Association of Glucose-Lowering Medications With Cardiovascular Outcome Appendix

Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Zhu J, Yu X, Zheng Y, et al. Association of glucose-lowering

medications with cardiovascular outcomes: an umbrella review and evidence map.
Lancet Diabetes Endocrinol 2020; published online Jan 29. https://doi.org/10.1016/
S2213-8587(19)30422-X.
Supplementary appendix
Contents Page
eAppendix A. Search strategies Page 1
eTable 1. Characteristics and quality assessment of the included meta-analyses Page 2-4
eTable 2. eTable 2. Baseline characteristics of CVOTs included Page 5-8
eTable 3: AMSTAR items for individual studies included in the umbrella review Page 9
eTable 4: Quantitative synthesis, and bias assessment of the 237 eligible meta-analyses of glucose-lowering Page 10-19
medications on cardiovascular outcomes
eTable 5: GRADE of quality evidence for glucose-lowering medications on cardiovascular outcomes Page 20-25
eFigure 1-31. Association of Glucose-lowering medications and cardiovascular outcomes Page 26-165
0
eAppendix A. Search strategies
Search strategy of Pubmed for meta-analysis
("Diabetes mellitus"[Mesh] OR "Prediabetic State"[Mesh] OR "Diabetes"[tiab] OR "Prediabetes"[tiab] OR

"Pre-diabetes"[tiab] ) AND ("Cardiovascular System"[Mesh] OR "Cardiovascular Diseases"[Mesh] OR
"Cerebrovascular Disorders"[Mesh] OR “Cardiovascular”[tiab] OR “Heart”[tiab] OR “Cardiac”[tiab] OR
“valvular”[tiab] OR “ischaemic”[tiab] OR “atrial fibrillation”[tiab] OR “myocardial infarction”[tiab] OR
“cerebrovascular”[tiab] OR “stroke”[tiab] OR “arrhythmia”[tiab]) AND ("Meta-Analysis as Topic"[Mesh]
OR "Meta-Analysis"[Publication Type] OR "Meta-analysis"[tiab] OR "Systematic review"[tiab] OR
"Cochrane Database Syst Rev"[jour])
This strategy is adapted to identify trials in other electronic databases
Search strategy of Pubmed for RCT
("Diabetes mellitus"[Mesh] OR "Prediabetic State"[Mesh] OR "Diabetes"[tiab] OR "Prediabetes"[tiab] OR

"Pre-diabetes"[tiab] ) AND ("Cardiovascular System"[Mesh] OR "Cardiovascular Diseases"[Mesh] OR
"Cerebrovascular Disorders"[Mesh] OR “Cardiovascular”[tiab] OR “Heart”[tiab] OR “Cardiac”[tiab] OR
“valvular”[tiab] OR “ischaemic”[tiab] OR “atrial fibrillation”[tiab] OR “myocardial infarction”[tiab] OR
“cerebrovascular”[tiab] OR “stroke”[tiab] OR “arrhythmia”[tiab]) AND ("Meta-Analysis as Topic"[Mesh]
OR "Meta-Analysis"[Publication Type] OR "Meta-analysis"[tiab] OR "Systematic review"[tiab] OR
"Cochrane Database Syst Rev"[jour])
"Randomized Controlled Trials as Topic"[Mesh] OR "Randomized Controlled Trial" [Publication Type] OR
"random*"[tiab]
This strategy is adapted to identify trials in other electronic databases
1
eTable 1. Characteristics and quality assessment of the included meta-analyses
Study Intervention Databases Patients Guideline Quality Publication bias Duration Type of data AMSTAR
(n) score
Kaneko 2016 DPP-4I 4 T2DM PRISMA Cochrane Funnel plot 24-206w Trial level 9
Savarese 2016 DPP-4I 4 T2DM PRISMA ND Macaskill's test 4-209w Trial level 7
Kongwatcharapong DPP-4I 8 Adults using PRISMA Cochrane and Jadad Begg test and 12-156w Trial level 9
2016 any DPP-4 Eggers test
inhibitors
Elgendy 2017 DPP-4I 3 T2DM PRISMA Based on previous Egger test 2-156w Trial level 9
study
Wang 2016 DPP-4I 4 T2DM PRISMA Cochrane Begg test and 24-52w Trial level 9
Eggers test
Rosenstock 2015 Linagliptin / T2DM / / / 12-104w Patient level /
McInnes 2015 Vildagliptin / T2DM / / / 50.3w Patient level /
Liu 2019 DPP-4I 4 T2DM PRISMA Cochrane Funnel plot 52-152w Trial level 9
Monami 2014 GLP-1RA 4 T2DM PRISMA Jadad Funnel plots and 42w (mean) Trial level 9
Begg test
Monami 2017A GLP-1RA 5 T2DM PRISMA Cochrane Funnel plots and 41.7±38.2w Trial level 10
Begg test
Gargiulo 2017 GLP-1RA 5 T2DM PRISMA ND Funnel plots 12-195w Trial level 7
Monami 2017B GLP-1RA 5 T2DM PRISMA Cochrane Funnel plots and 80.6w(mean) Trial level 10
Begg test
Fisher 2015 Albiglutide / T2DM / / / 16w-3y Trial level /
Ferdinand 2016 Dulaglutide / T2DM / / / 12-104w Trial level /
Seshasai 2015 Taspoglutide / T2DM / / / 7478 person- Trial level /

years
Kristensen 2019 GLP-1 2 T2DM Unclear Cochrane ND 1.3-5.4y Trial level 8
Usman 2018 SGLT2I 4 T2DM PRISMA Cochrane Funnel plots and 24-188w Trial level 9
Begg test
Monami 2017 SGLT2I 4 T2DM PRISMA Cochrane Funnel plots and 40.2w Trial level 10
Begg test
Sonesson 2016 Dapagliflozin / T2DM / / / 12-208w Trial level /
Salsali 2016 Empagliflozin / T2DM / / / 24w-3.1y Trial level /
Zelniker 2019 SGLT2I 2 T2DM PRISMA Cochrane ND 2.4-4.2y Trial level 9
Varvaki 2016 Sulfonylurea 5 T2DM PRISMA Cochrane Funnel plots, 12-133m Trial level 10
Begg and Egger
tests
Monami 2013 Sulfonylurea 6 T2DM PRISMA Jadad Funnel plots and 24-577w Trial level 8
Begg test
Nissen 2010 Rosiglitazone 3 T2DM Unclear No No >24w Trial level 7
Cheng 2018 Rosiglitazone 3 T2DM PRISMA Cochrane Funnel plots 6-72m Trial level 9
Lincoff 2007 Pioglitazone / T2DM / / / 4 m to 3.5 y Patient level /
Mannucci 2008 Pioglitazone 3 T2DM Unclear No No 8-156w Trial level 7
Liao 2017 Pioglitazone 4 pre-diabetes or PRISMA Cochrane Begg and Egger 1-4.8y Trial level 9
insulin tests
resistance or
type 2 diabetes
mellitus
Lamanna 2011 Metformin 3 non-diabetic PRISMA Jadad Begg and Egger 52-556w Trial level 8
and diabetic tests
patients
Selvin 2008 Metformin 3 T2DM Unclear Jadad No 3-133m Trial level 7
Griffin 2017 Metformin 3 T2DM PRISMA Cochrane Funnel plots 6-212m Trial level 8
Moelands 2018 AGI 5 People at risk Cochrane Cochrane Funnel plots 1-6y Trial level 11
of developing
of T2DM
Hanefeld 2004 Acarbose / T2DM / / / 57.6w Patient level /
Erpeldinger 2016 Insulin 3 T2DM PRISMA Cochrane No 24w-10y Trial level 7
Li 2016 Insulin 7 T2DM Unclear Cochrane No 1.1-10y Trial level 7
DPP4i, Dipeptidyl peptidase-4 inhibitors; GLP-1RAs, Glucagon-like peptide-1 receptor agonists; SGLT2I, Sodium-glucose co-transporter-2
inhibitors; T2DM, type 2 diabetes; ND,not done
2
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cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014 Jan;16(1):38-
47.
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cardiovascular events: A comprehensive meta-analysis of randomized controlled trials. Int J Cardiol. 2017
Aug 1;240:414-421.
11 Gargiulo P, Savarese G, D'Amore C, et al. Efficacy and safety of glucagon-like peptide-1 agonists on
macrovascular and microvascular events in type 2 diabetes mellitus: A meta-analysis. Nutr Metab Cardiovasc
Dis. 2017 Dec;27(12):1081-1088.
12 Monami M, Nreu B, Scatena A, et al. Glucagon-like peptide-1 receptor agonists and atrial fibrillation: a
systematic review and meta-analysis of randomised controlled trials. J Endocrinol Invest. 2017
Nov;40(11):1251-1258.
13 Fisher M, Petrie MC, Ambery PD, et al. Cardiovascular safety of albiglutide in the Harmony programme:
a meta-analysis. Lancet Diabetes Endocrinol 2015;3(9):697-703.
14 Ferdinand KC, Botros FT, Atisso CM, et al. Cardiovascular safety for once-weekly dulaglutide in type 2
diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events. Cardiovasc
Diabetol. 2016 Feb 24;15:38.
15 Seshasai SR, Bennett RL, Petrie JR, et al. Cardiovascular safety of the glucagon-like peptide-1 receptor
agonist taspoglutide in people with type 2 diabetes: an individual participant data meta-analysis of
randomized controlled trials. Diabetes Obes Metab. 2015 May;17(5):505-10.
16 Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1
receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular
outcome trials. Lancet Diabetes Endocrinol 2019;7(10):776-785.
17 Usman MS, Siddiqi TJ, Memon MM, et al. Sodium-glucose co-transporter 2 inhibitors and cardiovascular
outcomes: A systematic review and meta-analysis. Eur J Prev Cardiol. 2018 Mar;25(5):495-502.
18 Monami M, Dicembrini I, Mannucci E. Effects of SGLT-2 inhibitors on mortality and cardiovascular
events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol. 2017 Jan;54(1):19-36.
19 Sonesson C, Johansson PA, Johnsson E, et al. Cardiovascular effects of dapagliflozin in patients with type
2 diabetes and different risk categories: a meta -analysis. Cardiovasc Diabetol. 2016 Feb 19;15:37.
20 Salsali A, Kim G, Woerle HJ, et al. Cardiovascular safety of empagliflozin in patients with type 2 diabetes:
a meta-analysis of data from randomized placebo-controlled trials. Diabetes Obes Metab. 2016
3
Oct;18(10):1034-40.
21 Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of
cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of
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4
eTable 2. Baseline characteristics of CVOTs included.
Study Characterizing CVD risk Intervention Number Mean Age BMI Mean duration Trial Cardiovascular outcomes
of (year) (kg/m2) of diabetes duration
patients (year) (year)
EXAMINE Established CVD Alogliptin 2701 61 28.7 7.1 1.5 3-Point MACE, CVD, MI,
Stroke, HF,UA
Placebo 2679 61 28.7 7.3
CARMELINA High risk of CVD Linagliptin 3494 66.1 (9.1) 31.4 15.0 (9.6) 2.2 3-Point MACE, CVD, MI,
(5.3) Stroke, HF,UA
Placebo 3485 65.6 (9.1) 31.3 14.5 (9.3)
(5.4)
CAROLINA High risk of CVD Linagliptin 3023 63.9 (9.5) 30.2 6.3 (3.0, 11.1) 6.3 3-Point MACE, CVD, MI,
(5.2) Stroke, HF,UA
Glimepiride 3010 64.2 (9.5) 30.0 6.2 (2.9, 10.9)
(5.1)
SAVOR-TIMI 53 Established CVD or High Saxagliptin 8280 65.1 (8.5) 31.1 10.3 2.1 3-Point MACE, CVD, MI,
risk of CVD (5.5) Stroke, HF,UA
Placebo 8212 65.0 (8.6) 31.2 10.3
(5.7)
TECOS Established CVD Sitagliptin 7332 65.4 (7.9) 30.2 11.6 (8.1) 3 3-Point MACE, CVD, MI,
(5.6) Stroke, HF,UA
Placebo 7339 65.5 (8.0) 30.2 11.6 (8.1)
(5.7)
OMNEON Established CVD Omarigliptin 2092 63.7 (8.5) 31.2 12.0 (7.6) 1.85 3-Point MACE, CVD, MI,
(5.5) Stroke, HF
Placebo 2100 63.6 (8.5) 31.4 12.1 (8.0)
(5.6)
Harmony Established CVD Albiglutide 4731 64·1 (8·7) 32·3 14·1 (8·6) 1.6 3-Point MACE, CVD, MI,
(5·9) Stroke, HF,UA
Placebo 4732 64·2 (8·7) 32·3 14·2 (8·9)
(5·9)
REWIND Established CVD or High Dulaglutide 4949 66·2 (6·5) 32·3 10·5 (7·3) 5.4 3-Point MACE, CVD, MI,
risk of CVD (5·7) Stroke, HF,UA
Placebo 4952 66·2 (6·5) 32·3 10·6 (7·2)
(5·8)
EXSCEL With or without previous Exenatide 7356 62 31.8 12 3.2 3-Point MACE, CVD, MI,
CVD Placebo 7396 62 31.7 12 Stroke, HF,UA
LEADER High risk of CVD Liraglutide 4668 64.2 (7.2) 32.5 12.8 (8.0) 3.8 3-Point MACE, CVD, MI,
(6.3) Stroke, HF,UA
Placebo 4672 64.4 (7.2) 32.5 12.9 (8.1)
(6.3)
ELIXA Established CVD Lixisenatide 3034 60.6 (9.6) 30.2 9.4 (8.3) 2.08 4-Point MACE, CVD, MI,
(5.8) Stroke, HF,UA
Placebo 3034 59.9 (9.7) 30.2 9.2 (8.2)
(5.8)
SUSTAIN-6 High risk of CVD Semaglutide 1648 64.6 (7.3) 32.7 14.3 (8.2) 2.1 3-Point MACE, CVD, MI,
(6.29) Stroke, HF,UA
Placebo 1649 64.8 (7.6) 32.9 14.0 (8.5)
(6.35)
PIONEER 6 High risk of CVD Semaglutide 1591 66 (7) 32.3 14.7 (8.5) 1.33 3-Point MACE, CVD, MI,
(6.6) Stroke, HF,UA
Placebo 1592 66 (7) 32.3 15.1 (8.5)
(6.4)
CANVAS High risk of CVD Canagliflozin 5795 63.2 (8.3) 31.9 13.5 (7.7) 2.42 3-Point MACE, CVD, MI,
(5.9) Stroke, HF
Placebo 4347 63.4 (8.2) 32.0 13.7 (7.8)
(6.0)
CREDENCE 1 With or without previous Canagliflozin 1089 61.1 ( 9.7) 31.2 14.8 (8.4) 2.62 3-Point MACE, CVD, MI,
CVD (6.4) Stroke, HF,UA
Placebo 1092 61.7 ( 9.4) 31.0 15.5 (8.4)
( 6.3)
CREDENCE 2 With or without previous Canagliflozin 1113 64.6 (8.2) 31.6 16.3 (8.9)
CVD (6.0)
Placebo 1107 64.6 (8.9) 31.6 16.5 (8.7)
(6.1)
DECLARE–TIMI Established CVD or High Dapagliflozin 8582 63.9±6.8 32.1±6.0 11 4.2 3-Point MACE, CVD, MI,
58 risk of CVD Placebo 8578 64.0 (6.8) 32.0 10 Stroke, HF
(6.1)
DAPA-HF Established CVD Dapagliflozin 2373 66.2 (11.0) 28.2 / 18.2m CVD, HF
(6.0)
Placebo 2371 66.5 (10.8) 28.1(5.9)
EMPA-REG High risk of CVD Empagliflozin 4687 63.1 ( 8.6) 30.6 / 3.1 3-Point MACE, CVD, MI,
(5.3) Stroke, HF,UA
Placebo 2333 63.2 ( 8.8) 30.7
(5.2)
ACE Established CVD Acarbose 3272 64·4 (8·2) 25·3 / 5 3-Point MACE, CVD, MI,
(3·1) Stroke, HF,UA
Placebo 3250 64·3 (8·0) 25·5 /
(3·1)
STOP-NIDDM With or without previous Acarbose 682 54·5 (7·9) 30·9 / 3.3 Any MACE, CVD, MI, Stroke,
CVD (4·2) HF,UA
Placebo 686 54·3 (7·9) 31.0 /
(4·3)
DREAM With or without previous Rosiglitazone 2635 54·6 (10·9) 30·8 / 3 3-Point MACE, CVD, MI,
CVD (5·6) Stroke, HF,UA
Placebo 2634 54·8 (10·9) 31·0 /
(5·6)
RECORD With or without previous Rosiglitazone 2220 58.4 (8.3) 31·6 7.0 (5.0) 5.5 3-Point MACE, CVD, MI,
CVD (4·7) Stroke, HF
Metformin or 2227 58.5 (8.3) 31·5 7.1 (4.9)
sulfonylurea (4·9)
Placebo 1937 63.5 (10.7) 30.0 /
5
(5.3)
PROactive High risk of CVD Pioglitazone 2605 61·9 (7·6) 30·7 8 (4–13) 34·5 m 3-Point MACE, CVD, MI,
(4·7) Stroke, HF
Placebo 2633 61·6 (7·8) 31·0 8 (4–14)
(4·8)
TOSCA.IT With or without previous Pioglitazone 1535 62·4 (6·4) 30·2 8·4 (5·6) 57·3 m 4-MACEb, CVD, MI, Stroke,
CVD (4·4) HF
Sulfonylurea 1493 62·2 (6·5) 30·4 8·5 (5·8)
(4·5)
UKPDS With or without previous Insulin 911 54 (8) 27·0 / 10.7 MI, Stroke, HF
CVD (4·8)
Chlorpropamide 619 54 (9) 27·0 /
(4·9)
Glibenclamide 615 54 (8) 27·4 /
(5·0)
Diet 896 54 (9) 27·5 /
(5·3)
Metformin 342 53 (8) 31·6 /
(4·8)
Diet 411 53 (9) 31·8 /
(4·9)
NAVIGATOR Established CVD or High Nateglinide 4645 63.7 (6.8) 30.5 / 5 4-Point MACE, CVD, MI,
risk of CVD (5.4) Stroke, HF,UA
Placebo 4661 63.8 (6.9) 30.5 /
(5.4)
Cycloset Safety Established CVD or High Bromocriptine-QR 2054 59.5 (10.2) 32.4 7.9 (7.42) 1 3-Point MACE, CVD, MI,
Trial risk of CVD (5.1) Stroke, HF, UA
Placebo 1016 60.2 (9.97) 32.3 8.0 (7.41)
(5.1)
ORIGIN High risk of CVD Basal Insulin 6264 63.6 (7.8) 29.8 5.5 (6.1) 6.2 3-Point MACE, CVD, MI,
(5.2) Stroke, HF, UA
Standard care 6273 63.5 (7.9) 29.9 5.3 (5.9)
(5.3)
DEVOTE High risk of CVD Insulin degludec 3818 64.9 (7.3) 33.6 16.6 (8.8) 1.99 3-Point MACE, CVD, MI,
(6.8) Stroke, UA
Insulin glargine 3819 65.0 (7.5) 33.6 16.2 (8.9)
(6.8)
HEART2D T2DM Insulin lispro 557 61.1 (9.7) 29.0 9.3 (7.2) 2.64 3-Point MACE, CVD, MI,
(4.6) Stroke, HF,
NPH/glargine 558 60.9 (9.8) 29.2 9.0 (7.3)
(5.0)
T2DM, type 2 diabetes; IFG, impaired fasting glucose; IGT, impaired glucose tolerance3-Point MACE (composite of death from cardiovascular
causes, nonfatal myocardial infarction, nonfatal stroke); 4-Point MACE (composite of death from cardiovascular causes, nonfatal myocardial
infarction, nonfatal stroke, or hospitalization for heart failure); MACE, major cardiovascular event; CVD death, cardiovascular death; MI,
myocardial infarction; stroke; HF, heart failure; UA, unstable angina; AF, atrial fibrillation
6
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14 Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2
Diabetes Bruce Neal. N Engl J Med. 2017 Aug 17;377(7):644-657.
15 Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and Cardiovascular and Renal Outcomes in
Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention
Groups. Circulation. 2019 Aug 27;140(9):739-750.
16 Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N
Engl J Med. 2019 Jan 24;380(4):347-357.
17 McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced
Ejection Fraction. N Engl J Med. 2019 Sep 19. doi: 10.1056/NEJMoa1911303.
18 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2
Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.
19 Holman RR, Coleman RL, Chan JCN, et al. Effects of acarbose on cardiovascular and diabetes outcomes
in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind,
placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Nov;5(11):877-886.
20Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and
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23;290(4):486-94.
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Diabetes Care. 2008 May;31(5):1007-14.
7
22 Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral
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Lancet. 2009 Jun 20;373(9681):2125-35.
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N Engl J Med. 2016 Apr 7;374(14):1321-31.
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25 Vaccaro O, Masulli M, Nicolucci A, et al. Effects on the incidence of cardiovascular events of the addition
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8
eTable 3: AMSTAR items for individual studies included in the umbrella review
Study A priori Duplicate At least Status of List of Characterist Scientific scientific Appropriate Publication Conflict Total
design study two publication included ics of quality of quality of the methods to bias of AMSTAR
provided selection electronic used as an AND included included included combine assessed interest Score
& data databases inclusion excluded studies studies studies used studies included
extraction searched criteria studies provided assessed appropriately
provided to form
conclusions
Kaneko 2016 0 1 1 1 0 1 1 1 1 1 1 9
Savarese 2016 0 1 1 0 0 1 0 1 1 1 1 7
Kongwatcharapong 0 1 1 1 0 1 1 1 1 1 1 9
2016
Elgendy 2017 1 1 1 0 0 1 1 1 1 1 1 9
Wang 2016 0 1 1 1 0 1 1 1 1 1 1 9
Liu 2019 0 1 1 1 0 1 1 1 1 1 1 9
Monami 2014 0 1 1 1 0 1 1 1 1 1 1 9
Monami 2017A 1 1 1 1 0 1 1 1 1 1 1 10
Gargiulo 2017 0 1 1 0 0 1 0 1 1 1 1 7
Monami 2017B 1 1 1 1 0 1 1 1 1 1 1 10
Kristensen 2019 0 1 1 0 0 1 1 1 1 1 1 8
Usman 2018 0 1 1 1 0 1 1 1 1 1 1 9
Monami 2017 1 1 1 1 0 1 1 1 1 1 1 10
Zelniker 2019 1 1 1 0 0 1 1 1 1 1 1 9
Varvaki 2016 1 1 1 1 0 1 1 1 1 1 1 10
Monami 2013 0 1 1 0 0 1 1 1 1 1 1 8
Nissen 2010 0 1 1 1 0 1 0 1 1 0 1 7
Cheng 2018 0 1 1 1 0 1 1 1 1 1 1 9
Mannucci 2008 0 1 1 1 0 1 0 1 1 0 1 7
Liao 2017 0 1 1 1 0 1 1 1 1 1 1 9
Lamanna 2011 0 1 1 0 0 1 1 1 1 1 1 8
Selvin 2008 0 1 1 0 0 1 1 1 1 0 1 7
Griffin 2017 0 1 1 0 0 1 1 1 1 1 1 8
Moelands 2018 1 1 1 1 1 1 1 1 1 1 1 11
Erpeldinger 2016 0 1 1 0 0 1 1 1 0 1 1 7
Li 2016 0 1 1 0 0 1 1 1 0 1 1 7
9
eTable 4: Quantitative synthesis, and bias assessment of the 237 eligible meta-analyses of glucose-lowering medications on cardiovascular outcomes
Outcome Published meta-analyses CVOTs Pooled analysis GRADE
of
Author N. of N. of RR (95% CI) I2 N. of N. of HR (95% CI) I2 (%) N. of N. of RR (95% CI) 95% PI I2 Egger's evidence
patients studies (%) patients studies patients studies (%) P value
DPP-4
Overall analysis
MACE Kaneko 2016 67770 69 0.98 (0.87-1.09) 0 53747 6 0.99 (0.94-1.05) 0 99645 73 0.98 (0.92-1.03) 0.92-1.03 0 0.039 Moderate
CVD death Savarese 2016 68151 43 0.98 (0.89-1.08) 0 53747 6 0.99 (0.92-1.07) 0 85355 46 0.99 (0.91-1.07) 0.91-1.07 0 0.881 High
MI Savarese 2016 86698 74 0.93 (0.84-1.02) 0 53747 6 1.01 (0.93-1.09) 0 103902 77 0.97 (0.90-1.05) 0.90-1.05 0 0.243 High
Stroke Savarese 2016 76974 66 0.96 (0.84-1.10) 0 53747 6 0.96 (0.86-1.08) 0 94178 69 0.93 (0.83-1.04) 0.83-1.04 0 0.873 High
HF Kongwatcharapong 74737 54 1.11 (0.99-1.23) 0 53747 6 1.04 (0.89-1.21) 60.1 91941 57 1.03 (0.89-1.18) 0.70-1.51 54.6 / Moderate
2016
UA / / / / / 49555 5 0.94 (0.82-1.09) 11.3 49555 5 0.94 (0.82-1.09) 0.71-1.26 11.3 / High
DPP-4 vs Placebo
MACE Kaneko 2016 41942 37 1.05 (0.93-1.18) 0 47714 5 0.99 (0.94-1.06) 0 67784 41 0.99 (0.93-1.05) 0.93-1.05 0 0.951 High
CVD death Elgendy 2017 44209 21 1.01 (0.91-1.12) 0 47714 5 0.99 (0.91-1.08) 0 55376 23 1.00 (0.92-1.09) 0.91-1.09 0 0.396 High
MI Elgendy 2017 49047 35 0.97 (0.88-1.08) 0 47714 5 1.00 (0.92-1.09) 0 60214 37 1.00 (0.92-1.08) 0.91-1.09 0 0.552 High
Stroke Elgendy 2017 43752 23 0.98 (0.84-1.14) 0 47714 5 0.98 (0.87-1.12) 0 54919 25 0.97 (0.86-1.10) 0.85-1.11 0 0.593 High
HF Elgendy 2017 42031 16 1.10 (0.99-1.24) 0 47714 5 1.01 (0.84-1.20) 65.1 53198 18 1.03 (0.93-1.14) 0.91-1.16 1.1 0.151 High
UA / / / / / 43522 4 0.93 (0.79-1.09) 24.5 43522 4 0.93 (0.79-1.09) 0.56-1.54 24.5 / High
Alogliptin
MACE Kaneko 2016 13602 10 0.99 (0.85-1.15) 0 5380 1 0.96 (0.82-1.12) / 13602 10 0.93 (0.80-1.08) 0.78-1.10 0 0.748 High
CVD death Elgendy 2017 6790 4 0.80 (0.61-1.05) 0 5380 1 0.85 (0.66–1.10) / 6790 4 0.86 (0.67–1.11) 0.49-1.51 0 / Moderate
MI Elgendy 2017 6707 4 1.07 (0.88-1.31) 0 5380 1 1.09 (0.92-1.29) / 6707 4 1.09 (0.92-1.29) 0.75-1.58 0 / Moderate
Stroke Elgendy 2017 6813 5 0.89 (0.55-1.44) 0 5380 1 0.81 (0.51, 1.29) / 6813 5 0.81 (0.52-1.27) 0.39-1.67 0 / Low
HF Kongwatcharapong 12547 9 1.17 (0.90–1.52) / 5380 1 1.07 (0.79-1.46) / 12547 9 1.17 (0.90–1.52) / / / Moderate
2016
Unstable angina Wang 2016 9140 5 0.86 (0.58-1.28) 25.2 5380 1 0.82 (0.65-1.04) / 9140 5 0.73 (0.34-1.55) 0.11-4.92 22.7 / Low
Linagliptin
MACE Rosenstock 2015 9459 19 0.74 (0.49-1.13) / 13012 2 1.00 (0.90-1.11) 0 22471 21 0.98 (0.89-1.09) 0.50-1.96 2.7 / High
CVD death Rosenstock 2015 9459 19 1.04 (0.42–1.60) / 13012 2 0.98 (0.85-1.11) 0 22471 21 0.98 (0.86-1.11) 0.42-2.30 0 / High
MI Rosenstock 2015 9459 19 0.86 (0.47-1.56) / 13012 2 1.08 (0.92-1.26) 0 22471 21 1.06 (0.91–1.23) 0.39-2.86 0 / High
Stroke Rosenstock 2015 9459 19 0.34 (0.15-0.75) / 13012 2 0.88 (0.72-1.08) 0 22471 21 0.77 (0.54-1.10) 0.02- 61.1 / Low
34.27
HF Rosenstock 2015 9459 19 1.04 (0.43-2.47) / 13012 2 1.03 (0.77-1.37) 0 22471 21 1.02 (0.82-1.27) 0.13-8.03 34.5 / Moderate
Unstable angina Wang 2016 4535 5 1.40 (0.47-4.15) 2.6 13012 2 0.98 (0.74-1.29) 0 17547 7 1.00 (0.77–1.30) 0.70-1.42 0 / Moderate
10
Saxagliptin
MACE Kaneko 2016 24799 14 1.03 (0.82-1.31) 0 16492 1 1.00 (0.89–1.12) / 24799 14 0.99 (0.88-1.10) 0.87-1.12 0 0.821 High
CVD death Elgendy 2017 18709 6 1.03 (0.87-1.22) 0 16492 1 1.03 (0.87–1.22) / 18709 6 1.04 (0.88-1.23) 0.82-1.32 0 / High
MI Elgendy 2017 19977 9 0.83 (0.45-1.54) 11.9 16492 1 0.95 (0.80–1.12) / 19977 9 0.84 (0.45-1.54) 0.26-2.67 11.9 / Low
Stroke Elgendy 2017 18909 6 1.10 (0.88-1.37) 0 16492 1 1.11 (0.88–1.39) / 18909 6 1.10 (0.88-1.38) 0.80-1.52 0 / Moderate
HF Kongwatcharapong 21708 9 1.22 (1.03–1.44) / 16492 1 1.27 (1.07–1.51) / 21708 9 1.22 (1.03–1.44) / / / Moderate
2016
Unstable angina Wang 2016 19744 6 1.17 (0.87-1.55) 0 16492 1 1.19 (0.89–1.60) / 19744 6 1.17 (0.88-1.56) 0.78-1.75 0 / Moderate
Sitagliptin /
MACE Kaneko 2016 20396 29 1.03 (0.73-1.44) 0 14671 1 0.99 (0.89–1.10) / 35067 30 0.99 (0.90–1.10) 0.89-1.10 0 0.858 High
CVD death Elgendy 2017 16059 5 1.06 (0.91-1.24) 0 14671 1 1.03 (0.89–1.19) / 16059 5 1.02 (0.89–1.18) 0.81-1.29 0 / High
MI Elgendy 2017 17721 8 0.95 (0.81-1.12) 0 14671 1 0.95 (0.81–1.11) / 17721 8 0.94 (0.81–1.10) 0.78-1.15 0 / High
Stroke Elgendy 2017 16031 5 0.93 (0.75-1.16) 0 14671 1 0.97 (0.79–1.19) / 16031 5 0.98 (0.80–1.20) 0.70-1.36 0 / High
HF Kongwatcharapong 27539 19 1.01 (0.85-1.20) / 14671 1 1.00 (0.83–1.20) / 27539 19 1.01 (0.85-1.20) / / / High
2016
Unstable angina Wang 2016 23994 14 0.88 (0.69-1.12) 0 14671 1 0.90 (0.70–1.16) / 23994 14 0.88 (0.69-1.12) 0.67-1.15 0 0.443 Moderate
Vildagliptin
MACE McInnes 2015 16701 40 0.82 (0.61-1.11) / / / / / 16701 40 0.82 (0.61-1.11) / / / Low
CVD death McInnes 2015 16701 40 0.77 (0.45-1.31) / / / / / 16701 40 0.77 (0.45-1.31) / / / Very
Low
MI McInnes 2015 16701 40 0.87 (0.56-1.38) / / / / / 16701 40 0.87 (0.56-1.38) / / / Very
Low
Stroke McInnes 2015 16701 40 0.84 (0.47-1.50) / / / / / 16701 40 0.84 (0.47-1.50) / / / Very
Low
HF McInnes 2015 16701 40 1.08 (0.68-1.70) / / / / / 16701 40 1.08 (0.68-1.70) / / / Very
Low
Omarigliptin
MACE / / / / / 4192 1 1.00 (0.77-1.29) / 4192 1 1.00 (0.77-1.29) / / / Moderate
CVD death / / / / / 4192 1 1.06 (0.66-1.68) / 4192 1 1.06 (0.66-1.68) / / / Low
MI / / / / / 4192 1 0.87 (0.60-1.26) / 4192 1 0.87 (0.60-1.26) / / / Low
Stroke / / / / / 4192 1 0.94 (0.58-1.52) / 4192 1 0.94 (0.58-1.52) / / / Low
HF / / / / / 4192 1 0.60 (0.35-1.05) / 4192 1 0.60 (0.35-1.05) / / / Moderate
GLP-1
Overall analysis
MACE Monami 2014 12870 27 0.77 (0.54-1.10) 0 56004 7 0.88 (0.84-0.93) 40.9 68874 34 0.88 (0.84-0.92) 0.84-0.93 0 0.194 High
CVD death Monami 2017 32634 25 0.85 (0.75-0.96) 0 56004 7 0.88 (0.81-0.95) 13.5 69933 29 0.87 (0.81-0.94) 0.80-0.94 0 0.026 High
MI Gargiulo 2017 45917 51 0.91 (0.83-1.01) 0 56004 7 0.92 (0.86-0.99) 33.6 83216 55 0.92 (0.86-0.99) 0.86-0.99 0 0.99 High
Stroke Gargiulo 2017 45196 49 0.89 (0.76-1.03) 0 56004 7 0.84 (0.76-0.93) 0 82495 53 0.84 (0.77-0.93) 0.77-0.93 0 0.553 High
HF Monami 2017 34943 32 0.93 (0.81-1.05) 0 56004 7 0.91 (0.83-0.99) 0 72242 36 0.90 (0.83-0.99) 0.83-0.99 0 0.99 High
11
UA / / / / / 56004 7 1.06 (0.93-1.21) 0 56004 7 1.06 (0.93-1.21) 0.89-1.26 0 / High
AF Monami 2017 33410 32 0.87 (0.71-1.05) 0 28137 4 0.86 (0.73-1.00) 0 42842 33 0.85 (0.73-0.99) 0.72-1.00 0 0.712 Moderate
GLP-1 vs Placebo
MACE Monami 2014 3995 10 0.47 (0.25-0.91) 0 56004 7 0.88 (0.84-0.93) 40.9 59999 17 0.88 (0.83-0.92) 0.81-0.94 3.7 0.038 High
MI Gargiulo 2017 28559 27 0.91 (0.82-1.01) 0 56004 7 0.92 (0.86-0.99) 33.6 65858 31 0.92 (0.86-0.99) 0.86-0.99 0 0.491 High
Stroke Gargiulo 2017 27920 24 0.87 (0.75-1.02) 0 56004 7 0.84 (0.76-0.93) 0 65219 28 0.84 (0.76-0.92) 0.76-0.93 0 0.559 High
HF Monami 2017 23666 16 0.92 (0.81-1.05) 0 56004 7 0.91 (0.83-0.99) 0 60965 20 0.90 (0.83-0.99) 0.82-0.99 0 0.449 High
UA / / / / / 56004 7 1.06 (0.93-1.21) 0 56004 7 1.06 (0.93-1.21) / 0 / High
AF Monami 2017 23741 17 0.85 (0.70-1.04) 0 28137 4 0.86 (0.73-1.00) 0 33173 18 0.84 (0.72-0.98) 0.71-1.00 0 0.285 Moderate
Albiglutide
MACE Fisher 2015 5107 8 0.99 (0.65-1.49) / 9463 1 0·78 (0·68–0·90) / 14570 9 0·81 (0·68–0·96) / / / High
CVD death Fisher 2015 5107 8 1.06 (0.55-2.06) / 9463 1 0·93 (0·73–1·19) / 14570 9 0·94 (0·75–1·19) / / / Moderate
MI Fisher 2015 5107 8 0.96 (0.52-1.76) / 9463 1 0·75 (0·61–0·90) / 14570 9 0·77 (0·64–0·92) / / / High
Stroke Fisher 2015 5107 8 1.02 (0.45-2.33) / 9463 1 0·86 (0·66–1·14) / 14570 9 0·87 (0·67–1·13) / / / Moderate
HF Fisher 2015 5107 8 0.74 (0.34-1.62) / 9463 1 0.71 (0.53, 0.94) / 14570 9 0.71 (0.55, 0.93) / / / High
UA Fisher 2015 5107 8 0.77 (0.25-2.37) / 9463 1 0.88 (0.56, 1.38) / 14570 9 0.86 (0.57, 1.31) / / / Low
AF Monami 2017 3745 8 2.02 (0.71-5.70) 0 9432 1 0.82 (0.64-1.06) / 13177 9 0.87 (0.68-1.11) 0.64-1.16 0 / Low
Dulaglutide
MACE Ferdinand 2016 6010 9 0.60 (0.33-1.08) / 9901 1 0·88 (0·79–0·99) / 15911 10 0.82 (0.60-1.10) / / / Moderate
CVD death Ferdinand 2016 6010 9 0.35 (0.07-1.87) / 9901 1 0·91 (0·78–1·06) / 15911 10 0·81 (0·44–1·49) / / / Low
MI Ferdinand 2016 6010 9 0.35 (0.13-0.95) / 9901 1 0·96 (0·79–1·15) / 15911 10 0·66 (0·25–1·71) / / / Low
Stroke Gargiulo 2017 7694 11 1.23 (0.55-2.76) 0 9901 1 0·76 (0·62–0·94) / 17595 12 0·78 (0·64–0·96) 0.62-0.98 0.07 / High
HF Ferdinand 2016 6010 9 2.02 (0.41-9.88) / 9901 1 0·93 (0·77–1·12) / 15911 10 0·82 (0·58–1·16) / / / High
UA Ferdinand 2016 6010 9 0.28 (0.05-1.46) / 9901 1 1·14 (0·84–1·54) / 15911 10 0·73 (0·20–2·63) / / / Very
Low
AF Monami 2017 3236 5 0.61 (0.18-2.07) 0 / / / / 3236 5 0.61 (0.18-2.07) 0 / / Very
Low
Exenatide
MACE Monami 2014 5601 15 0.87 (0.53-1.44) 0 14752 1 0.91 (0.83−1.00) / 20353 16 0.91 (0.83−1.00) 0.82−1.00 0 0.508 High
CVD death Monami 2017 2375 5 0.84 (0.22-3.16) 16.8 14752 1 0.88 (0.76−1.02) / 17127 6 0.88 (0.76−1.02) 0.71-1.08 0 / High
MI Gargiulo 2017 5505 12 0.91 (0.42-1.95) 0 14752 1 0.97 (0.85−1.10) / 20257 13 0.97 (0.85−1.10) 0.84-1.12 0 0.75 High
Stroke Gargiulo 2017 5847 11 1.07 (0.47-2.45) 0 14752 1 0.85 (0.70−1.03) / 20599 12 0.86 (0.71−1.04) 0.70-1.06 0 0.498 Moderate
HF Monami 2017 1847 5 0.83 (0.22-3.14) 0 14752 1 0.94 (0.78−1.13) / 16599 6 0.94 (0.78−1.13) 0.72-1.22 0 / High
UA Wang 2016 2369 5 0.93 (0.27-3.24) 0 14752 1 1.14 (0.92, 1.41) / 17121 6 1.13 (0.92, 1.40) 0.84-1.53 0 / Moderate
AF Monami 2017 2580 6 0.77 (0.25-2.42) 0 / / / / 2580 6 0.77 (0.25-2.42) 0.15-3.89 0 / Very
12
Low
Liraglutide
MACE Monami 2014 5849 9 0.61 (0.32-1.16) 0 9340 1 0.87 (0.78–0.97) / 15189 10 0.86 (0.77–0.96) 0.76-0.98 0 0.264 High
CVD death Monami 2017 10581 3 0.48 (0.15-1.60) 30.5 9340 1 0.78 (0.66–0.93) / 10581 3 0.41 (0.13-1.29) 0.01-23.0 30.5 / Low
MI Gargiulo 2017 16883 13 0.87 (0.75-1.01) 0 9340 1 0.86 (0.73–1.00) / 16883 13 0.87 (0.75-1.01) 0.73-1.03 0 0.064 Moderate
Stroke Gargiulo 2017 16355 12 0.86 (0.71-1.05) 0 9340 1 0.86 (0.71–1.06) / 16355 12 0.85 (0.70-1.04) 0.69-1.06 0 0.254 Moderate
HF Monami 2017 14106 9 0.89 (0.75-1.07) 0 9340 1 0.87 (0.73–1.05) / 14106 9 0.89 (0.74-1.06) 0.71-1.10 0 / Moderate
UA / / / / / 9340 1 0.98 (0.76–1.26) / 9340 1 0.98 (0.76–1.26) / / / Moderate
AF Monami 2017 12381 7 0.89 (0.68-1.17) 0 9340 1 0.92(0.69–1.22) / 12381 7 0.89 (0.68-1.17) 0.62-1.27 0 Low
Lixisenatide
MACE / / / / / 6068 1 1·02 (0·89–1·17) / 6068 1 1·02 (0·89–1·17) / / / High
CVD death Monami 2017 8194 5 0.98 (0.79-1.21) 0 6068 1 0.98 (0.78–1.22) / 8194 5 0.97 (0.78-1.21) 0.68=1.39 0 / High
MI Gargiulo 2017 8779 7 1.01 (0.86-1.19) 0 6068 1 1.03 (0.87–1.22) / 8779 7 1.01 (0.86-1.20) 0.82-1.25 0 / High
Stroke Gargiulo 2017 8049 6 1.14 (0.82-1.60) 0 6068 1 1.12 (0.79–1.58) / 8049 6 1.14 (0.82-1.60) 0.71-1.84 0 / Moderate
HF Monami 2017 7710 4 0.96 (0.76-1.23) 0 6068 1 0.96 (0.75–1.23) / 7710 4 0.96 (0.75-1.23) 0.56-1.65 0 / Moderate
UA / / / / / 6068 1 1.11 (0.47–2.62) / 6068 1 1.11 (0.47–2.62) / / / Low
AF Monami 2017 8171 5 0.71 (0.43-1.17) 0 6068 1 0.77 (0.45-1.32) / 8171 5 0.71 (0.43-1.17) 0.31-1.60 0 / Very
Low
Semaglutide
MACE / / / / / 6480 2 0.76 (0.62–0.92) 0 6480 2 0.76 (0.62–0.92) 0 / High
CVD death Monami 2017 3297 1 0.96 (0.64-1.44) / 6480 2 0.72 (0.37–1.41) 70.5 6480 2 0.72 (0.37–1.41) / 70.5 / Very
Low
MI Gargiulo 2017 3613 2 0.73 (0.51-1.05) 0 6480 2 0.94 (0.66–1.36) 34.7 6796 3 0.93 (0.70–1.23) 0.15-5.83 0 / Moderate
Stroke Gargiulo 2017 3298 1 0.61 (0.38-0.93) 0 6480 2 0.67 (0.45–1.00) 0 6480 2 0.67 (0.45–1.00) / 0 / High
HF Monami 2017 3297 1 1.09 (0.76-1.57) / 6480 2 1.03 (0.76–1.41) 0 6480 2 1.03 (0.76–1.41) / 0 / Moderate
UA / / / / / 6480 2 1.00 (0.56–1.80) 23.5 6480 2 1.00 (0.56–1.80) / 23.5 / Low
AF Monami 2017 3297 1 0.86 (0.59-1.25) / 3297 1 0.86 (0.59-1.25) / 3297 1 0.86 (0.59-1.25) / / / Very
Low
Taspoglutide
MACE Seshasai 2015 7056 9 0.97 (0.57-1.66) / / / / / 7056 9 0.97 (0.57-1.66) / / / Very
Low
MI Gargiulo 2017 1345 3 1.82 (0.28-11.61) 0 / / / / 1345 3 1.82 (0.28-11.61) / 0 / Very
Low
Stroke Gargiulo 2017 667 2 0.41 (0.04-4.05) 10.7 / / / / 667 2 0.41 (0.04-4.05) / 10.7 / Very
Low
SGLT-2
Overall analysis
MACE Usman 2018 33722 31 0.83 (0.76-0.92) 0 38723 4 0.88 (0.82-0.94) 0 55283 32 0.87 (0.82-0.93) 0.82-0.93 0 0.342 High
13
MI Monami 2017 27937 36 0.78 (0.65-0.95) 0 38723 4 0.88 (0.80-0.97) 0 59640 40 0.86 (0.78-0.94) 0.78-0.95 0 0.013 High
Stroke Monami 2017 29323 34 1.09 (0.86-1.37) 0 38723 4 0.96 (0.82-1.12) 36.5 61026 37 0.96 (0.85-1.08) 0.85-1.08 0 0.453 High
HF Usman 2018 25043 14 0.67 (0.59-0.76) 0 43467 5 0.68 (0.62-0.75) 0 51348 17 0.68 (0.63-0.73) 0.63-0.74 0 0.307 High
UA Usman 2018 18389 18 0.95 (0.72-1.25) 0 / / / / 18389 18 0.95 (0.72-1.25) 0.70-1.28 0 0.261 Very
Low
AF Usman 2018 10512 16 0.72 (0.36-1.46) 0 / / / / 10512 16 0.72 (0.36-1.46) 0.33-1.57 0 0.393 Very
Low
SGLT2 vs Placebo
MACE Usman 2018 33722 31 0.83 (0.76-0.92) 0 38723 4 0.88 (0.82-0.94) 0 55283 32 0.87 (0.82-0.93) 0.82-0.93 0 0.342 High
MI Usman 2018 32167 27 0.85 (0.74-0.99) 0 38723 4 0.88 (0.80-0.97) 0 53728 29 0.88 (0.80-0.96) 0.79-0.96 0 0.189 High
Stroke Usman 2018 32077 28 1.00 (0.84-1.20) 0 38723 4 0.96 (0.82-1.12) 36.5 53638 30 0.96 (0.85-1.07) 0.85-1.08 0 0.606 High
HF Usman 2018 25043 14 0.67 (0.59-0.76) 0 43467 5 0.68 (0.62-0.75) 0 51348 17 0.68 (0.63-0.73) 0.63-0.74 0 0.307 High
UA Usman 2018 18389 18 0.95 (0.72-1.25) 0 / / / / 18389 18 0.95 (0.72-1.25) 0.70-1.28 0 0.261 Very
Low
AF Usman 2018 10512 16 0.72 (0.36-1.46) 0 / / / / 10512 16 0.72 (0.36-1.46) 0.33-1.57 0 0.393 Very
Low
Canagliflozin
MACE Usman 2018 14017 9 0.85 (0.75-0.98) 0 14543 2 0.84 (0.76-0.93) 0 18418 10 0.84 (0.75-0.93) 0.74-0.95 0 0.214 High
CVD death Monami 2017 7816 8 0.70 (0.37-1.32) 0 14543 2 0.83 (0.72-0.97) 0 22778 11 0.82 (0.71-0.96) 0.70-0.98 0 0.494 High
MI Monami 2017 4916 6 0.57 (0.26-1.24) 0 14543 2 0.88 (0.75-1.04) 0 19459 8 0.86 (0.73-1.02) 0.71-1.06 0 / Moderate
Stroke Monami 2017 6169 7 1.48 (0.58-3.78) 0 14543 2 0.84 (0.69-1.01) 0 20712 9 0.86 (0.71-1.03) 0.69-1.06 0 / Moderate
HF Usman 2018 11125 4 0.69 (0.53-0.90) 0 14543 2 0.64 (0.53-0.77) 0 15526 5 0.65 (0.54-0.78) 0.43-0.97 0 / High
UA Usman 2018 1665 4 0.66 (0.17-2.50) 0 / / / / 1665 4 0.66 (0.17-2.50) 0.04- 0 / Very
12.28 Low
AF Usman 2018 2736 4 1.18 (0.34-4.11) 0 / / / / 2736 4 1.18 (0.34-4.11) 0.08- 0 / Very
18.21 Low
Dapagliflozin
MACE Sonesson 2016 8519 21 0.77 (0.54-1.10) / 17160 1 0.93 (0.84−1.03) 25679 22 0.92 (0.83−1.01) / / / High
CVD death Sonesson 2016 6025 21 0.70 (0.36-1.36) / 21904 2 0.98 (0.82−1.17) 0 27929 23 0.89 (0.77−1.02) / / / High
MI Sonesson 2016 8258 21 0.57 (0.34-0.95) / 17160 1 0.89 (0.77−1.01) 25418 22 0.77 (0.51−1.16) / / / Moderate
Stroke Sonesson 2016 6639 21 1.00 (0.54-1.86) / 17160 1 1.01 (0.84−1.21) 23799 22 1.01 (0.85−1.20) / / / High
HF Sonesson 2016 4356 21 0.36 (0.16-0.84) / 21904 2 0.73 (0.61−0.88) 0 26260 23 0.70 (0.60-0.82) / / / High
UA Sonesson 2016 7289 21 0.87 (0.47-1.59) / / / / / 7289 21 0.87 (0.47-1.59) / / / Very
Low
AF Usman 2018 3676 7 0.55 (0.17-1.79) 0 / / / / 3676 7 0.55 (0.17-1.79) 0.12-2.58 0 / Very
Low
Empagliflozin
MACE Salsali 2016 11292 8 0.84 (0.73-0.96) 7020 1 0.86 (0.74–0.99) / 18312 9 0.85 (0.77–0.94) / / / High
CVD death Monami 2017 11949 8 0.63 (0.51-0.78) 0 7020 1 0.62 (0.49–0.77) / 11949 8 0.62 (0.50-0.78) 0.47-0.82 0 / High
14
MI Monami 2017 15422 15 0.84 (0.68-1.04) 0 7020 1 0.87 (0.70–1.09) / 15750 15 0.84 (0.68-1.04) 0.67-1.06 0 0.336 Moderate
Stroke Monami 2017 16744 15 1.11 (0.86-1.44) 0 7020 1 1.18 (0.89–1.56) / 16744 15 1.11 (0.86-1.43) 0.84-1.47 0 0.187 Moderate
HF Salsali 2016 11292 8 0.63 (0.48-0.81) / 7020 1 0.65 (0.50–0.85) / 18312 9 0.64 (0.53-0.77) / / / High
UA Salsali 2016 11292 8 0.93 (0.70-1.24) / 7020 1 0.99 (0.74-1.34) / 18312 9 0.96 (0.78-1.18) / / / High
AF Usman 2018 2251 5 0.60 (0.17-2.09) 0 / / / / 2251 5 0.60 (0.17-2.09) 0.08-4.58 0 / Very
Low
Sulfonylureas
Overall analysis
MACE Monami 2013 29479 29 0.99 (0.90-1.09) 0 9061 2 1.01 (0.88-1.15) 0 38540 31 1.00 (0.93-1.08) 0.93-1.09 0 0.118 High
CVD death Varvaki 2016 17966 21 1.08 (0.86-1.35) 0 6033 1 1.00 (0.81-1.23) 23999 22 1.03 (0.89-1.21) 0.88-1.22 0 0.108 High
MI Monami 2013 21102 21 0.89 (0.78-1.03) 0 11191 3 0.88 (0.77-1.01) 0 30163 23 0.90 (0.79-1.01) 0.79-1.02 0 0.334 High
Stroke Monami 2013 22016 15 1.25 (0.98-1.59) 2.9 11191 3 1.10 (0.89-1.35) 0 31077 17 1.17 (0.98-1.39) 0.97-1.41 0 0.197 Moderate
HF / / / / / 11191 3 1.04 (0.79-1.37) 0 11191 3 0.92 (0.70-1.21) 0.16-5.41 0 / Moderate
Unstable angina / / / / / 6033 1 0.93 (0.65-1.35) / 6033 1 0.93 (0.65-1.35) / / / Low
Sulfonylureas vs
Placebo
MACE Monami 2013 2275 2 0.90 (0.77-1.05) 0 / / / / 2275 2 0.90 (0.77-1.05) / 0 / Moderate
CVD death Varvaki 2016 1450 3 0.98 (0.68-1.40) 0 / / / / 1450 3 0.98 (0.68-1.40) / 0 / Very
Low
MI Monami 2013 2289 2 0.85 (0.70-1.03) 0 2130 1 0.83 (0.69-0.99) / 2289 2 0.85 (0.70-1.03) / 0 / Moderate
Stroke Monami 2013 2275 2 1.22 (0.86-1.73) 0 2130 1 1.10 (0.76-1.61) / 2275 2 1.22 (0.86-1.73) / 0 / Moderate
HF / / / / / 2130 1 1.06 (0.64-1.75) / 2130 1 1.06 (0.64-1.75) / / / Low
Chlorpropamide
MACE Monami 2013 2426 1 0.93 (0.79-1.10) / / / / / 2426 1 0.93 (0.79-1.10) / / / Moderate
CVD death Varvaki 2016 2422 2 0.97 (0.75-1.25) / / / / / 2422 2 0.97 (0.75-1.25) / / / Very
Low
MI Monami 2013 2426 1 0.94 (0.76-1.15) / / / / / 2426 1 0.94 (0.76-1.15) / / / Moderate
Stroke Monami 2013 2426 1 1.08 (0.73-1.60) / / / / / 2426 1 1.08 (0.73-1.60) / / / Very
Low
Glibenclamide
MACE Monami 2013 11341 10 1.01 (0.87-1.16) / / / / / 11341 10 1.01 (0.87-1.16) 0.85-1.19 0 0.189 Moderate
CVD death Varvaki 2016 4637 10 1.73 (0.72-4.16) / / / / / 4637 10 1.73 (0.72-4.16) 0.62-4.85 0 0.992 Very
Low
MI Monami 2013 11287 9 0.85 (0.70-1.03) / / / / / 11287 9 0.85 (0.70-1.03) 0.67-1.07 0 / Low
Stroke Monami 2013 9244 4 1.21 (0.85-1.72) / / / / / 9244 4 1.21 (0.85-1.72) 0.45-3.25 0 / Low
Glimepiride
MACE Monami 2013 9273 9 1.33 (0.97-1.83) / 6033 1 1.02 (0.88-1.19) / 15306 10 1.09 (0.92-1.30) 0.89-1.34 0 0.5 Moderate
CVD death Varvaki 2016 4883 3 0.51 (0.15-1.70) / 6033 1 1.00 (0.81-1.23) / 10916 4 0.98 (0.80-1.20) 0.62-1.54 0 / High
MI Monami 2013 3206 5 1.55 (0.75-3.19) / 6033 1 0.97 (0.78-1.22) / 9239 6 1.01 (0.82-1.25) 0.75-1.37 0 / Moderate
15
Stroke Monami 2013 6521 6 4.17 (1.64-10.64) / 6033 1 1.16 (0.89-1.52) / 12554 7 2.01 (1.02-3.98) 0.48-8.46 21 / High
HF / / / / / 6033 1 0.83 (0.63-1.09) / 6033 1 0.83 (0.63-1.09) / / / Moderate
Unstable angina / / / / / 6033 1 0.93 (0.65-1.35) / 6033 1 0.93 (0.65-1.35) / / / Low
Gliclazide
MACE Monami 2013 1795 3 0.83 (0.40-1.74) / / / / / 1795 3 0.83 (0.40-1.74) 0.01-99.6 0 / Very
Low
MI Monami 2013 2142 3 0.81 (0.15-4.22) / / / / / 2142 3 0.81 (0.15-4.22) / 0 / Very
Low
Stroke Monami 2013 1880 2 0.84 (0.19-3.60) / / / / / 1880 2 0.84 (0.19-3.60) 0 / Very
Low
Glipizide
MACE Monami 2013 4133 5 0.96 (0.47-1.96) / / / / / 4133 5 0.96 (0.47-1.96) 0.14-6.13 40.8 / Very
Low
CVD death Varvaki 2016 6024 6 1.87 (1.01-3.45) / / / / / 6024 6 1.87 (1.01-3.45) 0.78-4.46 0 / Moderate
MI Monami 2013 1530 2 0.97 (0.39-2.46) / / / / / 1530 2 0.97 (0.39-2.46) / 0 / Very
Low
Stroke Monami 2013 1530 2 0.58 (0.04-7.99) / / / / / 1530 2 0.58 (0.04-7.99) / 0 / Very
Low
Tolbutamide
MACE Monami 2013 96 1 1.00 (0.06-15.53) / / / / / 96 1 1.00 (0.06-15.53) / / / Very
Low
TZDs
Rosiglitazone vs
control
MACE / / / / / 9716 2 1.07 (0.72–1.60) 53.2 9716 2 1.07 (0.72–1.60) 53.2 Very
Low
CVD death Nissen 2010 25847 26 1.03 (0.78-1.36) 0 9716 2 0.89 (0.64-1.22) 0 25847 26 1.03 (0.78-1.36) 0.77-1.39 0 0.003 Low
MI Nissen 2010 31707 41 1.28 (1.02-1.63) 0 9716 2 1.22 (0.88-1.70) 0 31707 41 1.28 (1.02-1.62) 1.01-1.63 0 0.367 High
Stroke Cheng 2018 16220 7 0.91 (0.74-1.13) 0 9716 2 0.80 (0.50-1.28) 0 16220 7 0.77 (0.59-1.01) 0.54-1.10 0 / Low
HF Cheng 2018 15899 9 1.72 (1.29-2.28) 15.3 9716 2 3.10 (1.02–9.39) 57.4 15899 9 1.72 (1.31-2.27) 1.04-2.85 15.1 / High
Rosiglitazone vs
Placebo
MACE / / / / / 5269 1 1.43 (0.84–2.44) / 5269 1 1.43 (0.84–2.44) / / / Low
CVD death Nissen 2010 10833 9 1.44 (0.76-2.73) 0 5269 1 1.20 (0.52–2.77) / 10833 9 1.44 (0.76-2.73) 0.67-3.12 0 / Low
MI Nissen 2010 11395 11 1.59 (0.88-2.88) 0 5269 1 1.78 (0.79–4.03) / 11395 11 1.66 (0.91-3.01) 0.83-3.30 0 0.762 Low
Stroke Cheng 2018 5864 3 1.10 (0.47-2.61) 0 5269 1 1.40 (0.44–4.40) / 5864 3 1.10 (0.47-2.61) 0-296.9 0 / Low
HF Cheng 2018 6028 5 2.50 (1.42-4.41) 0 5269 1 7.04 (1.60–31.0) / 6028 5 2.50 (1.42-4.41) 1-6.28 0 / High
Pioglitazone vs
control
MACE Lincoff 2007 16062 18 0.84 (0.73-0.95) 0 8266 2 0·86 (0·74-0·98) 0 19090 19 0.84 (0.74-0.96) 0.73-0.96 0 0.095 High
CVD death Mannucci 2008 9456 10 0.90 (0.72-1.13) 0 5238 1 0.94 (0.74-1.20) / 9456 10 0.90 (0.71-1.13) 0.68-1.18 0 0.037 Low
MI Lincoff 2007 16062 18 0.80 (0.64-1.01) 12142 3 0·80 (0·66-0·97) 0 22966 20 0·80 (0·67-0·95) 0.66-0.96 0 0.555 High
16
Stroke Liao 2017 10836 7 0.83 (0.71-0.99) 0 12142 3 0·81 (0·67-0·99) 0 13864 8 0·79 (0·65-0·95) 0.62-1.00 0 / High
HF Lincoff 2007 14065 13 1.42 (1.14-1.79) 0 12142 3 1.38 (1.12–1.69) 0 20969 15 1.40 (1.16-1.69) 1.14-1.73 0 0.705 High
Pioglitazone vs
Placebo
MACE Lincoff 2007 7179 7 0.84 (0.73-0.97) 0 5238 1 0·82 (0·70-0·97) / 7179 7 0.81 (069-0.95) 0.65-1.00 0 / High
CVD death Mannucci 2008 5710 5 0.93 (0.73-1.17) 0 5238 1 0.94 (0.74-1.20) / 5710 5 0.93 (0.73-1.17) 0.63-1.35 0 / Moderate
MI Lincoff 2007 7179 7 0.79 (0.61-1.02) 9114 2 0·80 (0·65-0·97) 0 11055 8 0.78 (0.64-0.95) 0.61-1.00 0 / Moderate
Stroke Liao 2017 9114 2 0.86 (0.72-1.02) 0 9114 2 0·81 (0·66-1·00) 0 9114 2 0·81 (0·66-1·00) / High
HF Lincoff 2007 6419 4 1.40 (1.10-1.78) 0 9114 2 1.36 (1.10–1.69) 0 9447 5 1.43 (1.13-1.80) 0.98-2.08 0 / High
Metformin
Metformin vs
control
MACE Lamanna 2011 14451 12 0.95 (0.85-1.06) 0 / / / / 14451 12 0.95 (0.85-1.06) 0.83-1.08 0 0.54 Moderate
CVD death Selvin 2008 11986 7 0.85 (0.69-1.05) / / / / / 11986 7 0.85 (0.69-1.05) / / / Low
MI Lamanna 2011 7947 8 0.91 (0.74-1.12) 0 753 1 0.67 (0.51–0.89) / 7947 8 0.91 (0.74-1.12) 0.70-1.18 0 / Low
Stroke Lamanna 2011 7032 5 0.92 (0.66-1.28) 0 753 1 0.80 (0.50–1.27) / 7032 5 0.92 (0.66-1.28) 0.54-1.57 0 / Very
Low
HF Lamanna 2011 6031 4 1.07 (0.72-1.59) 0 / / / / 6031 4 1.07 (0.72-1.59) 0.45-2.56 0 / Very
Low
Metformin vs
placebo
MACE Lamanna 2011 5680 8 0.84 (0.71-1.00) 4.9 / / / / 5680 8 0.84 (0.71-1.00) 0.65-1.09 4.7 / Low
CVD death Griffin 2017 2423 5 1.09 (0.75-1.59) 52.6 / / / / 2423 5 1.09 (0.75-1.59) 0.38-3.12 52 / Low
MI Griffin 2017 2502 7 0.88 (0.74-1.05) 0 753 1 0.67 (0.51–0.89) / 2502 7 0.88 (0.74-1.05) 0.71-1.10 0 / Low
Stroke Griffin 2017 2051 4 1.03 (0.72-1.48) 0 753 1 0.80 (0.50–1.27) / 2051 4 1.03 (0.72-1.48) 0.47-2.27 0 / Very
Low
HF Lamanna 2011 1680 3 0.94 (0.54-1.64) 0 / / / / 1680 3 0.94 (0.54-1.64) 0.45-2.56 0 / Very
Low
Alpha-glucosidase
Acarbose vs
placebo
MACE / / / / / 7890 2 0.75 (0.41–1.35) 73.2 7890 2 0.75 (0.41–1.35) / 73.2 / Very
Low
CVD death Moelands 2018 8069 3 0.88 (0.71-1.10) / 7890 2 0.89 (0.71–1.11) 0 8069 3 0.88 (0.71-1.10) / / Moderate
MI Hanefeld 2004 2180 7 0.36 (0.16-0.80) / 7890 2 0.34 (0.03–4.00) 94.2 10070 9 0.46 (0.14–1.50) / 83 / Very
Low
Stroke Hanefeld 2004 2180 7 0.75 (0.31-1.81) / 7890 2 0.95 (0.69–1.31) 0 10070 9 0.93 (0.69–1.25) 0.14-6.36 0 / Low
HF Moelands 2018 7890 2 0.87 (0.63-1.12) / 6522 1 0.89 (0.63–1.25) / 7890 2 0.87 (0.63-1.12) / / / Moderate
Angina Hanefeld 2004 2180 7 0.79 (0.45-1.36) / 7890 2 0.80 (0.38–1.66) 56.2 10070 9 0.89 (0.64–1.23) 0.04- 29.2 / Moderate
18.45
Voglibose vs
placebo
CVD death Moelands 2018 1778 1 2.95 (0.12-72.23) / / / / / / / / / / / Very
Low
17
Meglitinides
Nateglinide vs
placebo
MACE / / / / / 9306 1 0.94 (0.82-1.09) / 9306 1 0.94 (0.82-1.09) / / / High
CVD death / / / / / 9306 1 1.07 (0.83-1.38 / 9306 1 1.07 (0.83-1.38 / / / Moderate
MI / / / / / 9306 1 0.95 (0.75-1.20) / 9306 1 0.95 (0.75-1.20) / / / Moderate
Stroke / / / / / 9306 1 0.89 (0.69-1.15) / 9306 1 0.89 (0.69-1.15) / / / Moderate
HF / / / / / 9306 1 0.85 (0.64-1.14) / 9306 1 0.85 (0.64-1.14) / / / Moderate
UA / / / / / 9306 1 0.87 (0.73-1.05) / 9306 1 0.87 (0.73-1.05) / / / Moderate
Bromocriptine
Bromocriptine-QR
MACE / / / / / 3070 1 0.48 (0.23-1.00) / 3070 1 0.48 (0.23-1.00) / / / Low
CVD death / / / / / 3070 1 0.48 (0.07- 3.43) / 3070 1 0.48 (0.07- 3.43) / / / Low
MI / / / / / 3070 1 0.41 (0.15-1.11) / 3070 1 0.41 (0.15-1.11) / / / Low
Stroke / / / / / 3070 1 0.44 (0.13- 1.43) / 3070 1 0.44 (0.13- 1.43) / / / Low
HF / / / / / 3070 1 0.77 (0.27- 2.16) / 3070 1 0.77 (0.27- 2.16) / / / Low
UA / / / / / 3070 1 0.52 (0.21- 1.30) / 3070 1 0.52 (0.21- 1.30) / / / Low
Insulin
Insulin vs control
MACE / / / / / 12537 1 1.02 (0.94–1.11) / 12537 1 1.02 (0.94–1.11) / / / High
CVD death Erpeldinger 2016 15371 3 1.00 (0.91-1.10) 0 12537 1 1.00 (0.89–1.13) / 15371 3 1.00 (0.90-1.10) 0.53-1.88 0 / High
MI Erpeldinger 2016 16313 4 1.01 (0.90-1.13) 31 14344 2 0·96 (0·83-1·12) / 16313 4 0·97 (0·85-1·10) 0.74-1.27 0 / High
Stroke Li 2016 15971 3 1.00 (0.93-1.16) 32.3 14344 2 1.01 (0.87–1.16) / 16833 3 1.02 (0.88–1.17) 0.40-2.56 0 / High
HF Li 2016 15971 3 0.87 (0.75-0.99) 0 14344 2 0·89 (0·77-1·04) / 16833 3 0.82 (0.62-1.08) 0.06- 23 / Moderate
10.82
Angina Li 2016 15024 2 0.97 (0.88-1.06) / 12537 1 0.91 (0.76–1.08) / 15578 2 0.98 (0.81-1.17) / 28.9 / High
Insulin vs.
placebo/diet
CVD death Erpeldinger 2016 2426 2 0.95 (0.77-1.18) / / / / / 2426 2 0.95 (0.77-1.18) / / / Moderate
MI Erpeldinger 2016 2426 2 1.27 (0.62-2.62) / 1807 1 0.87 (0.70–1.09) / 2426 2 1.27 (0.62-2.62) / / / Very
Low
Stroke Erpeldinger 2016 1807 1 0.88 (0.59–1.32) / 1807 1 0.86 (0.57–1.31) / 1807 1 0.86 (0.57–1.31) / / / Low
HF / / / / / 1807 1 0.78 (0.39–1.55) / 1807 1 0.78 (0.39–1.55) / / / Low
Degludec versus
Glargine
MACE / / / / / 7637 1 0.91 (0.78–1.06) / 7637 1 0.91 (0.78–1.06) / / / High
CVD death / / / / / 7637 1 0.96 (0.76–1.21) / 7637 1 0.96 (0.76–1.21) / / / High
MI / / / / / 7637 1 0.85 (0.68–1.06) / 7637 1 0.85 (0.68–1.06) / / / Moderate
18
Stroke / / / / / 7637 1 0.90 (0.65–1.23) / 7637 1 0.90 (0.65–1.23) / / / Moderate
Angina / / / / / 7637 1 0.95 (0.68–1.31) / 7637 1 0.95 (0.68–1.31) / / / Low
Lisproc versus
NPH/Glargine
MACE / / / / / 1115 1 1.04 (0.78-1.37) / 1115 1 1.04 (0.78-1.37) / / / Moderate
CVD death / / / / / 1115 1 1.05 (0.69-1.60) / 1115 1 1.05 (0.69-1.60) / / / Low
MI / / / / / 1115 1 1.01 (0.71-1.43) / 1115 1 1.01 (0.71-1.43) / / / Low
Stroke / / / / / 1115 1 1.20 (0.63-2.29) / 1115 1 1.20 (0.63-2.29) / / / Low
HF / / / / / 1115 1 0.90 (0.56, 1.44) / 1115 1 0.90 (0.56, 1.44) / / / Low
MACE, major cardiovascular event; CVD death, cardiovascular death; MI, myocardial infarction; stroke; HF, heart failure; UA, unstable angina; AF, atrial fibrillation
* included data from patients with pre-daibetes
19
eTable 5: GRADE of quality evidence for glucose-lowering medications on cardiovascular outcomes
Comparison Risk of Bias Inconsistency Indirectness Imprecision Publication bias Quality
DPP-4 vs control
MACE No Serious No Serious No Serious No Serious Reporting biasf Moderate
CVD No Serious No Serious No Serious No Serious Undetected High
MI No Serious No Serious No Serious No Serious Undetected High
Stroke No Serious No Serious No Serious No Serious Undetected High
HF No Serious Seriousb No Serious No Serious Undetected Moderate
UA No Serious No Serious No Serious No Serious Undetected High
DPP-4 vs Placebo
MACE No Serious No Serious No Serious No Serious Undetected High
HF No Serious No Serious No Serious No Serious Undetected High
Alogliptin
CVD No Serious No Serious No Serious Seriousc Undetected Moderate

c
MI No Serious No Serious No Serious Serious Undetected Moderate
Stroke No Serious No Serious No Serious Very Seriousd Undetected Low

c
HF No Serious No Serious No Serious Serious Undetected Moderate
UA No Serious No Serious No Serious Very Seriousd Undetected Low
Linagliptin
Stroke No Serious Seriousb No Serious Seriousc Undetected Low

c
UA No Serious No Serious No Serious Seriousc Undetected Moderate
Saxagliptin
MI No Serious No Serious No Serious Very Seriousd Undetected Low

c
Stroke No Serious No Serious No Serious Serious Undetected Moderate
e
Sitagliptin

c
UA No Serious No Serious No Serious Serious Undetected Moderate
Vildagliptin
MACE Seriousa No Serious No Serious Seriousc Undetected Low

a d
CVD Serious No Serious No Serious Very Serious Undetected Very Low
MI Seriousa No Serious No Serious Very Seriousd Undetected Very Low

a d
Stroke Serious No Serious No Serious Very Serious Undetected Very Low
HF Seriousa No Serious No Serious Very Seriousd Undetected Very Low
Omarigliptin
20
MACE No Serious No Serious No Serious Seriousc Undetected Moderate
d
CVD No Serious No Serious No Serious Very Serious Undetected Low

d
Stroke No Serious No Serious No Serious Very Serious Undetected Low
c
GLP-1
GLP-1 vs Control

a
AF Serious No Serious No Serious No Serious Undetected Moderate
GLP-1 vs Placebo

a
AF Serious No Serious No Serious No Serious Undetected Moderate
Albiglutide

c
CVD No Serious No Serious No Serious Serious Undetected Moderate

c

d
UA No Serious No Serious No Serious Very Serious Undetected Low
AF Seriousa No Serious No Serious Seriousc Undetected Low
Dulaglutide
MACE No Serious No Serious No Serious Seriouse Undetected Moderate

d
d
MI No Serious No Serious No Serious Very Serious Undetected Low

e
HF No Serious No Serious No Serious Serious Undetected High
UA No Serious No Serious No Serious Very Seriousc’e Undetected Very Low

a d
AF Serious No Serious No Serious Very Serious Undetected Very Low
Exenatide
Stroke No Serious No Serious No Serious Seriousc’e Undetected Moderate

c
AF Seriousa No Serious No Serious Very Seriousd Undetected Very Low
Liraglutide

d
MI No Serious No Serious No Serious Seriousc Undetected Moderate

c
21
HF No Serious No Serious No Serious Seriousc Undetected Moderate
c
AF Seriousa No Serious No Serious Seriousc Undetected Low
Lixisenatide
Stroke No Serious No Serious No Serious Seriousc Undetected Moderate

c

a d
Semaglutide

b d
CVD No Serious Serious No Serious Very Serious Undetected Very Low
MI No Serious Seriousb No Serious Seriousc Undetected Moderate

b d
UA No Serious Serious No Serious Very Serious Undetected Low
AF Seriousa Seriousb No Serious Very Seriousd Undetected Very Low
Taspoglutide
MACE Seriousa Seriousb No Serious Very Seriousd Undetected Very Low

a b d
MI Serious Serious No Serious Very Serious Undetected Very Low
Stroke Seriousa Seriousb No Serious Very Seriousd Undetected Very Low
SGLT-2
SGLT-2 vs Control
MI No Serious No Serious No Serious No Serious Reporting biasf High

a b d
UA Serious Serious No Serious Very Serious Undetected Very Low
SGLT-2 vs Placebo
UA Seriousa Seriousb No Serious Very Seriousd Undetected Very Low

a b d
AF Serious Serious No Serious Very Serious Undetected Very Low
Canagliflozin

e
e

a b d
Dapagliflozin
22
MI No Serious No Serious No Serious Seriouse Undetected Moderate

a b d
a b d
AF Serious Serious No Serious Very Serious Undetected Very Low
Empagliflozin

c

a d
Sulfonylureas
Sulfonylureas vs Control

c
Sulfonylureas vs Placebo
MACE Seriousa No Serious No Serious No Serious Undetected Moderate

a d
CVD Serious No Serious No Serious Very Serious Undetected Very Low
c

d
HF No Serious No Serious No Serious Very Serious Undetected Low
Chlorpropamide
CVD Seriousa No Serious No Serious Very Seriousd Undetected Very Low

a
MI Serious No Serious No Serious No Serious Undetected Moderate
Stroke Seriousa No Serious No Serious Very Seriousd Undetected Very Low
Glibenclamide

a c
MI Serious No Serious No Serious Serious Undetected Low
Stroke Seriousa No Serious No Serious Seriousc Undetected Low
Glimepiride
MACE No Serious No Serious No Serious Seriouse Undetected Moderate
MI No Serious No Serious No Serious Seriouse Undetected Moderate

a
Stroke Serious No Serious No Serious No Serious Undetected Highg

d
Gliclazide
MACE Seriousa No Serious No Serious Very Seriousd Undetected Very Low

a d
MI Serious No Serious No Serious Very Serious Undetected Very Low
Glipizide

a
CVD Serious No Serious No Serious No Serious Undetected Moderate
23
MI Seriousa No Serious No Serious Very Seriousd Undetected Very Low
a d
Stroke Serious No Serious No Serious Very Serious Undetected Very Low
Tolbutamide
TZDs
Rosiglitazone vs control
MACE No Serious Seriousb No Serious Very Seriousd Undetected Very Low
CVD No Serious No Serious No Serious Seriousc Reporting biasf Low

b
HF No Serious Serious No Serious No Serious Undetected Highg
Rosiglitazone vs Placebo
MACE No Serious No Serious No Serious Very Seriousd Undetected Low

d

d
HF No Serious No Serious No Serious No Serious Undetected Highg
Pioglitazone vs control

c f
CVD No Serious No Serious No Serious Serious Reporting bias Low
Pioglitazone vs Placebo
Metformin
Metformin vs control

a c
CVD Serious No Serious No Serious Serious Undetected Low
a c

a d
HF Serious No Serious No Serious Very Serious Undetected Very Low
Metformin vs placebo
MACE Seriousa No Serious No Serious Seriousc Undetected Low
CVD Seriousa No Serious No Serious Seriousc Undetected Low

a c

a d
HF Serious No Serious No Serious Very Serious Undetected Very Low
Alpha-glucosidase
Acarbose vs placebo
MACE No Serious Seriousb No Serious Very Seriousd Undetected Very Low

b d
MI No Serious Serious No Serious Very Serious Undetected Very Low

c
Voglibose vs placebo
24
Meglitinides
Nateglinide vs placebo

c
CVD No Serious No Serious No Serious Serious Undetected Moderate
MI No Serious No Serious No Serious Seriousc Undetected Moderate

c

c
Bromocriptine-QR
MACE No Serious No Serious No Serious Very Seriousd Undetected Low
CVD No Serious No Serious No Serious Very Seriousd Undetected Low

d
d
HF No Serious No Serious No Serious Very Seriousd Undetected Low

d
Insulin
Insulin vs control
Insulin vs. placebo/diet
CVD Seriousa No Serious No Serious No Serious Undetected Moderate

a c,e
MI Serious No Serious No Serious Serious Undetected Very Low

d
Degludec versus Glargine

c
c
Lisproc versus NPH/Glargine

MACE No Serious No Serious No Serious Seriousc Undetected Moderate
CVD No Serious No Serious No Serious Very Seriousd Undetected Low

d

d
a, Cardiovascular events was not the primary outcomes in most of included trials;
b, Significant heterogeneity between these studies was observed (I2>50%);
c, Serious imprecision was considered if the 95% confidence intervals overlaps with the minimally important difference for clinical benefit (RR<0.75) or harm (RR>1.25);
d, Very serious imprecision was considered if the 95% confidence intervals include both clinically important benefit (RR<0.75) and harm (RR>1.25) or with borderline
significance of benefit or harm
e, The point estimate were differed in the direction between meta-analysis and CVOTs;
f, Egger's P value less than 0.05;
g, large effect (RR<0.5 or RR>2)
25
eFigure 1A DPP-4 vs Control on MACE
Study %
ID ES (95% CI) Weight
Thrasher 2014 3.43 (0.14, 85.01) 0.03

Bajaj 2014 0.16 (0.01, 3.99) 0.03
Leiter 2014 2.06 (0.61, 6.93) 0.20
Ahre?n 2014 0.31 (0.07, 1.36) 0.13
Skrivanek 2014 0.96 (0.24, 3.87) 0.15
Rosenstock 2013 3.71 (0.18, 77.45) 0.03
Pratley 2014 0.49 (0.04, 5.45) 0.05
Barnett, 2013 0.99 (0.18, 5.49) 0.10
Schernthaner 2013 3.01 (0.31, 29.05) 0.06
Inagaki 2013 1.09 (0.10, 12.13) 0.05
Charbonnel 2013 0.99 (0.06, 15.96) 0.04
Barnett 2013 1.48 (0.06, 36.66) 0.03
Go¨ke 2013 0.67 (0.09, 2.38) 0.11
Ferreira 2013 1.01 (0.35, 2.93) 0.26
Ferreira 2013 0.50 (0.04, 5.66) 0.05
Dobs 2013 3.87 (0.20, 75.65) 0.03
Yki?J?rvinen 2013 1.38 (0.55, 3.45) 0.35
Lavalle-Gonza? lez 2013 1.34 (0.22, 8.06) 0.09
Roden 2013 1.52 (0.28, 8.36) 0.10
Yang 2012 2.02 (0.18, 22.46) 0.05
Gallwitz 2012 0.44 (0.23, 0.85) 0.69
Aschner 2012 0.90 (0.06, 14.43) 0.04
DeFronzo 2012 0.50 (0.10, 2.47) 0.11
Haak 2012 0.85 (0.05, 13.60) 0.04
Pan 2012 5.04 (0.24, 105.35) 0.03
Russell-Jones 2012 0.80 (0.04, 16.78) 0.03
Barnett 2012 0.25 (0.02, 2.76) 0.05
Frederich 2012 0.04 (0.00, 0.69) 0.02
Yang 2011 1.01 (0.06, 16.29) 0.04
Bosi 2011 0.66 (0.11, 3.95) 0.09
Owens 2011 1.00 (0.04, 24.59) 0.03
Gomis 2011 2.53 (0.12, 53.17) 0.03
Chacra 2011 0.26 (0.07, 1.06) 0.16
Hollander 2011 1.70 (0.35, 8.28) 0.12
Pfu¨ tzner 2011 0.78 (0.20, 3.04) 0.16
Yoon 2011 0.20 (0.01, 4.12) 0.03
Arechavaleta 2011 0.14 (0.01, 2.77) 0.04
Taskinen 2011 0.34 (0.02, 5.42) 0.04
Bergenstal 2010 0.65 (0.07, 6.30) 0.06
Seck 2010 0.12 (0.02, 0.98) 0.08
Williams-Herman 2010 1.18 (0.36, 3.88) 0.21
Vilsb?ll 2010 0.49 (0.04, 5.47) 0.05
Aschner 2010 0.33 (0.01, 8.09) 0.03
Rosenstock 2009 0.16 (0.01, 4.06) 0.03
Rosenstock 2009 0.93 (0.10, 9.05) 0.06
Pratley 2009 2.23 (0.12, 41.77) 0.03
Pratley 2009 0.75 (0.03, 18.43) 0.03
Chan 2008 2.08 (0.23, 18.75) 0.06
Hermansen 2007 1.49 (0.25, 8.98) 0.09
Charbonnel 2006 1.02 (0.25, 4.12) 0.15
Raz 2006 2.99 (0.16, 54.49) 0.03
NCT00856284 0.53 (0.25, 1.13) 0.52
NCT01076088 1.02 (0.06, 16.44) 0.04
NCT00121667 0.63 (0.16, 2.55) 0.15
NCT00395512 0.33 (0.02, 5.32) 0.04
NCT00722371 2.26 (0.46, 11.25) 0.12
NCT01183013 0.77 (0.16, 3.86) 0.12
NCT01087502 0.15 (0.02, 1.21) 0.07
NCT01006603 0.60 (0.14, 2.52) 0.14
NCT01462266 0.66 (0.11, 4.00) 0.09
NCT01177384 5.00 (0.24, 104.84) 0.03
NCT00614939 2.05 (0.37, 11.50) 0.10
NCT00800683 0.69 (0.23, 2.11) 0.24
NCT00482729 0.79 (0.21, 2.97) 0.17
NCT01215097 0.16 (0.01, 4.00) 0.03
NCT01214239 0.16 (0.01, 4.06) 0.03
NCT01590797 2.00 (0.18, 22.21) 0.05
CARMELINA 1.02 (0.89, 1.17) 15.74
EXAMINE 0.96 (0.82, 1.12) 12.12
OMNEON 1.00 (0.77, 1.29) 4.42
SAVOR-TIMI 53 1.00 (0.89, 1.12) 22.30
TECOS 0.99 (0.89, 1.10) 26.25
CAROLINA 0.98 (0.84, 1.14) 12.63
Overall (I-squared = 0.0%, p = 0.961) 0.98 (0.92, 1.03) 100.00
with estimated predictive interval . (0.92, 1.03)
NOTE: Weights are from random effects analysis
1.0e-04 1 10000
26
eFigure 1B DPP-4 vs Control on CVD
Study %
Del Prato S (ENDURE)17* 0.49 (0.12, 1.97) 0.31

NaucK M44* 0.74 (0.03, 18.11) 0.06
NCT0028642946* 1.51 (0.06, 36.71) 0.06
NCT0032862746* 0.17 (0.01, 4.08) 0.07
Pratley RE52* 0.74 (0.03, 18.04) 0.06
Rosenstock J57* 1.02 (0.09, 11.18) 0.10
Seino Y68* 1.49 (0.06, 36.16) 0.06
Bajaj M6* 0.16 (0.01, 3.96) 0.07
Barnett AH7* 1.52 (0.06, 36.87) 0.06
Barnett AH8* 1.50 (0.06, 36.48) 0.06
Duran-Garcia S19* 6.96 (0.36, 134.38) 0.07
Gallwitz B26* 1.00 (0.14, 7.05) 0.16
Haak T29* 0.28 (0.01, 6.92) 0.06
Lewin AJ37* 1.57 (0.06, 38.23) 0.06
Chacra AR16* 0.18 (0.02, 1.69) 0.12
Fonseca V22* 0.35 (0.01, 8.56) 0.05
Hermans MP (PROMPT)30* 2.82 (0.12, 68.59) 0.06
Hollander PL31* 1.45 (0.06, 35.49) 0.06
NCT0057558846* 0.50 (0.05, 5.52) 0.11
Pan CY49* 3.00 (0.12, 73.33) 0.06
Pfützner A50* 0.33 (0.08, 1.33) 0.31
Rosenstock J56* 0.10 (0.00, 2.54) 0.02
Schernthaner G64* 2.99 (0.12, 73.19) 0.06
Arechavaleta R3* 0.34 (0.01, 8.21) 0.05
Leiter LA36* 0.50 (0.05, 5.50) 0.11
Mohan V43* 1.52 (0.06, 37.15) 0.06
Nauck M45* 1.92 (0.12, 30.65) 0.08
NCT0050926246* 3.01 (0.12, 73.57) 0.06
Olansky L47* 0.99 (0.06, 15.82) 0.08
Pratley RE53* 5.99 (0.24, 146.35) 0.06
Roden M55* 2.62 (0.11, 63.67) 0.06
Seck T67* 0.20 (0.01, 4.09) 0.07
Williams-Herman D71* 0.98 (0.06, 15.57) 0.08
Yoon KH73* 2.80 (0.11, 68.22) 0.06
Blonde L (GALIANT Trial)12* 0.17 (0.01, 4.09) 0.07
Ferrannini E20* 1.99 (0.18, 21.95) 0.11
Fonseca V23* 0.33 (0.01, 8.07) 0.05
Kothny W34* 3.53 (0.17, 72.91) 0.07
Schweizer A65* 2.95 (0.12, 71.83) 0.06
Strain WD (INTERVAL)70* 2.98 (0.12, 72.49) 0.06
CARMELINA 0.96 (0.81, 1.14) 20.88
EXAMINE 0.85 (0.66, 1.10) 9.35
OMNEON 1.06 (0.66, 1.68) 2.79
SAVOR-TIMI 53 1.03 (0.87, 1.22) 21.33
TECOS 1.03 (0.89, 1.19) 28.90
CAROLINA 1.00 (0.81, 1.24) 13.45
1.0e-04 1 10000
27
eFigure 1C DPP-4 vs Control on MI
Study %
Ahren B (HARMONY 3)1* 0.43 (0.10, 1.92) 0.27

Arechavaleta R3* 0.34 (0.01, 8.21) 0.05
Aschner P (EASIE)4* 2.83 (0.12, 69.17) 0.06
Aschner P5* 0.33 (0.01, 8.07) 0.05
Bajaj M6* 0.16 (0.01, 3.96) 0.07
Barnett AH7* 0.50 (0.03, 7.94) 0.08
Barnett AH8* 2.49 (0.12, 51.58) 0.06
Blonde L (GALIANT Trial)12* 0.17 (0.01, 4.09) 0.06
Bolli G13* 0.95 (0.06, 15.16) 0.08
Bosi E14* 0.20 (0.01, 4.07) 0.07
Bosi E15* 0.25 (0.02, 2.76) 0.10
Chacra AR16* 0.40 (0.09, 1.77) 0.26
Dobs AS18* 2.69 (0.13, 55.52) 0.06
Duran-Garcia S19* 2.00 (0.37, 10.86) 0.21
Ferrannini E20* 0.71 (0.23, 2.24) 0.45
Fonseca V22* 0.35 (0.01, 8.46) 0.05
Frederich R.25* 0.05 (0.00, 1.06) 0.05
Gallwitz B26* 0.60 (0.22, 1.64) 0.58
Haak T29* 0.85 (0.05, 13.51) 0.07
Hollander PL31* 0.48 (0.03, 7.68) 0.08
Kawamori R32* 1.53 (0.06, 37.30) 0.06
Kikuchi M33* 0.11 (0.00, 2.69) 0.04
Leiter LA36* 1.01 (0.06, 16.09) 0.08
Lewin AJ37* 1.57 (0.06, 38.23) 0.06
Mathieu C40* 0.33 (0.03, 3.19) 0.11
Mita T (SPEAD-A)42* 0.33 (0.01, 7.98) 0.05
Mohan V43* 0.51 (0.03, 8.04) 0.08
Nauck M45* 1.28 (0.22, 7.64) 0.19
NCT0008651546* 0.26 (0.02, 2.80) 0.10
NCT0009475746* 1.35 (0.07, 27.86) 0.07
NCT0010670446* 0.33 (0.01, 8.03) 0.05
NCT0028646846* 0.75 (0.03, 18.18) 0.06
NCT0030960846* 1.09 (0.04, 26.48) 0.06
NCT0032862746* 0.17 (0.01, 4.08) 0.07
NCT0039534346* 0.50 (0.05, 5.44) 0.11
NCT0039551246* 1.00 (0.04, 24.38) 0.06
NCT0050926246* 0.75 (0.17, 3.33) 0.27
NCT0057558846* 1.00 (0.06, 16.01) 0.08
NCT0060125046* 1.02 (0.04, 24.90) 0.06
NCT0060247246* 1.00 (0.04, 24.44) 0.06
NCT0064104346* 1.51 (0.06, 36.85) 0.06
NCT0072237146* 5.26 (0.27, 101.73) 0.07
NCT0091577246* 1.29 (0.13, 12.29) 0.11
NCT0108750246* 0.12 (0.01, 2.20) 0.08
NCT0118301346* 0.78 (0.16, 3.86) 0.23
NCT0121423946* 0.17 (0.01, 4.03) 0.07
NCT0126348346* 0.16 (0.01, 3.94) 0.07
NCT0126349646* 0.64 (0.03, 15.64) 0.06
NCT0159079746* 2.99 (0.12, 72.95) 0.06
NCT0170890246* 0.65 (0.03, 15.94) 0.06
NCT0188290746* 2.85 (0.12, 69.17) 0.06
Olansky L47* 6.96 (0.36, 134.37) 0.07
Pan CY49* 3.00 (0.12, 73.33) 0.06
Pfützner A50* 0.50 (0.08, 3.00) 0.18
Philis-Tsimikas51* 0.51 (0.05, 5.55) 0.11
Pratley RE52* 1.73 (0.09, 33.18) 0.07
Pratley RE53* 0.40 (0.02, 8.30) 0.06
Ristic S54* 0.09 (0.00, 2.15) 0.04
Rosenstock J56* 0.31 (0.02, 4.92) 0.08
Rosenstock J57* 0.33 (0.01, 8.03) 0.05
Rosenstock J58* 0.11 (0.01, 1.01) 0.11
Ross SA61* 0.30 (0.01, 7.29) 0.05
Russel-Jones D (DURATION-4)62* 0.50 (0.02, 12.25) 0.06
Schernthaner G64* 1.00 (0.02, 4.92) 0.08
Schweizer A65* 0.33 (0.01, 7.98) 0.05
Schweizer A66* 0.10 (0.00, 2.01) 0.04
Seck T67* 0.11 (0.01, 2.05) 0.08
Seino Y68* 1.49 (0.06, 36.16) 0.06
Strain WD (INTERVAL)70* 1.00 (0.06, 15.83) 0.08
CARMELINA 1.12 (0.90, 1.40) 12.04
EXAMINE 1.09 (0.92, 1.29) 20.56
OMNEON 0.87 (0.60, 1.26) 4.27
SAVOR-TIMI 53 0.95 (0.80, 1.12) 20.75
TECOS 0.95 (0.81, 1.11) 23.67
CAROLINA 1.03 (0.82, 1.29) 11.45
.001 1 1000
28
eFigure 1D DPP-4 vs Control on Stroke
Study %

Mita T (SPEAD-A)42* 0.33 (0.01, 7.98) 0.10
NaucK M44* 0.38 (0.02, 7.98) 0.13
NCT0028642946* 0.17 (0.01, 4.08) 0.13
NCT0032862746* 1.00 (0.09, 10.97) 0.20
NCT0039551246* 0.11 (0.00, 2.71) 0.04
NCT0102358146* 2.43 (0.12, 50.26) 0.13
NCT0126348346* 0.16 (0.01, 3.94) 0.13
NCT0126349646* 3.21 (0.19, 55.73) 0.14
NCT0131807046* 0.17 (0.01, 4.19) 0.13
Rosenstock J57* 2.87 (0.16, 53.00) 0.14
Seino Y68* 1.49 (0.06, 36.16) 0.11
Seino Y69* 1.18 (0.06, 24.25) 0.13
Barnett AH7* 0.17 (0.01, 4.10) 0.13
Barnett AH8* 1.47 (0.06, 35.74) 0.11
Gallwitz B26* 0.27 (0.08, 0.97) 0.75
Kawamori R32* 1.53 (0.06, 37.30) 0.11
NCT0060125046* 0.11 (0.00, 2.77) 0.04
NCT0091577246* 0.43 (0.03, 6.82) 0.16
NCT0108750246* 0.54 (0.05, 5.87) 0.21
NCT0120429446* 0.15 (0.01, 3.59) 0.14
NCT0121509746* 0.16 (0.01, 3.98) 0.13
NCT0170890246* 0.65 (0.03, 15.94) 0.12
Chacra AR16* 0.27 (0.02, 2.93) 0.19
Barnett AH9* 0.17 (0.01, 4.05) 0.13
Hollander PL31* 2.42 (0.12, 50.18) 0.13
NCT0057558846* 0.33 (0.03, 3.21) 0.21
NCT0066136246* 1.01 (0.06, 16.13) 0.15
Pan CY49* 3.00 (0.12, 73.33) 0.11
Pfützner A50* 0.67 (0.06, 7.37) 0.20
Rosenstock J56* 1.53 (0.06, 37.49) 0.11
Schernthaner G64* 0.33 (0.01, 8.16) 0.10
Arechavaleta R3* 0.34 (0.01, 8.21) 0.10
Ahren B (HARMONY 3)1* 0.34 (0.02, 6.47) 0.14
Al Sifri (RAMADAN study)2* 0.34 (0.01, 8.28) 0.10
Bergenstal RM (DURATION-2)10* 0.99 (0.06, 15.76) 0.15
Dobs AS18* 1.62 (0.07, 39.28) 0.12
Leiter LA36* 2.02 (0.37, 10.95) 0.41
Mohan V43* 1.52 (0.06, 37.15) 0.11
NCT0008651546* 2.56 (0.12, 53.09) 0.13
NCT0009475746* 1.35 (0.07, 27.86) 0.13
NCT0010670446* 1.97 (0.18, 21.60) 0.20
NCT0039763146* 0.33 (0.01, 8.08) 0.10
NCT0050926246* 1.00 (0.14, 7.07) 0.30
NCT0072237146* 0.75 (0.11, 5.32) 0.31
NCT0081399546* 5.03 (0.24, 104.01) 0.13
NCT0107607546* 3.01 (0.12, 73.57) 0.11
NCT0107608846* 3.17 (0.13, 77.15) 0.11
NCT0117738446* 2.98 (0.12, 72.80) 0.11
NCT0159079746* 2.99 (0.12, 72.95) 0.11
NCT0200868246* 3.00 (0.12, 73.17) 0.11
Olansky L47* 0.20 (0.01, 4.13) 0.13
Philis-Tsimikas51* 1.01 (0.06, 16.10) 0.15
Russel-Jones D (DURATION-4)62* 0.50 (0.02, 12.25) 0.11
Yoon KH73* 0.31 (0.01, 7.58) 0.11
Bolli G13* 0.48 (0.04, 5.22) 0.20
Bosi E14* 1.51 (0.06, 36.94) 0.11
Ferrannini E20* 0.07 (0.00, 1.16) 0.05
Pan C48* 0.16 (0.01, 4.00) 0.13
Rosenstock J58* 1.56 (0.08, 32.29) 0.13
Rosenstock J59* 0.33 (0.01, 8.03) 0.10
Yang W72* 0.32 (0.01, 7.72) 0.11
CARMELINA 0.91 (0.67, 1.23) 12.68
EXAMINE 0.81 (0.51, 1.29) 5.43
OMNEON 0.94 (0.58, 1.52) 5.04
SAVOR-TIMI 53 1.11 (0.88, 1.39) 22.40
TECOS 0.97 (0.79, 1.19) 27.88
CAROLINA 0.86 (0.66, 1.12) 16.73
1.0e-04 1 10000
29
eFigure 1E DPP-4 vs Control on HF
Study %
CARMELINA 0.90 (0.74, 1.08) 18.45
EXAMINE 1.07 (0.79, 1.46) 11.80
OMNEON 0.60 (0.35, 1.05) 5.19
SAVOR-TIMI 53 1.27 (1.07, 1.51) 19.59
TECOS 1.00 (0.83, 1.20) 18.77
CAROLINA 1.21 (0.92, 1.59) 13.41
Kongwatcharapong 2016 0.93 (0.70, 1.24) 12.79
.35 1 2.86
30
eFigure 1F DPP-4 vs Control on UA
Study %
CARMELINA 0.87 (0.57, 1.31) 10.65
EXAMINE 0.82 (0.65, 1.04) 29.52
SAVOR-TIMI 53 1.19 (0.89, 1.60) 20.18
TECOS 0.90 (0.70, 1.16) 26.16
CAROLINA 1.07 (0.74, 1.54) 13.49
.57 1 1.75
31
eFigure 2A DPP-4 vs Placebo on MACE
Study %
Pratley 2014 0.49 (0.04, 5.45) 0.06

DeFronzo 2012 0.50 (0.10, 2.47) 0.14
Rosenstock 2009 0.16 (0.01, 4.06) 0.04
Pratley 2009 2.23 (0.12, 41.77) 0.04
Pratley 2009 0.75 (0.03, 18.43) 0.03
Thrasher 2014 3.43 (0.14, 85.01) 0.03
Bajaj 2014 0.16 (0.01, 3.99) 0.04
Barnett 2013 1.48 (0.06, 36.66) 0.03
Yki?J?rvinen 2013 1.38 (0.55, 3.45) 0.42
Haak 2012 0.85 (0.05, 13.60) 0.04
Owens 2011 1.00 (0.04, 24.59) 0.03
Gomis 2011 2.53 (0.12, 53.17) 0.04
Taskinen 2011 0.34 (0.02, 5.42) 0.04
NCT00800683 0.69 (0.23, 2.11) 0.29
NCT01215097 0.16 (0.01, 4.00) 0.04
NCT01214239 0.16 (0.01, 4.06) 0.04
Barnett, 2013 0.99 (0.18, 5.49) 0.12
Pan 2012 5.04 (0.24, 105.35) 0.04
Yang 2011 1.01 (0.06, 16.29) 0.04
Chacra 2011 0.26 (0.07, 1.06) 0.19
Hollander 2011 1.70 (0.35, 8.28) 0.14
Rosenstock 2009 0.93 (0.10, 9.05) 0.07
NCT00121667 0.63 (0.16, 2.55) 0.18
NCT00614939 2.05 (0.37, 11.50) 0.12
Dobs 2013 3.87 (0.20, 75.65) 0.04
Yang 2012 2.02 (0.18, 22.46) 0.06
Yoon 2011 0.20 (0.01, 4.12) 0.04
Vilsb?ll 2010 0.49 (0.04, 5.47) 0.06
Hermansen 2007 1.49 (0.25, 8.98) 0.11
Charbonnel 2006 1.02 (0.25, 4.12) 0.18
NCT01076088 1.02 (0.06, 16.44) 0.04
NCT01462266 0.66 (0.11, 4.00) 0.11
NCT01177384 5.00 (0.24, 104.84) 0.04
NCT00482729 0.79 (0.21, 2.97) 0.20
NCT01590797 2.00 (0.18, 22.21) 0.06
CARMELINA 1.02 (0.89, 1.17) 18.85
EXAMINE 0.96 (0.82, 1.12) 14.51
OMNEON 1.00 (0.77, 1.29) 5.30
SAVOR-TIMI 53 1.00 (0.89, 1.12) 26.70
TECOS 0.99 (0.89, 1.10) 31.43
.00949 1 105
32
eFigure 2B DPP-4 vs Placebo on CVD
Study %
Bajaj et al 0.05 (0.00, 3.09) 0.04

Barnett et al 4.47 (0.07, 286.87) 0.04
Strain et al 7.39 (0.15, 372.38) 0.05
Yki-jarvinen et al 3.81 (0.77, 18.93) 0.28
Fonseca et al 0.13 (0.00, 6.78) 0.05
Lewin et al 4.58 (0.07, 284.55) 0.04
Kothny et al 5.55 (0.33, 92.75) 0.09
Barnett et al 4.50 (0.07, 286.14) 0.04
Pan et al 7.39 (0.15, 372.38) 0.05
Barnett et al 4.47 (0.07, 286.87) 0.04
Hollander et al 4.41 (0.07, 288.68) 0.04
Nowicki et al 1.00 (0.20, 5.08) 0.27
Nauck et al 3.48 (0.03, 478.41) 0.03
Pratley et al 3.47 (0.03, 480.64) 0.03
Rosenstock et al 4.48 (0.07, 286.49) 0.04
Mohan et al 4.51 (0.07, 285.90) 0.04
Raz et al 0.14 (0.00, 6.97) 0.05
Goldstein et al 0.13 (0.00, 6.71) 0.05
CARMELINA 0.96 (0.81, 1.14) 24.76
EXAMINE 0.85 (0.66, 1.10) 11.08
OMNEON 1.06 (0.66, 1.68) 3.31
SAVOR-TIMI 53 1.03 (0.87, 1.22) 25.30
TECOS 1.03 (0.89, 1.19) 34.27
.00073 1 1364
33
eFigure 2C DPP-4 vs Placebo on MI
Study %
Pratley et al 2014 1.46 (0.06, 35.55) 0.07

Pratley et al 2009 1.73 (0.09, 33.18) 0.08
Pratley et al 2009 0.75 (0.03, 18.18) 0.07
Wang et al 2015 1.47 (0.06, 35.79) 0.07
Bajaj et al 2014 0.16 (0.01, 3.98) 0.07
Thrasher et al 2014 3.39 (0.14, 82.40) 0.07
McGIll et al 2013 1.91 (0.36, 10.08) 0.25
Ross et al 2012 0.30 (0.01, 7.29) 0.07
Lewin et al 2012 1.57 (0.06, 38.23) 0.07
Barnett et al 2012 0.50 (0.03, 7.94) 0.09
Haak et al 2012 1.53 (0.06, 37.13) 0.07
Forst et al 2011 0.82 (0.04, 19.30) 0.07
Owens et al 2011 1.00 (0.04, 24.44) 0.07
Taskinen et al 2011 1.02 (0.04, 24.90) 0.07
Forst et al 2010 1.09 (0.04, 26.48) 0.07
White et al 2014 3.48 (0.14, 84.16) 0.07
Barnett et al 2013 1.50 (0.06, 36.48) 0.07
Rosenstock et al 2013 0.11 (0.01, 1.01) 0.14
Pan et al 2012 3.00 (0.12, 73.33) 0.07
Frederich et al 2012 0.05 (0.00, 1.06) 0.08
Barnett et al 2012 1.50 (0.06, 36.48) 0.07
Hollander et al 2011 0.48 (0.03, 7.68) 0.09
Nowicki et al 2011 2.00 (0.18, 21.64) 0.12
Mathieu et al 2015 0.33 (0.01, 8.15) 0.07
Ahren et al 2014 0.32 (0.01, 7.92) 0.07
Dobs et al 2013 1.63 (0.07, 39.65) 0.07
Visboll et al 2010 0.99 (0.06, 15.77) 0.09
Mohan et al 2009 1.52 (0.06, 37.15) 0.07
Raz et al 2008 0.34 (0.01, 8.25) 0.07
Nonaka et al 2007 0.33 (0.01, 8.06) 0.07
Odawara et al 2014 0.34 (0.01, 8.16) 0.07
Kikuchi et al 2009 0.11 (0.00, 2.69) 0.07
CARMELINA 1.12 (0.90, 1.40) 14.42
EXAMINE 1.09 (0.92, 1.29) 24.64
OMNEON 0.87 (0.60, 1.26) 5.11
SAVOR-TIMI 53 0.95 (0.80, 1.12) 24.86
TECOS 0.95 (0.81, 1.11) 28.36
.00249 1 401
34
eFigure 2D DPP-4 vs Placebo on Stroke
Study %
Pratley et al 2014 2.43 (0.12, 50.26) 0.17

Seino et al 2012 1.49 (0.06, 36.16) 0.15
Seino et al 2011 0.71 (0.03, 17.16) 0.15
Rosenstock et al 2009 0.17 (0.01, 4.08) 0.15
Pattzi et al 2010 0.09 (0.00, 2.09) 0.15
Garcia et al 2008 0.10 (0.00, 2.52) 0.15
Wang et al 2015 0.16 (0.01, 3.98) 0.15
Barnett et al 2013 1.47 (0.06, 35.74) 0.15
McGIll et al 2013 0.96 (0.06, 14.97) 0.20
Rosenstock et al 2013 2.87 (0.16, 53.00) 0.18
Frederich et al 2012 0.09 (0.00, 2.08) 0.15
Yang et al 2011 1.01 (0.06, 16.13) 0.20
Hollander et al 2011 1.45 (0.06, 35.49) 0.15
Nowicki et al 2011 1.00 (0.06, 15.73) 0.20
Ahren et al 2014 0.32 (0.01, 7.92) 0.15
Hage et al 2013 3.08 (0.13, 73.27) 0.15
Kashiwagi et al 2011 3.09 (0.13, 74.51) 0.15
Mohan et al 2009 1.52 (0.06, 37.15) 0.15
Yang et al 2015 0.09 (0.00, 2.06) 0.15
Bosi et al 2007 0.50 (0.03, 7.99) 0.20
CARMELINA 0.91 (0.67, 1.23) 16.70
EXAMINE 0.81 (0.51, 1.29) 7.16
OMNEON 0.94 (0.58, 1.52) 6.64
SAVOR-TIMI 53 1.11 (0.88, 1.39) 29.50
TECOS 0.97 (0.79, 1.19) 36.73
.00352 1 284
35
eFigure 2E DPP-4 vs Placebo on HF
Study %
Nauck 2009 0.74 (0.03, 18.11) 0.10

Pratley 2009 1.73 (0.09, 33.18) 0.11
Pratley 2009 0.75 (0.03, 18.18) 0.10
Yang 2015 0.20 (0.01, 4.75) 0.10
Matthaei 2015 0.53 (0.05, 5.78) 0.17
Rosenstock 2013 0.48 (0.08, 2.83) 0.31
Hollander 2011 0.16 (0.01, 3.94) 0.10
Nowicki 2011 2.00 (0.18, 21.64) 0.18
Ahren 2014 1.00 (0.04, 24.44) 0.10
Visboll 2010 0.20 (0.01, 4.11) 0.11
Iwamoto 2010 0.76 (0.03, 18.54) 0.10
Rosenstock 2008 2.97 (0.12, 71.87) 0.10
Garber 2007 0.52 (0.03, 8.23) 0.13
CARMELINA 0.90 (0.74, 1.08) 26.16
EXAMINE 1.07 (0.79, 1.46) 10.30
OMNEON 0.60 (0.35, 1.05) 3.27
SAVOR-TIMI 53 1.27 (1.07, 1.51) 31.13
TECOS 1.00 (0.83, 1.20) 27.43
.00661 1 151
36
eFigure 2F DPP-4 vs Placebo on UA
Study %
CARMELINA 0.87 (0.57, 1.31) 13.46
EXAMINE 0.82 (0.65, 1.04) 32.88
SAVOR-TIMI 53 1.19 (0.89, 1.60) 23.89
TECOS 0.90 (0.70, 1.16) 29.77
.57 1 1.75
37
eFigure 3A Alogliptin vs Control on MACE
Study %
EXAMINE 0.96 (0.82, 1.12) 92.81
Rosenstock 2013 3.71 (0.18, 77.45) 0.25
Pratley 2014 0.49 (0.04, 5.45) 0.37
DeFronzo 2012 0.50 (0.10, 2.47) 0.88
Bosi 2011 0.66 (0.11, 3.95) 0.70
Rosenstock 2009 0.16 (0.01, 4.06) 0.25
Pratley 2009 2.23 (0.12, 41.77) 0.26
Pratley 2009 0.75 (0.03, 18.43) 0.22
NCT00856284 0.53 (0.25, 1.13) 3.96
NCT00395512 0.33 (0.02, 5.32) 0.29
.01 1 100
38
eFigure 3B Alogliptin vs Control on CVD
Study %
EXAMINE 0.85 (0.66, 1.10) 99.09
Nauck et al 3.48 (0.03, 478.41) 0.27
Pratley et al 3.47 (0.03, 480.64) 0.27
Rosenstock et al 4.48 (0.07, 286.49) 0.37
.00208 1 481
39
eFigure 3C Alogliptin vs Control on MI
Study %
EXAMINE 1.09 (0.92, 1.29) 99.12
Pratley et al 2014 1.46 (0.06, 35.55) 0.28
Pratley et al 2009 1.73 (0.09, 33.18) 0.32
Pratley et al 2009 0.75 (0.03, 18.18) 0.28
.0281 1 35.6
40
eFigure 3D Alogliptin vs Control on Stroke
Study %
EXAMINE 0.81 (0.51, 1.29) 92.01
Pratley et al 2014 2.43 (0.12, 50.26) 2.16
Seino et al 2012 1.49 (0.06, 36.16) 1.94
Seino et al 2011 0.71 (0.03, 17.16) 1.95
Rosenstock et al 2009 0.17 (0.01, 4.08) 1.94
.00686 1 146
41
eFigure 3E Alogliptin vs Control on UA
Study %
EXAMINE 0.82 (0.65, 1.04) 66.72
Del Prato (2014) 0.64 (0.16, 2.55) 21.33
Nauck (2008) 0.01 (0.00, 0.88) 2.31
Rosenstock (2009b) 0.47 (0.02, 8.90) 6.07
Rosenstock (2010) 7.34 (0.15, 370.13) 3.57
4.8e-05 1 21008
42
eFigure 4A Linagliptin vs Control on MACE
Study %
CARMELINA 1.02 (0.89, 1.17) 52.02
CAROLINA 0.98 (0.84, 1.14) 42.15
Rosenstock 2015(19trials) 0.74 (0.49, 1.13) 5.83
.49 1 2.04
43
eFigure 4B Linagliptin vs Control on CVD
Study %
CARMELINA 0.96 (0.81, 1.14) 59.55
CAROLINA 1.00 (0.81, 1.24) 38.36
.385 1 2.6
44
eFigure 4C Linagliptin vs Control on MI
Study %
CARMELINA 1.12 (0.90, 1.40) 47.93
CAROLINA 1.03 (0.82, 1.29) 45.57
.47 1 2.13
45
eFigure 4D Linagliptin vs Control on Stroke
Study %
CARMELINA 0.91 (0.67, 1.23) 41.06
CAROLINA 0.86 (0.66, 1.12) 44.27
.15 1 6.67
46
eFigure 4E Linagliptin vs Control on HF
Study %
CARMELINA 0.90 (0.74, 1.08) 55.52
CAROLINA 1.21 (0.92, 1.59) 38.48
.405 1 2.47
47
eFigure 4F Linagliptin vs Control on UA
Study %
CARMELINA 0.87 (0.57, 1.31) 40.95
CAROLINA 1.07 (0.74, 1.54) 52.80
Gallwitz (2012b) 1.00 (0.20, 4.93) 2.78
Haak (2012) 6.13 (0.25, 149.44) 0.69
Laakso (2015) 3.24 (0.13, 78.65) 0.70
Owens (2011) 0.11 (0.00, 2.72) 0.69
Yki-Jarvinen (2013) 3.00 (0.31, 28.72) 1.39
.00453 1 221
48
eFigure5A Saxagliptin vs Control on MACE
Study %
SAVOR-TIMI 53 1.00 (0.89, 1.12) 94.83
Barnett, 2013 0.99 (0.18, 5.49) 0.43
Go¨ke 2013 0.67 (0.09, 2.38) 0.47
Pan 2012 5.04 (0.24, 105.35) 0.14
Russell-Jones 2012 0.80 (0.04, 16.78) 0.14
Frederich 2012 0.04 (0.00, 0.69) 0.06
Yang 2011 1.01 (0.06, 16.29) 0.16
Chacra 2011 0.26 (0.07, 1.06) 0.68
Hollander 2011 1.70 (0.35, 8.28) 0.50
Pfu¨ tzner 2011 0.78 (0.20, 3.04) 0.68
Rosenstock 2009 0.93 (0.10, 9.05) 0.25
NCT00121667 0.63 (0.16, 2.55) 0.65
NCT01006603 0.60 (0.14, 2.52) 0.60
NCT00614939 2.05 (0.37, 11.50) 0.42
1.0e-04 1 10000
49
eFigure5B Saxagliptin vs Control on CVD
Study %
Barnett et al 4.47 (0.07, 286.87) 0.16
Pan et al 7.39 (0.15, 372.38) 0.18
Barnett et al 4.47 (0.07, 286.87) 0.16
Hollander et al 4.41 (0.07, 288.68) 0.16
Nowicki et al 1.00 (0.20, 5.08) 1.06
SAVOR-TIMI 53 1.03 (0.87, 1.22) 98.27
.00269 1 372
50
eFigure5C Saxagliptin vs Control on MI
Study %
White et al 2014 3.48 (0.14, 84.16) 3.50
Barnett et al 2013 1.50 (0.06, 36.48) 3.48
Rosenstock et al 2013 0.11 (0.01, 1.01) 6.64
Pan et al 2012 3.00 (0.12, 73.33) 3.48
Frederich et al 2012 0.05 (0.00, 1.06) 3.86
Barnett et al 2012 1.50 (0.06, 36.48) 3.48
Hollander et al 2011 0.48 (0.03, 7.68) 4.57
Nowicki et al 2011 2.00 (0.18, 21.64) 6.02
SAVOR-TIMI 53 0.95 (0.80, 1.12) 64.96
.00249 1 401
51
eFigure5D Saxagliptin vs Control on Stroke
Study %
Rosenstock et al 2013 2.87 (0.16, 53.00) 0.60
Frederich et al 2012 0.09 (0.00, 2.08) 0.50
Yang et al 2011 1.01 (0.06, 16.13) 0.66
Hollander et al 2011 1.45 (0.06, 35.49) 0.50
Nowicki et al 2011 1.00 (0.06, 15.73) 0.67
SAVOR-TIMI 53 1.11 (0.88, 1.39) 97.08
.00352 1 284
52
eFigure5E Saxagliptin vs Control on UA
Study %
SAVOR-TIMI 53 1.19 (0.89, 1.60) 95.79
DeFronzo (2009) 0.11 (0.00, 2.60) 0.81
Frederich (2012) 0.77 (0.03, 18.73) 0.81
Goke (2013) 0.20 (0.01, 4.17) 0.90
Pan (2012) 5.00 (0.24, 103.69) 0.90
Schernthaner (2015) 3.00 (0.12, 73.40) 0.81
.00435 1 230
53
eFigure 6A Sitagliptin vs Control on MACE
Study %
TECOS 0.99 (0.89, 1.10) 91.22

Leiter 2014 2.06 (0.61, 6.93) 0.69
Ahre′n 2014 0.31 (0.07, 1.36) 0.47
Skrivanek 2014 0.96 (0.24, 3.87) 0.53
Schernthaner 2013 3.01 (0.31, 29.05) 0.20
Charbonnel 2013 0.99 (0.06, 15.96) 0.13
Ferreira 2013 1.01 (0.35, 2.93) 0.91
Ferreira 2013 0.50 (0.04, 5.66) 0.17
Dobs 2013 3.87 (0.20, 75.65) 0.12
Lavalle-Gonza′ lez 2013 1.34 (0.22, 8.06) 0.32
Roden 2013 1.52 (0.28, 8.36) 0.35
Yang 2012 2.02 (0.18, 22.46) 0.18
Aschner 2012 0.90 (0.06, 14.43) 0.14
Yoon 2011 0.20 (0.01, 4.12) 0.11
Arechavaleta 2011 0.14 (0.01, 2.77) 0.13
Bergenstal 2010 0.65 (0.07, 6.30) 0.20
Seck 2010 0.12 (0.02, 0.98) 0.27
Williams-Herman 2010 1.18 (0.36, 3.88) 0.72
Vilsb?ll 2010 0.49 (0.04, 5.47) 0.17
Aschner 2010 0.33 (0.01, 8.09) 0.09
Chan 2008 2.08 (0.23, 18.75) 0.21
Hermansen 2007 1.49 (0.25, 8.98) 0.32
Charbonnel 2006 1.02 (0.25, 4.12) 0.52
Raz 2006 2.99 (0.16, 54.49) 0.12
NCT01076088 1.02 (0.06, 16.44) 0.13
NCT00722371 2.26 (0.46, 11.25) 0.40
NCT01462266 0.66 (0.11, 4.00) 0.32
NCT01177384 5.00 (0.24, 104.84) 0.11
NCT00482729 0.79 (0.21, 2.97) 0.58
NCT01590797 2.00 (0.18, 22.21) 0.18
.00954 1 105
54
eFigure 6B Sitagliptin vs Control on CVD
Study %
Fonseca et al 0.13 (0.00, 6.78) 0.14
Mohan et al 4.51 (0.07, 285.90) 0.12
Raz et al 0.14 (0.00, 6.97) 0.14
Goldstein et al 0.13 (0.00, 6.71) 0.14
TECOS 1.03 (0.89, 1.19) 99.47
.00264 1 379
55
eFigure 6C Sitagliptin vs Control on MI
Study %
Mathieu et al 2015 0.33 (0.01, 8.15) 0.24
Ahren et al 2014 0.32 (0.01, 7.92) 0.24
Dobs et al 2013 1.63 (0.07, 39.65) 0.24
Visboll et al 2010 0.99 (0.06, 15.77) 0.32
Mohan et al 2009 1.52 (0.06, 37.15) 0.24
Raz et al 2008 0.34 (0.01, 8.25) 0.24
Nonaka et al 2007 0.33 (0.01, 8.06) 0.24
TECOS 0.95 (0.81, 1.11) 98.25
.0132 1 75.5
56
eFigure 6D Sitagliptin vs Control on Stroke
Study %
Ahren et al 2014 0.32 (0.01, 7.92) 0.40
Hage et al 2013 3.08 (0.13, 73.27) 0.41
Kashiwagi et al 2011 3.09 (0.13, 74.51) 0.41
Mohan et al 2009 1.52 (0.06, 37.15) 0.40
TECOS 0.97 (0.79, 1.19) 98.37
.0132 1 75.5
57
eFigure 6E Sitagliptin vs Control on UA
Study %
TECOS 0.90 (0.70, 1.16) 92.43
Ahren (2014) 0.45 (0.02, 11.01) 0.58
Arjona Ferreira (2013) 0.34 (0.01, 8.21) 0.58
Aschner (2012) 0.18 (0.01, 3.72) 0.64
Bergenstal (2010) 0.33 (0.01, 8.07) 0.58
Henry (2014) 3.01 (0.12, 73.73) 0.58
Lavalle-Gonzalez (2013) 6.02 (0.25, 147.32) 0.58
NCT00094757 0.81 (0.03, 19.70) 0.58
NCT01189890 0.33 (0.01, 7.97) 0.58
Russell-Jones (2012) 0.83 (0.03, 20.35) 0.58
Schernthaner (2013) 0.33 (0.01, 8.14) 0.58
Seck (2010) 2.98 (0.12, 72.99) 0.58
Vilsboll (2010) 0.33 (0.01, 8.08) 0.58
Williams-Herman (2010) 0.33 (0.01, 7.98) 0.58
.00679 1 147
58
eFigure 7A GLP-1 vs Control on MACE
Study %
Buse 2004 0.24 (0.02, 2.73) 0.04

DeFronzo 2005 0.25 (0.02, 2.79) 0.04
Kendall 2005 0.59 (0.20, 1.77) 0.20
NCT00603239 1.48 (0.06, 36.92) 0.02
NCT00701935 0.16 (0.01, 3.51) 0.03
Buse 2011 0.44 (0.04, 4.93) 0.04
Marre 2009 0.24 (0.04, 1.47) 0.07
Russell-Jones 2009 0.99 (0.09, 11.05) 0.04
Zinman 2009 1.49 (0.06, 36.64) 0.02
Raz 2012 0.50 (0.03, 8.06) 0.03
NCT00976391 1.74 (0.50, 6.02) 0.16
NCT01098539 0.36 (0.09, 1.37) 0.13
Davies 2009 2.97 (0.12, 73.77) 0.02
Gallwitz 2011 2.88 (0.12, 71.27) 0.02
Heine 2005 1.59 (0.38, 6.71) 0.12
Nauck 2007 2.00 (0.67, 5.94) 0.20
NCT00360334 0.98 (0.14, 7.10) 0.06
Bergenstal 2010 0.16 (0.01, 2.79) 0.03
Diamant 2012 2.88 (0.12, 71.17) 0.02
NCT00935532 0.99 (0.14, 7.06) 0.06
Russell-Jones 2012 0.13 (0.01, 2.72) 0.03
Garber 2011 0.50 (0.07, 3.54) 0.06
Nauck 2009 1.00 (0.20, 5.00) 0.09
Pratley 2010 0.73 (0.12, 4.43) 0.07
Russell-Jones 2009 0.40 (0.08, 2.07) 0.09
Seino 2010 0.49 (0.10, 2.45) 0.09
Marre 2009 2.35 (0.12, 45.67) 0.03
Harmony 0.78 (0.68, 0.90) 12.26
REWIND 0.88 (0.79, 0.99) 18.91
EXSCEL 0.91 (0.83, 1.00) 27.74
LEADER 0.87 (0.78, 0.97) 20.26
ELIXA 1.02 (0.89, 1.17) 12.87
SUSTAIN-6 0.74 (0.58, 0.95) 3.96
PIONEER 6 0.79 (0.57, 1.11) 2.17
.0062 1 161
59
eFigure 7B GLP-1 vs Control on CVD
Study %
Ahrén 2014 0.67 (0.07, 6.48) 0.11

Ahrén 2014 0.33 (0.02, 5.36) 0.08
Rosenstock 2014 (2) 2.97 (0.12, 73.18) 0.06
Leiter 2014 (6) 0.99 (0.14, 7.07) 0.15
Reusch 2014 (7) 0.50 (0.04, 5.57) 0.10
Weissman 2014 (9) 0.48 (0.10, 2.37) 0.23
Home 2015 (10) 1.02 (0.14, 7.31) 0.15
Home 2015 (10) 0.85 (0.08, 9.44) 0.10
Inagaki 2012 (67) 2.97 (0.12, 73.37) 0.06
Blonde 2015 (11) 0.07 (0.00, 1.38) 0.07
NCT01064687 (15) 0.76 (0.03, 18.72) 0.06
Giorgino 2015 (16) 0.48 (0.03, 7.70) 0.08
Weinstock 2015 (18) 0.29 (0.02, 4.67) 0.08
Diamant 2014 (26) 3.21 (0.13, 79.09) 0.06
Bergenstal 2009 (27) 0.66 (0.03, 16.38) 0.06
Kendall 2005 (35) 0.17 (0.01, 4.16) 0.06
Nauck 2007 (36) 1.97 (0.18, 21.84) 0.10
Buse 2011 (58) 0.29 (0.01, 7.30) 0.06
Pratley 2011 (69) 0.10 (0.00, 2.04) 0.06
Russell-Jones 2009 (78) 0.20 (0.01, 4.19) 0.06
Russell-Jones 2009 (78) 0.10 (0.00, 2.05) 0.06
Riddle 2013 (104) 1.53 (0.06, 37.87) 0.06
Pinget 2013 (109) 0.17 (0.01, 4.08) 0.06
Riddle 2013 (110) 0.33 (0.01, 8.19) 0.06
Rosenstock 2016 (135) 1.00 (0.09, 11.06) 0.10
Harmony 0.93 (0.73, 1.19) 9.76
REWIND 0.91 (0.78, 1.06) 24.77
EXSCEL 0.88 (0.76, 1.02) 26.92
LEADER 0.78 (0.66, 0.93) 19.82
ELIXA 0.98 (0.78, 1.22) 11.65
SUSTAIN-6 0.98 (0.65, 1.48) 3.44
PIONEER 6 0.49 (0.27, 0.92) 1.55
.00367 1 273
60
eFigure 7C GLP-1 vs Control on MI
Study %
Ahmann A 3.00 (0.12, 73.25) 0.05

Ahrén B (GetGoal-M) 0.67 (0.06, 7.31) 0.08
Ahrén B (HARMONY-3) 0.84 (0.16, 4.24) 0.18
Ahrén B (HARMONY-3) 2.50 (0.49, 12.79) 0.18
Ahrén B (HARMONY-3) s3 2.54 (0.50, 13.00) 0.18
Araki E s5 2.98 (0.12, 72.75) 0.05
AWARD-5 0.37 (0.06, 2.22) 0.14
AWARD-5 0.67 (0.11, 3.96) 0.15
Bailey T S (LIRA-SWITCH) 3.03 (0.12, 73.93) 0.05
Blonde L (AWARD-4) 0.13 (0.03, 0.59) 0.21
Buse JB 0.30 (0.01, 7.23) 0.04
Buse JB (Exendin-4) 0.48 (0.03, 7.68) 0.06
Charbonnel B 0.33 (0.01, 8.13) 0.04
Davies MJ (LIRA RENAL) 1.96 (0.18, 21.34) 0.08
Davies MJ (HEELA) 2.95 (0.12, 71.67) 0.05
Fonseca VA (GetGoal-Mono) 0.17 (0.01, 4.16) 0.05
Garber A (LEAD-3 Mono) 0.75 (0.13, 4.44) 0.15
Giorgino F (AWARD-2) 1.44 (0.15, 13.80) 0.09
Gough SCL (DUAL-I) 1.00 (0.06, 15.90) 0.06
Henry R 1.30 (0.05, 31.51) 0.05
Hollander P (T-Emerge 7) 2.88 (0.12, 70.12) 0.05
Home PD (HARMONY 5) 0.42 (0.03, 6.73) 0.06
Home PD (HARMONY 5) 0.51 (0.05, 5.60) 0.08
Kaku K 1.48 (0.16, 14.07) 0.09
Leiter LA 0.49 (0.05, 5.41) 0.09
Meneilly GS (GetGoal-O) 0.33 (0.01, 8.03) 0.04
Nauck MA ( LEAD-2) 0.67 (0.17, 2.65) 0.25
Nauck MA ( LEAD-2) 2.19 (0.12, 38.58) 0.06
Nauck MA 0.87 (0.04, 17.78) 0.05
Nauck MA (HARMONY 2) 0.10 (0.00, 2.09) 0.03
Nauck MA 2.45 (0.48, 12.51) 0.18
NCT00359762 (EUREXA) 0.40 (0.08, 2.04) 0.18
NCT00360334 2.95 (0.12, 71.67) 0.05
NCT00434954 2.87 (0.12, 69.93) 0.05
NCT00614120 1.00 (0.04, 24.36) 0.05
NCT00641056 (DURATION 3) 2.87 (0.12, 70.13) 0.05
NCT00960661 0.21 (0.01, 4.41) 0.05
NCT01272232 1.00 (0.10, 9.59) 0.09
NCT01648582 1.50 (0.06, 36.77) 0.05
NCT01652729 0.11 (0.00, 2.75) 0.02
NCT02152371 3.00 (0.12, 73.06) 0.05
Pinget M (GetGoal-P) 0.50 (0.03, 7.92) 0.06
Pratley RE (T-Emerge 6) 1.58 (0.06, 38.65) 0.05
Pratley RE 2.46 (0.12, 51.04) 0.05
Reusch J (HARMONY 1) 2.01 (0.18, 21.97) 0.08
Riddle MC (GetGoal-Duo-1) 0.20 (0.01, 4.14) 0.05
Rosenstock J 2.96 (0.31, 28.27) 0.09
Russell-Jones D (DURATION 4) 0.22 (0.01, 5.36) 0.05
Seino Y 0.34 (0.01, 8.30) 0.04
Umpierrez G (AWARD-3) 1.49 (0.06, 36.56) 0.05
Weissman P N (HARMONY 4) 1.12 (0.29, 4.28) 0.26
Yu M (AWARD) 0.76 (0.03, 18.57) 0.05
Yu M (AWARD) 1.53 (0.06, 37.24) 0.05
Yu Pan C (GetGoal-M-Asia) 2.97 (0.12, 72.45) 0.05
Harmony 0.75 (0.61, 0.90) 12.47
REWIND 0.96 (0.79, 1.15) 13.38
EXSCEL 0.97 (0.85, 1.10) 28.37
LEADER 0.86 (0.73, 1.00) 19.04
ELIXA 1.03 (0.87, 1.22) 16.50
SUSTAIN-6 0.81 (0.57, 1.16) 3.74
PIONEER 6 1.18 (0.73, 1.90) 2.06
1.0e-04 1 10000
61
eFigure 7D GLP-1 vs Control on Stroke
Study %
Ahrén B (HARMONY-3) s3 0.67 (0.06, 7.30) 0.16

Ahrén B (HARMONY-3) s3 5.00 (0.24, 103.71) 0.10
Ahrén B (HARMONY-3) s3 5.08 (0.25, 105.43) 0.10
Araki E s5 6.96 (0.36, 133.81) 0.10
AWARD-5 s7 1.25 (0.06, 25.96) 0.10
AWARD-5 s7 2.22 (0.11, 46.15) 0.10
Bailey T S (LIRA-SWITCH) s8 0.34 (0.01, 8.21) 0.08
Bergenstal RM (DURATION-2) s10 0.35 (0.01, 8.43) 0.08
Blonde L (AWARD-4) s12 0.76 (0.13, 4.49) 0.29
D’Alessio D s17 1.01 (0.14, 7.11) 0.24
Davies MJ (LIRA RENAL) s18 2.94 (0.12, 71.46) 0.09
Dungan KM (AWARD-8) s20 0.76 (0.03, 18.49) 0.09
Ferdinand KC s21 0.17 (0.01, 4.04) 0.10
Gao Y s23 0.33 (0.01, 8.07) 0.08
Giorgino F (AWARD-2) s25 0.96 (0.09, 10.56) 0.16
Henry R s27 0.14 (0.01, 3.50) 0.11
Home PD (HARMONY 5) s29 0.14 (0.01, 3.46) 0.11
Home PD (HARMONY 5) s29 0.15 (0.01, 2.81) 0.11
Inagaki N s30 2.96 (0.12, 72.21) 0.09
Kaku K s31 0.10 (0.00, 2.05) 0.04
Kaku K s31 1.51 (0.06, 36.70) 0.09
Leiter LA s32 0.49 (0.09, 2.67) 0.32
Meneilly GS (GetGoal-O) s35 0.33 (0.01, 8.03) 0.08
Nauck MA ( LEAD-2) s36 1.01 (0.04, 24.60) 0.09
Nauck MA ( LEAD-2) s36 0.50 (0.02, 12.32) 0.09
Nauck MA (HARMONY 2) s39 0.50 (0.03, 7.99) 0.12
Nauck MA s40 0.20 (0.01, 4.06) 0.10
NCT00359762 (EUREXA) s41 6.96 (0.36, 134.33) 0.10
NCT00614120 s41 1.00 (0.04, 24.36) 0.09
NCT00641056 (DURATION 3) s41 2.87 (0.12, 70.13) 0.09
NCT00935532 s41 3.19 (0.13, 78.03) 0.09
NCT01117350 s41 1.01 (0.14, 7.13) 0.24
NCT01272232 s41 0.67 (0.06, 7.34) 0.16
NCT01388361 s41 0.34 (0.01, 8.16) 0.08
NCT01644500 s41 1.54 (0.06, 37.75) 0.09
NCT01648582 s41 3.51 (0.18, 67.64) 0.10
NCT01652729 s41 2.03 (0.08, 49.36) 0.09
NCT01652729 s41 1.02 (0.04, 24.76) 0.09
NCT02008682 s41 0.34 (0.01, 8.17) 0.08
NCT02152371 3.00 (0.12, 73.06) 0.09
Pinget M (GetGoal-P) s43 1.50 (0.06, 36.62) 0.09
Raz I s46 1.45 (0.06, 35.32) 0.09
Riddle MC (GetGoal-Duo-1) s48 3.00 (0.12, 73.25) 0.09
Russell-Jones D (DURATION 4) s53 0.33 (0.01, 8.08) 0.08
Seino Y s54 0.11 (0.00, 2.72) 0.04
Seino Y s55 0.34 (0.01, 8.30) 0.08
Seino Y (GetGoal-L-Asia) s56 5.10 (0.25, 105.31) 0.10
Umpierrez G (AWARD-3) s57 1.49 (0.06, 36.56) 0.09
Weissman P N (HARMONY 4) s58 2.40 (0.12, 49.72) 0.10
Xu W (CONFIDENCE) s59 0.96 (0.06, 15.16) 0.12
Xu W (CONFIDENCE) s59 0.97 (0.06, 15.38) 0.12
Yu M (AWARD) s60 0.76 (0.03, 18.57) 0.09
Yu M (AWARD) s60 1.53 (0.06, 15.71) 0.12
Yu Pan C (GetGoal-M-Asia) s61 0.99 (0.06, 15.71) 0.12
Harmony 0.86 (0.66, 1.14) 12.22
REWIND 0.76 (0.62, 0.94) 21.08
EXSCEL 0.85 (0.70, 1.03) 24.47
LEADER 0.86 (0.71, 1.06) 22.73
ELIXA 1.12 (0.79, 1.58) 7.60
SUSTAIN-6 0.65 (0.41, 1.03) 4.30
PIONEER 6 0.74 (0.35, 1.57) 1.62
1.0e-04 1 10000
62
eFigure 7E GLP-1 vs Control on HF
Study %
Ahrén 2014 7.04 (0.29, 172.32) 0.08

Lepore 2016 (4) 0.25 (0.01, 5.98) 0.08
Leiter 2014 (6) 0.33 (0.01, 8.05) 0.08
Reusch 2014 (7) 0.34 (0.01, 8.17) 0.08
Nauck 2016 (8) 0.50 (0.07, 3.53) 0.20
Weissman 2014 (9) 0.48 (0.07, 3.37) 0.20
Home 2015 (10) 0.13 (0.01, 2.37) 0.09
Inagaki 2012 (67) 2.96 (0.12, 72.21) 0.08
Blonde 2015 (11) 0.50 (0.03, 8.02) 0.10
NCT01648582 (12) 1.48 (0.06, 36.20) 0.08
NCT01064687 (15) 0.76 (0.03, 18.54) 0.08
Giorgino 2015 (16) 1.44 (0.15, 13.80) 0.15
Umpierrez 2014 (17) 0.25 (0.02, 2.73) 0.13
Diamant 2014 (26) 1.06 (0.07, 16.93) 0.10
Gallwitz 2012 (31) 2.98 (0.12, 73.01) 0.08
Jaiswal 2015 (40) 1.09 (0.07, 16.41) 0.10
NCT00701935 (41) 0.29 (0.01, 6.86) 0.08
Davies 2009 (50) 0.33 (0.01, 7.96) 0.08
Pratley 2011 (69) 2.46 (0.12, 51.04) 0.08
Lind 2015 (73) 0.31 (0.01, 7.53) 0.08
Nauck 2009 (75) 2.51 (0.12, 52.15) 0.08
Garber 2011 (76) 1.50 (0.06, 36.61) 0.08
Zinman 2009 (77) 1.48 (0.06, 36.22) 0.08
Davies 2016 (80) 4.96 (0.24, 102.48) 0.08
NCT00614120 (84) 1.00 (0.04, 24.36) 0.08
NCT01907854 (86) 3.03 (0.12, 73.93) 0.08
Riddle 2013 (104) 1.53 (0.06, 37.40) 0.08
Riddle 2013 (110) 3.00 (0.12, 73.25) 0.08
Rosenstock 2016 (135) 0.40 (0.02, 8.26) 0.08
Harmony 0.71 (0.53, 0.94) 9.36
REWIND 0.93 (0.77, 1.12) 21.89
EXSCEL 0.94 (0.78, 1.13) 22.36
LEADER 0.87 (0.73, 1.05) 23.25
ELIXA 0.96 (0.75, 1.23) 12.56
SUSTAIN-6 1.11 (0.77, 1.61) 5.65
PIONEER 6 0.86 (0.48, 1.55) 2.24
.0058 1 172
63
eFigure 7F GLP-1 vs Control on UA
Study %
Harmony 0.88 (0.56, 1.38) 8.33
REWIND 1.14 (0.84, 1.54) 18.44
EXSCEL 1.14 (0.92, 1.41) 37.16
LEADER 0.98 (0.76, 1.26) 26.50
ELIXA 1.11 (0.47, 2.62) 2.29
SUSTAIN-6 0.82 (0.47, 1.44) 5.40
PIONEER 6 1.56 (0.60, 4.01) 1.88
.249 1 4.01
64
eFigure 7G GLP-1 vs Control on AF
Study %
Ahrén 2014 0.33 (0.01, 8.15) 0.23

Rosenstock 2014 4.93 (0.24, 102.23) 0.26
Lepore 2016 0.25 (0.01, 5.98) 0.23
Leiter 2014 3.95 (0.44, 35.11) 0.49
Reusch 2014 3.02 (0.12, 73.54) 0.23
Nauck 2016 1.52 (0.06, 37.04) 0.23
Weissman 2014 3.35 (0.17, 64.68) 0.27
Home 2015 4.33 (0.18, 106.01) 0.23
Blonde 2015 2.52 (0.12, 52.35) 0.25
NCT01064687 0.25 (0.04, 1.77) 0.62
Umpierrez 2014 0.17 (0.01, 4.06) 0.23
Weinstock 2015 0.88 (0.04, 21.50) 0.23
Grunberger 2012 3.30 (0.14, 77.95) 0.23
Gallwitz 2012 0.99 (0.14, 7.03) 0.61
Nauck 2007 0.33 (0.01, 7.98) 0.23
Heine 2005 2.84 (0.12, 69.44) 0.23
Jaiswal 2015 0.22 (0.01, 4.29) 0.26
NCT00701935 0.29 (0.01, 6.86) 0.23
Inagaki 2012 2.96 (0.12, 72.21) 0.23
Lind 2015 0.13 (0.01, 2.54) 0.27
Nauck 2009 1.00 (0.09, 11.02) 0.41
Garber 2011 0.17 (0.01, 4.07) 0.23
Marso 2016 0.92 (0.69, 1.22) 29.54
Zang 2016 0.34 (0.01, 8.17) 0.23
von Scholten 2016 3.00 (0.13, 71.00) 0.23
Charbonnel 2013 0.33 (0.01, 8.13) 0.23
Pfeffer 2015 0.77 (0.45, 1.32) 8.02
Bolli 2014 0.50 (0.07, 3.50) 0.62
Riddle 2013A 0.17 (0.01, 4.16) 0.23
Ahrén 2013 1.00 (0.04, 24.53) 0.23
Riddle 2013B 0.33 (0.01, 8.14) 0.23
Marso 2016 0.86 (0.59, 1.25) 16.94
Hernandez 2018 0.82 (0.64, 1.06) 37.06
.00679 1 147
65
eFigure 8A GLP-1 vs Placebo on MACE
Study %
Buse 2004 0.24 (0.02, 2.73) 0.05

DeFronzo 2005 0.25 (0.02, 2.79) 0.05
Kendall 2005 0.59 (0.20, 1.77) 0.23
NCT00603239 1.48 (0.06, 36.92) 0.03
NCT00701935 0.16 (0.01, 3.51) 0.03
Buse 2011 0.44 (0.04, 4.93) 0.05
Marre 2009 0.24 (0.04, 1.47) 0.09
Russell-Jones 2009 0.99 (0.09, 11.05) 0.05
Zinman 2009 1.49 (0.06, 36.64) 0.03
Raz 2012 0.50 (0.03, 8.06) 0.04
Harmony 0.78 (0.68, 0.90) 12.97
REWIND 0.88 (0.79, 0.99) 19.12
EXSCEL 0.91 (0.83, 1.00) 26.48
LEADER 0.87 (0.78, 0.97) 20.31
ELIXA 1.02 (0.89, 1.17) 13.57
SUSTAIN-6 0.74 (0.58, 0.95) 4.45
PIONEER 6 0.79 (0.57, 1.11) 2.47
.00759 1 132
66
eFigure 8B GLP-1 vs Placebo on CVD
Study %
Ahrén 2014 (1) 0.33 (0.02, 5.36) 0.08

Reusch 2014 (7) 0.50 (0.04, 5.57) 0.10
Home 2015 (10) 0.85 (0.08, 9.44) 0.10
NCT01064687 (15) 0.76 (0.03, 18.72) 0.06
Kendall 2005 (35) 0.17 (0.01, 4.16) 0.06
Buse 2011 (58) 0.29 (0.01, 7.30) 0.06
Russell-Jones 2009 (78) 0.10 (0.00, 2.05) 0.06
Riddle 2013 (104) 1.53 (0.06, 37.87) 0.06
Pinget 2013 (109) 0.17 (0.01, 4.08) 0.06
Riddle 2013 (110) 0.33 (0.01, 8.19) 0.06
Harmony 0.93 (0.73, 1.19) 9.90
REWIND 0.91 (0.78, 1.06) 25.13
EXSCEL 0.88 (0.76, 1.02) 27.31
LEADER 0.78 (0.66, 0.93) 20.10
ELIXA 0.98 (0.78, 1.22) 11.81
SUSTAIN-6 0.98 (0.65, 1.48) 3.49
PIONEER 6 0.49 (0.27, 0.92) 1.57
.00465 1 215
67
eFigure 8C GLP-1 vs Placebo on MI
Study %
Ahmann A 3.00 (0.12, 73.25) 0.05

Ahrén B (GetGoal-M) 0.67 (0.06, 7.31) 0.08
Ahrén B (HARMONY-3) 0.84 (0.16, 4.24) 0.18
Buse JB 0.30 (0.01, 7.23) 0.04
Buse JB (Exendin-4) 0.48 (0.03, 7.68) 0.06
Henry R 1.30 (0.05, 31.51) 0.05
Hollander P (T-Emerge 7) 2.88 (0.12, 70.12) 0.05
Home PD (HARMONY 5) 0.42 (0.03, 6.73) 0.07
Nauck MA ( LEAD-2) 2.19 (0.12, 38.58) 0.06
Nauck MA 0.87 (0.04, 17.78) 0.05
Nauck MA (HARMONY 2) 0.10 (0.00, 2.09) 0.03
NCT01272232 1.00 (0.10, 9.59) 0.09
NCT01652729 0.11 (0.00, 2.75) 0.02
NCT02152371 3.00 (0.12, 73.06) 0.05
Reusch J (HARMONY 1) 2.01 (0.18, 21.97) 0.08
Seino Y 0.34 (0.01, 8.30) 0.04
Yu M (AWARD) 0.76 (0.03, 18.57) 0.05
Yu M (AWARD) 1.53 (0.06, 37.24) 0.05
Harmony 0.75 (0.61, 0.90) 12.86
REWIND 0.96 (0.79, 1.15) 13.80
EXSCEL 0.97 (0.85, 1.10) 29.26
LEADER 0.86 (0.73, 1.00) 19.64
ELIXA 1.03 (0.87, 1.22) 17.01
SUSTAIN-6 0.81 (0.57, 1.16) 3.85
PIONEER 6 1.18 (0.73, 1.90) 2.13
1.0e-04 1 10000
68
eFigure 8D GLP-1 vs Placebo on Stroke
Study %
Ahrén B (HARMONY-3) s3 0.67 (0.06, 7.30) 0.16

AWARD-5 s7 1.25 (0.06, 25.96) 0.10
Dungan KM (AWARD-8) s20 0.76 (0.03, 18.49) 0.09
Ferdinand KC s21 0.17 (0.01, 4.04) 0.11
Gao Y s23 0.33 (0.01, 8.07) 0.08
Henry R s27 0.14 (0.01, 3.50) 0.11
Home PD (HARMONY 5) s29 0.14 (0.01, 3.46) 0.11
Nauck MA ( LEAD-2) s36 0.50 (0.02, 12.32) 0.09
Nauck MA (HARMONY 2) s39 0.50 (0.03, 7.99) 0.12
NCT01272232 s41 0.67 (0.06, 7.34) 0.16
NCT01652729 s41 1.02 (0.04, 24.76) 0.09
NCT02152371 3.00 (0.12, 73.06) 0.09
Raz I s46 1.45 (0.06, 35.32) 0.09
Seino Y s54 0.11 (0.00, 2.72) 0.04
Seino Y s55 0.34 (0.01, 8.30) 0.08
Yu M (AWARD) s60 0.76 (0.03, 18.57) 0.09
Yu M (AWARD) s60 1.53 (0.06, 15.71) 0.12
Harmony 0.86 (0.66, 1.14) 12.69
REWIND 0.76 (0.62, 0.94) 21.89
EXSCEL 0.85 (0.70, 1.03) 25.42
LEADER 0.86 (0.71, 1.06) 23.61
ELIXA 1.12 (0.79, 1.58) 7.89
SUSTAIN-6 0.65 (0.41, 1.03) 4.47
PIONEER 6 0.74 (0.35, 1.57) 1.68
1.0e-04 1 10000
69
eFigure 8E GLP-1 vs Placebo on HF
Study %
Ahrén 2014 (1) 1.01 (0.04, 24.60) 0.08

Lepore 2016 (4) 0.25 (0.01, 5.98) 0.08
Reusch 2014 (7) 0.34 (0.01, 8.17) 0.08
Nauck 2016 (8) 0.50 (0.07, 3.53) 0.21
Home 2015 (10) 0.14 (0.01, 3.46) 0.08
NCT01064687 (15) 0.76 (0.03, 18.54) 0.08
NCT00701935 (41) 0.29 (0.01, 6.86) 0.08
Lind 2015 (73) 0.31 (0.01, 7.53) 0.08
Nauck 2009 (75) 0.84 (0.04, 17.42) 0.08
Zinman 2009 (77) 1.48 (0.06, 36.22) 0.08
Davies 2016 (80) 4.96 (0.24, 102.48) 0.09
Riddle 2013 (104) 1.53 (0.06, 37.40) 0.08
Riddle 2013 (110) 3.00 (0.12, 73.25) 0.08
Harmony 0.71 (0.53, 0.94) 9.51
REWIND 0.93 (0.77, 1.12) 22.24
EXSCEL 0.94 (0.78, 1.13) 22.72
LEADER 0.87 (0.73, 1.05) 23.63
ELIXA 0.96 (0.75, 1.23) 12.76
SUSTAIN-6 1.11 (0.77, 1.61) 5.74
PIONEER 6 0.86 (0.48, 1.55) 2.27
.00583 1 171
70
eFigure 8F GLP-1 vs Placebo on AF
Study %
Lepore 2016 0.25 (0.01, 5.98) 0.24

Reusch 2014 3.02 (0.12, 73.54) 0.24
Nauck 2016 1.52 (0.06, 37.04) 0.24
Home 2015 1.28 (0.05, 31.18) 0.24
NCT01064687 0.25 (0.04, 1.77) 0.64
Grunberger 2012 3.30 (0.14, 77.95) 0.25
NCT00701935 0.29 (0.01, 6.86) 0.24
Lind 2015 0.13 (0.01, 2.54) 0.28
Nauck 2009 0.84 (0.04, 17.42) 0.27
Marso 2016 0.92 (0.69, 1.22) 30.89
von Scholten 2016 3.00 (0.13, 71.00) 0.24
Pfeffer 2015 0.77 (0.45, 1.32) 8.38
Bolli 2014 0.50 (0.07, 3.50) 0.64
Riddle 2013A 0.17 (0.01, 4.16) 0.24
Ahrén 2013 1.00 (0.04, 24.53) 0.24
Riddle 2013B 0.33 (0.01, 8.14) 0.24
Marso 2016 0.86 (0.59, 1.25) 17.72
Hernandez 2018 0.82 (0.64, 1.06) 38.75
.00697 1 143
71
eFigure 9 Albiglutide vs Control on cardiovascular outcomes
Study %
MACE
Fisher 2015 (8 TRIALS) 0.99 (0.65, 1.49) 15.10
CVOT 0.78 (0.68, 0.90) 84.90
Subtotal (I-squared = 12.2%, p = 0.286) 0.81 (0.68, 0.96) 100.00
.
CVD
Fisher 2015 (8 TRIALS) 1.06 (0.55, 2.06) 12.04
CVOT 0.93 (0.73, 1.19) 87.96
.
MI
Fisher 2015 (8 TRIALS) 0.96 (0.52, 1.76) 9.24
CVOT 0.75 (0.61, 0.90) 90.76
.
Stroke
Fisher 2015 (8 TRIALS) 1.02 (0.45, 2.33) 9.95
CVOT 0.86 (0.66, 1.14) 90.05
.
HF
Fisher 2015 (8 TRIALS) 0.74 (0.34, 1.62) 11.87
CVOT 0.71 (0.53, 0.94) 88.13
.
UA
Fisher 2015 (8 TRIALS) 0.77 (0.25, 2.37) 13.85
CVOT 0.88 (0.56, 1.38) 86.15
.
.25 1 4
72
eFigure 10 Dulaglutide vs Control on cardiovascular outcomes
Study %
MACE
Ferdinand 2016(8 TRIALS) 0.60 (0.33, 1.08) 19.95
CVOT 0.88 (0.79, 0.99) 80.05
.
CVD
CVOT 0.91 (0.78, 1.06) 88.13
.
MI
CVOT 0.96 (0.79, 1.15) 62.19
.
Stroke
CVOT 0.76 (0.62, 0.94) 84.10
.
UA
CVOT 1.14 (0.84, 1.54) 68.19
.
.05 1 20
73
eFigure 11A Exenatide vs Control on MACE
Study %
Buse 2004 0.24 (0.02, 2.73) 0.14

DeFronzo 2005 0.25 (0.02, 2.79) 0.14
Kendall 2005 0.59 (0.20, 1.77) 0.69
NCT00603239 1.48 (0.06, 36.92) 0.08
NCT00701935 0.16 (0.01, 3.51) 0.09
Buse 2011 0.44 (0.04, 4.93) 0.14
Davies 2009 2.97 (0.12, 73.77) 0.08
Gallwitz 2011 2.88 (0.12, 71.27) 0.08
Heine 2005 1.59 (0.38, 6.71) 0.40
Nauck 2007 2.00 (0.67, 5.94) 0.71
NCT00360334 0.98 (0.14, 7.10) 0.21
Bergenstal 2010 0.16 (0.01, 2.79) 0.10
Diamant 2012 2.88 (0.12, 71.17) 0.08
NCT00935532 0.99 (0.14, 7.06) 0.22
Russell-Jones 2012 0.13 (0.01, 2.72) 0.09
EXSCEL 0.91 (0.83, 1.00) 96.72
.0062 1 161
74
eFigure 11B Exenatide vs Control on CVD
Study %
Diamant 2014 (26) 3.21 (0.13, 79.09) 0.21
Bergenstal 2009 (27) 0.66 (0.03, 16.38) 0.21
Kendall 2005 (35) 0.17 (0.01, 4.16) 0.21
Nauck 2007 (36) 1.97 (0.18, 21.84) 0.37
Buse 2011 (58) 0.29 (0.01, 7.30) 0.21
EXSCEL 0.88 (0.76, 1.02) 98.80
.00686 1 146
75
eFigure 11C Exenatide vs Control on MI
Study %
Davies MJ (HEELA) 2.95 (0.12, 71.67) 0.16
Nauck MA 2.45 (0.48, 12.51) 0.61
NCT00359762 (EUREXA) 0.40 (0.08, 2.04) 0.62
NCT00360334 2.95 (0.12, 71.67) 0.16
NCT00434954 2.87 (0.12, 69.93) 0.16
NCT00641056 (DURATION 3) 2.87 (0.12, 70.13) 0.16
NCT00960661 0.21 (0.01, 4.41) 0.17
Russell-Jones D (DURATION 4) 0.22 (0.01, 5.36) 0.16
Buse JB 0.30 (0.01, 7.23) 0.15
Buse JB (Exendin-4) 0.48 (0.03, 7.68) 0.21
NCT01652729 0.11 (0.00, 2.75) 0.06
Yu M (AWARD) 1.53 (0.06, 37.24) 0.16
EXSCEL 0.97 (0.85, 1.10) 97.23
1.0e-04 1 10000
76
eFigure 11D Exenatide vs Control on Stroke
Study %
Inagaki N s30 2.96 (0.12, 72.21) 0.35
Nauck MA s40 0.20 (0.01, 4.06) 0.39
NCT00359762 (EUREXA) s41 6.96 (0.36, 134.33) 0.40
NCT00641056 (DURATION 3) s41 2.87 (0.12, 70.13) 0.35
NCT00935532 s41 3.19 (0.13, 78.03) 0.35
NCT01652729 s41 2.03 (0.08, 49.36) 0.34
Russell-Jones D (DURATION 4) s53 0.33 (0.01, 8.08) 0.32
Xu W (CONFIDENCE) s59 0.96 (0.06, 15.16) 0.46
Xu W (CONFIDENCE) s59 0.97 (0.06, 15.38) 0.46
Gao Y s23 0.33 (0.01, 8.07) 0.32
NCT01652729 s41 1.02 (0.04, 24.76) 0.34
Yu M (AWARD) s60 1.53 (0.06, 15.71) 0.46
EXSCEL 0.85 (0.70, 1.03) 94.85
.00744 1 134
77
eFigure 11E Exenatide vs Control on HF
Study %
Diamant 2014 (26) 1.06 (0.07, 16.93) 0.44
Gallwitz 2012 (31) 2.98 (0.12, 73.01) 0.33
Jaiswal 2015 (40) 1.09 (0.07, 16.41) 0.46
NCT00701935 (41) 0.29 (0.01, 6.86) 0.34
Davies 2009 (50) 0.33 (0.01, 7.96) 0.33
EXSCEL 0.94 (0.78, 1.13) 98.11
.0121 1 82.8
78
eFigure 11F Exenatide vs Control on UA
Study %
Bergenstal (2009) 0.34 (0.01, 8.37) 0.43
Buse (2011) 0.30 (0.01, 7.23) 0.43
Diamant (2014b) 1.98 (0.18, 21.73) 0.77
Nauck (2007) 1.96 (0.18, 21.48) 0.77
Russell-Jones (2012) 0.55 (0.02, 13.42) 0.43
EXSCEL 1.14 (0.92, 1.41) 97.15
.0122 1 81.9
79
eFigure 11G Exenatide vs Control on AF
Study %
Gallwitz 2012 0.99 (0.14, 7.03) 34.08
Nauck 2007 0.33 (0.01, 7.98) 12.77
Heine 2005 2.84 (0.12, 69.44) 12.76
Jaiswal 2015 0.22 (0.01, 4.29) 14.65
NCT00701935 0.29 (0.01, 6.86) 12.97
Inagaki 2012 2.96 (0.12, 72.21) 12.77
.011 1 90.8
80
eFigure 12A Liraglutide vs Control on MACE
Study %
Marre 2009 0.24 (0.04, 1.47) 0.36
Russell-Jones 2009 0.99 (0.09, 11.05) 0.20
Zinman 2009 1.49 (0.06, 36.64) 0.11
Garber 2011 0.50 (0.07, 3.54) 0.30
Nauck 2009 1.00 (0.20, 5.00) 0.45
Pratley 2010 0.73 (0.12, 4.43) 0.36
Russell-Jones 2009 0.40 (0.08, 2.07) 0.42
Seino 2010 0.49 (0.10, 2.45) 0.44
Marre 2009 2.35 (0.12, 45.67) 0.13
LEADER 0.87 (0.78, 0.97) 97.23
.0219 1 45.7
81
eFigure 12B Liraglutide vs Control on CVD
Study %
Pratley 2011 (69) 0.10 (0.00, 2.04) 11.85
Russell-Jones 2009 (78) 0.20 (0.01, 4.19) 11.84
Russell-Jones 2009 (78) 0.10 (0.00, 2.05) 11.82
LEADER 0.78 (0.66, 0.93) 64.49
.00465 1 215
82
eFigure 12C Liraglutide vs Control on MI
Study %
Bailey T S (LIRA-SWITCH) 3.03 (0.12, 73.93) 0.23
Charbonnel B 0.33 (0.01, 8.13) 0.21
Garber A (LEAD-3 Mono) 0.75 (0.13, 4.44) 0.75
Gough SCL (DUAL-I) 1.00 (0.06, 15.90) 0.30
Kaku K 1.48 (0.16, 14.07) 0.47
Nauck MA ( LEAD-2) 0.67 (0.17, 2.65) 1.25
NCT00614120 1.00 (0.04, 24.36) 0.23
Pratley RE 2.46 (0.12, 51.04) 0.26
Ahmann A 3.00 (0.12, 73.25) 0.23
Nauck MA ( LEAD-2) 2.19 (0.12, 38.58) 0.28
NCT01272232 1.00 (0.10, 9.59) 0.45
LEADER 0.86 (0.73, 1.00) 94.93
.01 1 100
83
eFigure 12D Liraglutide vs Control on Stroke
Study %
Bailey T S (LIRA-SWITCH) s8 0.34 (0.01, 8.21) 0.34
D’Alessio D s17 1.01 (0.14, 7.11) 0.98
Kaku K s31 0.10 (0.00, 2.05) 0.15
Kaku K s31 1.51 (0.06, 36.70) 0.37
Nauck MA ( LEAD-2) s36 1.01 (0.04, 24.60) 0.37
NCT00614120 s41 1.00 (0.04, 24.36) 0.37
NCT01117350 s41 1.01 (0.14, 7.13) 0.98
NCT01388361 s41 0.34 (0.01, 8.16) 0.34
NCT02008682 s41 0.34 (0.01, 8.17) 0.34
Nauck MA ( LEAD-2) s36 0.50 (0.02, 12.32) 0.37
NCT01272232 s41 0.67 (0.06, 7.34) 0.65
Seino Y s55 0.34 (0.01, 8.30) 0.33
LEADER 0.86 (0.71, 1.06) 94.06
1.0e-04 1 10000
84
eFigure 12E Liraglutide vs Control on HF
Study %
Pratley 2011 (69) 2.46 (0.12, 51.04) 0.35
Lind 2015 (73) 0.31 (0.01, 7.53) 0.32
Nauck 2009 (75) 2.51 (0.12, 52.15) 0.35
Garber 2011 (76) 1.50 (0.06, 36.61) 0.31
Zinman 2009 (77) 1.48 (0.06, 36.22) 0.31
Davies 2016 (80) 4.96 (0.24, 102.48) 0.35
NCT00614120 (84) 1.00 (0.04, 24.36) 0.31
NCT01907854 (86) 3.03 (0.12, 73.93) 0.32
LEADER 0.87 (0.73, 1.05) 97.37
.00976 1 102
85
eFigure 12F Liraglutide vs Control on AF
Study %
Lind 2015 0.13 (0.01, 2.54) 0.87
Nauck 2009 1.00 (0.09, 11.02) 1.31
Garber 2011 0.17 (0.01, 4.07) 0.74
Marso 2016 0.92 (0.69, 1.22) 94.86
Zang 2016 0.34 (0.01, 8.17) 0.74
von Scholten 2016 3.00 (0.13, 71.00) 0.75
Charbonnel 2013 0.33 (0.01, 8.13) 0.74
.0068 1 147
86
eFigure 13A Lixisenatide vs Control on CVD
Study %
ELIXA 0.98 (0.78, 1.22) 97.73
Riddle 2013 (104) 1.53 (0.06, 37.87) 0.48
Pinget 2013 (109) 0.17 (0.01, 4.08) 0.48
Riddle 2013 (110) 0.33 (0.01, 8.19) 0.48
Rosenstock 2016 (135) 1.00 (0.09, 11.06) 0.84
.0067 1 149
87
eFigure 13B Lixisenatide vs Control on MI
Study %
Ahrén B (GetGoal-M) 0.67 (0.06, 7.31) 0.48
Seino Y 0.34 (0.01, 8.30) 0.25
ELIXA 1.03 (0.87, 1.22) 97.77
.01 1 100
88
eFigure 13C Lixisenatide vs Control on Stroke
Study %
ELIXA 1.12 (0.79, 1.58) 94.10
.0095 1 105
89
eFigure 13D Lixisenatide vs Control on HF
Study %
Riddle 2013 (104) 1.53 (0.06, 37.40) 0.59
Riddle 2013 (110) 3.00 (0.12, 73.25) 0.59
Rosenstock 2016 (135) 0.40 (0.02, 8.26) 0.65
ELIXA 0.96 (0.75, 1.23) 98.17
.0137 1 73.2
90
eFigure 13E Lixisenatide vs Control on AF
Study %
Pfeffer 2015 0.77 (0.45, 1.32) 86.00
Bolli 2014 0.50 (0.07, 3.50) 6.61
Riddle 2013A 0.17 (0.01, 4.16) 2.46
Ahrén 2013 1.00 (0.04, 24.53) 2.46
Riddle 2013B 0.33 (0.01, 8.14) 2.46
.00697 1 143
91
eFigure 14A SGLT-2 vs Control on MACE
Study %
Lavalle-González FJ 2013 0.75 (0.08, 7.22) 0.08

Wilding JPH 2013 0.50 (0.03, 8.00) 0.05
Stenlof K 2013 0.49 (0.03, 7.85) 0.05
Forst T 2014 0.50 (0.03, 8.14) 0.05
Yale JF 2014 0.59 (0.17, 1.99) 0.27
Bode B 2015 1.50 (0.40, 5.59) 0.23
NCT02025907(2016) 0.20 (0.01, 4.14) 0.04
Roden M(2013) 0.43 (0.06, 3.05) 0.11
Rosenstock J (2014) 1.00 (0.09, 11.07) 0.07
Kovacs CS(2014) 1.49 (0.06, 36.85) 0.04
Barnett AH (2014) 0.76 (0.24, 2.37) 0.31
Haring HU(2014) 0.72 (0.34, 1.51) 0.73
Rosenstock J (2015) 5.38 (0.68, 42.40) 0.10
Strojek K (2011) 0.32 (0.02, 5.20) 0.05
Henry RR(2012) 0.48 (0.03, 7.75) 0.05
Rosenstock J(2012) 1.49 (0.06, 36.86) 0.04
Ljunggren O(2012) 3.03 (0.12, 75.48) 0.04
Wilding JP(2012) 0.21 (0.03, 1.26) 0.12
Bailey CJ(2013) 0.30 (0.08, 1.12) 0.23
Bailey CJ(2014) 1.67 (0.09, 31.37) 0.05
Leiter LA(2014) 1.00 (0.32, 3.14) 0.31
Kaku K(2014) 0.17 (0.01, 4.10) 0.05
NCT00528372(2015) 1.67 (0.09, 31.37) 0.05
Mathieu C (2015) 3.02 (0.12, 74.66) 0.04
Cefalu WT(2015) 1.34 (0.30, 6.03) 0.18
NCT01095653(2016) 1.52 (0.16, 14.79) 0.08
NCT00663260(2016) 0.25 (0.02, 2.75) 0.07
NCT00683878(2017) 1.49 (0.06, 36.86) 0.04
CANVAS 0.86 (0.75, 0.97) 24.64
CREDENCE 0.80 (0.67, 0.95) 13.37
DECLARE–TIMI 58 0.93 (0.84, 1.03) 39.21
EMPA-REG 0.86 (0.74, 0.99) 19.24
.01 1 100
92
eFigure 14B SGLT-2 vs Control on CVD
Study %
Neal 0.64 (0.29, 1.39) 1.24

Inagaki 0.75 (0.03, 18.34) 0.07
Inagaki 0.50 (0.03, 7.94) 0.10
Bode 1.49 (0.06, 36.53) 0.07
Schernthaner [45] 2.01 (0.18, 22.02) 0.13
Cefalu 0.17 (0.01, 4.06) 0.07
Henry (Study 1) 2.97 (0.12, 72.49) 0.07
Henry (Study 2) 0.33 (0.01, 8.02) 0.07
Henry (Study 2) 0.32 (0.01, 7.73) 0.07
Cefalu 2.02 (0.18, 22.17) 0.13
Leiter 2.01 (0.18, 22.07) 0.13
Bailey 1.68 (0.08, 34.84) 0.08
Kohan 0.50 (0.03, 7.90) 0.10
Wilding 2.23 (0.12, 43.05) 0.09
Nauck 0.20 (0.01, 4.16) 0.08
Tikkanen 1.48 (0.06, 36.10) 0.07
Ha¨ring 1.53 (0.06, 37.50) 0.07
Roden 0.17 (0.01, 4.16) 0.07
Roden 0.16 (0.01, 4.03) 0.07
Lewin 1.49 (0.06, 36.31) 0.07
Kovacs 0.99 (0.09, 10.85) 0.13
Ridderstra°le 0.51 (0.05, 5.58) 0.13
CANVAS 0.87 (0.72, 1.06) 20.41
CREDENCE 0.78 (0.61, 1.00) 12.50
DECLARE–TIMI 58 0.98 (0.82, 1.17) 24.17
DAPA-HF 0.82 (0.69, 0.98) 24.80
EMPA-REG 0.62 (0.49, 0.77) 14.95
.00674 1 148
93
eFigure 14C SGLT-2 vs Control on MI
Study %
Wildinga [41] 0.17 (0.01, 4.07) 0.08

Yale [42] 0.50 (0.10, 2.44) 0.34
Inagaki [33] 0.75 (0.05, 11.92) 0.11
Bode [44] 0.83 (0.20, 3.44) 0.42
Schernthaner [45] 0.20 (0.01, 4.16) 0.09
Cefalu [46] 0.66 (0.15, 2.95) 0.38
Kaku [48] 0.73 (0.03, 17.68) 0.08
List [49] 0.59 (0.02, 14.28) 0.08
Henry (Study 1) [56] 3.11 (0.13, 75.83) 0.08
Henry (Study 2) [56] 0.48 (0.03, 7.70) 0.11
Rosenstock [57] 2.95 (0.12, 71.93) 0.08
Strojek [62] 0.32 (0.02, 5.15) 0.11
Cefalu [63] 1.01 (0.06, 16.08) 0.11
Leiterb [68] 1.51 (0.25, 8.97) 0.27
Bolinder [69] 0.16 (0.01, 3.74) 0.08
Bailey [70] 1.90 (0.09, 39.12) 0.09
Bailey [71] 0.22 (0.04, 1.32) 0.27
Kohan [72] 0.20 (0.04, 1.01) 0.33
Wilding [73] 0.21 (0.04, 1.26) 0.27
Nauck [74] 0.60 (0.14, 2.50) 0.42
Ferrannini (Study 1) 0.79 (0.03, 19.18) 0.08
Ferrannini (Study 2) [75] 0.51 (0.02, 12.45) 0.08
Rosenstock [76] 0.40 (0.03, 6.39) 0.11
Ferrannini [75] 3.33 (0.16, 68.84) 0.09
Kadowaki [77] 0.05 (0.00, 1.04) 0.09
Ha¨ring [80] 0.51 (0.03, 8.12) 0.11
Roden [81] 0.50 (0.05, 5.53) 0.15
Barnett [82] 0.15 (0.01, 3.16) 0.09
Rosenstock [83] 1.51 (0.06, 36.84) 0.08
DeFronzo [84] 2.36 (0.11, 48.78) 0.09
Merker [87] 0.48 (0.07, 3.37) 0.22
Rosenstock [88] 3.68 (0.19, 70.89) 0.10
Araki [89] 0.70 (0.03, 17.00) 0.08
Ridderstra°le [90] 0.14 (0.02, 1.17) 0.19
Amin [91] 2.50 (0.12, 51.63) 0.09
CANVAS 0.89 (0.73, 1.09) 21.20
CREDENCE 0.86 (0.64, 1.16) 9.63
DECLARE–TIMI 58 0.89 (0.77, 1.01) 46.28
EMPA-REG 0.87 (0.70, 1.09) 17.37
.00242 1 413
94
eFigure 14D SGLT-2 vs Control on Stroke
Study %
Ji [36] 0.17 (0.01, 4.11) 0.13

Stenlof [40] 0.16 (0.01, 4.00) 0.13
Wildinga [41] 1.50 (0.06, 36.61) 0.13
Yale [42] 2.53 (0.12, 52.10) 0.14
Inagaki [33] 3.74 (0.18, 77.67) 0.14
Bode [44] 4.48 (0.24, 82.89) 0.15
Schernthaner [45] 3.01 (0.12, 73.60) 0.13
Cefalu [46] 1.74 (0.36, 8.34) 0.54
NCT01137474 [54] 0.34 (0.01, 8.39) 0.13
Henry (Study 1) [56] 0.35 (0.01, 8.43) 0.13
Kaku [61] 0.17 (0.01, 4.07) 0.13
Strojek [62] 1.63 (0.08, 33.75) 0.14
Cefalu [63] 1.01 (0.14, 7.13) 0.34
Leiterb [68] 0.33 (0.03, 3.21) 0.26
Bailey [70] 1.14 (0.05, 27.68) 0.13
Bailey [71] 0.33 (0.02, 5.32) 0.17
Kohan [72] 2.51 (0.12, 51.80) 0.14
Wilding [73] 0.48 (0.08, 2.83) 0.41
Nauck [74] 3.01 (0.31, 28.79) 0.26
Kadowaki [77] 0.75 (0.03, 18.33) 0.13
Tikkanen [78] 1.48 (0.06, 36.10) 0.13
NCT01649297 [79] 0.12 (0.01, 1.98) 0.17
Ha¨ring [80] 1.53 (0.06, 37.50) 0.13
Roden [81] 0.50 (0.05, 5.53) 0.23
Barnett [82] 3.05 (0.34, 27.11) 0.28
Rosenstock [83] 0.50 (0.03, 7.97) 0.17
DeFronzo [84] 0.48 (0.04, 5.22) 0.23
Kovacsa [86] 1.49 (0.06, 36.40) 0.13
Merker [87] 0.48 (0.07, 3.37) 0.34
Rosenstock [88] 1.57 (0.16, 15.02) 0.26
Ridderstra°le [90] 2.37 (0.61, 9.12) 0.72
CANVAS 0.87 (0.69, 1.09) 25.17
CREDENCE 0.77 (0.55, 1.08) 11.56
DECLARE–TIMI 58 1.01 (0.84, 1.21) 39.51
EMPA-REG 1.18 (0.89, 1.56) 16.71
.00595 1 168
95
eFigure 14E SGLT-2 vs Control on HF
Study %
Yale JF (2014) 1.52 (0.16, 14.79) 0.11

Bode B (2015) 1.50 (0.06, 36.84) 0.06
Neal B(2017)8-CANVAS-R 0.56 (0.38, 0.84) 3.70
Neal B(2017)8-CANVAS 0.79 (0.56, 1.13) 4.73
Haring HU(2014) 4.41 (0.24, 79.87) 0.07
Rosenstock J (2014) 1.00 (0.09, 11.13) 0.10
Zinman B(2015) 0.66 (0.57, 0.76) 28.16
Strojek K (2011) 0.11 (0.00, 2.66) 0.02
Leiter LA(2014) 0.50 (0.05, 5.56) 0.10
Bailey CJ(2014) 0.55 (0.02, 13.71) 0.05
Cefalu WT(2015) 0.33 (0.01, 8.22) 0.05
Matthaei S(2015) 5.06 (0.24, 106.30) 0.06
NCT00528372(2015) 0.55 (0.02, 13.71) 0.05
NCT00663260(2016) 1.51 (0.06, 37.55) 0.06
CANVAS 0.67 (0.52, 0.87) 8.80
CREDENCE 0.61 (0.47, 0.80) 8.24
DECLARE–TIMI 58 0.73 (0.61, 0.88) 17.35
DAPA-HF 0.70 (0.59, 0.83) 20.00
EMPA-REG 0.65 (0.50, 0.85) 8.28
1.0e-04 1 10000
96
eFigure 14F SGLT-2 vs Control on UA
Study %
Wilding JPH (2013) 0.17 (0.01, 4.08) 0.83

Yale JF (2014) 1.52 (0.06, 37.71) 0.73
Bode B (2015) 0.49 (0.07, 3.53) 1.96
NCT02025907 3.03 (0.12, 75.16) 0.73
Roden M(2013) 1.29 (0.05, 31.80) 0.72
Haring HU(2014) 0.40 (0.02, 6.39) 0.91
Barnett AH (2014) 0.15 (0.01, 3.16) 0.91
Zinman B(2015) 1.00 (0.74, 1.35) 83.31
Rosenstock J (2015) 0.17 (0.01, 4.30) 0.82
Strojek K (2011) 0.98 (0.04, 24.13) 0.73
Henry RR(2012) 1.46 (0.06, 35.90) 0.74
Bailey CJ(2013) 0.88 (0.05, 14.09) 0.95
Jabbour SA(2014) 3.03 (0.12, 74.70) 0.73
Leiter LA(2014) 1.51 (0.25, 9.07) 2.33
Cefalu WT(2015) 0.33 (0.03, 3.21) 1.38
NCT00528372 0.78 (0.04, 16.49) 0.83
Mathieu C (2015) 3.02 (0.12, 74.66) 0.73
NCT02096705 0.32 (0.01, 7.84) 0.68
.01 1 100
97
eFigure 14G SGLT-2 vs Control on AF
Study %
Lavalle-González FJ(2013) 0.75 (0.03, 18.47) 4.85
Wilding JPH (2013) 1.50 (0.06, 37.09) 4.85
Yale JF (2014) 2.55 (0.12, 53.66) 5.37
Bode B (2015) 0.99 (0.18, 5.46) 17.19
Barnett AH (2014) 0.38 (0.03, 4.20) 8.20
Kovacs CS(2014) 1.49 (0.06, 36.85) 4.86
Haring HU(2014) 0.20 (0.02, 2.20) 9.06
Rosenstock J (2015) 1.58 (0.06, 39.02) 4.77
NCT01734785 1.50 (0.06, 37.04) 4.85
Wilding JP(2012) 0.11 (0.00, 2.60) 1.94
Bailey CJ(2013) 1.14 (0.05, 28.26) 4.98
Leiter LA(2014) 0.67 (0.11, 4.02) 15.46
Bailey CJ(2014) 0.06 (0.00, 1.50) 2.17
Matthaei S(2015) 0.33 (0.01, 8.20) 4.45
Mathieu C (2015) 3.02 (0.12, 74.66) 4.84
NCT00528372 0.06 (0.00, 1.50) 2.17
1.0e-04 1 10000
98
eFigure 15A SGLT-2 vs Placebo on CVD
Study %
Neal 0.64 (0.29, 1.39) 1.25

Inagaki 0.75 (0.03, 18.34) 0.08
Bode 1.49 (0.06, 36.53) 0.08
Henry (Study 2) 0.33 (0.01, 8.02) 0.08
Cefalu 2.02 (0.18, 22.17) 0.13
Leiter 2.01 (0.18, 22.07) 0.13
Bailey 1.68 (0.08, 34.84) 0.08
Kohan 0.50 (0.03, 7.90) 0.10
Wilding 2.23 (0.12, 43.05) 0.09
Tikkanen 1.48 (0.06, 36.10) 0.08
Ha¨ring 1.53 (0.06, 37.50) 0.08
Roden 0.16 (0.01, 4.03) 0.08
Lewin 1.49 (0.06, 36.31) 0.08
Kovacs 0.99 (0.09, 10.85) 0.13
CANVAS 0.87 (0.72, 1.06) 20.56
CREDENCE 0.78 (0.61, 1.00) 12.59
DECLARE–TIMI 58 0.98 (0.82, 1.17) 24.35
DAPA-HF 0.82 (0.69, 0.98) 24.99
EMPA-REG 0.62 (0.49, 0.77) 15.06
.00674 1 148
99
eFigure 15B SGLT-2 vs Placebo on MI
Study %
Stenlof K (2013) 1.48 (0.06, 36.38) 0.08

Wilding JPH (2013) 0.17 (0.01, 4.08) 0.10
Yale JF (2014) 0.37 (0.08, 1.67) 0.37
Forst T (2014) 0.17 (0.01, 4.15) 0.10
Bode B (2015)4 0.83 (0.20, 3.49) 0.42
Roden M(2013) 0.43 (0.03, 6.87) 0.12
Rosenstock J (2014) 1.50 (0.06, 37.05) 0.08
Barnett AH (2014) 0.51 (0.08, 3.04) 0.26
Haring HU(2014) 0.71 (0.24, 2.13) 0.73
Rosenstock J (2015) 6.66 (0.36, 124.48) 0.10
Strojek K (2011) 0.11 (0.00, 2.66) 0.03
Rosenstock J(2012) 1.49 (0.06, 36.86) 0.08
Henry RR(2012) 0.48 (0.03, 7.75) 0.11
Bailey CJ(2013) 0.37 (0.07, 1.88) 0.32
Bailey CJ(2014) 1.30 (0.07, 25.36) 0.10
Leiter LA(2014) 2.53 (0.49, 13.09) 0.32
Cefalu WT(2015) 2.01 (0.18, 22.28) 0.15
NCT00528372 1.30 (0.07, 25.36) 0.10
Mathieu C (2015) 3.02 (0.12, 74.66) 0.08
NCT01095653 0.17 (0.01, 4.14) 0.10
NCT00663260 0.10 (0.00, 2.06) 0.04
NCT02096705 0.32 (0.01, 7.84) 0.08
NCT00683878 1.49 (0.06, 36.86) 0.08
CANVAS 0.89 (0.73, 1.09) 21.52
CREDENCE 0.86 (0.64, 1.16) 9.78
DECLARE–TIMI 58 0.89 (0.77, 1.01) 46.99
EMPA-REG 0.87 (0.70, 1.09) 17.64
1.0e-04 1 10000
100
eFigure 15C SGLT-2 vs Placebo on Stroke
Study %
Bode B (2015) 4.51 (0.24, 84.19) 0.15

Forst T (2014) 1.53 (0.06, 37.85) 0.13
NCT02025907 0.20 (0.01, 4.14) 0.15
Stenlof K (2013) 0.16 (0.01, 4.01) 0.15
Wilding JPH (2013) 1.50 (0.06, 37.09) 0.13
Yale JF (2014) 1.52 (0.16, 14.79) 0.26
Barnett AH (2014) 1.02 (0.23, 4.57) 0.59
Haring HU(2014) 0.73 (0.27, 1.98) 1.34
Kovacs CS(2014) 1.49 (0.06, 36.85) 0.13
Roden M(2013) 2.34 (0.15, 37.54) 0.17
Rosenstock J (2014) 3.19 (0.38, 26.70) 0.29
Rosenstock J (2015) 3.19 (0.38, 26.70) 0.29
Bailey CJ(2013) 0.19 (0.02, 2.08) 0.25
Bailey CJ(2014) 0.55 (0.02, 13.71) 0.12
Cefalu WT(2015) 1.00 (0.14, 7.16) 0.34
Kaku K(2014) 0.17 (0.01, 4.10) 0.15
Leiter LA(2014) 0.25 (0.03, 2.24) 0.29
Ljunggren O(2012) 3.03 (0.12, 75.48) 0.13
NCT00528372 0.55 (0.02, 13.71) 0.12
NCT00663260 1.50 (0.06, 37.33) 0.13
NCT01095653 3.59 (0.18, 69.98) 0.15
NCT02096705 0.32 (0.01, 7.84) 0.12
Strojek K (2011) 0.98 (0.04, 24.13) 0.13
Wilding JP(2012) 0.21 (0.03, 1.26) 0.38
CANVAS 0.87 (0.69, 1.09) 25.39
CREDENCE 0.77 (0.55, 1.08) 11.66
DECLARE–TIMI 58 1.01 (0.84, 1.21) 39.86
EMPA-REG 1.18 (0.89, 1.56) 16.86
.01 1 100
101
eFigure 16A Canagliflozin vs Control on MACE
Study %
Lavalle-González FJ 2013 0.75 (0.08, 7.22) 0.21
Wilding JPH 2013 0.50 (0.03, 8.00) 0.13
Stenlof K 2013 0.49 (0.03, 7.85) 0.14
Forst T 2014 0.50 (0.03, 8.14) 0.13
Yale JF 2014 0.59 (0.17, 1.99) 0.69
Bode B 2015 1.50 (0.40, 5.59) 0.60
NCT02025907(2016) 0.20 (0.01, 4.14) 0.12
CANVAS 0.86 (0.75, 0.97) 63.51
CREDENCE 0.80 (0.67, 0.95) 34.46
.01 1 100
102
eFigure 16B Canagliflozin vs Control on CVD
Study %
Neal 0.64 (0.29, 1.39) 3.56
Inagaki 0.75 (0.03, 18.34) 0.21
Inagaki 0.50 (0.03, 7.94) 0.29
Bode 1.49 (0.06, 36.53) 0.21
Schernthaner [45] 2.01 (0.18, 22.02) 0.38
Cefalu 0.17 (0.01, 4.06) 0.21
Henry (Study 1) 2.97 (0.12, 72.49) 0.21
Henry (Study 2) 0.33 (0.01, 8.02) 0.21
Henry (Study 2) 0.32 (0.01, 7.73) 0.21
CANVAS 0.87 (0.72, 1.06) 58.60
CREDENCE 0.78 (0.61, 1.00) 35.88
.00677 1 148
103
eFigure 16C Canagliflozin vs Control on MI
Study %
Wildinga [41] 0.17 (0.01, 4.07) 0.26
Yale [42] 0.50 (0.10, 2.44) 1.06
Inagaki [33] 0.75 (0.05, 11.92) 0.34
Bode [44] 0.83 (0.20, 3.44) 1.30
Schernthaner [45] 0.20 (0.01, 4.16) 0.29
Cefalu [46] 0.66 (0.15, 2.95) 1.18
CANVAS 0.89 (0.73, 1.09) 65.71
CREDENCE 0.86 (0.64, 1.16) 29.86
.00683 1 146
104
eFigure 16D Canagliflozin vs Control on Stroke
Study %
Ji [36] 0.17 (0.01, 4.11) 0.34
Stenlof [40] 0.16 (0.01, 4.00) 0.34
Wildinga [41] 1.50 (0.06, 36.61) 0.34
Yale [42] 2.53 (0.12, 52.10) 0.38
Inagaki [33] 3.74 (0.18, 77.67) 0.37
Bode [44] 4.48 (0.24, 82.89) 0.40
Schernthaner [45] 3.01 (0.12, 73.60) 0.34
Cefalu [46] 1.74 (0.36, 8.34) 1.40
CANVAS 0.87 (0.69, 1.09) 65.86
CREDENCE 0.77 (0.55, 1.08) 30.24
.0067 1 149
105
eFigure 16E Canagliflozin vs Control on HF
Study %
Yale JF (2014) 1.52 (0.16, 14.79) 0.66
Bode B (2015) 1.50 (0.06, 36.84) 0.33
CANVAS 0.67 (0.52, 0.87) 51.13
CREDENCE 0.61 (0.47, 0.80) 47.88
.0271 1 36.8
106
eFigure 16F Canagliflozin vs Control on UA
Study %
Wilding JPH (2013) 0.17 (0.01, 4.08) 19.64
Yale JF (2014) 1.52 (0.06, 37.71) 17.09
Bode B (2015) 0.49 (0.07, 3.53) 46.16
NCT02025907 3.03 (0.12, 75.16) 17.11
.01 1 100
107
eFigure 16G Canagliflozin vs Control on AF
Study %
Wilding JPH (2013) 1.50 (0.06, 37.09) 15.02
Yale JF (2014) 2.55 (0.12, 53.66) 16.66
Bode B (2015) 0.99 (0.18, 5.46) 53.28
.0186 1 53.7
108
eFigure 17A Dapagliflozin vs Control on cardiovascular outcomes
Study %
MACE
Sonesson 2016 (21 trials) 0.77 (0.54, 1.10) 7.59
DECLARE–TIMI 58 0.93 (0.84, 1.03) 92.41
.
CVD
Sonesson 2016 (21 trials) 0.70 (0.36, 1.36) 4.65
DECLARE–TIMI 58 0.98 (0.82, 1.17) 47.24
DAPA-HF 0.82 (0.69, 0.98) 48.11
.
MI
Sonesson 2016 (21 trials) 0.57 (0.34, 0.95) 33.90
DECLARE–TIMI 58 0.89 (0.77, 1.01) 66.10
.
Stroke
Sonesson 2016 (21 trials) 1.00 (0.54, 1.86) 8.01
DECLARE–TIMI 58 1.01 (0.84, 1.21) 91.99
.
HF
Sonesson 2016 (21 trials) 0.36 (0.16, 0.84) 3.47
DECLARE–TIMI 58 0.73 (0.61, 0.88) 46.16
DAPA-HF 0.70 (0.59, 0.83) 50.37
.
UA
Sonesson 2016 (21 trials) 0.87 (0.47, 1.59) 100.00
Subtotal (I-squared = .%, p = .) 0.87 (0.47, 1.60) 100.00
.
.16 1 6.25
109
eFigure 17不 Dapagliflozin vs Control on AF
Study %
Wilding JP(2012) 0.11 (0.00, 2.60) 5.38
Bailey CJ(2013) 1.14 (0.05, 28.26) 13.85
Leiter LA(2014) 0.67 (0.11, 4.02) 42.95
Bailey CJ(2014) 0.06 (0.00, 1.50) 6.01
Matthaei S(2015) 0.33 (0.01, 8.20) 12.35
Mathieu C (2015) 3.02 (0.12, 74.66) 13.44
NCT00528372 0.06 (0.00, 1.50) 6.01
1.0e-04 1 10000
110
eFigure 18A Empagliflozin vs Control on cardiovascular outcomes
Study %
MACE
Salsali 2016(8 trials) 0.84 (0.73, 0.96) 53.04
EMPA-REG 0.86 (0.74, 0.99) 46.96
HF
Salsali 2016(8 trials) 0.63 (0.48, 0.81) 50.70
EMPA-REG 0.65 (0.50, 0.85) 49.30
UA
Salsali 2016(8 trials) 0.93 (0.70, 1.24) 51.89
EMPA-REG 0.99 (0.74, 1.34) 48.11
.
.48 1 2.08
111
eFigure 18B Empagliflozin vs Control on CVD
Study %
Tikkanen 1.48 (0.06, 36.10) 0.48
Ha¨ring 1.53 (0.06, 37.50) 0.48
Roden 0.17 (0.01, 4.16) 0.48
Roden 0.16 (0.01, 4.03) 0.48
Lewin 1.49 (0.06, 36.31) 0.48
Kovacs 0.99 (0.09, 10.85) 0.86
Ridderstra°le 0.51 (0.05, 5.58) 0.85
EMPA-REG 0.62 (0.49, 0.77) 95.90
.00674 1 148
112
eFigure 18C Empagliflozin vs Control on MI
Study %
Ferrannini (Study 1) 0.79 (0.03, 19.18) 0.44

Rosenstock [76] 0.40 (0.03, 6.39) 0.58

Ferrannini [75] 3.33 (0.16, 68.84) 0.49
Kadowaki [77] 0.05 (0.00, 1.04) 0.49
Ha¨ring [80] 0.51 (0.03, 8.12) 0.58
Roden [81] 0.50 (0.05, 5.53) 0.78
Barnett [82] 0.15 (0.01, 3.16) 0.49
Rosenstock [83] 1.51 (0.06, 36.84) 0.44
DeFronzo [84] 2.36 (0.11, 48.78) 0.49
Merker [87] 0.48 (0.07, 3.37) 1.17
Rosenstock [88] 3.68 (0.19, 70.89) 0.51

Araki [89] 0.70 (0.03, 17.00) 0.44
Ridderstra°le [90] 0.14 (0.02, 1.17) 1.02
Amin [91] 2.50 (0.12, 51.63) 0.49
EMPA-REG 0.87 (0.70, 1.09) 91.16
.00242 1 413
113
eFigure 18D Empagliflozin vs Control on Stroke
Study %
Kadowaki [77] 0.75 (0.03, 18.33) 0.64
Tikkanen [78] 1.48 (0.06, 36.10) 0.64
NCT01649297 [79] 0.12 (0.01, 1.98) 0.86
Ha¨ring [80] 1.53 (0.06, 37.50) 0.64
Roden [81] 0.50 (0.05, 5.53) 1.14
Barnett [82] 3.05 (0.34, 27.11) 1.37
Rosenstock [83] 0.50 (0.03, 7.97) 0.86
DeFronzo [84] 0.48 (0.04, 5.22) 1.15
Kovacsa [86] 1.49 (0.06, 36.40) 0.64
Merker [87] 0.48 (0.07, 3.37) 1.72
Rosenstock [88] 1.57 (0.16, 15.02) 1.29
Ridderstra°le [90] 2.37 (0.61, 9.12) 3.61
EMPA-REG 1.18 (0.89, 1.56) 83.46
.00595 1 168
114
eFigure 18E Empagliflozin vs Control on AF
Study %
Barnett AH (2014) 0.38 (0.03, 4.20) 25.83
Kovacs CS(2014) 1.49 (0.06, 36.85) 15.30
Haring HU(2014) 0.20 (0.02, 2.20) 28.55
Rosenstock J (2015) 1.58 (0.06, 39.02) 15.03
NCT01734785 1.50 (0.06, 37.04) 15.28
.02 1 50
115
eFigure 19A Sulfonylureas vs Control on MACE
Study %
Birkeland 1996 0.33 (0.01, 7.68) 0.06

Chou 2008 0.52 (0.05, 5.67) 0.10
Perriello 2006 0.53 (0.14, 2.09) 0.32
Gerstein 2010 0.56 (0.33, 0.95) 2.13
UKPDS33 1998 0.94 (0.83, 1.08) 33.93
Hanefeld 2007 0.63 (0.07, 6.02) 0.12
Seino 2010 0.68 (0.07, 6.44) 0.12
Charbonnel2005 0.76 (0.27, 2.16) 0.54
Matthews 2005 0.87 (0.32, 2.39) 0.58
Rubin 2008 0.90 (0.48, 1.67) 1.54
Home 2009 0.99 (0.80, 1.21) 14.00
Arechavaleta 2011 0.99 (0.14, 7.03) 0.15
va der Laar 2004 1.00 (0.06, 15.53) 0.08
Mazzone 2006 1.01 (0.14, 7.10) 0.16
Riddle 1998 1.01 (0.06, 15.90) 0.08
Giles 2010 1.01 (0.49, 2.11) 1.10
Tolman 2009 1.11 (0.68, 1.82) 2.42
Kahn 2006 1.14 (0.71, 1.84) 2.61
Goke 2010 1.16 (0.39, 3.43) 0.51
Garber 2009 1.16 (0.40, 3.41) 0.51
Nissen 2008 1.17 (0.53, 2.56) 0.96
Ristic 2007 1.55 (0.26, 9.10) 0.19
Ferrannini 2009 1.84 (0.91, 3.70) 1.21
Bakris 2006 1.89 (0.56, 6.34) 0.40
Gallwitz 2012 2.17 (1.10, 4.27) 1.29
Jain 2006 2.67 (0.72, 9.94) 0.34
Johnston 1998 5.87 (0.62, 55.64) 0.12
Nauck 2011 6.98 (0.36, 134.74) 0.07
Seck 2010 9.06 (0.49, 167.93) 0.07
TOSCA.IT 1.04 (0.79, 1.35) 8.26
CAROLINA 1.02 (0.88, 1.19) 26.04
.00595 1 168
116
eFigure 19B Sulfonylureas vs Control on CVD
Study %
Lunderhausen[67] 5.12 (0.25, 103.45) 0.26

Johnston[64] 1.94 (0.12, 30.43) 0.31
UKPDS 0.94 (0.66, 1.36) 17.68
Bikeland[44] 0.33 (0.01, 7.68) 0.24
Johnston[64] 11.72 (0.48, 283.55) 0.23
UKPDS 1.00 (0.70, 1.43) 17.89
Marbury[69] 0.99 (0.09, 10.90) 0.41
Jain[63] 3.00 (0.12, 73.29) 0.23
Nauck[73] 4.98 (0.24, 103.32) 0.25
Hamann[59] 0.49 (0.04, 5.34) 0.41
Nissen[75] 0.33 (0.03, 3.15) 0.46
Ferranini[49] 0.50 (0.05, 5.52) 0.41
Tolman[83] 5.03 (0.59, 42.97) 0.51
Alvarsson[41] 0.30 (0.01, 6.94) 0.24
Gerstein[56] 0.74 (0.17, 3.27) 1.05
Giles[57] 3.04 (0.12, 74.03) 0.23
Nauck[74] 5.03 (0.24, 104.63) 0.25
Gallwitz[53] 0.67 (0.11, 3.98) 0.73
Hong[62] 2.11 (0.88, 5.08) 3.02
Ferreira[43] 1.99 (0.18, 21.79) 0.41
Delprato[48] 2.02 (0.51, 8.06) 1.22
CAROLINA 1.00 (0.81, 1.23) 53.57
.00353 1 284
117
eFigure 19C Sulfonylureas vs Control on MI
Study %
Bakris 2006 [30] 2.16 (0.20, 23.57) 0.26

Birkeland 1996 [33] 0.33 (0.01, 7.68) 0.15
Matthews 2005 [39] 1.00 (0.14, 7.05) 0.39
Charbonnel 2005 [40] 0.20 (0.02, 1.72) 0.32
Gallwitz 2012 [62] 1.67 (0.61, 4.57) 1.47
Garber 2009 [65] 1.49 (0.25, 8.86) 0.47
Gerstein 2010 [67] 0.86 (0.32, 2.34) 1.48
Giles 2008 [69] 0.41 (0.08, 2.09) 0.56
Goke 2010 [71] 1.99 (0.18, 21.87) 0.26
Hanefeld 2007 [76] 0.95 (0.09, 10.37) 0.26
Home 2009 [80] 0.77 (0.48, 1.24) 6.57
Jain 2006 [83] 1.00 (0.14, 7.04) 0.39
Kahn 2006 [85] 0.64 (0.35, 1.17) 4.17
Mazzone 2006 [90] 3.03 (0.12, 73.90) 0.15
Nissen 2008 [5] 1.98 (0.37, 10.71) 0.52
Ristic 2007 [107] 5.15 (0.25, 106.33) 0.16
Roberts 2006 [108] 0.47 (0.04, 5.07) 0.26
Seino 2010 [114] 0.68 (0.07, 6.44) 0.29
Tolman 2009 [126] 1.72 (0.68, 4.36) 1.73
va der Laar 2004 [132] 1.00 (0.06, 15.53) 0.20
TOSCA.IT 1.15 (0.65, 2.08) 4.41
UKPDS 0.83 (0.69, 0.99) 45.73
CAROLINA 0.97 (0.78, 1.22) 29.79
.00941 1 106
118
eFigure 19D Sulfonylureas vs Control on Stroke
Study %
Arechavaleta 2011 [29] 4.97 (0.24, 103.29) 0.33

Bakris 2006 [30] 3.23 (0.13, 78.83) 0.30
Matthews 2005 [39] 0.33 (0.03, 3.19) 0.60
Charbonnel 2005 [40] 1.52 (0.26, 9.03) 0.96
Ferrannini 2009 [56] 15.03 (0.86, 262.95) 0.37
Gallwitz 2012 [62] 3.67 (1.03, 13.11) 1.89
Gerstein 2010 [67] 0.20 (0.02, 1.67) 0.67
Goke 2010 [71] 2.99 (0.12, 73.10) 0.30
Home 2009 [80] 1.29 (0.77, 2.17) 11.48
Kahn 2006 [85] 0.81 (0.41, 1.57) 6.89
Mazzone 2006 [90] 3.03 (0.12, 73.90) 0.30
Nissen 2008 [5] 2.97 (0.12, 72.52) 0.30
Riddle 1998 [106] 3.04 (0.13, 73.44) 0.30
Tolman 2009 [126] 0.90 (0.37, 2.22) 3.81
TOSCA.IT 1.26 (0.65, 2.44) 7.00
UKPDS 1.10 (0.76, 1.61) 21.74
CAROLINA 1.16 (0.89, 1.52) 42.75
.0038 1 263
119
eFigure 19E Sulfonylureas vs Control on HF
Study %
TOSCA.IT 0.64 (0.31, 1.32) 14.28
UKPDS 1.06 (0.64, 1.75) 29.62
CAROLINA 0.93 (0.65, 1.35) 56.10
.31 1 3.23
120
eFigure 20A Glibenclamide vs Control on MACE
Study %
Birkeland 1996 0.33 (0.01, 7.68) 0.21
Hanefeld 2007 0.63 (0.07, 6.02) 0.41
Seino 2010 0.68 (0.07, 6.44) 0.41
Giles 2010 1.01 (0.49, 2.11) 3.83
Tolman 2009 1.11 (0.68, 1.82) 8.43
Kahn 2006 1.14 (0.71, 1.84) 9.10
Bakris 2006 1.89 (0.56, 6.34) 1.41
Jain 2006 2.67 (0.72, 9.94) 1.20
Johnston 1998 5.87 (0.62, 55.64) 0.41
UKPDS33 1998 0.95 (0.81, 1.13) 74.61
.0145 1 69.1
121
eFigure 20B Glibenclamide vs Control on CVD
Study %
Lunderhausen[67] 5.12 (0.25, 103.45) 8.48
Johnston[64] 1.94 (0.12, 30.43) 10.12
Bikeland[44] 0.33 (0.01, 7.68) 7.78
Johnston[64] 11.72 (0.48, 283.55) 7.54
Marbury[69] 0.99 (0.09, 10.90) 13.37
Jain[63] 3.00 (0.12, 73.29) 7.50
Hamann[59] 0.49 (0.04, 5.34) 13.35
Tolman[83] 5.03 (0.59, 42.97) 16.64
Alvarsson[41] 0.30 (0.01, 6.94) 7.70
Giles[57] 3.04 (0.12, 74.03) 7.51
.00353 1 284
122
eFigure 20C Glibenclamide vs Control on MI
Study %
Bakris 2006 [30] 2.16 (0.20, 23.57) 0.66
Birkeland 1996 [33] 0.33 (0.01, 7.68) 0.38
Giles 2008 [69] 0.41 (0.08, 2.09) 1.41
Hanefeld 2007 [76] 0.95 (0.09, 10.37) 0.65
Jain 2006 [83] 1.00 (0.14, 7.04) 0.98
Kahn 2006 [85] 0.64 (0.35, 1.17) 10.48
Seino 2010 [114] 0.68 (0.07, 6.44) 0.74
Tolman 2009 [126] 1.72 (0.68, 4.36) 4.35
UKPDS 33 1998 [130] 0.85 (0.69, 1.06) 80.35
.0145 1 69.1
123
eFigure 20D Glibenclamide vs Control on Stroke
Study %
Bakris 2006 [30] 3.23 (0.13, 78.83) 1.19
Kahn 2006 [85] 0.81 (0.41, 1.57) 23.40
Tolman 2009 [126] 0.90 (0.37, 2.22) 13.87
UKPDS 33 1998 [130] 1.49 (1.05, 2.10) 61.55
.0127 1 78.8
124
eFigure 21A Glimepiride vs Control on MACE
Study %
Chou 2008 0.52 (0.05, 5.67) 0.53
Rubin 2008 0.90 (0.48, 1.67) 7.86
Arechavaleta 2011 0.99 (0.14, 7.03) 0.79
Mazzone 2006 1.01 (0.14, 7.10) 0.79
Riddle 1998 1.01 (0.06, 15.90) 0.40
Garber 2009 1.16 (0.40, 3.41) 2.61
Nissen 2008 1.17 (0.53, 2.56) 4.91
Ferrannini 2009 1.84 (0.91, 3.70) 6.18
Gallwitz 2012 2.17 (1.10, 4.27) 6.60
CAROLINA 1.00 (0.81, 1.23) 69.32
.0473 1 21.1
125
eFigure 21B Glimepiride vs Control on CVD
Study %
Nissen[75] 0.33 (0.03, 3.15) 0.83
Ferranini[49] 0.50 (0.05, 5.52) 0.74
Gallwitz[53] 0.67 (0.11, 3.98) 1.33
CAROLINA 1.00 (0.81, 1.23) 97.10
.0345 1 29
126
eFigure 21C Glimepiride vs Control on MI
Study %
Gallwitz 2012 [62] 1.67 (0.61, 4.57) 4.50
Garber 2009 [65] 1.49 (0.25, 8.86) 1.44
Mazzone 2006 [90] 3.03 (0.12, 73.90) 0.45
Nissen 2008 [5] 1.98 (0.37, 10.71) 1.60
Roberts 2006 [108] 0.47 (0.04, 5.07) 0.81
CAROLINA 0.97 (0.78, 1.22) 91.21
.0135 1 73.9
127
eFigure 21D Glimepiride vs Control on Stroke
Study %
Arechavaleta 2011 [29] 4.97 (0.24, 103.29) 4.68
Ferrannini 2009 [56] 15.03 (0.86, 262.95) 5.21
Gallwitz 2012 [62] 3.67 (1.03, 13.11) 19.74
Mazzone 2006 [90] 3.03 (0.12, 73.90) 4.25
Nissen 2008 [5] 2.97 (0.12, 72.52) 4.24
Riddle 1998 [106] 3.04 (0.13, 73.44) 4.27
CAROLINA 1.16 (0.89, 1.52) 57.61
.0038 1 263
128
eFigure 22A Gliclazide vs Control on MACE
Study %
Perriello 2006 0.53 (0.14, 2.09) 29.16
Matthews 2005 0.87 (0.32, 2.39) 53.53
Ristic 2007 1.55 (0.26, 9.10) 17.32
.11 1 9.1
129
eFigure 22B Gliclazide vs Control on MI
Study %
Matthews 2005 [39] 1.00 (0.14, 7.05) 40.71
Charbonnel 2005 [40] 0.20 (0.02, 1.72) 36.59
Ristic 2007 [107] 5.15 (0.25, 106.33) 22.70
with estimated predictive interval . (0.00, 3.9e+06)
.00941 1 106
130
eFigure 23A Glipizide vs Control on MACE
Study %
Gerstein 2010 0.56 (0.33, 0.95) 41.34
Charbonnel2005 0.76 (0.27, 2.16) 24.59
Goke 2010 1.16 (0.39, 3.43) 23.70
Nauck 2011 6.98 (0.36, 134.74) 5.12
Seck 2010 9.06 (0.49, 167.93) 5.25
.00595 1 168
131
eFigure 23B Glipizide vs Control on CVD
Study %
Nauck[73] 4.98 (0.24, 103.32) 4.09
Gerstein[56] 0.74 (0.17, 3.27) 16.95
Nauck[74] 5.03 (0.24, 104.63) 4.08
Hong[62] 2.11 (0.88, 5.08) 48.67
Ferreira[43] 1.99 (0.18, 21.79) 6.57
Delprato[48] 2.02 (0.51, 8.06) 19.64
.00956 1 105
132
eFigure 24A Rosiglitazone vs control on MACE
Study %
49653/011 1.48 (0.06, 36.23) 0.73

49653/094 1.51 (0.06, 36.70) 0.73
49653/211 1.30 (0.36, 4.70) 4.48
AVM100264 2.05 (0.19, 22.54) 1.30
49653/015 2.51 (0.12, 52.09) 0.81
49653/079 0.52 (0.03, 8.27) 0.97
49653/082 1.52 (0.06, 37.03) 0.73
49653/085 3.02 (0.12, 73.54) 0.73
49653/095 1.48 (0.06, 35.93) 0.73
49653/134 1.48 (0.06, 36.18) 0.73
49653/135 1.91 (0.18, 20.81) 1.31
49653/136 4.83 (0.23, 99.78) 0.81
49653/145 3.14 (0.13, 76.74) 0.73
49653/162 3.07 (0.13, 74.86) 0.73
49653/330 0.97 (0.04, 23.68) 0.73
49653/331 1.38 (0.06, 33.87) 0.73
49653/137 0.30 (0.01, 7.38) 0.73
SB-712753/002 2.92 (0.12, 71.30) 0.73
49653/132 0.77 (0.03, 18.66) 0.73
AVA100193 0.95 (0.04, 23.16) 0.73
AVD102209 0.33 (0.01, 8.05) 0.73
AVD100521 1.36 (0.31, 6.02) 3.35
AVA105640 0.25 (0.01, 6.16) 0.73
ADOPT 0.80 (0.15, 4.09) 2.77
DREAM 1.20 (0.52, 2.77) 10.63
RECORD 0.84 (0.59, 1.18) 61.91
.01 1 99.8
133
eFigure 24B Rosiglitazone vs control on CVD
Study %
49653/011 4.45 (0.07, 287.32) 0.45

49653/094 4.48 (0.07, 286.49) 0.45
49653/211 1.31 (0.35, 4.95) 4.39
AVM100264 2.01 (0.21, 19.36) 1.51
49653/015 4.50 (0.24, 85.20) 0.90
49653/079 0.50 (0.03, 9.26) 0.91
49653/082 4.50 (0.07, 285.99) 0.45
49653/085 7.44 (0.15, 375.10) 0.51
49653/095 4.44 (0.07, 287.73) 0.45
49653/134 4.45 (0.07, 287.45) 0.45
49653/135 1.87 (0.19, 18.22) 1.50
49653/136 7.19 (0.45, 115.59) 1.01
49653/145 7.75 (0.15, 390.96) 0.51
49653/162 7.57 (0.15, 381.46) 0.51
49653/330 3.75 (0.04, 361.05) 0.37
49653/331 4.31 (0.06, 292.62) 0.44
49653/137 0.12 (0.00, 6.18) 0.50
SB-712753/002 7.19 (0.14, 362.32) 0.51
49653/132 3.50 (0.03, 461.09) 0.33
AVA100193 3.72 (0.04, 367.95) 0.37
AVD102209 0.13 (0.00, 6.77) 0.51
AVD100521 1.36 (0.31, 6.02) 3.51
AVA105640 0.10 (0.00, 5.13) 0.50
ADOPT 0.80 (0.17, 3.86) 3.15
DREAM 1.20 (0.52, 2.77) 11.11
RECORD 0.84 (0.59, 1.18) 64.73
.00187 1 535
134
eFigure 24C Rosiglitazone vs control on MI
Study %
49653/011 4.46 (0.23, 85.24) 0.63

49653/020 1.06 (0.10, 11.47) 0.96
49653/024 0.14 (0.00, 4.66) 0.44
49653/093 0.05 (0.00, 3.28) 0.32
49653/094 4.48 (0.07, 286.49) 0.32
100684 0.15 (0.00, 7.46) 0.35
49653/143 7.57 (0.15, 381.85) 0.35
49653/211 2.50 (0.56, 11.25) 2.42
49653/284 7.43 (0.15, 374.34) 0.35
712753/008 4.37 (0.07, 289.87) 0.31
AVM100264 0.14 (0.00, 7.01) 0.35
BRL 49653C/185 3.50 (0.11, 111.28) 0.46
BRL 49653/334 1.96 (0.20, 18.91) 1.06
BRL 49653/347 4.52 (0.24, 85.20) 0.63
49653/015 1.00 (0.09, 11.09) 0.94
49653/079 0.50 (0.03, 9.26) 0.64
49653/080 0.49 (0.05, 4.72) 1.05
49653/082 4.52 (0.24, 85.58) 0.63
49653/085 2.77 (0.39, 19.87) 1.40
49653/097 0.13 (0.00, 6.71) 0.35
49653/125 0.13 (0.00, 6.74) 0.35
49653/127 7.66 (0.15, 386.16) 0.35
49653/128 7.20 (0.14, 363.08) 0.35
49653/134 0.05 (0.00, 0.92) 0.63
49653/135 0.64 (0.11, 3.73) 1.74
49653/136 7.14 (0.14, 360.22) 0.35
49653/145 7.75 (0.15, 390.96) 0.35
49653/147 7.31 (0.14, 368.25) 0.35
49653/162 7.57 (0.15, 381.46) 0.35
49653/330 3.75 (0.04, 361.05) 0.26
49653/137 0.46 (0.05, 4.49) 1.06
SB-712753/002 7.19 (0.14, 362.32) 0.35
SB-712753/003 7.93 (0.16, 400.65) 0.35
SB-712753/007 4.44 (0.07, 287.64) 0.31
49653/132 3.50 (0.03, 461.09) 0.23
AVA100193 3.72 (0.04, 367.95) 0.26
AVD100521 1.17 (0.42, 3.25) 5.21
AVA105640 0.75 (0.05, 12.39) 0.69
ADOPT 1.33 (0.80, 2.21) 21.16
DREAM 1.78 (0.79, 4.03) 8.21
RECORD 1.14 (0.80, 1.63) 43.06
.00083 1 1207
135
eFigure 24E Rosiglitazone vs control on Stroke
Study %
Bach 2013 0.74 (0.37, 1.46) 15.89
Dargie 2007 1.04 (0.15, 7.23) 1.96
Florez 2015 0.33 (0.07, 1.61) 2.98
Gram 2011 0.66 (0.11, 3.88) 2.34
Kahn 2006 0.88 (0.49, 1.59) 21.57
DREAM 1.40 (0.44, 4.40) 5.58
RECORD 0.72 (0.49, 1.06) 49.68
.0691 1 14.5
136
eFigure 24F Rosiglitazone vs control on HF
Study %
Bach 2013 1.22 (0.86, 1.74) 33.68
Dargie 2007 1.97 (0.96, 4.04) 12.24
Gram 2011 1.64 (0.40, 6.76) 3.59
Kahn 2006 1.56 (0.90, 2.72) 18.55
Mcgavock 2011 1.77 (0.17, 18.26) 1.36
Mcguire 2010 7.00 (0.37, 132.35) 0.86
Varghese 2009 5.36 (0.27, 106.78) 0.83
DREAM 7.04 (1.60, 31.00) 3.29
RECORD 2.10 (1.35, 3.27) 25.59
.00756 1 132
137
eFigure 25A Rosiglitazone vs Placebo on CVD
Study %
49653/011 4.45 (0.07, 287.32) 2.35
49653/211 1.31 (0.35, 4.95) 23.00
49653/134 4.45 (0.07, 287.45) 2.34
49653/136 7.19 (0.45, 115.59) 5.28
49653/330 3.75 (0.04, 361.05) 1.95
49653/331 4.31 (0.06, 292.62) 2.29
AVA100193 3.72 (0.04, 367.95) 1.93
AVA105640 0.10 (0.00, 5.13) 2.60
DREAM 1.20 (0.52, 2.77) 58.25
.00187 1 535
138
eFigure 25B Rosiglitazone vs Placebo on MI
Study %
49653/011 4.46 (0.23, 85.24) 4.09
49653/024 0.14 (0.00, 4.66) 2.88
49653/211 2.50 (0.56, 11.25) 15.78
BRL 49653/334 1.96 (0.20, 18.91) 6.93
49653/128 7.20 (0.14, 363.08) 2.32
49653/134 0.05 (0.00, 0.92) 4.09
49653/136 7.14 (0.14, 360.22) 2.32
49653/330 3.75 (0.04, 361.05) 1.71
AVA100193 3.72 (0.04, 367.95) 1.69
AVA105640 0.75 (0.05, 12.39) 4.54
DREAM 1.78 (0.79, 4.03) 53.65
.00251 1 398
139
eFigure 25C Rosiglitazone vs Placebo on Stroke
Study %
Dargie 2007 1.04 (0.15, 7.23) 19.74
Gerstein 2006 1.40 (0.44, 4.40) 56.68
Gram 2011 0.66 (0.11, 3.88) 23.57
.111 1 9.02
140
eFigure 25D Rosiglitazone vs Placebo on HF
Study %
Dargie 2007 1.97 (0.96, 4.04) 62.06
DREAM 7.04 (1.60, 31.00) 14.63
Gram 2011 1.64 (0.40, 6.76) 16.01
Mcguire 2010 7.00 (0.37, 132.35) 3.72
Varghese 2009 5.36 (0.27, 106.78) 3.59
.00756 1 132
141
eFigure 26A Pioglitazone vs control on MACE
Study %
PNFP-010 0.33 (0.06, 1.98) 0.51

PNFP-014 1.48 (0.06, 36.26) 0.16
PNFP-026 0.32 (0.01, 7.69) 0.16
OPI-502 0.34 (0.01, 8.24) 0.16
PNFP-012 0.10 (0.00, 1.98) 0.18
OPI-504 1.47 (0.67, 3.20) 2.63
GLAI 0.40 (0.08, 2.03) 0.60
PNFP-001 0.24 (0.02, 3.80) 0.21
EC405 1.15 (0.42, 3.14) 1.58
OPI-501 0.50 (0.09, 2.71) 0.56
EC404 0.75 (0.26, 2.15) 1.45
EC409 0.50 (0.21, 1.23) 2.01
EC410 1.32 (0.46, 3.75) 1.46
OPI-520 0.99 (0.25, 3.87) 0.86
GLAT 0.51 (0.05, 5.61) 0.28
CHICAGO 0.50 (0.05, 5.43) 0.28
OPI-506 0.72 (0.38, 1.37) 3.94
PROactive 0.82 (0.70, 0.97) 60.32
TOSCA.IT 0.96 (0.74, 1.26) 22.66
.00466 1 214
142
eFigure 26B Pioglitazone vs control on CVD
Study %
NCT00521820 0.83 (0.26, 2.70) 3.89
PNFP012 0.16 (0.01, 3.89) 0.53
Saad 1.38 (0.06, 33.00) 0.53
Sourij 0.33 (0.01, 7.74) 0.54
Miyazaky 0.31 (0.01, 6.85) 0.56
NCT00521742 0.33 (0.01, 8.12) 0.53
Lawrence 0.33 (0.01, 7.74) 0.54
Kendall 0.09 (0.01, 1.68) 0.64
Bays 2.00 (0.08, 49.07) 0.52
PROactive 0.94 (0.74, 1.20) 91.73
.00517 1 193
143
eFigure 26C Pioglitazone vs control on MI
Study %
PNFP-010 0.50 (0.07, 3.53) 0.81

PNFP-014 1.48 (0.06, 36.26) 0.30
PNFP-026 0.32 (0.01, 7.69) 0.30
OPI-502 0.34 (0.01, 8.24) 0.30
PNFP-012 0.16 (0.01, 3.89) 0.30
OPI-504 2.44 (0.48, 12.48) 1.16
GLAI 0.50 (0.05, 5.45) 0.54
PNFP-001 0.24 (0.02, 3.80) 0.40
EC405 1.00 (0.14, 7.10) 0.80
OPI-501 1.00 (0.14, 7.04) 0.81
EC404 0.75 (0.17, 3.34) 1.38
EC409 0.80 (0.22, 2.96) 1.81
EC410 4.94 (0.58, 42.02) 0.67
OPI-520 0.99 (0.14, 6.91) 0.81
GLAT 0.34 (0.01, 8.34) 0.30
CHICAGO 0.33 (0.01, 8.07) 0.30
OPI-506 0.58 (0.23, 1.47) 3.58
IRIS 0.73 (0.51, 1.03) 24.94
PROactive 0.83 (0.65, 1.06) 51.51
TOSCA.IT 0.87 (0.48, 1.55) 8.97
.00659 1 152
144
eFigure 26D Pioglitazone vs control on Stroke
Study %
J SPIRIT 0.52 (0.16, 1.67) 2.53
CHICIGO 2006 0.33 (0.01, 8.07) 0.34
J SPIRIT 2015 0.52 (0.16, 1.67) 2.53
PERISCOPE 2008 0.34 (0.01, 8.24) 0.34
PROFIT J 2014 0.79 (0.18, 3.50) 1.58
IRIS 0.82 (0.61, 1.10) 40.26
PROactive 0.81 (0.61, 1.07) 44.33
TOSCA.IT 0.79 (0.41, 1.53) 8.07
.0135 1 73.9
145
eFigure 26E Pioglitazone vs control on HF
Study %
PNFP-010 0.10 (0.00, 2.08) 0.38

PNFP-014 3.47 (0.18, 66.88) 0.40
PNFP-027 2.86 (0.12, 69.65) 0.35
OPI-504 2.61 (1.24, 5.50) 6.33
EC405 0.14 (0.01, 2.77) 0.40
EC404 1.50 (0.25, 8.94) 1.11
EC409 2.01 (0.18, 22.01) 0.61
EC410 0.49 (0.04, 5.42) 0.61
OPI-520 8.88 (0.48, 163.53) 0.42
GLAT 0.34 (0.01, 8.34) 0.35
CHICAGO 2.97 (0.12, 72.62) 0.35
OPI-506 1.09 (0.48, 2.45) 5.32
IRIS 1.23 (0.79, 1.89) 18.53
PROactive 1.41 (1.10, 1.80) 58.14
TOSCA.IT 1.57 (0.76, 3.24) 6.71
.00485 1 206
146
eFigure 27A Pioglitazone vs Placebo on MACE
Study %
PNFP-014 1.48 (0.06, 36.26) 0.26
PNFP-026 0.32 (0.01, 7.69) 0.26
OPI-502 0.34 (0.01, 8.24) 0.26
PNFP-012 0.10 (0.00, 1.98) 0.29
PNFP-001 0.24 (0.02, 3.80) 0.34
GLAT 0.51 (0.05, 5.61) 0.46
PROactive 0.82 (0.70, 0.97) 98.15
.00466 1 214
147
eFigure 27B Pioglitazone vs Placebo on CVD
Study %
Dormandy 0.94 (0.75, 1.19) 97.81
PNFP012 0.16 (0.01, 3.89) 0.53
Saad 1.38 (0.06, 33.00) 0.54
Sourij 0.33 (0.01, 7.74) 0.55
Miyazaky 0.31 (0.01, 6.85) 0.56
.00659 1 152
148
eFigure 27C Pioglitazone vs Placebo on MI
Study %
PNFP-014 1.48 (0.06, 36.26) 0.38
PNFP-026 0.32 (0.01, 7.69) 0.39
OPI-502 0.34 (0.01, 8.24) 0.39
PNFP-012 0.16 (0.01, 3.89) 0.39
PNFP-001 0.24 (0.02, 3.80) 0.52
GLAT 0.34 (0.01, 8.34) 0.39
IRIS 0.73 (0.51, 1.03) 31.82
PROactive 0.83 (0.65, 1.06) 65.73
.00659 1 152
149
eFigure 27D Pioglitazone vs Placebo on HF
Study %
PNFP-014 3.47 (0.18, 66.88) 0.61
PNFP-027 2.86 (0.12, 69.65) 0.52
GLAT 0.34 (0.01, 8.34) 0.52
PROactive 1.41 (1.10, 1.80) 88.17
TOSCA.IT 1.57 (0.76, 3.24) 10.17
.0141 1 71
150
eFigure 28A Insulin vs control on CVD
Study %
UGDP 0.96 (0.72, 1.29) 11.38
UKPDS 1998 1.00 (0.81, 1.24) 20.71
ORIGIN 1.00 (0.89, 1.13) 67.91
.718 1 1.39
151
eFigure 28B Insulin vs control on MI
Study %
Davles 2009 0.34 (0.01, 8.24) 0.15
Aschner 2012 0.37 (0.02, 9.07) 0.15
ORIGIN 1.02 (0.88, 1.19) 68.08
UKPDS 0.87 (0.70, 1.09) 31.62
.014 1 71.7
152
eFigure 28C Insulin vs control on Stroke
Study %
DIGAMI 2 2011 1.47 (0.60, 3.60) 2.54
ORIGIN 1.03 (0.89, 1.21) 85.78
UKPDS 0.86 (0.57, 1.31) 11.69
.278 1 3.6
153
eFigure 28D Insulin vs control on HF
Study %
DIGAMI 2 2011 0.49 (0.24, 1.03) 1.94
ORIGINrigin 2012 0.91 (0.78, 1.05) 46.92
UKPDS 1998 0.76 (0.49, 1.18) 5.31
ORIGIN 0.90 (0.77, 1.05) 43.63
UKPDS 0.78 (0.39, 1.55) 2.20
.235 1 4.25
154
eFigure 28E Insulin vs control on UA
Study %
UKPDS 1998 1.11 (0.84, 1.45) 35.44
ORIGIN 0.91 (0.76, 1.08) 64.56
Inestimable predictive distribution with <3 studies . ( - , - )
.689 1 1.45
155
eFigure 29A Metformin vs control on MACE
Study %
Hermann [32] 3.53 (0.15, 81.11) 0.13
Klein [35] 5.00 (0.25, 99.16) 0.14
Shernthaner [40] 1.05 (0.59, 1.85) 3.86
Teupe [43] 3.00 (0.13, 71.92) 0.13
Kahn (ADOPT, [47]) 1.12 (0.82, 1.54) 12.75
Kooy 1.01 (0.71, 1.45) 9.81
Home (RECORD) 1.02 (0.84, 1.24) 32.23
UKPDS 34 0.72 (0.56, 0.93) 19.38
UKPDS 34 0.98 (0.74, 1.29) 16.25
Lund 0.42 (0.08, 2.05) 0.50
Ramachandran 0.86 (0.26, 2.77) 0.92
Knowler (DPP) 0.77 (0.43, 1.36) 3.89
.0101 1 99.2
156
eFigure 29B Metformin vs control on MI
Study %
Hermann 3.53 (0.15, 81.11) 0.44
Klein 3.00 (0.13, 70.30) 0.44
Schweizer 10.33 (0.50, 214.45) 0.48
Teupe 3.00 (0.13, 71.92) 0.43
Kahn (ADOPT) 1.02 (0.62, 1.68) 17.59
Kooy 1.11 (0.67, 1.83) 17.38
UKPDS 34 0.73 (0.53, 1.01) 42.60
UKPDS 34 0.94 (0.60, 1.49) 20.64
.00466 1 214
157
eFigure 29C Metformin vs control on Stroke
Study %
Klein 3.00 (0.13, 70.30) 1.09
Kahn (ADOPT) 1.15 (0.65, 2.01) 34.33
Kooy 0.99 (0.40, 2.44) 13.27
UKPDS 34 0.58 (0.32, 1.04) 30.66
UKPDS 34 1.16 (0.56, 2.39) 20.66
.0142 1 70.3
158
eFigure 29D Metformin vs control on HF
Study %
Kahn (ADOPT) 1.22 (0.69, 2.15) 49.08
Kooy 0.74 (0.17, 3.27) 7.18
UKPDS 34 0.78 (0.37, 1.64) 28.51
UKPDS 34 1.51 (0.54, 4.17) 15.23
.168 1 5.94
159
eFigure 30A Metformin vs placebo on MACE
Study %
Hermann 3.53 (0.15, 81.11) 0.31
Teupe 3.00 (0.13, 71.92) 0.30
Kooy 1.01 (0.71, 1.45) 21.51
UKPDS 34 0.65 (0.49, 0.87) 31.79
UKPDS 34 0.98 (0.74, 1.29) 33.64
Lund 0.42 (0.08, 2.05) 1.20
Ramachandran 0.86 (0.26, 2.77) 2.20
Knowler (DPP) 0.77 (0.43, 1.36) 9.04
.0123 1 81.1
160
eFigure 30B Metformin vs placebo on CVD
Study %
Holman et al (2008) 0.81 (0.64, 1.03) 40.86
Horton et al (2000a) 2.90 (0.12, 70.69) 1.32
Kooy et al (2009) 3.96 (0.45, 35.10) 2.74
Rachmani et al (2002) 0.98 (0.70, 1.36) 35.34
UKPDS (1998) 1.93 (1.01, 3.69) 19.74
.0141 1 70.7
161
eFigure 30C Metformin vs placebo on MI
Study %
Gram et al (2011) 0.95 (0.49, 1.87) 6.41
Hermann et al (2001) 2.82 (0.12, 64.39) 0.30
Holman et al (2008) 0.77 (0.61, 0.98) 50.85
H?llsten et al (2002) 3.21 (0.14, 72.55) 0.30
Kooy et al (2009) 0.99 (0.25, 3.90) 1.55
Rachmani et al (2002) 0.98 (0.70, 1.36) 26.82
UKPDS (1998) 1.07 (0.67, 1.69) 13.77
.0138 1 72.5
162
eFigure 30D Metformin vs placebo on Stroke
Study %
Gram et al (2011) 1.52 (0.26, 9.02) 4.06
Holman et al (2008) 0.97 (0.63, 1.49) 69.74
Kooy et al (2009) 0.99 (0.06, 15.71) 1.68
UKPDS (1998) 1.16 (0.56, 2.39) 24.52
.0624 1 16
163
eFigure 30E Metformin vs placebo on HF
Study %
Kahn (ADOPT) 1.22 (0.69, 2.15) 49.08
Kooy 0.74 (0.17, 3.27) 7.18
UKPDS 34 0.78 (0.37, 1.64) 28.51
UKPDS 34 1.51 (0.54, 4.17) 15.23
.168 1 5.94
164
eFigure 31 Acarbose vs placebo on cardiovascular outcomes
Study %
MI
Hanefeld 2004(7 trials) 0.36 (0.16, 0.80) 37.43
ACE 1.12 (0.87, 1.46) 44.39
STOP-NIDDM 0.09 (0.01, 0.72) 18.17
.with estimated predictive interval . (0.00, 397906.89)
.
Stroke
Hanefeld 2004(7 trials) 0.75 (0.31, 1.81) 11.33
ACE 0.97 (0.70, 1.33) 85.66
STOP-NIDDM 0.56 (0.10, 3.07) 3.01
.
UA
Hanefeld 2004(7 trials) 0.79 (0.45, 1.36) 25.13
ACE 1.02 (0.82, 1.26) 66.05
STOP-NIDDM 0.45 (0.16, 1.28) 8.82
.
.01 1 100
165

Association of Glucose-Lowering Medications With Cardiovascular Outcome Appendix

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Association of Glucose-Lowering Medications With Cardiovascular Outcome Appendix

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Supplementary appendix

Supplement to: Zhu J, Yu X, Zheng Y, et al. Association of glucose-lowering

eAppendix A. Search strategies Page 1

eTable 2. eTable 2. Baseline characteristics of CVOTs included Page 5-8

medications on cardiovascular outcomes

Search strategy of Pubmed for meta-analysis

("Diabetes mellitus"[Mesh] OR "Prediabetic State"[Mesh] OR "Diabetes"[tiab] OR "Prediabetes"[tiab] OR

This strategy is adapted to identify trials in other electronic databases

Search strategy of Pubmed for RCT

("Diabetes mellitus"[Mesh] OR "Prediabetic State"[Mesh] OR "Diabetes"[tiab] OR "Prediabetes"[tiab] OR

This strategy is adapted to identify trials in other electronic databases

McInnes 2015 Vildagliptin / T2DM / / / 50.3w Patient level /

Ferdinand 2016 Dulaglutide / T2DM / / / 12-104w Trial level /

Seshasai 2015 Taspoglutide / T2DM / / / 7478 person- Trial level /

Salsali 2016 Empagliflozin / T2DM / / / 24w-3.1y Trial level /

Zelniker 2019 SGLT2I 2 T2DM PRISMA Cochrane ND 2.4-4.2y Trial level 9

Lincoff 2007 Pioglitazone / T2DM / / / 4 m to 3.5 y Patient level /

Mannucci 2008 Pioglitazone 3 T2DM Unclear No No 8-156w Trial level 7

Erpeldinger 2016 Insulin 3 T2DM PRISMA Cochrane No 24w-10y Trial level 7

Li 2016 Insulin 7 T2DM Unclear Cochrane No 1.1-10y Trial level 7

MACE No Serious No Serious No Serious No Serious Reporting biasf Moderate

CVD No Serious No Serious No Serious No Serious Undetected High

MI No Serious No Serious No Serious No Serious Undetected High

Stroke No Serious No Serious No Serious No Serious Undetected High

HF No Serious Seriousb No Serious No Serious Undetected Moderate

UA No Serious No Serious No Serious No Serious Undetected High

MACE No Serious No Serious No Serious No Serious Undetected High

CVD No Serious No Serious No Serious No Serious Undetected High

MI No Serious No Serious No Serious No Serious Undetected High

Stroke No Serious No Serious No Serious No Serious Undetected High

HF No Serious No Serious No Serious No Serious Undetected High

UA No Serious No Serious No Serious No Serious Undetected High

MACE No Serious No Serious No Serious No Serious Undetected High

CVD No Serious No Serious No Serious Seriousc Undetected Moderate

Stroke No Serious No Serious No Serious Very Seriousd Undetected Low

UA No Serious No Serious No Serious Very Seriousd Undetected Low

MACE No Serious No Serious No Serious No Serious Undetected High

CVD No Serious No Serious No Serious No Serious Undetected High

MI No Serious No Serious No Serious No Serious Undetected High

Stroke No Serious Seriousb No Serious Seriousc Undetected Low

UA No Serious No Serious No Serious Seriousc Undetected Moderate

MACE No Serious No Serious No Serious No Serious Undetected High

CVD No Serious No Serious No Serious No Serious Undetected High

MI No Serious No Serious No Serious Very Seriousd Undetected Low

UA No Serious No Serious No Serious Seriousc Undetected Moderate

MACE No Serious No Serious No Serious No Serious Undetected High

CVD No Serious No Serious No Serious No Serious Undetected High

MI No Serious No Serious No Serious No Serious Undetected High

Stroke No Serious No Serious No Serious No Serious Undetected High

HF No Serious No Serious No Serious No Serious Undetected High

MACE Seriousa No Serious No Serious Seriousc Undetected Low

MI Seriousa No Serious No Serious Very Seriousd Undetected Very Low

HF Seriousa No Serious No Serious Very Seriousd Undetected Very Low

MI No Serious No Serious No Serious Very Seriousd Undetected Low

MACE No Serious No Serious No Serious No Serious Undetected High

CVD No Serious No Serious No Serious No Serious Undetected High

MI No Serious No Serious No Serious No Serious Undetected High

Stroke No Serious No Serious No Serious No Serious Undetected High

HF No Serious No Serious No Serious No Serious Undetected High

UA No Serious No Serious No Serious No Serious Undetected High

MACE No Serious No Serious No Serious No Serious Undetected High

CVD No Serious No Serious No Serious No Serious Undetected High