Abstract
In view of the significant cardiovascular (CV) morbidity and mortality in patients with type 2 diabetes mellitus, and concerns raised about the CV safety of some glucose-lowering drugs, the US Food and Drug Administration (FDA) issued guidance for the industry in 2008 to demonstrate CV safety for the approval of all new antihyperglycemic drugs. Seven randomized controlled trials involving around 60,000 participants have been completed so far and have demonstrated the CV safety of dipeptidyl peptidase 4 inhibitors (saxagliptin, alogliptin and sitagliptin), glucagon-like peptide-1 receptor agonists (lixisenatide, liraglutide and semaglutide) and a sodium-glucose co-transporter 2 inhibitor (empagliflozin) in patients with type 2 diabetes. Three of these trials have in fact reported superiority of the study drug over placebo in terms of CV outcomes. However, all these trials were primarily designed as non-inferiority trials to exclude an unacceptable risk of CV events with these drugs in the shortest possible time period. The potential long-term benefit or risks were not assessed effectively as the median follow-up in these studies was limited to 1.5–3 years. Also, these trials included patients with relatively long duration of diabetes, advanced atherosclerosis and higher CV risk. Thus, these trials were not intended to assess CV benefit and are best interpreted as evidence for CV safety of these antihyperglycemic medications.
Similar content being viewed by others
References
Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njolstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829–41.
Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, Williams DE, Geiss L. Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med. 2014;370:1514–23.
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;32:405–12.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.
Group AC, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.
DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977–86.
Rojas LBA, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6.
Kappel BA, Marx N, Federici M. Oral hypoglycemic agents and the HF conundrum: lessons from and for outcome trials. Nutr Metab Cardiovas Dis. 2015;25:697–705.
Sgambato S, Varricchio M, Tesauro P, Passariello N, Carbone L. The use of metformin in ischemic cardiopathy. Clin Ther. 1980;94:77–85.
Cheng YY, Leu HB, Chen TJ, Chen CL, Kuo CH, Lee SD, Kao CL. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow up study. J Stroke Cerebrovasc Dis. 2014;23:e99–105.
Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, Johnson JA. Benefits and harms of antihyperglycemic agents in patients with diabetes and HF: systematic review. BMJ. 2007;335:497.
Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, Zhou Z, Tang W, Zhao J, Cui L, Zou D, Wang D, Li H, Liu C, Wu G, Shen J, Zhu D, Wang W, Shen W, Ning G. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36:1304–11.
Feinglos MN, Bethel MA. Therapy of type 2 diabetes, cardiovascular death, and the UGDP [University Group Diabetes Program]. Am Heart J. 1999;138:S346–52.
Forst T, Hanefeld M, Jacob S, Moeser G, Schwenk G, Pfützner A, Haupt A. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: a systematic review and meta-analysis of observational studies. Diab Vasc Dis Res. 2013;10:302–14.
Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, Brancati FL. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168:2070–80.
Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15:938–53.
Abdelmoneim AS, Eurich DT, Light PE, Senior PA, Seubert JM, Makowsky MJ, Simpson SH. Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. Diabetes Obes Metab. 2015;17:523–32.
Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Espeland MA, Bluhmki E, Mattheus M, Ryckaert B, Patel S, Johansen OE, Woerle HJ. Design and baseline characteristics of the CARdiovascular outcome trial of LINAgliptin versus glimepiride in type 2 diabetes (CAROLINA). Diab Vasc Dis Res. 2015;12:164–74.
van Wijk JP, de Koning EJ, Martens EP, Rabelink TJ. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol. 2003;23:1744–9.
Erdmann E, Dormandy J, Wilcox R, Massi-Benedetti M, Charbonnel B. PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study. Vasc Health Risk Manag. 2007;3:355–70.
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;20:2125–35.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of MI and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.
Diamond GA, Bax L, Sanjay Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578–81.
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–8.
Spring S. Guidance for industry. Diabetes mellitus: evaluating cardiovascular risk in new antihyperglycemic therapies to treat type 2 diabetes. Food and Drug Administration; 2008.
European Medicines Agency recommends suspension of Avandia, Avandamet and Avaglim. http://www.ema.europa.eu/ema/index.jsp. Accessed 21 June 2016.
Hirshberg B, Raz MI. Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabetes Care. 2011;34:S101–6.
Monami M, Lamanna C, Desideri CM, et al. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther. 2012;29:14–25.
Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011;34:S276–8.
Mason RP, Jacob RF, Kubant R, et al. Dipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive rats. J Cardiovasc Pharmacol. 2012;60:467–73.
Ta NN, Schuyler CA, Li Y, Lopes-Virella MF, Huang Y. DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 2011;58:157–66.
Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A, Paolisso G. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis. 2013;227:349–54.
Williams-Herman D, Round E, Swern AS, Musser B, Davies MJ, Stein PP, Kaufman KD, Amatruda JM. Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis. BMC Endocr Disord. 2008;8:14.
Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N, Harris S, Chen R, Wolf R, Mahaffey KW. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122:16–27.
Johansen OE, Neubacher D, Von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3.
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.
White WB, Pratley R, Fleck P, Munsaka M, Hisada M, Wilson C, Menon V. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:668–73.
Monami M, Ahren B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15:112–20.
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.
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.
Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. HF 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.
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.
Doggrell SA. Are we waiting too long for the cardiovascular outcome trials with the glucagon-like peptide-1 receptor agonists? Expert Opin Drug Saf. 2015;14:801–5.
Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L. Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol. 2011;10:22.
Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16:38–47.
Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016.
Kouvatsos ID, Jabbour SA. SGLT2 inhibitors. Biochem Pharmacol. 2016;101:27–39.
Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262–74.
Hach T, Gerich J, Salsali A, Kim G, Hantel S, Woerle HJ, Broedl UC. Empagliflozin improves glycaemic parameters and cardiovascular risk factors in patients with type 2 diabetes: pooled data from four pivotal phase III trials. Diabetol Stoffwechs 2014; 9:142.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No sources of funding were used to assist with the preparation of this review.
Conflict of interest
Dr. Himika Chawla and Dr. Nikhil Tandon have no conflicts of interest that are relevant to the content of this review.
Rights and permissions
About this article
Cite this article
Chawla, H., Tandon, N. Interpreting Cardiovascular Endpoints in Trials of Antihyperglycemic Drugs. Am J Cardiovasc Drugs 17, 203–215 (2017). https://doi.org/10.1007/s40256-017-0215-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40256-017-0215-6