Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Risk in Type-2 Diabetes Mellitus: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 WANGChong ¹ , ZHANGJing-bin ² , LIRui-fei ¹ , SUNSi-hao ¹ , ZOUMei-juan ¹ ,  CHENGGang ¹

1. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China;
2. Department of Endocrinology, General Hospital of Shenyang Military Region, Shenyang 110016, China;

Corresponding author：

CHENGGang, Email: chenggang63@hotmail.com

Keywords：

DPP-4 inhibitors; Cardiovascular adverse event; Type-2 diabetes mellitus; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.20150053

Video：

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Objective To systematically evaluate the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors on the risk of cardiovascular events in type 2 diabetes mellitus (T2DM) patients. Methods Databases such as the Cochrane Library, PubMed, Elsevier ScienceDirect and EMbase were searched to collect randomized controlled trials (RCTs) about DPP-4 inhibitors for T2DM patients from inception to February 2014. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data and assessed the methodological quality of included studies. Then, meta-analysis was performed using RevMan5.2 software. Results A total of 20 RCTs involving 10 402 patients were included. The results of meta-analysis showed that:there were no significant differences between the DPP-4 inhibitors group and the control group in the cardiovascular adverse events (RR=0.86, 95%CI 0.62 to 1.20, P=0.38) and acute coronary syndrome (RR=0.66, 95%CI 0.37 to 1.17, P=0.15). Subgroup analyses by type of liptins and durations showed there were lower risks of adverse cardiovascular events in the DPP-4 inhibitors group of the sitagliptin subgroup (RR=0.49, 95%CI 0.29 to 0.82, P=0.007) and the duration of ≥52 weeks subgroup (RR=0.62, 95%CI 0.39 to 0.97, P=0.04). No significant difference was found between the two groups in hypertension events (RR=1.09, 95%CI 0.84 to 1.40, P=0.52). Conclusion The DPP-4 inhibitors are relatively safe. In the long-term treatment of T2DM, the sitagliptin could not only effectively control the level of blood sugar but also might obtain benefits in cardiovascular aspects.

Citation： WANGChong, ZHANGJing-bin, LIRui-fei, SUNSi-hao, ZOUMei-juan, CHENGGang. Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Risk in Type-2 Diabetes Mellitus: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2015, 15(3): 312-319. doi: 10.7507/1672-2531.20150053 Copy

1.	Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome a summary of the evidence. Diabetes Care, 2005, 28(7):1769-1778.
2.	Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med, 2007, 356(24):2457-2471.
3.	Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). Available at:http://www.cochrane-handbook.org.
4.	Williams-Herman D, Engel SS, Round E, et al. Safety and tolerability of sitagliptin in clinical studies:a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocrine Disorders, 2010, 10(1):7.
5.	DeFronzo RA, Fleck PR, Wilson CA, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control a randomized, double-blind, placebo-controlled study. Diabetes Care, 2008, 31(12):2315-2317.
6.	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, Obesity and Metabolism, 2010, 12(3):252-261.
7.	Pfutzner A, Paz-Pacheco E, Allen E, et al. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes, Obesity and Metabolism, 2011, 13(6):567-576.
8.	Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin, 2009, 25(10):2401-2411.
9.	Bosi E, Dotta F, Jia Y, et al. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus. Diabetes, Obesity and Metabolism, 2009, 11(5):506-515.
10.	Rosenstock J, Niggli M, Maldonado-Lutomirsky M, et al. Long term 2 year safety and efficacy of vildagliptin compared with rosiglitazone in drug naive patients with type 2 diabetes mellitus. Diabetes, Obesity and Metabolism, 2009, 11(6):571-578.
11.	Schweizer A, Couturier A, Foley JE, et al. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naive patients with Type 2 diabetes. Diabetic Medicine, 2007, 24(9):955-961.
12.	Schweizer A, Dejager S, Bosi E, et al. Comparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes:a 24-week, double-blind, randomized trial. Diabetes, Obesity and Metabolism, 2009, 11(8):804-812.
13.	Cook W, Bryzinski B, Slater J, et al. Saxagliptin efficacy and safety in patients with type 2 diabetes mellitus and cardiovascular disease history or cardiovascular risk factors:Results of a pooled analysis of phase 3 clinical trials. Postgraduate Medicine, 2013, 125(3):145-154.
14.	Barzilai N, Guo H, Mahoney EM, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes:a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin, 2011, 27(5):1049-1058.
15.	Bergenstal RM, Wysham C, MacConell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2):a randomised trial. Lancet, 2010, 376(9739):431-439.
16.	Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with Type 2 diabetes (DURATION-4) a 26-week double-blind study. Diabetes Care, 2012, 35(2):252-258.
17.	Rosenstock J, Wilson C, Fleck P, et al. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia:a prospective, double-blind, randomized, 1 year study. Diabetes, Obesity and Metabolism, 2013, 15(10):906-914.
18.	Pan C, Yang W, Barona JP, et al. Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes:a 24-week, double-blind, randomized trial. Diabetic Medicine, 2008, 25(4):435-441.
19.	Pan CY, Yang W, Tou C, et al. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus:a randomized controlled trial. Diabetes-Metab Res, 2012, 28(3):268-275.
20.	Ferreira JCA, Marre M, Barzilai N, et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care, 2013, 36(5):1067-1073.
21.	Arjona FJC, Corry D, Mogensen CE, et al. Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis:a 54-week randomized trial. Am J Kidney Dis, 2013, 61(4):579-587.
22.	Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes:a randomized, double-blind, placebo-controlled study. Diabetes, Obesity and Metabolism, 2012, 14(6):565-574.
23.	Rosenstock J, Inzucchi SE, Seufert J, et al. Initial combination therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes. Diabetes Care, 2010, 33(11):2406-2408.
24.	Green BD, Irwin N, Gault VA, et al. Development and therapeutic potential of incretin hormone analogues for type 2 diabetes. Br J Diabetes Vasc Dis, 2005, 5(3):134-140.
25.	Ahren B. Dipeptidyl peptidase-4 inhibitors. Clinical data and clinical implicat. Diabetes Care, 2007, 30(6):1344-1350.
26.	Druker DJ, Nauck MA. GLP-1R agonists (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) for the treatment of type 2 diabetes. Lancet, 2006, 368(3):1696-1705.
27.	Mason RP, Jacob RF, Kubant R, et al. Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. J Atheroscler Thromb, 2010, 18(9):774-783.
28.	Huisamen B, Genis A, Marais E, et al. Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc Drug Ther, 2011, 25(1):13-20.
29.	Khan FZ, Heck PM, Hoole SP, et al. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ-Cardiovasc Imag, 2010, 3(2):195-201.
30.	Patil HR, Al Badarin FJ, Al Shami HA, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. J Am Coll Cardio, 2012, 110(6):826-833.
31.	Monami M, Ahren B, Dicembrini I, et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk:a meta-analysis of randomized clinical trials. Diabetes Obes Metab, 2013, 15(1):112-120.
32.	Wu S, Hopper I, Skiba M, et al. Dipeptidyl Peptidase-4 Inhibitors and Cardiovascular Outcomes:Meta-Analysis of Randomized Clinical Trials with 55,141 Participants. Cardiovas Ther, 2014, 32(4):147-158.
33.	Gordon HG, Andrew DO, Victor M, 等. Grade指南证据质量评价——发表偏倚. 中国循证医学杂志, 2011, 11(12):1430-1434.

1. Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome a summary of the evidence. Diabetes Care, 2005, 28(7):1769-1778.
2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med, 2007, 356(24):2457-2471.
3. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). Available at:http://www.cochrane-handbook.org.
4. Williams-Herman D, Engel SS, Round E, et al. Safety and tolerability of sitagliptin in clinical studies:a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocrine Disorders, 2010, 10(1):7.
5. DeFronzo RA, Fleck PR, Wilson CA, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control a randomized, double-blind, placebo-controlled study. Diabetes Care, 2008, 31(12):2315-2317.
6. 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, Obesity and Metabolism, 2010, 12(3):252-261.
7. Pfutzner A, Paz-Pacheco E, Allen E, et al. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes, Obesity and Metabolism, 2011, 13(6):567-576.
8. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin, 2009, 25(10):2401-2411.
9. Bosi E, Dotta F, Jia Y, et al. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus. Diabetes, Obesity and Metabolism, 2009, 11(5):506-515.
10. Rosenstock J, Niggli M, Maldonado-Lutomirsky M, et al. Long term 2 year safety and efficacy of vildagliptin compared with rosiglitazone in drug naive patients with type 2 diabetes mellitus. Diabetes, Obesity and Metabolism, 2009, 11(6):571-578.
11. Schweizer A, Couturier A, Foley JE, et al. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naive patients with Type 2 diabetes. Diabetic Medicine, 2007, 24(9):955-961.
12. Schweizer A, Dejager S, Bosi E, et al. Comparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes:a 24-week, double-blind, randomized trial. Diabetes, Obesity and Metabolism, 2009, 11(8):804-812.
13. Cook W, Bryzinski B, Slater J, et al. Saxagliptin efficacy and safety in patients with type 2 diabetes mellitus and cardiovascular disease history or cardiovascular risk factors:Results of a pooled analysis of phase 3 clinical trials. Postgraduate Medicine, 2013, 125(3):145-154.
14. Barzilai N, Guo H, Mahoney EM, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes:a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin, 2011, 27(5):1049-1058.
15. Bergenstal RM, Wysham C, MacConell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2):a randomised trial. Lancet, 2010, 376(9739):431-439.
16. Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with Type 2 diabetes (DURATION-4) a 26-week double-blind study. Diabetes Care, 2012, 35(2):252-258.
17. Rosenstock J, Wilson C, Fleck P, et al. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia:a prospective, double-blind, randomized, 1 year study. Diabetes, Obesity and Metabolism, 2013, 15(10):906-914.
18. Pan C, Yang W, Barona JP, et al. Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes:a 24-week, double-blind, randomized trial. Diabetic Medicine, 2008, 25(4):435-441.
19. Pan CY, Yang W, Tou C, et al. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus:a randomized controlled trial. Diabetes-Metab Res, 2012, 28(3):268-275.
20. Ferreira JCA, Marre M, Barzilai N, et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care, 2013, 36(5):1067-1073.
21. Arjona FJC, Corry D, Mogensen CE, et al. Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis:a 54-week randomized trial. Am J Kidney Dis, 2013, 61(4):579-587.
22. Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes:a randomized, double-blind, placebo-controlled study. Diabetes, Obesity and Metabolism, 2012, 14(6):565-574.
23. Rosenstock J, Inzucchi SE, Seufert J, et al. Initial combination therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes. Diabetes Care, 2010, 33(11):2406-2408.
24. Green BD, Irwin N, Gault VA, et al. Development and therapeutic potential of incretin hormone analogues for type 2 diabetes. Br J Diabetes Vasc Dis, 2005, 5(3):134-140.
25. Ahren B. Dipeptidyl peptidase-4 inhibitors. Clinical data and clinical implicat. Diabetes Care, 2007, 30(6):1344-1350.
26. Druker DJ, Nauck MA. GLP-1R agonists (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) for the treatment of type 2 diabetes. Lancet, 2006, 368(3):1696-1705.
27. Mason RP, Jacob RF, Kubant R, et al. Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. J Atheroscler Thromb, 2010, 18(9):774-783.
28. Huisamen B, Genis A, Marais E, et al. Pre-treatment with a DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic rats. Cardiovasc Drug Ther, 2011, 25(1):13-20.
29. Khan FZ, Heck PM, Hoole SP, et al. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ-Cardiovasc Imag, 2010, 3(2):195-201.
30. Patil HR, Al Badarin FJ, Al Shami HA, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. J Am Coll Cardio, 2012, 110(6):826-833.
31. Monami M, Ahren B, Dicembrini I, et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk:a meta-analysis of randomized clinical trials. Diabetes Obes Metab, 2013, 15(1):112-120.
32. Wu S, Hopper I, Skiba M, et al. Dipeptidyl Peptidase-4 Inhibitors and Cardiovascular Outcomes:Meta-Analysis of Randomized Clinical Trials with 55,141 Participants. Cardiovas Ther, 2014, 32(4):147-158.
33. Gordon HG, Andrew DO, Victor M, 等. Grade指南证据质量评价——发表偏倚. 中国循证医学杂志, 2011, 11(12):1430-1434.

Chinese Journal of Evidence-Based Medicine

Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Risk in Type-2 Diabetes Mellitus: A Meta-analysis

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