Association Between Use of Sodium-Glucose Cotransporter 2

Supplementary Online Content

Zheng SL, Roddick Aj, Aghar-Jaffar R. Association between use of sodium- glucose cotransporter-2 inhibitors, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and metaanalysis. JAMA. doi:10.1001/jama.2018.3024

eMethods 1. Search strategy eMethods 2. Drug doses eMethods 3. Event definitions eMethods 4. Detailed Statistical Methods eMethods 5. Changes in protocol eTable 1. DIC for model selection eTable 2. Baseline Characteristics (All studies) eTable 3. Baseline characteristics for cardiovascular outcome trials eTable 4. Risk of bias of individual trials eTable 5. All-cause mortality network meta-analysis by individual drug type eTable 6. Clinical Endpoints in Cardiovascular Outcome Trials eTable 7. Sensitivity analysis (Bayesian fixed-effect) eTable 8. Frequentist network meta-analysis eFigure 1. Risk of bias summary eFigure 2. Funnel plot eFigure 3. Network plots eFigure 4. Forest plots and ranking plots for additional secondary outcomes eFigure 5. Network plot for individual drugs eFigure 6. Forest plot for all-cause mortality for individual drugs eFigure 7. Forest plots and ranking plots for safety outcomes eFigure 8. Forest plots of drug-class specific adverse effects of interest eFigure 9. Breakdown of direct and indirect evidence eMethods 1. Search strategy

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 1: Search strategy

SGLT2 inhibitor

Embase (via OVID): 1. (Diabetes mellitus or type 2 diabetes or type ii diabetes).af 2. Sodium glucose cotransporter 2 inhibitor.af or (sodium glucose transporter 2 inhibitor* or sodium glucose transporter ii inhibitor* or SGLT2 inhibitor*).af 3. (Canagliflozin or Dapagliflozin or Empagliflozin or Ertugliflozin or Tofogliflozin or Ipragliflozin or Remogliflozin).af 4. (randomi*ed controlled trial or randomi*ed trial).af 5. 2 or 3 6. 1 and 4 and 5

MEDLINE: o Diabetes mellitus or type 2 diabetes or type ii diabetes o AND o Sodium glucose cotransporter 2 inhibitor OR (sodium glucose transporter 2 inhibitor* or sodium glucose transporter ii inhibitor* or SGLT2 inhibitor*) o OR o Canagliflozin or Dapagliflozin or Empagliflozin or Ertugliflozin or Tofogliflozin or Ipragliflozin or Remogliflozin o AND o randomized controlled trial[Publication Type]) OR controlled clinical trial[Publication Type]) OR randomized[Title/Abstract]) OR placebo[Title/Abstract]) OR drug therapy[MeSH Subheading]) OR randomly[Title/Abstract]) OR trial[Title/Abstract]) OR groups[Title/Abstract])) NOT ((animals[mh]) NOT humans[mh]))

CENTRAL: o Diabetes mellitus or type 2 diabetes or type ii diabetes o (sodium glucose transporter 2 inhibitor* or sodium glucose transporter ii inhibitor* or SGLT2 inhibitor*) or (Canagliflozin or Dapagliflozin or Empagliflozin or Ertugliflozin or Tofogliflozin or Ipragliflozin or Remogliflozin)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 GLP-1 analogue

Embase (via OVID): 1. (Diabetes mellitus or type 2 diabetes or type ii diabetes).af 2. (glucagon like peptide 1 receptor agonist).af or (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*).af 3. Albiglutide or Dulaglutide or Semaglutide or Liraglutide or Lixisenatide or Taspoglutide or Exenatide 4. (randomi*ed controlled trial or randomi*ed trial).af 5. 2 or 3 6. 1 and 4 and 5

MEDLINE: o Diabetes mellitus or type 2 diabetes or type ii diabetes o AND o (glucagon like peptide 1 receptor agonist).af or (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*) o OR o Albiglutide or Dulaglutide or Semaglutide or Liraglutide or Lixisenatide or Taspoglutide or Exenatide o AND o randomized controlled trial[Publication Type]) OR controlled clinical trial[Publication Type]) OR randomized[Title/Abstract]) OR placebo[Title/Abstract]) OR drug therapy[MeSH Subheading]) OR randomly[Title/Abstract]) OR trial[Title/Abstract]) OR groups[Title/Abstract])) NOT ((animals[mh]) NOT humans[mh]))

CENTRAL: o Diabetes mellitus or type 2 diabetes or type ii diabetes o (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*) OR o Albiglutide or Dulaglutide or Semaglutide or Liraglutide or Lixisenatide or Taspoglutide or Exenatide

Downloaded From: https://jamanetwork.com/ on 10/02/2021 DPP-4 inhibitor

Embase (via OVID): 1. (Diabetes mellitus or type 2 diabetes or type ii diabetes).af 2. (dipeptidyl peptidase IV inhibitor).af 3. (dipeptidyl peptidase IV inhibitor* or dipeptidyl-peptidase 4 inhibitor* or DPP4 inhibitor* or DPP 4 inhibitor or DPP IV inhibitor).af 4. (Alogliptin or Anagliptin or Gemigliptin or Linagliptin or Omarigliptin or Saxagliptin or Sitagliptin or Teneligliptin or Vildagliptin).af 5. (randomi*ed controlled trial or randomi*ed trial).af 6. 2 or 3 7. 1 and 4 and 5

MEDLINE:

o Diabetes mellitus or type 2 diabetes or type ii diabetes AND o (dipeptidyl peptidase IV inhibitor) or (dipeptidyl peptidase IV inhibitor* or dipeptidyl-peptidase 4 inhibitor* or DPP4 inhibitor* or DPP 4 inhibitor or DPP IV inhibitor) OR o Alogliptin or Anagliptin or Gemigliptin or Linagliptin or Omarigliptin or Saxagliptin or Sitagliptin or Teneligliptin or Vildagliptin AND o randomized controlled trial[Publication Type] OR controlled clinical trial[Publication Type] OR randomized[Title/Abstract] OR placebo[Title/Abstract] OR drug therapy[MeSH Subheading] OR randomly[Title/Abstract] OR trial[Title/Abstract] OR groups[Title/Abstract] NOT o ((animals[mh]) NOT humans[mh]))

CENTRAL: o Diabetes mellitus or type 2 diabetes or type ii diabetes o (dipeptidyl peptidase IV inhibitor* or dipeptidyl-peptidase 4 inhibitor* or DPP4 inhibitor* or DPP 4 inhibitor or DPP IV inhibitor) OR o Alogliptin or Anagliptin or Gemigliptin or Linagliptin or Omarigliptin or Saxagliptin or Sitagliptin or Teneligliptin or Vildagliptin

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eMethods 2: Drug doses Data only extracted and analysed for study groups receiving either marketed drug doses or doses evaluated in phase 3 clinical trials SGLT-2 inhibitors o Empagliflozin total daily dose 10 to 25mg PO o Canagliflozin total daily dose 100 to 300mg PO Dapagliflozin total daily dose 5 to 10mg PO o Ipragliflozin total daily dose 50 to 100mg PO o Luseogliflozin total daily dose 2.5 to 5mg PO o Remogliflozin excluded as no phase 3/marketing dose o Tofogliflozin excluded as no phase 3/marketing dose Ertugliflozin total daily dose 5 to 10mg PO GLP-1 analogues o Dulaglutide 0.75-1.5mg SC once weekly o Semaglutide 0.5-1mg SC once weekly o Liraglutide 1.2 to 1.8mg SC daily o Lixisenatide 10 to 20mcg SC daily o Taspoglutide 10 to 20mg SC once weekly o Exenatide 5 to 10mcg SC twice daily o Albiglutide 30 to 50mg SC once weekly DPP-4 inhibitors o Alogliptin total daily dose 12.5 to 25mg PO o Saxagliptin total daily dose 2.5 to 5mg PO o Sitagliptin total daily dose 25 to 100mg PO o Linagliptin total daily dose 5mg PO o Vildagliptin total daily dose 50 to 100mg PO o Omarigliptin excluded as no phase 3/marketing dose o Tenelegliptin excluded as no phase 3/marketing dose o Gemigliptin excluded as no phase 3/marketing dose o Evogliptin excluded as no phase 3/marketing dose

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eMethods 3: Event definitions All-cause mortality: Death from any cause occurring during the duration of the randomised and controlled period.

Definitions of hypoglycaemia were: - Any: any episode not meeting criteria for major hypoglycaemia, study-defined minor hypoglycaemia - Major: any episode resulting in hospitalization, medical assistance or trial withdrawal, study-defined major or serious hypoglycaemia Note: Trial definitions of hypoglycaemia were variable and did not necessarily require recording of capillary blood glucose levels.

Adverse event category (any, serious, leading to trial withdrawal) were based on individual trial definitions.

From NCT registry: Additional events were identified from the NCT database trial entry for studies which had NCT reporting. The following are a list of definitions for events.

Myocardial infarction: • Acute myocardial infarction • Myocardial infarction • Acute coronary syndrome • Coronary artery occlusion Stroke: • Ischaemic stroke • Cerebrovascular accident • Transient ischaemic attack • Lacunar infarction • Brainstem infarction • Brainstem stroke • Cerebral infarction Heart failure: • Cardiac failure congestive • Cardiac failure • Cardiac failure acute • Left ventricular failure • Acute left ventricular failure • Cardiogenic shock • Congestive cardiomyopathy

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Note: For heart failure events it was unclear from reporting if patients required hospitalization. Therefore, the outcome is for heart failure events and not heart failure hospitalisation. Analysis of heart failure hospitalisation events in cardiovascular outcome trials is presented in eTable 6 of the Supplement.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eMethods 4: Detailed statistical methods

Several studies included in this analysis had open-label extensions for additional safety analysis. For these studies, data was extracted only from the randomized controlled phase to minimise bias.

Studies with multiple treatment group were incorporated into the network as multi- arm studies where appropriate, allowing for multiple pairwise comparisons from a single study to be incorporated into the network without duplication of data. In cases where this was not appropriate (for example where study groups contained different baseline anti-diabetic medication), these treatment groups were incorporated as independent pairwise comparisons, such that no data was duplicated.

Bayesian network meta-analysis

A Bayesian network meta-analysis approach was undertaken1 using the gemtc package in R (version 3.4.1)2 and JAGS (version 4.3.0)3.

Deviance information criterion was adopted to determine the model-used (fixed vs. random-effects) for individual outcomes4 using the approach in Kew et al5. For each outcome, the model with the lowest DIC value was used. Using this approach, fixed- effects model was used for primary and secondary outcomes, and random-effects model was used for safety outcomes. The DIC values are listed in the eTable 1 of the Supplement.

For studies reporting hazard ratio, the log hazard ratio and corresponding standard error were extracted for inclusion in the analysis. For studies that did not report hazard ratio, the number of events and length of follow-up (in person-years) for each group were extracted to permit comparison of studies with different durations of follow-up. It should be noted that this assumes a constant event rate over time in these trials.

For each outcome, a network was generated incorporating all studies that reported at least one event in at least one study group. Studies in which no events occurred were excluded from the network, as these studies do not contribute to the treatment effect estimate1.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Consistency models were generated from each network using a Poisson likelihood and log link, incorporating both data from event counts and from hazard ratios. Non- informative vague priors were used for all parameters. The Markov Chain Monte Carlo (MCMC) method was used with 5000 adaptation iterations followed by 100,000 iterations of 4 chains. Convergence was assessed using the Brooks-Gelman-Rubin, using a cut-off of 1.056.

Unless otherwise specified, all data are presented as hazard ratio (HR) with 95% credible intervals (CrI). 95% CrI that do not cross 1 were taken to represent statistical significance.

I2 statistic was used to determine heterogeneity, with a cut-off of ≤0.25 used to determine low heterogeneity7.

Inconsistency was evaluated by node-splitting analysis8, and quantitative assessment of inconsistency was achieved by comparing the difference in direct and indirect estimates using the following formula9:

Δ = � − �′

�� ∆ = ��(�) + ��(� ) )

Δ � = ��(Δ)

Where:

Δ = difference between direct and indirect estimates

TAB = direct estimate of A vs. B (log hazard ratio)

T’AB = indirect estimate of A vs. B (log hazard ratio)

SE = standard error

z = z-score

Treatment estimates and standard errors were the logarithms.

Two-tailed P-values calculated using R, with significance threshold of P=0.05.

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

Absolute risk difference (ARD)

We used the risk in the pooled comparator population (defined as events/total participants) and applied the relative risk difference to determine the absolute risk difference. The 95% CI for ARD was calculated by applying the 95% CrI to the risk difference.

Negative results indicate a reduction in events with treatment. Positive results indicate an increase in events with treatment.

Frequentist network meta-analysis

Standard pairwise random-effects meta-analysis was used to analyse direct treatment effects10. For the primary and secondary outcomes, event counts were extracted and trials reporting at least one event in any group were pooled and presented in relative risk (RR) format with 95% confidence intervals (CI). A continuity correction of 0.5 was applied to all studies with zero events in one or more treatment arms. Studies with no events in any arm were excluded from the network.

Treatments were ranked according to the P-score statistic, which ranks treatments by the mean extent of certainty that a given treatment is superior to an alternative treatment within the network11.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eMethods 5: Changes in protocol

The following changes were made to the protocol during revision of the manuscript:

1. Primary analysis done with Bayesian statistics (see detailed Statistical Methods). 2. Ranking plots were used to demonstrate treatment hierarchy 3. Additional pair-wise meta-analysis for drug-class specific safety outcomes was undertaken: o SGLT-2 inhibitors – lower limb amputations, urinary tract infections, genital infections (stratified by gender) o DPP-4 inhibitors – acute pancreatitis o GLP-1 agonists – acute pancreatitis, retinopathy 4. Absolute risk difference was calculated for all results where the upper Credible Interval limit was <1. o The pooled HR was applied to the overall risk in the control group (eventscontrol/ participantscontrol) o The same was done for the upper and lower 95% CrI to derive the 95% CI for ARD. 5. Sensitivity analysis restricted to trials using placebo as a control treatment 6. Overall risk of bias assessment not adopted

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 1: Deviance information criterion for model selection (fixed- vs. random-effects)

Deviance Information Outcome Model Criterion (DIC) Accepted Model Random 310.9 All-cause mortality Fixed Fixed 309.8

Random 182.7 Cardiovascular mortality Fixed Fixed 182.5 Random 191.6 Heart failure events Fixed Fixed 191.1 Random 325.6 Fixed All myocardial infarction Fixed 323.5 Random 289.8 All stroke Fixed Fixed 288.1 Random 172.9 Unstable angina Fixed Fixed 171.4

Non-fatal myocardial Random 156.0 Fixed infarction Fixed 154.3 Random 150.8 Non-fatal stroke Fixed Fixed 149.7 Random 598.6 All adverse events Random Fixed 613.8 Random 591.3 Serious adverse events Random Fixed 631.0

Adverse events leading Random 636.6 Random to withdrawal Fixed 696.4 Random 654.9 Any hypoglycaemia Random Fixed 833.0 Random 271.7 Major hypoglycaemia Random Fixed 274.1

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies)

Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c DPP-4 Inhibitor vs. Control (83 studies)

12 54.0 (45.6- 30.5 (24.9- 7.85 (6.1- Alba 2013 Sitagliptin Placebo 12 105 57.1% 62.2)a 35.4)a 11.6)a 13 57.0 (48.0- 25.4 (22.2- 8.54 (7.57- Ba 2017 Sitagliptin Placebo 24 497 50.1% a a a 67.0) 28.6) 8.78) 14 53.8 (43.4- 28.2 (22.6- 8.40 (7.55- Bajaj 2014 Linagliptin Placebo 24 272 48.5% 63.6)a 33.6)a 9.25)a Barnett 201215 Linagliptin Placebo 18 227 38.8% 56.5 ± 10.3 29.5 ± 5.4 8.10 ± 0.90 Barnett A 201316 Saxagliptin Placebo 24 455 41.3% 57.2 ± 9.4 32.3 ± 5.4 8.70 ± 0.90

17 74.9 (70.0- Barnett B 2013 Linagliptin Placebo 24 241 68.5% 29.7 ± 4.7 7.80 ± 0.80 91.0)a 18 71.9 (65.5- 31.0 (23.9- 7.80 (6.30- Barzilai 2011 Sitagliptin Placebo 24 206 51.9% a a a 78.1) 38.3) 10.00) 19 a 30.4 (27.4- 6.30 (5.59- Boer 2017 Linagliptin Placebo 26 44 61.4% 63.0 (54-66) 34.2)a 6.70)a Bosi 200720 Vildagliptin Placebo 24 541 44.2% 54.2 ± 9.9 32.7 ± 5.6 8.40 ± 0.95 Bosi 200921 Vildagliptin Placebo 24 589 58.0% 52.6 ± 10.7 31.4 ± 4.7 8.70 ± 0.98

22 7.70 ± 6.20- Chan 2008 Sitagliptin Placebo 12 91 51.6% 66.5 ± 9.8 26.7 ± 4.3 a 10.30) Charbonnel 8.00 (6.40- Sitagliptin Placebo 24 701 58.3% 54.5 ± 10.1 31.1 ± 5.1 200623 11.00)a DeFronzo 200824 Alogliptin Placebo 26 328 53.2% 53.4 ± 11.1 NR 7.90 ± 0.08 DeFronzo 201225 Alogliptin Placebo 26 776 46.4% 54.1 ± 9.6 31.1 ± 5.1 8.53 ± 0.69 Dobs 201326 Sitagliptin Placebo 54 262 42.4% 54.6 ± 9.2 30.4 ± 5.9 8.80 ± 1.00 EXAMINE 29.5 (15.6- Alogliptin Placebo 77 5380 67.9% 60.9 (NR) 8.00 ± 1.10 (White) 201327 68.3)b Fonseca 200728 Vildagliptin Placebo 24 296 51.4% 59.2 ± 10.6 33.1 ± 5.6 8.40 ± 0.10 Frederich 201229 Saxagliptin Placebo 76 365 46.0% 55.0 ± 10.4 30.5 ± 4.9 7.90 ± 0.90 Garber 200830 Vildagliptin Placebo 24 515 46.8% 58.2 ± 10.7 31.3 ± 5.2 8.50 ± 1.00

31 8.80 (6.30- Goldstein 2007 Sitagliptin Placebo 24 1091 47.6% 53.5 ± 10.1 32.1 ± 6.3 a 11.90) Haak 201232 Linagliptin Placebo 24 791 53.9% 55.3 ± 10.9 29.1 ± 4.9 8.70 ± 1.00 6.80 (5.90- Henry 201133 Saxagliptin Placebo 12 36 38.9% 55.6 ± 7.8 32.9 ± 3.8 8.10)a Henry 201434 Sitagliptin Placebo 54 1146 57.0% 51.8 (23-76)a 30.9 ± 5.4 8.80 ± 1.1

Hermansen a 8.30 (6.70- Sitagliptin Placebo 24 441 75.7% 56.1 (28-75) 30.9 ± 6.3 200735 10.60)a Hirose 201536 Vildagliptin Placebo 12 151 73.5% 59.3 ± 9.3 25.7 ± 3.3 8.10 ± 0.10 Hollander 201137 Saxagliptin Placebo 76 565 49.6% 54.0 ± 10.1 30.0 ± 5.6 8.30 ± 1.10 Ji 201738 Alogliptin Placebo 26 642 56.6% 53.6 ± 10.1 26.3 ± 3.8 8.37 ± 0.77 Kadowaki A Teneligliptin Placebo 12 204 70.6% 60.4 ± 9.3 25.9 ± 4.5 8.00 ± 0.90 201339 Kadowaki B Teneligliptin Placebo 12 240 58.6% 61.2 ± 9.6 25.2 ± 3.9 8.90 ± 0.70 201340 Kadowaki A 41 Teneligliptin Placebo 12 194 66.0% 59.4 ± 8.2 24.7 ± 3.6 8.40 ± 0.80 2014 Kanazawa No Vildagliptin 104 73 63.0% 69.1 ± 12.0 24.3 ± 4.1 7.90 ± 1.30 201742 treatment Kikuchi 200943 Vildagliptin Placebo 12 148 67.0% 59.0 ± 8.5 24.4 ± 2.8 7.40 ± 0.83 Kikuchi 201044 Vildagliptin Placebo 12 202 71.3% 59.7 ± 9.9 24.5 ± 2.8 7.90 ± 0.80

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies)

Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c Kim 201545 Teneligliptin Placebo 16 204 53.4% 55.9 ± 8.9 NR 7.75 ± 0.73 Kothny 201246 Vildagliptin Placebo 52 356 58.1% 66.5 ± 9.0 30.3 ± 5.2 7.80 ± 1.00 Kothny 201347 Vildagliptin Placebo 24 448 51.1% 59.2 ± 10.0 29.0 ± 4.5 8.80 ± 1.00 Lewin 201248 Linagliptin Placebo 18 245 52.7% 56.7 ± 10.0 28.3 ± 5.1 8.60 ± 0.80 Lukashevich Vildagliptin Placebo 24 317 47.9% 55.1 ± 10.6 28.0 ± 4.5 8.80 ± 0.90 201449 Macauley 201550 Vildagliptin Placebo 24 44 NR 62.1 ± 1.5 30.3 ± 0.7 6.60 ± 0.10 MARLINA-T2D Linagliptin Placebo 24 360 63.6% 60.5 ± 9.7 28.5 ± 4.9 7.84 ± 0.88 (Groop) 201751 Mathieu A 201552 Sitagliptin Placebo 24 658 47.9% 59.0 ± 9.3 32.1 ± 6.2 8.75 ± 1.00 Matthaei A 53 Saxagliptin Placebo 24 315 47.3% 54.6 ± 9.6 31.4 ± 5.3 7.91 ± 0.88 2015 McGill 201454 Linaglitpin Placebo 52 133 42.9% 69.8 ± 9.3 30.7 ± 5.3 8.20 ± 0.85

55 a 25.0 (16.3- 8.70 (6.2- Mohan 2009 Sitagliptin Placebo 18 530 57.7% 50.9 (25-75) a a 38.2) 12.2) 56 No Moses 2016 Sitagliptin 24 422 45.7% 54.9 ± 9.9 29.1 ± 4.9 8.40 ± 0.90 treatment Mu 201757 Linagliptin Placebo 24 583 61.9% 51.3 ± 10.0 26.0 ± 3.6 8.70 ± 1.00 Nauck 200958 Alogliptin Placebo 26 527 50.3% 55.0 ± 10.0 32.0 ± 4.0 7.90 ± 1.10 NCT01778049 59 Linagliptin Placebo 24 482 56.7% 56.8 ± 9.8 NR NR Ning 201660 Vildagliptin Placebo 24 293 43.3% 58.1 ± 9.4 26.1 ± 3.1 8.70 ± 0.90 Nowicki 201161 Saxagliptin Placebo 52 170 42.9% 66.5 ± 8.7 30.7 ± 6.5 8.30 ± 1.20 Odawara 201462 Vildagliptin Placebo 12 138 66.7% 58.1 ± 9.5 25.6 ± 3.8 8.00 ± 0.90 Olansky 201163 Sitagliptin Placebo 44 1246 56.5% 49.7 ± 10.5 33.3 ± 7.5 9.90 ± 1.80 Pan 201264 Saxagliptin Placebo 24 568 55.5% 51.4 ± 10.2 25.9 ± 3.6 8.20 ± 0.80 Pan 201765 Alogliptin Placebo 16 505 54.5% 52.6 ± 9.7 25.7 ± 3.1 8.00 ± 0.90 Peng 201766 Sitagliptin Placebo 12 123 52.0% 54.0 ± 9.8 33.1 ± 5.5 8.50 ± 0.90 Pfutzner 201167 Saxagliptin Placebo 76 648 49.2% 52.0 ± 10.7 30.2 ± 4.9 9.50 ± 1.30 30.1 (22.3- Pratley A 200968 Alogliptin Placebo 26 500 52.2% 56.6 (21-80)a NR 45.1)a Pratley B 200969 Alogliptin Placebo 26 494 58.1% 55.4 ± 10.0 32.8 ± 5.7 8.00 ± 0.83 Pratley 201470 Alogliptin Placebo 26 768 47.7% 53.5 ± 10.3 30.7 ± 5.2 NR

71 a 30.3 (20.1- 9.20 (7.50- Raz 2008 Sitagliptin Placebo 30 190 36.7% 54.8 (29-73) 40.9)a 11.10)a Rosenstock 72 Saxagliptin Placebo 12 169 52.7% 53.7 ± 10.1 30.9 ± 4.0 7.90 ± 0.99 2008 Rosenstock A No Saxaglitpin 24 303 52.5% 53.6 ± 11.0 31.7 ± 4.7 7.90 ± 0.90 200973 treatment Rosenstock B a 74 Alogliptin Placebo 26 389 41.4% 55.4 (23-80) 32.6 ± 5.6 9.30 ± 1.10 2009 Rosenstock A Saxagliptin Placebo 208 562 50.2% 54.7 ± 10.0 31.5 ± 4.9 8.10 ± 0.90 201375 Ross 201276 Linagliptin Placebo 12 491 57.0% 58.6 ± 10.3 29.6 ± 5.1 7.97 ± 0.75 Saito 201777 Vildagliptin Placebo 26 24 79.2% 60.8 ± 10.7 25.2 ± 5.4 7.90 ± 0.70 SAVOR-TIMI 53 Saxagliptin Placebo 109.2 16492 66.9% 65.0 ± 8.6 31.1 ± 5.6 NR (Scirica) 201378 Scherbaum 79 Vildagliptin Placebo 52 306 59.5% 63.1 ± 10.6 30.2 ± 4.9 6.80 ± 0.40 2008 80 No Seino A 2012 Alogliptin 12 312 47.8% 60.2 ± 24.7 ± 4.1 8.57 ± 0.79 treatment 9.2

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies) Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c 81 No Seino B 2012 Alogliptin 12 288 68.8% 52.6 ± 8.3 25.9 ± 4.1 7.97 ± 0.80 treatment Strain 201382 Vildagliptin Placebo 24 278 45.3% 74.8 ± 4.2 29.8 ± 4.3 7.90 ± 0.80 Tajima 201183 Sitagliptin Placebo 12 138 58.0% 60.8 ± 9.0 24.6 ± 3.6 8.40 ± 0.80 TECOS (Green) 84 Sitagliptin Placebo 156 14671 70.7% 65.5 ± 8.0 30.2 ± 5.6 7.20 ± 0.50 2015 Tinahones Linagliptin Placebo 24 482 52.7% 56.6 ± 9.8 31.3 ± 5.0 8.00 ± 0.86 201785 Van Raalte 86 Alogliptin Placebo 16 49 71.5% 58.9 ± 6.5 31.6 ± 3.9 6.70 ± 0.70 2014 8.70 (6.6- Vilsboll 201087 Sitagliptin Placebo 24 641 50.9% 57.8 ± 9.2 31.0 ± 5.0 12.1)a Wang 201688 Linagliptin Placebo 24 305 49.8% 55.5 ± 9.7 25.6 ± 4.0 8.00 ± 0.82 Wang 201789 Sitagliptin Placebo 24 381 50.9% 57.1 ± 9.2 26.0 ± 4.5 8.10 (NR)

90 33.1 (20.0- White 2014 Saxagliptin Placebo 12 160 53.1% 55.4 ± 10.2 7.95 ± 0.89 45.0)a 91 8.50 (6.20- Yang 2012 Sitagliptin Placebo 24 395 50.6% 54.6 ± 9.4 25.3 ± 3.4 a 11.40) Yang 201592 Vildagliptin Placebo 24 278 56.8% 58.5 ± 9.6 24.9 ± 2.9 8.70 ± 1.00 Yki-Jarvinen Linagliptin Placebo 52 1261 52.2% 60.0 ± 10.0 31.0 ± 5.2 8.30 ± 0.85 201393 No Younis 201794 Vildagliptin 12 57 75.0% 67.0 ± 9.0 28.0 ± 4.0 7.20 ± 0.60 treatment GLP-1 agonist vs. Control (65 studies) Apovian 201095 Exenatide Placebo 24 194 37.6% 54.7 ± 9.5 33.8 ± 4.0 7.60 ± 0.86 AWARD-1 Dulaglutide/ Placebo 26 976 58.4% 55.6 ± 9.7 33.0 ± 5.5 8.10 ± 1.27 (Wysham) 201496 Exenatide AWARD-8 Dulaglutide Placebo 24 300 44.1% 58.0 ± 9.7 31.7 ± 5.4 8.40 ± 0.7 (Dungan) 201697 AWARD-9 98 Dulaglutide Placebo 28 300 57.3% 60.4 ± 9.8 32.7 ± 4.9 8.40 ± 0.85 (Pozzilli) 2017 Buse 200499 Exenatide Placebo 30 377 59.7% 55.3 ± 10.7 33.3 ± 5.7 8.60 ± 1.17 Buse 2011100 Exenatide Placebo 30 259 57.1% 59.0 ± 9.5 33.5 ± 9.0 8.40 ± 0.91 Chaudhuri No Exenatide 12 24 NR 55.0 ± 3.7 39.2 ± 1.8 8.55 ± 0.36 2012101 treatment DeFronzo 102 Exenatide Placebo 30 336 57.1% 53.0 ± 10.4 34.2 ± 6.0 8.20 ± 1.03 2005 Derosa 2013103 Exenatide Placebo 52 171 51.5% 57.0 (NR) 31.8 (NR) 8.00 (NR) DUAL-I (Gough) No Liraglutide 26 1246 50.8% 55.0 ± 9.8 31.2 ± 5.2 8.30 ± 0.93 2014104 treatment ELIXA (Pfeffer) 105 Lixisenatide Placebo 108.3 6068 69.3% 60.3 ± 9.7 30.2 ± 5.7 7.70 ± 1.30 2015 EXSCEL 62.7 (56.4- 31.8 (28.2- a 106 Exenatide Placebo 166.4 14752 62.0% a a 8.0 (7.3-8.9) (Holman) 2017 68.8) 36.2) Ferdinand Dulaglutide Placebo 26 755 51.9% 56.5 ± 10.3 33.0 ± 6.0 7.90 ± 0.80 2014107 Gao 2009108 Exenatide Placebo 16 466 44.4% 54.5 ± 9.0 26.3 ± 3.3 8.30 ± 1.00 GetGoal L 109 Lixisenatide Placebo 30 495 46.1% 57.0 ± 10.0 32.1 ± 6.2 8.40 ± 0.90 (Riddle) 2013 GetGoal L Asia Lixisenatide Placebo 24 311 47.9% 58.4 ± 10.2 25.3 ± 3.8 8.50 ± 0.76 (Seino) 2012110 GetGoal M 111 Lixisenatide Placebo 24 680 43.1% 54.7 ± 9.7 32.9 ± 6.4 8.00 ± 0.90 (Ahren) 2013 GetGoal M Asia Lixisenatide Placebo 24 390 49.2% 54.8 ± 10.4 26.9 ± 3.9 7.90 ± 0.76 (Pan) 2014 112 GetGoal O (Meneilly) Lixisenatide Placebo 24 350 52.0% 74.2 ± 3.9 30.0 ± 4.1 8.10 ± 0.70 2017113

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies) Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c GetGoal P Lixisenatide Placebo 24 484 52.0% 55.8 ± 9.5 33.9 ± 6.8 8.10 ± 0.87 (Pinget) 2013114 GetGoal S (Rosenstock) Lixisenatide Placebo 24 859 50.5% 57.3 ± 9.9 30.2 ± 6.6 8.30 ± 0.87 2014115 GetGoal-Duo 1 Lixisenatide Placebo 24 446 49.8% 56.0 ± 10.0 31.8 ± 6.3 NR (Riddle) 2013116 GetGoal-F1 117 Lixisenatide Placebo 76 482 27.8% 56.1 ± 9.3 32.5 ± 5.4 8.00 ± 0.87 (Bolli) 2014 Grunberger 2012 Dulaglutide Placebo 24 85 45.1% 56.6 ± 8.8 32.1 ± 4.7 7.20 ± 0.59 118 HARMONY-1 119 Albiglutide Placebo 52 301 59.8% 55.0 ± 9.7 34.1 ± 5.8 8.10 ± 0.90 (Reusch) 2014 HARMONY-2 Albiglutide Placebo 52 301 55.1% 52.9 ± 11.5 33.5 ± 5.3 8.10 ± 0.87 (Nauck) 2016120 HARMONY-5 Albiglutide Placebo 52 386 53.1% 55.2 ± 9.5 32.2 ± 5.3 8.24 ± 0.93 (Home)121 Idorn 2016122 Liraglutide Placebo 12 47 68.1% 64.5 ± 4.4 31.0 ± 2.0 7.30 ± 0.72 Kadowaki 123 Exenatide Placebo 12 114 68.9% 60.3 ± 10.2 25.3 ± 4.5 8.00 ± 0.81 2009 Kadowaki Exenatide Placebo 24 179 68.2% 58.4 ± 10.0 25.5 ± 4.1 8.20 ± 0.91 2011124 Kaku 2010125 Liraglutide Placebo 24 264 64.0% 59.7 ± 10.4 24.9 ± 3.7 8.40 ± 0.91

126 b 29.6 (20.7- 7.30 (5.9- Kapitza 2017 Semaglutide Placebo 12 75 68.0% 56.5 (44-64) b b 35.3) 9.0) Kendall 2005127 Exenatide Placebo 30 733 58.1% 55.3 ± 9.7 33.7 ± 5.7 8.50 ± 1.03 Kim 2007128 Exenatide Placebo 15 45 60.2% 53.7 ± 11.0 35.6 ± 6.0 8.43 ± 1.21 LEAD-1 SU Liraglutide Placebo 26 576 49.6% 56.1 ± 9.7 29.9 ± 5.2 8.40 ± 1.00 (Marre) 2009129 LEAD-2 (2 year) Liraglutide Placebo 104 846 58.2% 56.7 ± 9.6 31.0 ± 4.7 8.40 ± 0.99 (Nauck) 2013130 LEAD-4 (Zinman) 131 Liraglutide Placebo 26 533 56.7% 55.0 ± 10.3 33.6 ± 5.2 8.50 ± 1.20 2009 LEAD-5 MET+SU Liraglutide Placebo 26 347 53.0% 57.6 ± 9.5 30.9 ± 5.2 8.30 ± 0.90 (Russell-Jones) 2009132 LEADER (Marso) 133 Liraglutide Placebo 197.6 9340 64.3% 64.3 ± 7.2 32.5 ± 6.3 NR 2016 LIRA-RENAL Liraglutide Placebo 26 277 46.9% 67.1 ± 8.2 33.9 ± 5.4 8.04 ± 0.82 (Davies) 2016134 Liutkus 2010135 Exenatide Placebo 26 165 59.4% 54.7 ± 8.4 33.7 ± 5.7 8.20 ± 0.90 LixiLan (Aroda) No 136 Lixisenatide 30 736 53.1% 60.0 ± 9.1 31.1 ± 4.3 8.50 ± 0.70 2016 treatment LixiLan-O No (Rosenstock) Lixisenatide 30 936 50.6% 58.4 ± 9.5 31.7 ± 4.5 8.09 ± 0.70 treatment 2016137 LixiLan POC (Rosenstock) Liraglutide Placebo 24 323 51.1% 56.7 ± 9.5 32.1 ± 4.6 8.05 ± 0.80 2016138 Lu 2013139 Exenatide Placebo 16 50 54.0% 50.9 ± 9.5 NR NR MEXELIN (NCT00667732)1 Exenatide Placebo 24 34 41.2% NR NR NR 40 Miyagawa Dulaglutide/ 141 Placebo 26 487 81.3% 57.4 ± 9.6 25.5 ±3.5 8.14 ± 0.81 2015 Liraglutide Moretto 2008142 Exenatide Placebo 24 233 72.5% 54.0 ± 9.7 31.0 ± 5.0 7.80 ± 0.97 NCT00375492 Exenatide Placebo 24 194 37.6% 54.8 ± 9.5 NR 7.62 ± 0.85 143

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies) Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c NCT00701935 Exenatide Placebo 26 80 52.5% 58.1 ± 11.6 NR NR 144 NCT01001104 145 Dulaglutide Placebo 12 72 79.2% 52.0 ± 8.8 NR 8.00 ± 0.64

NCT01617434 Liraglutide Placebo 26 450 56.9% 58.4 ± 10.2 NR 8.25 ± 0.86 146 NCT01733758 147 Albiglutide Placebo 24 387 75.2% 58.4 ± 9.7 NR NR (Albiglutide) NCT01733758 Liraglutide Placebo 24 103 78.6% 58.4 ± 9.7 NR NR (Liraglutide)147 Ratner 2010148 Lixisenatide Placebo 13 325 49.2% 56.3 ± 9.0 31.9 ± 4.3 7.55 ± 0.64 SCALE (Davies) Liraglutide Placebo 56 846 50.2% 54.9 ± 10.5 37.2 ± 6.8 7.90 ± 0.80 2015149 Seino 2014150 Albiglutide Placebo 16 160 69.8% 57.0 ± 9.7 25.1 ± 3.6 8.60 ± 0.82 Seino 2016151 Liraglutide Placebo 36 257 56.0% 60.5 ± 11.2 25.6 ± 4.5 8.80 ± 0.90 SUSTAIN-6 152 Semaglutide Placebo 104 3297 60.7% 64.4 ± 7.4 32.8 ± 6.2 8.70 ± 1.50 (Marso) 2016 T-Emerge 1 Taspoglutide Placebo 24 368 35.3% 55.0 ± 9.6 32.4 ± 5.1 7.60 ± 1.00 (Raz) 2012153 T-Emerge 3 154 Taspoglutide Placebo 24 313 54.3% 54.3 ± 10.1 32.5 ± 5.2 8.20 ± 0.94 (Henry 2012) T-Emerge 7 (Hollander) Taspoglutide Placebo 24 292 40.8% 53.5 ± 10.0 36.7 ± 4.9 7.60 ± 0.84 2013155 Terauchi 2014156 Dulaglutide Placebo 12 72 73.8% 52.2 ± 8.8 27.0 ± 4.3 8.00 ± 0.60 Vanderheiden 157 Liraglutide Placebo 26 71 36.6% 54.2 ± 7.4 41.2 ± 8.7 NR 2016 Wu 2011158 Exenatide Placebo 12 23 39.1% 55.5 ± 9.9 26.3 ± 2.5 7.75 ± 0.76 Zinman 2007159 Exenatide Placebo 16 233 56.7% 55.0 ± 10.5 33.5 ± 5.1 8.50 ± 0.85 SGLT-2 Inhibitor vs. Control (65 studies) No Araki 2016 160 Dapagliflozin 16 183 70.9% 58.0 ± 9.8 26.6 ± 4.5 8.34 ± 0.85 treatment Bailey 2012161 Dapagliflozin Placebo 24 136 32.4% 54.0 ± 11.4 31.2 ± 5.4 7.85 ± 1.08 Bailey 2013162 Dapagliflozin Placebo 102 409 51.3% 54.0 ± 9.9 31.7 ± 5.1 8.03 ± 0.92 Bode 2015163 Canagliflozin Placebo 26 714 55.5% 63.6 ± 6.2 31.6 ± 4.6 7.70 ± 0.80 Bolinder 2014164 Dapagliflozin Placebo 102 182 55.5% 61.0 ± 7.6 32.0 ± 3.9 7.20 ± 0.49 CANTATA-M Canagliflozin Placebo 26 584 44.0% 55.3 ± 10.6 31.3 ± 6.2 8.00 ± 1.00 (Stenlof) 2013165 CANTATA-MP 166 Canagliflozin Placebo 26 342 63.2% 57.4 ± 10.0 32.5 ± 6.8 7.90 ± 1.00 (Forst) 2014 CANTATA-MSU Canagliflozin Placebo 26 469 51.0% 56.8 ± 9.3 33.1 ± 6.5 8.10 ± 0.90 (Wilding) 2013167 CANVAS (Neal) 168,169 Canagliflozin Placebo 295.9 4330 66.1% 62.4 ± 8.0 32.1 ± 6.2 8.20 ± 0.90 2017 CANVAS-R Canagliflozin Placebo 108 5812 62.8% 64.0 ± 8.4 31.9 ± 5.7 8.30 ± 1.00 (Neal) 2017169 Cefalu 2015170 Dapagliflozin Placebo 52 922 68.5% 63.0 ± 7.4 33.0 ± 6.0 8.10 ± 0.82 DIA3400 (Yale) Canagliflozin Placebo 52 269 60.6% 68.5 ± 8.3 33.0 ± 6.2 8.00 ± 0.90 2014171 EMPA-REG BASAL Empagliflozin Placebo 78 494 55.9% 58.8 ± 9.9 32.2 ± 5.9 8.20 ± 0.80 (Rosenstock) 2015172 EMPA-REG BP (Tikkanen) Empagliflozin Placebo 12 823 60.0% 60.2 ± 9.0 32.7 ± 5.1 7.90 ± 0.74 2015173

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies) Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c EMPA-REG EXTEND MET Empagliflozin Placebo 24 637 56.7% 55.7 ± 9.9 29.2 ± 5.5 7.90 ± 0.90 (Merker) 2015174 EMPA-REG EXTEND Empagliflozin Placebo 72 666 51.3% 57.0 ± 9.2 28.0 ± 5.3 8.10 ± 0.83 METSU (Haering) 2015175 EMPA-REG EXTEND PIO Empagliflozin Placebo 24 498 48.4% 54.5 ± 9.8 29.2 ± 5.5 8.09 ± 0.88 (Kovacs) 2015176 EMPA-REG MDI (Rosenstock) Empagliflozin Placebo 52 563 42.0% 56.7 ± 9.5 34.8 ± 4.1 8.34 ± 0.73 2014177 EMPA-REG OUTCOME Empagliflozin Placebo 161.2 7020 71.3% 63.0 ± 8.7 31.0 ± 5.3 8.10 ± 0.85 (Zinman) 2015178 EMPA-REG RENAL (Barnett) Empagliflozin Placebo 52 738 58.1% 64.0 ± 8.8 30.4 ± 5.5 8.04 ± 0.79 2014179 No Fadini 2017180 Dapagliflozin 12 33 67.7% 63.7 ± 1.3 30.5 ± 1.0 8.20 ± 0.10 treatment Ferrannini Dapagliflozin Placebo 24 353 46.9% 53.0 ± 10.5 32.0 ± 5.4 7.88 ± 0.95 2010181 Ferrannini A No c 28.4 (20.1- 182 Empagliflozin 12 245 52.8% 57.7 (28-80) c 7.87 ± 0.81 2013 treatment 39.6) Fonseca 2013183 Ipragliflozin Placebo 12 136 36.4% 53.8 ± 10.2 31.0 ± 5.7 8.04 ± 0.80 Henry 2012184 Dapagliflozin Placebo 24 816 46.3% 51.8 ± 10.0 NR 9.15 ± 1.30 ILLUMINATE (Kashiwagi) Ipragliflozin Placebo 24 168 58.9% 56.7 ± 10.2 25.8 ± 4.0 8.29 ± 0.73 2015185 Inagaki 2013186 Canagliflozin Placebo 12 300 68.1% 57.4 ± 10.6 25.7 ± 4.3 8.09 ± 0.83 Inagaki 2014187 Canagliflozin Placebo 24 271 70.9% 58.0 ± 10.8 26.0 ± 4.3 8.00 ± 0.73 Inagaki 2016188 Canagliflozin Placebo 16 146 63.8% 58.1 ± 10.3 26.5 ± 4.6 8.90 ± 0.82 IOLITE (Ishihara) Ipragliflozin Placebo 16 255 61.2% 58.9 ± 10.5 25.9 ± 3.6 8.65 ± 0.80 2017189 Jabbour 2014190 Dapagliflozin Placebo 48 451 55.0% 55.0 ± 10.3 NR 7.95 ± 0.80 Ji 2014191 Dapagliflozin Placebo 24 393 NR 51.0 ± 10.7 25.4 ± 3.5 8.20 ± 0.89 Ji 2015192 Canagliflozin Placebo 18 676 53.6% 56.0 ± 9.0 25.8 ± 3.5 8.00 ± 0.90 J-STEP/INS (Terauchi) Tofogliflozin Placebo 16 211 65.4% 58.2 ± 10.6 26.2 ± 3.7 8.49 ± 0.72 2017193 Kadowaki B Empagliflozin Placebo 12 327 73.7% 57.5 ± 9.3 25.5 ± 3.9 7.95 ± 0.74 2014194 Kadowaki 195 Canagliflozin Placebo 24 138 77.5% 57.2 ± 9.3 26.0 ± 4.1 8.03 ± 0.88 2017 Kaku 2013196 Dapagliflozin Placebo 12 164 76.0% 56.4 ± 10.4 NR 8.10 ± 0.69 Kaku 2014197 Dapagliflozin Placebo 24 271 59.3% 59.0 ± 9.9 25.0 ± 4.3 7.50 ± 0.65 Kohan 2014198 Dapagliflozin Placebo 24 252 65.1% 67.0 ± 8.5 NR 8.35 ± 1.12 Lambers 2013199 Dapagliflozin Placebo 12 49 69.4% 55.5 ± 9.7 NR 7.60 ± 0.83 LANTERN (Kashiwagi) Ipragliflozin Placebo 24 213 60.1% 64.5 ± 6.7 25.5 ± 3.4 7.54 ± 0.53 2015200 Leiter 2014201 Dapagliflozin Placebo 52 962 67.0% 64.0 ± 7.3 33.0 ± 5.5 8.05 ± 0.80 List 2009202 Dapagliflozin Placebo 12 139 51.0% 53.0 ± 10.9 32.0 ± 5.0 7.73 ± 0.87 Lu 2016203 Ipragliflozin Placebo 24 170 45.6% 53.5 ± 11.3 27.0 ± 4.2 7.75 ± 0.75 Mathieu B 204 Dapagliflozin Placebo 24 320 46.0% 55.1 ± 9.1 31.5 ± 5.1 8.20 ± 0.97 2015

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies) Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c Matthaei B Dapagliflozin Placebo 52 218 48.5% 61.0 ± 9.5 32.0 ± 4.7 8.15 ± 0.89 2015205 NCT01137474 206 Dapagliflozin Placebo 12 778 NR NR NR NR

Mudaliar 2014207 Dapagliflozin Placebo 12 44 65.9% 54.0 ± 8.6 NR 7.50 ± 0.75 Qiu 2014208 Canagliflozin Placebo 18 279 46.6% 57.4 ± 9.5 32.5 ± 6.5 7.60 ± 0.90 Rodbard 2016209 Canagliflozin Placebo 26 213 56.8% 57.4 ± 9.7 32.0 ± 5.7 8.50 ± 0.80 Rosenstock B Dapagliflozin Placebo 48 420 57.0% 54.0 ± 10.9 NR 8.37 ± 1.00 2012210 Ross 2015211 Empagliflozin Placebo 16 965 53.9% 58.2 ± 10.3 31.8 ± 5.2 7.77 ± 0.80 Schumm- 212 Dapagliflozin Placebo 16 399 44.8% 57.5 ± 9.5 32.7 ± 5.0 7.83 ± 0.77 Draeger 2015 Seino A 2014213 Luseogliflozin Placebo 12 178 66.9% 57.5 ± 9.9 24.8 ± 3.7 8.10 ± 0.88 Seino B 2014214 Luseogliflozin Placebo 12 167 71.9% 57.1 ± 10.3 25.2 ± 6.3 7.90 ± 0.77 Seino C 2014215 Luseogliflozin Placebo 24 158 73.5% 59.5 ± 9.7 25.5 ± 4.6 8.15 ± 0.86 Sha 2014216 Canagliflozin Placebo 12 36 86.1% 63.0 ± 5.6 29.8 ± 3.4 7.60 ± 0.55 Softeland Empagliflozin Placebo 24 333 59.2% 55.2 ± 9.8 30.2 ± 5.7 7.97 ± 0.84 2017217 Strojek 2014218 Dapagliflozin Placebo 48 438 50.3% 60.0 ± 9.4 30.0 ± 5.2 8.12 ± 0.77 Terra 2017219 Ertugliflozin Placebo 26 461 56.6% 56.4 ± 11.0 33.0 ± 6.7 8.21 ± 0.98 Weber 2016220 Dapagliflozin Placebo 12 449 55.0% 56.5 ± 9.0 NR 8.05 ± 0.95 Wilding 2009221 Dapagliflozin Placebo 12 47 59.2% 56.6 ± 9.0 35.7 ± 4.3 8.40 ± 0.84 Wilding 2013222 Ipragliflozin Placebo 12 134 51.0% 57.0 ± 8.1 32.0 ± 4.9 7.72 ± 0.63 Wilding 2014223 Dapagliflozin Placebo 24 598 47.2% 59.1 ± 8.2 33.1 ± 5.3 8.55 ± 0.82

224 No Yang 2016 Dapagliflozin 24 444 54.3% 53.7 ± 9.3 26.1 ± 3.3 8.13 ± 0.81 treatment DPP-4 Inhibitor vs. GLP-1 Agonist (14 studies) AWARD-5 Sitagliptin 225 Dulaglutide 52 1098 47.4% 54.2 ± 9.9 31.0 ± 4.3 8.10 ± 1.10 (Nauck) 2014 /Placebo Charbonnel Sitagliptin Liraglutide 26 653 54.8% 57.3 ± 10.4 32.7 ± 6.0 8.15 ± 1.01 2013226 DURATION 2 (Bergenstal) Sitagliptin Exenatide 26 326 53.7% 52.0 ± 10.5 32.0 ± 5.0 8.55 ± 1.20 2010227 DURATION 4 (Russell-Jones) Sitagliptin Exenatide 26 411 59.0% 54.0 ± 11.0 31.1 ± 5.3 8.50 ± 1.24 2012228 DURATION Exenatide/ NEO-2 (Gadde) Sitagliptin No 28 364 52.7% 53.7 ± 9.5 31.9 ± 5.5 8.50 ± 1.00 2017229 treatment HARMONY-3 Albiglutide/ Sitagliptin 104 705 45.9% 54.5 ± 10.0 32.6 ± 5.5 8.10 ± 0.82 (Ahren) 2014230 Placebo LIRA-DPP-4 231 Sitagliptin Liraglutide 26 665 37.9% 55.3 ± 9.2 32.8 ± 5.2 8.40 ± 0.74 (Pratley) 2010 LIRA-SWITCH Sitagliptin Liraglutide 26 404 59.5% 56.4 ± 10.2 32.0 ± 6.1 8.25 ± 0.60 (Bailey) 2016 232 NCT00976937 Sitagliptin Lixisenatide 24 319 40.1% 43.1 ± 4.9 36.8 ± 6.3 8.12 ± 0.93 233 Pratley 2011 234 Sitagliptin Liraglutide 52 658 53.5% 55.3 ± 9.2 32.9 ± 5.2 8.40 ± 0.74 SUSTAIN-2 235 Sitagliptin Semaglutide 56 1225 50.6% 55.1 ± 10.0 32.5 ± 6.2 8.10 ± 0.90 (Ahren) 2017 T-Emerge 4 (Bergenstal) Sitagliptin Taspoglutide 156 573 55.9% 55.8 ± 9.5 32.5 ± 5.1 7.95 ± 0.87 2012236 Van Gaal 2014237 Sitagliptin Lixisenatide 24 319 40.1% 43.1 ± 5.0 36.8 ± 6.8 8.13 ± 0.95 Zang 2016238 Sitagliptin Liraglutide 26 367 59.7% 51.6 ± 10.9 27.3 ± 3.7 8.13 ± 0.81

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2: Baseline Characteristics (All studies) Follow up Total Mean Mean Trial Drug Comparator Male % Mean HbA (weeks) randomised age (years) BMI 1c DPP-4 Inhibitor vs. SGLT-2 Inhibitor (8 studies) CANTATA-D (Lavalle- Sitagliptin Canagliflozin 52 1101 47.1% 55.4 ± 9.4 31.8 ± 6.3 7.90 ± 0.90 Gonzalez) 2013 239 CANTATA-D2 (Schernthaner) Sitagliptin Canagliflozin 52 755 55.9% 56.7 ± 9.5 31.6 ± 6.9 8.10 ± 0.90 2013240 DeFronzo Empagliflozi Linagliptin 24 405 51.1% 55.9 ± 10.2 31.1 ± 5.4 8.01 ± 0.89 2015241 n EMPA-REG Empagliflozi EXTEND MONO Sitagliptin 24 899 61.3% 55.0 ± 11.0 28.4 ± 5.6 7.88 ± 0.82 242 n (Roden) 2015 Empagliflozi Ferrannini B b 30.0 (20.4- 243 Sitagliptin n/No 78 444 51.3% 59.7 (32-79) b 7.94 ± 0.81 2013 40.2) treatment Rosenstock A Sitagliptin/ 244 Canagliflozin 12 323 NR 52.0 ± 8.5 31.3 ± 4.9 7.70 ± 0.92 2012 Placebo Rosenstock B Sitagliptin/ Empagliflozi 12 283 50.3% 58.3 ± 9.0 31.8 ± 4.5 7.92 ± 0.78 2013245 Placebo n Rosenstock Saxagliptin Dapagliflozin 24 355 NR NR 31.7 ± 5.2 8.90 ± 1.11 2015246 GLP-1 Agonist vs. SGLT-2 Inhibitor (1 study) DURATION 8 Exenatide Dapagliflozin 28 458 47.9% 54.3 ± 9.5 32.7 ± 6.0 9.30 ± 1.05 (Frias) 2016247 Mean data reported as mean ± standard deviation unless otherwise specified. a data reported as median (interquartile range); b data reported as mean (range); c data reported as median (range). HbA1c measured as %. BMI – body mass index; DPP-4 – dipeptidyl peptidase-4; GLP-1 – glucagon-like peptide- 1; HbA1c – glycated haemoglobin; NR – not reported; SGLT-2 – sodium-glucose cotransporter-2.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3: Baseline characteristics for cardiovascular outcome trials

Characteristic DPP-4 inhibitor GLP-1 agonist SGLT-2 inhibitor (3 trials27,78,84, (4 (2 trials178,248, n=36543) trials105,106,133,152, n=17170) Number (%) n=33457) Number (%) Number (%) White 26205 (71.7%) 25718 (76.9%) 13025 (75.9%) Asian 6120 (16.7%) 3416 (10.2%) 2801 (16.3%) Black 1221 (3.3%) 2093 (6.3%) 693 (4.0%)

Mean HbA1c (%) 7.7 ± 1.2 8.2 ± 1.0 8.1 ± 0.9 Mean diabetes duration 11.1 11.9 13.6 (years)a Mean BMI (kg/m2) 30.7 ± 5.6b 31.8 ± 5.8 31.4 ± 5.7 Any CV disease 29202 (79.9%) 27183 (81.2%) 13620 (79.3%) CVA 6066 (16.6%) 4848 (14.5%) 3595 (20.9%) CAD 23519 (64.4%) 21159 (63.2%) 11029 (64.2%) PAD 4909 (13.4%) 4910 (16.3%)c 3574 (20.8%) Heart failure 6246 (17.1%) 6191 (18.5%) 2167 (12.6%) Metformin 26330 (72.1%) 24868 (74.3%) 13018 (75.8%) Sulphonylurea 14537 (39.8%) 13549 (40.5%) 7367 (42.9%) Thiazolidinediones 1505 (4.1%) 1325 (4.0%) 299 (4.3%)d Insulin 15273 (41.8%) 15275 (45.7%) 8482 (49.4%) Beta-blocker 22739 (62.2%) 20407 (61.0%) 9975 (58.1%) ACEi/ARB 29134 (79.7%) 27036 (80.8%) 13782 (80.3%) Statin 28603 (78.3%) 25603 (76.5%) 13002 (75.7%) Anti-platelet 29183 (79.9%) 24211 (72.4%) 13456 (78.4%) aMeasure of spread not able to be calculated due to heterogeneity of reporting of spread in individual trials

bOut of 31163 patients (measure of spread not reported in EXAMINE)

cOut of 30160 patients (not reported in SUSTAIN-6)

dOut of 7028 patients (not reported in CANVAS and CANVAS-R)

Plus or minus values are means ± SD

ACEi – angiotensin converting enzyme inhibitor; ARB – angiotensin receptor blocker; CAD – coronary artery disease; CV – cardiovascular; CVA – cerebrovascular accident; DPP-4 – dipeptidyl peptidase-4; GLP-1 – glucagon-like peptide-1; PAD – peripheral artery disease; SGLT-2 – sodium-glucose cotransporter 2.

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

eTable 4: Risk of bias of individual trials

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias DPP4 inhibitor vs. Control (83 studies) Alba 201312 Low Low Low Low Low Ba 201713 Low Low Low Low High Bajaj 201414 Low Low Low Low Unclear Barnett 201215 Low Low Low Low Unclear Barnett A 201316 Low Low Low Low High Barnett B 201317 Low Low Low Low Low Barzilai 201118 Low Unclear Low Unclear Unclear Boer 201719 Low Low Low Low Low Bosi 200720 Low Low Low Low High Bosi 200921 Low Low Low Low High Chan 200822 Low Low Low Low Low Charbonnel Low Low Low Low Unclear 200623 DeFronzo 200824 Low Low Low Low High DeFronzo 201225 Low Low Low Low High DeFronzo 2015241 Low Low Low Low High Dobs 201326 Low Low Low Low High EXAMINE (White) Low Low Low Low Low 201327 Fonseca 200728 Low Low Low Low High Frederich 2012 29 Low Low Low Low High Garber 2008 30 Low Low Low Low High Goldstein 2007 31 Low Low Low Unclear Low Haak 2012 32 Low Low Low Low Unclear Henry 2011 33 Low Low Low Low High Henry 2014 34 Low Low Low Low High Hermansen 2007 Low Low Low Low High 35 Hirose 2015 36 Low Low Low Low Low Hollander 2011 37 Low Low Low Low High Ji 2017 38 Low Low Low Low Unclear Kadowaki A Low Low Low Low Low 201339 Kadowaki B Low Low Low Low Low 201340 Kadowaki A 2014 Low Low Low Low Low 41 Kanazawa 2017 42 Low Unclear High Low Low Kikuchi 2009 43 Low Low Low Low High

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4: Risk of bias of individual trials continued

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias Kikuchi 2010 44 Low Low Low Low Low Kim 2015 45 Low Low Low Low Unclear Kothny 2012 46 Low Low Low Low Low Kothny 2013 47 Low Low Low Low Unclear Lewin 2012 48 Low Low Low Low Low Lukashevich 2014 Low Low Low Low High 49 Macauley 2015 50 Low Low Low Low Unclear MARLINA-T2D Low Low Low Low Low (Groop) 201751 Mathieu A 201552 Low Low Low Low Low Matthaei A 201553 Low Low Low Low Low McGill 2014 54 Low Low Low Low Low Mohan 2009 55 Low Low Low Low Low Moses 2016 56 Low High High Low High Mu 2017 57 Low Low Low Low Low Nauck 200958 Low Low Low Low High NCT01778049 59 Unclear Unclear Unclear Unclear Unclear Ning 2016 60 Low Low Low Low Low Nowicki 201161 Low Low Low Low High Odawara 2014 62 Low Low Low Low High Olansky 2011 63 Low Low Low Low Low Pan 2012 64 Low Low Low Low High Pan 2017 65 Low Low Low Low Low Peng 2017 66 Low Low Low Low Low Pfutzner 2011 67 Low Low Low Low High Pratley A 200968 Low Low Low Low Unclear Pratley B 200969 Low Low Low Low Unclear Pratley 2014 70 Low Low Low Low High Raz 2008 71 Low Low Low Low Unclear Rosenstock 2008 Low Low Low Low High 72 Rosenstock A Low Low High Low Low 200973 Rosenstock B Low Low Low Low High 200974 Rosenstock A Low Low Low Low High 201375 Ross 2012 76 Low Low Low Low Low Saito 2017 77 Low Low Low Low Low SAVOR-TIMI 53 Low Low Low Low Low (Scirica) 201378 Scherbaum Low Low Low Low High 200879 Seino A 201280 Low Low High Low Unclear Seino B 201281 Low Low High Low Unclear

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4: Risk of bias of individual trials continued

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias Strain 2013 82 Low Low Low Low Low Tajima 2011 83 Low Low Low Low High TECOS (Green) Low Low Low Low Low 201584 Tinahones 2017 85 Low Low Low Low Low Van Raalte 2014 Low Low Low Low Low 86 Vilsboll 2010 87 Low Low Low Low Unclear Wang 2016 88 Low Low Low Low Low Wang 201789 Low Low Low Low Low White 2014 90 Low Low Low Low High Yang 2012 91 Low Low Low Low Low Yang 2015 92 Low Low Low Low Low Yki-Jarvinen 2013 Low Low Low Low Low 93 Younis 2017 94 Low Low High Low Low GLP-1 Agonist vs. Control (65 studies) Apovian (2010)95 Low Low Low Low Low AWARD-1 Low Low Low Low Unclear (Wysham) 2014 96 AWARD-8 Low Low Low Low Unclear (Dungan) 201697 AWARD-9 Low Low Low Low Low (Pozzilli) 201798 Buse 2011 100 Low Low Low Low High Buse 2004 99 Low Low Low Low High Chaudhuri 2012 Unclear Unclear High Unclear Unclear 101 DeFronzo 2005 Low Low Low Low High 102 Derosa 2013 103 Low Low Low Low Low DUAL-I (Gough) Low Low High Low Unclear 2014104 ELIXA (Pfeffer) Low Low Low Low Low 2015105 EXSCEL Low Low Low Low Low (Holman) 2017106 Ferdinand 2014107 Low Low Low Low High Gao 2009 108 Low Low Low Low Low GetGoal L Low Low Low Low High (Riddle) 2013109 GetGoal L Asia Low Low Low Low Unclear (Seino) 2012110 GetGoal M Low Low Low Low Low (Ahren) 2013111

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4: Risk of bias of individual trials continued

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias GetGoal M Asia Low Low Low Low Low (Pan) 2014112 GetGoal O Low Low Low Low Unclear (Meneilly) 2017113 GetGoal P Low Low Low Low Unclear (Pinget) 2013114 GetGoal S (Rosenstock) Low Low Low Low Low 2014115 GetGoal-Duo 1 Low Low Low Low Unclear (Riddle) 2013116 GetGoal-F1 (Bolli) Low Low Low Low High 2014117 Grunberger Low Low Low Low Low 2012118 HARMONY-1 Low Low Low Low High (Reusch) 2014119 HARMONY-2 Low Low Low Low High (Nauck) 2016120 HARMONY-5 Low Low Low Low Low (Home)121 Idorn 2016 122 Low Low Low Low High Kadowaki 2009 123 Low Low Low Low High Kadowaki 2011124 Low Low Low Low High Kaku 2010125 Low Low Low Low High Kapitza 2017126 Unclear High Low Low Unclear Kendall 2005127 Low Low Low Low High Kim 2007128 Low Low Low Unclear Low LEAD-1 SU Low Low Low Low Low (Marre) 2009129 LEAD-2 (2 year) Low Low Low Low High (Nauck) 2013130 LEAD-4 (Zinman) Low Low Low Low Low 2009131 LEAD-5 MET+SU (Russell-Jones) Low Low Low Low Unclear 2009132 LEADER (Marso) Low Low Low Low Low 2016133 LIRA-RENAL Low Low Low Low High (Davies) 2016134 Liutkus 2010135 Low Low Low Low High LixiLan (Aroda) Low Low High Low Low 2016136 LixiLan-O (Rosenstock) Low Low High Low High 2016137

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4: Risk of bias of individual trials continued

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias LixiLan POC (Rosenstock) Low Low Low Low Low 2016138 Lu 2013139 Low Low Low Low Low MEXELIN Unclear Unclear Unclear Unclear Unclear (NCT00667732)140 Miyagawa 2015141 Low Low Low Low Low Moretto 2008142 Low Low Low Low Unclear NCT00375492 143 Unclear Unclear Unclear Unclear Unclear NCT00701935 144 Unclear Unclear Unclear Unclear Unclear NCT01001104 145 Unclear Unclear Unclear Unclear Unclear NCT01617434 146 Unclear Unclear Unclear Unclear Unclear NCT01733758 147 Unclear Unclear Unclear Unclear Unclear Ratner 2010148 Low Low Low Low Low SCALE (Davies) Low Low Low Low High 2015149 Seino 2014150 Low Low Low Low Low Seino 2016151 Low Low Low Low Low SUSTAIN-6 Low Low Low Low Low (Marso) 2016152 T-Emerge 1 (Raz) Low Unclear Low Low Low 2012153 T-Emerge 3 Low Low Low Low High (Henry) 2012154 T-Emerge 7 (Hollander) Low Low Low Low Low 2013155 Terauchi 2014156 Low Low Low Low Low Vanderheiden Low Low Low Low Low 2016157 Wu 2011158 Unclear Unclear Low Low Low Zinman 2007159 Low Low Low Low High SGLT2 Inhibitor vs. Control (65 studies) Araki 2016160 Low Low High Low Low Bailey 2012161 Low Low Unclear Low Low Bailey 2013162 Low Low Low Low Low Bode 2015163 Low Low Low Low Low Bolinder 2014164 Low Low Low Low Low CANTATA-M Low Unclear Low Low Low (Stenlof) 2013165 CANTATA-MP Low Low Low Low Unclear (Forst) 2014166 CANTAT-MSU Low Low Low Low High (Wilding) 2013167 CANVAS (Neal) Low Low Low Low Low 2017168,169

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4: Risk of bias of individual trials continued

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias CANVAS-R (Neal) Low Low Low Low Low 2017169 Cefalu 2015170 Low Low Low Low Low DIA3400 (Yale) Low Low Low Low Low 2014171 EMPA-REG BASAL Low Low Low Low Low (Rosenstock) 2015172 EMPA-REG BP (Tikkanen) Low Low Low Low Low 2015173 EMPA-REG EXTEND MET Low Low Low Low Low (Merker) 2015174 EMPA-REG EXTEND METSU Low Low Low Low Low (Haering) 2015175 EMPA-REG EXTEND PIO Low Low Low Low Low (Kovacs) 2015176 EMPA-REG MDI (Rosenstock) Low Low Unclear Low Low 2014177 EMPA-REG OUTCOME Low Low Low Low Low (Zinman) 2015178 EMPA-REG RENAL (Barnett) Low Low Low Low Low 2014179 Fadini 2017180 Low Low High Low Low Ferrannini 2010181 Unclear Unclear Low Low Low Ferrannini A Low Low Low Low Low 2013182 Fonseca 2013183 Unclear Unclear Unclear Low Low Henry 2012184 Low Low Low Low Low ILLUMINATE (Kashiwagi) Low Low Low Low Low 2015185 Inagaki 2013186 Low Low Low Low Low Inagaki 2014187 Low Low Low Low Low Inagaki 2016188 Low Low Low Unclear Low IOLITE (Ishihara) Low Low Low Low Low 2016189 Jabbour 2014190 Low Unclear Unclear Low Low Ji 2014191 Low Low Low Low Low Ji 2015192 Low Low Low Low Low

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4: Risk of bias of individual trials continued

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias J-STEP/INS Low Unclear Low Low Low (Terauchi) 2017193 Kadowaki B Low Low Low Low Low 2014194 Kadowaki 2017195 Low Unclear Low Low Unclear Kaku 2013196 Low Low Unclear Low Low Kaku 2014197 Unclear Unclear Unclear Low Low Kohan 2014198 Low Low Low Low High Lambers 2013199 Low Low Low Low Unclear LANTERN (Kashiwagi) Low Low Low Low Low 2015200 Leiter 2014201 Low Unclear Unclear Low Low List 2009202 Unclear Unclear Unclear Low Low Lu 2016203 Low Low Low Low Low Mathieu B 2015204 Low Low Low Low Low Matthaei B Unclear Unclear Low Low Low 2015205 Mudaliar 2014207 Unclear Unclear Low Low Low NCT01137474206 Unclear Unclear Unclear Unclear Unclear Qiu 2014208 Low Low Low Low Low Rodbard 2016209 Low Low Low Low Low Rosenstock B Low Unclear Unclear Low Low 2012210 Ross 2015211 Low Low Low Low Low Schumm-Draeger Low Low Low Low Low 2015212 Seino A 2014213 Low Low Low Low Low Seino B 2014214 Low Low Low Low Low Seino C 2014215 Low Low Low Low Low Sha 2014216 Low Unclear Unclear Low Low Softeland 2017217 Low Low Unclear Unclear Low Strojek 2014218 Low Low Low Low Low Terra 2017219 Low Low Low Low Low Weber 2016220 Low Low Low Low Low Wilding 2009221 Low Unclear Unclear Low Low Wilding 2013222 Unclear Unclear Unclear Low Low Wilding 2014223 Low Low Low Low Low Yang 2016224 Low Unclear High Low Low DPP-4 Inhibitor vs. GLP-1 Agonist (14 studies) AWARD-5 Low Low Low Low High (Nauck) 2014225 Charbonnel Low Low High Unclear High 2013226

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4: Risk of bias of individual trials continued

Sequence Allocation Detection Attrition Trial Blinding generation concealment Bias Bias DURATION-2 (Bergenstal) 2010 Low Low Low Unclear High 227 DURATION-4 (Russell-Jones) Low Low Low Low Unclear 2012228 DURATION NEO- Low Low High Low High 2 (Gadde) 2017229 HARMONY-3 Low Low Low Low High (Ahren) 2014230 LIRA-DPP-4 Low High High Low Unclear (Pratley) 2010231 LIRA-SWITCH Low Low Low Low Low (Bailey) 2016232 NCT00976937 233 Unclear Unclear Unclear Unclear Unclear Pratley 2011234 Low Low Low Low Unclear SUSTAIN-2 Low Low Low Low Low (Ahren) 2017235 T-Emerge 4 (Bergenstal) Low Low Low Low Low 2012236 Van Gaal 2014237 Unclear Unclear Low Low High Zang 2016238 Low Low Unclear Unclear Low DPP-4 Inhibitor vs. SGLT-2 Inhibitor (8 studies) CANTATA-D (Lavalle- Low Low Low Low Low Gonzalez) 2013239 CANTATA-D2 (Schernthaner) Low Low Low Low Low 2013240 DeFronzo 2015241 Low Low Low Low Low EMPA-REG EXTEND MONO Low Low Unclear Low Unclear (Roden) 2015242 Ferrannini B Low Low High Low Low 2013243 Rosenstock A Unclear Unclear Unclear Low Low 2012244 Rosenstock B Low Low Low Low Low 2013245 Rosenstock Low Low Low Low Low 2015246 GLP-1 Agonist vs. SGLT-2 inhibitor (1 study) DURATION-8 Low Low Low Low Low (Frias) 2016 247 DPP-4 – dipeptidyl peptidase-4; GLP-1 – glucagon-like peptide-1; SGLT-2 – sodium-glucose cotransporter-2.

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

Data are presented as hazard ratio (95% credible interval). credible (95%ratio as hazard presented are Data analysis by individual drug type drug byindividual analysis effects model. model. effects -

- meta network mortality cause - indicatesstatistically significant results favoring thetreatment (row). Red indicatesstatistically significant results

: All ring the comparator(column). the ring eTable 5 eTable Analysiswas performedusing a bayesian fixed favo Greenshading

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 6: Clinical endpoints in cardiovascular outcome trials (Bayesian fixed- effects model)

All-cause mortality 9 trials, 5827 events, 87,162 patients, 247,034 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 2877 events, Reference 0.98 (0.90-1.06) 1.14 (1.05-1.23) 1.28 (1.14-1.44) 41,661 patients DPP-4i 1120 events, 1.02 (0.94-1.11) Reference 1.16 (1.04-1.30) 1.31 (1.13-1.51) 18,313 patients GLP-1a 1161 events, 0.88 (0.81-0.95) 0.86 (0.77-0.96) Reference 1.12 (0.98-1.29) 16,706 patients SGLT-2i 669 events, 0.78 (0.70-0.88) 0.77 (0.66-0.88) 0.89 (0.77-1.02) Reference 10,482 patients

Composite cardiovascular outcome (Cardiovascular Mortality, Non-fatal MI, non-fatal stroke) 9 trials, 9203 events, 87,162 patients, 247,034 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 4513 events, Reference 1.01 (0.94-1.09) 1.10 (1.04-1.17) 1.14 (1.03-1.26) 41,661 patients DPP-4i 1663 events, 0.99 (0.92-1.07) Reference 1.09 (0.99-1.20) 1.13 (1.00-1.28) 18,313 patients GLP-1a 1952 events, 0.91 (0.85-0.96) 0.91 (0.83-1.01) Reference 1.03 (0.92-1.16) 16,706 patients SGLT-2i 1075 events, 0.88 (0.79-0.97) 0.88 (0.78-1.00) 0.97 (0.86-1.09) Reference 10,482 patients

Cardiovascular mortality 9 trials, 3728 events, 87,162 patients, 247,034 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 1859 events, Reference 1.01 (0.91-1.12) 1.17 (1.06-1.29) 1.32 (1.14-1.52) 41,661 patients DPP-4i 738 events, 0.99 (0.90-1.10) Reference 1.16 (1.00-1.34) 1.31 (1.10-1.56) 18,313 patients GLP-1a 691 events, 0.86 (0.77-0.95) 0.86 (0.75-1.00) Reference 1.13 (0.95-1.35) 16,706 patients SGLT-2i 440 events, 0.76 (0.66-0.88) 0.76 (0.64-0.91) 0.89 (0.74-1.06) Reference 10,482 patients

Heart failure hospitalisation 8 trials, 2716 events, 81,782 patients, 239,053 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 1332 events, Reference 0.88 (0.71-1.10) 1.07 (0.90-1.25) 1.59 (1.27-1.94) 38,982 patients DPP-4i 517 events, 1.13 (0.91-1.41) Reference 1.21 (0.91-1.58) 1.80 (1.30-2.40) 15,612 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 6: Clinical endpoints in cardiovascular outcome trials (Bayesian fixed- effects model) continued

Placebo DPP-4i GLP-1a SGLT-2i

GLP-1a 618 events, 0.93 (0.80-1.12) 0.82 (0.63-1.10) Reference 1.49 (1.14-1.93) 16,706 patients SGLT-2i 249 events, 0.63 (0.52-0.79) 0.55 (0.42-0.77) 0.67 (0.52-0.88) Reference 10,482 patients

All myocardial infarction 8 trials, 4173 events, 81,782 patients, 239,053 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 2045 events, Reference 1.05 (0.94-1.18) 1.06 (0.95-1.18) 1.13 (0.97-1.32) 38,982 patients DPP-4i 565 events, 0.95 (0.84-1.07) Reference 1.01 (0.86-1.18) 1.07 (0.88-1.30) 15,612 patients GLP-1a 1096 events, 0.94 (0.85-1.05) 0.99 (0.85-1.16) Reference 1.06 (0.88-1.28) 16,706 patients SGLT-2i 467 events, 0.89 (0.76-1.03) 0.93 (0.77-1.13) 0.94 (0.78-1.14) Reference 10,482 patients

All stroke 6 trials, 1848 events, 68,343 patients, 195,748 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 892 events, Reference 0.97 (0.80-1.17) 1.12 (0.94-1.31) 1.05 (0.86-1.29) 32,986 patients DPP-4i 335 events, 1.03 (0.85-1.25) Reference 1.15 (0.89-1.48) 1.09 (0.82-1.44) 15,612 patients GLP-1a 427 events, 0.90 (0.76-1.06) 0.87 (0.68-1.12) Reference 0.94 (0.73-1.23) 15,058 patients SGLT-2i 194 events, 0.95 (0.77-1.17) 0.92 (0.69-1.22) 1.06 (0.81-1.37) Reference 4687 patients

Unstable angina 6 trials, 938 events, 56,888 patients, 155,136 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 437 events, Reference 0.98 (0.76-1.25) 1.04 (0.79-1.38) 1.01 (0.70-1.46) 27,239 patients DPP-4i 213 events, 1.02 (0.80-1.31) Reference 1.07 (0.74-1.55) 1.03 (0.66-1.62) 15,612 patients GLP-1a 155 events, 0.96 (0.72-1.26) 0.94 (0.64-1.36) Reference 0.97 (0.61-1.53) 9350 patients SGLT-2i 133 events, 0.99 (0.68-1.44) 0.97 (0.62-1.52) 1.04 (0.65-1.65) Reference 4687 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 6: Clinical endpoints in cardiovascular outcome trials (Bayesian fixed- effects model) continued

Non-fatal myocardial infarction 7 trials, 3204 events, 55,999 patients, 168,388 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 1551 events, Reference 0.93 (0.70-1.22) 1.07 (0.95-1.24) 1.16 (0.97-1.41) 26,110 patients DPP-4i 187 events, 1.08 (0.82-1.43) Reference 1.16 (0.86-1.60) 1.26 (0.90-1.77) 2701 patients GLP-1a 1038 events, 0.93 (0.81-1.06) 0.86 (0.63-1.17) Reference 1.08 (0.86-1.36) 16,706 patients SGLT-2i 428 events, 0.86 (0.71-1.04) 0.79 (0.57-1.11) 0.92 (0.74-1.17) Reference 10,482 patients

Non-fatal stroke 7 trials, 1387 events, 55,999 patients, 168,388 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 655 events, Reference 1.10 (0.59-2.04) 1.15 (0.91-1.48) 0.99 (0.75-1.32) 26,110 patients DPP-4i 29 events, 0.91 (0.49-1.69) Reference 1.05 (0.54-2.04) 0.90 (0.46-1.79) 2701 patients GLP-1a 395 events, 0.87 (0.68-1.10) 0.95 (0.49-1.85) Reference 0.86 (0.59-1.25) 16,706 patients SGLT-2i 308 events, 1.01 (0.76-1.34) 1.11 (0.56-2.18) 1.17 (0.80-1.69) Reference 10,482 patients Data are reported as hazard ratio (95% credible interval). Point estimates and 95% credible interval are for comparison of drug type or control (vertical) with reference drug type or control (horizontal). A hazard ratio of less than 1 indicates that the outcome is more likely with treatment (row) than reference (column).

Composite cardiovascular outcome: cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke. This is the primary outcome reported by all included cardiovascular outcome trials. All trials were placebo-controlled.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model)

Primary and secondary outcomes excluding trials with low cardiovascular risk

All-cause mortality 23 trials, 5887 events, 92,470 patients, 252,293 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2901 events, Reference 0.98 (0.90-1.06) 1.14 (1.05-1.23) 1.27 (1.13-1.42) 43,906 patients DPP-4i 1129 events, 1.02 (0.94-1.11) Reference 1.16 (1.04-1.30) 1.30 (1.13-1.49) 18,747 patients GLP-1a 1166 events, 0.88 (0.81-0.95) 0.86 (0.77-0.96) Reference 1.12 (0.97-1.28) 17,629 patients SGLT-2i 691 events, 0.79 (0.70-0.88) 0.77 (0.67-0.89) 0.90 (0.78-1.03) Reference 12,188 patients

Cardiovascular mortality 20 trials, 3759 events, 92,375 patients, 252,345 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1868 events, Reference 1.01 (0.91-1.12) 1.17 (1.05-1.29) 1.29 (1.12-1.49) 43,597 patients DPP-4i 742 events, 0.99 (0.90-1.10) Reference 1.16 (1.00-1.34) 1.28 (1.08-1.53) 18,712 patients GLP-1a 695 events, 0.86 (0.78-0.95) 0.86 (0.75-1.00) Reference 1.11 (0.93-1.32) 17,878 patients SGLT-2i 454 events, 0.77 (0.67-0.89) 0.78 (0.65-0.93) 0.90 (0.76-1.08) Reference 12,188 patients

Heart failure events 19 trials, 2743 events, 86,846 patients, 244,295 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1346 events, Reference 0.87 (0.69-1.08) 1.07 (0.88-1.24) 1.63 (1.33-2.03) 49,918 patients DPP-4i 523 events, 1.14 (0.92-1.45) Reference 1.22 (0.91-1.60) 1.87 (1.40-2.58) 16,011 patients GLP-1a 621 events, 0.94 (0.81-1.14) 0.82 (0.63-1.10) Reference 1.53 (1.20-2.06) 17,729 patients SGLT-2i 253 events, 0.61 (0.49-0.75) 0.54 (0.39-0.72) 0.65 (0.49-0.84) Reference 12,188 patients

All myocardial infarction 19 trials, 4221 events, 86,846 patients, 244,295 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2064 events, Reference 1.04 (0.92-1.16) 1.06 (0.96-1.19) 1.14 (1.00-1.30) 49,918 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Control DPP-4i GLP-1a SGLT-2i DPP-4i 576 events, 0.96 (0.86-1.09) Reference 1.02 (0.88-1.21) 1.09 (0.92-1.31) 16,011 patients GLP-1a 1102 events, 0.94 (0.84-1.05) 0.98 (0.83-1.14) Reference 1.07 (0.91-1.27) 17,729 patients SGLT-2i 479 events, 0.88 (0.77-1.00) 0.91 (0.76-1.08) 0.93 (0.79-1.10) Reference 12,188 patients

All stroke 17 trials, 1888 events, 74,185 patients, 201,170 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 908 events, Reference 0.97 (0.77-1.23) 1.12 (0.90-1.35) 1.06 (0.84-1.36) 35,233 patients DPP-4i 341 events, 1.03 (0.81-1.30) Reference 1.15 (0.83-1.54) 1.09 (0.78-1.54) 16,011 patients GLP-1a 433 events, 0.90 (0.74-1.12) 0.87 (0.65-1.20) Reference 0.95 (0.71-1.33) 16,081 patients SGLT-2i 206 events, 0.94 (0.74-1.19) 0.92 (0.65-1.28) 1.05 (0.75-1.42) Reference 6860 patients

Unstable angina 13 trials, 959 events, 61,253 patients, 159,566 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 450 events, Reference 0.98 (0.59-1.63) 1.09 (0.73-1.95) 1.11 (0.69-2.22) 28,869 patients DPP-4i 214 events, 1.02 (0.61-1.70) Reference 1.11 (0.61-2.46) 1.13 (0.59-2.76) 15,926 patients GLP-1a 155 events, 0.92 (0.51-1.37) 0.90 (0.41-1.63) Reference 1.02 (0.50-2.18) 10,233 patients SGLT-2i 140 events, 0.90 (0.45-1.45) 0.88 (0.36-1.69) 0.98 (0.46-2.00) Reference 6225 patients

Non-fatal myocardial infarction 9 trials, 3208 events, 56,169 patients, 168,558 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1552 events, Reference 0.91 (0.67-1.20) 1.07 (0.94-1.25) 1.17 (0.96-1.42) 26,195 patients DPP-4i 190 events, 1.10 (0.83-1.49) Reference 1.18 (0.87-1.67) 1.28 (0.92-1.85) 2786 patients GLP-1a 1038 events, 0.93 (0.80-1.06) 0.85 (0.60-1.14) Reference 1.09 (0.85-1.37) 16,706 patients SGLT-2i 428 events, 0.86 (0.70-1.04) 0.78 (0.54-1.09) 0.92 (0.73-1.18) Reference 10,482 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Non-fatal stroke 10 trials, 1389 events, 56,947 patients, 168,737 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 657 events, Reference 1.15 (0.61-2.27) 1.15 (0.89-1.52) 1.00 (0.75-1.41) 26,506 patients DPP-4i 29 events, 0.87 (0.44-1.64) Reference 1.00 (0.48-1.98) 0.87 (0.42-1.79) 2786 patients GLP-1a 395 events, 0.87 (0.66-1.13) 1.00 (0.50-2.07) Reference 0.87 (0.58-1.34) 16,706 patients SGLT-2i 308 events, 1.00 (0.71-1.34) 1.15 (0.56-2.40) 1.15 (0.75-1.72) Reference 10,949 patients Data are reported as hazard ratio (95% credible interval). Point estimates and 95% credible interval are for comparison of drug type or control (vertical) with reference drug type or control (horizontal). A hazard ratio of less than 1 indicates that the outcome is more likely with treatment (row) than reference (column). Control refers to placebo or no treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Primary and secondary outcomes excluding trials enrolling participants with recent history of acute coronary syndrome

All-cause mortality 95 trials, 5275 events, 122,712 patients, 270,622 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2559 events, Reference 0.98 (0.90-1.06) 1.14 (1.06-1.23) 1.25 (1.12-1.40) 51,309 patients DPP-4i 1018 events, 1.02 (0.94-1.11) Reference 1.17 (1.04-1.30) 1.28 (1.11-1.47) 27,477 patients GLP-1a 984 events, 0.88 (0.81-0.94) 0.86 (0.77-0.96) Reference 1.10 (0.96-1.26) 24,339 patients SGLT-2i 714 events, 0.80 (0.71-0.89) 0.78 (0.68-0.90) 0.91 (0.80-1.04) Reference 19,587 patients

Cardiovascular mortality 54 trials, 3437 events, 103,901 patients, 251,381 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1679 events, Reference 1.00 (0.90-1.10) 1.17 (1.06-1.30) 1.27 (1.10-1.46) 445,156 patients DPP-4i 674 events, 1.00 (0.91-1.11) Reference 1.18 (1.02-1.35) 1.27 (1.07-1.51) 21,818 patients GLP-1a 616 events, 0.85 (0.77-0.94) 0.85 (0.74-0.98) Reference 1.08 (0.91-1.29) 20,520 patients SGLT-2i 468 events, 0.79 (0.69-0.91) 0.79 (0.66-0.94) 0.93 (0.78-1.10) Reference 16,407 patients

Heart failure events 57 trials, 2569 events, 103,973 patients, 255,061 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1243 events, Reference 0.90 (0.74-1.11) 1.06 (0.89-1.23) 1.57 (1.26-1.89) 45,328 patients DPP-4i 544 events, 1.12 (0.90-1.36) Reference 1.19 (0.89-1.49) 1.76 (1.28-2.27) 22,327 patients GLP-1a 516 events, 0.94 (0.81-1.13) 0.84 (0.67-1.12) Reference 1.48 (1.14-1.90) 20,329 patients SGLT-2i 266 events, 0.64 (0.53-0.80) 0.57 (0.44-0.78) 0.68 (0.53-0.88) Reference 15,989 patients

All myocardial infarction 96 trials, 3863 events, 120,851 patients, 266,887 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1872 events, Reference 1.06 (0.96-1.20) 1.06 (0.96-1.19) 1.16 (1.03-1.32) 50,065 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Control DPP-4i GLP-1a SGLT-2i DPP-4i 616 events, 0.94 (0.84-1.04) Reference 1.00 (0.86-1.15) 1.09 (0.93-1.29) 27,462 patients GLP-1a 870 events, 0.94 (0.84-1.04) 1.00 (0.87-1.17) Reference 1.09 (0.93-1.29) 23,366 patients SGLT-2i 505 events, 0.86 (0.76-0.97) 0.92 (0.78-1.07) 0.92 (0.78-1.07) Reference 19,958 patients

All stroke 82 trials, 1897 events, 103,713 patients, 221,378 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 895 events, Reference 0.98 (0.80-1.21) 1.11 (0.91-1.33) 1.09 (0.89-1.38) 42,978 patients DPP-4i 371 events, 1.02 (0.83-1.25) Reference 1.13 (0.85-1.47) 1.12 (0.84-1.52) 25,106 patients GLP-1a 388 events, 0.90 (0.75-1.10) 0.88 (0.68-1.18) Reference 0.98 (0.76-1.36) 20,296 patients SGLT-2i 243 events, 0.92 (0.72-1.12) 0.89 (0.66-1.19) 1.02 (0.73-1.32) Reference 15,333 patients

Unstable angina 49 trials, 995 events, 75,658 patients, 167,024 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 460 events, Reference 0.99 (0.71-1.40) 1.10 (0.80-1.66) 1.05 (0.69-1.57) 33,328 patients DPP-4i 227 events, 1.01 (0.71-1.41) Reference 1.11 (0.71-1.88) 1.06 (0.62-1.79) 21,211 patients GLP-1a 154 events, 0.91 (0.60-1.25) 0.90 (0.53-1.40) Reference 0.95 (0.53-1.57) 11,244 patients SGLT-2i 154 events, 0.96 (0.64-1.45) 0.95 (0.56-1.62) 1.05 (0.64-1.90) Reference 9875 patients

Non-fatal myocardial infarction 44 trials, 2405 events, 60,583 patients, 158,268 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2405 events, Reference 0.96 (0.75-1.31) 1.07 (0.93-1.25) 1.20 (1.01-1.51) 25,825 patients DPP-4i 21 events, 1.04 (0.76-1.33) Reference 1.12 (0.79-1.48) 1.25 (0.90-1.73) 5255 patients GLP-1a 787 events, 0.93 (0.80-1.08) 0.89 (0.67-1.27) Reference 1.12 (0.90-1.48) 14,920 patients SGLT-2i 438 events, 0.83 (0.66-0.99) 0.80 (0.58-1.11) 0.89 (0.68-1.12) Reference 14,583 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Non-fatal stroke 41 trials, 1271 events, 59,409 patients, 157,360 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 593 events, Reference 0.91 (0.50-1.47) 1.18 (0.92-1.69) 1.02 (0.77-1.48) 26,245 patients DPP-4i 14 events, 1.10 (0.68-1.99) Reference 1.30 (0.77-2.74) 1.13 (0.66-2.33) 4114 patients GLP-1a 344 events, 0.85 (0.59-1.08) 0.77 (0.37-1.30) Reference 0.87 (0.56-1.32) 15,429 patients SGLT-2i 320 events, 0.98 (0.68-1.30) 0.89 (0.43-1.52) 1.16 (0.76-1.79) Reference 13,621 patients Data are reported as hazard ratio (95% credible interval). Point estimates and 95% credible interval are for comparison of drug type or control (vertical) with reference drug type or control (horizontal). A hazard ratio of less than 1 indicates that the outcome is more likely with treatment (row) than reference (column). Control refers to placebo or no treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Primary and secondary outcomes restricted to trials with low risk of bias in all domains

All-cause mortality 43 trials, 5911 events, 105,695 patients, 265,844 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2902 events, Reference 0.98 (0.90-1.06) 1.14 (1.05-1.23) 1.25 (1.12-1.40) 47,503 patients DPP-4i 1141 events, 1.02 (0.94-1.11) Reference 1.17 (1.04-1.31) 1.28 (1.11-1.48) 22,394 patients GLP-1a 1169 events, 0.88 (0.81-0.95) 0.86 (0.77-0.96) Reference 1.10 (0.96-1.26) 19,135 patients SGLT-2i 699 events, 0.80 (0.71-0.90) 0.78 (0.68-0.90) 0.91 (0.79-1.04) Reference 16,663 patients

Cardiovascular mortality 29 trials, 3769 events, 99,508 patients, 259,183 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1865 events, Reference 1.00 (0.90-1.11) 1.17 (1.06-1.29) 1.27 (1.10-1.46) 45,550 patients DPP-4i 748 events, 1.00 (0.90-1.11) Reference 1.17 (1.01-1.35) 1.27 (1.07-1.51) 20,449 patients GLP-1a 695 events, 0.86 (0.77-0.95) 0.86 (0.74-0.99) Reference 1.09 (0.91-1.29) 18,475 patients SGLT-2i 461 events, 0.79 (0.68-0.91) 0.79 (0.66-0.94) 0.92 (0.77-1.10) Reference 15,034 patients

Heart failure events 23 trials, 2754 events, 90,036 patients, 248,061 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1348 events, Reference 0.88 (0.70-1.08) 1.07 (0.89-1.25) 1.58 (1.26-1.91) 42,061 patients DPP-4i 526 events, 1.14 (0.92-1.43) Reference 1.22 (0.92-1.60) 1.81 (1.32-2.40) 16,513 patients GLP-1a 620 events, 0.93 (0.80-1.12) 0.82 (0.63-1.08) Reference 1.48 (1.13-1.91) 17,418 patients SGLT-2i 260 events, 0.63 (0.52-0.79) 0.55 (0.42-0.76) 0.68 (0.52-0.89) Reference 14,044 patients

All myocardial infarction 38 trials, 4249 events, 97,708 patients, 253,764 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2076 events, Reference 1.05 (0.93-1.17) 1.06 (0.95-1.18) 1.16 (1.02-1.32) 43,865 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Control DPP-4i GLP-1a SGLT-2i DPP-4i 584 events, 0.96 (0.85-1.07) Reference 1.01 (0.87-1.19) 1.11 (0.94-1.32) 19,130 patients GLP-1a 1100 events, 0.94 (0.85-1.05) 0.99 (0.84-1.15) Reference 1.10 (0.93-1.29) 17,614 patients SGLT-2i 489 events, 0.86 (0.76-0.98) 0.90 (0.76-1.07) 0.91 (0.77-1.08) Reference 17,099 patients

All stroke 39 trials, 1938 events, 85,892 patients, 212,024 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 927 events, Reference 0.96 (0.74-1.21) 1.12 (0.90-1.40) 1.09 (0.88-1.42) 38,766 patients DPP-4i 349 events, 1.04 (0.83-1.35) Reference 1.17 (0.85-1.65) 1.14 (0.85-1.66) 18,624 patients GLP-1a 429 events, 0.89 (0.71-1.11) 0.85 (0.60-1.17) Reference 0.97 (0.72-1.38) 15,924 patients SGLT-2i 233 events, 0.92 (0.70-1.13) 0.88 (0.60-1.18) 1.03 (0.72-1.38) Reference 12,578 patients

Unstable angina 22 trials, 976 events, 65,978 patients, 164,909 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 453 events, Reference 0.96 (0.62-1.37) 1.04 (0.68-1.53) 1.10 (0.72-1.79) 39,560 patients DPP-4i 218 events, 1.04 (0.73-1.61) Reference 1.08 (0.63-1.94) 1.14 (0.68-2.23) 16,907 patients GLP-1a 158 events, 0.96 (0.65-1.46) 0.93 (0.51-1.59) Reference 1.06 (0.60-2.05) 9987 patients SGLT-2i 147 events, 0.91 (0.56-1.38) 0.88 (0.45-1.47) 0.95 (0.49-1.66) Reference 8524 patients

Non-fatal myocardial infarction 20 trials, 3220 events, 61,418 patients, 171,874 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1560 events, Reference 0.96 (0.74-1.44) 1.07 (0.93-1.26) 1.19 (0.98-1.48) 27,817 patients DPP-4i 188 events, 1.04 (0.69-1.35) Reference 1.11 (0.72-1.51) 1.23 (0.81-1.72) 3956 patients GLP-1a 1039 events, 0.93 (0.79-1.08) 0.90 (0.66-1.38) Reference 1.10 (0.87-1.44) 16,902 patients SGLT-2i 433 events, 0.84 (0.68-1.02) 0.81 (0.58-1.23) 0.91 (0.70-1.15) Reference 12,743 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Non-fatal stroke 24 trials, 1413 events, 62,221 patients, 172,567 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 665 events, Reference 0.91 (0.43-1.65) 1.16 (0.88-1.65) 1.02 (0.76-1.53) 28,544 patients DPP-4i 35 events, 1.10 (0.61-2.32) Reference 1.27 (0.67-3.02) 1.13 (0.59-2.73) 4068 patients GLP-1a 397 events, 0.86 (0.61-1.14) 0.78 (0.33-1.48) Reference 0.88 (0.57-1.44) 17,370 patients SGLT-2i 316 events, 0.98 (0.65-1.31) 0.89 (0.37-1.68) 1.14 (0.70-1.75) Reference 12,239 patients Data are reported as hazard ratio (95% credible interval). Point estimates and 95% credible interval are for comparison of drug type or control (vertical) with reference drug type or control (horizontal). A hazard ratio of less than 1 indicates that the outcome is more likely with treatment (row) than reference (column). Control refers to placebo or no treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Primary and secondary outcomes excluding trials with follow-up <52 weeks

All-cause mortality 49 trials, 5962 events, 103,713 patients, 221,378 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2925 events, Reference 0.98 (0.90-1.06) 1.14 (1.06-1.23) 1.25 (1.12-1.41) 48,307 patients DPP-4i 1152 events, 1.02 (0.94-1.11) Reference 1.16 (1.04-1.30) 1.28 (1.11-1.47) 23,856 patients GLP-1a 1179 events, 0.88 (0.81-0.95) 0.86 (0.77-0.96) Reference 1.10 (0.96-1.26) 21,561 patients SGLT-2i 706 events, 0.80 (0.71-0.89) 0.78 (0.68-0.90) 0.91 (0.79-1.04) Reference 16,466 patients

Cardiovascular mortality 32 trials, 3790 events, 102,597 patients, 266,091 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1872 events, Reference 1.00 (0.90-1.10) 1.17 (1.06-1.30) 1.27 (1.10-1.46) 46,352 patients DPP-4i 756 events, 1.00 (0.91-1.11) Reference 1.18 (1.02-1.36) 1.27 (1.07-1.52) 21,852 patients GLP-1a 697 events, 0.85 (0.77-0.94) 0.85 (0.74-0.98) Reference 1.08 (0.91-1.29) 19,452 patients SGLT-2i 465 events, 0.79 (0.68-0.91) 0.79 (0.66-0.94) 0.92 (0.78-1.10) Reference 14,941 patients

Heart failure events 34 trials, 2781 events, 97,639 patients, 261,345 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1359 events, Reference 0.90 (0.74-1.12) 1.06 (0.89-1.23) 1.58 (1.28-1.90) 44,420 patients DPP-4i 533 events, 1.12 (0.90-1.35) Reference 1.19 (0.89-1.49) 1.76 (1.29-2.29) 19,051 patients GLP-1a 627 events, 0.94 (0.81-1.12) 0.84 (0.67-1.13) Reference 1.49 (1.15-1.91) 19,404 patients SGLT-2i 262 events, 0.63 (0.52-0.78) 0.57 (0.44-0.78) 0.67 (0.52-0.87) Reference 14,764 patients

All myocardial infarction 44 trials, 4304 events, 103,345 patients, 268,297 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 2093 events, Reference 1.05 (0.94-1.18) 1.06 (0.96-1.18) 1.16 (1.02-1.33) 45,260 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Control DPP-4i GLP-1a SGLT-2i DPP-4i 595 events, 0.95 (0.85-1.07) Reference 1.01 (0.87-1.18) 1.10 (0.93-1.32) 20,627 patients GLP-1a 1120 events, 0.94 (0.85-1.05) 0.99 (0.85-1.15) Reference 1.09 (0.93-1.29) 20,332 patients SGLT-2i 496 events, 0.86 (0.75-0.98) 0.91 (0.76-1.07) 0.92 (0.77-1.08) Reference 17,126 patients

All stroke 40 trials, 1971 events, 89,258 patients, 224,598 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 934 events, Reference 0.97 (0.78-1.19) 1.11 (0.90-1.32) 1.07 (0.87-1.35) 39,300 patients DPP-4i 359 events, 1.03 (0.84-1.28) Reference 1.14 (0.85-1.49) 1.10 (0.84-1.52) 20,117 patients GLP-1a 444 events, 0.90 (0.76-1.11) 0.88 (0.67-1.17) Reference 0.96 (0.74-1.35) 18,095 patients SGLT-2i 234 events, 0.93 (0.74-1.14) 0.91 (0.66-1.20) 1.04 (0.74-1.34) Reference 11,746 patients

Unstable angina 29 trials, 988 events, 70,796 patients, 174,035 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 459 events, Reference 0.98 (0.67-1.45) 1.07 (0.74-1.65) 1.11 (0.74-1.79) 31,958 patients DPP-4i 220 events, 1.02 (0.69-1.49) Reference 1.09 (0.66-1.94) 1.13 (0.67-2.09) 18,548 patients GLP-1a 158 events, 0.93 (0.61-1.34) 0.91 (0.52-1.52) Reference 1.03 (0.58-1.88) 11,207 patients SGLT-2i 151 events, 0.90 (0.56-1.35) 0.89 (0.48-1.50) 0.97 (0.53-1.73) Reference 9083 patients

Non-fatal myocardial infarction 17 trials, 3224 events, 60,312 patients, 173,694 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 1559 events, Reference 0.92 (0.68-1.21) 1.08 (0.94-1.26) 1.18 (0.98-1.46) 27,296 patients DPP-4i 195 events, 1.09 (0.83-1.46) Reference 1.17 (0.87-1.65) 1.29 (0.93-1.86) 4001 patients GLP-1a 1038 events, 0.93 (0.80-1.06) 0.85 (0.61-1.15) Reference 1.10 (0.87-1.40) 16,706 patients SGLT-2i 432 events, 0.84 (0.69-1.02) 0.78 (0.54-1.07) 0.91 (0.71-1.15) Reference 12,309 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Non-fatal stroke 16 trials, 1403 events, 59,335 patients, 173,028 patient-years

Control DPP-4i GLP-1a SGLT-2i Control 660 events, Reference 0.83 (0.29-1.53) 1.15 (0.80-1.71) 1.04 (0.76-1.70) 427,299 patients DPP-4i 34 events, 1.21 (0.66-3.49) Reference 1.39 (0.71-4.48) 1.26 (0.65-4.37) 3332 patients GLP-1a 395 events, 0.87 (0.59-1.24) 0.72 (0.22-1.40) Reference 0.90 (0.56-1.69) 16,706 patients SGLT-2i 314 events, 0.96 (0.59-1.32) 0.79 (0.23-1.54) 1.11 (0.59-1.77) Reference 11,998 patients Data are reported as hazard ratio (95% credible interval). Point estimates and 95% credible interval are for comparison of drug type or control (vertical) with reference drug type or control (horizontal). A hazard ratio of less than 1 indicates that the outcome is more likely with treatment (row) than reference (column). Control refers to placebo or no treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Primary and secondary outcomes excluding open-label trials

All-cause mortality 90 trials, 6021 events, 129,429 patients, 288,658 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 2948 events, Reference 0.98 (0.90-1.06) 1.14 (1.06-1.23) 1.25 (1.12-1.41) 55,525 patients DPP-4i 1169 events, 1.02 (0.94-1.11) Reference 1.16 (1.04-1.30) 1.28 (1.11-1.47) 29,386 patients GLP-1a 1190 events, 0.88 (0.81-0.95) 0.86 (0.77-0.96) Reference 1.10 (0.96-1.26) 24,931 patients SGLT-2i 714 events, 0.80 (0.71-0.89) 0.78 (0.68-0.90) 0.91 (0.79-1.04) Reference 19,587 patients

Cardiovascular mortality 54 trials, 3814 events, 113,167 patients, 270,841 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 1881 events, Reference 1.00 (0.90-1.10) 1.17 (1.06-1.30) 1.27 (1.10-1.46) 49,989 patients DPP-4i 763 events, 1.00 (0.91-1.11) Reference 1.17 (1.02-1.35) 1.27 (1.07-1.51) 24,519 patients GLP-1a 702 events, 0.85 (0.77-0.94) 0.85 (0.74-0.98) Reference 1.08 (0.91-1.29) 22,252 patients SGLT-2i 468 events, 0.79 (0.69-0.91) 0.79 (0.66-0.94) 0.93 (0.78-1.10) Reference 16,407 patients

Heart failure events 55 trials, 2813 events, 108,137 patients, 266,691 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 1368 events, Reference 0.89 (0.74-1.09) 1.06 (0.89-1.22) 1.57 (1.26-1.89) 47,800 patients DPP-4i 543 events, 1.13 (0.91-1.36) Reference 1.20 (0.90-1.50) 1.77 (1.29-2.27) 21,900 patients GLP-1a 636 events, 0.94 (0.82-1.12) 0.83 (0.67-1.11) Reference 1.48 (1.15-1.89) 22,448 patients SGLT-2i 266 events, 0.64 (0.53-0.79) 0.56 (0.44-0.77) 0.68 (0.53-0.87) Reference 15,989 patients

All myocardial infarction 92 trials, 4384 events, 123,055 patients, 277,511 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 2128 events, Reference 0.88 (0.71-1.10) 1.07 (0.90-1.24) 1.59 (1.27-1.94) 52,158 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Placebo DPP-4i GLP-1a SGLT-2i DPP-4i 615 events, 1.13 (0.91-1.41) Reference 1.21 (0.91-1.57) 1.80 (1.31-2.40) 26,795 patients GLP-1a 1136 events, 0.93 (0.80-1.11) 0.83 (0.64-1.10) Reference 1.49 (1.14-1.93) 24,144 patients SGLT-2i 505 events, 0.63 (0.52-0.78) 0.56 (0.42-0.76) 0.67 (0.52-0.88) Reference 19,958 patients

All stroke 77 trials, 2017 events, 106,825 patients, 232,494 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 953 events, Reference 0.97 (0.79-1.21) 1.12 (0.91-1.34) 1.09 (0.89-1.38) 45,042 patients DPP-4i 368 events, 1.03 (0.82-1.26) Reference 1.15 (0.85-1.50) 1.12 (0.84-1.52) 24,097 patients GLP-1a 453 events, 0.90 (0.75-1.10) 0.87 (0.67-1.17) Reference 0.98 (0.75-1.35) 22,353 patients SGLT-2i 243 events, 0.92 (0.73-1.12) 0.89 (0.66-1.19) 1.02 (0.74-1.33) Reference 15,333 patients

Unstable angina 47 trials, 1010 events, 79,464 patients, 178,689 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 466 events, Reference 0.99 (0.70-1.37) 1.06 (0.76-1.53) 1.03 (0.70-1.57) 35,610 patients DPP-4i 226 events, 1.01 (0.73-1.44) Reference 1.08 (0.68-1.77) 1.05 (0.64-1.79) 21,003 patients GLP-1a 164 events, 0.94 (0.65-1.31) 0.93 (0.57-1.47) Reference 0.97 (0.56-1.67) 12,976 patients SGLT-2i 154 events, 0.97 (0.64-1.44) 0.95 (0.56-1.57) 1.03 (0.60-1.77) Reference 9875 patients

Non-fatal myocardial infarction 44 trials, 3262 events, 70,482 patients, 178,128 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 1577 events, Reference 0.95 (0.74-1.30) 1.07 (0.93-1.25) 1.20 (1.01-1.51) 31,030 patients DPP-4i 207 events, 1.05 (0.77-1.34) Reference 1.13 (0.80-1.49) 1.26 (0.91-1.75) 7748 patients GLP-1a 1040 events, 0.93 (0.80-1.08) 0.89 (0.67-1.25) Reference 1.12 (0.89-1.47) 17,121 patients SGLT-2i 438 events, 0.83 (0.66-0.99) 0.80 (0.57-1.10) 0.89 (0.68-1.12) Reference 14,583 patients

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 7: Sensitivity analysis (Bayesian fixed-effects model) continued

Non-fatal stroke 39 trials, 1430 events, 68,918 patients, 176,980 patient-years

Placebo DPP-4i GLP-1a SGLT-2i Placebo 672 events, Reference 0.95 (0.53-1.62) 1.17 (0.91-1.63) 1.02 (0.77-1.45) 31,049 patients DPP-4i 40 events, 1.05 (0.62-1.89) Reference 1.23 (0.69-2.47) 1.08 (0.59-2.16) 6254 patients GLP-1a 398 events, 0.86 (0.61-1.09) 0.81 (0.40-1.44) Reference 0.87 (0.57-1.33) 17,994 patients SGLT-2i 320 events, 0.98 (0.69-1.29) 0.93 (0.46-1.68) 1.15 (0.75-1.75) Reference 13,621 patients Data are reported as hazard ratio (95% credible interval). Point estimates and 95% credible interval are for comparison of drug type or control (vertical) with reference drug type or control (horizontal). A hazard ratio of less than 1 indicates that the outcome is more likely with treatment (row) than reference (column). Control refers to placebo or no treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 8: Frequentist network meta-analysis

Primary, secondary and safety outcomes

Comparator P-score Control DPP-4 inhibitor GLP-1 agonist SGLT-2 inhibitor Primary outcome All-cause mortality (RR) Control 0.98 1.14a 1.24a Reference 0.23 (0.90 to 1.06) (1.05 to 1.22) (1.11 to 1.39) DPP-4 inhibitor 1.02 1.16b 1.27a Reference 0.10 (0.94 to 1.10) (1.04 to 1.29) (1.11 to 1.45) GLP-1 agonist 0.88a 0.86b 1.09 Reference 0.70 (0.82 to 0.95) (0.77 to 0.96) (0.96 to 1.25) SGLT-2 inhibitor 0.80a 0.79a 0.91 Reference 0.97 (0.72 to 0.90) (0.69 to 0.90) (0.80 to 1.04) Secondary outcomes Cardiovascular mortality (RR) Control 1.00 1.16b 1.27a Reference 0.18 (0.90 to 1.10) (1.05 to 1.22) (1.11 to 1.46) DPP-4 inhibitor 1.00 1.17c 1.28b Reference 0.16 (0.91 to 1.11) (1.01 to 1.28) (1.08 to 1.51) GLP-1 agonist 0.86b 0.86c 1.09 Reference 0.71 (0.78 to 0.95) (0.75 to 0.99) (0.95 to 1.30) SGLT-2 inhibitor 0.79a 0.78b 0.91 Reference 0.95 (0.69 to 0.90) (0.66 to 0.93) (0.77 to 1.08) Heart failure events Control 0.90 1.07 1.47a Reference 0.36 (0.79 to 1.01) (0.96 to 1.19) (1.23 to 1.76) DPP-4 inhibitor 1.12 1.19c 1.64a Reference 0.02 (0.99 to 1.26) (1.01 to 1.40) (1.33 to 2.04) GLP-1 agonist 0.94 0.84b 1.38b Reference 0.62 (0.84 to 1.04) (0.72 to 0.99) (1.12 to 1.70) SGLT-2 inhibitor 0.68a 0.61a 0.72b Reference 1.00 (0.57 to 0.81) (0.49 to 0.75) (0.59 to 0.89) All myocardial infarction (RR) Control 1.07 1.05 1.16 Reference 0.07 (0.96 to 1.19) (0.97 to 1.14) (1.01 to 1.33) DPP-4 inhibitor 0.93 0.99 1.08 Reference 0.48 (0.84 to 1.04) (0.86 to 1.13) (0.91 to 1.29) GLP-1 agonist 0.95 1.01 1.10 Reference 0.55 (0.88 to 1.03) (0.89 to 1.16) (0.94 to 1.28) SGLT-2 inhibitor 0.86c 0.92 0.91 Reference 0.89 (0.75 to 0.99) (0.78 to 1.10) (0.78 to 1.07) Unstable angina (RR) Control 1.00 1.07 1.05 Reference 0.38 (0.83 to 1.20) (0.87 to 1.32) (0.81 to 1.36) DPP-4 inhibitor 1.00 1.07 1.05 Reference 0.39 (0.84 to 1.20) (0.81 to 1.42) (0.76 to 1.44) GLP-1 agonist 0.93 0.93 0.98 Reference 0.66 (0.76 to 1.15) (0.71 to 1.23) (0.70 to 1.37) SGLT-2 inhibitor 0.95 0.95 1.02 Reference 0.57 (0.73 to 1.24) (0.69 to 1.31) (0.73 to 1.43) All stroke (RR) Control 0.98 1.13 1.05 Reference 0.33 (0.85 to 1.13) (0.99 to 1.28) (0.85 to 1.30) DPP-4 inhibitor 1.03 1.15 1.07 Reference 0.24 (0.89 to 1.18) (0.96 to 1.39) (0.83 to 1.39)

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 8: Frequentist network meta-analysis continued

Comparator P-score Control DPP-4 inhibitor GLP-1 agonist SGLT-2 inhibitor GLP-1 agonist 0.89 0.87 0.93 Reference 0.87 (0.78 to 1.01) (0.72 to 1.05) (0.73 to 1.19) SGLT-2 inhibitor 0.95 0.93 1.07 Reference 0.55 (0.77 to 1.18) (0.72 to 1.20) (0.84 to 1.38) Any adverse event (RR) Control 0.98 0.88a 0.99 Reference 0.94 (0.95 to 1.00) (0.85 to 0.90) (0.96 to 1.01) DPP-4 inhibitor 1.02 0.90a 1.01 Reference 0.45 (1.00 to 1.05) (0.87 to 0.93) (0.97 to 1.05) GLP-1 agonist 1.14a 1.12a 1.13a Reference 0.00 (1.11 to 1.18) (1.08 to 1.16) (1.08 to 1.17) SGLT-2 inhibitor 1.01 0.99 0.89a Reference 0.62 (0.99 to 1.04) (0.96 to 1.03) (0.85 to 0.92) Serious adverse event (RR) Control 1.02 1.02 1.11a Reference 0.13 (0.93 to 1.12) (0.99 to 1.06) (1.06 to 1.17) DPP-4 inhibitor 0.98 1.00 1.09 Reference 0.39 (0.89 to 1.07) (0.91 to 1.10) (0.98 to 1.21) GLP-1 agonist 0.98 1.00 1.09c Reference 0.49 (0.95 to 1.01) (0.91 to 1.10) (1.03 to 1.15) SGLT-2 inhibitor 0.90a 0.92 0.92c Reference 0.98 (0.86 to 0.94) (0.83 to 1.02) (0.87 to 0.97) Adverse events leading to withdrawal (RR) Control 1.03 0.59a 0.96 Reference 0.69 (0.90 to 1.17) (0.52 to 0.67) (0.84 to 1.10) DPP-4 inhibitor 0.97 0.57a 0.94 Reference 0.81 (0.85 to 1.11) (0.49 to 0.68) (0.78 to 1.12) GLP-1 agonist 1.69a 1.74a 1.63a Reference 0.00 (1.49 to 1.92) (1.48 to 2.05) (1.36 to 1.96) SGLT-2 inhibitor 1.04 1.07 0.61a Reference 0.51 (0.91 to 1.19) (0.89 to 1.28) (0.51 to 0.73) Hypoglycaemia (RR) Control 0.85b 0.78a 0.86b Reference 1.00 (0.76 to 0.96) (0.71 to 0.86) (0.77 to 0.96) DPP-4 inhibitor 1.17b 0.92 1.01 Reference 0.46 (1.04 to 1.31) (0.80 to 1.05) (0.86 to 1.17) GLP-1 agonist 1.28a 1.09 1.10 Reference 0.07 (1.16 to 1.41) (0.95 to 1.25) (0.95 to 1.27) SGLT-2 inhibitor 1.16 0.99 0.91 Reference 0.47 (1.04 to 1.30) (0.85 to 1.16) (0.79 to 1.05) Major hypoglycaemia (RR) Control 0.87 1.09c 1.01 Reference 0.49 (0.76 to 1.01) (1.00 to 1.18) (0.80 to 1.28) DPP-4 inhibitor 1.15 1.25b 1.16 Reference 0.06 (0.99 to 1.32) (1.06 to 1.47) (0.89 to 1.51) GLP-1 agonist 0.92c 0.80b 0.93 Reference 0.90 (0.85 to 1.00) (0.68 to 0.94) (0.72 to 1.19) SGLT-2 inhibitor 0.99 0.86 1.08 Reference 0.56 (0.78 to 1.25) (0.66 to 1.13) (0.84 to 1.38) Summary of primary and secondary outcomes with 95% confidence interval. Point estimates (presented as relative risk, RR) and 95% confidence intervals are for comparison of drug type or control (vertical) with reference drug type or control (horizontal). A RR less than 1 indicates that the outcome is more likely with treatment (row) than reference (column). P-score is the probability that a given treatment is superior to its comparators for a given outcome. Control refers to placebo or no treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Any hypoglycaemia: any episode not meeting criteria for major hypoglycaemia, study-defined minor hypoglycaemia; major hypoglycaemia: any episode resulting in hospitalization, medical assistance or trial withdrawal, study-defined major or serious hypoglycaemia

aStatistically significant at P≤0.001; bStatistically significant at P≤0.01; cStatistically significant at P<0.05

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 1: Risk of bias summary

Sequence generation

Allocation concealment

Blinding

Detection Bias

Attrition Bias

0% 20% 40% 60% 80% 100%

Low Unclear High

Total of 236 trials were assessed for risk of bias.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 2: Funnel plot

Egger test for funnel plot asymmetry in the primary outcome of all-cause mortality (97 studies): bias = 0.10 (standard error 0.09); t = -1.10; d.f. = 101; P = 0.273.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3: Network plots

Primary outcome: All-cause mortality

Cardiovascular mortality

Heart failure events

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3: Network plots continued

All myocardial infarction

All stroke

Unstable angina

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 3: Network plots continued

Non-fatal myocardial infarction

Non-fatal stroke

All adverse events

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

eFigure 3: Network plots continued Serious adverse events

Adverse events leading to withdrawal

Any hypoglycaemia

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

eFigure 3: Network plots continued Major hypoglycaemia

Graphical representation of networks for primary, secondary and safety endpoints. Connecting lines represent head-to-head comparisons (thickness proportional to number of trials) between drugs, indicated by nodes (size proportional to number of patients).

k - number of trials per comparison; n – number of patients per comparison.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 4: Forest plots and ranking plots for additional secondary outcomes

0.8

0.6

0.4 Probability 0.2

0 1 2 3 4 Best Rank Worst Control DPP-4i

GLP-1a SGLT-2i

0.8

0.6

0.4 Probability 0.2

0 1 2 3 4 Best Control Rank DPP-4i Worst

GLP-1a SGLT-2i

All outcomes reported in hazard ratio (HR) for treatment vs comparator, and 95% credible intervals

(CrI). Absolute risk difference (ARD) was calculated by multiplying risk difference by the event rate in

the comparator group. The 95% confidence intervals (CI) for ARD are calculated by multiplying the

95% CrI by the event rate in the comparator group. Heterogeneity assessed using I2 statistic, low

heterogeneity determined by I2 ≤25%. The sizes of the data markers are uniform. Control refers to

placebo or no treatment.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure 5: Network plot for individual drugs

Network plot of all-cause mortality network incorporating individual drug types. Line thickness is proportional to the number of pairwise comparisons between treatments; the size of the circle is proportional to the number of patients at that node. Control refers to placebo or no treatment. k – number of studies per comparison; n – number of patients per comparison.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Association between use of sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis

Zheng et al. Absoluterisk difference (ARD)

group.

control

group. The95% confidence intervals (CI)for ARDare

control inthe by eventratethe in the

effect model. Control includes placebo or no treatment. treatment. no or placebo includes Control model. effect - - cause mortality for individual drugs k difference by the event rate event the by difference k

hazard ratio.hazard

– eFigure 6 : Forest plot for all Analysiswas performedusing a bayesian fixed ris by multiplying calculated was HR ulated byulated multiplying calc 95%the credibleinterval (CrI)

Zheng et al. eFigure 7: Forest plot and ranking plots for safety outcome

0.8

0.6

0.4 Probability

0.2

0 1 2 3 4 Worst Best Rank Control DPP-4i

GLP-1a SGLT-2i

0.8

0.6

0.4 Probability

0.2

0 1 2 3 4 Best Rank Worst Control DPP-4i

GLP-1a SGLT-2i

Zheng et al. eFigure 7: Forest plot and ranking plots for safety outcomes continued

0.8

0.6

0.4 Probability

0.2

0 1 2 3 4 Rank Best Worst Control DPP-4i

GLP-1a SGLT-2i

0.8

0.6

0.4 Probability

0.2

0 1 2 3 4 Best Rank Worst Control DPP-4i

GLP-1a SGLT-2i

Zheng et al. eFigure 7: Forest plot and ranking plots for safety outcomes continued

0.8

0.6

0.4 Probability

0.2

0 1 2 3 4

Best Rank Worst Control DPP-4i

GLP-1a SGLT-2i

Forest plot of Bayesian random-effects network meta-analysis of safety outcomes: any adverse event, serious adverse events, adverse events leading to withdrawal, any hypoglycaemia. All outcomes reported in hazard ratio (HR) for treatment vs comparator, and 95% credible intervals (CrI). Absolute risk difference (ARD) was calculated by multiplying risk difference by the event rate in the comparator group. The 95% confidence intervals (CI) for ARD are calculated by multiplying the 95% CrI by the event rate in the comparator group. Heterogeneity assessed using I2 statistic, low heterogeneity determined by I2 ≤25%. The sizes of the data markers are uniform. Control refers to placebo or no treatment. Any hypoglycaemia: any episode not meeting criteria for major hypoglycaemia, study-defined minor hypoglycaemia; major hypoglycaemia: any episode resulting in hospitalization, medical assistance or trial withdrawal, study-defined major or serious hypoglycaemia.

Zheng et al. eFigure 8: Forest plots of drug-class specific adverse effects of interest

Genital and urinary tract infections

Favors treatment Favors control Amputations

Favors treatment Favors control Pancreatitis

Favors treatment Favors control

Zheng et al. eFigure 8: Forest plots of drug-class specific adverse effects of interest continued

Retinopathy

Favors treatment Favors control Forest plots presenting frequentist pairwise meta-analysis of drug-class specific adverse effects of interest: Genital and urinary tract infections (SGLT-2 inhibitors), amputations (SGLT-2 inhibitors), pancreatitis (DPP-4 inhibitors and GLP-1 agonists) and retinopathy (DPP-4 inhibitors and GLP-1 agonists). A risk ratio (RR) less than 1 favors treatment, while RR greater than 1 favors control. The size of the square is proportional to study weight in the fixed effect model. CI – confidence interval; RR – risk ratio.

Zheng et al. eFigure 9: Breakdown of direct and indirect evidence Each comparison between treatments is broken down into direct evidence (derived from pairwise comparison data) and indirect evidence (calculated by the network meta-analysis). The ratio of these (the ratio of ratios, RoR) gives an estimate of inconsistency within the network. An RoR value with 95% CI that does not cross 1 is evidence of statistically significant inconsistency within that comparison. ‘Trials’ and ‘Events’ correspond to the number of trials and events contributing direct evidence for each comparison. Blue: Direct evidence; Green: Indirect evidence; Orange: Ratio of ratios

All-cause mortality

RoR (95% CI) Cardiovascular mortality

RoR (95% CI) Heart failure events

RoR (95% CI)

Zheng et al. eFigure 9: Breakdown of direct and indirect evidence continued

All myocardial infarction

RoR (95% CI) All stroke

RoR (95% CI) Unstable angina

RoR (95% CI) Non-fatal myocardial infarction

RoR (95% CI)

Zheng et al. eFigure 9: Breakdown of direct and indirect evidence continued

All myocardial infarction

RoR (95% CI) All stroke

RoR (95% CI) Unstable angina

RoR (95% CI) Non-fatal myocardial infarction

RoR (95% CI)

Zheng et al. eFigure 9: Breakdown of direct and indirect evidence continued

Non-fatal stroke

RoR (95% CI) Any adverse event

RoR (95% CI) Serious adverse events

RoR (95% CI)

Zheng et al. eFigure 9: Breakdown of direct and indirect evidence continued

Adverse events leading to withdrawal

RoR (95% CI) Any hypoglycaemia

RoR (95% CI) Major hypoglycaemia

RoR (95% CI) Any hypoglycaemia: any episode not meeting criteria for major hypoglycaemia, study-defined minor hypoglycaemia; major hypoglycaemia: any episode resulting in hospitalization, medical assistance or trial withdrawal, study-defined major or serious hypoglycaemia. CI – confidence interval; CrI – credible interval’; HR – hazard ratio; RoR – ratio of ratios.

Zheng et al. Supplemental references 1. Dias S, Sutton AJ, Ades AE, Welton NJ. Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. Medical decision making : an international journal of the Society for Medical Decision Making. 2013;33(5):607-617. 2. R: A language and environment for statistical computing [computer program]. R Foundation for Statistical Computing, Vienna, Austria; 2008. 3. Plummer M. JAGS: a program for analysis of Bayesian graphical models using Gibbs sampling. Proceedings of the 3rd International Workshop on Distributed Statistical Computing (DSC 2003). 2003. 4. Spieglhalter DJ, Best NG, Carlin BP, Van Der Linde A. Bayesian measures of model complexity and fit. Series B Statistical Methodology. 2002;64(4):583-639. 5. Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis. The Cochrane database of systematic reviews. 2014(3):Cd010844. 6. Brooks SP, Gelman A. General methods for monitoring convergence of iterative simulations. Journal of Computational and Graphical Statistics. 1998;7:434-455. 7. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed). 2003;327(7414):557-560. 8. van Valkenhoef G, Dias S, Ades AE, Welton NJ. Automated generation of node- splitting models for assessment of inconsistency in network meta-analysis. Research Synthesis Methods. 2016;7(1):80-93. 9. Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ (Clinical research ed). 2003;326(7387):472. 10. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: An update. Contemporary Clinical Trials. 2007;28(2):105-114. 11. Rücker G, Schwarzer G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Medical Research Methodology. 2015;15(1):58. 12. Alba M, Ahren B, Inzucchi SE, et al. Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function. Diabetes, obesity & metabolism. 2013;15(12):1101-1110. 13. Ba J, Han P, Yuan G, et al. Randomized trial assessing the safety and efficacy of sitagliptin in Chinese patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea alone or combined with metformin. Journal of Diabetes. 2017;9(7):667- 676. 14. Bajaj M, Gilman R, Patel S, Kempthorne-Rawson J, Lewis-D'Agostino D, Woerle HJ. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: a 24-week randomized, double-blind study. Diabet Med. 2014;31(12):1505-1514. 15. Barnett AH, Patel S, Harper R, et al. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: an 18-week randomized, double-blind, placebo-controlled phase III trial with a 34-week active-controlled extension. Diabetes, obesity & metabolism. 2012;14(12):1145-1154. 16. Barnett AH, Charbonnel B, Li J, Donovan M, Fleming D, Iqbal N. Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clin Drug Investig. 2013;33(10):707-717. 17. Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with

Zheng et al. common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9902):1413-1423. 18. Barzilai N, Guo H, Mahoney EM, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin. 2011;27(5):1049-1058. 19. Boer S, Heerspink H, Juarez OL, et al. Effect of linagliptin on pulse wave velocity in early type 2 diabetes: a randomized, double-blind, controlled 26-week trial (RELEASE). Diabetes, obesity & metabolism. 2017;(no pagination). http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/807/CN-01365807/frame.html http://onlinelibrary.wiley.com/doi/10.1111/dom.12925/abstract. 20. Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes care. 2007;30(4):890-895. 21. Bosi E, Dotta F, Jia Y, Goodman M. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus. Diabetes, obesity & metabolism. 2009;11(5):506-515. 22. Chan JCN, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes, Obesity and Metabolism. 2008;10(7):545-555. 23. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes care. 2006;29(12):2638-2643. 24. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes care. 2008;31(12):2315-2317. 25. DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin- treated patients with type 2 diabetes. The Journal of clinical endocrinology and metabolism. 2012;97(5):1615-1622. 26. Dobs AS, Goldstein BJ, Aschner P, et al. Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo- controlled 54-week trial in patients with type 2 diabetes. J Diabetes. 2013;5(1):68-79. 27. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. The New England journal of medicine. 2013;369(14):1327-1335. 28. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50(6):1148-1155. 29. Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr. 2012;4(1):36. 30. Garber AJ, Foley JE, Banerji MA, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes, obesity & metabolism. 2008;10(11):1047-1056. 31. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes care. 2007;30(8):1979-1987. 32. Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial combination of linagliptin and metformin improves glycaemic control in type 2

Zheng et al. diabetes: a randomized, double-blind, placebo-controlled study. Diabetes, obesity & metabolism. 2012;14(6):565-574. 33. Henry RR, Smith SR, Schwartz SL, et al. Effects of saxagliptin on beta-cell stimulation and insulin secretion in patients with type 2 diabetes. Diabetes, obesity & metabolism. 2011;13(9):850-858. 34. Henry RR, Staels B, Fonseca VA, et al. Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone--a factorial study. Diabetes, obesity & metabolism. 2014;16(3):223-230. 35. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes, obesity & metabolism. 2007;9(5):733-745. 36. Hirose T, Suzuki M, Tsumiyama I. Efficacy and Safety of Vildagliptin as an Add-on to Insulin with or without Metformin in Japanese Patients with Type 2 Diabetes Mellitus: A 12-week, Double-Blind, Randomized Study. Diabetes Ther. 2015;6(4):559-571. 37. Hollander PL, Li J, Frederich R, Allen E, Chen R. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2011;8(2):125-135. 38. Ji L, Li L, Kuang J, et al. Efficacy and safety of fixed-dose combination therapy, alogliptin plus metformin, in Asian patients with type 2 diabetes: a phase 3 trial. Diabetes, obesity & metabolism. 2017;(no pagination). http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/911/CN-01328911/frame.html http://onlinelibrary.wiley.com/store/10.1111/dom.12875/asset/dom12875.pdf?v=1&t=j5v1o0e7&s =01cd243ea08aa105c33bc6846045fe490c935662. 39. Kadowaki T, Kondo K. Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus. Journal of diabetes investigation. 2013;4(6):576-584. 40. Kadowaki T, Kondo K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes, obesity & metabolism. 2013;15(9):810-818. 41. Kadowaki T, Kondo K. Efficacy and safety of teneligliptin added to glimepiride in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study with an open-label, long-term extension. Diabetes, obesity & metabolism. 2014;16(5):418-425. 42. Kanazawa I, Tanaka K-I, Notsu M, et al. Long-term efficacy and safety of vildagliptin add-on therapy in type 2 diabetes mellitus with insulin treatment. Diabetes research and clinical practice. 2017;123:9-17. http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/601/CN-01301601/frame.html. 43. Kikuchi M, Abe N, Kato M, Terao S, Mimori N, Tachibana H. Vildagliptin dose- dependently improves glycemic control in Japanese patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2009;83(2):233-240. 44. Kikuchi M, Haneda M, Koya D, et al. Efficacy and tolerability of vildagliptin as an add- on to glimepiride in Japanese patients with Type 2 diabetes mellitus. Diabetes Res Clin Pract. 2010;89(3):216-223. 45. Kim MK, Rhee EJ, Han KA, et al. Efficacy and safety of teneligliptin, a dipeptidyl peptidase-4 inhibitor, combined with metformin in Korean patients with type 2 diabetes mellitus: a 16-week, randomized, double-blind, placebo-controlled phase III trial. Diabetes, obesity & metabolism. 2015;17(3):309-312. 46. Kothny W, Shao Q, Groop PH, Lukashevich V. One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment. Diabetes, obesity & metabolism. 2012;14(11):1032-1039. 47. Kothny W, Foley J, Kozlovski P, Shao Q, Gallwitz B, Lukashevich V. Improved glycaemic control with vildagliptin added to insulin, with or without metformin, in

Zheng et al. patients with type 2 diabetes mellitus. Diabetes, obesity & metabolism. 2013;15(3):252-257. 48. Lewin AJ, Arvay L, Liu D, Patel S, von Eynatten M, Woerle HJ. Efficacy and tolerability of linagliptin added to a sulfonylurea regimen in patients with inadequately controlled type 2 diabetes mellitus: an 18-week, multicenter, randomized, double- blind, placebo-controlled trial. Clin Ther. 2012;34(9):1909-1919.e1915. 49. Lukashevich V, Del Prato S, Araga M, Kothny W. Efficacy and safety of vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea. Diabetes, obesity & metabolism. 2014;16(5):403- 409. 50. Macauley M, Hollingsworth KG, Smith FE, et al. Effect of vildagliptin on hepatic steatosis. The Journal of clinical endocrinology and metabolism. 2015;100(4):1578- 1585. 51. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes, obesity & metabolism. 2017. 52. Mathieu C, Shankar RR, Lorber D, et al. A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co-Administration of Sitagliptin with Intensively Titrated Insulin Glargine. Diabetes Ther. 2015;6(2):127-142. 53. Matthaei S, Catrinoiu D, Celinski A, et al. Randomized, Double-Blind Trial of Triple Therapy With Saxagliptin Add-on to Dapagliflozin Plus Metformin in Patients With Type 2 Diabetes. Diabetes care. 2015;38(11):2018-2024. 54. McGill JB, Barnett AH, Lewin AJ, et al. Linagliptin added to sulphonylurea in uncontrolled type 2 diabetes patients with moderate-to-severe renal impairment. Diab Vasc Dis Res. 2014;11(1):34-40. 55. Mohan V, Yang W, Son HY, et al. Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract. 2009;83(1):106-116. 56. Moses RG, Round E, Shentu Y, et al. A randomized clinical trial evaluating the safety and efficacy of sitagliptin added to the combination of sulfonylurea and metformin in patients with type 2 diabetes mellitus and inadequate glycemic control. J Diabetes. 2016;8(5):701-711. 57. Mu Y, Pan C, Fan B, et al. Efficacy and safety of linagliptin/metformin single-pill combination as initial therapy in drug-naive Asian patients with type 2 diabetes. Diabetes Res Clin Pract. 2017;124:48-56. 58. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. International journal of clinical practice. 2009;63(1):46-55. 59. NCT01778049. https://clinicaltrials.gov/ct2/show/NCT01778049. 60. Ning G, Wang W, Li L, et al. Vildagliptin as add-on therapy to insulin improves glycemic control without increasing risk of hypoglycemia in Asian, predominantly Chinese, patients with type 2 diabetes mellitus. J Diabetes. 2016;8(3):345-353. 61. Nowicki M, Rychlik I, Haller H, Warren ML, Suchower L, Gause-Nilsson I. Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes, obesity & metabolism. 2011;13(6):523-532. 62. Odawara M, Hamada I, Suzuki M. Efficacy and Safety of Vildagliptin as Add-on to Metformin in Japanese Patients with Type 2 Diabetes Mellitus. Diabetes Ther. 2014;5(1):169-181. 63. Olansky L, Reasner C, Seck TL, et al. A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic

Zheng et al. control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. Diabetes, obesity & metabolism. 2011;13(9):841-849. 64. Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev. 2012;28(3):268-275. 65. Pan C, Han P, Ji Q, et al. Efficacy and safety of alogliptin in patients with type 2 diabetes mellitus: A multicentre randomized double-blind placebo-controlled Phase 3 study in mainland China, Taiwan, and Hong Kong. J Diabetes. 2017;9(4):386-395. 66. Peng XV, Marcinak JF, Raanan MG, Cao C. Combining the G-protein-coupled receptor 40 agonist fasiglifam with sitagliptin improves glycaemic control in patients with type 2 diabetes with or without metformin: A randomized, 12-week trial. Diabetes, Obesity and Metabolism. 2017;19(8):1127-1134. 67. Pfutzner A, Paz-Pacheco E, Allen E, Frederich R, Chen R. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes, obesity & metabolism. 2011;13(6):567-576. 68. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes, obesity & metabolism. 2009;11(2):167-176. 69. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 2009;25(10):2361-2371. 70. Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naive patients with type 2 diabetes: a randomized, double-blind, 6-month study. Diabetes, obesity & metabolism. 2014;16(7):613-621. 71. Raz I, Chen Y, Wu M, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24(2):537-550. 72. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes, obesity & metabolism. 2008;10(5):376-386. 73. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25(10):2401-2411. 74. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes, obesity & metabolism. 2009;11(12):1145-1152. 75. Rosenstock J, Gross JL, Aguilar-Salinas C, et al. Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes. Diabet Med. 2013;30(12):1472-1476. 76. Ross SA, Rafeiro E, Meinicke T, Toorawa R, Weber-Born S, Woerle HJ. Efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, placebo- controlled trial. Curr Med Res Opin. 2012;28(9):1465-1474. 77. Saito D, Kanazawa A, Shigihara N, et al. Efficacy and Safety of Vildagliptin as an Add-On Therapy in Inadequately Controlled Type 2 Diabetes Patients Treated With Basal Insulin. J Clin Med Res. 2017;9(3):193-199. 78. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. The New England journal of medicine. 2013;369(14):1317-1326.

Zheng et al. 79. Scherbaum WA, Schweizer A, Mari A, et al. Efficacy and tolerability of vildagliptin in drug-naive patients with type 2 diabetes and mild hyperglycaemia*. Diabetes, obesity & metabolism. 2008;10(8):675-682. 80. Seino Y, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin added to sulfonylurea in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. Journal of diabetes investigation. 2012;3(6):517-525. 81. Seino Y, Miyata Y, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, double- blind, placebo-controlled trial with an open-label, long-term extension study. Diabetes, obesity & metabolism. 2012;14(10):927-936. 82. Strain WD, Lukashevich V, Kothny W, Hoellinger MJ, Paldanius PM. Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study. Lancet. 2013;382(9890):409-416. 83. Tajima N, Kadowaki T, Odawara M, Nishii M, Taniguchi T, Arjona Ferreira JC. Addition of sitagliptin to ongoing glimepiride therapy in Japanese patients with type 2 diabetes over 52 weeks leads to improved glycemic control. Diabetology International. 2011;2(1):32-44. 84. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2015;373(3):232-242. 85. Tinahones FJ, Gallwitz B, Nordaby M, et al. Linagliptin as add-on to empagliflozin and metformin in patients with type 2 diabetes: Two 24-week randomized, double- blind, double-dummy, parallel-group trials. Diabetes, Obesity and Metabolism. 2017;19(2):266-274. 86. Van Raalte DH, van Genugten RE, Eliasson B, et al. The effect of alogliptin and pioglitazone combination therapy on various aspects of beta-cell function in patients with recent-onset type 2 diabetes. Eur J Endocrinol. 2014;170(4):565-574. 87. Vilsboll T, Rosenstock J, Yki-Jarvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes, obesity & metabolism. 2010;12(2):167-177. 88. Wang W, Yang J, Yang G, et al. Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: A multinational 24-week, randomized clinical trial. J Diabetes. 2016;8(2):229-237. 89. Wang W, Ning G, Ma J, et al. A randomized clinical trial of the safety and efficacy of sitagliptin in patients with type 2 diabetes mellitus inadequately controlled by acarbose alone. Current Medical Research and Opinion. 2017;33(4):693-699. 90. White JL, Buchanan P, Li J, Frederich R. A randomized controlled trial of the efficacy and safety of twice-daily saxagliptin plus metformin combination therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy. BMC Endocr Disord. 2014;14:17. 91. Yang W, Guan Y, Shentu Y, et al. The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes. J Diabetes. 2012;4(3):227-237. 92. Yang W, Xing X, Lv X, et al. Vildagliptin added to sulfonylurea improves glycemic control without hypoglycemia and weight gain in Chinese patients with type 2 diabetes mellitus. J Diabetes. 2015;7(2):174-181. 93. Yki-Jarvinen H, Rosenstock J, Duran-Garcia S, et al. Effects of adding linagliptin to basal insulin regimen for inadequately controlled type 2 diabetes: a >/=52-week randomized, double-blind study. Diabetes care. 2013;36(12):3875-3881. 94. Younis A, Eskenazi D, Goldkorn R, et al. The addition of vildagliptin to metformin prevents the elevation of interleukin 1ss in patients with type 2 diabetes and coronary

Zheng et al. artery disease: a prospective, randomized, open-label study. Cardiovascular diabetology. 2017;16(1):69. 95. Apovian CM, Bergenstal RM, Cuddihy RM, et al. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. The American journal of medicine. 2010;123(5):468.e469-417. 96. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes care. 2014;37(8):2159-2167. 97. Dungan KM, Weitgasser R, Perez Manghi F, et al. A 24-week study to evaluate the efficacy and safety of once-weekly dulaglutide added on to glimepiride in type 2 diabetes (AWARD-8). Diabetes, obesity & metabolism. 2016;18(5):475-482. 98. Pozzilli P, Norwood P, Jodar E, et al. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9). Diabetes, obesity & metabolism. 2017;19(7):1024-1031. 99. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes. Diabetes care. 2004;27(11):2628-2635. 100. Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Annals of internal medicine. 2011;154(2):103-112. 101. Chaudhuri A, Ghanim H, Vora M, et al. Exenatide Exerts a Potent Antiinflammatory Effect. The Journal of clinical endocrinology and metabolism. 2012;97(1):198-207. 102. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin- treated patients with type 2 diabetes. Diabetes care. 2005;28(5):1092-1100. 103. Derosa G, Cicero AF, Franzetti IG, et al. Effects of exenatide and metformin in combination on some adipocytokine levels: a comparison with metformin monotherapy. Can J Physiol Pharmacol. 2013;91(9):724-732. 104. Gough SC, Bode B, Woo V, et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2014;2(11):885-893. 105. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. The New England journal of medicine. 2015;373(23):2247-2257. 106. Holman RR, Bethel MA, Mentz RJ, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2017;377(13):1228-1239. 107. Ferdinand KC, White WB, Calhoun DA, et al. Effects of the once-weekly glucagon- like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension. 2014;64(4):731-737. 108. Gao Y, Yoon KH, Chuang LM, et al. Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea. Diabetes Res Clin Pract. 2009;83(1):69-76. 109. Riddle MC, Aronson R, Home P, et al. Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin: A 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes care. 2013;36(9):2489-2496. 110. Seino Y, Min KW, Niemoeller E, Takami A. Randomized, double-blind, placebo- controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a

Zheng et al. sulfonylurea (GetGoal-L-Asia). Diabetes, obesity & metabolism. 2012;14(10):910- 917. 111. Ahren B, Leguizamo Dimas A, Miossec P, Saubadu S, Aronson R. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes care. 2013;36(9):2543- 2550. 112. Yu Pan C, Han P, Liu X, et al. Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia). Diabetes Metab Res Rev. 2014;30(8):726-735. 113. Meneilly GS, Roy-Duval C, Alawi H, et al. Lixisenatide Therapy in Older Patients With Type 2 Diabetes Inadequately Controlled on Their Current Antidiabetic Treatment: The GetGoal-O Randomized Trial. Diabetes care. 2017;40(4):485-493. 114. Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes, obesity & metabolism. 2013;15(11):1000-1007. 115. Rosenstock J, Hanefeld M, Shamanna P, et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complications. 2014;28(3):386-392. 116. Riddle MC, Forst T, Aronson R, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). Diabetes care. 2013;36(9):2497-2503. 117. Bolli GB, Munteanu M, Dotsenko S, et al. Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet Med. 2014;31(2):176-184. 118. Grunberger G, Chang A, Garcia Soria G, Botros FT, Bsharat R, Milicevic Z. Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled study. Diabet Med. 2012;29(10):1260- 1267. 119. Reusch J, Stewart MW, Perkins CM, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes, Obesity and Metabolism. 2014;16(12):1257-1264. 120. Nauck MA, Stewart MW, Perkins C, et al. Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetologia. 2016;59(2):266-274. 121. Home PD, Shamanna P, Stewart M, et al. Efficacy and tolerability of albiglutide versus placebo or pioglitazone over 1 year in people with type 2 diabetes currently taking metformin and glimepiride: HARMONY 5. Diabetes, obesity & metabolism. 2015;17(2):179-187. 122. Idorn T, Knop FK, Jorgensen MB, et al. Safety and Efficacy of Liraglutide in Patients With Type 2 Diabetes and End-Stage Renal Disease: An Investigator-Initiated, Placebo-Controlled, Double-Blind, Parallel-Group, Randomized Trial. Diabetes care. 2016;39(2):206-213. 123. Kadowaki T, Namba M, Yamamura A, Sowa H, Wolka AM, Brodows RG. Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes. Endocr J. 2009;56(3):415-424.

Zheng et al. 124. Kadowaki T, Namba M, Imaoka T, et al. Improved glycemic control and reduced bodyweight with exenatide: A double-blind, randomized, phase 3 study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks. Journal of diabetes investigation. 2011;2(3):210-217. 125. Kaku K, Rasmussen MF, Clauson P, Seino Y. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon- like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes, obesity & metabolism. 2010;12(4):341-347. 126. Kapitza C, Dahl K, Jacobsen JB, Axelsen MB, Flint A. Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2017;60(8):1390-1399. 127. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes care. 2005;28(5):1083-1091. 128. Kim D, MacConell L, Zhuang D, et al. Effects of Once-Weekly Dosing of a Long- Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes. Diabetes care. 2007;30(6):1487-1493. 129. Marre M, Shaw J, Brandle M, et al. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268-278. 130. Nauck M, Frid A, Hermansen K, et al. Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabetes, obesity & metabolism. 2013;15(3):204-212. 131. Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes care. 2009;32(7):1224- 1230. 132. Russell-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046-2055. 133. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2016;375(4):311-322. 134. Davies MJ, Bain SC, Atkin SL, et al. Efficacy and Safety of Liraglutide Versus Placebo as Add-on to Glucose-Lowering Therapy in Patients With Type 2 Diabetes and Moderate Renal Impairment (LIRA-RENAL): A Randomized Clinical Trial. Diabetes care. 2016;39(2):222-230. 135. Liutkus J, Rosas Guzman J, Norwood P, et al. A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin. Diabetes, obesity & metabolism. 2010;12(12):1058-1065. 136. Aroda VR, Rosenstock J, Wysham C, et al. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial. Diabetes care. 2016;39(11):1972-1980. 137. Rosenstock J, Aronson R, Grunberger G, et al. Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial. Diabetes care. 2016;39(11):2026-2035. 138. Rosenstock J, Diamant M, Aroda VR, et al. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Lixisenatide and Insulin Glargine, Versus

Zheng et al. Insulin Glargine in Type 2 Diabetes Inadequately Controlled on Metformin Monotherapy: The LixiLan Proof-of-Concept Randomized Trial. Diabetes care. 2016;39(9):1579-1586. 139. Lu CH, Wu TJ, Shih KC, et al. Safety and efficacy of twice-daily exenatide in Taiwanese patients with inadequately controlled type 2 diabetes mellitus. J Formos Med Assoc. 2013;112(3):144-150. 140. NCT00667732. https://clinicaltrials.gov/ct2/show/NCT00667732. 141. Miyagawa J, Odawara M, Takamura T, Iwamoto N, Takita Y, Imaoka T. Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once-daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26- week randomized phase III study. Diabetes, obesity & metabolism. 2015;17(10):974- 983. 142. Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30(8):1448-1460. 143. NCT00375492. https://clinicaltrials.gov/ct2/show/NCT00375492. 144. NCT00701935. https://clinicaltrials.gov/ct2/show/NCT00701935. 145. NCT01001104. https://clinicaltrials.gov/ct2/show/NCT01001104. 146. NCT01617434. https://clinicaltrials.gov/ct2/show/NCT01617434. 147. NCT01733758. https://clinicaltrials.gov/ct2/show/NCT01733758. 148. Ratner RE, Rosenstock J, Boka G, on behalf of the DRISI. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo- controlled trial. Diabetic Medicine. 2010;27(9):1024-1032. 149. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. Jama. 2015;314(7):687-699. 150. Seino Y, Inagaki N, Miyahara H, et al. A randomized dose-finding study demonstrating the efficacy and tolerability of albiglutide in Japanese patients with type 2 diabetes mellitus. Curr Med Res Opin. 2014;30(6):1095-1106. 151. Seino Y, Kaneko S, Fukuda S, et al. Combination therapy with liraglutide and insulin in Japanese patients with type 2 diabetes: A 36-week, randomized, double-blind, parallel-group trial. Journal of diabetes investigation. 2016;7(4):565-573. 152. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. The New England journal of medicine. 2016;375(19):1834-1844. 153. Raz I, Fonseca V, Kipnes M, et al. Efficacy and safety of taspoglutide monotherapy in drug-naive type 2 diabetic patients after 24 weeks of treatment: results of a randomized, double-blind, placebo-controlled phase 3 study (T-emerge 1). Diabetes care. 2012;35(3):485-487. 154. Henry RR, Mudaliar S, Kanitra L, Woloschak M, Balena R. Efficacy and safety of taspoglutide in patients with type 2 diabetes inadequately controlled with metformin plus pioglitazone over 24 weeks: T-Emerge 3 trial. The Journal of clinical endocrinology and metabolism. 2012;97(7):2370-2379. 155. Hollander P, Lasko B, Barnett AH, et al. Effects of taspoglutide on glycemic control and body weight in obese patients with type 2 diabetes (T-emerge 7 study). Obesity (Silver Spring). 2013;21(2):238-247. 156. Terauchi Y, Satoi Y, Takeuchi M, Imaoka T. Monotherapy with the once weekly GLP- 1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double- blind, placebo-controlled study. Endocr J. 2014;61(10):949-959.

Zheng et al. 157. Vanderheiden A, Harrison L, Warshauer J, Li X, Adams-Huet B, Lingvay I. Effect of adding liraglutide vs placebo to a high-dose lnsulin regimen in patients with type 2 diabetes: A randomized clinical trial. JAMA Internal Medicine. 2016;176(7):939-947. 158. Wu JD, Xu XH, Zhu J, et al. Effect of exenatide on inflammatory and oxidative stress markers in patients with type 2 diabetes mellitus. Diabetes Technol Ther. 2011;13(2):143-148. 159. Zinman B, Hoogwerf BJ, Duran Garcia S, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Annals of internal medicine. 2007;146(7):477-485. 160. Araki E, Onishi Y, Asano M, et al. Efficacy and safety of dapagliflozin in addition to insulin therapy in Japanese patients with type 2 diabetes: Results of the interim analysis of 16-week double-blind treatment period. Journal of diabetes investigation. 2016;7(4):555-564. 161. Bailey CJ, Iqbal N, T'Joen C, List JF. Dapagliflozin monotherapy in drug-naive patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes, obesity & metabolism. 2012;14(10):951-959. 162. Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add- on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43. 163. Bode B, Stenlof K, Harris S, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes, obesity & metabolism. 2015;17(3):294-303. 164. Bolinder J, Ljunggren O, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes, obesity & metabolism. 2014;16(2):159-169. 165. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes, obesity & metabolism. 2013;15(4):372-382. 166. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes, obesity & metabolism. 2014;16(5):467-477. 167. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. International journal of clinical practice. 2013;67(12):1267-1282. 168. Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes care. 2015;38(3):403-411. 169. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England journal of medicine. 2017. 170. Cefalu WT, Leiter LA, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin's Effects on Glycemia and Cardiovascular Risk Factors in High-Risk Patients With Type 2 Diabetes: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With a 28-Week Extension. Diabetes care. 2015;38(7):1218-1227. 171. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes, obesity & metabolism. 2014;16(10):1016-1027. 172. Rosenstock J, Jelaska A, Zeller C, Kim G, Broedl UC, Woerle HJ. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial. Diabetes, obesity & metabolism. 2015;17(10):936-948.

Zheng et al. 173. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes care. 2015;38(3):420-428. 174. Merker L, Haring HU, Christiansen AV, et al. Empagliflozin as add-on to metformin in people with Type 2 diabetes. Diabet Med. 2015;32(12):1555-1567. 175. Haering HU, Merker L, Christiansen AV, et al. Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes. Diabetes Res Clin Pract. 2015;110(1):82-90. 176. Kovacs CS, Seshiah V, Merker L, et al. Empagliflozin as Add-on Therapy to Pioglitazone With or Without Metformin in Patients With Type 2 Diabetes Mellitus. Clin Ther. 2015;37(8):1773-1788.e1771. 177. Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes care. 2014;37(7):1815-1823. 178. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2015;373(22):2117-2128. 179. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369-384. 180. Fadini GP, Bonora BM, Zatti G, et al. Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial. Cardiovascular diabetology. 2017;16(1):42. 181. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes care. 2010;33(10):2217-2224. 182. Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes, obesity & metabolism. 2013;15(8):721- 728. 183. Fonseca VA, Ferrannini E, Wilding JP, et al. Active- and placebo-controlled dose- finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J Diabetes Complications. 2013;27(3):268-273. 184. Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. International journal of clinical practice. 2012;66(5):446- 456. 185. Kashiwagi A, Kazuta K, Goto K, Yoshida S, Ueyama E, Utsuno A. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes, obesity & metabolism. 2015;17(3):304-308. 186. Inagaki N, Kondo K, Yoshinari T, Maruyama N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double- blind, placebo-controlled, 12-week study. Diabetes, obesity & metabolism. 2013;15(12):1136-1145. 187. Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo- controlled, Phase III study. Expert Opin Pharmacother. 2014;15(11):1501-1515.

Zheng et al. 188. Inagaki N, Harashima S, Maruyama N, Kawaguchi Y, Goda M, Iijima H. Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovascular diabetology. 2016;15:89. 189. Ishihara H, Yamaguchi S, Nakao I, Okitsu A, Asahina S. Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a multi-centre, randomized, placebo-controlled, double-blind study. Diabetes, obesity & metabolism. 2016;18(12):1207-1216. 190. Jabbour SA, Hardy E, Sugg J, Parikh S. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double- blind, placebo-controlled study. Diabetes care. 2014;37(3):740-750. 191. Ji L, Ma J, Li H, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther. 2014;36(1):84-100.e109. 192. Ji L, Han P, Liu Y, et al. Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea. Diabetes, obesity & metabolism. 2015;17(1):23-31. 193. Terauchi Y, Tamura M, Senda M, Gunji R, Kaku K. Efficacy and safety of tofogliflozin in Japanese patients with type 2 diabetes mellitus with inadequate glycaemic control on insulin therapy (J-STEP/INS): Results of a 16-week randomized, double-blind, placebo-controlled multicentre trial. Diabetes, Obesity and Metabolism. 2017;19(10):1397-1407. 194. Kadowaki T, Haneda M, Inagaki N, et al. Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, 12-week, double-blind, placebo- controlled, phase II trial. Adv Ther. 2014;31(6):621-638. 195. Kadowaki T, Inagaki N, Kondo K, et al. Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: Results of a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes, obesity & metabolism. 2017;19(6):874-882. 196. Kaku K, Inoue S, Matsuoka O, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo- controlled trial. Diabetes, obesity & metabolism. 2013;15(5):432-440. 197. Kaku K, Kiyosue A, Inoue S, et al. Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. Diabetes, obesity & metabolism. 2014;16(11):1102-1110. 198. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney International. 2014;85(4):962-971. 199. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose- regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes, obesity & metabolism. 2013;15(9):853-862. 200. Kashiwagi A, Takahashi H, Ishikawa H, et al. A randomized, double-blind, placebo- controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study. Diabetes, obesity & metabolism. 2015;17(2):152-160. 201. Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double- blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62(7):1252-1262.

Zheng et al. 202. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes care. 2009;32(4):650-657. 203. Lu CH, Min KW, Chuang LM, Kokubo S, Yoshida S, Cha BS. Efficacy, safety, and tolerability of ipragliflozin in Asian patients with type 2 diabetes mellitus and inadequate glycemic control with metformin: Results of a phase 3 randomized, placebo-controlled, double-blind, multicenter trial. Journal of diabetes investigation. 2016;7(3):366-373. 204. Mathieu C, Ranetti AE, Li D, et al. Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes. Diabetes care. 2015;38(11):2009-2017. 205. Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes, obesity & metabolism. 2015;17(11):1075-1084. 206. NCT01137474. https://clinicaltrials.gov/ct2/show/NCT01137474. 207. Mudaliar S, Henry RR, Boden G, et al. Changes in insulin sensitivity and insulin secretion with the sodium glucose cotransporter 2 inhibitor dapagliflozin. Diabetes Technol Ther. 2014;16(3):137-144. 208. Qiu R, Capuano G, Meininger G. Efficacy and safety of twice-daily treatment with canagliflozin, a sodium glucose co-transporter 2 inhibitor, added on to metformin monotherapy in patients with type 2 diabetes mellitus. Journal of Clinical & Translational Endocrinology. 2014;1(2):54-60. 209. Rodbard HW, Seufert J, Aggarwal N, et al. Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately controlled on metformin and sitagliptin. Diabetes, obesity & metabolism. 2016;18(8):812-819. 210. Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes care. 2012;35(7):1473-1478. 211. Ross S, Thamer C, Cescutti J, Meinicke T, Woerle HJ, Broedl UC. Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial. Diabetes, obesity & metabolism. 2015;17(7):699-702. 212. Schumm-Draeger PM, Burgess L, Koranyi L, Hruba V, Hamer-Maansson JE, de Bruin TW. Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial. Diabetes, obesity & metabolism. 2015;17(1):42-51. 213. Seino Y, Sasaki T, Fukatsu A, Sakai S, Samukawa Y. Efficacy and safety of luseogliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a 12- week, randomized, placebo-controlled, phase II study. Curr Med Res Opin. 2014;30(7):1219-1230. 214. Seino Y, Sasaki T, Fukatsu A, Ubukata M, Sakai S, Samukawa Y. Dose-finding study of luseogliflozin in Japanese patients with type 2 diabetes mellitus: a 12-week, randomized, double-blind, placebo-controlled, phase II study. Curr Med Res Opin. 2014;30(7):1231-1244. 215. Seino Y, Sasaki T, Fukatsu A, Ubukata M, Sakai S, Samukawa Y. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin. 2014;30(7):1245-1255. 216. Sha S, Polidori D, Heise T, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes, obesity & metabolism. 2014;16(11):1087-1095. 217. Softeland E, Meier JJ, Vangen B, Toorawa R, Maldonado-Lutomirsky M, Broedl UC. Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately

Zheng et al. controlled with linagliptin and metformin: A 24-week randomized, double-blind, parallel-group trial. Diabetes care. 2017;40(2):201-209. 218. Strojek K, Yoon KH, Hruba V, Sugg J, Langkilde AM, Parikh S. Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks: a randomized, double-blind, parallel-group, placebo- controlled trial. Diabetes Ther. 2014;5(1):267-283. 219. Terra SG, Focht K, Davies M, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes, Obesity and Metabolism. 2017;19(5):721-728. 220. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo- controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211-220. 221. Wilding JP, Norwood P, T'Joen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes care. 2009;32(9):1656-1662. 222. Wilding JP, Ferrannini E, Fonseca VA, Wilpshaar W, Dhanjal P, Houzer A. Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study. Diabetes, obesity & metabolism. 2013;15(5):403- 409. 223. Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes, obesity & metabolism. 2014;16(2):124-136. 224. Yang W, Han P, Min KW, et al. Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial. J Diabetes. 2016;8(6):796-808. 225. Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes care. 2014;37(8):2149-2158. 226. Charbonnel B, Steinberg H, Eymard E, et al. Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial. Diabetologia. 2013;56(7):1503- 1511. 227. Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010;376(9739):431-439. 228. Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes care. 2012;35(2):252-258. 229. Gadde KM, Vetter ML, Iqbal N, Hardy E, Ohman P. Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: The DURATION-NEO-2 randomized clinical study. Diabetes, Obesity and Metabolism. 2017;19(7):979-988. 230. Ahren B, Johnson SL, Stewart M, et al. HARMONY 3: 104-week randomized, double- blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes care. 2014;37(8):2141-2148. 231. Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26- week, randomised, parallel-group, open-label trial. Lancet. 2010;375(9724):1447- 1456.

Zheng et al. 232. Bailey TS, Takacs R, Tinahones FJ, et al. Efficacy and safety of switching from sitagliptin to liraglutide in subjects with type 2 diabetes (LIRA-SWITCH): a randomized, double-blind, double-dummy, active-controlled 26-week trial. Diabetes, obesity & metabolism. 2016;18(12):1191-1198. 233. NCT00976937. https://clinicaltrials.gov/ct2/show/NCT00976937. 234. Pratley R, Nauck M, Bailey T, et al. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. International journal of clinical practice. 2011;65(4):397-407. 235. Ahren B, Masmiquel L, Kumar H, et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. The Lancet Diabetes and Endocrinology. 2017;5(5):341-354. 236. Bergenstal RM, Forti A, Chiasson JL, Woloschak M, Boldrin M, Balena R. Efficacy and safety of taspoglutide versus sitagliptin for type 2 diabetes mellitus (T-emerge 4 trial). Diabetes Ther. 2012;3(1):13. 237. Van Gaal L, Souhami E, Zhou T, Aronson R. Efficacy and safety of the glucagon-like peptide-1 receptor agonist lixisenatide versus the dipeptidyl peptidase-4 inhibitor sitagliptin in young (<50 years) obese patients with type 2 diabetes mellitus. Journal of Clinical & Translational Endocrinology. 2014;1(2):31-37. 238. Zang L, Liu Y, Geng J, et al. Efficacy and safety of liraglutide versus sitagliptin, both in combination with metformin, in Chinese patients with type 2 diabetes: a 26-week, open-label, randomized, active comparator clinical trial. Diabetes, obesity & metabolism. 2016;18(8):803-811. 239. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56(12):2582-2592. 240. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes care. 2013;36(9):2508-2515. 241. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes care. 2015;38(3):384-393. 242. Roden M, Merker L, Christiansen AV, et al. Safety, tolerability and effects on cardiometabolic risk factors of empagliflozin monotherapy in drug-naive patients with type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial. Cardiovascular diabetology. 2015;14:154. 243. Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes care. 2013;36(12):4015-4021. 244. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes care. 2012;35(6):1232-1238. 245. Rosenstock J, Seman LJ, Jelaska A, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes, obesity & metabolism. 2013;15(12):1154-1160. 246. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin

Zheng et al. plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes care. 2015;38(3):376-383. 247. Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004-1016. 248. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England journal of medicine. 2017;377(7):644- 657.

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