Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
American Journal of Cardiovascular Drugs
Published in: American Journal of Cardiovascular Drugs 2/2017

01-04-2017 | Original Research Article

Cardiovascular Safety of Dipeptidyl-Peptidase IV Inhibitors: A Meta-Analysis of Placebo-Controlled Randomized Trials

Authors: Islam Y. Elgendy, Ahmed N. Mahmoud, Amr F. Barakat, Akram Y. Elgendy, Marwan Saad, Ahmed Abuzaid, Siddarth A. Wayangankar, Anthony A. Bavry

Published in: American Journal of Cardiovascular Drugs | Issue 2/2017

Login to get access

Abstract

Background

Large randomized trials have shown conflicting evidence regarding the cardiovascular safety of dipeptidyl-peptidase 4 (DPP-4) inhibitors. Systematic reviews have been limited by incomplete data and inclusion of observational studies. This study aimed to systematically evaluate the cardiovascular safety of DPP-4 inhibitors in patients with type 2 diabetes.

Methods

Electronic databases were searched for randomized trials that compared DPP-4 inhibitors versus placebo and reported cardiovascular outcomes. The main outcome assessed in this analysis was heart failure. Other outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction, and ischemic stroke. Summary odds ratios (ORs) were primarily constructed using Peto’s model.

Results

A total of 90 trials with 66,730 patients were included. Compared with placebo, DPP-4 inhibitors were associated with a non-significant increased risk of heart failure [OR 1.11, 95% confidence interval (CI) 0.99–1.25, P = 0.07] at a mean of 108 weeks. The risk of all-cause mortality (OR 1.03, 95% CI 0.94–1.12, P = 0.53), cardiovascular mortality (OR 1.02, 95% CI 0.92–1.14, P = 0.72), myocardial infarction (OR 0.98, 95% CI 0.88–1.09, P = 0.69), and ischemic stroke (OR 0.99, 95% CI 0.85–1.15, P = 0.92) was similar between both groups.

Conclusion

In patients with type 2 diabetes, the safety profile of DPP-4 inhibitors is similar to placebo. As a class, there is only weak evidence for an increased risk of heart failure.
Appendix
Available only for authorised users
Literature
1.
Selvin E, Parrinello CM, Sacks DB, Coresh J. Trends in prevalence and control of diabetes in the United States, 1988–1994 and 1999–2010. Ann Intern Med. 2014;160:517–25.PubMedPubMedCentralCrossRef
2.
3.
Kawalec P, Mikrut A, Łopuch S. The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014;30:269–83.PubMedCrossRef
4.
Murohara T. Dipeptidyl peptidase-4 inhibitor: another player for cardiovascular protection. J Am Coll Cardiol. 2012;59:277–9.PubMedCrossRef
5.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9.PubMedCrossRef
6.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.PubMedCrossRef
7.
Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Lam H, White WB. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067–76.PubMedCrossRef
8.
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.PubMedCrossRef
9.
Fadini GP, Avogaro A, Degli Esposti L, Russo P, Saragoni S, Buda S, Rosano G, Pecorelli S, Pani L. Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: a retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database. Eur Heart J. 2015;36:2454–62.PubMedCrossRef
10.
Wang KL, Liu CJ, Chao TF, Huang CM, Wu CH, Chen SJ, Yeh CM, Chen TJ, Lin SJ, Chiang CE. Sitagliptin and the risk of hospitalization for heart failure: a population-based study. Int J Cardiol. 2014;177:86–90.PubMedCrossRef
11.
Weir DL, McAlister FA, van Senthilsel A, Minhas-Sandhu JK, Eurich DT. Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study. JACC Heart Fail. 2014;2:573–82.PubMedCrossRef
12.
Ou SM, Shih CJ, Chao PW, Chu H, Kuo SC, Lee YJ, Wang SJ, Yang CY, Lin CC, Chen TJ, Tarng DC, Li SY, Chen YT. Effects on clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus. Ann Intern Med. 2015;163:663–72.PubMedCrossRef
13.
Fu AZ, Johnston SS, Ghannam A, Tsai K, Cappell K, Fowler R, Riehle E, Cole AL, Kalsekar I, Sheehan J. Association between hospitalization for heart failure and dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: an observational study. Diabetes Care. 2016;39:726–34.PubMedCrossRef
14.
Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptydil peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2010;20:224–35.PubMedCrossRef
15.
Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2008:CD006739.
16.
Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4:753–68.PubMedPubMedCentralCrossRef
17.
Savarese G, Perrone-Filardi P, D’Amore C, Vitale C, Trimarco B, Pani L, Rosano GM. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors in diabetic patients: a meta-analysis. Int J Cardiol. 2015;181:239–44.PubMedCrossRef
18.
Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:689–97.PubMedCrossRef
19.
Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large phase III type 2 diabetes population. Diabetes Obes Metab 2010;12:485–94.
20.
Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, Musser BJ, Davies MJ, Kaufman KD, Goldstein BJ. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord. 2010;10:7.PubMedPubMedCentralCrossRef
21.
Iqbal N, Parker A, Frederich R, Donovan M, Hirshberg B. Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. Cardiovasc Diabetol. 2014;13:33.PubMedPubMedCentralCrossRef
22.
Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, Zhang L, Shen J, Bala MM, Sohani ZN, Wong E, Busse JW, Ebrahim S, Malaga G, Rios LP, Wang Y, Chen Q, Guyatt GH, Sun X. Dipeptidyl peptidase 4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ 2016;352:i610.
23.
Booth A, Clarke M, Dooley G, Ghersi D, Moher D, Petticrew M, Stewart L. The nuts and bolts of PROSPERO: an international prospective register of systematic reviews. Syst Rev. 2012;1:2.PubMedPubMedCentralCrossRef
24.
25.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.PubMedPubMedCentralCrossRef
26.
27.
Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–71.PubMedCrossRef
28.
29.
30.
31.
Matthaei S, Catrinoiu D, Celiński A, Ekholm E, Cook W, Hirshberg B, Chen H, Iqbal N, Hansen L. Randomized, double-blind trial of triple therapy with saxagliptin add-on to dapagliflozin plus metformin in patients with type 2 diabetes. Diabetes Care. 2015;38:2018–24.PubMedCrossRef
32.
Mathieu C, Shankar RR, Lorber D, Umpierrez G, Wu F, Xu L, Golm GT, Latham M, Kaufman KD, Engel SS. A randomized clinical trial to evaluate the efficacy and safety of co-administration of sitagliptin with intensively titrated insulin glargine. Diabetes Ther. 2015;6:127–42.PubMedPubMedCentralCrossRef
33.
Yang HK, Min KW, Park SW, Chung CH, Park KS, Choi SH, Song KH, Kim DM, Lee MK, Sung YA, Baik SH, Kim IJ, Cha BS, Park JH, Ahn YB, Lee IK, Yoo SJ, Kim J, Park IeB, Park TS, Yoon KH. A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes. Endocr J. 2015;62:449–62.PubMedCrossRef
34.
Wang W, Yang J, Yang G, Gong Y, Patel S, Zhang C, Izumoto T, Ning G. Efficacy and safety of linagliptin in Asian patients with type 2 diabetes mellitus inadequately controlled by metformin: a multinational 24-week, randomized clinical trial. J Diabetes. 2016;8:229–37.PubMedCrossRef
35.
Yang W, Xing X, Lv X, Li Y, Ma J, Yuan G, Sun F, Wang W, Woloschak M, Lukashevich V, Kozlovski P, Kothny W. Vildagliptin added to sulfonylurea improves glycemic control without hypoglycemia and weight gain in Chinese patients with type 2 diabetes mellitus. J Diabetes. 2015;7:174–81.PubMedCrossRef
36.
Sheu WH, Gantz I, Chen M, Suryawanshi S, Mirza A, Goldstein BJ, Kaufman KD, Engel SS. Safety and efficacy of omarigliptin (MK-3102), a novel once-weekly DPP-4 inhibitor for the treatment of patients with type 2 diabetes. Diabetes Care. 2015;38:2106–14.PubMedCrossRef
37.
Ning G, Wang W, Li L, Ma J, Lv X, Yang M, Wang W, Woloschak M, Lukashevich V, Kothny W. Vildagliptin as add-on therapy to insulin improves glycemic control without increasing risk of hypoglycemia in Asian, predominantly Chinese, patients with type 2 diabetes mellitus. J Diabetes. 2016;8:345–53.PubMedCrossRef
38.
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;31:1505–14.PubMedPubMedCentralCrossRef
39.
Thrasher J, Daniels K, Patel S, Whetteckey J, Woerle HJ. Efficacy and safety of linagliptin in black/African American patients with type 2 diabetes: a 6-month, randomized, double-blind, placebo-controlled study. Endocr Pract. 2014;20:412–20.PubMedCrossRef
40.
Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug-naïve patients with type 2 diabetes: a randomized, double-blind, 6-month study. Diabetes Obes Metab. 2014;16:613–21.PubMedCrossRef
41.
White JL, Buchanan P, Li J, Frederich R. A randomized controlled trial of the efficacy and safety of twice-daily saxagliptin plus metformin combination therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy. BMC Endocr Disord. 2014;14:17.PubMedPubMedCentralCrossRef
42.
Odawara M, Hamada I, Suzuki M. Efficacy and safety of vildagliptin as add-on to metformin in Japanese patients with type 2 diabetes mellitus. Diabetes Ther. 2014;5:169–81.PubMedPubMedCentralCrossRef
43.
Ahrén B, Johnson SL, Stewart M, Cirkel DT, Yang F, Perry C, Feinglos MN. 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;37:2141–88.PubMedCrossRef
44.
Kadowaki T, Kondo K. Efficacy and safety of teneligliptin added to glimepiride in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study with an open-label, long-term extension. Diabetes Obes Metab. 2014;16:418–25.PubMedCrossRef
45.
Moses RG, Kalra S, Brook D, Sockler J, Monyak J, Visvanathan J, Montanaro M, Fisher SA. A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea. Diabetes Obes Metab. 2014;16:443–50.PubMedCrossRef
46.
Lukashevich V, Del Prato S, Araga M, Kothny W. Efficacy and safety of vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea. Diabetes Obes Metab. 2014;16:403–9.PubMedCrossRef
47.
Hage C, Brismar K, Efendic S, Lundman P, Rydén L, Mellbin L. Sitagliptin improves beta-cell function in patients with acute coronary syndromes and newly diagnosed glucose abnormalities–the BEGAMI study. J Intern Med. 2013;273:410–21.PubMedCrossRef
48.
Barnett AH, Charbonnel B, Li J, Donovan M, Fleming D, Iqbal N. Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clin Drug Investig. 2013;33:707–17.PubMedCrossRef
49.
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;382:1413–23.PubMedCrossRef
50.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.PubMedCrossRef
51.
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;382:409–16.PubMedCrossRef
52.
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;15:252–7.PubMedCrossRef
53.
McGill JB, Sloan L, Newman J, Patel S, Sauce C, von Eynatten M, Woerle HJ. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care. 2013;36:237–44.PubMedPubMedCentralCrossRef
54.
Yki-Järvinen H, Rosenstock J, Durán-Garcia S, Pinnetti S, Bhattacharya S, Thiemann S, Patel S, Woerle HJ. Effects of adding linagliptin to basal insulin regimen for inadequately controlled type 2 diabetes: a ≥52-week randomized, double-blind study. Diabetes Care. 2013;36:3875–81.PubMedPubMedCentralCrossRef
55.
Dobs AS, Goldstein BJ, Aschner P, Horton ES, Umpierrez GE, Duran L, Hill JS, Chen Y, Golm GT, Langdon RB, Williams-Herman DE, Kaufman KD, Amatruda JM, Ferreira JC. 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.PubMedCrossRef
56.
Kadowaki T, Kondo K. Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus. J Diabetes Investig. 2013;4:576–84.PubMedPubMedCentralCrossRef
57.
Rosenstock J, Gross JL, Aguilar-Salinas C, Hissa M, Berglind N, Ravichandran S, Fleming D. Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with type 2 diabetes. Diabet Med. 2013;30:1472–6.PubMedCrossRef
58.
Lavalle-González FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, Meininger G. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia. 2013;56:2582–92.PubMedPubMedCentralCrossRef
59.
Alba M, Ahrén B, Inzucchi SE, Guan Y, Mallick M, Xu L, O’Neill EA, Williams-Herman DE, Kaufman KD, Goldstein BJ. Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function. Diabetes Obes Metab. 2013;15:1101–10.PubMedCrossRef
60.
Kadowaki T, Kondo K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:810–8.PubMedCrossRef
61.
Kadowaki T, Tajima N, Odawara M, Nishii M, Taniguchi T, Ferreira JC. Addition of sitagliptin to ongoing metformin monotherapy improves glycemic control in Japanese patients with type 2 diabetes over 52 weeks. J Diabetes Investig. 2013;4:174–81.PubMedCrossRef
62.
Seino Y, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin added to sulfonylurea in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension study. J Diabetes Investig. 2012;3:517–25.PubMedPubMedCentralCrossRef
63.
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;28:1465–74.
64.
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;34:1909–19.PubMedCrossRef
65.
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;14:1032–9.PubMedCrossRef
66.
Barnett AH, Patel S, Harper R, Toorawa R, Thiemann S, von Eynatten M, Woerle HJ. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: an 18-week randomized, double-blind, placebo-controlled phase III trial with a 34-week active-controlled extension. Diabetes Obes Metab. 2012;14:1145–54.PubMedCrossRef
67.
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;28:268–75.PubMedCrossRef
68.
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.PubMedPubMedCentralCrossRef
69.
Fonseca V, Staels B, Morgan JD 2nd, Shentu Y, Golm GT, Johnson-Levonas AO, Kaufman KD, Goldstein BJ, Steinberg H. 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;27:177–83.PubMedCrossRef
70.
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;28:513–23.PubMedCrossRef
71.
Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, Sarashina A, Gong Y, von Eynatten M, Woerle HJ, Dugi KA. 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;14:348–57.PubMedCrossRef
72.
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.PubMedPubMedCentralCrossRef
73.
Eto T, Inoue S, Kadowaki T. Effects of once-daily teneligliptin on 24-h blood glucose control and safety in Japanese patients with type 2 diabetes mellitus: a 4-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2012;14:1040–6.PubMedCrossRef
74.
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;14:565–74.PubMedCrossRef
75.
Yang W, Guan Y, Shentu Y, Li Z, Johnson-Levonas AO, Engel SS, Kaufman KD, Goldstein BJ, Alba M. The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes. J Diabetes. 2012;4:227–37.PubMedCrossRef
76.
Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract. 2011;94:217–24.PubMedCrossRef
77.
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;27:1781–92.PubMedCrossRef
78.
Kashiwagi A, Kadowaki T, Tajima N, Nonaka K, Taniguchi T, Nishii M, Ferreira JC, Amatruda JM. Sitagliptin added to treatment with ongoing pioglitazone for up to 52 weeks improves glycemic control in Japanese patients with type 2 diabetes. J Diabetes Investig. 2011;2:381–90.PubMedPubMedCentralCrossRef
79.
Hollander PL, Li J, Frederich R, Allen E, Chen R. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2011;8:125–35.PubMedCrossRef
80.
Forst T, Uhlig-Laske B, Ring A, Ritzhaupt A, Graefe-Mody U, Dugi KA. The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011;13:542–50.PubMedCrossRef
81.
Nowicki M, Rychlik I, Haller H, Warren M, Suchower L, Gause-Nilsson I, Schützer KM. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J ClinPract. 2011;65:1230–9.
82.
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;13:947–54.PubMedCrossRef
83.
Kaku K, Itayasu T, Hiroi S, Hirayama M, Seino Y. Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study. Diabetes Obes Metab. 2011;13:1028–35.PubMedCrossRef
84.
Henry RR, Smith SR, Schwartz SL, Mudaliar SR, Deacon CF, Holst JJ, Duan RY, Chen RS, List JF. Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:850–8.PubMedCrossRef
85.
Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011;28:1352–61.PubMedCrossRef
86.
Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, Woerle HJ. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65–74.PubMedCrossRef
87.
Vilsbøll T, Rosenstock J, Yki-Järvinen H, Cefalu WT, Chen Y, Luo E, Musser B, Andryuk PJ, Ling Y, Kaufman KD, Amatruda JM, Engel SS, Katz L. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:167–77.PubMedCrossRef
88.
Pattzi HM, Pitale S, Alpizar M, Bennett C, O’Farrell AM, Li J, Cherrington JM, Guler HP. Dutogliptin, a selective DPP4 inhibitor, improves glycaemic control in patients with type 2 diabetes: a 12-week, double-blind, randomized, placebo-controlled, multicentre trial. Diabetes Obes Metab. 2010;12:348–55.PubMedCrossRef
89.
Iwamoto Y, Taniguchi T, Nonaka K, Okamoto T, Okuyama K, Arjona Ferreira JC, Amatruda J. Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Endocr J. 2010;57:383–94.PubMedCrossRef
90.
Stenlöf K, Raz I, Neutel J, Ravichandran S, Berglind N, Chen R. Saxagliptin and metformin XR combination therapy provides glycemic control over 24 hours in patients with T2DM inadequately controlled with metformin. Curr Med Res Opin. 2010;26:2355–63.PubMedCrossRef
91.
Kikuchi M, Haneda M, Koya D, Tobe K, Onishi Y, Couturier A, Mimori N, Inaba Y, Goodman M. Efficacy and tolerability of vildagliptin as an add-on to glimepiride in Japanese patients with Type 2 diabetes mellitus. Diabetes Res Clin Pract. 2010;89:216–23.PubMedCrossRef
92.
Aaboe K, Knop FK, Vilsbøll T, Deacon CF, Holst JJ, Madsbad S, Krarup T. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2010;12:323–33.PubMedCrossRef
93.
Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, Woerle HJ, Dugi KA. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med. 2010;27:1409–19.PubMedCrossRef
94.
Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63:46–55.PubMedCrossRef
95.
Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009;11:167–76.PubMedCrossRef
96.
Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11:1145–52.PubMedCrossRef
97.
Heise T, Graefe-Mody EU, Hüttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab. 2009;11:786–94.PubMedCrossRef
98.
Nonaka K, Tsubouchi H, Okuyama K, Fukao Y, Johnson-Levonas AO, Amatruda JM. Effects of once-daily sitagliptin on 24-h glucose control following 4 weeks of treatment in Japanese patients with type 2 diabetes mellitus. Horm Metab Res. 2009;41:232–7.PubMedCrossRef
99.
Goodman M, Thurston H, Penman J. Efficacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009;41:368–73.PubMedCrossRef
100.
Mohan V, Yang W, Son HY, Xu L, Noble L, Langdon RB, Amatruda JM, Stein PP, Kaufman KD. Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract. 2009;83:106–16.PubMedCrossRef
101.
Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, Langdon RB, Stein PP, Alba M. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24:537–50.PubMedCrossRef
102.
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;83:233–40.PubMedCrossRef
103.
Garcia-Soria G, Gonzalez-Galvez G, Argoud GM, Gerstman M, Littlejohn TW 3rd, Schwartz SL, O’Farrell AM, Li X, Cherrington JM, Bennett C, Guler HP. The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2008;10:293–300.PubMedCrossRef
104.
DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31:2315–7.PubMedPubMedCentralCrossRef
105.
Covington P, Christopher R, Davenport M, Fleck P, Mekki QA, Wann ER, Karim A. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther. 2008;30:499–512.PubMedCrossRef
106.
Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab. 2008;10:376–86.PubMedCrossRef
107.
Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjörnsdottir S, Camisasca RP, Couturier A, Baron MA. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab. 2008;10:1047–56.PubMedCrossRef
108.
Scherbaum WA, Schweizer A, Mari A. Efficacy and tolerability of vildagliptin in drug-naïve patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab. 2008;10:675–82.PubMedCrossRef
109.
Rosenstock J, Foley JE, Rendell M, Landin-Olsson M, Holst JJ, Deacon CF, Rochotte E, Baron MA. Effects of the dipeptidyl peptidase-IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance. Diabetes Care. 2008;31:30–5.PubMedCrossRef
110.
Nonaka K, Kakikawa T, Sato A, Okuyama K, Fujimoto G, Kato N, Suzuki H, Hirayama Y, Ahmed T, Davies MJ, Stein PP. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2008;79:291–8.
111.
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;30:890–5.PubMedCrossRef
112.
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;9:166–74.PubMedCrossRef
113.
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–87.PubMedCrossRef
114.
Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–45.PubMedCrossRef
115.
Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Curr Med Res Opin 2007;23:1329–39.
116.
Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract. 2007;61:171–80.PubMedCrossRef
117.
Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556–8.PubMedCrossRef
118.
Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, Udell JA, Mosenzon O, Im K, Umez-Eronini AA, Pollack PS, Hirshberg B, Frederich R, Lewis BS, McGuire DK, Davidson J, Steg PG, Bhatt DL. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579–88.PubMedCrossRef
119.
McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2:843–51.PubMedCrossRef
120.
Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK, Hu N, Paterson JM, Targownik L, Turin TC, Udell JA, Ernst P. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016;374:1145–54.PubMedCrossRef
Metadata
Title
Cardiovascular Safety of Dipeptidyl-Peptidase IV Inhibitors: A Meta-Analysis of Placebo-Controlled Randomized Trials
Authors
Islam Y. Elgendy
Ahmed N. Mahmoud
Amr F. Barakat
Akram Y. Elgendy
Marwan Saad
Ahmed Abuzaid
Siddarth A. Wayangankar
Anthony A. Bavry
Publication date
01-04-2017
Publisher
Springer International Publishing
Published in
American Journal of Cardiovascular Drugs / Issue 2/2017
Print ISSN: 1175-3277
Electronic ISSN: 1179-187X
DOI
https://doi.org/10.1007/s40256-016-0208-x

Other articles of this Issue 2/2017

American Journal of Cardiovascular Drugs 2/2017 Go to the issue

Original Research Article

Consensus on the Statin of Choice in Patients with Impaired Glucose Metabolism: Results of the DIANA Study

Review Article

The Rationale for and Clinical Pharmacology of Prasugrel 5 mg

Review Article

Clinical Pharmacology and Cardiovascular Safety of Naproxen

Adis Drug Evaluation

Pitavastatin: A Review in Hypercholesterolemia

Original Research Article

Cost Effectiveness of Apixaban versus Warfarin or Aspirin for Stroke Prevention in Patients with Atrial Fibrillation: A Greek Perspective

Review Article

Therapeutic Targeting of Cellular Stress to Prevent Cardiovascular Disease: A Review of the Evidence

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits