THEEFFECT OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS ON CARDIOVASCULAR DISEASE RISK IN TYPE 2 DIABETES MELLITUS
Keywords:Diabetes mellitus, Dipeptidyl peptidase-4 inhibitor, Cardiovascular disease
Objective: The aim of this study was is to investigate the proposed beneficial cardiovascular effects of a novel class of antidiabetic drugs named; dipeptidyl peptidase 4 inhibitors. In this study, we compared the effect of using add-on therapy of vildagliptin (dipeptidyl peptidase-4 inhibitor; DPP-4i) and gliclazide (sulphonylurea; SU) to that when using gliclazide monotherapy in patients with type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS) on different cardiovascular outcomes.
Methods: A total of 60 patients diagnosed with T2DM, and ACS were randomly recruited into two treatment groups each of 30 patients to receive either gliclazide monotherapy (SU) or vildagliptin (DPP4i)+gliclazide (SU) add-on therapy, administered in a double-blind fashion. Outpatient visits were scheduled at 3, 6, and 12 mo where patient was reevaluated for cardiovascular (CV) outcomes and followed up for any arising cardiovascular complication.
Results: The vildagliptin (DPP4i) plus gliclazide (SU) add-on therapy group have significantly shown more improved glycemic control, lipid profile and ventricular performance compared to gliclazide (SU) monotherapy group with p values<0.05.
Conclusion: Vildagliptin as a DPP4i provides favourable cardiovascular effects beyond glucose control. Yet, its long-term safety and efficacy data still needs further investigations.
Sebokova E, Christ AD, Boehringer M, Mizrahi J. Dipeptidyl peptidase IV inhibitors: the next generation of new promising therapies for the management of type 2 diabetes. Curr Top Med Chem 2007;7:547-55.
Preis SR, Hwang SJ, Coady S, Pencina MJ, D'Agostino RB, Savage PJ, et al. Trends in all-cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005. Circulation 2009;119:1728-35.
Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;22:1350-7.
Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215-22.
Santulli G. Epidemiology of cardiovascular disease in the 21st century: updated numbers and updated facts. J Cardiovasc Dis 2013;1:1-2.
Turner LW, Nartey D, Stafford RS, Singh S, Alexander GC. Ambulatory treatment of type 2 diabetes in the US, 1997â€“2012. Diabetes Care 2014;1:985-92.
Reddy KJ, Mohan GK. The comparative antidiabetic activity of marketed gliclazide formulation with gliclazide loaded pellets containing gum kondagogu as a drug retarding material in rats. Asian J Pharm Clin Res 2013;6:73-5.
Dhaliwall C, Richardson J. Effectiveness of telephone-delivered interventions for increasing physical activity levels in persons with type 2 diabetes or hypertension: a systematic review. J Crit Rev 2015;19:6-11.
Xu J, Zou MH. Molecular insights and therapeutic targets for diabetic endothelial dysfunction. Circulation 2009;120:1266-86.
Wagenknecht LE, Zaccaro D, Espeland MA, Karter AJ, Oâ€™Leary DH, Haffner SM. Diabetes and progression of carotid atherosclerosis the insulin resistance atherosclerosis study. Arterioscler Thromb Vasc Biol 2003;23:1035-41.
Nathanson D, NystrÃ¶m T. Hypoglycemic pharmacological treatment of type 2 diabetes: targeting the endothelium. Mol Cell Endocrinol 2009;297:112-26.
Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S, Fadini GP. Endothelial dysfunction in diabetes the role of preparatory mechanisms. Diabetes Care 2011;34:S285-90.
Simsek S, de Galan BE. Cardiovascular protective properties of incretin-based therapies in type 2 diabetes. Curr Opin Lipidol 2012;23:540-7.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New Eng J Med 2007;356:2457-71.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203.
Green BD, Flatt PR, Bailey CJ. Dipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes. Diab Vasc Dis Res 2006;3:159-65.
Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011;60:1917-25.
Wei Y, Mojsov S. Tissueâ€specific expression of the human receptor for glucagonâ€like peptideâ€I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS letters 1995;358:219-24.
Kazakos K. Incretin effect: GLP-1, GIP, DPP4. Diabetes Res Clin Pr 2011;93:S32-6.
Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev 2012 8;33:187-215.
Wu S, Hopper I, Skiba M, Krum H. Dipeptidyl Peptidaseâ€4 Inhibitors and Cardiovascular Outcomes: Metaâ€Analysis of Randomized Clinical Trials with 55,141 Participants. Cardiovas Ther. 2014;32:147-58.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New Engl J Med 2013 3;369:1317-26.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New Engl J Med 2013;369:1327-35.
Funnell MM, Brown TL, Childs BP, Haas LB, Hosey GM, Jensen B, et al. National standards for diabetes self-management education. Diabetes Care 2009;32:S87-94.
Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahon MM, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient-2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic and Bariatric Surgery. Obesity 2013;21:S1-27.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364-79.
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New Eng J Med 2015;373:232-42.
Mogensen UM, Andersson C, FosbÃ¸l EL, Schramm TK, Vaag A, Scheller NM, et al. Cardiovascular safety of combination therapies with incretinâ€based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitusâ€“a retrospective nationwide study. Diabetes Obes Metab 2014;16:1001-8.
Chang YC, Chuang LM, Lin JW, Chen ST, Lai MS, Chang CH. Cardiovascular risks associated with secondâ€line oral antidiabetic agents added to metformin in patients with type 2 diabetes: a nationwide cohort study. Diabetic Med 2015;32: 1460-9.
Fadini GP, Avogaro A, Degli Esposti L, Russo P, Saragoni S, Buda S, et al. Risk of hospitalisation 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.
ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;2011:818-28.
Scherbaum WA, Schweizer A, Mari A, Nilsson PM, Lalanne G, Jauffret S, et al. Efficacy and tolerability of vildagliptin in drugâ€naÃ¯ve patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab 2008;10:675-82.
Ferrannini E, Fonseca V, Zinman B, Matthews D, AhrÃ©n B, Byiers S, et al. Fiftyâ€twoâ€week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2009;11:157-66.
Rosenstock J, Kim SW, Baron MA, Camisasca RP, Cressier F, Couturier A, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 2007;9:175-85.
Garber AJ, Foley JE, Banerji MA, Ebeling P, GudbjÃ¶rnsdottir S, Camisasca RP, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab 2008;10:1047-56.
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;50:1148-55.
Matikainen N, MÃ¤nttÃ¤ri S, Schweizer A, Ulvestad A, Mills D, Dunning BE, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia 2006;49:2049-57.
Bachovchin DA, Cravatt BF. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat Rev Drug Discovery 2012;11:52-68.
Duvnjak L, Blaslov K. Dipeptidyl peptidase-4 inhibitors improve arterial stiffness, blood pressure, lipid profile and inflammation parameters in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 2016;8:1.
Khan FZ, Heck PM, Hoole SP, Dutka DP. 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. Circulation: Cardiovascular Imaging 2010;3:195-201.
Takasawa W, Ohnuma K, Hatano R, Endo Y, Dang NH, Morimoto C. Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines. Biochem Biophys Res Commun 2010;401:7-12.
Wu JD, Xu XH, Zhu J, Ding B, Du TX, Gao G, et al. Effect of exenatide on inflammatory and oxidative stress markers in patients with type 2 diabetes mellitus. Diabetes Technol Ther 2011;13:143-8.
Boschmann M, Engeli S, Dobberstein K, Budziarek P, Strauss A, Boehnke J, et al. Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients. J Clin Endocrinol Metab 2009;94:846-52.
Scheen AJ. A review of gliptins in 2011. Expert Opin Pharmacother 2012;13:81-99.
Inzucchi SE, McGuire DK. New drugs for the treatment of diabetes part II: incretin-based therapy and beyond. Circulation 2008;117:574-84.
Farngren J, Persson M, Schweizer A, Foley JE, AhrÃ©n B. Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counter regulation during hypoglycemia in type 1 diabetes. J Clin Endocrinol Metab 2012;97:3799-8.