 7 55 51 8.1 87 6 Sitagliptin 100 mg daily 185 6 55.5 59 7.94 92.5 5.5 DPP-4-i 20 mg Taspoglutide 198 5.7 56.8 52 7.97 91.8 5.5 T-Emerge NCT007 v GLP- weekly 4215 54988 1RA v 10 mg Taspoglutide 190 6.1 55.3 56 7.95 93.6 5.5 PCO weekly Placebo 93 5.5 56.1 52 8.03 91.1 5.5 Canagliflozin 300 mg daily 367 7.1 55.3 45 7.9 85.4 6 DPP-4-i CANATA NCT011 v SGLT- Canagliflozin 100 mg daily 368 6.7 55.5 47.3 7.9 88.8 6 216 TA-D 06677 2-i v Sitagliptin 100 mg daily 366 6.8 55.5 47 7.9 87.7 6 PCO Placebo 183 6.8 55.3 51.4 8 86.6 6 10-20 mcg GLP- Exenatide 113 4.9 52 60.2 8.2 101 7 DeFronzo daily 217 NA 1RA v 2005 Exenatide 10 mcg daily 110 6.2 53 51.8 8.3 100 7 PCO Placebo 113 6.6 54 59.3 8.2 100 7 GLP- 10-20 mcg Derosa Not Exenatide 86 50 8.1 89 12 218 1RA v daily 2013 provided PCO Placebo 85 48.2 7.9 90.5 12 10-20 mcg Lixisenatide 161 6 54.6 45 8.1 88 17.5 GLP- daily GetGoal- NCT007 219 1RA v 10-20 mcg F1 63451 Lixisenatide 161 5.8 55.4 44 8 90.3 17.5 PCO daily Placebo 160 6.2 58.2 45 8 87.9 17.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years 10-20 mcg Lixisenatide 255 6.2 54.5 38.4 8 90.1 5.5 GLP- daily GetGoal- NCT007 220 1RA v 10-20 mcg M 12673 Lixisenatide 255 6.2 54.8 44.7 8.1 89 5.5 PCO daily Placebo 170 5.9 55 47.6 8.1 90.4 5.5 GLP- 10-20 mcg Samson NCT014 Exenatide 11 12 221 1RA v daily 2011 32405 PCO Placebo 10 12 GLP- 10-20 mg T-Emerge NCT008 Taspoglutide 154 5.2 53 42 7.54 103.6 5.5 222 1RA v weekly 7 23992 PCO Placebo 151 4.9 54 39 7.55 101.4 5.5 Dapagliflozin 10 mg daily 135 6.1 52.7 57 7.92 86.3 5.5 Bailey NCT005 SGLT-2- Dapagliflozin 5 mg daily 137 6.4 54.3 50 8.17 84.7 5.5 223 2010 28879 i v PCO Dapagliflozin 2.5 mg daily 137 6 55 51 7.99 84.9 5.5 Placebo 137 5.8 53.7 55 8.11 87.7 5.5 Bolinder NCT008 SGLT-2- Dapagliflozin 10 mg daily 89 6 60.6 55.1 7.19 92.1 24 224 2012 55166 i v PCO Placebo 91 5.5 60.8 56 7.16 90.9 24 EMPA- Empagliflozin 25 mg daily 213 55.6 56 7.86 82.2 5.5 NCT011 SGLT-2- REG Empagliflozin 10 mg daily 217 55.5 58 7.9 81.6 5.5 225 59600 i v PCO MET Placebo 207 56 56 7.9 79.7 5.5 ILLUMINA NCT011 SGLT-2- Ipragliflozin 50 mg daily 112 7.5 56.2 58.9 8.25 68.52 5.5 226 TE 35433 i v PCO Placebo 56 8.05 57.7 58.9 8.38 67.51 5.5 150-600 mg Chiasson AGI v Acarbose 41 12 78 NA daily 1994 PCO Placebo 42 12 75-300 mg Gaal AGI v Miglitol 78 57.9 41.6 8.5 7.4 227 NA daily 2001 PCO Placebo 75 57.9 49.3 8.4 7.4 150-300 mg Halimi AGI v Acarbose 74 9.5 56 47.5 8.6 6 228 NA daily 2000 PCO Placebo 78 9 55 62.9 8.5 6 100-200 mg Phillips AGI v Acarbose 40 5.32 58.37 65 8.05 89.77 5.5 229 NA daily 2003 PCO Placebo 43 6.06 62.39 76.7 7.82 87.88 5.5 75-300 mg Rosensto AGI v Acarbose 84 7.8 57.4 61 8.46 94.4 5.5 230 NA daily ck 1998 PCO Placebo 84 7.8 55.9 49 8.17 91.5 5.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years GLITINI Nateglinide 360 mg daily 160 6.8 57.3 61.3 8.18 85.2 5.5 Marre 231 NA DE v Nateglinide 180 mg daily 155 7.2 57.9 61.3 7.99 84.8 5.5 2002 PCO Placebo 152 6.5 56.4 55.3 8.2 84.9 5.5 Bakris Not SU v Glyburide 5 mg daily 185 7.6 58.8 69 8.3 90.3 7.4 232 2006 provided TZD Rosiglitazone 4 mg daily 204 8 60 63 8.5 89.2 7.4 Derosa SU v Glimepiride 2 mg daily 47 4 52 48.9 7.9 75.6 12 217 NA 2005 TZD Rosiglitazone 4 mg daily 48 5 54 52.1 8 74.2 12 Glibenclamid 5-10 mg daily 160 5 56 56 8.5 93 5.5 Garber Not SU v e 2006233 provided TZD Rosiglitazone 4-8 mg daily 158 6 56 65 8.4 94 5.5 Kelly NCT001 SU v Glyburide 20 mg daily 16 63.1 62.5 7.3 95 6 234 2007 23643 TZD Rosiglitazone 8 mg daily 20 57.9 45 7.8 96.9 6 Khanolkar Not SU v Gliclazide 80 mg daily 25 56 60 7.08 6 235 2008 provided TZD Rosiglitazone 4 mg daily 25 59 56 7.33 6 Glibenclamid 10 mg daily 84 61.4 50 8.2 83.1 12 Maffioli Not SU v e 2013236 provided TZD Pioglitazone 30 mg daily 86 62.8 47.7 8.4 83.5 12 80-320 mg Gliclazide 313 5.5 57 49.2 8.53 92.7 12 Matthews SU v daily 237 NA 2005 TZD 15-45 mg Pioglitazone 317 5.8 56 50.8 8.71 91.8 12 daily Ohira Not SU v Glimepiride 1 mg daily 30 62.23 50 8.64 6 238 2014 provided TZD Pioglitazone 15 mg daily 30 63.7 63.3 8.54 6 Petrica Not SU v Glimepiride 4 mg daily 22 10.4 63.2 41.2 7.58 6 239 2009 provided TZD Rosiglitazone 4 mg daily 22 10.53 63 41.2 7.72 6 Petrica Not SU v Glimepiride 4 mg daily 39 10.17 58.82 7.49 12 240 2011 provided TZD Pioglitazone 30 mg daily 39 10 56.88 7.7 12

241 NCT007 SU v Glimepiride 4 mg daily 150 5.9 59 64.1 7.4 94.1 5.5 PIOfix 70653 TZD Pioglitazone 30 mg daily 155 6.2 59 65.8 7.1 96.2 5.5 Glimepiride 2-8 mg daily 101 4.9 51.6 55.2 8.4 6 Umpierrez Not SU v 242 30-45 mg 2006 provided TZD Pioglitazone 109 5.9 55.7 52.3 8.31 6 daily Glipizide 5-10 mg daily 40 53.6 58.3 8.65 5.5 Xiao SU v 243 NA 15-45 mg 2015 TZD Pioglitazone 40 54.2 58.8 8.73 5.5 daily

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years Glimepiride 2-6 mg daily 66 57.7 48.5 9 77.4 15 SU v Derosa Not 15-45 mg 108 TZD v Pioglitazone 69 57 49.3 9.3 76.4 15 2009a provided daily CON Control 67 55 50.7 9.1 77.7 15 Arechaval NCT007 SU v Glimepiride 1-6 mg daily 519 6.7 56.2 53.8 7.5 82 7 eta 244 01090 DPP-4-i 2011 Sitagliptin 100 mg daily 516 6.8 56.3 55 7.5 80.6 7 Berndt- 0.5-4 mg Not SU v Glimepiride 22 6.1 60 59 7.3 93.7 5.5 Zipfel daily 245 provided DPP-4-i 2013 Vildagliptin 100 mg daily 22 8.4 57 68.2 7.4 99.3 5.5 Glipizide 5-20 mg daily 874 5.5 55.4 50.5 7.6 85.6 24 Del Prato NCT008 SU v 246 Alogliptin 25 mg daily 885 5.4 55.5 51.1 7.6 86.3 24 2014 56284 DPP-4-i Alogliptin 12.5 mg daily 880 5.7 55.2 47.6 7.6 85.3 24 Derosa Not SU v Glimepiride 6 mg daily 81 0.56 57.2 49.4 7.7 77 5.5 247 2014 provided DPP-4-i Vildagliptin 100 mg daily 86 0.6 59.8 48.8 7.9 77.8 5.5 80-320 mg Gliclazide 494 6.8 59.7 51.8 8.5 84.2 12 Filozof Not SU v daily 2010248 provided DPP-4-i Vildagliptin 50 mg daily 513 6.4 59.2 52.2 8.5 85.7 12 Gallwitz NCT006 SU v Glimepiride 1 mg daily 775 59.8 61 7.7 86.6 24 249 2012 22284 DPP-4-i Linagliptin 5 mg daily 777 59.8 60 7.7 86.1 24 GENERA NCT010 SU v Glimepiride 1-6 mg daily 360 7.6 72.7 63.3 7.58 12 250 TION 06603 DPP-4-i Saxagliptin 5 mg daily 360 7.6 72.5 60.3 7.62 12 Goke Not SU v Glipizide 5-20 mg daily 430 5.4 57.6 54 7.7 88.6 12 251 2010 provided DPP-4-i Saxagliptin 5 mg daily 428 5.5 57.5 49.5 7.7 88.7 12 Jeon Not SU v Glimepiride 4 mg daily 52 5.92 55.38 60.8 8.13 -9 7.4 252 2011 reported DPP-4-i Vildagliptim 100 mg daily 54 5.89 53.51 68.6 8.01 -9 7.4 EudraC 155 Glimepiride 2-6 mg daily 5.7 57.5 53.9 7.3 88.9 24 Matthews T 2004- SU v 6 2010253 004559- DPP-4-i 156 Vildagliptin 100 mg daily 5.7 57.5 53.1 7.3 89.5 24 21 2 Nauck NCT000 SU v Glipizide 5-20 mg daily 584 6.2 56.5 61.3 7.6 89.7 12 254 2007b 94770 DPP-4-i Sitagliptin 100 mg daily 588 6.5 56.8 57.1 7.7 89.5 12 Sitagliptin NCT000 SU v Glipizide 5-20 mg daily 584 6.2 56.5 61.3 7.6 89.7 12 255 024 94770 DPP-4-i Sitagliptin 100 mg daily 588 6.5 56.8 57.1 7.7 89.5 12

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years Glimepiride 2- 4 mg daily 307 6 54.4 51.5 8.1 91.8 24 SU v Sitagliptin 100 mg daily 302 5.8 54.3 46 8.1 90.3 24 HARMON NCT008 DPP-4-i 256 30-50 mg Y 3 38903 v GLP- Albiglutide 302 6 54.3 44.7 8.1 89.6 24 1RA weekly Placebo 101 6.7 56.1 49.5 8.2 91.6 24 Glibenclamid 7.5-15 mg SU v 65 56 50.7 8.9 82.4 12 Derosa Not e daily 257 GLP- 2010 provided 10-20 mcg 1RA Exenatide 63 57 47.6 8.8 82 12 daily SU v Glimepiride 3-6 mg daily 54 55 48.1 8.8 81.4 12 Derosa Not 258 GLP- 10-20 mcg 2011a provided Exenatide 57 56 49.1 8.7 80.2 12 1RA daily 1 mg daily 2 SU v Glimepiride 514 5.5 56.8 52 7.4 91.1 26 EUREXA NCT003 titrated 59 GLP- 59762 10-20 mcg 1RA Exenatide 515 5.8 56.1 56 7.5 92.8 23.4 daily SU v Glimepiride 6-8 mg daily 482 6.6 56.3 54.6 7.8 86.5 12 CANTAT NCT009 260 SGLT-2- Canagliflozin 300 mg daily 485 6.7 55.8 49.6 7.8 86.6 12 A-SU 68812 i Canagliflozin 100 mg daily 483 6.5 54.6 52.1 7.8 86.9 12 EMPA- SU v Glimepiride 1-4 mg daily 780 55.7 54 7.92 83 24 REG NCT011 SGLT-2- H2H- 67881 Empagliflozin 25 mg daily 769 56.2 56 7.92 82.5 24 261 i SU SU v Glipizide 5-20 mg daily 408 7 59 54.9 7.7 12 Nauck NCT006 262 SGLT-2- 2.5-10 mg 2011 60907 Dapagliflozin 406 6 58 55.3 7.7 12 i daily Glimepiride 1-8 mg daily 36 7.97 54.9 47.1 8.9 66 12 263 NCT005 SU v BETA Insulin 62172 BASAL Titrated 39 6.58 51.3 31.6 8.8 62.7 12 glargine 30-90 mg Gliclazide 47 62.3 0 10.6 12 SU v daily Onuchin Not 127 BASAL Long-acting 2010 provided Titrated 44 61.4 0 10.8 12 v CON insulin Control 46 59.4 0 10.4 12 SU v Glibenclamid Derosa Not 15 mg daily 124 4 56 50.9 8.2 12 264 GLITINI e 2007 provided DE Nateglinide 360 mg daily 124 5 55 48.7 8.1 12 1.25-10 mg PRESER SU v Glyburide 209 2 53.5 48 8.3 24 VE- NA GLITINI daily beta265 DE Nateglinide 360 mg daily 219 1.5 52.6 51 8.4 24

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years 80-240 mg SU v Gliclazide 129 6.7 61.6 50.4 7.6 5.5 Ristic daily 266 NA GLITINI 2006 180-540 mg DE Nateglinide 133 7.16 62 54.1 7.67 5.5 daily 10-20 mg DeFronzo SU v Glyburide 213 7.8 55 46 8.8 92.1 6.7 19 NA daily 1995 CON Control 143 6 53 43.4 8.4 94.4 6.7 Bolli Not TZD v Pioglitazone 30 mg daily 281 6.4 57 64.1 8.4 91.2 12 267 2009 provided DPP-4-i Vildagliptin 100 mg daily 295 6.4 56.3 61.7 8.4 91.8 12 TZD v Pioglitazone 45 mg daily 165 6 53 48 8.5 88 6 DURATIO NCT006 DPP-4-i 268 Sitagliptin 100 mg daily 166 5 52 52 8.5 87 6 N-2 37273 v GLP- 1RA Exenatide 2 mg weekly 160 6 52 56 8.6 89 6 TZD v Rosiglitazone 8 mg daily 187 7.1 55.5 50.8 8.46 6 Raskin Not 269 GLITINI Repaglinide 8 mg daily 187 7.4 54.8 57.8 8.45 6 2009 provided DE Repaglinide 6 mg daily 187 7.3 54.5 58.8 8.29 6 Borges NCT003 TZD v Rosiglitazone 4-8 mg daily 348 2.3 51.5 53 8.6 87.1 20 270 2011 86100 CON Control 340 2.6 50.7 53 8.6 90.6 20 Kadoglou Not TZD v Rosiglitazone 4 mg daily 70 1.8 62 27 7.58 6 271 2011 provided CON Control 70 2.7 62.7 28 7.56 6 Rosensto Not TZD v Rosiglitazone 2-8 mg daily 155 2.3 50.1 57 8.9 7.4 113 ck 2006 provided CON Control 154 2.9 51.5 56 8.8 7.4 Sohn Not TZD v Rosiglitazone 8 mg daily 8 2.38 55.4 37.5 8.73 64.4 8 114 2008 provided CON Control 8 1.05 52 50 8.96 59.9 8 1860- DPP-4-i Sitagliptin 100 mg daily 219 6.3 55 55 8.5 93.1 6 NCT007 LIRA- v GLP- Liraglutide 1.8 mg daily 221 6.4 55 52 8.4 94.6 6 272 00817 DPP-4 1RA Liraglutide 1.2 mg daily 225 6 55.9 52 8.4 93.7 6 DPP-4-i Van Gaal NCT009 Sitagliptin 100 mg daily 161 4.4 43.4 45.3 8.1 100.6 5.5 273 v GLP- 2014 76937 1RA Lixisenatide 20 mcg daily 158 4.4 42.7 34.8 8.16 98.5 5.5 DPP-4-i Linagliptin 5 mg daily 128 56.2 50 8.02 85 12 DeFronzo NCT014 274 v SGLT- Empagliflozin 25 mg daily 140 55.5 46.4 8.02 87.7 12 2015 22876 2-i Empagliflozin 10 mg daily 137 56.1 56.9 8 86.1 12 DPP-4-i Efstathiou Saxagliptin 5 mg daily 34 6.5 5.5 275 NA v SGLT- 2015 2-i Dapagliflozin 10 mg daily 32 6.5 5.5 Rosensto NCT016 DPP-4-i Saxagliptin 5 mg daily 176 8.2 55 53 9.03 -9 5.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin Durati Durati on of Propo Mean on of Trial Drug diagn Mean rtion Mean body treatm Study registra compar Drug Dose N osed age, of HbA1C, weight, ent, tion ison(s) diabet years men, % kg month es, % s years ck 2015276 06007 v SGLT- Dapagliflozin 10 mg daily 179 7.4 54 50 8.87 -9 5.5 2-i DPP-4-i Sitagliptin 100 mg daily 265 53.3 52.2 8.5 84.2 5.5 EASIE NCT007 277 v Insulin 2012 51114 Titrated 250 53.9 50.2 8.5 83.4 5.5 BASAL glargine Wang Not DPP-4-i Saxagliptin 5 mg daily 45 12.3 64.3 43.9 8.26 65.2 12 278 2015 provided v AGI Acarbose 150 mg daily 45 14.2 65.1 47.5 8.3 63.9 12 NCT003 Vildagliptin 100 mg daily 295 1.9 52.8 58 8.7 89.79 6 Bosi 82096 DPP-4-i 279 2009 /NCT00 v CON Control 294 2.2 52.4 58.2 8.62 88.43 6 468039 Saxagliptin 10 mg daily 323 1.4 52.1 45.2 9.5 82.5 18 CV181- NCT003 DPP-4-i 119 Saxagliptin 5 mg daily 320 2 52 51.6 9.4 82.1 18 039 27015 v CON Control 328 1.7 51.8 49.7 9.4 83.1 18 Filozof NCT003 DPP-4-i Vildagliptin 100 mg daily 456 4.6 56.9 50.4 7.4 84.6 5.5 280 2010a 96357 v CON Control 458 4.7 57 45 7.3 84.4 5.5 Linagliptin 2.5 mg daily 143 55.6 51 8.7 80.8 6 Haak NCT007 DPP-4-i Linagliptin 2.5 mg daily 143 56.4 53.8 8.7 76.7 6 21 2012 98161 v CON Control 147 55.2 53.1 8.5 80 6 Control 144 52.9 56.9 8.7 79.9 6 Alogliptin 25 mg daily 114 4.22 54.6 70.7 8.43 86.57 6 Pratley NCT010 DPP-4-i Alogliptin 25 mg daily 111 4.13 53.7 53.3 8.5 82.69 6 22 2014 23581 v CON Control 111 4.08 52.6 56.6 8.39 81.79 6 Control 114 3.78 54.6 53.6 8.5 81.69 6 Sitagliptin 100 mg daily 182 4.5 53.3 42.3 8.7 5.5 Sitagliptin NCT001 DPP-4-i Sitagliptin 100 mg daily 190 4.4 54.1 55.3 8.8 5.5 23 036 03857 v CON Control 182 4.4 53.2 45.1 8.7 5.5 Control 182 4.5 53.4 48.9 8.9 5.5 10-40 mcg GLP- Exenatide 36 5.7 58.4 63.9 7.6 90.6 12 Bunck NCT000 daily 281 1RA v 2009 97500 Insulin BASAL Titrated 33 4 58.3 66.7 7.4 92.4 12 glargine GLP- Exenatide 10-20 µg 17 6.88 52.18 29.4 7.95 94.34 6 Gurkan Not 282 1RA v Insulin 2014 provided 0.2 U/kg 17 7.59 53.12 42 8.11 90.51 6 BASAL glargine

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP- 1RA = glucagon-like peptide-1 receptor agonist; HbA1C = glycated hemoglobin; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione. Data for age, HbA1C, and body weight are reported as the mean or median values of corresponding treatment group within the trial.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4. Description of Included Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin plus Sulfonylurea Durati on of Mea Propo Duratio Mean Trial Drug diagn n rtion Mean n of body Study registra compar Drug Dose N osed age, of HbA1C, treatme weight, tion ison(s) diabet year men, % nt, kg es, s % months years Dailey TZD v Rosiglitazone 4-8 mg daily 181 9 57 58 8.1 93 5.5 286 NA 2004 PCO Placebo 184 9 57 61 8.1 93 5.5 Sridhar NCT012 TZD v Pioglitazone 30 mg daily 25 2.2 47.9 100 6.8 70.4 6 287 2013 06400 PCO Placebo 25 2.9 44 100 6.8 69.6 6 30-45 mg Pioglitazone 288 9.2 55.7 53.4 8.29 91 12 TZD v daily HARMON NCT008 GLP- 30-50 mg 288 Albiglutide 281 8.5 54.5 49.8 8.19 90.9 12 Y 5 39527 1RA v daily PCO Placebo 116 9.3 55.7 60.9 8.26 89.9 12 Moses NCT011 DPP-4-i Saxagliptin 5 mg daily 129 57.2 62 8.4 82.4 5.5 289 2014 28153 v PCO Placebo 128 56.8 57.8 8.2 80.3 5.5 Owens NCT006 DPP-4-i Linagliptin 5 mg daily 793 58.3 46.8 8.15 76.5 5.5 290 2011 02472 v PCO Placebo 265 57.6 48.3 8.14 76.8 5.5 GLP- Exenatide 20 mcg daily 241 8.7 55 59.3 8.5 98 7 Kendall 291 NA 1RA v Exenatide 10 mcg daily 245 8.7 55 59.2 8.5 97 7 2005 PCO Placebo 247 9.4 56 55.9 8.5 99 7 0.6-1.8 mg Liraglutide 232 9.2 57.6 57 8.3 85.5 6 GLP- daily 292 NCT003 1RA v Insulin LEAD-5 Titrated 234 9.7 57.5 60 8.2 85 6 31851 BASAL glargine v PCO Placebo 115 9.4 57.5 49 8.3 85.7 6 Canagliflozin 300 mg daily 156 9.4 56.1 55.8 8.1 93.5 12 CANTAT NCT011 SGLT-2- 293 Canagliflozin 100 mg daily 157 9 57.4 48.4 8.1 93.8 12 A-MSU 06625 i v PCO Placebo 156 10.3 56.8 48.7 8.1 91.2 12 EMPA- Empagliflozin 25 mg daily 218 57.4 53 8.1 77.5 5.5 NCT011 SGLT-2- REG Empagliflozin 10 mg daily 226 57 50 8.07 77.1 5.5 294 59600 i v PCO METSU Placebo 225 56.9 50 8.15 76.2 5.5 Matthaei NCT013 SGLT-2- Dapagliflozin 10 mg daily 109 9.3 61.1 42.6 8.08 88.6 5.5 295 2015 92677 i v PCO Placebo 109 9.6 60.9 55.6 8.24 90.1 5.5 Lam AGI v Acarbose 100 mg daily 45 10.2 57.8 44.4 9.5 6 296 NA 1998 PCO Placebo 45 10.1 56.9 43.2 9.4 6 Liu NCT011 TZD v Pioglitazone 30 mg daily 60 7.8 58.1 38.3 8.54 65.4 5.5 297 2013 95090 DPP-4-i Sitagliptin 100 mg daily 60 7.8 60.1 36.7 8.27 60.4 5.5 Pioglitazone 45 mg daily 15 11.1 60.8 73.3 8.1 6 Dorkhan Not TZD v 298 Insulin 2009 provided BASAL Titrated 15 9.5 61.5 60 8.3 6 Glargine

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4. Description of Included Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin plus Sulfonylurea Durati on of Mea Propo Duratio Mean Trial Drug diagn n rtion Mean n of body Study registra compar Drug Dose N osed age, of HbA1C, treatme weight, tion ison(s) diabet year men, % nt, kg es, s % months years Harteman 15-45 mg NCT001 TZD v Pioglitazone 14 12 62 64.3 8.3 85 5.5 n-Heurtier daily 299 59211 BASAL 2009 NPH Insulin Titrated 14 12 58 53.8 8.6 90 5.5 Insulin Rosiglitazone 4-8 mg daily 112 8.1 55.3 58 8.7 5.5 Not TZD v Glargine Insulin 300 provided BASAL Titrated 104 8.5 55.9 45 8.8 5.5 4014 glargine Rosiglitazone 4-8 mg daily 20 9.1 6 Reynolds Not TZD v 301 Insulin 2007 provided BASAL Titrated 20 8.86 6 glargine TZD v Rosiglitazone 8 mg daily 9 7.6 47 8.7 6 Ovalle 302 NA BASAL- Insulin (70/30 2004 Titrated 8 7.6 56 9 6 BOLUS mixed) 15-45 mg Pioglitazone 175 55 49.1 7.9 74.9 6 Derosa Not TZD v daily 2009303 provided AGI 100-300 mg Acarbose 175 57 49.7 8 75.6 6 daily 59.0 Rosiglitazone 8 mg daily 25 5.29 40 8.53 8 Kadoglou NCT003 TZD v 4 2007304 06176 CON 60.3 Control 25 5.78 39.1 8.03 8 2 Kadoglou Not TZD v Rosiglitazone 8 mg daily 35 8.5 63.8 40 8.2 6 305 2008 provided CON Control 35 7.5 66.7 45.7 8 6 DPP-4-i Sitagliptin 100 mg daily 326 56.9 55 8.2 91 6 Charbonn NCT012 306 v GLP- 0.6-1.2 mg el 2013 96412 Liraglutide 327 57.6 55 8.1 92.1 6 1RA daily DPP-4-i CANTAT NCT011 Sitagliptin 100 mg daily 378 9.7 56.7 56.9 8.1 89.1 12 307 v SGLT- A-D2 37812 2-i Canagliflozin 300 mg daily 378 9.4 56.6 54.9 8.1 87.4 12 DPP-4-i Nogueira Not Sitagliptin 100 mg daily 18 10.9 55.1 50 8 69.4 5.5 308 v 2014 provided BASAL NPH Insulin Titrated 17 10.9 58.4 35 8.1 73.1 5.5 VISUAL30 NCT010 DPP-4-i Vildagliptin 100 mg daily 172 12.9 59 60.5 8.6 68.7 5.5 9 99137 v CON Control 172 13.3 59.6 52.3 8.6 67.7 5.5 1.5 mg 56.2 Dulaglutide 273 9.13 52.7 8.18 85.13 17.7 weekly 4 GLP- AWARD- NCT010 0.75 mg 56.5 310 1RA v Dulaglutide 272 9.28 50 8.13 86.18 17.7 2 75282 weekly 6 BASAL Insulin 57.2 Titrated 265 8.87 50.6 8.14 87.66 17.7 Glargine 1 GLP- 10-20 mcg Heine NCT000 Exenatide 283 9.9 59.8 55 8.2 87.5 6 311 1RA v daily 2005 82381 BASAL Insulin Titrated 268 9.2 58 56.6 8.3 88.3 6

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1C = glycated hemoglobin; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione. Data for age, HbA1C, and body weight are reported as the mean or median values of corresponding treatment group within the trial.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy Masking of Sponsor Sequen Allocati participa Outcom involved in ce on nts and e Selective authorship Drug(s) generati conceal investiga assess outcome and or data Study comparison on ment tors ment Attrition reporting management Chakraborty 201115 MET v PCO Unclear Unclear Low Unclear High High No Del Prato 200316 MET v PCO Unclear Unclear Low Unclear Low High No Dornan 199117 MET v PCO Unclear Unclear Low Unclear Unclear High No Grant 199618 MET v PCO Unclear Unclear Low Unclear High High No MET v SU v DeFronzo 199519 PCO Unclear Unclear Low Unclear High Low Yes MET v TZD Hallsten 200220 v PCO Unclear Unclear Low Unclear Low High No MET v DPP- Haak 201221 4-i v PCO Unclear Unclear Low Unclear High Low Yes MET v DPP- Pratley 201422 4-i v PCO Unclear Unclear Low Low High Low Yes MET v DPP- Sitagliptin 03623 4-i v PCO Unclear Unclear Low Unclear Low Low Yes MET v AGI v Wolever 200024 PCO Unclear Unclear Low Unclear High High No MET v GLITINIDE v Horton 200025 PCO Low Unclear Low Unclear High Low Yes Banerji 199526 SU v PCO Unclear Unclear Low Unclear Unclear High No Birkeland 199427 SU v PCO Unclear Unclear Low Unclear High High No Camerini- 28 SU v PCO Low Low Low Unclear High High No Davalos 1988 SU v AGI v Essen 199429 PCO Low Unclear High Unclear Low High Yes Johnston SU v AGI v 1998b30 PCO Unclear Unclear Low Unclear Low Low No SU v AGI v Segal 199731 PCO Unclear Unclear Low Unclear High High Yes Chou 201232 TZD v PCO Unclear Unclear Low Low High Low Yes Hong 201333 TZD v PCO Unclear Unclear Unclear Unclear High High No Hu 200734 TZD v PCO Unclear Low Low Unclear Unclear High No Kikuchi 201235 TZD v PCO Unclear Unclear Low Unclear High Low Yes Kim 201436 TZD v PCO Unclear Low Low Unclear Low High No Lebovitz 200137 TZD v PCO Unclear Unclear Low Unclear Low High Yes Miyazaki 200238 TZD v PCO Unclear Unclear Low Unclear Unclear High No Phillips 200139 TZD v PCO Unclear Unclear Low Unclear High High Yes Pioglitazone 00140 TZD v PCO Unclear Unclear Low Unclear High High Yes Rahman 201041 TZD v PCO Unclear Unclear Low Unclear Low High No Scherbaum 200242 TZD v PCO Unclear Unclear Low Unclear High High No Truitt 201043 TZD v PCO Unclear Unclear Low Unclear High High Yes Wajcberg 200744 TZD v PCO Unclear Unclear Low Unclear Unclear High Yes Yee 201045 TZD v PCO Unclear Unclear Low Unclear Low Low No

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy Masking of Sponsor Sequen Allocati participa Outcom involved in ce on nts and e Selective authorship Drug(s) generati conceal investiga assess outcome and or data Study comparison on ment tors ment Attrition reporting management Alogliptin Study DPP-4-i v 01046 PCO Unclear Unclear Low Unclear Unclear Low Yes DPP-4-i v Barzilai 201147 PCO Low Unclear Low Unclear High Low Yes DPP-4-i v Chen 201548 PCO Low Low Low Low Low Low Yes DPP-4-i v CV181-01149 PCO Unclear Unclear Low Unclear High Low Yes DPP-4-i v Dejager 200750 PCO Unclear Unclear Low Unclear High High Yes DPP-4-i v Del Prato 201151 PCO Low Low Low Unclear Low High Yes DPP-4-i v Foley 201152 PCO Unclear Unclear Low Unclear High High Yes DPP-4-i v Frederich 201253 PCO Unclear Unclear Unclear Unclear High Low Yes DPP-4-i v Inagaki 201554 PCO Low Low Low Unclear Low High Yes DPP-4-i v Mari 200855 PCO Unclear Unclear Low Unclear High High Yes DPP-4-i v Pan 2012a56 PCO Low Unclear Low Unclear High Low Yes DPP-4-i v Pi-Sunyer 200757 PCO Unclear Unclear Low Unclear High High Yes Scherbaum DPP-4-i v 200858 PCO Unclear Unclear Low Unclear Low Low Yes DPP-4-i v Sitagliptin 02159 PCO Unclear Unclear Low Unclear Low High Yes DPP-4-i v Thrasher 201460 PCO Low Low Low Unclear Low Low Yes DPP-4-i v Wu 201561 PCO Low Low Low Low Low High No DPP-4-i v Yang 201362 PCO Unclear Unclear Low Unclear Low High Yes DPP-4-i v EMPA-REG SGLT-2-i v MONO63 PCO Low Low Low Unclear Low Low Yes Gastaldelli GLP-1RA v 201464 PCO Unclear Unclear Low Unclear High High Yes GLP-1RA v HARMONY 265 PCO Low Low Low Low Low Low Yes Miyagawa GLP-1RA v 201566 PCO Low Low Low Low Low Low Yes GLP-1RA v Moretto 200867 PCO Low Low Low Unclear Low Low Yes T-Emerge 168 GLP-1RA v Unclear Unclear Low Unclear High Low Yes

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy Masking of Sponsor Sequen Allocati participa Outcom involved in ce on nts and e Selective authorship Drug(s) generati conceal investiga assess outcome and or data Study comparison on ment tors ment Attrition reporting management PCO SGLT-2-i v Bailey 201269 PCO Low Low Low Unclear Low Low Yes SGLT-2-i v CANTATA-M70 PCO Unclear Unclear Low Unclear High Low Yes Ferrannini SGLT-2-i v 201071 PCO Unclear Unclear Low Unclear Low Low Yes SGLT-2-i v Inagaki 201472 PCO Unclear Unclear Low Unclear Low Low Yes SGLT-2-i v Ji 201473 PCO Low Low Low Low Low Low Yes SGLT-2-i v Kaku 201474 PCO Low Low Low Unclear Low Low Yes SGLT-2-i v Kaku 2014a75 PCO Unclear Unclear Low Unclear Low High Yes Asian Acarbose Study76 AGI v PCO Unclear Unclear Low Unclear High High No Braun 199677 AGI v PCO Unclear Unclear Low Unclear High High No Chiasson 199478 AGI v PCO Unclear Unclear Low Unclear High High No Chiasson 200179 AGI v PCO Unclear Unclear Low Unclear High Low Yes Coniff 199480 AGI v PCO Unclear Unclear Low Unclear High High Yes Coniff 199581 AGI v PCO Unclear Unclear Low Unclear Low Low Yes Derosa 201182 AGI v PCO Low Unclear Low Unclear Low High No Drent 200283 AGI v PCO Unclear Unclear Low Unclear High Low No Fischer 199884 AGI v PCO Unclear Unclear Low Unclear Low High Yes Hanefeld 199185 AGI v PCO Unclear Unclear Low Unclear Unclear High Yes Hasche 199986 AGI v PCO Unclear Low Low Unclear Low High No Hegele 199587 AGI v PCO Unclear Unclear Unclear Unclear High High Yes Hotta 199388 AGI v PCO Unclear Unclear Low Unclear Unclear High No Josse 200389 AGI v PCO Unclear Unclear Low Unclear Low High No Leonhardt 199190 AGI v PCO Unclear Unclear Low Unclear Low High Yes Meneilly 200091 AGI v PCO Unclear Unclear Low Unclear Unclear High No Mitrakou 199892 AGI v PCO Unclear Unclear Low Unclear Low High Yes Patel 201393 AGI v PCO Unclear Unclear Low Unclear Unclear High No GLITINIDE v Jovanovic 200094 PCO Unclear Unclear Low Unclear High High Yes GLITINIDE v Saloranta 200295 PCO Unclear Unclear Low Unclear Unclear High Yes Bi 201396 MET v SU Low Unclear High Unclear Unclear High No Campbell 199497 MET v SU Unclear Unclear High Unclear Low High No Dalzell 198698 MET v SU Unclear Unclear High Unclear High High No Derosa 2004a99 MET v SU Unclear Unclear High Unclear Low High No Rahman 2011100 MET v SU Unclear Unclear Unclear Unclear Unclear High No SPREAD- MET v SU Low Unclear Low Low Unclear Low Yes

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy Masking of Sponsor Sequen Allocati participa Outcom involved in ce on nts and e Selective authorship Drug(s) generati conceal investiga assess outcome and or data Study comparison on ment tors ment Attrition reporting management DIMCAD101 MET v SU v ADOPT102 TZD Unclear Unclear Low Low High Low Yes MET v SU v Erem 2014103 TZD Unclear Unclear High Unclear Low Low No Lawrence MET v SU v 2004104 TZD Unclear Unclear High Low Unclear High No Yamanouchi MET v SU v 2005105 TZD Unclear Low High Unclear Low High No MET v SU v Wang 2013106 AGI Low Unclear Unclear Unclear Low High No Bilezikian 2013107 MET v TZD Low Unclear Low Unclear High Low Yes Derosa 2009a108 MET v TZD Unclear Unclear Low Unclear High High No Esposito 2011109 MET v TZD Low Low Low Unclear Low Low Yes Ma 2015110 MET v TZD Low Unclear Unclear Unclear Low No Pavo 2003111 MET v TZD Unclear Unclear Low Unclear Low High Yes QUARTER112 MET v TZD Low Low Low Unclear Low High No Rosenstock 2006113 MET v TZD Unclear Unclear Low Unclear High Low Yes Sohn 2008114 MET v TZD Low Unclear Low Unclear High High No Wu 2014115 MET v TZD Unclear Unclear Unclear Unclear Unclear High No MET v TZD v DPP-4-i v DURATION-4116 GLP-1RA Low Low Low Unclear High Low Yes MET v TZD Kiyici 2009117 v CON Unclear Unclear High Unclear Low High No Turkmen Kemal MET v TZD 2007118 v CON Unclear Unclear Unclear Unclear Low High No MET v DPP- CV181-039119 4-i Low Low Low Unclear High Low Yes Schweizer MET v DPP- 2007120 4-i Unclear Unclear Low Unclear High Low Yes Schweizer MET v DPP- 2009121 4-i Unclear Unclear Low Unclear High Low Yes MET v DPP- Sitagliptin 049122 4-i Low Unclear Low Unclear High Low Yes MET v GLP- AWARD-3123 1RA Low Low Low Unclear High Low Yes MET v GLP- Tanaka 2015124 1RA Unclear Unclear High Unclear High High No MET v GLP- Yuan 2012125 1RA Low Unclear Unclear Unclear Low High No MET v Henry 2012126 SGLT-2-i Low Low Low Unclear High Low Yes Onuchin 2010127 MET v Unclear Unclear High High Low High No

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy Masking of Sponsor Sequen Allocati participa Outcom involved in ce on nts and e Selective authorship Drug(s) generati conceal investiga assess outcome and or data Study comparison on ment tors ment Attrition reporting management BASAL MET v Pistrosch 2013128 BASAL Unclear Unclear High Unclear Low High Yes Yang 2014129 MET v AGI Low Unclear High Unclear High Low No Derosa 2003a130 MET v GLIN Unclear Unclear High Unclear High High No Nar 2009131 MET v CON Unclear Unclear High Unclear Unclear High No Teupe 1991132 MET v CON Unclear Unclear Unclear Unclear High Low No APPROACH133 SU v TZD Low Low Low Low High Low Yes Bakris 2003134 SU v TZD Unclear Unclear High Unclear Unclear High Yes Chou 2008135 SU v TZD Unclear Unclear Low Unclear Low Low Yes GLAC study136 SU v TZD Unclear Unclear Unclear Unclear High High Yes GLAL study137 SU v TZD Unclear Unclear Low Unclear High High Yes Hanefeld 2007138 SU v TZD Unclear Unclear Low Unclear High Low Yes Heliövaara 2007139 SU v TZD Unclear Unclear Low Unclear Unclear High Yes Jain 2006140 SU v TZD Unclear Unclear Low Unclear High Low Yes PERISCOPE141 SU v TZD Low Low Low Low High Low Yes Pop-Busui 2009142 SU v TZD Unclear Unclear Low Unclear High High No St. John Sutton 2002143 SU v TZD Unclear Unclear High Unclear Unclear High Yes Sun 2006144 SU v TZD Unclear Unclear Unclear Unclear Low High No Teramoto 2007145 SU v TZD Unclear Unclear High Unclear Unclear High No Tolman 2009146 SU v TZD Unclear Low Low Unclear High Low Yes Wantanabe 2005147 SU v TZD Unclear Unclear High Unclear Low High No Nakamura SU v TZD v 2004148 AGI Unclear Unclear High Unclear Low High No SU v TZD v Nakamura AGI v 2006149 GLITINIDE Unclear Unclear High Unclear Low High No Arjona Ferreira SU v DPP- 2013150 4-i Low Unclear Low Unclear High Low Yes Arjona Ferreira SU v DPP- 2013a151 4-i Low Unclear Low Unclear High Low Yes SU v DPP- Foley 2009152 4-i Unclear Unclear Low Unclear High High Yes SU v DPP- Hartley 2015153 4-i Low Low Low Unclear High Low Yes SU v DPP- Kondo 2016154 4-i Low Unclear High Unclear High Low No Rosenstock SU v DPP- 2013155 4-i Unclear Unclear Low Unclear High Low Yes SU v DPP- Gudipaty 2014156 4-i v GLP- Unclear Unclear High Unclear Low High Yes

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy Masking of Sponsor Sequen Allocati participa Outcom involved in ce on nts and e Selective authorship Drug(s) generati conceal investiga assess outcome and or data Study comparison on ment tors ment Attrition reporting management 1RA SU v GLP- Kaku 2011157 1RA Unclear Unclear High Unclear High Low Yes SU v GLP- LEAD-3 Mono158 1RA Low Low Low Unclear High Low Yes Birkeland 1994a159 SU v BASAL Unclear Unclear High Unclear High High No Nathan 1988160 SU v BASAL Low Unclear Low Unclear Unclear High No SU v Alvarsson BASAL- 2003161 BOLUS Unclear Unclear High Unclear High Low No SU v Forst 2003162 PRANDIAL Unclear Unclear High Unclear Unclear High Yes Marena 1993163 SU v AGI Unclear Unclear Low Unclear Unclear High No Pagano 1995164 SU v AGI Unclear Unclear Low Unclear Low High Yes Rosenthal 2002165 SU v AGI Unclear Unclear Unclear Unclear High High Yes Salman 2001166 SU v AGI Unclear Unclear High Unclear High High No Spengler 1989167 SU v AGI Unclear Unclear High Unclear Unclear High Yes SU v Derosa 2003168 GLITINIDE Unclear Unclear Low Unclear Low High No SU v Esposito 2004109 GLITINIDE Low Low High Unclear Low High Yes SU v Jibran 2006170 GLITINIDE Unclear Unclear Unclear Unclear Unclear High No Madsbad SU v 2001171 GLITINIDE Unclear Unclear Low Unclear High Low Yes SU v Marbury 1999172 GLITINIDE Unclear Unclear Low Unclear High Low Yes SU v Saleem 2011173 GLITINIDE Unclear Unclear Unclear Unclear Unclear High No SU v Shah 2011174 GLITINIDE Unclear Unclear Unclear Unclear Unclear High No Wolffenbuttel SU v 1999175 GLITINIDE Unclear Unclear Low Unclear High High No TZD v DPP- Henry 2014176 4-i Unclear Unclear Unclear Unclear High Low Yes Rosenstock TZD v DPP- 2007177 4-i Unclear Unclear Low Unclear Low High Yes Rosenstock TZD v DPP- 2007a178 4-i Unclear Unclear Low Unclear High High Yes TZD v GLP- 1RA v BASAL- CONFIDENCE179 BOLUS Low Low High Unclear High High No Goke 2002180 TZD v AGI Unclear Unclear High High Low High Yes

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin

Masking Sponsor of involved in Sequen Allocati participa Outcom authorship ce on nts and e Selective and or data Drug(s) generat conceal investiga assess outcome managemen Study comparison ion ment tors ment Attrition reporting t 192 SU v GLP- LEAD-2 Low Low Low Unclear High Low Yes 1RA v PCO Fonseca 2000193 TZD v PCO Low Unclear Low Low Low Low Yes Gomez-Perez 194 TZD v PCO Unclear Unclear Low Unclear Low High No 2002 Kaku 2009195 TZD v PCO Unclear Unclear Low Unclear Low High Yes Negro 2005196 TZD v PCO Unclear Unclear High Unclear Unclear High No Osman 2004197 TZD v PCO Unclear Unclear Low Unclear Low High No PRISMA198 TZD v PCO Unclear Unclear Low Unclear Low High Yes DeFronzo TZD v DPP- 199 Unclear Unclear Low Unclear High Low Yes 2012 4-i v PCO 200 DPP-4-i v Ahrén 2004 Unclear Unclear Low Unclear High Low Yes PCO 201 DPP-4-i v Bosi 2007 Unclear Unclear Low Unclear High Low Yes PCO 202 DPP-4-i v Derosa 2012 Low Unclear Low Unclear Low High Yes PCO 203 DPP-4-i v Derosa 2012a Unclear Unclear Low Unclear Low High No PCO Goodman DPP-4-i v 204 Unclear Unclear Low Unclear Low Low Yes 2009 PCO 205 DPP-4-i v Nauck 2009 Low Low Low Unclear High Low Yes PCO 206 DPP-4-i v Pan 2012 Unclear Unclear Low Unclear Low High Yes PCO 207 DPP-4-i v Raz 2008 Low Unclear Low Unclear Low Low Yes PCO Saxagliptin DPP-4-i v 208 Low Low Low Unclear High Low Yes 014 PCO 209 DPP-4-i v Sitagliptin 020 Unclear Unclear Low Unclear High High Yes PCO Taskinen DPP-4-i v 210 Unclear Unclear Low Unclear Low High Yes 2011 PCO 211 DPP-4-i v Wang 2016 Low Low Low Low Low Low Yes PCO 212 DPP-4-i v Yang 2011 Low Unclear Low Unclear High Low Yes PCO 213 DPP-4-i v Yang 2012 Low Unclear Low Unclear Low Low Yes PCO DPP-4-i v AWARD-5214 GLP-1RA v Unclear Unclear Low Unclear Low Low Yes PCO 215 DPP-4-i v T-Emerge 4 Unclear Low Low Unclear High Low Yes GLP-1RA v

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin

Masking Sponsor of involved in Sequen Allocati participa Outcom authorship ce on nts and e Selective and or data Drug(s) generat conceal investiga assess outcome managemen Study comparison ion ment tors ment Attrition reporting t PCO DPP-4-i v CANATATA- 216 SGLT-2-i v Low Unclear Low Unclear Low Low Yes D PCO DeFronzo GLP-1RA v 315 Unclear Unclear Low Unclear High Low Yes 2005 PCO 218 GLP-1RA v Derosa 2013 Unclear Unclear Low Unclear Low High No PCO 219 GLP-1RA v GetGoal-F1 Unclear Unclear Low Unclear Low Low Yes PCO 220 GLP-1RA v GetGoal-M Unclear Unclear Low Unclear High Low Yes PCO 221 GLP-1RA v Samson 2011 Low Low High High Unclear High No PCO 222 GLP-1RA v T-Emerge 7 Unclear Unclear Unclear Low High Low Yes PCO 223 SGLT-2-i v Bailey 2010 Low Low Low Unclear Low Low Yes PCO 224 SGLT-2-i v Bolinder 2012 Low Unclear Low Unclear High Low Yes PCO EMPA-REG SGLT-2-i v 225 Low Low Low Unclear Low Low Yes MET PCO 226 SGLT-2-i v ILLUMINATE Unclear Unclear Low Unclear Low Low Yes PCO Chiasson 199478 AGI v PCO Unclear Unclear Low Unclear High High No Gaal 2001227 AGI v PCO Unclear Unclear Low Unclear High High No Halimi 2000228 AGI v PCO Unclear Unclear Low Unclear High High No Phillips 2003229 AGI v PCO Unclear Unclear Low Unclear Low Low No Rosenstock 230 AGI v PCO Unclear Unclear Low Unclear Unclear High No 1998 231 GLITINIDE v Marre 2002 Low Unclear Low Unclear Low High Yes PCO Bakris 2006232 SU v TZD Unclear Unclear Low Unclear High High Yes Derosa 2005217 SU v TZD Unclear Unclear Low Unclear Low High No Garber 2006233 SU v TZD Unclear Unclear Low Unclear High High Yes Kelly 2007234 SU v TZD Unclear Unclear Low Unclear Low Low No Khanolkar 235 SU v TZD Unclear Unclear High Unclear Low High No 2008 Maffioli 2013236 SU v TZD Low Low Low Unclear Low High No Matthews 237 SU v TZD Unclear Unclear Low Unclear High Low No 2005 Ohira 2014238 SU v TZD Unclear Low High Unclear Low High No Petrica 2009239 SU v TZD Unclear Unclear High High Low High No

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Goke 2010251 SU v DPP-4-i Low Low Low Unclear High Low Yes Jeon 2011252 SU v DPP-4-i Unclear Unclear High Unclear Low High Yes Matthews 253 SU v DPP-4-i Unclear Unclear Low Unclear High Low Yes 2010 Nauck 2007b254 SU v DPP-4-i Unclear Unclear Low Unclear High Low Yes Sitagliptin 024255 SU v DPP-4-i Unclear Unclear Low Unclear High Low Yes 256 SU v DPP-4-i HARMONY 3 Unclear Unclear Low Unclear High Low Yes v GLP-1RA 257 SU v GLP- Derosa 2010 Unclear Unclear High Unclear Low High No 1RA 258 SU v GLP- Derosa 2011a Unclear Unclear High Unclear Low High No 1RA 259 SU v GLP- EUREXA Low Unclear High Unclear High Low Yes 1RA CANTATA- SU v SGLT- 260 Low Low Low Unclear Low Low Yes SU 2-i EMPA-REG SU v SGLT- 261 Low Low Low Unclear High Low Yes H2H-SU 2-i 262 SU v SGLT- Nauck 2011 Low Low Low Unclear High Low Yes 2-i BETA263 SU v BASAL Unclear Unclear High Unclear Low High Yes 127 SU v BASAL Onuchin 2010 Unclear Unclear High High Low High No v CON 264 SU v Derosa 2007 Low Unclear Low Unclear Low High No GLITINIDE

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin

Masking Sponsor of involved in Sequen Allocati participa Outcom authorship ce on nts and e Selective and or data Drug(s) generat conceal investiga assess outcome managemen Study comparison ion ment tors ment Attrition reporting t PRESERVE- SU v 265 Unclear Unclear Low Unclear High Low Yes beta GLITINIDE 266 SU v Ristic 2006 Low Low Low Unclear High High Yes GLITINIDE DeFronzo 19 SU v CON Unclear Unclear Low Unclear High Low Yes 1995 267 TZD v DPP- Bolli 2009 Unclear Low Low Unclear Unclear Low Yes 4-i TZD v DPP- DURATION-2268 4-i v GLP- Low Low Low Unclear High Low Yes 1RA 269 TZD v Raskin 2009 Unclear Unclear High Unclear High High Yes GLITINIDE Borges 2011270 TZD v CON Unclear Unclear Low Unclear High Low Yes Kadoglou 271 TZD v CON Unclear Unclear High Unclear Low High No 2011 Rosenstock 113 TZD v CON Unclear Unclear Low Unclear High Low Yes 2006 Sohn 2008114 TZD v CON Low Unclear Low Unclear High High No 1860-LIRA- DPP-4-i v 272 Low Low High Unclear High Low Yes DPP-4 GLP-1RA Van Gaal DPP-4-i v 273 Unclear Unclear Low Unclear High High Yes 2014 GLP-1RA DeFronzo DPP-4-i v 274 Low Low Low Unclear High Low Yes 2015 SGLT-2-i Efstathiou DPP-4-i v 275 Unclear Unclear High Unclear Unclear High No 2015 SGLT-2-i Rosenstock DPP-4-i v 276 Unclear Unclear Low Unclear Low Low Yes 2015 SGLT-2-i 277 DPP-4-i v EASIE 2012 Low Low High Unclear High High Yes BASAL 278 DPP-4-i v Wang 2015 Unclear Unclear Unclear Unclear Low High No AGI 279 DPP-4-i v Bosi 2009 Unclear Unclear Low Unclear Low Low Yes CON 119 DPP-4-i v CV181-039 Low Low Low Unclear High Low Yes CON 280 DPP-4-i v Filozof 2010a Unclear Unclear Low High Low High Yes CON 21 DPP-4-i v Haak 2012 Unclear Unclear Low Unclear High Low Yes CON 22 DPP-4-i v Pratley 2014 Unclear Unclear Low Low High Low Yes CON Sitagliptin 03623 DPP-4-i v Unclear Unclear Low Unclear Low Low Yes

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin plus Sulfonylurea

Masking Sponsor of involved in Sequen Allocati participa Outcom authorship ce on nts and e Selective and or data Drug(s) generat conceal investiga assess outcome manageme Study comparison ion ment tors ment Attrition reporting nt Dailey 2004286 TZD v PCO Unclear Unclear Low Unclear High Low Yes Sridhar 2013287 TZD v PCO Unclear Unclear Low Unclear Unclear High No 288 TZD v GLP- HARMONY 5 Low Low Low Low High Low Yes 1RA v PCO 289 DPP-4-i v Moses 2014 Low Low Low Unclear Low Low Yes PCO 290 DPP-4-i v Owens 2011 Unclear Unclear Low Unclear Low Low Yes PCO 291 GLP-1RA v Kendall 2005 Unclear Unclear Low Unclear High High Yes PCO GLP-1RA v LEAD-5292 BASAL v Unclear Low Low Unclear High High Yes PCO CANTATA- SGLT-2-i v 293 Low Low Low Low Low Low Yes MSU PCO EMPA-REG SGLT-2-i v 294 Low Low Low Unclear Low Low Yes METSU PCO 295 SGLT-2-i v Matthaei 2015 Low Low Low Unclear Low Low Yes PCO Lam 1998296 AGI v PCO Unclear Unclear Low Unclear Low High No 297 TZD v DPP- Liu 2013 Unclear Unclear High Unclear Low High Yes 4-i 298 TZD v Dorkhan 2009 Unclear Unclear High Unclear Low Low No BASAL Hartemann- TZD v 299 Unclear Low High Unclear Low High Yes Heurtier 2009 BASAL Insulin Glargine TZD v 300 Unclear Unclear Low Unclear High High Yes 4014 BASAL Reynolds TZD v 301 Unclear Unclear High Unclear Low High No 2007 BASAL TZD v Ovalle 2004302 BASAL- Unclear Unclear High Unclear Low High No BOLUS Derosa 2009303 TZD v AGI Low Unclear Low Unclear High High No Kadoglou 304 TZD v CON Unclear Unclear Unclear Unclear Low High No 2007 Kadoglou 305 TZD v CON Unclear Unclear High Unclear Low High No 2008 Charbonnel DPP-4-i v 306 Low Low High Unclear High High Yes 2013 GLP-1RA 307 DPP-4-i v CANTATA-D2 Low Low Low Unclear High Low Yes SGLT-2-i Nogueira DPP-4-i v 308 Unclear Unclear High Unclear High High No 2014 BASAL

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Masking Sponsor of involved in Sequen Allocati participa Outcom authorship ce on nts and e Selective and or data Drug(s) generat conceal investiga assess outcome manageme Study comparison ion ment tors ment Attrition reporting nt 309 DPP-4-i v VISUAL Low Unclear High Unclear Unclear High Yes CON 310 GLP-1RA v AWARD-2 Low Low High Low Low Low Yes BASAL 311 GLP-1RA v Heine 2005 Low Low High Unclear High Low Yes BASAL GLP-1RA v Bergenstal 312 BASAL- Low Low Low Unclear High High Yes 2009 BOLUS GLP-1RA v Nauck 2007a313 BASAL- Low Low High Unclear High Low Yes BOLUS BASAL v Strojek 2009314 BASAL- Low Low High Unclear Low High Yes BOLUS

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 8. Estimated Global Inconsistency in Networks of Outcomes

Network meta-analysis draws information from different sources including between drug comparisons across different studies. Consistency is the term used specifically to infer agreement (or disagreement) between direct evidence from head-to-head drug comparisons within trials and indirect evidence from drug comparisons drawn from a common comparator between trials. Inconsistency is a statistical consequence of differences in trial populations, treatments, outcomes and risks of bias. Global consistency is tested here using the ‘design-by- interaction’ test that infers consistency across an entire treatment network, using a chi square test. A p value <0.05 is taken to infer evidence of global inconsistency in the network. For example, there is no evidence of global inconsistency across the network for drugs used as monotherapy and the association with cardiovascular mortality.

eTable 8.1. Estimated Global Inconsistency in Networks of Outcomes for Drug Classes Given as Monotherapy

Outcome Chi square P value CV mortality 7.33 0.92 All-cause mortality 9.76 0.97 Myocardial infarction 12.55 0.70 Stroke 6.20 0.91 Serious adverse events 20.3 0.44 HbA1C 37.3 0.64 Treatment failure 34.9 0.33 Hypoglycemia 32.9 0.23 Body weight 12.8 0.69

eTable 8.2. Estimated Global Inconsistency in Networks of Outcomes for Drug Classes Given as Dual Therapy in Addition to Metformin

Outcome Chi square P value CV mortality 4.11 0.97 All-cause mortality 5.92 0.99 Myocardial infarction 7.18 0.99 Stroke 7.27 0.95 Serious adverse events 15.1 0.93 HbA1C 13.8 0.68 Treatment failure 37.9 0.009 Hypoglycemia 26.5 0.38 Body weight 11.5 0.31

eTable 8.3. Estimated Global Inconsistency in Networks for Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea

Outcome Chi square P value CV mortality 0.06 0.80 All-cause mortality 0.32 0.96 Myocardial infarction Insufficient -- observations Stroke Insufficient -- observations Serious adverse events 10.9 0.21 HbA1C 78.1 <0.001 Treatment failure 3.44 0.75 Hypoglycemia 11.9 0.22 Body weight 0.04 0.98

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 9. Estimated Heterogeneity in Networks

The extent of heterogeneity was evaluated in each network analysis by comparing the magnitude of a common heterogeneity variance for the network (tau [τ]) with an empirical distribution of heterogeneity variances, considering the range of treatment effects expected, in which tau values from 0.1 to 0.5 were considered reasonable, 0.5 to 1.0 were considered fairly high and above 1.0 represented fairly extreme heterogeneity.10 For example, a heterogeneity tau <0.001 for cardiovascular mortality associated with monotherapy was indicative of very low level heterogeneity in this treatment network. eTable 9.1. Estimated Heterogeneity in Networks for Drug Classes Given as Monotherapy Outcome Number of Number of Number of Heterogeneity events trials participants tau [τ] Cardiovascular mortality 67 25 14,477 <0.001 All-cause mortality 241 41 27,670 <0.001 Myocardial infarction 157 31 22,154 <0.001 Stroke 132 20 17,192 <0.001 Serious adverse events 2910 68 38,466 0.04 HbA1C -- 98 21,703 0.31 Treatment failure 3366 89 41,498 0.35 Hypoglycemia 2962 80 40,082 0.21 Body weight -- 42 7024 0.08 eTable 9.2. Estimated Heterogeneity in Networks for Drug Classes Given as Dual Therapy in Addition to Metformin Outcome Number of Number of Number of Heterogeneity events trials participants tau Cardiovascular mortality 45 26 20,690 <0.001 All-cause mortality 128 42 34,822 <0.001 Myocardial infarction 87 28 25,127 <0.001 Stroke 79 26 25,567 <0.001 Serious adverse events 3626 68 44,470 0.12 HbA1C -- 51 17,022 0.69 Treatment failure 3875 59 40,364 0.30 Hypoglycemia 4619 74 45,710 0.40 Body weight -- 24 6580 0.41 eTable 9.3. Estimated Heterogeneity in Networks for Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea Outcome Number of Number of Number of Heterogeneity events trials participants tau Cardiovascular mortality 6 5 3267 <0.001 All-cause mortality 19 9 5263 <0.001 Myocardial infarction Insufficient ------observations Stroke Insufficient ------observations Serious adverse events 498 17 9338 0.03 HbA1C -- 16 4941 0.54 Treatment failure 811 13 7649 0.16 Hypoglycemia 2854 19 9312 0.30 Body weight -- 9 2935 <0.001

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 10. Definitions of Treatment Failure Outcome

eTable 10.1. Definitions of Treatment Failure Outcome for Drug Classes Given as Monotherapy

Biochemical Rescue Drug Definition of treatment definition (if therapy Study name comparison failure provided) given Del Prato 200316 MET v PCO Poor glycemic control N DeFronzo 199519 MET v SU v PCO Treatment failure N 21 MET v DPP-4-i v Haak 2012 Rescue therapy FPG > 13.3 mmol/l Y PCO 22 MET v DPP-4-i v Pratley 2014 Hyperglycemic rescue HbA1c > 8.5% Y PCO 23 MET v DPP-4-i v Sitagliptin 036 Glycemic rescue therapy FPG > 11.1 mmol/l Y PCO 24 MET v AGI v Wolever 2000 Poor glycemic control FPG > 13.3 mmol/l N PCO Camerini-Davalos 28 SU v PCO Ketonuria 1988 Segal 199731 SU v AGI v PCO Lack of efficacy N Kikuchi 201235 TZD v PCO Lack of efficacy N Kim 201436 TZD v PCO Lack of Efficacy N Lebovitz 200137 TZD v PCO Lack of efficacy N Pioglitazone 00140 TZD v PCO Poor glycemic control N 43 Lack of acceptable glycemic Truitt 2010 TZD v PCO FPG > 11.1 mmol/l N control Wajcberg 200744 TZD v PCO Comparable glycemic control FPG > 8.3 mmol/l Y Yee 201045 TZD v PCO Lack of glycemic control N Alogliptin Study 01046 DPP-4-i v PCO Insufficient therapeutic effect N Barzilai 201147 DPP-4-i v PCO Lack of efficacy FPG > 15 mmol/l Y Chen 201548 DPP-4-i v PCO Lack of efficacy N CV181-01149 DPP-4-i v PCO Lack of efficacy FPG > 11.1 mmol/l N 50 Unsatisfactory therapeutic Dejager 2007 DPP-4-i v PCO FPG > 15 mmol/l N effect Del Prato 201151 DPP-4-i v PCO Rescue therapy FPG > 13.3 mmol/l Y Frederich 201253 DPP-4-i v PCO Rescued FPG > 11.1 mmol/l Y Inagaki 201554 DPP-4-i v PCO Lack of efficacy N 55 Unsatisfactory therapeutic Mari 2008 DPP-4-i v PCO N effect Pan 2012a56 DPP-4-i v PCO Rescue medication FPG > 11.1 mmol/l Y 57 Unsatisfactory therapeutic Pi-Sunyer 2007 DPP-4-i v PCO N effect 58 Unsatisfactory therapeutic Scherbaum 2008 DPP-4-i v PCO N effect Sitagliptin 02159 DPP-4-i v PCO Glycemic rescue therapy FPG > 11.1 mmol/l Y Thrasher 201460 DPP-4-i v PCO Rescue therapy FPG > 11.1 mmol/l Y Wu 201561 DPP-4-i v PCO Lack of efficacy N Yang 201362 DPP-4-i v PCO Rescue therapy FPG > 15 mmol/l Y 63 DPP-4-i v SGLT- EMPA-REG MONO Rescue therapy FPG > 11.1 mmol/l Y 2-i v PCO HARMONY 265 GLP-1RA v PCO Hyperglycemia rescue Variable Y Moretto 200867 GLP-1RA v PCO Loss of glycemic control HbA1c > 10.5% N

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 10.1. Definitions of Treatment Failure Outcome for Drug Classes Given as Monotherapy

Biochemical Rescue Drug Definition of treatment definition (if therapy Study name comparison failure provided) given T-Emerge 168 GLP-1RA v PCO Rescue medication Y Bailey 201269 SGLT-2-i v PCO Poor glycemic control FPG > 15 mmol/L N CANTATA-M70 SGLT-2-i v PCO Glycemic rescue therapy FPG > 11.1 mmol/l Y Ferrannini 201071 SGLT-2-i v PCO Lack of efficacy N 72 FPG exceeding the limit Inagaki 2014 SGLT-2-i v PCO FPG > 11.1 mmol/l N specified for withdrawal 73 Failure to achieve glycemic Ji 2014 SGLT-2-i v PCO FPG > 11.1 mmol/l Y targets Kaku 201474 SGLT-2-i v PCO Inadequate efficacy N Kaku 2014a75 SGLT-2-i v PCO Lack of efficacy N Drent 200283 AGI v PCO Hyperglycemia N 94 GLITINIDE v Jovanovic 2000 Lack of efficacy FPG > 19.4 mmol/l N PCO 99 Unsatisfactory glycemic Derosa 2004a MET v SU N control 102 Had insufficient treatment ADOPT MET v SU v TZD N response Lawrence 2004104 MET v SU v TZD Hyperglycemia FPG > 13.3 mmol/l Y Yamanouchi 2005105 MET v SU v TZD Treatment failure N Pavo 2003111 MET v TZD Lack of efficacy N QUARTER112 MET v TZD Lack of efficacy N Rosenstock 2006113 MET v TZD Insufficient therapeutic effect FPG > 13.3 mmol/l N MET v TZD v DURATION-4116 DPP-4-i v GLP- Loss of glucose control N 1RA CV181-039119 MET v DPP-4-i Rescue FPG > 11.1 mmol/l Y 120 Unsatisfactory therapeutic Schweizer 2007 MET v DPP-4-i FPG > 15 mmol/l N effect 121 Unsatisfactory therapeutic Schweizer 2009 MET v DPP-4-i N effect Sitagliptin 049122 MET v DPP-4-i Lack of efficacy FPG > 11.1 mmol/l N AWARD-3123 MET v GLP-1RA Lack of efficacy N Henry 2012126 MET v SGLT-2-i Rescue FPG > 11.1 mmol/l Y Yang 2014129 MET v AGI Add-on therapy FPG > 7 mmol/l Y Teupe 1991132 MET v CON Confirmed therapeutic failure N APPROACH133 SU v TZD Insufficient therapeutic effect N Chou 2008135 SU v TZD Lack of efficacy FPG > 13.3 mmol/l N GLAC study136 SU v TZD Perceived lack of efficacy N GLAL study137 SU v TZD Lack of efficacy N Hanefeld 2007138 SU v TZD Lack of efficacy N St. John Sutton 143 SU v TZD Lack of efficacy N 2002 Tolman 2009146 SU v TZD Treatment failure HbA1c > 7.5% N Arjona Ferreira 150 SU v DPP-4-i Glycemic rescue therapy FPG > 13.3 mmol/l Y 2013 Arjona Ferreira 151 SU v DPP-4-i Insulin rescue therapy FPG > 13.3 mmol/l Y 2013a

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 10.1. Definitions of Treatment Failure Outcome for Drug Classes Given as Monotherapy

Biochemical Rescue Drug Definition of treatment definition (if therapy Study name comparison failure provided) given Foley 2009152 SU v DPP-4-i Rescue FPG > 13.3 mmol/l Y Hartley 2015153 SU v DPP-4-i Lack of efficacy N Kondo 2016154 SU v DPP-4-i Additional drugs Y Rosenstock 2013155 SU v DPP-4-i Hyperglycemic rescue HbA1c > 8% Y Kaku 2011157 SU v GLP-1RA Ineffective therapy N LEAD-3 Mono158 SU v GLP-1RA Ineffective therapy N Nathan 1988160 SU v BASAL Hyperglycemia Y 161 SU v BASAL- Needed insulin to control HbA1c > 3% above Alvarsson 2003 Y BOLUS diabetes upper reference 168 Unsatisfactory glycemic Derosa 2003 SU v GLITINIDE N control Madsbad 2001171 SU v GLITINIDE Ineffective therapy N Marbury 1999172 SU v GLITINIDE Ineffective therapy N Henry 2014176 TZD v DPP-4-i Lack of efficacy HbA1c > 8% N 177 Unsatisfactory therapeutic Rosenstock 2007 TZD v DPP-4-i N effect 178 Unsatisfactory therapeutic Rosenstock 2007a TZD v DPP-4-i N effect 179 TZD v GLP-1RA v CONFIDENCE Poor glucose control N BASAL-BOLUS Goke 2002180 TZD v AGI Lack of efficacy HbA1c > 11.5% N Jovanovic 2004182 TZD v GLITINIDE Lack of efficacy FPG > 15 mmol/l N Raskin 2004183 TZD v GLITINIDE Lack of efficacy FPG > 15 mmol/l N 188 DPP-4-i v SGLT- Lewin 2015 Rescue therapy HbA1c > 8% Y 2-i 189 Unsatisfactory therapeutic Pan 2008 DPP-4-i v AGI N effect

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; FPG = fasting plasma glucose; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 10.2. Definitions of Treatment Failure Outcome for Drug Classes Given as Dual Therapy Added to Metformin

Biochemical Rescue Definition of treatment definition (if therapy Study name Drug comparison failure provided) given 192 SU v GLP-1RA v LEAD-2 Ineffective therapy N PCO Fonseca 2000193 TZD v PCO Lack of efficacy N Gomez-Perez Variable based on 194 TZD v PCO Lack of efficacy N 2002 treatment duration Kaku 2009195 TZD v PCO Lack of efficacy N 198 Unsatisfactory therapeutic PRISMA TZD v PCO N effect 199 TZD v DPP-4-i v DeFronzo 2012 Hyperglycemic rescue HbA1c > 8.5% N PCO Nauck 2009205 DPP-4-i v PCO Hyperglycemic rescue HbA1c > 8.5% Y 206 Unsatisfactory therapeutic Pan 2012 DPP-4-i v PCO N effect Raz 2008207 DPP-4-i v PCO Rescued FPG > 12.2 mmol/l Y Saxagliptin 014208 DPP-4-i v PCO Rescue FPG > 11.1 mmol/l Y Sitagliptin 020209 DPP-4-i v PCO Glycemic rescue therapy FPG > 11.1 mmol/l Y Taskinen 2011210 DPP-4-i v PCO Rescue medication FPG > 11.1 mmol/l Y Wang 2016211 DPP-4-i v PCO Lack of efficacy N Yang 2012213 DPP-4-i v PCO Rescue therapy FPG > 11.1 mmol/l Y 214 DPP-4-i v GLP- AWARD-5 Lack of efficacy N 1RA v PCO 215 DPP-4-i v GLP- T-Emerge 4 Rescue medication HbA1c > 8% Y 1RA v PCO 216 DPP-4-i v SGLT- CANTATA-D Glycemic rescue therapy FPG > 11.1 mmol/l Y 2-i v PCO DeFronzo 200519 GLP-1RA v PCO Loss of glucose control FPG > 13.3 mmol/l N GetGoal-F1219 GLP-1RA v PCO Rescue therapy N GetGoal-M220 GLP-1RA v PCO Rescue therapy FPG > 11.1 mmol/l Y Bailey 2010223 SGLT-2-i v PCO Lack of efficacy FPG > 15 mmol/L Y Bolinder 2012224 SGLT-2-i v PCO Rescue therapy FPG > 13.3 mmol/l Y 225 FPG>11.1 mmol/l EMPA-REG MET SGLT-2-i v PCO Rescue therapy Y or HbA1C >8.5% ILLUMINATE226 SGLT-2-i v PCO Lack of efficacy N Marre 2002231 GLITINIDE v PCO Unsatisfactory efficacy FPG > 15 mmol/l N Bakris 2006232 SU v TZD Lack of efficacy N Garber 2006233 SU v TZD Hyperglycemia N PIOfix241 SU v TZD Glycemic deterioration N Umpierrez 2006242 SU v TZD Treatment failure N Arechavaleta 2011244 SU v DPP-4-i Lack of efficacy FPG > 13.3 mmol/l N 246 Variable based on Del Prato 2014 SU v DPP-4-i Hyperglycemic rescue Y treatment duration 248 Unsatisfactory therapeutic Filozof 2010 SU v DPP-4-i N effect Gallwitz 2012249 SU v DPP-4-i Rescue treatment FPG > 13.3 mmol/l Y Goke 2010251 SU v DPP-4-i High fasting plasma glucose N Matthews 2010253 SU v DPP-4-i Rescue medication HbA1c > 8% Y Nauck 2007b254 SU v DPP-4-i Lack of efficacy HbA1c > 8% N

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 10.2. Definitions of Treatment Failure Outcome for Drug Classes Given as Dual Therapy Added to Metformin

Biochemical Rescue Definition of treatment definition (if therapy Study name Drug comparison failure provided) given Sitagliptin 024255 SU v DPP-4-i Lack of efficacy FPG > 11.1 mmol/l N EUREXA259 SU v GLP-1RA Lack of efficacy N CANTATA-SU260 SU v SGLT-2-i Glycemic rescue therapy HbA1c > 8% Y EMPA-REG H2H- 261 SU v SGLT-2-i Rescue treatment HbA1c > 8% Y SU PRESERVE-beta265 SU v GLITINIDE Rescue FPG > 13.3 mmol/l Y DeFronzo 199519 SU v CON Treatment failure N 268 TZD v DPP-4-i v DURATION-2 Loss of glucose control N GLP-1RA Raskin 2009269 TZD v GLITINIDE Ineffective therapy N Borges 2011270 TZD v CON Insufficient therapeutic effect HbA1c > 8% N Rosenstock 2006113 TZD v CON Insufficient therapeutic effect FPG > 13.3 mmol/l N 272 DPP-4-i v GLP- 1860-LIRA-DPP-4 Ineffective therapy N 1RA 315 DPP-4-i v SGLT- DeFronzo 2015 Lack of efficacy HbA1c > 8.5% N 2-i EASIE 2012277 DPP-4-i v BASAL Lack of efficacy N Wang 2015278 DPP-4-i v AGI Unsatisfactory effect N CV181-039119 DPP-4-i v CON Rescued FPG > 11.1 mmol/l Y 280 Unsatisfactory therapeutic Filozof 2010a DPP-4-i v CON FPG > 13.3 mmol/l N effect Haak 201221 DPP-4-i v CON Rescue therapy FPG > 13.3 mmol/l Y Pratley 201422 DPP-4-i v CON Hyperglycemic rescue HbA1c > 8.5% Y Sitagliptin 03623 DPP-4-i v CON Glycemic rescue therapy FPG > 11.1 mmol/l Y Henry 2012126 SGLT-2-i v CON Rescue FPG > 11.1 mmol/l Y 285 BASAL v Robbins 2007 Lack of efficacy N PRANDIAL Wolever 200024 AGI v CON Poor glycemic control FPG > 13.3 mmol/l N

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; FPG = fasting plasma glucose; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 10.3. Definitions of Treatment Failure Outcome for Treatments Given as Triple Therapy in Addition to Metformin and Sulfonylurea

Biochemical Rescue Definition of treatment definition (if therapy Study name Drug comparison failure provided) given Dailey 2004286 TZD v PCO Hyperglycemia FPG > 13.3 mmol/l N 288 TZD v GLP-1RA v HARMONY 5 Hyperglycemic rescue HbA1C > 8.5% Y PCO 289 Worsening of glycemic Moses 2014 DPP-4-i v PCO FPG > 12.2 mmol/l N control Owens 2011290 DPP-4-i v PCO Rescue medication FPG > 11.1 mmol/l Y Kendall 2005291 GLP-1RA v PCO Loss of glucose control FPG > 13.3 mmol/l N 292 GLP-1RA v BASAL LEAD-5 Ineffective therapy FPG > 13.3 mmol/l N v PCO EMPA-REG 294 SGLT-2-i v PCO Rescue medication FPG > 11.1 mmol/l Y METSU 295 FPG > 13.33 Matthaei 2015 SGLT-2-i v PCO Rescue Y mmol/l 306 DPP-4-i v GLP- Charbonnel 2013 Anti-hyperglycemic therapy Y 1RA 307 DPP-4-i v SGLT-2- CANTATA-D2 Glycemic withdrawal FPG > 11.1 mmol/l N i 310 Persistent, severe HbA1C =8.0% or AWARD-2 GLP-1RA v BASAL Y hyperglycemia FPG >15 mmol/l Heine 2005311 GLP-1RA v BASAL Loss of glucose control N 314 BASAL v BASAL- Strojek 2009 Ineffective therapy N BOLUS

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; FPG = fasting plasma glucose; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11. Contributions of Direct Evidence to the Networks of Treatments

eTable 11.1. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Monotherapy Contribution Number to the Intervention Comparison of trials network, % Cardiovascular mortality MET SU 3 20.2 MET TZD 2 4.3 MET DPP-4-i 4 10.3 MET SGLT-2-i 2 6.8 MET PCO 3 4.7 MET GLITINIDE 1 3.0 SU TZD 5 8.2 SU DPP-4-i 1 4.9 SU BASAL-BOLUS 1 1.6 SU PCO 1 6.5 SU AGI 1 2.1 SU GLITINIDE 1 4.3 TZD DPP-4-i 1 1.8 TZD PCO 1 3.3 DPP-4-i SGLT-2-i 1 2.9 DPP-4-i PCO 3 6.7 SGLT-2-i PCO 1 3.5 AGI PCO 2 3.2 GLITINIDE PCO 1 1.8 All-cause mortality MET SU 3 7.8 MET TZD 5 7.3 MET DPP-4-i 6 3.9 MET SGLT-2-i 2 3.5 MET GLP-1RA 1 1.8 MET PCO 3 3.1 MET GLITINIDE 1 2.5 SU TZD 5 9.1 SU DPP-4-i 3 8.4 SU GLP-1RA 2 3.6 SU BASAL-BOLUS 1 8.7 SU PCO 1 1.2 SU AGI 1 6.5 SU GLITINIDE 1 5.1 TZD DPP-4-i 3 1.3 TZD GLP-1RA 1 1.2 TZD PCO 1 1.2 DPP-4-i SGLT-2-i 2 3.0 DPP-4-i GLP-1RA 1 1.2 DPP-4-i PCO 6 5.5 SGLT-2-i PCO 3 5.1 GLP-1RA PCO 1 2.6 AGI PCO 2 4.4 GLITINIDE PCO 1 2.1

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.1. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Monotherapy Contribution Number to the Intervention Comparison of trials network, % Serious adverse events MET SU 1 7.7 MET TZD 5 8.0 MET DPP-4-i 8 5.0 MET SGLT-2-i 2 2.9 MET GLP-1RA 2 1.0 MET PCO 4 1.5 MET AGI 1 4.4 SU TZD 7 11.4 SU DPP-4-i 4 6.3 SU GLP-1RA 2 5.4 SU GLITINIDE 1 7.0 TZD DPP-4-i 3 0.9 TZD GLP-1RA 2 1.9 TZD BASAL-BOLUS 1 3.7 TZD PCO 5 1.3 TZD CON 1 7.0 DPP-4-i SGLT-2-i 2 0.7 DPP-4-i GLP-1RA 1 0.7 DPP-4-i PCO 19 8.1 DPP-4-i AGI 1 2.1 SGLT-2-i PCO 8 5.2 GLP-1RA BASAL-BOLUS 1 3.5 GLP-1RA PCO 3 3.5 AGI PCO 1 1.0 Myocardial infarction MET SU 4 7.4 MET TZD 3 6.5 MET DPP-4-i 6 8.1 MET GLP-1RA 1 2.3 MET PCO 2 3.8 MET CON 1 4.8 SU TZD 7 9.6 SU DPP-4-i 3 5.7 SU GLP-1RA 1 4.0 TZD DPP-4-i 2 1.0 TZD GLP-1RA 1 2.3 TZD PCO 4 7.6 TZD CON 1 4.8 DPP-4-i SGLT-2-i 1 6.4 DPP-4-i GLP-1RA 1 2.1 DPP-4-i PCO 6 8.5 SGLT-2-i PCO 2 5.5 AGI PCO 1 9.4 Stroke MET SU 2 7.7 MET TZD 2 7.6 MET DPP-4-i 2 5.6 MET GLP-1RA 1 3.3 MET PCO 1 2.2

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.1. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Monotherapy Contribution Number to the Intervention Comparison of trials network, % SU TZD 5 10.2 SU DPP-4-i 2 7.1 SU GLP-1RA 1 3.6 TZD DPP-4-i 1 4.1 TZD GLP-1RA 1 4.2 TZD BASAL-BOLUS 1 7.4 TZD PCO 1 3.9 DPP-4-i SGLT-2-i 1 6.6 DPP-4-i PCO 4 8.5 SGLT-2-i PCO 1 6.3 GLP-1RA BASAL-BOLUS 1 6.5 GLP-1RA PCO 1 5.1 HbA1C MET SU 9 4.0 MET TZD 12 3.7 MET DPP-4-i 6 6.3 MET SGLT-2-i 2 4.5 MET GLP-1RA 2 3.5 MET BASAL 2 1.0 MET PCO 6 1.0 MET Control 3 2.2 MET AGI 1 0.8 SU TZD 14 5.9 SU DPP-4-i 1 0.3 SU GLP-1RA 3 6.7 SU BASAL 2 2.5 SU PRANDIAL 1 6.4 SU PCO 3 0.2 SU AGI 9 4.1 SU GLITINIDE 4 2.7 TZD DPP-4-i 2 0.8 TZD GLP-1RA 1 3.0 TZD PCO 10 2.4 TZD CON 4 7.3 TZD AGI 4 3.4 TZD GLITINIDE 3 2.3 DPP-4-i SGLT-2-i 1 3.1 DPP-4-i GLP-1RA 3 3.3 DPP-4-i PCO 8 4.6 SGLT-2-i PCO 2 1.2 GLP-1RA PCO 2 2.5 BASAL CON 1 3.4 AGI PCO 8 1.4 GLITINIDE PCO 1 3.3 GLITINIDE CON 1 1.4 GLITINIDE AGI 1 0.6 Treatment failure MET SU 5 1.7 MET TZD 7 6.5 MET DPP-4-i 8 5.9

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.1. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Monotherapy Contribution Number to the Intervention Comparison of trials network, % MET SGLT-2-i 2 4.3 MET GLP-1RA 2 1.4 MET PCO 5 1.2 MET CON 1 6.6 MET AGI 2 0.4 SU TZD 10 4.3 SU DPP-4-i 6 8.0 SU GLP-1RA 2 4.4 SU BASAL 1 6.5 SU BASAL-BOLUS 1 2.6 SU PCO 3 1.4 SU AGI 1 0.2 SU GLITINIDE 3 5.3 TZD DPP-4-i 4 0.6 TZD GLP-1RA 2 0.7 TZD BASAL-BOLUS 1 2.4 TZD PCO 7 4.6 TZD AGI 1 1.3 TZD GLITINIDE 2 0.9 DPP-4-i SGLT-2-i 2 2.7 DPP-4-i GLP-1RA 1 0.4 DPP-4-i PCO 19 7.2 DPP-4-i AGI 1 1.5 SGLT-2-i PCO 8 3.3 GLP-1RA BASAL-BOLUS 1 1.6 GLP-1RA PCO 2 4.5 AGI PCO 3 4.1 GLITINIDE PCO 1 3.4 Hypoglycemia MET SU 3 0.7 MET TZD 4 7.9 MET DPP-4-i 8 3.1 MET SGLT-2-i 2 1.5 MET GLP-1RA 3 4.7 MET BASAL 1 2.7 MET PCO 4 2.3 MET AGI 1 0.6 MET GLITINIDE 1 2.0 SU TZD 8 8.2 SU DPP-4-i 6 4.6 SU GLP-1RA 1 5.1 SU PCO 1 3.3 SU PRANDIAL 1 5.9 SU PCO 3 0.9 SU AGI 3 4.3 SU GLITINIDE 4 6.2 TZD DPP-4-i 4 2.8 TZD GLP-1RA 2 1.4 TZD BASAL-BOLUS 1 2.5 TZD PCO 3 1.1

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.1. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Monotherapy Contribution Number to the Intervention Comparison of trials network, % TZD CON 1 5.9 TZD GLITINIDE 2 0.5 DPP-4-i SGLT-2-i 2 1.3 DPP-4-i GLP-1RA 1 0.9 DPP-4-i PCO 15 3.5 SGLT-2-i PCO 6 3.9 GLP-1RA BASAL-BOLUS 1 4.1 GLP-1RA PCO 3 0.7 AGI PCO 5 2.9 GLITINIDE PCO 3 4.6 Body weight MET SU 5 9.8 MET TZD 3 1.8 MET SGLT-2-i 2 7.9 MET GLP-1RA 1 2.1 MET PCO 3 1.4 MET CON 1 5.0 MET AGI 1 5.3 SU TZD 3 5.2 SU GLP-1RA 1 6.4 SU BASAL 2 4.8 SU PRANDIAL 1 6.4 SU BASAL-BOLUS 1 5.6 SU AGI 3 3.6 SU GLITINIDE 5 1.9 TZD PCO 4 5.1 TZD CON 1 2.5 DPP-4-i SGLT-2-i 1 4.6 DPP-4-i GLP-1RA 1 1.7 DPP-4-i PCO 3 4.7 SGLT-2-i PCO 2 2.9 GLP-1RA PCO 1 2.9 AGI PCO 5 8.5 eTable 11.2. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Dual Therapy in Addition to Metformin Intervention Comparison Number Contribution of trials to the network, % Cardiovascular mortality SU TZD 1 2.9 SU DPP-4-i 6 15.3 SU SGLT-2-i 1 5.4 SU GLITINIDE 1 6.7 TZD DPP-4-i 2 4.3 TZD GLP-1RA 1 2.5 TZD PCO 3 6.9 TZD CON 1 6.2 DPP-4-i SGLT-2-I 1 2.8 DPP-4-i GLP-1RA 3 9.1

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.2. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Dual Therapy in Addition to Metformin Intervention Comparison Number Contribution of trials to the network, % DPP-4-i PCO 5 9.7 DPP-4-i CON 3 11.6 SGLT-2-i CON 2 6.6 GLP-1RA PCO 1 3.5 GLITINIDE CON 1 6.5 All-cause mortality SU TZD 2 2.3 SU DPP-4-i 10 11.6 SU SGLT-2-i 3 7.9 SU GLP-1RA 2 9.8 SU PCO 1 1.6 SU GLITINIDE 2 5.9 TZD DPP-4-i 2 2.8 TZD GLP-1RA 1 1.3 TZD PCO 3 4.5 TZD CON 1 3.5 DPP-4-i SGLT-2-i 2 1.5 DPP-4-i GLP-1RA 4 5.2 DPP-4-i PCO 7 5.1 DPP-4-i CON 4 8.5 SGLT-2-i PCO 2 2.5 SGLT-2-i CON 2 2.6 GLP-1RA BASAL 1 9.7 GLP-1RA PCO 4 7.4 GLITINIDE PCO 1 3.1 GLITINIDE CON 1 3.0 Serious adverse events SU TZD 4 3.5 SU DPP-4-i 10 10.9 SU SGLT-2-i 3 3.1 SU GLP-1RA 3 8.0 SU BASAL 1 1.1 SU PCO 2 2.0 SU CON 1 0.6 SU GLITINIDE 1 7.1 TZD DPP-4-i 3 1.8 TZD GLP-1RA 1 0.9 TZD PCO 5 2.1 TZD CON 1 3.4 DPP-4-i SGLT-2-i 3 1.5 DPP-4-i GLP-1RA 5 3.9 DPP-4-i BASAL 1 3.4 DPP-4-i PCO 15 6.6 DPP-4-i CON 5 5.7 SGLT-2-i PCO 5 4.6 SGLT-2-i CON 2 1.9 GLP-1RA BASAL 1 4.7 GLP-1RA BASAL-BOLUS 1 5.0 GLP-1RA PCO 7 7.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.2. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Dual Therapy in Addition to Metformin Intervention Comparison Number Contribution of trials to the network, % BASAL BASAL-BOLUS 1 3.7 AGI PCO 2 7.1 Myocardial infarction SU TZD 1 1.8 SU DPP-4-i 7 13.3 SU SGLT-2-i 2 6.4 SU GLP-1RA 3 8.3 SU PCO 2 2.5 TZD DPP-4-i 3 5.4 TZD GLP-1RA 1 2.6 TZD PCO 1 2.1 TZD CON 1 3.3 DPP-4-i SGLT-2-i 1 1.8 DPP-4-i GLP-1RA 4 6.2 DPP-4-i BASAL 1 9.7 DPP-4-i PCO 6 7.0 DPP-4-i CON 3 9.2 SGLT-2-i PCO 2 3.9 GLP-1RA BASAL-BOLUS 1 9.7 GLP-1RA PCO 4 7.0 Stroke SU DPP-4-i 8 14.0 SU SGLT-2-i 2 6.2 SU GLP-1RA 3 5.7 SU PCO 2 2.7 TZD DPP-4-i 3 10.9 TZD GLP-1RA 1 3.1 TZD PCO 1 2.9 TZD CON 1 9.1 DPP-4-i SGLT-2-i 1 2.4 DPP-4-i GLP-1RA 3 4.2 DPP-4-i BASAL 1 11.4 DPP-4-i PCO 8 9.7 DPP-4-i CON 1 5.8 SGLT-2-i PCO 3 6.1 GLP-1RA PCO 3 5.7 HbA1C SU TZD 10 2.0 SU DPP-4-i 7 8.7 SU SGLT-2-i 1 8.0 SU GLP-1RA 4 3.2 SU BASAL 2 3.8 SU PCO 1 6.0 SU CON 2 0.7 SU GLITINIDE 2 7.0 TZD DPP-4-i 1 5.2 TZD GLP-1RA 1 5.1 TZD PCO 3 1.5 TZD CON 3 0.2

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.2. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Dual Therapy in Addition to Metformin Intervention Comparison Number Contribution of trials to the network, % DPP-4-i GLP-1RA 2 3.3 DPP-4-i PCO 5 0.4 DPP-4-i CON 3 9.5 DPP-4-i AGI 1 2.0 SGLT-2-i PCO 3 1.1 SGLT-2-i CON 2 6.4 GLP-1RA BASAL 1 2.9 GLP-1RA PCO 3 0.6 BASAL BASAL-BOLUS 1 7.0 BASAL CON 1 6.9 AGI PCO 2 4.8 AGI CON 1 4.0 Treatment failure SU TZD 4 0.9 SU DPP-4-i 8 9.0 SU SGLT-2-i 2 5.7 SU GLP-1RA 2 1.9 SU PCO 1 0.9 SU CON 2 0.4 SU GLITINIDE 2 1.4 TZD DPP-4-i 2 3.6 TZD GLP-1RA 1 0.2 TZD PCO 5 5.0 TZD CON 1 2.0 DPP-4-i SGLT-2-i 2 3.8 DPP-4-i GLP-1RA 4 2.2 DPP-4-i BASAL 1 12.8 DPP-4-i PCO 12 8.9 DPP-4-i CON 5 8.9 DPP-4-i AGI 1 2.7 SGLT-2-i PCO 5 5.9 SGLT-2-i CON 2 1.2 GLP-1RA PCO 6 5.2 BASAL BASAL-BOLUS 1 7.1 AGI CON 1 5.9 GLITINIDE PCO 1 4.5 Hypoglycemia SU TZD 6 5.2 SU DPP-4-i 11 6.0 SU SGLT-2-i 3 5.6 SU GLP-1RA 3 6.9 SU BASAL 1 1.5 SU PCO 2 1.6 SU CON 1 2.8 SU GLITINIDE 2 3.0 TZD DPP-4-i 2 0.6 TZD GLP-1RA 1 0.4 TZD PCO 2 1.0 TZD CON 1 3.5

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.2. Contributions of Direct Evidence to the Networks of Treatments for Drugs Given as Dual Therapy in Addition to Metformin Intervention Comparison Number Contribution of trials to the network, % DPP-4-i SGLT-2-i 3 1.2 DPP-4-i GLP-1RA 5 4.1 DPP-4-i BASAL 1 6.5 DPP-4-i PCO 13 4.2 DPP-4-i CON 6 8.3 DPP-4-i AGI 1 0.7 SGLT-2-i PCO 3 3.0 SGLT-2-i CON 2 0.5 GLP-1RA BASAL 2 5.2 GLP-1RA BASAL-BOLUS 1 3.5 GLP-1RA PCO 7 3.7 BASAL BASAL-BOLUS 1 5.6 AGI PCO 2 1.5 AGI CON 1 3.2 GLITINIDE PCO 1 5.6 GLITINIDE CON 1 5.1 Body weight SU TZD 4 5.0 SU DPP-4-i 2 8.2 SU SGLT-2-i 1 13.9 SU GLP-1RA 2 8.5 TZD PCO 2 5.1 TZD CON 1 1.1 DPP-4-i PCO 3 9.8 DPP-4-i AGI 1 9.1 SGLT-2-i PCO 3 12.9 SGLT-2-i CON 2 9.5 GLP-1RA BASAL 1 9.1 GLP-1RA PCO 2 7.9 eTable 11.3. Contributions of Direct Evidence to the Networks of Treatments for Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea Intervention Comparison Number Contribution of trials to the network, % Cardiovascular mortality TZD PCO 1 9.5 TZD GLP-1RA 1 11.9 DPP-4-i SGLT-2-i 1 16.9 SGLT-2-i PCO 1 20.3 GLP-1RA BASAL 1 20.7 GLP-1RA BASAL-BOLUS 1 13.5 GLP-1RA PCO 1 7.3 All-cause mortality TZD GLP-1RA 1 5.5 TZD PCO 2 12.4 DPP-4-i SGLT-2-i 1 11.6 DPP-4-i GLP-1RA 1 13.1 SGLT-2-i PCO 1 7.6

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 11.3. Contributions of Direct Evidence to the Networks of Treatments for Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea Intervention Comparison Number Contribution of trials to the network, % GLP-1RA BASAL-BOLUS 1 21.2 GLP-1RA PCO 2 13.7 BASAL BASAL-BOLUS 1 14.9 Serious adverse events TZD GLP-1RA 1 9.0 TZD BASAL 1 4.1 TZD PCO 2 3.2 DPP-4-i SGLT-2-i 1 8.6 DPP-4-i GLP-1RA 1 8.5 DPP-4-i PCO 2 6.9 SGLT-2-i PCO 3 11.3 GLP-1RA BASAL 3 14.7 GLP-1RA BASAL-BOLUS 2 4.3 GLP-1RA PCO 3 13.9 BASAL BASAL-BOLUS 1 9.8 BASAL PCO 1 5.8 HbA1C TZD GLP-1RA 1 10.8 TZD BASAL 2 1.5 TZD BASAL-BOLUS 1 0.6 TZD PCO 2 0.6 TZD CON 1 3.5 TZD AGI 1 7.4 DPP-4-i GLP-1RA 1 12.9 DPP-4-i BASAL 1 1.2 DPP-4-i CON 1 8.4 SGLT-2-i PCO 1 9.0 GLP-1RA BASAL 2 10.6 GLP-1RA BASAL-BOLUS 1 5.2 GLP-1RA PCO 2 9.6 BASAL BASAL-BOLUS 1 6.2 BASAL PCO 1 7.8 AGI PCO 1 4.8 Treatment failure TZD GLP-1RA 1 12.8 TZD PCO 2 10.9 DPP-4-i SGLT-2-i 1 11.9 DPP-4-i GLP-1RA 1 17.0 DPP-4-i PCO 2 3.0 SGLT-2-i PCO 2 6.2 GLP-1RA BASAL 3 19.3 GLP-1RA PCO 3 4.7 BASAL BASAL-BOLUS 1 12.3 BASAL PCO 1 1.9 Hypoglycemia TZD DPP-4-i 1 1.4 TZD GLP-1RA 1 7.3 TZD BASAL 2 0.8 TZD PCO 2 7.8

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes Given as Monotherapy

Treatment estimates were odds ratios calculated using random effects network meta-analysis. In the upper part of the tables, the comparisons between drugs should be read from right to left and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. An odds ratio <1 favored the column- defining treatment and an odds ratio >1 favored the row-defining treatment. A standardized mean difference (HbA1C or body weight) <0 indicated that the column-defining treatment was associated with a lower HbA1C level or body weight than the row-defining treatment. A standardized mean difference >0 indicated that the column- defining treatment was associated with a higher HbA1C level or body weight than the row-defining treatment.

In the lower part of the tables the drug comparisons were reversed. The comparisons between drug classes should be read from left to right. An odds ratio lower than 1 favored the column-defining treatment and an odds ratio higher than 1 favored the row-defining treatment. A standardized mean difference (HbA1C or body weight) <0 indicated that the column-defining treatment was associated with a lower HbA1C level or body weight than the row-defining treatment. A standardized mean difference >0 indicated that the column-defining treatment was associated with a higher HbA1C level or body weight than the row-defining treatment.

For example, reading the upper part of Table 12.1 from right to left, sulfonylurea (SU) was associated with an odds of cardiovascular mortality of 1.25 (95% confidence interval 0.59 to 2.67) compared with metformin (MET) monotherapy. In reverse reading the lower part of Table 12.1 from left to right, metformin (MET) was associated with an odds of cardiovascular mortality of 0.80 (0.38‒1.70) compared with sulfonylurea (SU) monotherapy. For example, reading the upper part of Table 12.6 from right to left, sulfonylurea (SU) monotherapy was associated with a higher HbA1C level than metformin (MET) monotherapy (0.18, 0.01 to 0.34). In reverse, reading the lower part of Table 12.6 from left to right, metformin (MET) monotherapy was associated with a lower HbA1C level than sulfonylurea (SU) monotherapy (-0.18, -0.34 to -0.01).

Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; BASAL_BOLUS = basal-bolus insulin; CON = control or standard therapy; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP- 1RA = glucagon-like peptide-1 receptor agonist; HbA1C = glycated hemoglobin; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

eTable 12.1. Cardiovascular Mortality (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

1.25 0.87 1.00 0.75 0.92 0.55 1.38 MET (0.59,2.67) (0.30,2.49) (0.37,2.65) (0.14,3.96) (0.13,6.38) (0.07,4.61) (0.41,4.72) 0.80 0.69 0.79 0.60 0.73 0.44 1.10 SU (0.38,1.70) (0.29,1.68) (0.28,2.25) (0.10,3.50) (0.11,4.78) (0.05,3.58) (0.31,3.92) 1.15 1.44 1.15 0.86 1.06 0.64 1.59 TZD (0.40,3.31) (0.59,3.50) (0.33,3.99) (0.13,5.76) (0.14,8.03) (0.07,6.02) (0.39,6.56) 1.00 1.26 0.87 0.75 0.92 0.55 1.39 DPP-4-i (0.38,2.67) (0.44,3.56) (0.25,3.04) (0.13,4.35) (0.12,7.06) (0.06,5.35) (0.37,5.20) 1.22 0.73 1.84 1.33 1.67 1.16 1.33 SGLT-2-i (0.11,14.05 (0.05,10.45 (0.30,11.47 (0.25,7.04) (0.29,9.74) (0.17,7.71) (0.23,7.64) ) ) ) 1.51 1.09 1.37 0.95 1.09 0.82 0.60 AGI (0.23,10.01 (0.16,7.59) (0.21,8.91) (0.12,7.20) (0.14,8.31) (0.07,9.42) (0.04,9.53) ) 1.81 2.27 1.57 1.80 1.36 1.66 2.51 (0.22,15.15 (0.28,18.46 (0.17,14.90 (0.19,17.41 (0.10,19.34 (0.10,26.32 GLITINIDE (0.24,25.71 ) ) ) ) ) ) ) 0.72 0.91 0.63 0.72 0.54 0.66 0.40 PCO (0.21,2.46) (0.25,3.21) (0.15,2.58) (0.19,2.69) (0.09,3.37) (0.10,4.39) (0.04,4.09) *Data were not available for GLP-1 receptor agonists or basal insulin monotherapy.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12.2. All-Cause Mortality (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

7.88 1.19 1.09 0.73 0.84 0.91 0.79 1.10 1.09 MET (0.35,176. (0.81,1.75) (0.72,1.65) (0.41,1.30) (0.22,3.21) (0.18,4.46) (0.17,3.79) (0.17,7.05) (0.44,2.75) 92) 6.63 0.84 0.92 0.61 0.70 0.76 0.67 0.93 0.92 SU (0.30,145. (0.57,1.24) (0.62,1.35) (0.36,1.05) (0.18,2.73) (0.16,3.69) (0.14,3.09) (0.15,5.83) (0.37,2.30) 26) 7.22 0.92 1.09 0.67 0.77 0.83 0.73 1.01 1.00 TZD (0.32,162. (0.61,1.39) (0.74,1.61) (0.36,1.23) (0.19,3.04) (0.17,4.13) (0.15,3.49) (0.16,6.54) (0.39,2.59) 16) 10.80 1.51 1.37 1.63 1.50 1.15 1.24 1.09 1.50 DPP-4-i (0.47,248. (0.23,10.1 (0.77,2.44) (0.95,2.80) (0.81,2.76) (0.30,4.42) (0.24,6.31) (0.22,5.33) (0.61,3.71) 25) 3) 9.43 1.32 1.20 1.42 1.31 0.87 1.09 0.95 1.31 SGLT-2-i (0.32,275. (0.14,12.6 (0.31,4.60) (0.37,5.54) (0.33,5.19) (0.23,3.37) (0.15,8.09) (0.13,6.80) (0.35,4.96) 23) 3) 8.69 1.22 1.10 1.31 1.20 0.80 0.92 0.87 1.21 GLP-1RA (0.27,278. (0.11,13.5 (0.22,5.42) (0.27,6.34) (0.24,5.98) (0.16,4.08) (0.12,6.86) (0.10,7.57) (0.22,6.48) 28) 1) 0.13 0.15 0.14 0.09 0.11 0.12 BASAL_B 0.10 0.14 0.14 (0.01,2.85) (0.01,3.31) (0.01,3.11) (0.00,2.13) (0.00,3.09) (0.00,3.69) OLUS (0.00,3.16) (0.00,5.09) (0.01,3.48) 9.93 1.39 1.26 1.50 1.38 0.92 1.05 1.14 1.38 (0.32,311. AGI (0.13,15.0 (0.26,6.03) (0.32,6.94) (0.29,6.62) (0.19,4.51) (0.15,7.54) (0.13,9.89) (0.28,6.92) 89) 2) 7.14 0.91 1.08 0.99 0.66 0.76 0.82 0.72 GLITINID 0.99 (0.20,259. (0.14,5.78) (0.17,6.77) (0.15,6.40) (0.10,4.42) (0.08,7.23) (0.07,9.12) (0.07,7.76) E (0.13,7.39) 42) 7.20 0.91 1.09 1.00 0.67 0.76 0.83 0.72 1.01 (0.29,180. PCO (0.36,2.30) (0.43,2.72) (0.39,2.58) (0.27,1.64) (0.20,2.89) (0.15,4.45) (0.14,3.63) (0.14,7.52) 28) *Data were not available for basal insulin monotherapy

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12.3. Serious Adverse Events (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.96 1.00 1.08 1.25 0.86 0.15 0.73 1.65 1.05 MET (0.83,1.12) (0.86,1.16) (0.87,1.34) (0.81,1.92) (0.62,1.20) (0.02,1.17) (0.31,1.71) (0.82,3.30) (0.79,1.39) 1.04 1.03 1.12 1.30 0.90 0.15 0.76 1.71 1.09 SU (0.89,1.21) (0.91,1.17) (0.90,1.39) (0.83,2.01) (0.65,1.24) (0.02,1.21) (0.32,1.79) (0.87,3.36) (0.82,1.45) 1.00 0.97 1.08 1.25 0.87 0.15 0.73 1.65 1.05 TZD (0.86,1.17) (0.85,1.10) (0.86,1.35) (0.81,1.95) (0.62,1.21) (0.02,1.17) (0.31,1.73) (0.83,3.29) (0.79,1.40) 0.93 0.89 0.93 1.16 0.80 0.14 0.68 1.53 0.97 DPP-4-i (0.75,1.15) (0.72,1.11) (0.74,1.16) (0.76,1.77) (0.56,1.15) (0.02,1.09) (0.29,1.60) (0.75,3.11) (0.77,1.24) 0.80 0.77 0.80 0.86 0.69 0.12 0.58 1.32 0.84 SGLT-2-i (0.52,1.23) (0.50,1.20) (0.51,1.24) (0.57,1.32) (0.41,1.16) (0.01,0.98) (0.23,1.50) (0.59,2.96) (0.56,1.26) 1.16 1.11 1.15 1.25 1.44 0.17 0.84 1.91 1.21 GLP-1RA (0.83,1.60) (0.81,1.54) (0.83,1.60) (0.87,1.78) (0.86,2.42) (0.02,1.35) (0.34,2.09) (0.90,4.03) (0.83,1.77) 6.70 6.46 6.68 7.22 8.37 5.79 4.88 11.05 7.03 BASAL (0.85,52.5 (0.82,50.5 (0.85,52.2 (0.92,56.9 (1.03,68.2 (0.74,45.4 (0.53,45.2 (1.27,96.3 (0.89,55.8 BOLUS 4) 9) 0) 4) 7) 8) 4) 7) 1) 1.37 1.32 1.37 1.48 1.71 1.19 0.20 2.26 1.44 AGI (0.59,3.22) (0.56,3.13) (0.58,3.24) (0.63,3.49) (0.67,4.39) (0.48,2.94) (0.02,1.90) (0.76,6.76) (0.60,3.46) 0.61 0.58 0.60 0.65 0.76 0.52 0.09 0.44 GLITINID 0.64 (0.30,1.21) (0.30,1.15) (0.30,1.20) (0.32,1.33) (0.34,1.70) (0.25,1.11) (0.01,0.79) (0.15,1.32) E (0.31,1.33) 0.95 0.92 0.95 1.03 1.19 0.82 0.14 0.69 1.57 PCO (0.72,1.26) (0.69,1.22) (0.71,1.26) (0.81,1.31) (0.79,1.78) (0.56,1.20) (0.02,1.13) (0.29,1.67) (0.75,3.27) *Data were not available for basal insulin monotherapy.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12.4. Myocardial Infarction (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.94 0.99 0.90 0.63 0.80 0.87 1.15 MET (0.58,1.50) (0.62,1.59) (0.36,2.23) (0.06,6.24) (0.15,4.17) (0.03,26.44) (0.35,3.74) 1.07 1.06 0.96 0.68 0.85 0.92 1.22 SU (0.66,1.71) (0.71,1.59) (0.39,2.40) (0.07,6.68) (0.17,4.39) (0.03,28.34) (0.37,4.05) 1.01 0.94 0.91 0.64 0.80 0.87 1.15 TZD (0.63,1.61) (0.63,1.42) (0.36,2.29) (0.06,6.32) (0.15,4.21) (0.03,26.66) (0.35,3.78) 1.11 1.04 1.10 0.70 0.89 0.96 1.27 DPP-4-i (0.45,2.74) (0.42,2.60) (0.44,2.78) (0.08,5.97) (0.14,5.49) (0.03,28.73) (0.41,3.90) 1.58 1.48 1.57 1.42 1.26 1.37 1.81 SGLT-2-i (0.16,15.53) (0.15,14.64) (0.16,15.54) (0.17,12.10) (0.08,20.40) (0.03,70.04) (0.18,17.72) 1.25 1.17 1.24 1.13 0.79 1.08 1.44 GLP-1RA (0.24,6.54) (0.23,6.06) (0.24,6.51) (0.18,7.01) (0.05,12.84) (0.02,47.23) (0.20,10.48) 1.16 1.08 1.15 1.04 0.73 0.92 1.32 AGI (0.04,35.30) (0.04,33.28) (0.04,35.16) (0.03,31.20) (0.01,37.55) (0.02,40.22) (0.05,32.77) 0.87 0.82 0.87 0.79 0.55 0.70 0.76 PCO (0.27,2.84) (0.25,2.71) (0.26,2.84) (0.26,2.42) (0.06,5.42) (0.10,5.09) (0.03,18.68) *Data were not available for basal insulin or meglitinide monotherapy

eTable 12.5. Stroke (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

1.08 1.04 1.43 0.70 0.74 0.89 1.35 MET (0.67,1.75) (0.60,1.80) (0.50,4.09) (0.05,9.71) (0.17,3.21) (0.07,11.34) (0.33,5.46) 0.93 0.96 1.33 0.65 0.69 0.82 1.25 SU (0.57,1.50) (0.59,1.56) (0.47,3.74) (0.05,8.94) (0.16,2.93) (0.06,10.39) (0.31,5.00) 0.96 1.04 1.38 0.67 0.71 0.85 1.30 TZD (0.56,1.66) (0.64,1.69) (0.49,3.91) (0.05,9.26) (0.17,3.02) (0.07,10.53) (0.33,5.10) 0.70 0.75 0.73 0.49 0.52 0.62 0.94 DPP-4-i (0.24,1.99) (0.27,2.12) (0.26,2.06) (0.04,5.88) (0.10,2.62) (0.04,8.93) (0.27,3.34) 1.42 1.54 1.48 2.04 1.06 1.26 1.92 SGLT-2-i (0.10,19.72) (0.11,21.20) (0.11,20.32) (0.17,24.53) (0.06,18.62) (0.04,45.28) (0.16,23.11) 1.35 1.45 1.40 1.93 0.94 1.19 1.82 GLP-1RA (0.31,5.81) (0.34,6.21) (0.33,5.92) (0.38,9.75) (0.05,16.61) (0.10,14.73) (0.32,10.44) 1.13 1.22 1.17 1.62 0.79 0.84 BASAL 1.53 (0.09,14.47) (0.10,15.49) (0.10,14.52) (0.11,23.43) (0.02,28.47) (0.07,10.38) BOLUS (0.09,24.68) 0.74 0.80 0.77 1.06 0.52 0.55 0.66 PCO (0.18,3.00) (0.20,3.20) (0.20,3.02) (0.30,3.76) (0.04,6.24) (0.10,3.16) (0.04,10.60)

*Data were not available for basal insulin, meglitinide, or alpha glucosidase inhibitor monotherapy.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12.6. HbA1C (Continuous Outcome Reported as Standardized Mean Difference With 95% Confidence Interval)

0.18 0.16 0.33 0.18 (- -0.04 (- 0.13 (- -0.02 (- 0.35 -0.09 (- 1.01 MET (0.01,0.3 (0.00,0.3 (0.13,0.5 0.15,0.5 0.31,0.2 0.24,0.5 0.75,0.7 (0.12,0.5 0.42,0.2 (0.84,1.1 4) 1) 2) 1) 3) 1) 0) 8) 4) 8) -0.18 (- -0.02 (- 0.15 (- 0.01 (- -0.22 (- -0.04 (- -0.20 (- 0.17 (- -0.27 (- 0.83 0.34,- SU 0.18,0.1 0.07,0.3 0.35,0.3 0.49,0.0 0.43,0.3 0.90,0.5 0.05,0.4 0.59,0.0 (0.64,1.0 0.01) 4) 8) 6) 5) 5) 0) 0) 4) 3) -0.16 (- 0.02 (- 0.17 (- 0.03 (- -0.20 (- -0.02 (- -0.18 (- 0.19 (- -0.25 (- 0.85 0.31,- 0.14,0.1 TZD 0.04,0.3 0.32,0.3 0.47,0.0 0.41,0.3 0.90,0.5 0.03,0.4 0.57,0.0 (0.68,1.0 0.00) 8) 8) 7) 8) 7) 4) 2) 7) 3) -0.33 (- -0.15 (- -0.17 (- -0.15 (- -0.37 (- -0.20 (- -0.35 (- 0.02 (- -0.42 (- 0.68 0.52,- 0.38,0.0 0.38,0.0 DPP-4-i 0.49,0.2 0.65,- 0.61,0.2 1.09,0.3 0.24,0.2 0.78,- (0.49,0.8 0.13) 7) 4) 0) 0.08) 2) 9) 8) 0.06) 7) -0.18 (- -0.01 (- -0.03 (- 0.15 (- -0.22 (- -0.05 (- -0.21 (- 0.17 (- -0.28 (- 0.83 SGLT-2- 0.51,0.1 0.36,0.3 0.37,0.3 0.20,0.4 0.63,0.1 0.54,0.4 0.99,0.5 0.21,0.5 0.73,0.1 (0.50,1.1 i 5) 5) 2) 9) 8) 5) 8) 5) 8) 6) 0.04 (- 0.22 (- 0.20 (- 0.37 0.22 (- 0.17 (- 0.02 (- 0.39 -0.05 (- 1.05 GLP- 0.23,0.3 0.05,0.4 0.08,0.4 (0.08,0.6 0.18,0.6 0.28,0.6 0.74,0.7 (0.07,0.7 0.45,0.3 (0.78,1.3 1RA 1) 9) 7) 5) 3) 3) 7) 1) 4) 2) -0.13 (- 0.04 (- 0.02 (- 0.20 (- 0.05 (- -0.17 (- -0.16 (- 0.22 (- -0.23 (- 0.88 0.51,0.2 0.35,0.4 0.37,0.4 0.22,0.6 0.45,0.5 0.63,0.2 BASAL 0.96,0.6 0.21,0.6 0.71,0.2 (0.47,1.2 4) 3) 1) 1) 4) 8) 5) 5) 5) 8) 0.02 (- 0.20 (- 0.18 (- 0.35 (- 0.21 (- -0.02 (- 0.16 (- 0.37 (- -0.07 (- 1.03 PRANDI 0.70,0.7 0.50,0.9 0.54,0.9 0.39,1.0 0.58,0.9 0.77,0.7 0.65,0.9 0.37,1.1 0.84,0.7 (0.30,1.7 AL 5) 0) 0) 9) 9) 4) 6) 1) 0) 6) -0.35 (- -0.17 (- -0.19 (- -0.02 (- -0.17 (- -0.39 (- -0.22 (- -0.37 (- -0.44 (- 0.66 0.58,- 0.40,0.0 0.42,0.0 0.28,0.2 0.55,0.2 0.71,- 0.65,0.2 1.11,0.3 AGI 0.81,- (0.44,0.8 0.12) 5) 3) 4) 1) 0.07) 1) 7) 0.08) 8) 0.09 (- 0.27 (- 0.25 (- 0.42 0.28 (- 0.05 (- 0.23 (- 0.07 (- 0.44 1.11 GLITINI 0.24,0.4 0.04,0.5 0.07,0.5 (0.06,0.7 0.18,0.7 0.34,0.4 0.25,0.7 0.70,0.8 (0.08,0.8 (0.77,1.4 DE 2) 9) 7) 8) 3) 5) 1) 4) 1) 4) -1.01 (- -0.83 (- -0.85 (- -0.68 (- -0.83 (- -1.05 (- -0.88 (- -1.03 (- -0.66 (- -1.11 (- 1.18,- 1.03,- 1.03,- 0.87,- 1.16,- 1.32,- 1.28,- 1.76,- 0.88,- 1.44,- PCO 0.84) 0.64) 0.68) 0.49) 0.50) 0.78) 0.47) 0.30) 0.44) 0.77)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12.7. Treatment Failure (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

1.19 1.21 1.53 0.47 0.62 0.22 0.35 2.54 2.58 3.83 MET (0.86,1.6 (0.87,1.6 (1.16,2.0 (0.31,0.7 (0.37,1.0 (0.01,5.5 (0.04,3.3 (0.67,9.6 (1.43,4.6 (2.88,5.1 5) 7) 1) 1) 4) 1) 0) 0) 6) 0) 0.84 1.02 1.29 0.39 0.52 0.19 0.29 2.17 0.72 3.23 (0.61,1.1 SU (0.76,1.3 (0.96,1.7 (0.25,0.6 (0.32,0.8 (0.01,4.5 (0.03,2.7 (1.18,3.9 (0.45,1.1 (2.39,4.3 7) 5) 2) 2) 5) 6) 4) 8) 6) 6) 0.83 0.98 1.26 0.39 0.52 0.18 0.29 2.13 0.71 3.17 (0.60,1.1 (0.74,1.3 TZD (0.94,1.7 (0.25,0.6 (0.31,0.8 (0.01,4.5 (0.03,2.7 (1.18,3.8 (0.44,1.1 (2.38,4.2 5) 1) 1) 1) 5) 4) 0) 6) 4) 2) 0.65 0.78 0.79 0.31 0.41 0.15 0.23 1.69 0.56 2.51 (0.50,0.8 (0.58,1.0 (0.59,1.0 DPP-4-i (0.20,0.4 (0.25,0.6 (0.01,3.5 (0.02,2.1 (0.95,2.9 (0.34,0.9 (2.02,3.1 6) 4) 7) 6) 7) 9) 5) 9) 3) 1) 2.14 2.54 2.58 3.26 1.33 0.47 0.74 5.50 1.82 8.18 (1.41,3.2 (1.61,4.0 (1.64,4.0 (2.18,4.8 SGLT-2-i (0.73,2.4 (0.02,11. (0.08,7.2 (2.83,10. (0.99,3.3 (5.55,12. 3) 1) 7) 8) 2) 96) 2) 71) 6) 06) 1.61 1.91 1.94 2.45 0.75 0.36 0.56 4.14 1.37 6.15 (0.97,2.6 (1.18,3.0 (1.17,3.2 (1.50,4.0 (0.41,1.3 GLP-1RA (0.01,9.0 (0.06,5.4 (2.01,8.5 (0.72,2.6 (3.81,9.9 7) 8) 2) 1) 7) 2) 0) 1) 2) 5) 4.50 5.34 5.44 6.87 2.11 2.80 1.56 11.59 3.84 17.24 (0.18,111 (0.22,130 (0.22,134 (0.28,169 (0.08,53. (0.11,70. BASAL (0.03,77. (0.45,299 (0.15,97. (0.70,426 .47) .29) .20) .71) 06) 77) 06) .22) 09) .20) 2.89 3.43 3.49 4.41 1.35 1.80 0.64 7.44 2.47 11.07 BASAL_ (0.30,27. (0.36,32. (0.37,32. (0.46,41. (0.14,13. (0.19,17. (0.01,31. (0.74,75. (0.25,24. (1.17,105 BOLUS 57) 28) 93) 93) 20) 49) 77) 15) 23) .16) 0.39 0.46 0.47 0.59 0.18 0.24 0.09 0.13 0.33 1.49 (0.21,0.7 (0.25,0.8 (0.26,0.8 (0.33,1.0 (0.09,0.3 (0.12,0.5 (0.00,2.2 (0.01,1.3 AGI (0.16,0.6 (0.85,2.6 0) 5) 5) 5) 5) 0) 3) 6) 9) 0) 1.17 1.39 1.41 1.79 0.55 0.73 0.26 0.41 3.02 4.48 GLITINID (0.69,1.9 (0.86,2.2 (0.88,2.2 (1.08,2.9 (0.30,1.0 (0.38,1.3 (0.01,6.5 (0.04,3.9 (1.46,6.2 (2.74,7.3 E 8) 4) 8) 6) 1) 9) 7) 8) 3) 5) 0.26 0.31 0.32 0.40 0.12 0.16 0.06 0.09 0.67 0.22 (0.20,0.3 (0.23,0.4 (0.24,0.4 (0.32,0.4 (0.08,0.1 (0.10,0.2 (0.00,1.4 (0.01,0.8 (0.38,1.1 (0.14,0.3 PCO 5) 2) 2) 9) 8) 6) 3) 6) 8) 7)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12.8. Hypoglycemia (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

3.13 0.67 0.69 0.63 1.06 17.89 1.32 1.86 0.65 2.16 0.58 MET (2.39,4. (0.50,0. (0.50,0. (0.30,1. (0.74,1. (1.97,16 (0.35,5. (0.81,4. (0.37,1. (1.49,3. (0.40,0. 12) 88) 94) 32) 52) 2.29) 06) 26) 13) 12) 83) 0.32 0.21 0.22 0.20 0.34 5.71 0.42 0.59 0.21 0.69 0.18 (0.24,0. SU (0.17,0. (0.17,0. (0.09,0. (0.24,0. (0.63,51 (0.11,1. (0.26,1. (0.12,0. (0.51,0. (0.13,0. 42) 26) 29) 42) 49) .72) 57) 35) 35) 94) 26) 1.50 4.71 1.03 0.94 1.60 26.90 1.99 2.79 0.97 3.24 0.87 (1.13,2. (3.84,5. TZD (0.76,1. (0.44,2. (1.10,2. (2.95,24 (0.53,7. (1.23,6. (0.55,1. (2.28,4. (0.61,1. 00) 78) 40) 01) 33) 4.97) 52) 34) 70) 60) 24) 1.45 4.55 0.97 0.91 1.55 25.99 1.92 2.70 0.94 3.13 0.84 (1.06,1. (3.44,6. (0.71,1. DPP-4-i (0.43,1. (1.03,2. (2.84,23 (0.50,7. (1.15,6. (0.53,1. (2.13,4. (0.59,1. 98) 03) 31) 93) 33) 8.19) 36) 30) 66) 60) 19) 1.59 4.99 1.06 1.10 1.70 28.50 2.11 2.96 1.03 3.43 0.92 SGLT- (0.75,3. (2.36,10 (0.50,2. (0.52,2. (0.76,3. (2.80,28 (0.47,9. (0.99,8. (0.43,2. (1.58,7. (0.45,1. 2-i 36) .54) 26) 32) 76) 9.84) 55) 80) 45) 45) 88) 0.94 2.94 0.63 0.65 0.59 16.81 1.24 1.74 0.61 2.03 0.54 GLP- (0.66,1. (2.06,4. (0.43,0. (0.43,0. (0.27,1. (1.82,15 (0.32,4. (0.79,3. (0.33,1. (1.29,3. (0.35,0. 1RA 35) 22) 91) 97) 31) 5.57) 85) 84) 12) 17) 84) 0.06 0.18 0.04 0.04 0.04 0.06 0.07 0.10 0.04 0.12 0.03 (0.01,0. (0.02,1. (0.00,0. (0.00,0. (0.00,0. (0.01,0. BASAL (0.01,0. (0.01,1. (0.00,0. (0.01,1. (0.00,0. 51) 59) 34) 35) 36) 55) 96) 08) 35) 11) 30) 0.76 2.37 0.50 0.52 0.47 0.80 13.52 1.40 0.49 1.63 0.44 PRAND (0.20,2. (0.64,8. (0.13,1. (0.14,1. (0.10,2. (0.21,3. (1.04,17 (0.30,6. (0.12,2. (0.42,6. (0.11,1. IAL 89) 80) 90) 99) 15) 14) 5.71) 61) 01) 27) 69) 0.54 1.69 0.36 0.37 0.34 0.57 9.64 0.71 BASAL 0.35 1.16 0.31 (0.23,1. (0.74,3. (0.16,0. (0.16,0. (0.11,1. (0.26,1. (0.92,10 (0.15,3. _BOLU (0.13,0. (0.49,2. (0.13,0. 23) 85) 81) 87) 01) 26) 0.67) 36) S 91) 77) 74) 1.55 4.85 1.03 1.07 0.97 1.65 27.71 2.05 2.88 3.34 0.90 (0.89,2. (2.84,8. (0.59,1. (0.60,1. (0.41,2. (0.89,3. (2.89,26 (0.50,8. (1.10,7. AGI (1.86,5. (0.53,1. 70) 28) 80) 88) 31) 05) 6.18) 46) 55) 99) 51) 0.46 1.45 0.31 0.32 0.29 0.49 8.30 0.61 0.86 0.30 0.27 GLITINI (0.32,0. (1.07,1. (0.22,0. (0.22,0. (0.13,0. (0.32,0. (0.90,76 (0.16,2. (0.36,2. (0.17,0. (0.19,0. DE 67) 98) 44) 47) 63) 77) .54) 37) 05) 54) 39) 1.73 5.42 1.15 1.19 1.09 1.84 30.96 2.29 3.21 1.12 3.73 (1.21,2. (3.90,7. (0.81,1. (0.84,1. (0.53,2. (1.19,2. (3.35,28 (0.59,8. (1.36,7. (0.66,1. (2.58,5. PCO 47) 54) 64) 69) 22) 84) 5.72) 87) 61) 89) 38)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 12.9. Body Weight (Continuous Outcome Reported as Standardized Mean Difference With 95% Confidence Interval)

0.19 0.24 0.12 (- -0.06 (- -0.28 (- 0.07 (- 0.35 (- -0.22 (- 0.03 (- -0.09 (- 0.09 (- MET (0.04,0. (0.04,0. 0.09,0.3 0.21,0.0 0.52,- 0.45,0.6 0.05,0.7 0.90,0.4 0.18,0.2 0.30,0.1 0.05,0.2 33) 43) 2) 8) 0.04) 0) 4) 5) 3) 3) 4) -0.19 (- 0.05 (- -0.07 (- -0.25 (- -0.47 (- -0.11 (- 0.16 (- -0.41 (- -0.16 (- -0.27 (- -0.09 (- 0.33,- SU 0.11,0.2 0.29,0.1 0.44,- 0.69,- 0.62,0.3 0.20,0.5 1.07,0.2 0.37,0.0 0.43,- 0.27,0.0 0.04) 1) 6) 0.06) 0.24) 9) 3) 5) 5) 0.11) 8) -0.24 (- -0.05 (- -0.12 (- -0.30 (- -0.52 (- -0.16 (- 0.11 (- -0.46 (- -0.21 (- -0.32 (- -0.14 (- 0.43,- 0.21,0.1 TZD 0.37,0.1 0.52,- 0.79,- 0.69,0.3 0.29,0.5 1.14,0.2 0.45,0.0 0.54,- 0.35,0.0 0.04) 1) 3) 0.08) 0.24) 7) 2) 2) 3) 0.10) 6) -0.12 (- 0.07 (- 0.12 (- -0.18 (- -0.40 (- -0.05 (- 0.23 (- -0.34 (- -0.09 (- -0.20 (- -0.03 (- 0.32,0.0 0.16,0.2 0.13,0.3 DPP-4-i 0.37,0.0 0.68,- 0.60,0.5 0.20,0.6 1.03,0.3 0.32,0.1 0.48,0.0 0.19,0.1 9) 9) 7) 0) 0.12) 1) 6) 6) 4) 7) 4) 0.06 (- 0.25 0.30 0.18 (- -0.22 (- 0.14 (- 0.41 -0.16 (- 0.09 (- -0.02 (- 0.16 SGLT- 0.08,0.2 (0.06,0. (0.08,0. 0.00,0.3 0.48,0.0 0.40,0.6 (0.00,0. 0.84,0.5 0.12,0.3 0.27,0.2 (0.01,0. 2-i 1) 44) 52) 7) 5) 7) 83) 3) 0) 2) 30) 0.28 0.47 0.52 0.40 0.22 (- 0.35 (- 0.63 0.06 (- 0.31 0.19 (- 0.37 GLP- (0.04,0. (0.24,0. (0.24,0. (0.12,0. 0.05,0.4 0.20,0.9 (0.20,1. 0.64,0.7 (0.03,0. 0.09,0.4 (0.12,0. 1RA 52) 69) 79) 68) 8) 0) 06) 5) 59) 7) 62) -0.07 (- 0.11 (- 0.16 (- 0.05 (- -0.14 (- -0.35 (- 0.28 (- -0.29 (- -0.04 (- -0.16 (- 0.02 (- 0.60,0.4 0.39,0.6 0.37,0.6 0.51,0.6 0.67,0.4 0.90,0.2 BASAL 0.35,0.9 1.12,0.5 0.59,0.5 0.69,0.3 0.51,0.5 5) 2) 9) 0) 0) 0) 0) 3) 0) 7) 5) -0.35 (- -0.16 (- -0.11 (- -0.23 (- -0.41 (- -0.63 (- -0.28 (- -0.57 (- -0.32 (- -0.44 (- -0.26 (- PRAND 0.74,0.0 0.53,0.2 0.52,0.2 0.66,0.2 0.83,- 1.06,- 0.90,0.3 1.33,0.1 0.75,0.1 0.84,- 0.66,0.1 IAL 5) 0) 9) 0) 0.00) 0.20) 5) 8) 0) 0.04) 5) 0.22 (- 0.41 (- 0.46 (- 0.34 (- 0.16 (- -0.06 (- 0.29 (- 0.57 (- BASAL 0.25 (- 0.13 (- 0.31 (- 0.45,0.9 0.25,1.0 0.22,1.1 0.36,1.0 0.53,0.8 0.75,0.6 0.53,1.1 0.18,1.3 _BOLU 0.44,0.9 0.54,0.8 0.37,0.9 0) 7) 4) 3) 4) 4) 2) 3) S 4) 1) 9) -0.03 (- 0.16 (- 0.21 (- 0.09 (- -0.09 (- -0.31 (- 0.04 (- 0.32 (- -0.25 (- -0.11 (- 0.06 (- 0.23,0.1 0.05,0.3 0.03,0.4 0.14,0.3 0.30,0.1 0.59,- 0.50,0.5 0.10,0.7 0.94,0.4 AGI 0.38,0.1 0.11,0.2 8) 7) 5) 2) 2) 0.03) 9) 5) 4) 5) 3) 0.09 (- 0.27 0.32 0.20 (- 0.02 (- -0.19 (- 0.16 (- 0.44 -0.13 (- 0.11 (- 0.18 (- GLITINI 0.13,0.3 (0.11,0. (0.10,0. 0.07,0.4 0.22,0.2 0.47,0.0 0.37,0.6 (0.04,0. 0.81,0.5 0.15,0.3 0.05,0.4 DE 0) 43) 54) 8) 7) 9) 9) 84) 4) 8) 1) -0.09 (- 0.09 (- 0.14 (- 0.03 (- -0.16 (- -0.37 (- -0.02 (- 0.26 (- -0.31 (- -0.06 (- -0.18 (- 0.24,0.0 0.08,0.2 0.06,0.3 0.14,0.1 0.30,- 0.62,- 0.55,0.5 0.15,0.6 0.99,0.3 0.23,0.1 0.41,0.0 PCO 5) 7) 5) 9) 0.01) 0.12) 1) 6) 7) 1) 5)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 13. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes When Used in Dual Therapy (in Addition to Metformin)

For example, reading the upper part of Table 13.1 from right to left, thiazolidinedione (TZD) given in addition to metformin was associated with an odds of cardiovascular mortality of 2.10 (95% confidence interval 0.48 to 9.15) compared with sulfonylurea (SU) therapy added to metformin. In reverse reading the lower part of the Table 13.1 from left to right, sulfonylurea (SU) added to metformin was associated with an odds of cardiovascular mortality of 0.48 (0.11 to 2.08) compared with thiazolidinedione (TZD) given in addition to metformin. For example, reading the upper part of Table 13.6 from right to left, thiazolidinedione (TZD) given in addition to metformin was associated with a higher HbA1C level than sulfonylurea (SU) therapy added to metformin (standardized mean difference, 0.03, -0.36 to 0.41). In reverse, in reading the lower part of Table 13.6 from left to right, sulfonylurea (SU) therapy added to metformin was associated with a lower HbA1C level than thiazolidinedione (TZD) given in addition to metformin (-0.03, -0.41 to 0.36).

eTable 13.1. Cardiovascular Mortality (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

2.10 0.81 0.86 0.52 1.03 1.60 SU (0.48,9.15) (0.36,1.82) (0.14,5.27) (0.08,3.44) (0.10,10.92) (0.35,7.37) 0.48 0.39 0.41 0.25 0.49 0.76 TZD (0.11,2.08) (0.10,1.47) (0.05,3.45) (0.03,1.91) (0.04,6.86) (0.18,3.28) 1.24 2.59 1.07 0.65 1.27 1.98 DPP-4-i (0.55,2.79) (0.68,9.88) (0.18,6.38) (0.12,3.58) (0.12,13.86) (0.52,7.53) 1.16 2.43 0.94 0.61 1.19 1.85 SGLT-2-i (0.19,7.09) (0.29,20.42) (0.16,5.61) (0.05,7.11) (0.07,20.07) (0.21,16.59) 1.91 4.00 1.54 1.64 1.96 3.05 GLP-1RA (0.29,12.51) (0.52,30.53) (0.28,8.51) (0.14,19.22) (0.11,36.43) (0.43,21.54) 0.97 2.04 0.78 0.84 0.51 1.55 GLITINIDE (0.09,10.30) (0.15,28.40) (0.07,8.53) (0.05,14.06) (0.03,9.44) (0.10,22.99) 0.63 1.31 0.51 0.54 0.33 0.64 PCO (0.14,2.89) (0.30,5.65) (0.13,1.92) (0.06,4.83) (0.05,2.32) (0.04,9.54) *Data were not available for basal insulin or alpha glucosidase inhibitors added to metformin.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 13.2. All-Cause Mortality (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

3.76 1.29 0.75 0.83 0.87 1.20 1.12 SU (0.30,47.2 (0.39,4.23) (0.45,1.24) (0.37,1.86) (0.39,1.91) (0.25,5.72) (0.45,2.78) 4) 2.92 0.78 0.58 0.64 0.67 0.93 0.87 TZD (0.19,45.3 (0.24,2.55) (0.18,1.91) (0.16,2.56) (0.18,2.53) (0.14,6.12) (0.25,3.05) 9) 5.00 1.33 1.71 1.10 1.15 1.59 1.49 DPP-4-i (0.39,63.6 (0.80,2.20) (0.52,5.60) (0.45,2.67) (0.50,2.65) (0.32,7.85) (0.60,3.69) 7) 4.54 1.21 1.55 0.91 1.05 1.45 1.35 SGLT-2-i (0.32,63.4 (0.54,2.71) (0.39,6.18) (0.37,2.20) (0.35,3.10) (0.26,8.10) (0.44,4.12) 4) 4.34 1.15 1.49 0.87 0.96 1.38 1.29 GLP-1RA (0.39,48.0 (0.52,2.54) (0.40,5.58) (0.38,2.00) (0.32,2.83) (0.25,7.56) (0.50,3.32) 3) 0.27 0.34 0.20 0.22 0.23 0.32 0.30 BASAL (0.02,3.34) (0.02,5.32) (0.02,2.55) (0.02,3.08) (0.02,2.55) (0.02,6.05) (0.02,3.94) 3.13 0.83 1.07 0.63 0.69 0.72 GLITINID 0.93 (0.17,59.4 (0.17,3.97) (0.16,7.06) (0.13,3.09) (0.12,3.87) (0.13,3.94) E (0.18,4.94) 7) 3.36 0.89 1.15 0.67 0.74 0.77 1.07 (0.25,44.5 PCO (0.36,2.22) (0.33,4.04) (0.27,1.67) (0.24,2.26) (0.30,1.99) (0.20,5.68) 1) *Data were not available for alpha glucosidase inhibitors added to metformin.

eTable 13.3. Serious Adverse Effects (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

1.23 0.94 0.92 1.14 1.13 1.59 2.11 0.87 0.93 SU (0.92,1.65) (0.82,1.07) (0.73,1.15) (0.91,1.41) (0.66,1.92) (0.72,3.54) (0.73,6.09) (0.46,1.63) (0.73,1.17) 0.81 0.76 0.75 0.92 0.92 1.30 1.72 0.71 0.75 TZD (0.61,1.09) (0.57,1.02) (0.52,1.07) (0.65,1.31) (0.51,1.67) (0.56,3.01) (0.58,5.10) (0.35,1.42) (0.53,1.06) 1.07 1.31 0.98 1.21 1.21 1.70 2.26 0.93 0.99 DPP-4-i (0.94,1.22) (0.98,1.76) (0.77,1.25) (0.97,1.52) (0.71,2.05) (0.77,3.78) (0.79,6.49) (0.49,1.76) (0.78,1.25) 1.09 1.34 1.02 1.24 1.23 1.74 2.30 0.95 1.01 SGLT-2-i (0.87,1.37) (0.93,1.92) (0.80,1.31) (0.92,1.67) (0.70,2.18) (0.76,3.97) (0.79,6.71) (0.48,1.85) (0.76,1.34) 0.88 1.08 0.82 0.81 0.99 1.40 1.86 0.76 0.82 GLP-1RA (0.71,1.10) (0.77,1.53) (0.66,1.03) (0.60,1.09) (0.59,1.67) (0.64,3.05) (0.64,5.38) (0.39,1.49) (0.63,1.05) 0.88 1.09 0.83 0.81 1.01 1.41 1.87 0.77 0.82 BASAL (0.52,1.50) (0.60,1.97) (0.49,1.41) (0.46,1.44) (0.60,1.69) (0.64,3.12) (0.58,6.03) (0.34,1.75) (0.47,1.43) 0.63 0.77 0.59 0.58 0.71 0.71 BASAL 1.33 0.54 0.58 (0.28,1.39) (0.33,1.79) (0.26,1.31) (0.25,1.31) (0.33,1.55) (0.32,1.57) BOLUS (0.36,4.92) (0.20,1.51) (0.26,1.31) 0.47 0.58 0.44 0.43 0.54 0.53 0.75 0.41 0.44 AGI (0.16,1.36) (0.20,1.73) (0.15,1.27) (0.15,1.26) (0.19,1.55) (0.17,1.72) (0.20,2.80) (0.12,1.41) (0.16,1.23) 1.15 1.42 1.08 1.06 1.31 1.30 1.84 2.43 GLITINID 1.07 (0.61,2.16) (0.71,2.84) (0.57,2.05) (0.54,2.06) (0.67,2.55) (0.57,2.97) (0.66,5.07) (0.71,8.33) E (0.54,2.09) 1.08 1.33 1.01 0.99 1.23 1.22 1.72 2.28 0.94 PCO (0.85,1.37) (0.94,1.88) (0.80,1.28) (0.74,1.32) (0.95,1.58) (0.70,2.13) (0.76,3.88) (0.81,6.40) (0.48,1.84)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 13.4. Myocardial Infarction (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

1.59 0.59 0.42 0.89 0.22 0.31 1.00 SU (0.43,5.91) (0.32,1.09) (0.12,1.48) (0.35,2.22) (0.01,5.70) (0.01,8.76) (0.36,2.79) 0.63 0.37 0.27 0.56 0.14 0.20 0.63 TZD (0.17,2.35) (0.11,1.29) (0.05,1.54) (0.13,2.34) (0.00,4.28) (0.01,6.59) (0.15,2.74) 0.53 1.70 2.69 0.72 1.51 0.37 1.70 DPP-4-i (0.02,14.9 (0.92,3.15) (0.78,9.36) (0.19,2.68) (0.59,3.84) (0.01,9.12) (0.64,4.53) 6) 3.75 0.51 0.74 2.36 1.39 2.10 2.37 (0.65,21.5 SGLT-2-i (0.02,16.4 (0.02,25.0 (0.68,8.25) (0.37,5.18) (0.48,9.12) (0.58,9.69) 5) 4) 8) 1.13 1.79 0.66 0.48 0.25 0.35 1.13 GLP-1RA (0.45,2.82) (0.43,7.46) (0.26,1.69) (0.11,2.08) (0.01,6.91) (0.01,8.68) (0.39,3.28) 4.59 7.29 2.70 1.94 4.08 1.43 4.60 (0.18,120. (0.23,226. (0.11,66.7 (0.06,62.2 (0.14,114. BASAL (0.01,146. (0.16,131. 14) 96) 0) 0) 90) 84) 43) 3.20 5.08 1.89 1.36 2.84 0.70 3.21 BASAL (0.11,89.8 (0.15,169. (0.07,53.1 (0.04,46.1 (0.12,70.1 (0.01,71.3 (0.11,94.0 BOLUS 1) 86) 5) 2) 1) 7) 6) 1.00 1.58 0.59 0.42 0.89 0.22 0.31 PCO (0.36,2.77) (0.37,6.85) (0.22,1.56) (0.10,1.73) (0.31,2.57) (0.01,6.20) (0.01,9.13) *Data were not available for meglitinide or alpha glucosidase inhibitor monotherapy.

eTable 13.5. Stroke (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.81 0.47 2.75 0.88 1.58 1.40 SU (0.20,3.29) (0.23,0.95) (0.76,10.02) (0.26,2.97) (0.06,42.12) (0.50,3.89) 1.23 0.58 3.40 1.08 1.95 1.73 TZD (0.30,5.01) (0.17,2.02) (0.58,20.03) (0.21,5.57) (0.06,60.79) (0.40,7.46) 2.12 1.72 5.84 1.86 3.36 2.97 DPP-4-i (1.05,4.27) (0.50,5.96) (1.56,21.87) (0.55,6.25) (0.14,82.76) (1.18,7.47) 0.36 0.29 0.17 0.32 0.57 0.51 SGLT-2-i (0.10,1.32) (0.05,1.73) (0.05,0.64) (0.06,1.65) (0.02,18.41) (0.14,1.91) 1.14 0.92 0.54 3.13 1.80 1.59 GLP-1RA (0.34,3.84) (0.18,4.74) (0.16,1.80) (0.61,16.23) (0.06,55.44) (0.45,5.68) 0.63 0.51 0.30 1.74 0.56 0.89 BASAL (0.02,16.81) (0.02,15.94) (0.01,7.35) (0.05,55.74) (0.02,17.08) (0.03,24.87) 0.71 0.58 0.34 1.97 0.63 1.13 PCO (0.26,1.98) (0.13,2.49) (0.13,0.85) (0.52,7.40) (0.18,2.23) (0.04,31.73) *Data were not available for meglitinide or alpha glucosidase inhibitor monotherapy.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 13.6. HbA1C (Continuous Outcome Reported as Standardized Mean Difference With 95% Confidence Interval)

0.03 (- -0.02 (- 0.17 (- 0.10 (- 0.07 (- -0.35 (- 0.58 (- -0.83 (- 1.24 SU 0.36,0.41) 0.43,0.39) 0.49,0.82) 0.41,0.62) 0.75,0.88) 1.95,1.24) 0.22,1.37) 1.81,0.14) (0.76,1.72) -0.03 (- -0.05 (- 0.14 (- 0.08 (- 0.04 (- -0.38 (- 0.55 (- -0.86 (- 1.21 TZD 0.41,0.36) 0.54,0.44) 0.55,0.83) 0.51,0.66) 0.84,0.92) 2.01,1.25) 0.27,1.37) 1.91,0.19) (0.70,1.73) 0.02 (- 0.05 (- 0.19 (- 0.13 (- 0.09 (- -0.33 (- 0.60 (- -0.81 (- 1.26 DPP4 0.39,0.43) 0.44,0.54) 0.48,0.86) 0.44,0.69) 0.79,0.96) 1.96,1.30) 0.17,1.36) 1.87,0.25) (0.81,1.72) -0.17 (- -0.14 (- -0.19 (- -0.06 (- -0.10 (- -0.52 (- 0.41 (- -1.00 (- 1.08 SGLT-2-i 0.82,0.49) 0.83,0.55) 0.86,0.48) 0.82,0.69) 1.10,0.90) 2.22,1.18) 0.49,1.31) 2.17,0.17) (0.46,1.69) -0.10 (- -0.08 (- -0.13 (- 0.06 (- -0.04 (- -0.46 (- 0.47 (- -0.94 (- 1.14 GLP-1RA 0.62,0.41) 0.66,0.51) 0.69,0.44) 0.69,0.82) 0.91,0.84) 2.09,1.17) 0.40,1.34) 2.04,0.16) (0.57,1.70) -0.07 (- -0.04 (- -0.09 (- 0.10 (- 0.04 (- -0.42 (- 0.51 (- -0.90 (- 1.18 BASAL 0.88,0.75) 0.92,0.84) 0.96,0.79) 0.90,1.10) 0.84,0.91) 1.79,0.95) 0.59,1.61) 2.17,0.37) (0.27,2.08) 0.35 (- 0.38 (- 0.33 (- 0.52 (- 0.46 (- 0.42 (- BASAL 0.93 (- -0.48 (- 1.59 (- 1.24,1.95) 1.25,2.01) 1.30,1.96) 1.18,2.22) 1.17,2.09) 0.95,1.79) BOLUS 0.83,2.69) 2.35,1.39) 0.05,3.24) -0.58 (- -0.55 (- -0.60 (- -0.41 (- -0.47 (- -0.51 (- -0.93 (- -1.41 (- 0.67 (- AGI 1.37,0.22) 1.37,0.27) 1.36,0.17) 1.31,0.49) 1.34,0.40) 1.61,0.59) 2.69,0.83) 2.67,-0.15) 0.07,1.40) 0.83 (- 0.86 (- 0.81 (- 1.00 (- 0.94 (- 0.90 (- 0.48 (- 1.41 GLITINID 2.07 0.14,1.81) 0.19,1.91) 0.25,1.87) 0.17,2.17) 0.16,2.04) 0.37,2.17) 1.39,2.35) (0.15,2.67) E (0.99,3.16) -1.24 (- -1.21 (- -1.26 (- -1.08 (- -1.14 (- -1.18 (- -1.59 (- -0.67 (- -2.07 (- PCO 1.72,-0.76) 1.73,-0.70) 1.72,-0.81) 1.69,-0.46) 1.70,-0.57) 2.08,-0.27) 3.24,0.05) 1.40,0.07) 3.16,-0.99)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 13.7. Treatment Failure (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

12.38 1.18 1.37 0.68 0.84 0.10 1.16 3.43 SU (1.84,83.28 (0.70,1.98) (1.07,1.76) (0.48,0.96) (0.54,1.30) (0.01,1.89) (0.59,2.26) (2.50,4.72) ) 10.52 0.85 1.17 0.57 0.71 0.08 0.98 2.92 TZD (1.51,73.03 (0.51,1.43) (0.73,1.86) (0.33,1.01) (0.40,1.27) (0.00,1.65) (0.44,2.20) (1.84,4.63) ) 9.02 0.73 0.86 0.49 0.61 0.07 0.84 2.50 DPP-4-i (1.36,59.76 (0.57,0.93) (0.54,1.37) (0.35,0.70) (0.41,0.92) (0.00,1.36) (0.43,1.68) (1.95,3.21) ) 18.32 1.48 1.74 2.03 1.24 0.15 1.72 5.08 SGLT-2-i (2.69,124.9 (1.04,2.10) (0.99,3.06) (1.43,2.89) (0.76,2.04) (0.01,2.82) (0.82,3.57) (3.54,7.28) 0) 14.74 1.19 1.40 1.63 0.80 0.12 1.38 4.09 GLP-1RA (2.13,101.8 (0.77,1.84) (0.79,2.50) (1.08,2.46) (0.49,1.32) (0.01,2.29) (0.64,2.97) (2.79,5.99) 0) 10.09 11.87 13.83 6.81 8.47 124.84 11.69 34.62 (0.53,191.9 (0.61,231.9 (0.73,260.4 (0.35,131.0 (0.44,164.1 BASAL (3.80,4098. (0.57,238. (1.82,658. ) 8) 6) 2) 0) 98) 16) 80) 0.08 0.10 0.11 0.05 0.07 0.01 0.09 0.28 AGI (0.01,0.54) (0.01,0.66) (0.02,0.73) (0.01,0.37) (0.01,0.47) (0.00,0.26) (0.01,0.70) (0.04,1.86) 10.68 0.86 1.02 1.18 0.58 0.72 0.09 GLITINID 2.96 (1.43,79.65 (0.44,1.68) (0.45,2.27) (0.60,2.35) (0.28,1.22) (0.34,1.56) (0.00,1.74) E (1.48,5.92) ) 3.61 0.29 0.34 0.40 0.20 0.24 0.03 0.34 (0.54,24.21 PCO (0.21,0.40) (0.22,0.54) (0.31,0.51) (0.14,0.28) (0.17,0.36) (0.00,0.55) (0.17,0.67) )

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 13.8. Hypoglycemia (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.14 0.12 0.12 0.19 0.56 0.59 0.13 0.55 0.14 SU (0.09,0.24) (0.10,0.16) (0.08,0.18) (0.13,0.27) (0.32,0.98) (0.27,1.30) (0.05,0.40) (0.32,0.93) (0.10,0.21) 6.97 4.12 0.87 0.82 1.30 3.92 0.94 3.83 1.00 (4.24,11.4 TZD (1.64,10.3 (0.51,1.47) (0.44,1.54) (0.71,2.35) (1.90,8.12) (0.29,3.01) (1.90,7.75) (0.56,1.80) 7) 4) 8.04 4.75 1.15 0.94 1.49 4.52 1.08 4.42 1.16 (6.28,10.3 DPP-4-i (2.16,10.4 (0.68,1.96) (0.61,1.47) (1.03,2.16) (2.62,7.80) (0.37,3.19) (2.53,7.71) (0.80,1.66) 0) 4) 8.51 5.03 1.22 1.06 1.58 4.79 1.15 4.68 1.22 (5.64,12.8 SGLT-2-i (2.10,12.0 (0.65,2.30) (0.68,1.65) (0.94,2.67) (2.45,9.37) (0.37,3.59) (2.45,8.96) (0.75,2.00) 6) 7) 5.39 0.77 0.67 0.63 3.03 3.18 0.73 2.96 0.77 GLP-1RA (3.72,7.79) (0.43,1.40) (0.46,0.97) (0.38,1.07) (1.79,5.13) (1.52,6.67) (0.24,2.22) (1.60,5.49) (0.52,1.16) 1.78 0.25 0.22 0.21 0.33 1.05 0.24 0.98 0.26 BASAL (1.02,3.09) (0.12,0.53) (0.13,0.38) (0.11,0.41) (0.20,0.56) (0.51,2.15) (0.07,0.79) (0.46,2.06) (0.14,0.47) 1.69 0.24 0.21 0.20 0.31 0.95 BASAL 0.23 0.93 0.24 (0.77,3.73) (0.10,0.61) (0.10,0.46) (0.08,0.48) (0.15,0.66) (0.47,1.95) BOLUS (0.06,0.85) (0.37,2.37) (0.11,0.55) 7.42 4.17 4.38 4.08 1.06 0.92 0.87 1.38 1.07 (2.50,21.9 (1.27,13.7 (1.17,16.3 AGI (1.27,13.0 (0.33,3.40) (0.31,2.72) (0.28,2.72) (0.45,4.21) (0.36,3.19) 8) 5) 9) 9) 1.82 0.26 0.23 0.21 0.34 1.02 1.08 0.25 GLITINID 0.26 (1.07,3.09) (0.13,0.53) (0.13,0.39) (0.11,0.41) (0.18,0.63) (0.49,2.16) (0.42,2.74) (0.08,0.79) E (0.14,0.47) 6.96 1.00 0.87 0.82 1.29 3.92 4.11 0.94 3.83 (4.77,10.1 PCO (0.56,1.79) (0.60,1.25) (0.50,1.33) (0.86,1.94) (2.14,7.16) (1.81,9.33) (0.31,2.81) (2.12,6.91) 5)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 13.9. Body Weight (Continuous Outcome Reported as Standardized Mean Difference With 95% Confidence Interval)

-0.26 (- -0.58 (- -0.96 (- -1.05 (- -0.99 (- -0.63 (- -0.63 (- SU 0.65,0.13) 1.06,-0.11) 1.46,-0.47) 1.54,-0.57) 2.14,0.16) 1.65,0.40) 1.05,-0.21) 0.26 (- -0.33 (- -0.70 (- -0.80 (- -0.73 (- -0.37 (- -0.37 (- TZD 0.13,0.65) 0.87,0.22) 1.24,-0.17) 1.36,-0.23) 1.92,0.45) 1.43,0.69) 0.83,0.08) 0.58 0.33 (- -0.38 (- -0.47 (- -0.41 (- -0.04 (- -0.05 (- DPP-4-i (0.11,1.06) 0.22,0.87) 0.93,0.18) 1.05,0.12) 1.60,0.79) 0.95,0.87) 0.47,0.37) 0.96 0.70 0.38 (- -0.09 (- -0.03 (- 0.33 (- 0.33 (- SGLT-2-i (0.47,1.46) (0.17,1.24) 0.18,0.93) 0.68,0.50) 1.23,1.17) 0.73,1.40) 0.09,0.74) 1.05 0.80 0.47 (- 0.09 (- 0.06 (- 0.43 (- 0.42 (- GLP-1RA (0.57,1.54) (0.23,1.36) 0.12,1.05) 0.50,0.68) 0.98,1.11) 0.65,1.51) 0.05,0.90) 0.99 (- 0.73 (- 0.41 (- 0.03 (- -0.06 (- 0.36 (- 0.36 (- BASAL 0.16,2.14) 0.45,1.92) 0.79,1.60) 1.17,1.23) 1.11,0.98) 1.14,1.87) 0.79,1.51) 0.63 (- 0.37 (- 0.04 (- -0.33 (- -0.43 (- -0.36 (- -0.01 (- AGI 0.40,1.65) 0.69,1.43) 0.87,0.95) 1.40,0.73) 1.51,0.65) 1.87,1.14) 1.00,0.99) 0.63 0.37 (- 0.05 (- -0.33 (- -0.42 (- -0.36 (- 0.01 (- PCO (0.21,1.05) 0.08,0.83) 0.37,0.47) 0.74,0.09) 0.90,0.05) 1.51,0.79) 0.99,1.00)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 14. Network Meta-analysis Estimates of Comparative Treatment Effects for Drug Classes Given as Triple Therapy

For example, in reading the upper part of Table 14.1 from right to left, DPP-4 inhibitors (DPP-4-i) added to metformin and sulfonylurea therapy were associated with an odds of cardiovascular mortality of 0.73 (95% confidence interval 0.00 to 136.19) compared with thiazolidinediones (TZD) added to metformin and sulfonylurea therapy. In reverse, reading the lower part of Table 14.1 from left to right, thiazolidinediones (TZD) added to metformin and sulfonylurea therapy were associated with an odds of cardiovascular mortality of 1.36 (0.01‒252.34) compared with DPP-4 inhibitors (DPP-4-i) added to metformin and sulfonylurea therapy. In reading the upper part of Table 14.6 from right to left, DPP-4 inhibitors (DPP-4-i) added to metformin and sulfonylurea therapy were associated with a higher HbA1C level than (0.23, -0.62 to 1.08) than thiazolidinediones (TZD) added to metformin and sulfonylurea therapy. In reverse, reading the lower part of Table 14.6 from left to right, thiazolidinediones (TZD) added to metformin and sulfonylurea therapy were associated with a lower HbA1C than DPP-4 inhibitors (DPP-4-i) added to metformin and sulfonylurea therapy level (-0.23, -1.08 to 0.62).

eTable 14.1. Cardiovascular Mortality (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.73 3.69 1.02 2.13 1.54 2.42 TZD (0.00,136.19) (0.05,257.78) (0.06,16.46) (0.04,108.29) (0.02,107.55) (0.15,39.11) 1.36 5.03 1.39 2.90 2.10 3.30 DPP-4-i (0.01,252.34) (0.24,105.06) (0.01,257.27) (0.01,1071.04) (0.00,961.33) (0.04,273.20) 0.27 0.20 0.28 0.58 0.42 0.66 SGLT-2-i (0.00,18.90) (0.01,4.16) (0.00,19.27) (0.00,91.84) (0.00,85.29) (0.03,16.17) 0.98 0.72 3.61 2.08 1.51 2.37 GLP-1RA (0.06,15.75) (0.00,132.89) (0.05,251.51) (0.13,33.46) (0.06,37.31) (0.15,38.19) 0.47 0.34 1.73 0.48 0.72 1.14 BASAL (0.01,23.86) (0.00,127.35) (0.01,275.92) (0.03,7.70) (0.01,50.36) (0.02,57.78) 0.65 0.48 2.39 0.66 1.38 BASAL 1.57 (0.01,45.20) (0.00,218.04) (0.01,488.80) (0.03,16.39) (0.02,96.06) BOLUS (0.02,109.49) 0.41 0.30 1.53 0.42 0.88 0.64 PCO (0.03,6.67) (0.00,25.16) (0.06,37.61) (0.03,6.81) (0.02,44.75) (0.01,44.45) *Data for meglitinides or alpha glucosidase inhibitors added to metformin and sulfonylurea were not available.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 14.2. All-Cause Mortality (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.44 2.16 0.15 0.69 0.11 1.37 TZD (0.02,11.57) (0.10,45.20) (0.01,2.22) (0.02,19.30) (0.00,2.64) (0.27,6.94) 2.26 4.88 0.35 1.56 0.25 3.09 DPP-4-i (0.09,59.00) (0.34,69.82) (0.02,5.45) (0.05,46.68) (0.01,6.39) (0.13,71.83) 0.46 0.21 0.07 0.32 0.05 0.63 SGLT-2-i (0.02,9.69) (0.01,2.94) (0.00,1.65) (0.01,13.20) (0.00,1.83) (0.04,9.99) 6.53 2.89 14.10 4.51 0.72 8.94 GLP-1RA (0.45,94.53) (0.18,45.59) (0.61,327.69) (0.62,32.93) (0.13,4.00) (0.59,135.25) 1.45 0.64 3.13 0.22 0.16 1.98 BASAL (0.05,40.55) (0.02,19.24) (0.08,129.39) (0.03,1.62) (0.02,1.35) (0.07,57.52) 9.10 4.03 19.66 1.39 6.28 BASAL 12.47 (0.38,218.43) (0.16,103.95) (0.55,708.77) (0.25,7.78) (0.74,53.26) BOLUS (0.50,310.36) 0.73 0.32 1.58 0.11 0.50 0.08 PCO (0.14,3.70) (0.01,7.51) (0.10,24.87) (0.01,1.69) (0.02,14.61) (0.00,2.00) *Data for meglitinides or alpha glucosidase inhibitors added to metformin and sulfonylurea were not available.

eTable 14.3. Serious Adverse Events (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.62 0.53 0.64 0.73 0.60 0.93 TZD (0.32,1.20) (0.27,1.06) (0.39,1.07) (0.42,1.27) (0.28,1.27) (0.54,1.62) 1.61 0.85 1.04 1.17 0.96 1.50 DPP-4-i (0.83,3.11) (0.53,1.38) (0.63,1.72) (0.66,2.10) (0.45,2.05) (0.97,2.34) 1.88 1.17 1.21 1.37 1.13 1.76 SGLT-2-i (0.95,3.76) (0.72,1.90) (0.69,2.13) (0.74,2.56) (0.50,2.52) (1.11,2.80) 1.55 0.96 0.82 1.13 0.93 1.45 GLP-1RA (0.94,2.57) (0.58,1.60) (0.47,1.45) (0.81,1.58) (0.52,1.66) (0.97,2.16) 1.37 0.85 0.73 0.88 0.82 1.28 BASAL (0.79,2.40) (0.48,1.53) (0.39,1.36) (0.63,1.23) (0.45,1.49) (0.79,2.08) 1.67 1.04 0.89 1.08 1.22 BASAL 1.56 (0.79,3.56) (0.49,2.22) (0.40,1.98) (0.60,1.93) (0.67,2.21) BOLUS (0.79,3.10) 1.07 0.67 0.57 0.69 0.78 0.64 PCO (0.62,1.86) (0.43,1.04) (0.36,0.90) (0.46,1.03) (0.48,1.27) (0.32,1.27)

*Data for meglitinides or alpha glucosidase inhibitors added to metformin and sulfonylurea were not available

eTable 14.4. Myocardial infarction

Insufficient data observations to generate evidence network.

eTable 14.5. Stroke

Insufficient data observations to generate evidence network.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 14.6. HbA1C (Continuous Outcome Reported as Standardized Mean Difference With 95% Confidence Interval)

0.23 (- 0.12 (- 0.07 (- -0.00 (- -0.23 (- 1.42 0.86 TZD 0.62,1.08) 1.12,1.35) 0.56,0.70) 0.61,0.61) 1.03,0.56) (0.57,2.26) (0.25,1.48) -0.23 (- -0.12 (- -0.16 (- -0.23 (- -0.46 (- 1.19 0.63 (- DPP-4-i 1.08,0.62) 1.52,1.29) 0.93,0.62) 1.03,0.56) 1.45,0.53) (0.04,2.33) 0.29,1.55) -0.12 (- 0.12 (- -0.04 (- -0.12 (- -0.35 (- 1.30 (- 0.75 (- SGLT-2-i 1.35,1.12) 1.29,1.52) 1.30,1.21) 1.39,1.15) 1.73,1.04) 0.07,2.67) 0.32,1.82) -0.07 (- 0.16 (- 0.04 (- -0.07 (- -0.30 (- 1.34 0.79 GLP-1RA 0.70,0.56) 0.62,0.93) 1.21,1.30) 0.64,0.49) 1.04,0.44) (0.37,2.32) (0.14,1.45) 0.00 (- 0.23 (- 0.12 (- 0.07 (- -0.23 (- 1.42 0.86 BASAL 0.61,0.61) 0.56,1.03) 1.15,1.39) 0.49,0.64) 0.97,0.51) (0.44,2.39) (0.18,1.55) 0.23 (- 0.46 (- 0.35 (- 0.30 (- 0.23 (- BASAL 1.65 1.09 0.56,1.03) 0.53,1.45) 1.04,1.73) 0.44,1.04) 0.51,0.97) BOLUS (0.54,2.76) (0.22,1.97) -1.42 (- -1.19 (- -1.30 (- -1.34 (- -1.42 (- -1.65 (- -0.55 (- AGI 2.26,-0.57) 2.33,-0.04) 2.67,0.07) 2.32,-0.37) 2.39,-0.44) 2.76,-0.54) 1.41,0.30) -0.86 (- -0.63 (- -0.75 (- -0.79 (- -0.86 (- -1.09 (- 0.55 (- PCO 1.48,-0.25) 1.55,0.29) 1.82,0.32) 1.45,-0.14) 1.55,-0.18) 1.97,-0.22) 0.30,1.41) *Data for meglitinides added to metformin and sulfonylurea were not available.

eTable 14.7. Treatment Failure (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

1.35 2.20 0.78 0.95 0.44 4.67 TZD (0.05,37.3 (1.32,3.68) (0.39,1.57) (0.60,1.50) (0.20,0.99) (3.04,7.17) 4) 0.61 0.45 0.35 0.43 0.20 2.12 DPP-4-i (0.02,16.7 (0.27,0.76) (0.21,0.59) (0.29,0.64) (0.10,0.43) (1.45,3.09) 6) 1.73 5.99 1.28 2.83 1.22 0.57 SGLT-2-i (0.06,48.2 (3.45,10.4 (0.64,2.58) (1.71,4.68) (0.67,2.22) (0.25,1.30) 3) 2) 1.42 1.05 2.31 0.82 0.47 4.90 GLP-1RA (0.05,37.8 (0.66,1.66) (1.57,3.40) (0.45,1.49) (0.24,0.89) (3.36,7.14) 5) 4.95 3.04 10.51 2.25 1.75 2.14 (2.34,10.4 BASAL (0.12,76.1 (5.08,21.7 (1.01,5.02) (0.77,4.00) (1.13,4.08) 8) 6) 2) 0.74 1.63 0.58 0.71 3.46 0.33 BASAL (0.03,20.5 (0.06,44.5 (0.02,16.0 (0.03,18.8 (0.13,94.0 (0.01,8.25) BOLUS 0) 5) 5) 7) 1) 0.21 0.47 0.17 0.20 0.10 0.29 PCO (0.14,0.33) (0.32,0.69) (0.10,0.29) (0.14,0.30) (0.05,0.20) (0.01,7.86) *Data for meglitinides or alpha glucosidase inhibitors added to metformin and sulfonylurea were not available.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 14.8. Hypoglycemia (Binary Outcome Reported as Odds Ratio With 95% Confidence Interval)

0.87 0.86 0.60 0.95 1.57 0.37 TZD (0.50,1.51) (0.48,1.54) (0.39,0.94) (0.60,1.52) (0.81,3.02) (0.24,0.57) 1.15 0.99 0.69 1.10 1.80 0.42 DPP-4-i (0.66,1.99) (0.61,1.58) (0.42,1.14) (0.63,1.92) (0.88,3.67) (0.28,0.64) 1.17 1.01 0.70 1.11 1.83 0.43 SGLT-2-i (0.65,2.10) (0.63,1.63) (0.41,1.22) (0.61,2.03) (0.87,3.85) (0.28,0.66) 1.66 1.44 1.42 1.58 2.59 0.61 GLP-1RA (1.07,2.57) (0.87,2.37) (0.82,2.46) (1.13,2.21) (1.52,4.43) (0.42,0.90) 1.05 0.91 0.90 0.63 1.64 0.39 BASAL (0.66,1.67) (0.52,1.60) (0.49,1.64) (0.45,0.88) (0.97,2.78) (0.25,0.61) 0.64 0.56 0.55 0.39 0.61 BASAL 0.24 (0.33,1.23) (0.27,1.13) (0.26,1.15) (0.23,0.66) (0.36,1.03) BOLUS (0.12,0.44) 2.71 2.36 2.33 1.64 2.59 4.25 PCO (1.75,4.20) (1.56,3.58) (1.52,3.55) (1.12,2.41) (1.65,4.06) (2.26,8.01) *Data for meglitinides or alpha glucosidase inhibitors added to metformin and sulfonylurea were not available.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 14.9. Body Weight (Continuous Outcome Reported as Standardized Mean Difference With 95% Confidence Interval)

-0.23 (- -0.33 (- -0.23 (- 0.16 (- -0.08 (- -0.26 (- -0.28 (- TZD 0.46,-0.00) 0.59,-0.07) 0.39,-0.06) 0.36,0.68) 0.35,0.19) 0.50,-0.02) 0.48,-0.08) 0.23 -0.09 (- 0.01 (- 0.40 (- 0.16 (- -0.03 (- -0.05 (- DPP-4-i (0.00,0.46) 0.40,0.22) 0.16,0.17) 0.12,0.91) 0.12,0.43) 0.36,0.30) 0.31,0.22) 0.33 0.09 (- 0.10 (- 0.49 (- 0.25 (- 0.07 (- 0.05 (- SGLT-2-i (0.07,0.59) 0.22,0.40) 0.16,0.37) 0.08,1.06) 0.09,0.59) 0.29,0.42) 0.11,0.21) 0.23 -0.01 (- -0.10 (- 0.39 (- 0.15 (- -0.04 (- -0.05 (- GLP-1RA (0.06,0.39) 0.17,0.16) 0.37,0.16) 0.13,0.90) 0.07,0.36) 0.33,0.25) 0.26,0.16) -0.16 (- -0.40 (- -0.49 (- -0.39 (- -0.24 (- -0.42 (- -0.44 (- BASAL 0.68,0.36) 0.91,0.12) 1.06,0.08) 0.90,0.13) 0.80,0.32) 0.99,0.15) 0.99,0.10) 0.08 (- -0.16 (- -0.25 (- -0.15 (- 0.24 (- BASAL -0.18 (- -0.20 (- 0.19,0.35) 0.43,0.12) 0.59,0.09) 0.36,0.07) 0.32,0.80) BOLUS 0.55,0.18) 0.50,0.10) 0.26 0.03 (- -0.07 (- 0.04 (- 0.42 (- 0.18 (- -0.02 (- AGI (0.02,0.50) 0.30,0.36) 0.42,0.29) 0.25,0.33) 0.15,0.99) 0.18,0.55) 0.33,0.30) 0.28 0.05 (- -0.05 (- 0.05 (- 0.44 (- 0.20 (- 0.02 (- PCO (0.08,0.48) 0.22,0.31) 0.21,0.11) 0.16,0.26) 0.10,0.99) 0.10,0.50) 0.30,0.33)

*Data for meglitinides added to metformin and sulfonylurea were not available

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 15. Meta-regression Analyses for Drug Classes Given as Monotherapy (Compared With Metformin)

Results of the meta-regression analyses are shown as the beta coefficient and the corresponding 95% confidence interval. The beta coefficient is measured in units of standard deviation. For example, a beta value of 0.01 for the regression of baseline age on the standardized mean difference in HbA1C at end of treatment for basal insulin treatment versus metformin indicates that a change of one standard deviation in the predictor variable (baseline HbA1C) resulted in a change of -0.01 standard deviations in the end of treatment mean difference in HbA1C between treatments. For every 1 standard deviation increase in baseline age, the effect of metformin on HbA1C compared to basal insulin increased by 0.01 standard deviations (or had a greater relative effect on HbA1C during treatment). The confidence interval for the beta coefficient did not include 0, indicating that there was a possibility that baseline age had an association with the comparative effects of metformin versus sulfonylurea treatment. Results shown underlined and in bold indicate a significant result.

eTable 15.1. HbA1C

Duration of diagnosed Duration of Age, years HbA1C, % Body weight, kg diabetes, years treatment, months SU -0.004 (-0.008 to -0.02(-0.05 to 0.01) 0.002 (0.000 to -0.02 (-0.05 to 0.02) 0.004 (-0.02 to 0.000) 0.004) 0.03) TZD -0.003 (-0.007 to -0.01 (-0.04 to 0.01) 0.000 (-0.001 to -0.01 (-0.04 to 0.02) 0.006 (-0.03 to 0.000) 0.002) 0.04) DPP-4-i -0.002 (-0.007 to 0.01 (-0.02 to 0.04) 0.000 (-0.001 to -0.007(-0.05 to 0.002 (-0.05 to 0.003) 0.002) 0.04) 0.05) SGLT-2-i -0.003 (-0.01 to 0.03 (-0.03 to 0.13) -0.001 (-0.01 to -0.04 (-0.25 to 0.17) Insufficient 0.007) 0.01) observations GLP-1RA 0.000 (-0.006 to 0.006 (-0.02 to 0.000 (-0.002 to -0.04 (-0.11 to 0.03) -0.05 (-0.15 to 0.04) 0.01) 0.19) 0.003) BASAL 0.01 (0.000 to 0.02) 0.08 (-0.02 to 0.19) -0.005 (-0.009 to - -0.06 (-0.17 to 0.06) 0.004 (-0.04 to 0.001) 0.05) AGI -0.008 (-0.02 to -0.04 (-0.09 to 0.001 (-0.001 to -0.02 (-0.05 to 0.02) 0.06 (0.001 to 0.12) 0.001) 0.004) 0.003) GLITINID 0.001 (-0.009 to -0.01 (-0.07 to 0.05) 0.001 (-0.004 to -0.009 (-0.04 to 0.04 (-0.07 to 0.16) E 0.01) 0.005) 0.02) PCO -0.007 (-0.01 to - 0.03 (-0.006 to 0.000 (-0.003 to 0.001 (-0.03 to 0.04 (0.005 to 0.09) 0.004) 0.07) 0.004) 0.04)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 15.2. Hypoglycemia

Duration of diagnosed Duration of Age, years HbA1C, % Body weight, kg diabetes, years treatment, months SU 0.01 (0.004 to 0.02) 0.08 (0.02 to 0.14) 0.002 (0.000 to -0.04 (-0.08 to 0.01) 0.009 (-0.006 to 0.005) 0.02) TZD 0.007 (0.001 to 0.03 (-0.02 to 0.8) 0.001 (-0.001 to -0.04 (-0.09 to 0.02) 0.01 (-0.003 to 0.01) 0.003) 0.02) DPP-4-i 0.003 (-0.006 to 0.01 (-0.04 to 0.07) 0.002 (-0.001 to -0.03 (-0.09 to 0.03) 0.004 (-0.05 to 0.01) 0.005) 0.06) SGLT-2-i 0.01 (-0.03 to 0.04) -0.06 (-0.34 to 0.23) -0.002 (-0.03 to 0.02 (-0.15 to 0.19) Insufficient 0.02) observations GLP-1RA 0.005 (-0.002 to 0.03 (-0.02 to 0.07) 0.001 (-0.003 to -0.07 (-0.17 to 0.03) 0.01 (-0.11 to 0.13) 0.01) 0.006) BASAL -0.02 (-0.05 to 0.02) 1.01 (-0.32 to 2.35) -0.15 (-0.34 to 0.05) -0.66 (-1.48 to 0.16) 1.10 (-0.37 to 2.58) AGI 0.001 (-0.01 to -0.006 (-0.12 to 0.006 (-0.000 to -0.04 (-0.13 to 0.04) -0.13 (-0.32 to 0.06) 0.01) 0.11) 0.012) GLITINID -0.006 (-0.02 to -0.03 (-0.11 to 0.05) 0.004 (-0.000 to -0.04 (-0.11 to 0.01) 0.06 (-0.04 to 0.16) E 0.006) 0.01) PCO 0.001 (-0.008 to -0.04 (-0.12 to 0.04) 0.003 (-0.001 to -0.05 (-0.11 to 0.01) 0.03 (-0.06 to 0.11) 0.01) 0.007)

eTable 15.3. Body Weight

Duration of diagnosed Duration of Age, years HbA1C, % Body weight, kg diabetes, years treatment, months SU 0.02 (-0.07 to 0.11) 0.05 (-0.54 to 0.65) 0.02 (-0.04 to 0.09) 0.03 (-0.40 to 0.45) -0.02 (-0.19 to 0.15) TZD -0.13 (-0.24 to - -0.92 (-1.90 to 0.06) -0.06 (-0.13 to - 0.79 (-0.35 to 1.94) 0.04 (-0.44 to 0.52) 0.03) 0.001) DPP-4-i 0.05 (-0.05 to 0.15) -0.24 (-1.38 to 0.89) 0.008 (-0.09 to -0.29 (-2.03 to 1.46) -6.92 (-20.9 to 6.44) 0.10) SGLT-2-i 0.05 (-0.04 to 0.14) -0.15 (-1.28 to 0.98) 0.01 (-0.09 to 0.11) 0.19 (-1.50 to 1.87) Insufficient observations GLP-1RA 0.22 (-0.35 to 0.80) 1.11 (-1.36 to 3.58) -0.07 (-0.23 to 0.10) 0.25 (-0.45 to 0.94) 0.38 (-0.70 to 1.45) BASAL -0.07 (-0.24 to 0.10) -2.79 (-7.24 to 1.65) -0.54 (-1.36 to 0.30) -0.98 (-2.62 to 0.65) 3.21 (-1.78 to 8.21) AGI 0.02 (-0.09 to 0.14) -0.05 (-0.82 to 0.72) 0.02 (-0.07 to 0.11) 0.37 (-0.64 to 1.38) -1.73 (-4.43 to 0.96) GLITINIDE 0.25 (0.10 to 0.40) 0.27 (-0.40 to 0.94) 0.30 (0.13 to 0.47) Insufficient Insufficient observations observations PCO 0.04 (-0.01 to 0.10) -0.35 (-1.10 to 0.41) 0.01 (-0.06 to 0.09) 0.39 (-0.59 to 1.37) -1.51 (-3.96 to 0.94)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 16. Subgroup Analyses of Individual Sulfonylurea Drugs (as Monotherapy) on Hypoglycemia

The network for drug monotherapy on hypoglycemia included five sulfonylurea treatments (glyburide, glibenclamide, glipizide, glimepiride, and gliclazide). These drugs were considered separately within network analyses to assess whether there were statistical and/or clinical differences in the odds of hypoglycemia with the different sulfonylurea drugs. These analyses were post-hoc.

An odds ratio <1 indicated that metformin was associated with lower odds of hypoglycemia than the comparator drug. The lower the odds ratio, the greater the likelihood of hypoglycemia during active treatment, when compared to metformin. The drugs are shown in order of the surface under the ranking (SUCRA) curve where a SUCRA of 100% is consistent with the drug being the best for the specified outcome and 0% being the worst for the outcome.

Surface Mean under ranking cumulative (best to ranking worst) Odds ratio (95% CI) for (SUCRA) among 17 Intervention Comparator hypoglycemia curve drugs Placebo 1.69 (1.19−2.41) 85.6 3.3 DPP-4-i 1.54 (1.12−2.11) 80.2 4.2 SGLT-2-I 1.59 (0.76−3.33) 80.1 4.2 TZD 1.52 (1.15−2.01) 79.1 4.3 AGI 1.44 (0.84−2.49) 75.7 4.9 GLP-1RA 1.00 (0.70−1.42) 57.9 7.7 Metformin GLITINIDE 0.43 (0.30−0.63) 31.6 12.0 Gliclazide 0.39 (0.13−1.21) 28.2 12.5 Glipizide 0.38 (0.25−0.57) 26.5 12.8 Glimepiride 0.37 (0.25−0.56) 25.7 12.9 Glibenclamide 0.34 (0.21−0.55) 20.6 13.7 Glyburide 0.26 (0.19−0.36) 9.3 15.5 BASAL insulin 0.06 (0.006−0.53) 2.3 16.6

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 17. Sensitivity Analysis: Summary Treatment Estimates of Glucose- Lowering Interventions Restricted to Clinical Trials at Low Risk of Bias From Allocation Concealment Methods

Drugs given as monotherapy GLP- GLITINID Outcome MET SU TZD DPP-4-i SGLT-2-i BASAL 1RA E AGI PCO Cardiovas 0.90 0.51 (0. cular Referent -- -- (0.13,6.1 ------11,2.43) mortality 4) 1.44 0.38 0.65 0. 70 0.76 All-cause 1.66 (0. Referent (0.33,6.3 (0.10,1.4 (0.12,3.6 -- (0.09,5.6 -- -- (0.08,7.56 mortality 32,8.61) 4) 1) 2) 9) ) Serious 1.14 1.19 1.35 1.24 2.25 1.15 0.80 (0. adverse Referent (0.78,1.6 (0.83,1.7 (0.87,2.1 -- (0.83,1.8 -- (0.18,27 (0.67,2.00 46,1.39) events 8) 2) 4) 7) .5) ) Myocardi 2.64 1.94 0.37 0.18 0.73 0.04 al Referent (0.09,81. (0.07,55. (0.03,5.0 (0.01,5.5 -- (0.05,10. -- -- (0.00,1.87 infarction 3) 9) 6) 5) 7) ) 1.08 1.04 1.43 0.70 0.74 1.35 Stroke Referent (0.67,1.7 (0.60,1.8 (0.50,4.0 (0.05,9.7 -- (0.17,3.2 -- -- (0.33,5.46 5) 0) 9) 1) 1) ) -0.05 (- 0.00 (- 0.28 0.15 (- -0.07 (- 0.14 (- 0.96 HbA1C Referent 0.28,0.18 0.19,0.19 (0.10,0.4 0.04,0.34 -- 0.29,0.15 -- 0.29,0.5 (0.76,1.17 ) ) 6) ) ) 7) ) 1.61 1. 58 1.78 0.55 0.80 4.35 Treatment Referent (0.88,2.9 (0.92,2.7 (1.36,2.3 (0.39,0.7 -- (0.49,1.3 -- -- (3.02,6.28 failure 9) 2) 4) 8) 3) ) 2.39 0.65 0.48 0.90 1.65 0.68 Hypoglyc 0.55 (0. Referent (1.48,3.8 (0.40,1.0 (0.27,0.8 -- (0.62,1.3 (0.56,4.8 -- (0.29,1.55 emia 22,1.45) 7) 9) 4) 1) 5) ) 0.02 (- Body -0.20 (-0. -0.13 (- Referent -- -- 0.11,0.16 ------weight 41,0.0) 0.32,0.06) )

Summary estimates of treatment associations with individual endpoints were calculated in trials in which allocation concealment was considered low risk of bias. Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; SGLT-2-i = sodium glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 1. Summary Study-Level Characteristics According to Drug Class

Age Gender 80 100 90 70 80 60 70 50 60 ge, years 50 40 40 Mean a 30 Proportion men, of % 30 20 20 10 10 0 0

Body weight Duration of diabetes diagnosis 10 100 9 90 8 80 7 70 6 60 5 50 diagnosis duration, years 4 40 Meanweight, body kg 3 30 2 20 Mean diabetes 1 10 0 0

HbA1C Year 12 2020 11 10 9 2010 8 7 6 Year 2000 5 Mean HbA1C, % 4 3 1990 2 1 0 1980

eFigure 1.1. Summary Study-Level Characteristics According to Drug Class for Drugs Given as Monotherapy

Box plots showing the distribution of trial-level characteristics according to drug class. These characteristics were used to consider whether the trials included in network analyses were sufficiently similar that a network analysis was appropriate. The limits of the boxes represent the 25th and 75th centile, the middle line represents the median and the error bars show the adjacent values (spanning all data points within 1.5 interquartile ranges of the nearest (upper or lower quartile).

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 1.2. Summary Study-Level Characteristics According to Drug Class for Drugs Given as Dual Therapy in Addition to Metformin

Age Gender 80 100 90 70 80 60 70 50 60 ge, years 40 50 40 Mean a 30 Proportion men, of % 30 20 20 10 10 0 0

Body weight Duration of diabetes diagnosis 15 100 14 90 13 12 80 11 70 10 9 60 8 50 7 diagnosis duration, years 6 40 5 Meanweight, body kg 30 4 3 20 Mean diabetes 2 10 1 0 0

HbA1C Year 12 2020 11 10 9 2010 8 7 Year 6 2000 Mean HbA1C, % 5 4 3 1990 2 1 0 1980

Downloaded From: https://jamanetwork.com/ on 10/02/2021 appropriate. The limits of the boxes represent the 25th and 75th centile, the middle line represents the median and the error bars show the adjacent values (spanning all data points within 1.5 interquartile ranges of the nearest (upper or lower quartile

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 1.3. Summary Study-Level Characteristics According to Drug Class for Drugs Given as Triple Therapy in Addition to Metformin and Sulfonylurea

Age Gender 80 100 90 70 80 60 70 50 60 ge, years 50 40 40 Mean a 30 Proportion men, of % 30 20 20 10 10 0 0

Body weight Duration of diabetes diagnosis 15 100 14 90 13 80 12 11 70 10 9 60 8 50 7 diagnosis duration, years 6 40 Meanweight, body kg 5 30 4 3 20 Mean diabetes 2 10 1 0 0

HbA1C Year 12 2020 11 10 9 2010 8 7 6 2000 Year 5 Mean HbA1C, % 4 3 1990 2 1 0 1980

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 1.4. Summary Study Follow-up According to Drug Class (Months)

30 Monotherapy 25 20 15 10 Duration of treatment 5 0

30 Dual therapy 25 20 15 Duration of treatment 10 5 0

30 Triple therapy 25 20 15 Duration of treatment 10 5 0

Box plots showing the distribution of trial duration of following according to drug class. This characteristic was used to consider whether the trials included in network analyses were sufficiently similar that a network analysis was appropriate. The limits of the boxes represent the 25th and 75th centile, the middle line represents the median and the

Downloaded From: https://jamanetwork.com/ on 10/02/2021 error bars show the adjacent values (spanning all data points within 1.5 interquartile ranges of the nearest (upper or lower quartile). eFigure 2. Networks of Secondary Outcomes Nodes indicate the classes which are evaluated in clinical trials. Lines represent head-to-head comparisons of the two drug classes indicated by the connected nodes. The thickness of the line connecting two nodes is proportional to the number of clinical trials directly evaluating the two connected drug classes. The size of the node is proportional to the number of trials evaluating the treatment.

eFigure 2.1. Networks of Secondary Outcomes for Drug Classes Given as Monotherapy

All-cause mortality Myocardial infarction Stroke

DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SU SU SGLT-2-I SU

SGLT-2-I

GLP1-RA SGLT-2-I MET MET MET

GLP-1RA BASAL BOLUS GLITINIDE INSULIN AGI GLP-1RA PCO

BASAL BOLUS AGI PCO PCO CON INSULIN 41 trials; 27,670 patients (497,563 patient-months) 31 trials; 22,574 patients (441,495 patient-months) 20 trials; 17,192 patients (401,743 patient-months)

Serious adverse events HbA1C Treatment failure

DPP-4-i DPP-4-i DPP-4-i TZD TZD SGLT-2-I SGLT-2-I TZD SGLT-2-I SU GLP1-RA SU SU GLP1-RA

GLP1-RA

BASAL MET BASAL INSULIN MET MET INSULIN

BASAL-BOLUS INSULIN PRA NDIA L GLITINIDE BASAL-BOLUS INSULIN GLITINIDE GLITINIDE INSULIN

PCO PCO AGI AGI AGI CON PCO CON CON

68 trials; 38,466 patients (548,489 patient-months) 98 trials; 21,703 patients (190,886 patient-months) 89 trials; 41,498 patients (600,585 patient-months)

eFigure 2.1. Networks of Secondary Outcomes for Drug Classes Given as Monotherapy (continued)

Hypoglycemia Body weight

DPP-4-i SGLT-2-I DPP-4-i SGLT-2-I TZD TZD GLP1-RA GLP1-RA SU SU

BASAL BASAL INSULIN INSULIN MET MET PRA NDIA L PRA NDIA L INSULIN INSULIN

GLITINIDE GLITINIDE BASAL-BOLUS INSULIN BASAL-BOLUS © INSULIN2016 American Medical Association. All rights reserved. AGI AGI PCO CON PCO CON 80 trials; 40,082 patients (589,486 patient-months) 42 trials; 7024 patients (69,506 patient-months) Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 2.2. Network Plots of Secondary Outcomes for Drug Classes Given as Dual Therapy in Addition to Metformin (continued on next page)

All-cause mortality Serious adverse events Myocardial infarction

DPP-4-i SGLT-2-I DPP-4-i DPP-4-i SGLT-2-I GLP-1-RA SGLT-2-I

TZD TZD TZD

GLP-1RA GLP-1RA BASAL INSULIN

SU SU SU

BASAL BOLUS BASAL INSULIN BASAL INSULIN INSULIN GLITINIDE

GLITINIDE CON PCO AGI BASAL BOLUS PCO CON INSULIN CON PCO 42 trials; 34,822 patients (490,825 patient-months) 68 trials; 44,470 patients (543,338 patient-months) 28 trials; 25,127 patients (342,290 patient-months)

Stroke HbA1C Treatment failure

SGLT-2-I SGLT-2-I DPP-4-i DPP-4-i DPP-4-i GLP-1RA GLP-1RA

SGLT-2-I TZD TZD TZD

BASAL BASAL INSULIN INSULIN

GLP-1RA SU SU SU BASAL BASAL BOLUS BOLUS INSULIN INSULIN GLITINIDE GLITINIDE

PCO BASAL CON PCO INSULIN AGI AGI CON CON

PCO

26 trials; 25,567 patients (394,122 patient-months) 51 trials; 17,022 patients (208,858 patient-months) 59 trials; 40,364 patients (490,123 patient-months)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 2.2: Network Plots of Secondary Outcomes for Drug Classes Given as Dual Therapy in Addition to Metformin (continued)

Hypoglycemia Body weight

SGLT-2-I DPP-4-i DPP-4-i

GLP-1-RA SGLT-2-I TZD

TZD

GLP-1-RA BASAL INSULIN

SU SU

BASAL BOLUS INSULIN BASAL GLITINIDE INSULIN

AGI PCO AGI PCO CON CON

74 trials; 45,710 patients (558,520 patient-months) 24 trials; 6580 patients (76,857 patient-months)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 2.3. Networks of Secondary Outcomes for Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea

All-cause mortality Serious adverse events HbA1C

SGLT-2-I SGLT-2-I GLP-1RA SGLT-2-I DPP-4-i DPP-4-i DPP-4-i GLP-1RA GLP-1RA BASAL INSULIN

TZD TZD TZD

BASAL INSULIN BASAL BASAL BOLUS INSULIN INSULIN AGI PCO PCO BASAL BASAL PCO CON BOLUS BOLUS INSULIN INSULIN

9 trials; 5263 patients (52,023 patient-months) 17 trials; 9338 patients (79,147 patient-months) 16 trials; 4941 patients (42,457 patient-months)

Treatment failure Hypoglycemia Body weight

SGLT-2-I SGLT-2-I SGLT-2-I DPP-4-i GLP-1RA GLP-1RA DPP-4-i DPP-4-i GLP-1RA

BASAL INSULIN

TZD BASAL INSULIN TZD TZD

BASAL BASAL BOLUS INSULIN INSULIN AGI BASAL CON BASAL PCO BOLUS BOLUS INSULIN PCO INSULIN CON PCO 13 trials; 7649 patients (63,302 patient-months) 19 trials; 9312 patients (75,741 patient-months) 9 trials; 2935 patients (21,021 patient-months) Nodes indicate the classes which are evaluated in clinical trials. Lines represent head-to-head comparisons of the two drug classes indicated by the connected nodes. The thickness of the line connecting two nodes is proportional to the number of clinical trials directly evaluating the two connected drug classes. The size of the node is proportional to the number of trials evaluating the treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3. Evaluation of Loop Specific Consistency in Effect Estimates in Triangular and Quadratic Treatment Loops Within Each Network for Drug Classes Given as Monotherapy

Consistency refers to similarities (or differences) between direct and various indirect treatment estimates for the same drug comparison. For example, the estimated effect of metformin monotherapy (MET) compared with sulfonylurea (SU) monotherapy based on head-to-head data within clinical trials with indirect evidence based on a common treatment comparator in different trials.

Evaluation of loop consistency is done by looking at evidence within each closed loop in the network, considering triangular (formed by three treatments all compared with each other) and quadratic (formed by four treatments that each one is compared with two other treatments in the loop) loops.

An inconsistency factor is then generated as the relative difference between estimates of treatment associations obtained by direct evidence and indirect evidence within a triangular loop or quadratic loop. The inconsistency factor is the ratio of two odds ratios (ROR) from direct and indirect evidence, together with the 95% confidence interval for the ratio. The ratio of odds ratios) RORs for all triangular and quadratic loops are presented together within a forest plot (see below) with information presented in order of large to small RORs. An ROR with a 95% confidence interval including 1, indicating that the direct and indirect treatment estimate are the same, indicates there is little evidence of loop inconsistency. The 95% confidence intervals are truncated, indicating that any value for the 95% confidence interval below 1 is not shown. For continuous outcomes, the ratio is the ratio of standard mean differences.

The size of the markers for the corresponding loop is proportional to the contribution of the loop to the evidence in the overall network.

Abbreviations: BASAL = basal insulin; BASAL-BOLUS = basal-bolus insulin; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; PRANDIAL = prandial insulin; ROR = ratio of odds ratios; SGLT-2-i = sodium-glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.1. Cardiovascular Mortality

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

SU-TZD-DPP-4-i 12.350 (1.00,556.17) 0.000

SU-TZD-PCO 11.629 (1.00,1211.75) 0.000

MET-TZD-DPP-4-i 11.218 (1.00,706.03) 0.000

MET-PCO-GLITINIDE 8.421 (1.00,2174.18) 0.000

DPP-4-i-SGLT-2-I-PCO 7.784 (1.00,1089.42) 0.000

MET-SGLT-2-I-PCO 4.201 (1.00,322.59) 0.000

MET-SU-PCO 3.264 (1.00,148.27) 0.000

MET-TZD-PCO 2.936 (1.00,227.81) 0.000

TZD-DPP-4-i-PCO 2.571 (1.00,359.24) 0.000

SU-DPP-4-i-PCO 2.421 (1.00,157.27) 0.000

SU-PCO-AGI 2.048 (1.00,329.24) 0.000

MET-SU-GLITINIDE 2.011 (1.00,153.72) 0.000

MET-DPP-4-i-PCO 1.643 (1.00,36.13) 0.000

SU-PCO-GLITINIDE 1.586 (1.00,515.39) 0.000

MET-DPP-4-i-SGLT-2-I 1.247 (1.00,77.78) 0.000

MET-SU-TZD 1.112 (1.00,17.45) 0.085

MET-SU-DPP-4-i 1.102 (1.00,12.00) 0.000

1 8 55 404 2981 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.2. All-cause Mortality

95%CI Loop-specific 2 Loop ROR (truncated) Heterogeneity( )

MET-GLP-1RA-PCO 15.797 (1.00,1821.81) 0.000 TZD-GLP-1RA-PCO 14.159 (1.00,4616.67) 0.000 SU-TZD-PCO 13.103 (1.00,992.51) 0.000 DPP-4-i-GLP-1RA-PCO 9.411 (1.00,1505.94) 0.000 MET-PCO-GLITINIDE 8.421 (1.00,2174.18) 0.000 SU-PCO-GLITINIDE 8.061 (1.00,1904.36) 0.000 MET-SU-PCO 6.320 (1.00,230.12) 0.000 MET-SU-GLITINIDE 5.414 (1.00,299.09) 0.047 SU-DPP-4-i-PCO 5.075 (1.00,146.59) 0.000 SU-PCO-AGI 3.432 (1.00,403.93) 0.000 SU-TZD-DPP-4-i 3.266 (1.00,24.67) 0.000 MET-TZD-DPP-4-i 2.880 (1.00,24.90) 0.000 DPP-4-i-SGLT-2-i-PCO 2.465 (1.00,62.74) 0.000 TZD-DPP-4-i-GLP-1RA 2.287 (1.00,863.75) 0.000 MET-TZD-GLP-1RA 2.230 (1.00,361.62) 0.000 MET-TZD-PCO 1.966 (1.00,71.26) 0.000 MET-SU-GLP-1RA 1.764 (1.00,94.70) 0.033 MET-SGLT-2-i-PCO 1.490 (1.00,45.28) 0.000 MET-DPP-4-i-GLP-1RA 1.449 (1.00,254.06) 0.000 SU-GLP-1RA-PCO 1.446 (1.00,180.13) 0.000 SU-TZD-GLP-1RA 1.338 (1.00,126.85) 0.000 MET-DPP-4-i-PCO 1.303 (1.00,15.40) 0.000 SU-DPP-4-i-GLP-1RA 1.282 (1.00,125.82) 0.000 TZD-DPP-4-i-PCO 1.265 (1.00,54.72) 0.000 MET-DPP-4-i-SGLT-2-i 1.256 (1.00,38.25) 0.000 MET-SU-TZD 1.154 (1.00,3.18) 0.000 MET-SU-DPP-4-i 1.040 (1.00,3.69) 0.000

1 21 149 1097 8104 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.3. Myocardial Infarction

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

TZD-DPP-4-i-GLP-1RA 46.504 (1.00,17156.09) 0.000

MET-TZD-DPP-4-i 6.862 (1.00,94.96) 0.000

MET-TZD-GLP-1RA 5.004 (1.00,299.35) 0.000

MET-DPP-4-i-GLP-1RA 4.374 (1.00,546.51) 0.000

SU-TZD-GLP-1RA 4.209 (1.00,237.63) 0.000

MET-DPP-4-i-PCO 3.308 (1.00,54.95) 0.000

SU-TZD-DPP-4-i 2.586 (1.00,40.47) 0.000

DPP-4-i-SGLT-2-I-PCO 2.459 (1.00,98.13) 0.019

MET-TZD-PCO 2.200 (1.00,32.61) 0.000

MET-SU-TZD 1.787 (1.00,4.72) 0.000

MET-SU-DPP-4-i 1.772 (1.00,14.30) 0.000

MET-SU-GLP-1RA 1.512 (1.00,50.06) 0.000

SU-DPP-4-i-GLP-1RA 1.440 (1.00,187.84) 0.000

SU-TZD-PCO 1.413 (1.00,106.84) 0.000

SU-DPP-4-i-PCO 1.384 (1.00,117.24) 0.000

TZD-DPP-4-i-PCO 1.322 (1.00,30.13) 0.000

MET-SU-PCO 1.210 (1.00,100.82) 0.000

MET-TZD-CON 1.147 (1.00,111.67) 0.000

1 21 149 2981 22027 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.4. Stroke

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

SU-DPP-4-i-GLP-1RA-PCO 25.044 (1.00,3784.60) 0.000

SU-TZD-GLP-1RA 13.181 (1.00,876.30) 0.000

MET-SU-GLP-1RA 9.345 (1.00,838.81) 0.000

MET-SU-TZD 6.850 (1.00,207.07) 0.000

MET-TZD-GLP-1RA 4.857 (1.00,993.89) 0.000

MET-TZD-DPP-4-i 4.191 (1.00,379.61) 0.000

MET-TZD-PCO 3.528 (1.00,1258.75) 0.000

TZD-GLP-1RA-PCO 2.872 (1.00,510.65) 0.000

MET-GLP-1RA-PCO 2.086 (1.00,839.82) 0.000

MET-DPP-4-i-PCO 1.503 (1.00,194.07) 0.118

SU-TZD-DPP-4-i 1.375 (1.00,31.03) 0.000

MET-SU-DPP-4-i 1.189 (1.00,20.87) 0.000

DPP-4-i-SGLT-2-I-PCO 1.158 (1.00,87.71) 0.000

TZD-DPP-4-i-PCO 1.099 (1.00,71.06) 0.051

1 21 149 1097 8104 *** Loop(s) [TZD-GLP-1RA-BB] are formed only by multi-arm trial(s) - Consistent by definition Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.5. Serious Adverse Events

95%CI Loop-specific 2 Loop ROR (truncated) Heterogeneity( )

TZD-DPP-4-i-GLP-1RA 2.941 (1.00,18.02) 0.000 MET-GLP-1RA-PCO 2.441 (1.00,11.96) 0.275 TZD-GLP-1RA-BASAL-BOLUS 2.398 (1.00,61.64) 0.000 TZD-GLP-1RA-PCO 2.361 (1.00,11.59) 0.132 MET-TZD-PCO 1.942 (1.00,6.13) 0.054 MET-TZD-GLP-1RA 1.922 (1.00,6.54) 0.079 DPP-4-i-SGLT-2-I-PCO 1.767 (1.00,4.80) 0.000 SU-TZD-GLP-1RA 1.715 (1.00,4.58) 0.000 MET-DPP-4-i-SGLT-2-I 1.600 (1.00,5.99) 0.053 MET-DPP-4-i-PCO 1.507 (1.00,3.34) 0.000 DPP-4-i-GLP-1RA-PCO 1.352 (1.00,7.26) 0.000 MET-DPP-4-i-GLP-1RA 1.350 (1.00,7.63) 0.037 TZD-DPP-4-i-PCO 1.338 (1.00,3.58) 0.000 MET-DPP-4-i-AGI 1.329 (1.00,10.28) 0.031 MET-SGLT-2-I-PCO 1.310 (1.00,4.14) 0.000 SU-TZD-DPP-4-i 1.181 (1.00,2.26) 0.006 MET-SU-DPP-4-i 1.180 (1.00,1.97) 0.000 SU-DPP-4-i-GLP-1RA 1.143 (1.00,5.82) 0.000 MET-TZD-DPP-4-i 1.141 (1.00,2.38) 0.033 DPP-4-i-PCO-AGI 1.138 (1.00,21.20) 0.000 MET-PCO-AGI 1.117 (1.00,25.67) 0.251 MET-SU-TZD 1.110 (1.00,1.48) 0.000 MET-SU-GLP-1RA 1.005 (1.00,4.06) 0.146

1 8 21 55 149 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.6. HbA1C

Ratio of 95%CI Loop-specific 2 Loop RORSMD (truncated) Heterogeneity( )

MET-SU-BASAL 3.665 (1.29,10.44) 0.096 MET-BASAL-CON 2.412 (1.00,11.99) 0.279 SU-BASAL-CON-GLITINIDE 2.412 (1.00,7.76) 0.044 MET-PCO-CON-GLITINIDE 2.254 (1.00,9.75) 0.116 MET-CON-AGI-GLITINIDE 1.951 (1.00,5.56) 0.000 SU-TZD-BASAL-CON 1.931 (1.00,4.62) 0.012 SU-TZD-PCO 1.607 (1.00,2.94) 0.063 SU-PCO-GLITINIDE 1.580 (1.00,4.74) 0.133 MET-SU-CON-GLITINIDE 1.566 (1.00,3.73) 0.033 SU-GLP-1RA-PCO 1.540 (1.00,3.54) 0.047 MET-TZD-GLP-1RA 1.470 (1.00,3.21) 0.062 TZD-CON-GLITINIDE 1.414 (1.00,2.47) 0.000 TZD-DPP-4-i-PCO 1.409 (1.00,2.38) 0.061 MET-SU-DPP-4-i 1.384 (1.00,3.62) 0.013 TZD-AGI-GLITINIDE 1.375 (1.00,2.93) 0.000 TZD-GLP-1RA-PCO 1.374 (1.00,3.26) 0.092 SU-DPP-4-i-GLP-1RA 1.372 (1.00,3.09) 0.000 MET-GLP-1RA-PCO 1.370 (1.00,3.52) 0.102 SU-TZD-GLP-1RA 1.367 (1.00,2.02) 0.014 TZD-DPP-4-i-GLP-1RA 1.364 (1.00,2.36) 0.000 MET-TZD-PCO 1.356 (1.00,2.27) 0.094 SU-PCO-AGI 1.355 (1.00,3.13) 0.210 MET-TZD-CON 1.353 (1.00,2.51) 0.045 DPP-4-i-GLP-1RA-PCO 1.322 (1.00,2.15) 0.026 SU-TZD-DPP-4-i 1.304 (1.00,3.26) 0.033 SU-AGI-GLITINIDE 1.282 (1.00,2.91) 0.023 MET-PCO-AGI 1.274 (1.00,4.79) 0.197 TZD-PCO-AGI 1.241 (1.00,2.40) 0.157 MET-TZD-DPP-4-i 1.237 (1.00,1.89) 0.030 MET-TZD-AGI 1.211 (1.00,2.92) 0.053 MET-SGLT-2-I-PCO 1.172 (1.00,2.80) 0.084 SU-DPP-4-i-PCO 1.165 (1.00,4.25) 0.048 DPP-4-i-SGLT-2-I-PCO 1.164 (1.00,2.06) 0.029 TZD-PCO-GLITINIDE 1.147 (1.00,2.64) 0.092 MET-DPP-4-i-SGLT-2-I 1.129 (1.00,1.45) 0.002 MET-DPP-4-i-GLP-1RA 1.128 (1.00,1.46) 0.000 SU-TZD-GLITINIDE 1.123 (1.00,1.72) 0.021 SU-TZD-AGI 1.121 (1.00,1.61) 0.017 MET-SU-PCO 1.117 (1.00,2.53) 0.107 MET-DPP-4-i-PCO 1.112 (1.00,1.73) 0.041 PCO-AGI-GLITINIDE 1.111 (1.00,6.12) 0.287 MET-SU-GLP-1RA 1.076 (1.00,1.73) 0.023 MET-SU-TZD 1.074 (1.00,1.50) 0.036 MET-SU-AGI 1.050 (1.00,2.25) 0.035

1 3 8 21 Ratio of standardized mean differences between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.7. Treatment Failure

95%CI Loop-specific 2 Loop ROR (truncated) Heterogeneity()

MET-TZD-GLP1-RA 2.488 (1.00,13.71) 0.000 MET-TZD-AGI 2.192 (1.00,15.69) 0.104 SU-GLP1-RA-BASAL-BOLUS 2.159 (1.00,326.60) 0.000 SU-GLP1-RA-PCO 2.158 (1.00,6.19) 0.000 SU-TZD-PCO 2.148 (1.00,6.80) 0.161 SU-TZD-AGI 2.096 (1.00,91.06) 0.269 SU-TZD-GLITINIDE 2.017 (1.00,7.80) 0.258 MET-PCO-AGI 1.907 (1.00,27.53) 0.564 DPP-4-i-PCO-AGI 1.891 (1.00,7.25) 0.042 MET-SU-GLP1-RA 1.869 (1.00,9.31) 0.210 MET-TZD-DPP-4-i 1.868 (1.00,5.54) 0.110 SU-DPP-4-i-GLP1-RA 1.811 (1.00,10.38) 0.021 TZD-DPP-4-i-GLP1-RA 1.767 (1.00,39.33) 0.589 SU-DPP-4-i-PCO 1.714 (1.00,4.26) 0.034 MET-SU-AGI 1.673 (1.00,92.77) 0.590 SU-TZD-DPP-4-i 1.644 (1.00,4.83) 0.182 TZD-PCO-GLITINIDE 1.541 (1.00,6.58) 0.139 SU-TZD-GLP1-RA 1.523 (1.00,8.98) 0.207 MET-SU-DPP-4-i 1.513 (1.00,3.58) 0.115 DPP-4-i-GLP1-RA-PCO 1.454 (1.00,8.61) 0.043 SU-PCO-GLITINIDE 1.420 (1.00,4.27) 0.000 MET-DPP-4-i-GLP1-RA 1.415 (1.00,15.62) 0.097 TZD-GLP1-RA-PCO 1.414 (1.00,6.36) 0.020 TZD-DPP-4-i-AGI 1.404 (1.00,24.40) 0.507 MET-SU-TZD 1.352 (1.00,4.34) 0.316 TZD-DPP-4-i-PCO 1.344 (1.00,3.26) 0.062 MET-SU-PCO 1.317 (1.00,7.43) 0.470 SU-TZD-BASAL-BOLUS 1.241 (1.00,136.79) 0.269 MET-SGLT-2-I-PCO 1.222 (1.00,5.71) 0.378 TZD-GLP1-RA-BASAL-BOLUS 1.221 (1.00,238.16) 0.000 MET-DPP-4-i-AGI 1.208 (1.00,11.15) 0.128 MET-DPP-4-i-SGLT-2-I 1.182 (1.00,3.14) 0.052 MET-TZD-PCO 1.182 (1.00,3.75) 0.270 SU-DPP-4-i-AGI 1.150 (1.00,36.52) 0.044 MET-DPP-4-i-PCO 1.142 (1.00,2.56) 0.172 SU-PCO-AGI 1.121 (1.00,32.98) 0.000 DPP-4-i-SGLT-2-I-PCO 1.117 (1.00,2.49) 0.040 MET-GLP1-RA-PCO 1.076 (1.00,12.64) 0.528 TZD-PCO-AGI 1.001 (1.00,4.86) 0.043

1 8 21 149 404 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.8. Hypoglycemia

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

MET-SU-BASAL 25.416 (1.00,3216.04) 0.438 MET-TZD-PCO 3.620 (1.03,12.79) 0.000 SU-TZD-PCO 3.226 (1.00,14.38) 0.076 MET-SU-GLITINIDE 2.555 (1.05,6.20) 0.025 MET-DPP-4-i-SGLT-2-I 2.470 (1.00,23.06) 0.000 TZD-DPP-4-i-PCO 2.468 (1.00,8.69) 0.000 TZD-PCO-GLITINIDE 2.258 (1.00,13.08) 0.000 SU-PCO-CON 2.163 (1.00,15.18) 0.326 MET-SU-DPP-4-i 2.107 (1.15,3.85) 0.000 MET-TZD-GLITINIDE 2.024 (1.00,9.13) 0.000 DPP-4-i-GLP-1RA-PCO 2.004 (1.00,9.42) 0.000 DPP-4-i-SGLT-2-I-PCO 1.994 (1.00,13.22) 0.000 SU-PCO-GLITINIDE 1.979 (1.00,5.25) 0.000 MET-TZD-DPP-4-i 1.850 (1.00,3.76) 0.000 TZD-GLP-1RA-BASAL-BOLUS 1.824 (1.00,9.12) 0.000 MET-GLP-1RA-PCO 1.819 (1.00,6.54) 0.000 SU-GLP-1RA-PCO 1.675 (1.00,19.20) 0.546 SU-DPP-4-i-PCO 1.580 (1.00,4.40) 0.000 MET-TZD-GLP-1RA 1.578 (1.00,3.69) 0.000 MET-PCO-CON 1.570 (1.00,10.83) 0.003 MET-SGLT-2-I-PCO 1.483 (1.00,9.40) 0.000 MET-PCO-GLITINIDE 1.304 (1.00,5.32) 0.000 SU-TZD-GLITINIDE 1.235 (1.00,5.23) 0.042 SU-DPP-4-i-GLP-1RA 1.235 (1.00,4.05) 0.000 TZD-GLP-1RA-PCO 1.227 (1.00,8.04) 0.161 MET-DPP-4-i-PCO 1.181 (1.00,3.11) 0.000 MET-DPP-4-i-GLP-1RA 1.145 (1.00,3.86) 0.000 SU-TZD-GLP-1RA 1.110 (1.00,3.35) 0.073 MET-SU-CON 1.108 (1.00,9.82) 0.156 MET-SU-PCO 1.106 (1.00,4.48) 0.118 SU-TZD-DPP-4-i 1.103 (1.00,2.32) 0.040 TZD-DPP-4-i-GLP-1RA 1.081 (1.00,4.30) 0.000 MET-SU-TZD 1.074 (1.00,2.16) 0.062 MET-SU-GLP-1RA 1.047 (1.00,4.03) 0.179

1 21 149 1097 8104 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3.9. Body Weight

Ratio of 95%CI Loop-specific

2 Loop RORSMD (truncated) Heterogeneity( )

DPP-4-i-GLP1-RA-PCO 1.431 (1.00,3.21) 0.000

MET-SU-TZD 1.320 (1.00,2.62) 0.028

MET-DPP-4-i-SGLT-2-I-GLP1-RA 1.315 (1.00,3.18) 0.000

SU-GLP1-RA-PCO-AGI 1.290 (1.00,2.45) 0.000

MET-TZD-PCO 1.280 (1.00,2.70) 0.042

MET-GLP1-RA-PCO 1.273 (1.00,3.59) 0.050

MET-SU-GLP1-RA 1.240 (1.00,2.34) 0.000

MET-TZD-CON 1.236 (1.00,6.26) 0.142

MET-PCO-AGI 1.217 (1.00,2.18) 0.000

SU-TZD-GLP1-RA-PCO 1.148 (1.00,3.27) 0.035

MET-SGLT-2-I-PCO 1.144 (1.00,1.62) 0.006

SU-TZD-PCO-AGI 1.039 (1.00,1.72) 0.000

DPP-4-i-SGLT-2-I-PCO 1.023 (1.00,1.39) 0.000

MET-SU-AGI 1.004 (1.00,1.89) 0.000

1 3 8 Ratio of standardized mean differences between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4. Evaluation of Loop Specific Consistency in Effect Estimates in Triangular and Quadratic Treatment Loops Within Each Network for Drug Classes Given as Dual Therapy in Addition to Metformin

eFigure 4.1. Cardiovascular Mortality

95%CI Loop-specific

2 Loop IF (truncated) Heterogeneity( )

TZD-DPP-4-i-CON 2.01 (0.00,5.61) 0.000

TZD-DPP-4-i-PCO 1.84 (0.00,5.23) 0.000

DPP-4-i-GLP-1RA-PCO 1.81 (0.00,5.87) 0.000

SU-TZD-DPP-4-i 1.48 (0.00,5.51) 0.000

DPP-4-i-SGLT-2-I-CON 1.26 (0.00,6.11) 0.000

SU-TZD-CON-GLITINIDE 1.14 (0.00,7.19) 0.000

SU-DPP-4-i-SGLT-2-I 1.05 (0.00,5.94) 0.000

SU-SGLT-2-I-CON-GLITINIDE 0.82 (0.00,6.69) 0.000

TZD-GLP-1RA-PCO 0.69 (0.00,6.10) 0.000

SU-DPP-4-i-CON-GLITINIDE 0.61 (0.00,5.44) 0.000

TZD-DPP-4-i-GLP-1RA 0.50 (0.00,5.57) 0.000

SU-TZD-SGLT-2-I-CON 0.32 (0.00,5.79) 0.000

0 2 4 6 8 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.2. All-cause Mortality

95%CI Loop-specific 2 Loop ROR (truncated) Heterogeneity( )

SU-TZD-CON-GLITINIDE 9.648 (1.00,1482.48) 0.000 DPP-4-i-PCO-CON-GLITINIDE 9.024 (1.00,1037.79) 0.000 TZD-PCO-CON-GLITINIDE 8.145 (1.00,1753.22) 0.000 TZD-DPP-4-i-PCO 5.975 (1.00,152.19) 0.000 TZD-DPP-4-i-CON 5.186 (1.00,172.23) 0.000 SU-TZD-SGLT-2-i-CON 3.882 (1.00,261.61) 0.000 TZD-SGLT-2-i-PCO-CON 3.332 (1.00,312.64) 0.000 DPP-4-i-SGLT-2-i-PCO 2.998 (1.00,97.19) 0.000 SU-TZD-PCO 2.516 (1.00,100.06) 0.000 SU-SGLT-2-i-CON-GLITINIDE 2.485 (1.00,264.04) 0.000 SGLT-2-i-PCO-CON-GLITINIDE 2.445 (1.00,632.19) 0.000 TZD-GLP-1RA-PCO 2.375 (1.00,216.77) 0.000 SU-DPP-4-i-PCO 2.244 (1.00,32.40) 0.000 SU-SGLT-2-i-PCO 2.159 (1.00,61.61) 0.000 SU-PCO-GLITINIDE 2.124 (1.00,162.95) 0.000 SU-DPP-4-i-CON-GLITINIDE 1.998 (1.00,113.97) 0.000 DPP-4-i-GLP-1RA-PCO 1.880 (1.00,20.63) 0.000 TZD-DPP-4-i-GLP-1RA 1.767 (1.00,212.21) 0.000 SU-DPP-4-i-SGLT-2-i 1.591 (1.00,19.80) 0.000 SU-GLP-1RA-PCO 1.518 (1.00,26.27) 0.000 SU-TZD-GLP-1RA 1.427 (1.00,143.39) 0.000 DPP-4-i-SGLT-2-i-CON 1.280 (1.00,44.83) 0.000 SU-DPP-4-i-GLP-1RA 1.082 (1.00,6.52) 0.000 SU-TZD-DPP-4-i 1.074 (1.00,26.68) 0.000

1 8 55 404 2981 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.3. Myocardial Infarction

95%CI Loop-specific

2 Loop IF (truncated) Heterogeneity( )

SU-SGLT-2-I-BASAL_BOLUS 2.20 (0.00,5.48) 0.000

TZD-GLP-1RA-BASAL_BOLUS 1.67 (0.00,6.28) 0.000

SU-DPP-4-i-SGLT-2-I 1.34 (0.00,4.96) 0.000

TZD-DPP-4-i-GLP-1RA 1.18 (0.00,5.01) 0.000

SU-GLP-1RA-BASAL_BOLUS 1.01 (0.00,4.17) 0.000

SU-TZD-DPP-4-i 0.87 (0.00,4.57) 0.000

DPP-4-i-GLP-1RA-BASAL_BOLUS 0.78 (0.00,3.21) 0.000

DPP-4-i-SGLT-2-I-BASAL_BOLUS 0.71 (0.00,4.80) 0.000

SU-TZD-GLP-1RA 0.57 (0.00,5.15) 0.000

SU-TZD-BASAL_BOLUS 0.48 (0.00,5.38) 0.000

SU-DPP-4-i-GLP-1RA 0.28 (0.00,2.28) 0.000

TZD-DPP-4-i-BASAL_BOLUS 0.24 (0.00,4.09) 0.000

SU-DPP-4-i-BASAL_BOLUS 0.15 (0.00,2.48) 0.000

TZD-DPP-4-i-PCO 0.07 (0.00,3.62) 0.000

0 2 4 6 7 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.4. Stroke

95%CI Loop-specific

2 Loop IF (truncated) Heterogeneity()

TZD-GLP-1RA-PCO 2.53 (0.00,7.34) 0.000

TZD-DPP-4-i-PCO 2.21 (0.00,5.92) 0.000

SU-DPP-4-i-SGLT-2-I 1.59 (0.00,5.19) 0.000

SU-DPP-4-i-PCO 1.51 (0.00,3.92) 0.000

SU-DPP-4-i-GLP-1RA 1.31 (0.00,3.87) 0.000

DPP-4-i-GLP-1RA-PCO 0.39 (0.00,3.12) 0.000

DPP-4-i-SGLT-2-I-PCO 0.24 (0.00,3.96) 0.000

TZD-DPP-4-i-GLP-1RA 0.23 (0.00,4.40) 0.000

TZD-DPP-4-i-CON 0.12 (0.00,3.28) 0.000

SU-SGLT-2-I-PCO 0.02 (0.00,3.24) 0.000

SU-GLP-1RA-PCO 0.02 (0.00,3.53) 0.000

0 2 4 6 8 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.5. Serious Adverse Effects

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

SU-TZD-GLP-1-RA 2.573 (1.00,9.28) 0.000 TZD-GLP-1-RA-BASAL-BOLUS 2.245 (1.00,9.52) 0.000 GLP-1-RA-BASAL-GLITINIDE 2.067 (1.00,10.41) 0.000 TZD-DPP-4-i-GLP-1-RA 2.047 (1.00,7.85) 0.008 DPP-4-i-GLP-1-RA-BASAL 1.974 (1.00,6.42) 0.000 TZD-DPP-4-i-PCO 1.554 (1.00,4.08) 0.035 SU-DPP-4-i-BASAL 1.464 (1.00,8.88) 0.000 SU-GLP-1-RA-BASAL 1.354 (1.00,7.73) 0.000 SU-TZD-DPP-4-i 1.291 (1.00,2.59) 0.009 SU-TZD-BASAL-BOLUS 1.266 (1.00,3.52) 0.000 SU-DPP-4-i-BASAL-BOLUS 1.256 (1.00,2.32) 0.000 SU-DPP-4-i-SGLT-2-I 1.207 (1.00,2.50) 0.033 TZD-SGLT-2-I-BASAL-BOLUS-PCO 1.167 (1.00,4.68) 0.000 SU-TZD-PCO 1.163 (1.00,6.12) 0.075 DPP-4-i-SGLT-2-I-BASAL-BOLUS 1.155 (1.00,2.56) 0.000 DPP-4-i-GLP-1-RA-BASAL-BOLUS 1.153 (1.00,2.05) 0.000 SU-GLP-1-RA-BASAL-BOLUS 1.122 (1.00,2.22) 0.000 TZD-DPP-4-i-BASAL-BOLUS 1.117 (1.00,2.92) 0.000 SU-SGLT-2-I-BASAL-BOLUS 1.096 (1.00,2.91) 0.106 SU-DPP-4-i-PCO 1.088 (1.00,4.10) 0.000 SU-SGLT-2-I-PCO 1.074 (1.00,7.30) 0.172 DPP-4-i-SGLT-2-I-PCO 1.020 (1.00,3.18) 0.000 SU-DPP-4-i-GLP-1-RA 1.006 (1.00,1.56) 0.000

1 3 8 21 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.6. HbA1C

Ratio of 95%CI Loop-specific 2 Loop RORSMD (truncated) Heterogeneity( )

SU-DPP-4-i-BASAL_BOLUS 4.598 (1.00,58.06) 0.355 DPP-4-i-GLP-1RA-BASAL_BOLUS 3.408 (1.00,55.30) 0.810 SU-GLP-1RA-BASAL_BOLUS 3.142 (1.00,29.15) 0.518 TZD-DPP-4-i-BASAL_BOLUS 2.438 (1.00,76.34) 0.961 DPP-4-i-BASAL_BOLUS-CON 2.146 (1.00,103.32) 0.924 SU-TZD-BASAL_BOLUS 2.114 (1.00,9.26) 0.300 TZD-GLP-1RA-BASAL-PCO 1.972 (1.00,61.20) 0.859 SU-SGLT-2-I-BASAL_BOLUS 1.958 (1.00,13.80) 0.218 DPP-4-i-SGLT-2-I-BASAL_BOLUS-PCO 1.759 (1.00,23.57) 0.359 SGLT-2-I-BASAL_BOLUS-PCO-CON 1.731 (1.00,7.18) 0.114 SU-TZD-PCO 1.632 (1.00,4.46) 0.179 DPP-4-i-PCO-CON 1.552 (1.00,2.73) 0.002 SU-TZD-GLP-1RA 1.518 (1.00,5.63) 0.199 TZD-SGLT-2-I-BASAL_BOLUS-PCO 1.491 (1.00,6.76) 0.213 DPP-4-i-GLP-1RA-BASAL-PCO 1.472 (1.00,3.67) 0.010 TZD-DPP-4-i-GLP-1RA 1.362 (1.00,1.93) 0.000 SU-DPP-4-i-GLP-1RA 1.298 (1.00,2.25) 0.040 SU-BASAL_BOLUS-PCO-CON 1.264 (1.00,2.47) 0.013 SU-BASAL-PCO 1.242 (1.00,2.34) 0.000 TZD-BASAL_BOLUS-PCO-CON 1.203 (1.00,8.29) 0.394 TZD-DPP-4-i-PCO 1.176 (1.00,4.25) 0.079 SU-SGLT-2-I-PCO 1.142 (1.00,1.77) 0.007 TZD-GLP-1RA-BASAL_BOLUS 1.140 (1.00,11.54) 0.629 SU-TZD-DPP-4-i 1.079 (1.00,2.99) 0.091 SU-DPP-4-i-PCO 1.079 (1.00,1.62) 0.009 SU-GLP-1RA-BASAL 1.041 (1.00,4.03) 0.093

1 8 21 55 149 Ratio of standardized mean differences between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.7. Treatment Failure

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

SU-TZD-DPP-4-i 6.209 (1.88,20.56) 0.035

SU-BASAL-BOLUS-AGI 6.192 (1.42,27.02) 0.000

SU-TZD-PCO 4.887 (1.00,49.22) 0.000

SU-SGLT-2-I-BASAL-BOLUS 4.755 (2.00,11.32) 0.000

DPP-4-i-SGLT-2-I-PCO 4.443 (1.29,15.30) 0.041

SU-TZD-GLP-1RA 3.388 (1.00,69.20) 0.000

SU-DPP-4-i-BASAL-BOLUS 2.424 (1.00,6.58) 0.052

TZD-SGLT-2-I-BASAL-BOLUS-PCO 2.413 (1.00,10.36) 0.000

TZD-DPP-4-i-BASAL-BOLUS 1.961 (1.00,4.46) 0.048

SU-GLP-1RA-BASAL-BOLUS 1.757 (1.00,6.92) 0.107

SU-SGLT-2-I-PCO 1.743 (1.00,14.96) 0.000

SU-DPP-4-i-PCO 1.721 (1.00,11.86) 0.043

SU-DPP-4-i-GLP-1RA 1.677 (1.00,4.47) 0.033

TZD-GLP-1RA-BASAL-BOLUS 1.525 (1.00,25.83) 0.000

SU-DPP-4-i-SGLT-2-I 1.452 (1.00,2.70) 0.032

SU-TZD-BASAL-BOLUS 1.423 (1.00,5.49) 0.000

TZD-DPP-4-i-PCO 1.390 (1.00,4.59) 0.047

DPP-4-i-SGLT-2-I-BASAL-BOLUS 1.385 (1.00,2.54) 0.021

DPP-4-i-PCO-CON 1.091 (1.00,51.24) 0.062

DPP-4-i-GLP-1RA-BASAL-BOLUS 1.031 (1.00,2.48) 0.049

TZD-DPP-4-i-GLP-1RA 1.029 (1.00,18.75) 0.000

1 8 21 55 149 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.8. Hypoglycemia

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

SU-SGLT-2-I-CON 12.623 (1.87,85.35) 0.120 SU-TZD-CON 12.455 (2.56,60.56) 0.106 SU-PCO-CON-AGI 9.667 (1.00,118.97) 0.000 TZD-DPP-4-i-PCO 7.883 (1.00,76.10) 0.015 DPP-4-i-CON-AGI 7.798 (1.00,201.03) 0.000 TZD-DPP-4-i-CON 5.802 (1.00,39.48) 0.000 SU-DPP-4-i-CON 5.666 (1.58,20.32) 0.161 DPP-4-i-PCO-AGI 4.036 (1.00,170.11) 0.024 SU-CON-GLITINIDE 3.484 (1.25,9.73) 0.000 SU-TZD-PCO 3.231 (1.00,16.67) 0.000 TZD-GLP-1RA-PCO 3.163 (1.00,71.84) 0.255 SU-GLP-1RA-BASAL 2.987 (1.00,9.78) 0.024 TZD-PCO-CON-AGI 2.640 (1.00,43.13) 0.000 SU-TZD-DPP-4-i 2.551 (1.00,20.39) 0.182 PCO-CON-AGI-GLITINIDE 2.481 (1.00,30.24) 0.000 SU-DPP-4-i-BASAL 2.283 (1.00,14.15) 0.189 TZD-SGLT-2-I-PCO-CON 1.870 (1.00,14.22) 0.000 DPP-4-i-GLP-1RA-PCO 1.825 (1.00,4.57) 0.104 SGLT-2-I-PCO-CON-GLITINIDE 1.821 (1.00,16.90) 0.159 SU-SGLT-2-I-PCO 1.716 (1.00,5.49) 0.057 SU-DPP-4-i-GLP-1RA 1.667 (1.00,4.16) 0.159 TZD-DPP-4-i-GLP-1RA 1.634 (1.00,32.45) 0.000 DPP-4-i-SGLT-2-I-CON 1.552 (1.00,7.16) 0.000 SGLT-2-I-PCO-CON-AGI 1.412 (1.00,18.99) 0.000 DPP-4-i-GLP-1RA-BASAL 1.349 (1.00,2.86) 0.000 SU-GLP-1RA-PCO 1.338 (1.00,5.05) 0.151 SU-DPP-4-i-SGLT-2-I 1.335 (1.00,5.24) 0.161 GLP-1RA-BASAL-BASAL-BOLUS 1.273 (1.00,3.11) 0.000 DPP-4-i-PCO-CON-GLITINIDE 1.269 (1.00,4.12) 0.000 SU-DPP-4-i-PCO 1.187 (1.00,3.72) 0.173 DPP-4-i-SGLT-2-I-PCO 1.121 (1.00,4.18) 0.000 SU-PCO-GLITINIDE 1.103 (1.00,5.22) 0.133 SU-TZD-GLP-1RA 1.065 (1.00,15.14) 0.067 TZD-PCO-CON-GLITINIDE 1.064 (1.00,7.12) 0.000

1 8 21 149 404 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4.9. Body Weight

Ratio of 95%CI Loop-specific

2 Loop SMDROR (truncated) Heterogeneity( )

SU-DPP-4-i-SGLT-2-I-PCO 5.114 (2.62,10.00) 0.034

SU-TZD-SGLT-2-I-PCO 3.020 (1.22,7.45) 0.061

SU-TZD-SGLT-2-I-CON 2.643 (1.00,13.08) 0.070

SU-DPP-4-i-BASAL-PCO 2.379 (1.00,7.28) 0.140

SU-SGLT-2-I-BASAL-PCO 2.264 (1.00,6.96) 0.095

SU-TZD-DPP-4-i-PCO 1.826 (1.00,4.72) 0.096

SU-TZD-BASAL-PCO 1.235 (1.00,4.32) 0.194

TZD-SGLT-2-I-PCO-CON 1.214 (1.00,3.58) 0.008

1 3 8 21 Ratio of standardized mean differences between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 5. Evaluation of Loop Specific Consistency in Effect Estimates in Triangular and Quadratic Treatment Loops Within Each Network of Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea

eFigure 5.1. Cardiovascular Mortality

Loop TZD-GLP-1RA-BASAL-BOLUS is formed only by multi-arm trial(s) - Consistent by definition

eFigure 5.2. All-cause Mortality

Loop ROR 95%CI Loop-specific

(truncated) Heterogeneity (τ2)

TZD-GLP-1RA-PCO 2.888 (1.00,652.94) 0.000

DPP-4-i-SGLT-2-I-GLP-1RA-PCO 1.385 (1.00,777.44) 0.000

GLP-1RA-BASAL-BASAL-BOLUS 1.263 (1.00,91.10) 0.000

1 8 55 404 1097 Ratio of odds ratios between direct and indirect estimates

eFigure 5.3. Myocardial Infarction

Insufficient data observations to generate evidence network.

eFigure 5.4. Stroke

Insufficient data observations to generate evidence network

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 5.5. Serious Adverse Effects

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

GLP-1RA-BASAL-BASAL-BOLUS 2.688 (1.00,8.76) 0.000

TZD-BASAL-PCO 2.100 (1.00,10.20) 0.000

TZD-GLP-1RA-BASAL 1.884 (1.00,7.04) 0.000

DPP-4-i-SGLT-2-I-PCO 1.800 (1.00,5.09) 0.000

DPP-4-i-GLP-1RA-PCO 1.699 (1.00,5.12) 0.000

TZD-GLP-1RA-PCO 1.140 (1.00,3.46) 0.000

GLP-1RA-BASAL-PCO 1.017 (1.00,2.98) 0.000

1 3 8 21 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 5.6. HbA1C

Ratio of Ratio 95%CI Loop-specific

Loop (truncated) Heterogeneity (τ2) SMD SMD

TZD-PCO-AGI 6.900 (3.87,12.30) 0.000

TZD-DPP-4-i-BASAL-CON 2.483 (1.00,6.82) 0.000

TZD-GLP-1RA-BASAL 2.074 (1.18,3.66) 0.000

TZD-BASAL-BASAL_BOLUS 1.747 (1.00,5.27) 0.000

GLP-1RA-BASAL-BASAL_BOLUS 1.724 (1.27,2.35) 0.000

TZD-BASAL-PCO 1.593 (1.00,9.41) 0.357

TZD-GLP-1RA-BASAL_BOLUS 1.452 (1.00,3.92) 0.000

GLP-1RA-BASAL-PCO 1.115 (1.00,1.53) 0.000

DPP-4-i-GLP-1RA-BASAL 1.115 (1.00,2.23) 0.000

TZD-DPP-4-i-GLP-1RA-CON 1.074 (1.00,1.96) 0.000

TZD-GLP-1RA-PCO 1.063 (1.00,1.51) 0.000

1 3 8 21 RatioRatio of standardized of standardized mean mean differences differences between between direct direct and indirectand indirect estimates estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 5.7. Treatment Failure

Loop ROR 95%CI Loop-specific

(truncated) Heterogeneity (τ2)

GLP-1RA-BASAL-BASAL-BOLUS 2.899 (1.00,42.19) 0.176

DPP-4-i-SGLT-2-I-BASAL-B OLUS 2.282 (1.00,15.19) 0.284

TZD-GLP-1RA -BASAL-BOLUS 1.221 (1.00,3.64) 0.000

DPP-4-i-GLP-1RA-BASAL-BOLUS 1.124 (1.00,6.66) 0.290

1 3 8 21 55 Ratio of odds ratios between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 5.8. Hypoglycemia

95%CI Loop-specific

2 Loop ROR (truncated) Heterogeneity( )

DPP-4-i-GLP-1RA-PCO 3.952 (1.78,8.76) 0.000

TZD-DPP-4-i-PCO 2.513 (1.00,9.63) 0.000

TZD-BASAL-PCO 2.156 (1.00,9.17) 0.093

GLP-1RA-BASAL-BASAL_BOLUS 1.962 (1.00,4.95) 0.052

TZD-GLP-1RA-BASAL 1.605 (1.00,5.64) 0.087

TZD-DPP-4-i-GLP-1RA 1.547 (1.00,6.63) 0.000

GLP-1RA-BASAL-PCO 1.427 (1.00,3.32) 0.030

DPP-4-i-SGLT-2-I-PCO 1.133 (1.00,1.99) 0.000

TZD-GLP-1RA-PCO 1.011 (1.00,1.90) 0.000

1 3 8 21 Ratio of odds ratios between direct and indirect estimates

eFigure 5.9. Body Weight

Loop Ratio 95%CI Loop-specific

2 SMD (truncated) Heterogeneity (τ )

TZD-DPP-4-i-GLP-1RA-BASAL 1.076 (1.00,3.04) 0.000

TZD-GLP-1RA -BASAL-BOLUS 1.050 (1.00,1.95) 0.000

1 3 8

Ratio of standardized mean differences between direct and indirect estimates

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 6. Direct (Pairwise) and Network Estimates of Treatment Effects for Drug Classes Given as Monotherapy

Figures showing drug comparisons derived from head-to-head (direct evidence) in black symbols and corresponding network treatment estimates (blue symbols). The total number of trials reporting the direct treatment estimates, together with the number of events is shown. The estimated associations of drug comparisons with cardiovascular mortality are shown as odds ratios together with 95% confident intervals. The first named treatment is the intervention and the second named treatment is the comparator. Abbreviations: AGI = alpha glucosidase inhibitor; BASAL = basal insulin; DPP-4-i = dipeptidyl peptidase-4 inhibitor; GLITINIDE = meglitinide; GLP-1RA = glucagon-like peptide-1 receptor agonist; MET = metformin; PCO = placebo; SGLT-2-i = sodium-glucose cotransporter-2 inhibitor; SU = sulfonylurea; TZD = thiazolidinedione.

eFigure 6.1. Cardiovascular Mortality

Direct and network treatment estimates for cardiovascular mortality - monotherapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

MET v PCO direct 3 2/833 1/420 0.71 0.11 4.54 MET v PCO network 0.72 0.21 2.46 SU v PCO direct 1 1/92 1/92 3.03 0.12 75.95 SU v PCO network 0.91 0.25 3.26 TZD v PCO direct 1 1/1749 0/137 0.24 0.01 5.69 TZD v PCO network 0.63 0.15 2.61 DPP-4-i v PCO direct 3 1/605 1/532 0.99 0.10 9.55 DPP-4-i v PCO network 0.72 0.19 2.71 SGLT-2-I v PCO direct 1 0/392 1/192 0.16 0.01 3.90 SGLT-2-I v PCO network 0.54 0.09 3.30 AGI v PCO direct 2 0/185 2/552 1.08 0.11 10.43 AGI v PCO network 0.66 0.10 4.37 MET v SU direct 3 9/387 11/379 0.76 0.31 1.86 MET v SU network 0.80 0.38 1.69 MET v TZD direct 2 1/132 1/135 1.02 0.10 10.03 MET v TZD network 1.15 0.40 3.31 MET v DPP-4-i direct 4 5/1148 3/823 1.40 0.36 5.45 MET v DPP-4-i network 1.00 0.38 2.65 MET v SGLT-2-I direct 2 1/409 1/422 1.03 0.11 9.94 MET v SGLT-2-I network 1.33 0.25 7.06 MET v GLITINIDE direct 1 1/178 0/179 3.03 0.12 74.81 MET v GLITINIDE network 1.81 0.22 15.04 SU v TZD direct 5 10/1931 8/1926 1.16 0.36 3.76 SU v TZD network 1.44 0.59 3.51 SU v DPP-4-i direct 1 3/212 2/210 1.49 0.25 9.03 SU v DPP-4-i network 1.26 0.44 3.58 SU v AGI direct 1 1/92 1/180 1.97 0.12 31.76 SU v AGI network 1.36 0.21 8.86 SU v GLITINIDE direct 1 1/193 1/383 1.99 0.12 31.96 SU v GLITINIDE network 2.27 0.28 18.45 TZD v DPP-4-i direct 1 0/565 1/186 0.11 0.00 2.83 TZD v DPP-4-i network 0.87 0.25 3.03 DPP-4-i v SGLT-2-I direct 1 0/135 1/270 0.66 0.03 16.33 DPP-4-i v SGLT-2-I network 1.33 0.23 7.67

0.01 0.1 1 10 100 Favors intervention Favors comparator

eFigure 6.2. All-cause Mortality

Downloaded From: https://jamanetwork.com/ on 10/02/2021

Direct and network treatment estimates for all-cause mortality - monotherapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

MET v PCO direct 3 2/833 1/420 0.71 0.11 4.54 MET v PCO network 0.91 0.36 2.30 SU v PCO direct 1 2/92 0/92 5.11 0.24 108.40 SU v PCO network 1.09 0.43 2.74 TZD v PCO direct 1 2/1749 0/137 0.39 0.02 7.92 TZD v PCO network 1.00 0.39 2.57 DPP-4-i v PCO direct 7 4/1431 4/1135 0.59 0.17 2.04 DPP-4-i v PCO network 0.67 0.27 1.65 SGLT-2-I v PCO direct 3 2/1038 2/496 0.46 0.08 2.65 SGLT-2-I v PCO network 0.76 0.20 2.89 GLP-1RA v PCO direct 1 3/204 0/105 3.67 0.19 71.24 GLP-1RA v PCO network 0.83 0.15 4.52 AGI v PCO direct 2 0/185 3/552 1.44 0.16 13.08 AGI v PCO network 0.72 0.14 3.67 GLITINIDE v PCO direct 1 0/172 0/179 0.96 0.02 47.37 GLITINIDE v PCO network 1.00 0.14 7.33 MET v SU direct 4 40/1841 45/1820 0.85 0.50 1.45 MET v SU network 0.84 0.57 1.23 MET v TZD direct 5 35/2129 38/2051 0.91 0.58 1.43 MET v TZD network 0.92 0.61 1.39 MET v DPP-4-i direct 7 9/2168 6/2033 1.43 0.55 3.74 MET v DPP-4-i network 1.37 0.77 2.44 MET v SGLT-2-I direct 2 1/409 1/422 1.03 0.11 9.80 MET v SGLT-2-I network 1.20 0.31 4.62 ME T v GLP -1RA direct 1 1/246 0/248 3.03 0.12 75.70 ME T v GLP -1RA network 1.10 0.22 5.46 MET v GLITINIDE direct 1 1/178 0/179 3.03 0.12 75.75 MET v GLITINIDE network 0.91 0.14 5.85 SU v TZD direct 6 48/3372 46/3382 0.99 0.65 1.50 SU v TZD network 1.08 0.73 1.59 SU v DPP-4-i direct 3 22/823 13/820 1.70 0.84 3.43 SU v DPP-4-i network 1.63 0.95 2.80 S U v GLP -1RA direct 2 1/380 1/765 2.02 0.21 19.47 S U v GLP -1RA network 1.31 0.27 6.35 SU v AGI direct 1 2/92 2/180 1.97 0.34 11.51 SU v AGI network 1.50 0.32 6.99 SU v GLITINIDE direct 1 1/193 3/383 0.66 0.07 6.31 SU v GLITINIDE network 1.08 0.17 6.82 TZD v DPP-4-i direct 3 1/995 2/864 0.53 0.08 3.42 TZD v DPP-4-i network 1.50 0.81 2.77 TZD v GLP-1RA direct 1 0/163 0/248 1.52 0.03 77.00 TZD v GLP-1RA network 1.20 0.24 5.99 DPP-4-i v S GLT-2-I direct 2 0/358 3/717 0.58 0.05 6.43 DPP-4-i v S GLT-2-I network 0.87 0.23 3.33 DPP-4-i v GLP -1RA direct 1 0/163 0/248 1.52 0.03 77.01 DPP-4-i v GLP -1RA network 0.80 0.16 4.04 0.01 0.1 1 10 100 Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 6.3. Serious Adverse Events

Direct and network treatment estimates for serious adverse events - monotherapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

MET v PCO direct 4 28/1164 18/501 0.68 0.29 1.59 MET v PCO network 0.95 0.72 1.26 TZD v PCO direct 5 80/2695 10/426 1.12 0.42 2.98 TZD v PCO network 0.95 0.71 1.27 DPP-4-i v PCO direct 19 169/4349 91/2421 1.05 0.79 1.39 DPP-4-i v PCO network 1.03 0.81 1.31 SGLT-2-I v PCO direct 8 55/2040 24/932 1.01 0.61 1.66 SGLT-2-I v PCO network 1.18 0.79 1.77 MET v SU direct 1 331/1454 308/1441 1.08 0.91 1.29 MET v SU network 1.04 0.89 1.21 MET v TZD direct 5 397/2562 395/2489 1.08 0.80 1.45 MET v TZD network 1.00 0.86 1.17 MET v DPP-4-i direct 8 74/2393 86/2258 0.82 0.57 1.16 MET v DPP-4-i network 0.93 0.75 1.15 MET v SGLT-2-I direct 2 11/409 14/422 0.80 0.36 1.79 MET v SGLT-2-I network 0.80 0.52 1.23 MET v GLP-1RA direct 2 28/514 38/787 0.91 0.50 1.68 MET v GLP-1RA network 1.16 0.84 1.61 MET v AGI direct 1 7/366 6/371 1.19 0.39 3.56 MET v AGI network 1.37 0.59 3.20 SU v TZD direct 7 663/3681 695/3682 0.95 0.84 1.07 SU v TZD network 0.97 0.85 1.10 SU v DPP-4-i direct 4 78/732 80/737 0.96 0.68 1.36 SU v DPP-4-i network 0.89 0.72 1.11 SU v GLP-1RA direct 2 27/380 44/765 1.26 0.77 2.07 SU v GLP-1RA network 1.11 0.81 1.53 SU v GLITINIDE direct 1 12/193 39/383 0.59 0.30 1.14 SU v GLITINIDE network 0.58 0.30 1.14 TZD v DPP-4-i direct 3 38/995 31/864 1.03 0.41 2.59 TZD v DPP-4-i network 0.93 0.74 1.16 TZD v GLP-1RA direct 2 16/299 9/390 2.28 0.97 5.37 TZD v GLP-1RA network 1.15 0.83 1.60 DPP-4-i v SGLT-2-I direct 2 8/358 32/717 0.47 0.11 2.09 DPP-4-i v SGLT-2-I network 0.86 0.57 1.31 DPP-4-i v GLP-1RA direct 1 3/163 4/248 1.14 0.25 5.18 DPP-4-i v GLP-1RA network 1.25 0.87 1.79 DPP-4-i v AGI direct 1 7/440 2/220 1.76 0.36 8.54 DPP-4-i v AGI network 1.48 0.63 3.48

0.01 0.1 1 10 100 Favors intervention Favors comparator

eFigure 6.4. Myocardial Infarction

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Direct and network treatment estimates for myocardial infarction - monotherapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

MET v SU direct 4 30/1841 25/1820 1.18 0.70 1.98 MET v SU network 1.07 0.66 1.72 MET v TZD direct 3 24/1629 28/1636 0.86 0.51 1.46 MET v TZD network 1.01 0.63 1.61 MET v DPP-4-i direct 6 6/1773 1/1916 2.55 0.78 8.34 MET v DPP-4-i network 1.11 0.45 2.74 MET v GLP-1RA direct 1 0/268 1/539 0.67 0.03 16.47 MET v GLP-1RA network 1.25 0.24 6.53 MET v PCO direct 3 2/714 0/320 1.29 0.14 11.55 MET v PCO network 0.87 0.27 2.82 SU v TZD direct 7 43/3594 46/3612 0.94 0.62 1.41 SU v TZD network 0.94 0.63 1.41 SU v DPP-4-i direct 3 3/496 3/496 1.00 0.23 4.36 SU v DPP-4-i network 1.04 0.42 2.59 SU v GLP-1RA direct 1 1/132 2/268 1.02 0.09 11.09 SU v GLP-1RA network 1.17 0.23 6.01 TZD v DPP-4-i direct 2 1/731 2/349 0.41 0.09 1.79 TZD v DPP-4-i network 1.10 0.44 2.76 TZD v GLP-1RA direct 1 1/163 0/248 4.55 0.19 111.04 TZD v GLP-1RA network 1.24 0.24 6.46 TZD v PCO direct 4 2/2106 0/231 0.37 0.04 3.51 TZD v PCO network 0.87 0.26 2.88 DPP-4-i v SGLT-2-i direct 1 1/223 1/447 2.00 0.13 31.89 DPP-4-i v SGLT-2-i network 1.42 0.17 11.98 DPP-4-i v PCO direct 6 4/1264 2/881 0.95 0.34 2.64 DPP-4-i v PCO network 0.79 0.26 2.41 SGLT-2-i v PCO direct 1 1/839 0/421 1.54 0.06 37.65 SGLT-2-i v PCO network 0.55 0.06 5.23 AGI v PCO direct 1 1/372 0/93 0.76 0.03 18.73 AGI v PCO network 0.76 0.03 18.96 1.00 0.85 1.17 0.01 0.1 1 10 100

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 6.5. Stroke

Direct and network treatment estimates for stroke - monotherapy Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

MET v SU direct 2 29/1610 32/1589 0.88 0.54 1.44 MET v SU network 0.93 0.57 1.51 MET v TZD direct 2 20/1565 16/1570 1.25 0.66 2.38 MET v TZD network 0.96 0.56 1.65 MET v DPP-4-i direct 2 1/553 3/560 0.43 0.06 2.92 MET v DPP-4-i network 0.70 0.24 2.02 MET v GLP-1RA direct 1 0/268 1/539 0.67 0.03 16.47 MET v GLP-1RA network 1.35 0.31 5.84 SU v TZD direct 5 28/3321 32/3340 0.88 0.54 1.45 SU v TZD network 1.04 0.64 1.69 SU v DPP-4-i direct 2 2/431 3/432 0.67 0.11 3.97 SU v DPP-4-i network 0.75 0.27 2.10 SU v GLP-1RA direct 1 2/132 0/268 10.10 0.49 208.80 SU v GLP-1RA network 1.45 0.34 6.20 TZD v DPP-4-i direct 1 2/568 1/186 0.66 0.06 7.17 TZD v DPP-4-i network 0.73 0.26 2.05 TZD v GLP-1RA direct 1 1/136 1/142 1.04 0.07 16.52 TZD v GLP-1RA network 1.40 0.33 5.93 TZD v PCO direct 1 3/1749 0/137 0.55 0.03 10.57 TZD v PCO network 0.77 0.20 2.99 DPP-4-i v SGLT-2-i direct 1 1/223 1/447 2.00 0.13 31.89 DPP-4-i v SGLT-2-i network 2.04 0.17 24.49 DPP-4-i v PCO direct 4 4/1023 2/696 0.96 0.28 3.31 DPP-4-i v PCO network 1.06 0.30 3.75 SGLT-2-i v PCO direct 1 1/447 1/229 0.51 0.03 8.17 SGLT-2-i v PCO network 0.52 0.04 6.49 GLP-1RA v PCO direct 1 1/245 0/123 1.51 0.06 36.86 GLP-1RA v PCO network 0.55 0.10 3.09

0.01 0.1 1 10 100

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 6.6. HbA1C

Direct and network treatment estimates for HbA1C- monotherapy

Standardized mean Standardized mean Tri als, Intervention Comparator difference difference Drug comparison n Sample size Sample size and 95% CI and 95% CI

MET v PCO direct 6 1037 499 -0.93 -1.26 -0.60 MET v PCO network -1.01 -1.18 -0.84 SU v PCO direct 3 72 58 -0.98 -1.90 -0.06 SU v PCO network -0.83 -1.02 -0.64 TZD v PCO direct 10 2391 465 -0.46 -0.71 -0.21 TZD v PCO network -0.85 -1.02 -0.68 DPP-4-i v PCO direct 8 1835 1155 -0.56 -0.71 -0.42 DPP-4-i v PCO network -0.68 -0.86 -0.50 SGLT-2-I v PCO direct 2 657 297 -0.72 -1.09 -0.35 SGLT-2-I v PCO network -0.83 -1.15 -0.51 GLP-1RA v PCO direct 2 252 123 -0.68 -0.90 -0.46 GLP-1RA v PCO network -1.05 -1.32 -0.78 AGI v PCO direct 8 391 399 -0.52 -0.92 -0.11 AGI v PCO network -0.66 -0.88 -0.44 GLITINIDE v PCO direct 1 281 74 -0.62 -0.88 -0.36 GLITINIDE v PCO network -1.11 -1.44 -0.78 MET v SU direct 9 485 469 -0.09 -0.28 0.10 MET v SU network -0.18 -0.34 -0.02 MET v TZD direct 12 1158 1069 -0.22 -0.43 0.00 MET v TZD network -0.16 -0.32 -0.00 MET v DPP-4-i direct 6 1793 1404 -0.21 -0.30 -0.12 MET v DPP-4-i network -0.33 -0.52 -0.14 MET v SGLT-2-I direct 2 398 412 -0.05 -0.19 0.09 MET v SGLT-2-I network -0.18 -0.51 0.15 MET v GLP-1RA direct 2 270 270 -0.06 -0.23 0.11 MET v GLP-1RA network -0.04 -0.31 0.23 MET v BASAL direct 2 82 84 -0.72 -1.87 0.43 MET v BASAL network -0.13 -0.50 0.24 MET v AGI direct 1 29 27 -0.17 -0.69 0.35 MET v AGI network 0.35 0.13 0.57 SU v TZD direct 14 961 954 0.03 -0.11 0.17 SU v TZD network 0.02 -0.14 0.18 SU v DPP-4-i direct 1 14 12 -0.42 -1.16 0.33 SU v DPP-4-i network -0.15 -0.36 0.06 SU v GLP-1RA direct 3 385 747 0.22 0.09 0.35 SU v GLP-1RA network 0.22 -0.05 0.49 SU v BASAL direct 2 32 33 0.72 -0.02 1.45 SU v BASAL network 0.04 -0.34 0.42 SU v AGI direct 9 237 231 0.09 -0.10 0.28 SU v AGI network -0.17 -0.39 0.05 SU v GLITINIDE direct 4 180 178 -0.16 -0.44 0.12 SU v GLITINIDE network 0.27 -0.04 0.58 TZD v DPP-4-i direct 2 678 335 -0.25 -0.69 0.20 TZD v DPP-4-i network -0.17 -0.38 0.04 TZD v GLP-1RA direct 1 163 248 -0.10 -0.30 0.10 TZD v GLP-1RA network -0.20 -0.47 0.07 TZD v AGI direct 4 181 187 -0.28 -0.48 -0.07 TZD v AGI network -0.19 -0.41 0.03 TZD v GLITINIDE direct 3 129 129 0.01 -0.27 0.29 TZD v GLITINIDE network 0.25 -0.07 0.57 DPP-4-i v SGLT-2-I direct 1 223 447 0.06 -0.10 0.22 DPP-4-i v SGLT-2-I network 0.14 -0.20 0.48 DPP-4-i v GLP-1RA direct 3 191 286 0.39 0.20 0.57 DPP-4-i v GLP-1RA network 0.37 0.09 0.65 AGI v GLITINIDE direct 1 17 16 0.00 -0.66 0.66 AGI v GLITINIDEnetwork 0.44 0.09 0.79 -2.0 -1.0 0 1.0 2.0

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 6.7. Treatment Failure

Direct and network treatment estimates for treatment failure - monotherapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

MET v PCO direct 5 115/1136 165/609 0.22 0.10 0.51 MET v PCO network 0.26 0.20 0.35 SU v PCO direct 3 8/316 29/241 0.19 0.08 0.41 SU v PCO network 0.31 0.23 0.42 TZD v PCO direct 7 170/1398 124/485 0.35 0.24 0.50 TZD v PCO network 0.32 0.24 0.42 DPP-4-i v PCO direct 19 396/4330 400/2453 0.41 0.34 0.50 DPP-4-i v PCO network 0.40 0.32 0.49 SGLT-2-i v PCO direct 8 34/2040 127/932 0.11 0.07 0.19 SGLT-2-i v PCO network 0.12 0.08 0.18 GLP-1RA v PCO direct 2 39/443 63/216 0.19 0.12 0.31 GLP-1RA v PCO network 0.16 0.10 0.26 AGI v PCO direct 3 26/478 22/202 0.59 0.31 1.13 AGI v PCO network 0.67 0.38 1.18 GLITINIDE v PCO direct 1 29/286 23/75 0.26 0.14 0.48 GLITINIDE v PCO network 0.22 0.13 0.36 MET v SU direct 5 80/1807 78/1790 1.22 0.52 2.87 MET v SU network 0.84 0.61 1.16 MET v TZD direct 7 71/2611 60/2539 1.09 0.71 1.67 MET v TZD network 0.83 0.60 1.15 MET v DPP-4-i direct 8 235/2387 300/2263 0.61 0.42 0.89 MET v DPP-4-- network 0.65 0.50 0.85 MET v SGLT-2-I direct 2 53/409 32/422 1.82 1.14 2.88 MET v SGLT-2-I network 2.13 1.41 3.22 MET v GLP-1RA direct 2 7/514 8/787 1.34 0.48 3.73 MET v GLP-1RA network 1.61 0.97 2.67 MET v AGI direct 2 4/428 15/416 0.21 0.02 2.17 MET v AGI network 0.39 0.10 1.46 SU v TZD direct 10 206/3817 164/3983 1.17 0.73 1.87 SU v TZD network 0.98 0.74 1.30 SU v DPP-4-i direct 6 191/1349 247/1349 0.79 0.54 1.13 SU v DPP-4-i network 0.78 0.58 1.04 SU v GLP-1RA direct 2 34/380 34/765 2.11 1.29 3.46 SU v GLP-1RA network 1.91 1.18 3.09 SU v BASAL direct 1 2/16 0/15 5.35 0.24 121.03 SU v BASAL network 5.34 0.22 130.80 SU v AGI direct 1 0/61 1/61 0.33 0.01 8.24 SU v AGI network 0.46 0.25 0.85 SU v GLITINIDE direct 3 37/329 69/603 1.04 0.67 1.61 SU v GLITINIDE network 1.39 0.86 2.24 TZD v DPP4-i direct 4 29/1282 23/1063 1.15 0.41 3.19 TZD v DPP4-i network 0.79 0.59 1.06 TZD v GLP-1RA direct 2 6/299 3/390 2.67 0.72 9.98 TZD v GLP-1RA network 1.94 1.17 3.22 TZD v AGI direct 1 4/129 7/136 0.59 0.17 2.07 TZD v AGI network 0.47 0.26 0.85 TZD v GLITINIDE direct 2 44/124 26/124 1.97 0.56 6.93 TZD v GLITINIDE network 1.41 0.87 2.30 DPP-4-i v SGLT-2-I direct 2 35/358 23/717 3.45 1.98 6.01 DPP-4-i v SGLT-2-I network 3.26 2.18 4.88 DPP-4-i v GLP-1RA direct 1 3/163 3/248 1.53 0.30 7.68 DPP-4-i v GLP-1RA network 2.45 1.50 4.01 DPP-4-i v AGI direct 1 6/440 8/220 0.37 0.13 1.07 DPP-4-i v AGI network 0.59 0.33 1.05

0.01 0.1 1 10 100 Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 6.8. Hypoglycemia

Direct and network treatment estimates for hypoglycemia - monotherapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

MET v PCO direct 4 37/1053 12/526 2.00 1.02 3.93 MET v PCO network 1.73 1.21 2.47 SU v PCO direct 3 45/129 8/132 7.27 2.53 20.90 SU v PCO network 5.42 3.90 7.54 TZD v PCO direct 3 17/2336 4/307 0.47 0.16 1.33 TZD v PCO network 1.15 0.81 1.64 DPP-4-i v PCO direct 15 67/3632 20/2058 1.29 0.77 2.16 DPP-4-i v PCO netowrk 1.19 0.84 1.69 SGLT-2-I v PCO direct 6 20/1474 7/653 1.09 0.46 2.57 SGLT-2-I v PCO network 1.09 0.53 2.23 GLP-1RA v PCO direct 3 23/866 6/294 1.34 0.31 5.75 GLP-1RA v PCO network 1.84 1.19 2.84 AGI v PCO direct 5 45/417 19/327 1.80 0.73 4.41 AGI v PCO network 1.12 0.66 1.90 GLITINIDE v PCO direct 3 191/977 25/410 3.31 2.12 5.18 GLITINIDE v PCO network 3.73 2.58 5.39 MET v SU direct 3 175/1820 567/1798 0.37 0.14 0.95 MET v SU network 0.32 0.24 0.42 MET v TZD direct 4 208/1965 177/1892 1.18 0.95 1.46 MET v TZD network 1.50 1.13 2.00 MET v DPP-4-i direct 8 69/2388 33/2255 1.84 1.20 2.85 MET v DPP-4-i network 1.45 1.06 1.98 MET v SGLT-2-I direct 2 6/409 2/422 3.22 0.64 16.14 MET v SGLT-2-I network 1.59 0.75 3.37 MET v GLP-1RA direct 3 45/540 80/820 0.91 0.37 2.26 MET v GLP-1RA network 0.94 0.66 1.34 MET v BASAL direct 1 0/36 1/39 0.35 0.01 8.88 MET v BASAL network 0.06 0.01 0.55 MET v AGI direct 1 4/366 2/371 1.34 0.54 3.30 MET v AGI network 1.55 0.89 2.70 MET v GLITINIDE direct 1 18/178 23/179 0.76 0.40 1.47 MET v GLITINIDE network 0.46 0.32 0.67 SU v TZD direct 8 1039/3888 281/4073 4.95 3.77 6.51 SU v TZD network 4.70 3.83 5.77 SU v DPP-4-i direct 6 139/1346 39/1349 4.06 2.79 5.91 SU v DPP-4-i network 4.55 3.44 6.02 SU v GLP-1RA direct 1 60/248 50/497 2.85 1.89 4.31 SU v GLP-1RA network 2.94 2.05 4.21 SU v BASAL direct 1 0/16 8/18 0.04 0.00 0.70 SU v BASAL network 0.18 0.02 1.60 SU v AGI direct 3 47/149 18/235 7.45 4.04 13.71 SU v AGI network 4.85 2.84 8.28 SU v GLITINIDE direct 4 76/500 119/932 1.26 0.92 1.72 SU v GLITINIDE network 1.45 1.07 1.97 TZD v DPP-4-i direct 4 59/1154 27/1018 0.89 0.55 1.45 TZD v DPP-4-i network 0.97 0.71 1.32 TZD v GLP-1RA direct 2 11/299 26/390 0.52 0.25 1.07 TZD v GLP-1RA network 0.63 0.43 0.92 TZD v GLITINIDE direct 2 3/124 9/124 0.32 0.08 1.22 TZD v GLITINIDE network 0.31 0.22 0.44 DPP-4-i v SGLT-2-I direct 2 2/358 7/717 0.60 0.12 2.99 DPP-4-i v SGLT-2-I network 1.10 0.52 2.32 DPP-4-i v GLP-1RA direct 1 5/163 13/248 0.57 0.20 1.64 DPP-4-i v GLP-1RA network 0.65 0.43 0.98

0.01 0.1 1 10 100 Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 6.9. Body Weight

Direct and network treatment estimates for body weight - monotherapy

Standardized mean Standardized mean Tri als, Intervention Comparator difference difference Drug comparison n Sample size Sample size and 95% CI and 95% CI

MET v PCO direct 3 322 182 0.04 -0.32 0.40 MET v PCO network -0.09 -0.23 0.05 TZD v PCO direct 4 102 66 0.09 -0.28 0.45 TZD v PCO network 0.14 -0.06 0.34 DPP-4-i v PCO direct 3 508 339 0.05 -0.09 0.19 DPP-4-i v PCO network 0.03 -0.13 0.19 SGLT-2-I v PCO direct 2 660 297 -0.18 -0.35 -0.01 SGLT-2- v PCO network -0.16 -0.30 -0.02 GLP-1RA v PCO direct 1 55 24 -0.35 -0.82 0.13 GLP-1RA v PCO network -0.37 -0.62 -0.12 AGI v PCO direct 5 247 248 -0.10 -0.28 0.07 AGI v PCO network -0.06 -0.23 0.11 MET v SU direct 5 329 318 -0.21 -0.36 -0.05 MET v SU network -0.19 -0.33 -0.05 MET v TZD direct 3 40 44 0.05 -0.63 0.73 MET v TZD network -0.24 -0.43 -0.05 MET v SGLT-2-I direct 2 408 422 0.03 -0.11 0.16 MET v SGLT-2-I network 0.06 -0.08 0.20 MET v GLP-1RA direct 1 24 22 0.14 -0.42 0.70 MET v GLP-1RA network 0.28 0.05 0.51 MET v AGI direct 1 29 27 -0.13 -0.64 0.38 MET v AGI network -0.03 -0.23 0.17 SU v TZD direct 3 429 431 -0.03 -0.28 0.23 SU v TZD network -0.05 -0.21 0.11 SU v GLP-1RA direct 1 130 265 0.56 0.35 0.78 SU v GLP-1RA network 0.46 0.24 0.68 SU v BASAL direct 2 32 33 0.12 -0.50 0.74 SU v BASAL network 0.11 -0.39 0.61 SU v AGI direct 3 77 76 0.31 0.04 0.57 SU v AGI network 0.16 -0.05 0.37 SU v GLITINIDE direct 5 401 548 0.07 -0.25 0.38 SU v GLITINIDE network 0.27 0.11 0.43 DPP-4-i v SGLT-2-I direct 1 223 447 0.20 0.04 0.36 DPP-4-i v SGLT-2-I network 0.18 -0.01 0.37 DPP-4-i v GLP-1RA direct 1 16 24 0.04 -0.57 0.65 DPP-4-i v GLP-1RA network 0.40 0.13 0.67

-2.00 -1.00 0.00 1.00 2.00 Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 7. Direct (Pairwise) and Network Estimates of Treatment Effects for Drug Classes Given as Dual Therapy in Addition to Metformin

eFigure 7.1. Cardiovascular Mortality

Direct and network treatment estimates for cardiovascular mortality – dual therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

TZD v PCO direct 3 3/624 0/253 1.70 0.26 11.13 TZD v PCO network 1.31 0.30 5.69 DPP-4-i v PCO direct 5 1/1655 2/683 0.35 0.07 1.64 DPP-4-i v PCO network 0.51 0.13 1.96 GLP-1RA v PCO direct 1 1/606 0/177 0.88 0.04 21.57 GLP-1RA v PCO network 0.33 0.05 2.25 SU v TZD direct 1 0/185 1/204 0.37 0.01 8.98 SU v TZD network 0.48 0.11 2.09 SU v DPP-4-i direct 6 10/4335 10/5219 1.32 0.55 3.15 SU v DPP-4-i network 1.24 0.55 2.79 SU v SGLT-2-I direct 1 1/408 1/406 1.00 0.06 15.97 SU v SGLT-2-I network 1.16 0.19 7.09 SU v GLITINIDE direct 1 0/187 1/374 0.66 0.03 16.35 SU v GLITINIDE network 0.97 0.09 10.38 TZD v DPP-4-i direct 2 1/552 1/423 0.82 0.08 7.87 TZD v DPP-4-i network 2.59 0.68 9.87 TZD v GLP-1RA direct 1 1/165 1/160 0.97 0.02 49.34 TZD v GLP-1RA network 4.00 0.52 30.63 DPP-4-i v SGLT-2-I direct 1 1/128 1/277 2.16 0.04 108.95 DPP-4-i v SGLT-2-I network 0.94 0.16 5.57 DPP-4-i v GLP-1RA direct 3 2/700 1/1205 2.24 0.35 14.24 DPP-4-i v GLP-1RA network 1.54 0.28 8.49

0.01 0.1 1 10 100

Favors intervention Favors comparator

eFigure 7.2. All-cause Mortality

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Direct and network treatment estimates for all-cause mortality – dual therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI SU v PCO direct 1 3/307 1/101 0.99 0.10 9.57 SU v PCO network 0.89 0.36 2.21 TZD v PCO direct 3 3/627 0/253 1.70 0.26 11.12 TZD v PCO network 1.15 0.33 4.02 DPP-4-i v PCO direct 7 2/2323 3/967 0.36 0.10 1.29 DPP-4-i v PCO network 0.67 0.27 1.67 GLP-1RA v PCO direct 4 7/1384 4/588 0.74 0.22 2.44 GLP-1RA v PCO network 0.77 0.30 1.98 GLITINIDE v PCO direct 1 2/315 0/152 2.43 0.12 50.98 GLITINIDE v PCO network 1.07 0.20 5.70 SU v TZD direct 2 2/498 1/521 0.70 0.05 9.16 SU v TZD network 0.78 0.24 2.54 SU v DPP-4-i direct 10 27/6467 24/7374 1.29 0.74 2.24 SU v DPP-4-i network 1.33 0.80 2.21 SU v SGLT-2-I direct 3 10/1670 8/2139 1.42 0.55 3.67 SU v SGLT-2-I network 1.21 0.54 2.71 SU v GLP-1RA direct 2 8/821 8/817 1.00 0.37 2.66 SU v GLP-1RA network 1.15 0.52 2.54 SU v GLITINIDE direct 2 1/396 2/593 0.86 0.11 7.02 SU v GLITINIDE network 0.83 0.17 4.01 TZD v DPP-4-i direct 2 1/552 1/423 0.82 0.08 7.87 TZD v DPP-4-i network 1.71 0.52 5.61 TZD v GLP-1RA direct 1 0/165 0/160 0.97 0.02 49.34 TZD v GLP-1RA network 1.48 0.40 5.53 DPP-4-i v SGLT-2-I direct 2 0/494 2/1012 0.69 0.07 6.76 DPP-4-i v SGLT-2-I network 0.91 0.37 2.22 DPP-4-i v GLP-1RA direct 4 3/1002 5/1507 0.88 0.22 3.55 DPP-4-i v GLP-1RA network 0.87 0.38 2.00 GLP-1RA v BASAL direct 1 1/717 2/332 0.23 0.02 2.60 GLP-1RA v BASAL network 0.22 0.02 2.48

0.01 0.1 1 10 100

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 7.3. Serious Adverse Events

Direct and network treatment estimates for serious adverse events – dual therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

SU v PCO direct 2 60/551 24/222 0.97 0.55 1.69 SU v PCO network 1.08 0.85 1.37 TZD v PCO direct 5 27/889 9/473 1.35 0.62 2.90 TZD v PCO network 1.32 0.93 1.87 DPP-4-i v PCO direct 15 162/4736 73/2343 1.01 0.75 1.35 DPP-4-i v PCO network 1.01 0.80 1.28 SGLT-2-I v PCO direct 5 64/1777 32/674 0.99 0.62 1.56 SGLT-2-I v PCO network 0.99 0.74 1.32 GLP-1RA v PCO direct 7 458/2842 180/992 1.20 0.89 1.62 GLP-1RA v PCO network 1.23 0.95 1.59 AGI v PCO direct 2 13/118 6/118 2.28 0.83 6.27 AGI v PCO network 2.28 0.81 6.41 SU v TZD direct 4 42/718 48/735 0.88 0.52 1.48 SU v TZD network 0.81 0.61 1.08 SU v DPP-4-i direct 10 765/6087 805/6997 1.08 0.97 1.21 SU v DPP-4-i network 1.07 0.94 1.22 SU v SGLT-12-I direct 3 174/1670 204/2139 1.13 0.65 1.96 SU v SGLT-12-I network 1.09 0.87 1.37 SU v GLP-1RA direct 3 128/1059 194/1538 0.88 0.69 1.13 SU v GLP-1RA network 0.88 0.71 1.10 SU v BASAL direct 1 3/36 4/38 0.77 0.16 3.73 SU v BASAL network 0.88 0.52 1.49 SU v GLITINIDE direct 1 27/209 25/219 1.15 0.64 2.06 SU v GLITINIDE network 1.15 0.61 2.16 TZD v DPP-4-i direct 3 48/833 28/718 1.54 0.75 3.15 TZD v DPP-4-i network 1.31 0.98 1.76 TZD v GLP-1RA direct 1 10/165 4/160 2.52 0.77 8.19 TZD v GLP-1RA network 1.08 0.77 1.52 DPP-4-i v SGLT-2-I direct 3 22/670 35/1191 1.28 0.59 2.74 DPP-4-i v SGLT-2-I network 1.02 0.80 1.31 DPP-4-i v GLP-1RA direct 5 59/1163 92/1665 0.81 0.58 1.15 DPP-4-i v GLP-1RA network 0.82 0.66 1.02 DPP-4-i v BASAL direct 1 8/265 15/250 0.49 0.20 1.17 DPP-4-i v BASAL network 0.83 0.49 1.41 GLP-1RA v BASAL direct 1 28/717 11/332 1.19 0.58 2.41 GLP-1RA v BASAL network 1.01 0.60 1.70

0.01 0.1 1 10 100 Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 7.4. Myocardial Infarction

Direct and network treatment estimates for myocardial infarction – dual therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

SU v TZD direct 1 0/313 1/317 0.34 0.01 8.21 SU v TZD network 0.63 0.17 2.34 SU v DPP-4-i direct 7 21/3996 14/4880 1.70 0.89 3.24 SU v DPP-4-i network 1.70 0.92 3.15 SU v SGLT-2-i direct 2 9/1188 2/1171 4.44 0.96 20.53 SU v SGLT-2-i network 2.36 0.68 8.22 SU v GLP-1RA direct 3 4/1059 7/1538 0.81 0.23 2.81 SU v GLP-1RA network 1.13 0.45 2.83 SU v PCO direct 2 2/551 1/223 0.69 0.10 4.90 SU v PCO network 1.00 0.36 2.77 TZD v DPP-4-i direct 3 4/833 1/718 2.28 0.44 11.78 TZD v DPP-4-i network 2.69 0.78 9.32 TZD v GLP-1RA direct 1 2/165 0/160 4.85 0.23 100.14 TZD v GLP-1RA network 1.79 0.43 7.46 TZD v PCO direct 1 1/387 0/129 1.01 0.04 24.58 TZD v PCO network 1.58 0.37 6.80 DPP-4-i v SGLT-2-i direct 1 0/366 1/735 0.67 0.03 16.45 DPP-4-i v SGLT-2-i network 1.39 0.37 5.20 DPP-4-i v GLP-1RA direct 4 1/1002 5/1507 0.48 0.11 2.15 DPP-4-i v GLP-1RA network 0.66 0.26 1.68 DPP-4-i v BASAL direct 1 1/264 0/237 2.69 0.11 65.89 DPP-4-i v BASAL network 2.70 0.11 66.49 DPP-4-i v PCO direct 6 3/2125 4/949 0.38 0.11 1.24 DPP-4-i v PCO network 0.59 0.22 1.57 SGLT-2-i v PCO direct 2 3/1144 0/320 1.20 0.14 10.52 SGLT-2-i v PCO network 0.42 0.10 1.75 GLP-1RA v PCO direct 4 8/1787 1/550 1.29 0.33 5.08 GLP-1RA v PCO network 0.89 0.31 2.56

0.01 0.1 1 10 100 Favors intervention Favors comparator

eFigure 7.5. Stroke

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Direct and network treatment estimates for stroke– dual therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

SU v DPP-4-i direct 8 26/5379 8/6269 3.22 1.55 6.70 SU v DPP-4-i network 2.12 1.05 4.28 SU v SGLT-2-i direct 2 1/118 6/1171 0.23 0.04 1.33 SU v SGLT-2-i network 0.36 0.10 1.31 SU v GLP-1RA direct 3 1/1059 4/1538 0.53 0.10 2.66 SU v GLP-1RA network 1.14 0.34 3.83 SU v PCO direct 2 1/551 1/223 0.33 0.02 5.18 SU v PCO network 0.71 0.26 1.96 TZD v DPP-4-i direct 3 5/833 2/718 2.59 0.51 13.18 TZD v DPP-4-i network 1.72 0.50 5.94 TZD v GLP-1RA direct 1 1/165 0/160 2.91 0.12 71.03 TZD v GLP-1RA network 0.92 0.18 4.72 TZD v PCO direct 1 0/387 1/129 0.11 0.00 2.61 TZD v PCO network 0.58 0.13 2.54 DPP-4-i v SGLT-2-i direct 1 0/366 2/735 0.40 0.02 8.40 DPP-4-i v SGLT-2-i network 0.17 0.05 0.61 DPP-4-i v GLP-1RA direct 3 1/783 2/1068 0.87 0.16 4.60 DPP-4-i v GLP-1RA network 0.54 0.16 1.81 DPP-4-i v BASAL direct 1 0/264 1/237 0.30 0.01 7.38 DPP-4-i v BASAL network 0.30 0.01 8.13 DPP-4-i v PCO direct 8 4/2376 6/1401 0.48 0.17 1.32 DPP-4-i v PCO network 0.34 0.13 0.87 SGLT-2-i v PCO direct 3 4/1235 0/411 1.59 0.27 9.28 SGLT-2-i v PCO network 1.97 0.52 7.43 GLP-1RA v PCO direct 3 3/1633 1/400 0.52 0.09 2.88 GLP-1RA v PCO network 0.63 0.18 2.22

0.01 0.1 1 10 100 Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 7.6. HbA1C

Direct and network treatment estimates for HbA1C- dual therapy

Standardized mean Standardized mean Tri als, Intervention Comparator difference difference Drug comparison n Sample size Sample size and 95% CI and 95% CI SU v PCO direct 1 302 100 -0.15 -0.38 0.08 SU v PCO network -1.24 -1.72 -0.76 TZD v PCO direct 3 137 130 -0.97 -1.56 -0.38 TZD v PCO network -1.21 -1.72 -0.70 DPP-4-i v PCO direct 5 1195 765 -1.62 -2.52 -0.72 DPP-4-i v PCO network -1.26 -1.71 -0.81 SGLT-2-I v PCO direct 3 942 397 -1.12 -2.36 0.13 SGLT-2-I v PCO network -1.07 -1.68 -0.46 GLP-1RA v PCO direct 3 700 342 -0.98 -1.95 -0.02 GLP-1RA v PCO network -1.14 -1.70 -0.58 AGI v PCO direct 2 114 118 -0.38 -0.64 -0.12 AGI v PCO network -0.67 -1.40 0.06 SU v TZD direct 10 614 622 0.21 -0.18 0.59 SU v TZD network 0.03 -0.35 0.41 SU v DPP-4-i direct 7 1776 1729 -0.06 -0.17 0.06 SU v DPP-4-i network 0.02 -0.39 0.43 SU v SGLT-2-I direct 1 780 765 0.13 0.03 0.23 SU v SGLT-2-I network 0.17 -0.48 0.82 SU v GLP-1RA direct 4 895 898 -0.18 -0.51 0.15 SU v GLP-1RA network -0.10 -0.61 0.41 SU v BASAL direct 1 77 78 -0.08 -0.66 0.50 SU v BASAL network -0.07 -0.88 0.74 SU v GLITINIDE direct 2 312 327 0.85 -0.96 2.65 SU v GLITINIDE network 0.83 -0.14 1.80 TZD v DPP-4-i direct 1 165 166 -0.23 -0.45 -0.01 TZD v DPP-4-i network -0.05 -0.54 0.44 TZD v GLP-1RA direct 1 165 160 0.15 -0.06 0.37 TZD v GLP-1RA network 0.08 -0.50 0.66 DPP-4-i v GLP-1RA direct 2 466 457 0.22 -0.08 0.52 DPP-4-i v GLP-1RA network -0.13 -0.69 0.43 DPP-4-i v AGI direct 1 41 40 -0.47 -0.90 -0.03 DPP-4-i v AGI network -0.60 -1.35 0.15 GLP-1RA v BASAL direct 1 17 17 0.06 -0.58 0.71 GLP-1RA v BASAL network 0.04 -0.80 0.88

-2.0 -1.0 0 1.0 2.0

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 7.7. Treatment Failure

Direct and network treatment estimates for treatment failure – dual therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

SU v PCO direct 1 9/244 29/122 0.12 0.06 0.27 SU v PCO network 0.28 0.21 0.38 TZD v PCO direct 5 56/890 57/473 0.32 0.21 0.49 TZD v PCO network 0.37 0.24 0.58 DPP-4-i v PCO direct 12 302/3889 294/1816 0.35 0.27 0.45 DPP-4-i v PCO network 0.38 0.30 0.48 SGLT-2-i v PCO direct 5 122/1777 101/674 0.32 0.24 0.43 SGLT-2-i v PCO network 0.19 0.13 0.27 GLP-1RA v PCO direct 6 82/2774 85/835 0.22 0.15 0.33 GLP-1RA v PCO network 0.24 0.17 0.34 GLITINIDE v PCO direct 1 8/315 6/152 0.63 0.22 1.86 GLITINIDE v PCO network 0.33 0.17 0.65 SU v TZD direct 4 4/588 21/617 0.27 0.10 0.74 SU v TZD network 0.76 0.46 1.25 SU v DPP-4-i direct 8 734/5811 1055/6722 0.79 0.65 0.97 SU v DPP-4-i network 0.75 0.59 0.95 SU v SGLT-2-I direct 2 236/1262 169/1733 1.83 1.48 2.28 SU v SGLT-2-I network 1.47 1.05 2.05 SU v GLITINIDE direct 2 20/396 28/593 0.94 0.10 8.84 SU v GLITINIDE network 0.86 0.45 1.65 TZD v DPP-4-i direct 2 44/553 35/423 0.82 0.51 1.32 TZD v DPP-4-i network 0.99 0.63 1.55 TZD v GLP-1RA direct 1 1/165 1/160 0.97 0.06 15.64 TZD v GLP-1RA 1.54 0.88 2.70 DPP-4-i v SGLT-2-I direct 2 66/494 89/1012 1.60 1.13 2.26 DPP-4-i v SGLT-2-I network 1.95 1.39 2.73 DPP-4-i v GLP-1RA direct 4 16/885 17/1593 1.87 0.94 3.74 DPP-4-i v GLP-1RA network 1.57 1.05 2.34 DPP-4-i v AGI direct 1 0/45 3/45 0.13 0.01 2.59 DPP-4-i v AGI network 0.11 0.02 0.72

0.01 0.1 1 10 100

Favors intervention Favors comparator

eFigure 7.8. Hypoglycemia

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Direct and network treatment estimates for hypoglycemia – dual therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

SU v PCO direct 2 96/551 8/225 4.85 2.40 9.81 SU v PCO network 6.96 4.76 10.2 TZD v PCO direct 2 9/315 2/202 2.17 0.55 8.64 TZD v PCO network 1.00 0.56 1.79 DPP-4-i v PCO direct 13 71/4276 37/2102 0.73 0.44 1.21 DPP-4-i v PCO network 0.87 0.60 1.25 SGLT-2-I v PCO direct 3 30/930 14/435 0.79 0.38 1.61 SGLT-2-I v PCO network 0.82 0.50 1.33 GLP-1RA v PCO direct 7 127/2842 33/995 1.50 0.82 2.75 GLP-1RA v PCO network 1.29 0.86 1.94 AGI v PCO direct 2 1/161 2/159 0.50 0.05 5.42 AGI v PCO network 0.94 0.31 2.81 GLITINIDE v PCO direct 1 43/315 7/152 2.96 1.37 6.43 GLITINIDE v PCO network 3.83 2.12 6.91 SU v TZD direct 6 212/919 50/947 6.09 2.63 14.1 SU v TZD network 6.97 4.24 11.5 SU v DPP-4-i direct 11 1608/6516 267/7422 6.46 4.82 8.67 SU v DPP-4-i network 8.04 6.28 10.3 SU v SGLT-2-i direct 3 524/1670 97/2139 7.24 5.24 10.0 SU v SGLT-2-I network 8.51 5.64 12.9 SU v GLP-1RA direct 3 434/1059 225/1538 3.37 1.59 7.14 SU v GLP-1RA network 5.39 3.72 7.79 SU v BASAL direct 1 19/34 10/38 3.55 1.32 9.54 SU v BASAL network 1.78 1.02 3.09 SU v GLITINIDE direct 2 69/335 50/349 1.57 0.69 3.56 SU v GLITINIDE network 1.82 1.07 3.09 TZD v DPP-4-i direct 2 2/446 6/461 0.37 0.07 2.03 TZD v DPP-4-i network 1.15 0.68 1.96 TZD v GLP-1RA direct 1 1/165 2/160 0.48 0.04 5.38 TZD v GLP-1RA network 0.77 0.43 1.40 DPP-4-i v SGLT-2-I direct 3 6/338 10/484 0.96 0.31 2.94 DPP-4-i v SGLT-2-I network 1.06 0.68 1.65 DPP-4-i v GLP-1RA direct 5 33/1163 60/1665 0.87 0.55 1.36 DPP-4-i v GLP-1RA network 0.67 0.46 0.97 DPP-4-i v BASAL direct 1 35/264 108/237 0.18 0.12 0.28 DPP-4-i v BASAL network 0.22 0.13 0.38 DPP-4-i v AGI direct 1 2/41 0/40 5.13 0.24 110.3 DPP-4-i v AGI network 0.92 0.31 2.72 GLP-1RA v BASAL direct 2 42/753 64/365 0.28 0.19 0.43 GLP-1RA v BASAL network 0.33 0.20 0.56

0.01 0.1 1 10 100 Favors intervention Favors comparator

eFigure 7.9. Body Weight

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Direct and network treatment estimates for body weight - dual therapy

Standardized mean Standardized mean Tri als, Intervention Comparator difference difference Drug comparison n Sample size Sample size and 95% CI and 95% CI

TZD v PCO direct 1 129 122 0.30 -0.16 0.75 TZD v PCO network 0.37 -0.08 0.82 DPP-4-i v PCO direct 3 445 443 -0.21 -0.54 0.13 DPP-4-i v PCO network 0.05 -0.37 0.47 SGLT-2-I v PCO direct 3 949 399 -0.09 -0.26 0.08 SGLT-2-I v PCO network -0.33 -0.74 0.08 GLP-1RA v PCO direct 2 403 242 -0.37 -1.13 0.40 GLP-1RA v PCO network -0.42 -0.89 0.05 SU v TZD direct 4 289 300 0.22 -0.21 0.65 SU v TZD network 0.26 -0.13 0.65 SU v DPP-4-i direct 2 92 105 0.16 -0.22 0.54 SU v DPP-4-i network 0.58 0.11 1.05 SU v SGLT-2-I direct 1 780 765 1.69 1.58 1.81 SU v SGLT-2-I network 1.05 0.57 1.53 SU v GLP-1RA direct 2 106 111 1.14 0.40 1.87 SU v GLP-1RA network 1.05 0.57 1.53 DPP-4-i v AGI direct 1 41 40 0.04 -0.39 0.47 DPP-4-i v AGI network 0.04 -0.85 0.93 GLP-1RA v BASAL direct 1 17 17 0.06 -0.58 0.71 GLP-1RA v BASAL network 0.06 -0.90 1.02

-2.0 -1.0 0 1.0 2.0

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 8. Direct (Pairwise) and Network Estimates of Treatment Effects for Drug Classes Given as Triple Therapy in Addition to Metformin and Sulfonylurea

eFigure 8.1. Cardiovascular Mortality

Direct and network treatment estimates for cardiovascular mortality – triple therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

TZD v PCO direct 1 1/277 1/115 0.42 0.03 6.20 TZD v PCO network 0.41 0.03 6.11 SGLT-2-I v PCO direct 1 1/444 0/225 1.53 0.06 37.55 SGLT-2-I v PCO network 1.53 0.06 38.30 GLP-1RA v PCO direct 1 1/277 1/115 0.42 0.03 6.33 GLP-1RA v PCO network 0.42 0.03 6.33 TZD v GLP-1RA direct 1 1/277 1/271 0.98 0.02 49.91 TZD v GLP-1RA network 0.98 0.02 48.75 DPP-4-i v SGLT-2-I direct 1 0/378 2/378 0.20 0.01 4.06 DPP-4-i v SGLT-2-I network 0.20 0.01 4.08 GLP-1RA v BASAL direct 1 1/545 1/262 0.48 0.03 7.69 GLP-1RA v BASAL network 0.48 0.03 7.69

0.01 0.1 1 10 100

Favors intervention Favors comparator

eFigure 8.2. All-cause Mortality

Downloaded From: https://jamanetwork.com/ on 10/02/2021

Direct and network treatment estimates for all-cause mortality – triple therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

TZD v PCO direct 2 3/458 2/299 0.74 0.14 3.83 TZD v PCO network 0.73 0.14 3.75 SGLT-2-I v PCO direct 1 1/444 0/225 1.53 0.06 37.55 SGLT-2-I v PCO network 1.58 0.10 24.93 GLP-1RA v PCO direct 1 0/271 1/115 0.14 0.01 3.39 GLP-1RA v PCO network 0.50 0.02 13.51 TZD v GLP-1RA direct 1 3/277 0/271 6.92 0.36 134.01 TZD v GLP-1RA nework 6.53 0.45 94.63 DPP4-i v SGLT-2-I direct 1 0/378 2/378 0.20 0.01 4.06 DPP-4-i v SGLT-2-I network 0.21 0.01 3.04 DPP-4-i v GLP-1RA direct 1 1/326 0/324 2.99 0.12 74.10 DPP-4-i v GLP-1RA network 2.89 0.18 46.00 GLP-1RA v BASAL direct 1 1/545 2/262 0.24 0.02 2.76 GLP-1RA v BASAL network 0.22 0.03 1.62

0.01 0.1 1 10 100

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 8.3. Serious Adverse Events

Direct and network treatment estimates for serious adverse events – triple therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

TZD v PCO direct 2 28/458 15/299 0.83 0.21 3.29 TZD v PCO network 1.07 0.62 1.85 DPP-4-i v PCO direct 2 28/921 17/391 0.70 0.37 1.36 DPP-4-i v PCO network 0.67 0.43 1.04 SGLT-2-I v PCO direct 3 28/866 33/490 0.45 0.26 0.77 SGLT-2-I v PCO network 0.57 0.36 0.90 GLP-1RA v PCO direct 3 53/987 30/476 0.84 0.52 1.33 GLP-1RA v PCO network 0.69 0.46 1.03 BASAL v PCO direct 1 16/232 8/114 0.98 0.41 2.36 BASAL v PCO network 0.78 0.48 1.27 TZD v GLP-1RA direct 1 25/277 17/271 1.48 0.78 2.81 TZD v GLP-1RA network 1.61 0.83 3.12 TZD v BASAL direct 1 11/112 5/104 2.16 0.72 6.43 TZD v BASAL network 1.37 0.78 2.42 DPP-4-i v SGLT-2-I direct 1 21/378 24/378 0.87 0.47 1.59 DPP-4-i v SGLT-2-I network 1.17 0.72 1.90 GLP-1RA v BASAL direct 3 77/1058 59/762 0.77 0.53 1.11 GLP-1RA v BASAL network 0.88 0.63 1.23

0.01 0.1 1 10 100

Favors intervention Favors comparator

eFigure 8.4. Myocardial Infarction

Insufficient data observations to generate evidence network.

eFigure 8.5. Stroke

Insufficient data observations to generate evidence network.

eFigure 8.6. HbA1C

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Direct and network treatment estimates for HbA1C- triple therapy

Standardized mean Standardized mean Tri als, Intervention Comparator difference difference Drug comparison n Sample size Sample size and 95% CI and 95% CI

TZD v PCO direct 2 293 140 -0.55 -1.55 0.46 TZD v PCO network -0.86 -1.47 -0.25 SGLT-2-I v PCO direct 1 441 225 -0.75 -0.91 -0.58 SGLT-2-I v PCO network -0.75 -1.82 0.32 GLP-1RA v PCO direct 2 495 229 -0.73 -0.90 -0.56 GLP-1RA v PCO network -0.79 -1.44 -0.14 BASAL v PCO direct 1 232 114 -0.52 -0.75 -0.30 BASAL v PCO network -0.86 -1.54 -0.18 AGI v PCO direct 1 41 40 -0.46 -0.89 -0.03 AGI v PCO network 0.55 -0.29 1.39 TZD v GLP-1RA direct 1 268 265 -0.18 -0.35 -0.01 TZD v GLP-1RA network -0.07 -0.70 0.56 TZD v BASAL direct 2 29 28 0.45 -0.07 0.97 TZD v BASAL network 0.00 -0.60 0.60 TZD v AGI direct 1 138 136 -2.36 -2.66 -2.05 TZD v AGI network -1.42 -2.26 -0.58 DPP-4-i v GLP-1RA direct 1 269 253 0.22 0.05 0.39 DPP-4-i v GLP-1RA network 0.15 -0.62 0.92 DPP-4-i v BASAL direct 1 18 17 0.00 -0.64 0.64 DPP-4-i v BASAL network 0.23 -0.53 0.99 GLP-1RA v BASAL direct 2 775 494 0.11 -0.01 0.23 GLP-1RA v BASAL network 0.07 -0.49 0.63

-2.0 -1.0 0 1.0 2.0

Favors intervention Favors comparator

eFigure 8.7. Treatment Failure

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Direct and network treatment estimates for treatment failure – triple therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

TZD v PCO direct 2 70/458 110/299 0.23 0.15 0.33 TZD v PCO network 0.21 0.14 0.32 DPP-4-i v PCO direct 2 51/921 41/391 0.60 0.21 1.70 DPP-4-i v PCO network 0.47 0.32 0.69 SGLT-2-I v PCO direct 2 7/550 36/334 0.11 0.05 0.26 SGLT-2-I v PCO network 0.17 0.10 0.29 GLP-1RA v PCO direct 3 65/987 83/476 0.21 0.10 0.43 GLP-1RA v PCO network 0.20 0.14 0.29 BASAL v PCO direct 1 1/232 13/114 0.03 0.00 0.24 BASAL v PCO network 0.10 0.05 0.20 DPP-4-i v SGLT-2-I direct 1 85/378 40/378 2.45 1.63 3.68 DPP-4-i v SGLT-2-I network 2.83 1.71 4.68 GLP-1RA v BASAL direct 3 64/1058 17/762 3.64 0.57 23.36 GLP-1RA v BASAL network 2.14 1.13 4.07

0.01 0.1 1 10 100

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 8.8. Hypoglycemia

Direct and network treatment estimates for hypoglycemia – triple therapy

Tri als, Intervention Comparator Odds ratio Drug comparison n n/N n/N and 95% CI Odds ratio and 95% CI

TZD v PCO direct 2 182/458 58/299 3.47 2.41 4.99 TZD v PCO network 2.71 1.75 4.20 DPP-4-i v PCO direct 2 193/921 47/391 1.69 1.19 2.39 DPP-4-i v PCO network 2.36 1.56 3.58 SGLT-2-I v PCO direct 3 187/863 54/490 2.15 1.39 3.32 SGLT-2-I v PCO network 2.33 1.52 3.56 GLP-1RA v PCO direct 3 234/987 63/476 2.05 1.51 2.78 GLP-1RA v PCO network 1.64 1.12 2.41 BASAL v PCO direct 1 67/232 19/114 2.03 1.15 3.58 BASAL v PCO network 2.59 1.65 4.06 TZD v DPP-4-i direct 1 5/60 6/60 0.82 0.24 2.84 TZD v DPP-4-i network 1.15 0.66 2.00 TZD v GLP-1RA direct 1 87/277 57/271 1.72 1.17 2.53 TZD v GLP-1RA network 1.66 1.07 2.57 TZD v BASAL direct 2 57/126 63/117 1.10 0.24 4.98 TZD v BASAL network 1.05 0.66 1.67 DPP-4-i v SGLT-2-I direct 1 154/378 163/378 0.91 0.68 1.21 DPP-4-i v SGLT-2-I network 1.01 0.63 1.62 DPP-4-i v GLP-1RA direct 1 39/326 13/324 3.25 1.70 6.22 DPP-4-i v GLP-1RA network 1.44 0.87 2.38 GLP-1RA v BASAL direct 3 518/1057 408/761 0.87 0.67 1.13 GLP-1RA v BASAL network 0.63 0.45 0.88

0.01 0.1 1 10 100

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 8.9. Body Weight

Direct and network treatment estimates for body weight - triple therapy

Standardized mean Standardized mean Tri als, Intervention Comparator difference difference Drug comparison n Sample size Sample size and 95% CI and 95% CI

TZD v PCO direct 1 297 140 0.28 0.07 0.48 TZD v PCO network 0.28 0.08 0.48 SGLT-2-I v PCO direct 1 441 225 -0.05 -0.21 0.11 SGLT-2-I v PCO network -0.05 -0.21 0.11 GLP-1RA v PCO direct 1 268 115 0.06 -0.16 0.28 GLP-1RA v PCO network 0.05 -0.16 0.26 TZD v GLP-1RA direct 1 272 268 0.23 0.06 0.39 TZD v GLP-1RA network 0.23 0.07 0.39 TZD v BASAL direct 1 14 13 -0.21 -0.93 0.51 TZD v BASAL network -0.16 -0.65 0.33 DPP-4-i v GLP-1RA direct 1 285 262 -0.01 -0.18 0.16 DPP-4-i v GLP-1RA network -0.01 -0.17 0.15

-2.0 -1.0 0 1.0 2.0

Favors intervention Favors comparator

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 9. Rankograms for Odds of Hypoglycemia Associated With Individual Sulfonylurea Drugs Given as Monotherapy

CON PCO DPP-4-i SGLT -2-I 100 100 100 100 80 80 80 80 60 95.3% 60 85.6% 60 80.2% 60 80.1% 40 40 40 40 20 20 20 20 0 0 0 0 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416

T ZD AGI ME T GLP1-RA 100 100 100 100 80 80 80 80 60 79.1% 60 75.7% 60 57.7% 60 57.9% 40 40 40 40 20 20 20 20 0 0 0 0 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416

PRANDIAL_INSULIN BASAL_BOLUS_INSULIN GLITINIDE GLICLAZIDE 100 100 100 100 80 80 80 80

of drug drug of ranking 32.6% 60 54.6% 60 40.2% 60 60 27.8% 40 40 40 40 20 20 20 20 0 0 0 0 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416

GLIMEPIRIDE GLIPIZIDE GLIBENCLAMIDE GLYBURIDE Probability 100 100 100 100 80 80 80 20.9% 80 60 25.5% 60 25.1% 60 60 9.4% 40 40 40 40 20 20 20 20 0 0 0 0 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416 2 4 6 8 10121416

BASAL_INSULIN 100 80 60 3.2% 40 20 0 2 4 6 8 10121416

Downloaded From: https://jamanetwork.com/ on 10/02/2021 The figure shows the rankograms for the association of all drug classes including individual sulfonylurea drugs given as monotherapy with hypoglycemia. The lines showed the probability of the drug ranking (from 1st (best) to 17th (worst)) for each outcome. The drug treatments were stratified according to the SUCRA (surface under the cumulative ranking) curve. The SUCRA expressed as a percentage the efficacy or safety of each intervention relative to an imaginary intervention that was always the best without uncertainty. A SUCRA of 80% meant that the intervention of interest was associated with 80% of the effectiveness of this imaginary intervention. In this figure basal insulin was ranked lowest for an association with hypoglycemia; the SUCRA of 3.2% for basal insulin indicated that basal insulin had a 3.2% probability of being the best treatment for hypoglycemia. The peak in the rankogram at position 17 for basal insulin indicated this drug classes had a 100% probability of ranking 17th of the 17 drug options evaluated. Abbreviations: AGI = alpha glucosidase inhibitor. BASAL = basal insulin. DPP-4-i = dipeptidyl peptidase-4 inhibitor. GLITINIDE = Meglitinide. GLP-1RA = glucagon-like peptide-1 agonist. MET = metformin. PCO = placebo. SGLT-2-i = sodium-glucose linked transporter-2 inhibitor. TZD = thiazolidinedione. The individual sulfonylurea drugs were likely to rank among the worst drugs for hypoglycemia with probabilities of being the best ranked drug ranging between 27.8% for gliclazide to 9.4% for glyburide.

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