International Journal of Cardiology · Web viewYale JF, Bakris G, Cariou B, et al. Efficacy and...

SUPPLEMENTAL MATERIAL

ONLINE REFERENCES

[1*] Ahren B, Johnson SL, Stewart M, et al. HARMONY 3: 104-Week Randomized,

Double-Blind, Placebo- and Active-Controlled Trial Assessing the Efficacy and Safety

of Albiglutide Compared With Placebo, Sitagliptin, and Glimepiride in Patients With

Type 2 Diabetes Taking Metformin. Diabetes Care 2014;37:2141–2148.

[2*] Al Sifri S, Basiounny A, Echtay A, et al. The incidence of hypoglycaemia in Muslim

patients with type 2 diabetes treated with sitagliptin or asulphonylurea during

Ramadan: a randomised trial. Int J Clin Pract 2011;65:1132-1140.

[3*] Arechavaleta R, Seck T, Chen Y, et al. Efficacy and safety of treatment with

sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on

metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes

Obes Metab 2011;13:160-168.

[4*] Aschner P, Chan J, Owens DR, et al. Insulin glargine versus sitagliptin in insulin-

naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a

multicentre, randomised open-label trial. Lancet 2012;379:2262-2269.

[5*] Aschner P, Katzeff HL, Guo H, et al. Efficacy and safety of monotherapy of

sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes

Metab 2010;12:252-261.

[6*] Bajaj M, Gilman R, Patel S, Kempthorne-Rawson J, Lewis-D’Agostino D, Woerle

HJ. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in

patients with Type 2 diabetes inadequately controlled by a combination of metformin

and pioglitazone: a 24-week randomized, double-blind study. Diabet Med

2014;31:1505–1514.

[7*] Barnett AH, Patel S, Harper R, et al. Linagliptin monotherapy in type 2 diabetes

patients for whom metformin is inappropriate: an 18-week randomized, double-blind,

1

placebo-controlled phase III trial with a 34-week active-controlled extension. Diabetes

Obes Metab 2012;14:1145-1154.

[8*] Barnett AH, Huisman H, Jones R, von Eynatten M, Patel S, Woerle HJ. Linagliptin

for patients aged 70 years or older with type 2 diabetes inadequately controlled with

common antidiabetes treatments: a randomised, double-blind, placebo-controlled

trial. Lancet 2013;382:1413–1423.

[9*] Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as

add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or

insulin combined with metformin. Curr Med Res Opin 2012;28:513-523.

[10*]Bergenstal RM, Wysham C, Macconell L, et al. Efficacy and safety of exenatide

once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for

treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet

2010;376:431-439.

[11*]Bergenstal RM, Forti A, Chiasson JL, Woloschak M, Boldrin M, Balena R. Efficacy

and safety of taspoglutide versus sitagliptin for type 2 diabetes mellitus (T-emerge 4

trial). Diabetes Ther 2012;3:13.

[12*]Blonde L, Dagogo-Jack S, Banerji MA, et al. Comparison of vildagliptin and

thiazolidinedione as add-on therapy in patients inadequately controlled with

metformin: results of the GALIANT trial--a primary care, type 2 diabetes study.

Diabetes Obes Metab 2009;11:978-986.

[13*]Bolli G, Dotta F, Colin L, Minic B, Goodman M. Comparison of vildagliptin and

pioglitazone in patients with type 2 diabetes inadequately controlled with metformin.

Diabetes Obes Metab 2009;11:589-595.

[14*]Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on

glucose control over 24 weeks in patients with type 2 diabetes inadequately

controlled with metformin. Diabetes Care 2007;30:890-895.

2

[15*]Bosi E, Dotta F, Jia Y, Goodman M. Vildagliptin plus metformin combination therapy

provides superior glycaemic control to individual monotherapy in treatment-naive

patients with type 2 diabetes mellitus. Diabetes Obes Metab 2009;11:506-515.

[16*]Chacra AR, Tan GH, Ravichandran S, List J, Chen R; CV181040 Investigators.

Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea

versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res 2011;8:150-159.

[17*]Del Prato S, Camisasca R, Wilson C, Fleck P. Durability of the efficacy and safety

of alogliptin compared with glipizide in type 2 diabetes mellitus: a 2-yearstudy.

Diabetes Obes Metab 2014;16:1239-1246.

[18*]Dobs AS, Goldstein BJ, Aschner P, et al. Efficacy and safety of sitagliptin added to

ongoing metformin and rosiglitazone combination therapy in a randomized placebo-

controlled 54-week trial in patients with type 2 diabetes. J Diabetes 2013;5:68-79.

[19*]Durán-Garcia S, Lee J, Yki-Järvinen H, et al. Efficacy and safety of linagliptin as

add-on therapy to basal insulin and metformin in people with Type 2diabetes. Diabet

Med 2015. doi: 10.1111/dme.13041.

[20*]Ferrannini E, Fonseca V, Zinman B, et al. Fifty-two-week efficacy and safety of

vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately

controlled on metformin monotherapy. Diabetes Obes Metab 2009;11:157-166.

[21*]Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and

gliclazide in combination with metformin in patients with Type 2 diabetes

inadequately controlled with metformin alone: a 52-week, randomized study. Diabet

Med 2010;27:318-326.

[22*]Fonseca V, Zhu T, Karyekar C, Hirshberg B. Adding saxagliptin to extended-release

metformin vs. uptitrating metformin dosage. Diabetes Obes Metab 2012; 14:365-371.

3

[23*]Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of

vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia

2007;50:1148-1155.

[24*]Fonseca V, Staels B, Morgan JD 2nd, et al. Efficacy and safety of sitagliptin added

to ongoing metformin and pioglitazone combination therapy in a randomized,

placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes

Complications 2013;27:177-183.

[25*]Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of

the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naïve patients with type 2

diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr 2012;4:36.

[26*]Gallwitz B, Rosenstock J, Rauch T, et al. 2-year efficacy and safety of linagliptin

compared with glimepiride in patients with type 2 diabetes inadequately controlled on

metformin: a randomised, double-blind, non-inferiority trial. Lancet 2012;380:475-

483.

[27*]Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in

combination with pioglitazone improves glycaemic control in patients with type 2

diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled

study. Diabetes Obes Metab 2007;9:166-174.

[28*]Göke B, Hershon K, Kerr D, et al. Efficacy and safety of vildagliptin monotherapy

during 2-year treatment of drug-naïve patients with type 2 diabetes: comparison with

metformin. Horm Metab Res 2008;40:892-895.

[29*]Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial

combination of linagliptin and metformin improves glycaemic control in type 2

diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes

Metab 2012;14:565-574.

4

[30*]Hermans MP, Delibasi T, Farmer I, et al. Effects of saxagliptin added to sub-

maximal doses of metformin compared with uptitration of metformin in type 2

diabetes: the PROMPT study. Curr Med Res Opin 2012;28:1635-1645.

[31*]Hollander PL, Li J, Frederich R, Allen E, Chen R; CV181013 Investigators. Safety

and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with

type 2 diabetes mellitus. Diab Vasc Dis Res 2011;8:125-135.

[32*]Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy provides superior

glycaemic control versus placebo or voglibose with comparable safety in Japanese

patients with type 2 diabetes: a randomized, placebo and active comparator-

controlled, double-blind study. Diabetes Obes Metab 2012;14:348-357.

[33*]Kikuchi M, Abe N, Kato M, Terao S, Mimori N, Tachibana H. Vildagliptin dose-

dependently improves glycemic control in Japanese patients with type 2 diabetes

mellitus. Diabetes Res Clin Pract 2009;83:233-240.

[34*]Kothny W, Shao Q, Groop PH, Lukashevich V. One-year safety, tolerability and

efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal

impairment. Diabetes Obes Metab 2012;14:1032-1039.

[35*]Kothny W, Foley J, Kozlovski P, Shao Q, Gallwitz B, Lukashevich V. Improved

glycaemic control with vildagliptin added to insulin, with or without metformin, in

patients with type 2 diabetes mellitus. Diabetes Obes Metab 2013;15:252-257.

[36*]Leiter LA, Carr MC, Stewart M, et al. Efficacy and safety of the once-weekly GLP-1

receptor agonist albiglutide versus sitagliptin in patients with type2 diabetes and renal

impairment: a randomized phase III study. Diabetes Care 2014;37:2723-2730.

[37*]Lewin AJ, Arvay L, Liu D, Patel S, von Eynatten M, Woerle HJ. Efficacy and

tolerability of linagliptin added to a sulfonylurea regimen in patients with inadequately

controlled type 2 diabetes mellitus: an 18-week, multicenter, randomized, double-

blind, placebo-controlled trial. Clin Ther 2012;34:1909-1919.

5

[38*]Lukashevich V, Del Prato S, Araga M, Kothny W. Efficacy and safety of vildagliptin

in patients with type 2 diabetes mellitus inadequately controlled with dualcombination

of metformin and sulphonylurea. Diabetes Obes Metab 2014;16:403-409.

[39*]Lukashevich V, Schweizer A, Shao Q, Groop PH, Kothny W. Safety and efficacy of

vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe

renal impairment: a prospective 24-week randomized placebo-controlled trial.

Diabetes Obes Metab 2011;13:947-954.

[40*]Mathieu C, Shankar RR, Lorber D, et al. A Randomized Clinical Trial to Evaluate

the Efficacy and Safety of Co-Administration of Sitagliptin withIntensively Titrated

Insulin Glargine. Diabetes Ther 2015;6:127-142.

[41*]Matthews DR, Dejager S, Ahren B, et al. Vildagliptin add-on to metformin produces

similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no

weight gain: results from a 2-year study. Diabetes Obes Metab 2010;12:780-789.

[42*]Mita T, Katakami N, Yoshii H, et al. Alogliptin, a Dipeptidyl Peptidase 4 Inhibitor,

Prevents the Progression of Carotid Atherosclerosis in PatientsWith Type 2 Diabetes:

The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A).

Diabetes Care 2016;39:139-148.

[43*]Mohan V, Yang W, Son HY, et al. Efficacy and safety of sitagliptin in the treatment

of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract

2009;83:106-116.

[44*]Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 008 Group.

Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to

metformin therapy in patients with type 2 diabetes inadequately controlled with

metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled

study. Int J Clin Pract 2009;63:46-55.

6

[45*]Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z.

Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2

Diabetes in a Randomized Controlled Trial (AWARD-5). Diabetes Care

2014;37:2149-2158.

[46*] www.clinicaltrials.gov

[47*]Olansky L, Reasner C, Seck TL, et al. A treatment strategy implementing

combination therapy with sitagliptin and metformin results in superior glycaemic

control versus metformin monotherapy due to a low rate of addition of

antihyperglycaemic agents. Diabetes Obes Metab 2011;13:841-849.

[48*]Pan C, Xing X, Han P, et al. Efficacy and tolerability of vildagliptin as add-on

therapy to metformin in Chinese patients with type 2 diabetes mellitus. Diabetes

Obes Metab 2012;14:737-744.

[49*]Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin

in drug-naïve Asian patients with type 2 diabetes mellitus: a randomized controlled

trial. Diabetes Metab Res Rev 2012;28:268-275.

[50*]Pfützner A, Paz-Pacheco E, Allen E, Frederich R, Chen R; CV181039 Investigators.

Initial combination therapy with saxagliptin and metformin provides sustained

glycaemic control and is well tolerated for up to 76 weeks. Diabetes Obes Metab

2011;13:567-576.

[51*]Philis-Tsimikas A, Del Prato S, Satman I, et al. Effect of insulin degludec versus

sitagliptin in patients with type 2 diabetes uncontrolled on oral antidiabeticagents.

Diabetes Obes Metab 2013;15(8):760-766.

[52*]Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to

pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-

controlled study. Curr Med Res Opin 2009;25:2361-2371.

7

[53*]Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with

type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-

week, randomised, parallel-group, open-label trial. Lancet 2010;375:1447-1456.

[54*]Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl

peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose

response. Diabetes Obes Metab 2005;7:692-698.

[55*]Roden M, Merker L, Christiansen AV, et al. Safety, tolerability and effects on

cardiometabolic risk factors of empagliflozin monotherapy in drug-naïvepatients with

type 2 diabetes: a double-blind extension of a Phase III randomized controlled trial.

Cardiovasc Diabetol 2015;14:154.

[56*]Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in

treatment-naïve patients with type 2 diabetes. Curr Med Res Opin 2009;25:2401-

2411.

[57*]Rosenstock J, Wilson C, Fleck P. Alogliptin versus glipizide monotherapy in elderly

type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-

blind, randomized, 1-year study. Diabetes Obes Metab 2013;15:906-914.

[58*]Rosenstock J, Niggli M, Maldonado-Lutomirsky M. Long-term 2-year safety and

efficacy of vildagliptin compared with rosiglitazone in drug-naïve patients with type 2

diabetes mellitus. Diabetes Obes Metab 2009;11:571-578.

[59*]Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of

vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-

week, double-blind, randomized trial. Diabetes Care 2007;30:217-223.

[60*]Rosenstock J, Gross JL, Aguilar-Salinas C, et al. Long-term 4-year safety of

saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes. Diabet

Med 2013;30:1472-1476.

8

[61*]Ross SA, Rafeiro E, Meinicke T, Toorawa R, Weber-Born S, Woerle HJ. Efficacy

and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in patients with

type 2 diabetes inadequately controlled on metformin: a randomised, double-blind,

placebo-controlled trial. Curr Med Res Opin 2012;28:1465-1474.

[62*]Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide

once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in

drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind

study. Diabetes Care 2012;35:252-258.

[63*]Scherbaum WA, Schweizer A, Mari A, et al. Efficacy and tolerability of vildagliptin in

drug-naïve patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes

Metab 2008;10:675-682.

[64*]Schernthaner G, Durán-Garcia S, Hanefeld M, et al. Efficacy and tolerability of

saxagliptin compared with glimepiride in elderly patients with type 2 diabetes:

arandomized, controlled study (GENERATION). Diabetes Obes Metab 2015;17:630-

638.

[65*]Schweizer A, Dejager S, Bosi E. Comparison of vildagliptin and metformin

monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind,

randomized trial. Diabetes Obes Metab 2009;11:804-812.

[66*]Schweizer A, Couturier A, Foley JE, Dejager S. Comparison between vildagliptin

and metformin to sustain reductions in HbA(1c) over 1 year in drug-naïve patients

with Type 2 diabetes. Diabet Med 2007;24:955-961.

[67*]Seck T, Nauck M, Sheng D, et al. Safety and efficacy of treatment with sitagliptin or

glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-

year study. Int J Clin Pract 2010;64:562-576.

[68*]Seino Y, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin added to

sulfonylurea in Japanese patients with type 2 diabetes: A randomized, double-blind,

9

placebo-controlled trial with an open-label, long-term extension study. J Diabetes

Investig 2012;3:517-525.

[69*]Seino Y, Fujita T, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin in

Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-

ranging comparison with placebo, followed by a long-term extension study. Curr Med

Res Opin 2011;27:1781-1792.

[70*]Strain WD, Lukashevich V, Kothny W, Hoellinger MJ, Paldánius PM. Individualised

treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or

lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled

study. Lancet 2013;382:409-416.

[71*]Williams-Herman D, Johnson J, Teng R, et al. Efficacy and safety of sitagliptin and

metformin as initial combination therapy and as monotherapy over 2 years in patients

with type 2 diabetes. Diabetes Obes Metab 2010;12:442-451.

[72*] Yang W, Xing X, Lv X, et al. Vildagliptin added to sulfonylurea improves glycemic

control without hypoglycemia and weight gain in Chinese patients with type 2

diabetes mellitus. J Diabetes 2015;7:174-181.

[73*]Yoon KH, Steinberg H, Teng R, et al. Efficacy and safety of initial combination

therapy with sitagliptin and pioglitazone in patients with type 2diabetes: a 54-week

study. Diabetes Obes Metab 2012;14:745-752.

[74*]Amin NB, Wang X, Jain SM, Lee DS, Nucci G, Rusnak JM. Dose-ranging efficacy

and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in

patientswith type 2 diabetes on a background of metformin. Diabetes Obes Metab

2015;17:591-598.

[75*]Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin

add-on to metformin in type 2 diabetes inadequately controlled with metformin: a

randomized, double-blind, placebo-controlled 102-week trial. BMC Med 2013;11:43.

10

[76*]Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added

to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney

disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes

Endocrinol 2014;2:369-384.

[77*]Bode B, Stenlöf K, Harris S, et al. Long-term efficacy and safety of canagliflozin

over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes

Metab 2015;17:294-303.

[78*]Cefalu WT, Leiter LA, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ.

Dapagliflozin's Effects on Glycemia and Cardiovascular Risk Factors in High-Risk

Patients With Type 2 Diabetes: A 24-Week, Multicenter, Randomized, Double-Blind,

Placebo-Controlled Study With a 28-Week Extension. Diabetes Care 2015;38:1218-

1227.

[79*]Del Prato S, Nauck M, Durán-Garcia S, et al. Long-term glycaemic response and

tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in

patients with type 2 diabetes: 4-year data. Diabetes Obes Metab 2015;17:581-590.

[80*]Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A

Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin

in patients with type 2 diabetes. Diabetes Obes Metab 2013;15:721-728.

[81*]Fulcher G, Matthews DR, Perkovic V, et al. Efficacy and safety of canagliflozin

when used in conjunction with incretin-mimetic therapy in patients with type 2

diabetes. Diabetes Obes Metab 2016;18:82-91.

[82*]Haering HU, Merker L, Christiansen AV, et al. Empagliflozin as add-on to metformin

plus sulphonylurea in patients with type 2 diabetes. Diabetes Res Clin Pract

2015;110:82-90.

11

[83*]Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF.

Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a

randomised controlled trial. Int J Clin Pract 2012;66:446-456.

[84*]Jabbour SA, Hardy E, Sugg J, Parikh S; Study 10 Group. Dapagliflozin is effective

as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter,

randomized, double-blind, placebo-controlled study. Diabetes Care 2014;37:740-750.

[85*]Kaku K, Inoue S, Matsuoka O, et al. Efficacy and safety of dapagliflozin as a

monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate

glycaemic control: a phase II multicentre, randomized, double-blind, placebo-

controlled trial. Diabetes Obes Metab 2013;15:432-440.

[86*]Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2

diabetes and moderate renal impairment shows that dapagliflozin reduces weight

and blood pressure but does not improve glycemic control. Kidney Int 2014;85:962-

971.

[87*]Kovacs CS, Seshiah V, Merker L, et al. Empagliflozin as Add-on Therapy to

Pioglitazone With or Without Metformin in Patients With Type 2 Diabetes Mellitus.

Clin Ther 2015;37:1773-1788.e1.

[88*]Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ.

Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with

preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-

blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc

2014;62:1252-1262.

[89*]Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides durable glycemic

improvements and body weight reduction over 104 weeks versus glimepiride in

patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3

study. Diabetes Care 2015; 38:355-364.

12

[90*]Mathieu C, Ranetti AE, Li D, et al. Randomized, Double-Blind, Phase 3 Trial of

Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2

Diabetes. Diabetes Care 2015;38:2009-2017.

[91*]Merker L, Häring HU, Christiansen AV, et al. Empagliflozin as add-on to metformin

in people with Type 2 diabetes. Diabet Med 2015;32:1555-1567.

[92*]Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an

inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin

therapy in patients with type 2 diabetes. Diabetes Care 2015;38:403-411.

[93*]Ridderstråle M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and

glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week

randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes

Endocrinol 2014;2:691-700.

[94*]Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2

inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2

diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care

2012;35:1473-1478.

[95*]Rosenstock J, Jelaska A, Zeller C, et al. Impact of empagliflozin added on to basal

insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week

randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab

2015;17:936-948.

[96*]Stenlöf K, Cefalu WT, Kim KA, et al. Long-term efficacy and safety of canagliflozin

monotherapy in patients with type 2 diabetes inadequately controlled with diet and

exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin

2014;30:163-175.

[97*]Strojek K, Yoon KH, Hruba V, Sugg J, Langkilde AM, Parikh S. Dapagliflozin added

to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and

13

weight loss over 48 weeks: a randomized, double-blind, parallel-group, placebo-

controlled trial. Diabetes Ther 2014;5:267-283.

[98*]Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in

patients with type 2 diabetes and hypertension. Diabetes Care 2015;38:420-428.

[99*]Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S; Dapagliflozin 006 Study

Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin:

efficacy and safety over 2 years. Diabetes Obes Metab 2014;16:124-136.

[100*] Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52

weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes

Obes Metab 2014;16:1016-1027.

14

Author/trialClinicalTrials.govIdentifier

Year Treatment Control Treatment

(n)Control

(n)Total

(n)

Follow-up

(weeks)

Age(yrs)

Women(%)

Years

DMBMI

DPP4-Is

Ahren B (HARMONY 3)1* NCT00838903 2014 Sita Pla/Met/Glime/Albi

302 710 1012 156 55 53 NA NA

Al Sifri (RAMADAN study)2* NCT01131182 2011 Sita Su 507 514 1021 4 55 49 5.5 31Arechavaleta R3* NCT00701090 2011 Sita Glime 516 519 1035 30 56 46 6.7 30Aschner P (EASIE)4* NCT00751114 2012 Sita Insuline

Glargine265 250 515 26 54 45 4.4 31

Aschner P5* NCT00449930 2010 Sita Met 528 522 1050 24 56 46 2.4 31Bajaj M6* NCT00996658 2014 Lina Pla 183 89 272 25 54 51 NA 28Barnett AH7* NCT00740051 2012 Lina Pla/

Glime151 76 227 52 57 61 NA 29

Barnett AH8* NCT01084005 2013 Lina Pla 162 79 241 24 75 32 NA 30Barnett AH9* NCT00757588 2012 Saxa Pla 304 151 455 52 57 59 11.9 32Bergenstal RM (DURATION-2)10*

NCT00637273 2010 Sita Pio 166 165 331 26 52 50 5.5 32

Bergenstal RM11* NCT00754988 2012 Sita Taspo 177 369 546 156 57 44 6 33Blonde L (GALIANT Trial)12* NCT00396627 2009 Vilda TZD 1776 888 2664 12 56 48 5.1 32Bolli G13* NCT00237237 2009 Vilda Pio 295 281 576 52 57 37 6.4 32Bosi E14* NCT00099892 2007 Vilda Pla 362 182 544 24 54 33 6.3 33Bosi E15* NCT00382096/

NCT004680392009 Vilda Met 300 294 594 24 53 41 2 31

Bosi E15* NCT00382096/NCT00468039

2009 Vilda Pla 585 294 879 24 53 43 2 31

Chacra AR16* NCT00313313 2011 Sax Pla 501 267 768 76 55 55 6.9 29Del Prato S (ENDURE)17* NCT00856284 2014 Alo Glipi 1765 874 2639 104 55 50 5.5 31Dobs AS18* NCT00350779 2013 Sita Pla 181 97 278 54 55 40 9.3 30Duran-Garcia S19* NCT00954447 2015 Lina Pla 631 630 1261 110 60 48 NA NA

15

Ferrannini E20* NCT00106340 2009 Vilda Glime 1396 1393 2789 52 57 47 5.7 32Filozof C21* NA 2010 Vilda Glicla 513 494 1007 52 59 48 6.6 31Fonseca V22* NCT00960076 2012 Saxa Pla 138 144 282 18 55 54 6.2 31Fonseca V23* NCT00099931 2007 Vilda Pla 144 152 296 24 59 49 14.7 33Fonseca V24* NCT00885352 2013 Sita Pla 157 156 313 26 56 38 9.8 30Frederich R.25* NCT00316082 2012 Saxa Pla 291 74 365 76 55 54 1.7 31Gallwitz B26* NCT00622284 2012 Lina Glime 776 775 1551 105 60 40 NA 30Garber AJ27* NCT00099853 2007 Vilda Pla 305 158 463 24 54 43 4.7 32Göke B28* NCT00138567 2008 Vilda Met 304 158 462 104 54 NA 2.4 NAGreen JB (TECOS)9 NCT00790205 2015 Sita Pla 7332 7339 14671 209 66 29 11.6 NAHaak T29* NCT00798161 2012 Lina Pla 428 363 791 24 55 66 NA 29Hermans MP (PROMPT)30* NCT01006590 2012 Saxa Pla 147 139 286 24 59 43 6.4 32Hollander PL31* NCT00295633 2011 Saxa Pla 381 184 565 76 54 50 5.2 30Kawamori R32* NCT00654381 2012 Lina Vogli 319 162 481 26 60 30 NA 25Kikuchi M33* NA 2009 Vilda Pla 219 72 291 12 59 40 5.3 24Kothny W34* NA 2012 Vilda Pla 216 153 369 52 66 44 24.1 30Kothny W35* NA 2013 Vilda Pla 228 221 449 24 59 50 63.8 29Leiter LA36* NCT01098539 2014 Sita Albi 246 249 495 26 NA 46 11.2 39Lewin AJ37* NCT00819091 2012 Lina Pla 161 84 245 19 57 47 NA 28Lukashevich V38* NA 2014 Vilda Pla 158 160 318 24 55 52 7.3 28Lukashevich V39* NA 2011 Vilda Pla 289 226 515 24 66 43 16.6 30Mathieu C40* NCT01462266 2015 Sita Pla 329 329 658 24 59 52 13.5 32Matthews DR41* NA 2010 Vilda Glime 1562 1556 3118 104 58 47 5.7 32McMurray J (VIVIDD study)10 NCT00894868 2013 Vilda Pla 128 126 254 52 NA NA NA NAMita T (SPEAD-A)42* NA 2016 Alo Conventi

onal Treatment

172 169 341 104 65 42 8.6 NA

Mohan V43* NCT00289848 2009 Sita Pla 352 178 530 18 51 42 2.0 25NaucK M44* NCT00286442 2009 Alo Pla 423 104 527 28 55 50 6.0 32Nauck M45* NCT00734474 2014 Sita Dula 315 606 921 54 54 53 7.0 31

16

NCT0008651546* NCT00086515 2015 Sita Pla/Glipi 464 237 701 104 55 43 NA NANCT0009475746* NCT00094757 2010 Sita Pla/Pio 411 110 521 54 55 46 NA NANCT0010670446* NCT00106704 2013 Sita Pla/Pio 222 219 441 54 56 47 NA NANCT0012719246* NCT00127192 2010 Sita Pla 290 73 363 12 60 38 NA NANCT0028642946* NCT00286429 2012 Alo Pla 260 130 390 26 NA 59 NA NANCT0028646846* NCT00286468 2012 Alo Pla 401 99 500 26 NA 48 NA NANCT0030960846* NCT00309608 2013 Lina Pla 197 71 268 16 60 43 NA 32NCT0032862746* NCT00328627 2013 Alo Pla 1037 517 1554 26 54 59 6.2 31NCT0039534346* NCT00395343 2010 Sita Pla 322 319 641 24 58 49 NA NANCT0039551246* NCT00395512 2013 Alo Pla/Pio 492 163 655 26 52 51 3.2 31NCT0039763146* NCT00397631 2015 Sita Pla 261 259 520 24 51 46 NA NANCT0050926246* NCT00509262 2014 Sita Gli 211 212 423 54 64 40 NA NANCT0057558846* NCT00575588 2012 Saxa Gli 428 430 858 104 58 48 NA NANCT0060125046* NCT00601250 2013 Lina Pla 523 177 700 24 57 46 NA 30NCT0060247246* NCT00602472 2013 Lina Pla 792 263 1055 24 58 53 NA 28NCT0064104346* NCT00641043 2014 Lina Pla 259 130 389 24 57 39 NA 29NCT0066136246* NCT00661362 2012 Saxa Pla 283 287 570 24 54 52 NA NANCT0072237146* NCT00722371 2015 Sita Pla 922 693 1615 54  NA 43 NA NANCT0081399546* NCT00813995 2011 Sita Pla 197 198 395 24 55 49 NA NANCT0091577246* NCT00915772 2013 Lina Pla 396 170 566 54 56 45 NA 29NCT0102358146* NCT01023581 2013 Alo Pla 225 109 334 26 53 50 3.9 31NCT0107607546* NCT01076075 2015 Sita Pla/Pio 213 214 427 54 55 54 NA NANCT0107608846* NCT01076088 2015 Sita Pla 120 127 247 24 53 35 NA NANCT0108750246* NCT01087502 2013 Lina Pla/

Glime113 122 235 52 67 37 NA 32

NCT0117738446* NCT01177384 2015 Sita Pla 191 190 381 24 57 49 NA NANCT0118301346* NCT01183013 2014 Lina Pla/Pio 501 392 893 54 57 46 NA NANCT0118989046* NCT01189890 2013 Sita Glime 241 239 480 30 71 58 NA NANCT0120429446* NCT01204294 2014 Lina Met 143 63 206 54 62 28 NA NANCT0121423946* NCT01214239 2013 Lina Pla 200 99 299 24 54 41 NA 25

17

NCT0121509746* NCT01215097 2013 Lina Pla 205 100 305 24 56 50 NA 26NCT0126348346* NCT01263483 2012 Alo Pla/Vogli 155 75 230 12  NA 38 NA NANCT0126349646* NCT01263496 2012 Alo Vogli 391 83 474 40 NA 28 NA NANCT0131807046* NCT01318070 2012 Alo Pla 224 115 339 12 NA NA NA NANCT0159079746* NCT01590797 2015 Sita Pla 234 233 467 26 58 47 NA NANCT0170890246* NCT01708902 2015 Lina Met 147 289 436 24 51 41 NA NANCT0188290746* NCT01882907 2015 Vilda Pio 117 111 228 16 55 57 NA 25NCT0200868246* NCT02008682 2015 Sita Lira 184 184 368 26 52 40 5.3 27Olansky L47* NCT00482729 2011 Sita Pla 625 621 1246 44 50 43 3.4 33Pan C48* NA 2012 Vilda Pla 294 144 438 24 54 53 5.0 26Pan CY49* NCT00698932 2012 Saxa Pla 284 284 568 24 51 45 1.0 26Pfützner A50* NCT00327015 2011 Saxa Pla/Met 978 328 1306 76 52 37 1.6 30Philis-Tsimikas51* NCT01046110 2013 Sita Insuline

Degludec222 225 447 26 56 36 7.8 30

Pratley RE52* NCT00286494 2009 Alo Pla 396 97 493 28 55 42 7.6 33Pratley RE53* NCT00700817 2010 Sita Lira 219 439 658 26 55 48 6.2 33Ristic S54* NA 2005 Vilda Pla 221 58 279 12 57 46 2.9 31Roden M55* NCT01289990 2015 Sita Pla 155 136 291 76 55 64 NA NARosenstock J56* NCT00121641 2009 Saxa Pla 306 95 401 209 53 49 NA 32Rosenstock J57* NCT00707993 2013 Alo Glipi 222 219 441 54 70 55 6.1 30Rosenstock J58* NCT00138619 2009 Vilda Rosi 396 202 598 80 54 43 2.2 38Rosenstock J59* NCT0009918 2007 Vilda Rosi 459 238 697 24 54 42 2.4 33Rosenstock J60* NCT00121667 2013 Saxa Pla 564 179 743 209 55 49 6.5 31Ross SA61* NCT01012037 2012 Lina Pla 447 44 491 12 59 43 NA 29Russel-Jones D (DURATION-4)62*

NCT00676338 2012 Sita Met/Pio 163 246 409 36 53 39 2.6 31

Scherbaum WA63* NCT00101712 2008 Vilda Pla 156 150 306 56 63 41 2.6 30Schernthaner G64* NCT01006603 2015 Saxa Glime 360 360 720 52 73 38 NA NASchweizer A65* NCT00246619 2009 Vilda Met 169 166 335 24 71 51 2.9 30Schweizer A66* NCT00099866 2007 Vilda Met 526 254 780 52 53 46 1.0 32Scirica BM (SAVOR-TIMI-53)7 NCT01107886 2013 Saxa Pla 8280 8212 16492 110 65 33 10.3 31

18

Seck T67* NCT00094770 2010 Sita Glipi 588 584 1172 104 57 41 5.8 31Seino Y68* NCT01318083 2012 Alo Pla 209 103 312 24 NA 35 NA 25Seino Y69* NCT01263470 2011 Alo Pla 322 75 397 52 59 27 6.6 25Strain WD (INTERVAL)70* NCT01257451 2013 Vilda Pla 139 139 278 24 75 55 11.4 30White WB (EXAMINE)8 NCT00968708 2013 Alo Pla 2701 2679 5380 174 61 32 7.2 30Williams-Herman D71* NCT00103857 2010 Sita Pla/Met 551 540 1091 54 NA NA NA 32Yang W72* NCT01357252 2015 Vilda Pla 143 136 279 24 58 43 6.9 25Yoon KH73* NCT01028391 2012 Sita Pla 164 153 317 30 52 44 2.1 30

SGLT2-IsAmin NB74* NCT01059825 2015 Ertug Pla 219 54 273 12 55 37 6.3 30Bailey CJ75* NCT00528879 2013 Dapa Pla 409 137 546 102 54 46 6.1 NABarnett AH (EMPA-REG RENAL)76*

NCT01164501 2014 Empa Pla 419 319 738 52 64 42 NA 32

Bode B77* NCT01106651 2015 Cana Pla 477 237 714 104 NA 44 11.7 32CANTATA-D46* NCT01106677 2013 Cana Pla 735 183 918 26 55 53 NA NACANTATA-MP46* NCT01106690 2013 Cana Pla 227 115 342 26 57 37 NA NACANTATAT-MSU46* NCT01106625 2013 Cana Pla 313 156 469 52 57 49 NA NACefalu WT78* NCT01031680 2015 Dapa Pla 455 459 914 52 63 32 12.4 32Del Prato S79* NCT00660907 2015 Dapa Glipi 406 408 814 209 59 45 6.5 31

Ferrannini E80* NCT00789035 2013 Empa Pla 244 82 326 12 58 50 NA 29Fulcher G (CANVAS-INCRETIN)81*

NCT01032629 2016 Cana Pla 214 102 316 18 62 34 13.4 32

Haering HU (EMPA-REG EXTENDED)82*

NCT01289990 2015 Empa Pla 441 225 666 76 57 49 NA NA

Henry RR83* NCT00859898 2012 Dapa Pla 430 208 638 24 NA NA NA NAHenry RR83* NCT00643851 2012 Dapa Pla 397 201 598 24 NA NA NA NAJabbour SA84* NCT00984867 2014 Dapa Pla 223 224 447 24 55 45 5.7 NAKaku K85* NCT00972244 2013 Dapa Pla 225 54 279 16 57 23 NA NAKohan DE86* NA 2014 Dapa Pla 168 84 252 104 67 35 16.9 NAKovacs CS (EMPA-REG EXTEND PIO)87*

NCT01210001 2015 Empa Pla 212 93 305 76 55 52 NA 29

Leiter LA88* NCT01042977 2014 Dapa Pla 480 482 962 52 64 33 13.2 33Leiter LA (CANTATA-SU)89* NCT00968812 2015 Cana Glime 968 482 1450 104 56 48 6.6 31

19

Mathieu C90* NCT01646320 2015 Dapa Pla 160 160 320 24 55 54 7.6 32Merker L (EMPA-REG EXTENDED MET)91*

NCT01289990 2015 Empa Pla 325 138 463 76 58 43 NA 29

NCT0052837246* NCT00528372 2015 Dapa Pla 483 75 558 102 NA 50 NA NANCT0064227846* NCT00642278 2013 Cana Pla 321 65 386 12 53 49 NA NANCT0074919046* NCT00749190 2014 Empa Pla 353 71 424 12 58 33 NA NANCT0088153046* NCT00881530 2014 Empa Met 215 56 271 78 58 50 NA NANCT0113747446* NCT01137474 2014 Dapa Pla 633 311 944 12 NA 44 NA NANCT0121789246* NCT01217892 2014 Dapa Pla 299 101 400 16 58 55 NA NANCT0136808146* NCT01368081 2014 Empa Met 273 63 336 52 61 28 NA NANCT0138190046* NCT01381900 2014 Cana Pla 450 226 676 18 56 46 NA NANCT0164929746* NCT01649297 2015 Empa Pla 876 107 983 17 58 45 NA NANeal B (CANVAS-INSULIN)92* NCT01032629 2015 Cana Pla 1382 690 2072 52 62 34 13.4 33Ridderstrale M (EMPA-REG H2H-SU)93*

NCT01167881 2014 Empa Glime 765 780 1545 104 56 45 NA 30

Roden M (EMPA-REG EXTENDED MONO)54*

NCT01289990 2015 Empa Pla 324 136 460 76 55 39 NA 29

Rosenstock J94* NCT00683878 2012 Dapa Pla 281 139 420 48 54 50 5.5 NARosenstock J (EMPA-REG BASAL)95*

NCT01011868 2015 Empa Pla 324 170 494 78 59 44 NA 32

Rosenstock J (EMPA-REG MDI)21

NCT01306214 2014 Empa Pla 375 188 563 52 57 55 NA 35

Stenlof K (CANTATA-M)96* NCT01081834 2014 Cana Pla 392 192 584 26 55 56 4.3 32Strojek K97* NCT00680745 2014 Dapa Pla 447 145 592 48 60 52 7.4 30Tikkanen I (EMPA-REG BP)98* NCT01370005 2015 Empa Pla 552 271 823 12 60 40 NA 33Wilding JP99* NCT00673231 2014 Dapa Pla 607 193 800 104 59 52 13.6 33Yale JF100* NCT01064414 2014 Cana Pla 179 90 269 52 69 39 17.3 33Zinman B (EMPA-REG OUTCOME)12

NCT01131676 2015 Empa Pla 4687 2333 7020 162 63 29 NA 31

Supplemental Table S1. Baseline characteristics of trials included in the analysis.

Albi: Albiglutide Alo: Alogliptin; Cana: Canagliflozin; Dapa: Dapagliflozin Dula: Dulaglutide; Empa: Empagliflozin; Ertu: Ertugliflozin; Glicla: Gliclazide; Glime: Glimepiride; Glipi: Glipizide; Glybu: Glyburide; Lina: Linagliptin; Lira: Liraglutide; Met: Metformin; NA: Not Available; Pio:

20

Pioglitazone; Pla: PlaCebo; Rosi: Rosigitazone; Saxa: Saxagliptin; Sita: Sitagliptin; Su: Sulfonylurea; Taspo: Taspoglutide; TZD: Thiazolidinediones; Vilda: Vildagliptin; Vogli: Voglibose; DM: Diabetes Mellitus; BMI: Body Mass Index. *denotes references reported in the Supplementary Data.

21

Supplemental Figure S1. Risk Ratios (RRs) of all-cause death in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

22

Supplemental Figure S2. Risk Ratios (RRs) of cardiovascular death in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

23

Supplemental Figure S3. Risk Ratios (RRs) of myocardial infarction in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

24

Supplemental Figure S4. Risk Ratios (RRs) of stroke in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

25

Supplemental Figure S5. Risk Ratios (RRs) of heart failure in DPP4-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

26

Supplemental Figure S6. Risk Ratios (RRs) of all-cause death in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

27

Supplemental Figure S7. Risk Ratios (RRs) of cardiovascular death in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

28

Supplemental Figure S8. Risk Ratios (RRs) of myocardial infarction in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

29

Supplemental Figure S9. Risk Ratios (RRs) of stroke in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

30

Supplemental Figure S10. Risk Ratios (RRs) of heart failure in SGLT2-Is. Solid squares represent RRs in trials and have a size proportional to the number of events. The 95% confidence intervals (CI) for individual trials are denoted by lines and those for the pooled RRs by empty diamonds.

31