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. © 2018 American Medical Association. All rights reserved. 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) © 2018 American Medical Association. All rights reserved. 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 © 2018 American Medical Association. All rights reserved. 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 © 2018 American Medical Association. All rights reserved. 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 © 2018 American Medical Association. All rights reserved. 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 © 2018 American Medical Association. All