[en] The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.
Food and Drug Administration. Guidance for industry diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/UCM071627.pdf (last updated: 2008; accessed: 24 July 2015).
Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294: 2581-2586.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-2471.
Zannad F, Stough WG, Pocock SJ, Sleight P, Cushman WC, Cleland JG, McMurray JJ, Lonn E, Geller NL, Wedel H, Abadie E, Alonso-Garcia A, Pitt B. Diabetes clinical trials: helped or hindered by the current shift in regulatory requirements? Eur Heart J 2012;33:1049-1057.
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: 1327-1335.
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: 1317-1326.
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 deWerf F, Peterson ED, Holman RR. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373: 232-242.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen O, Woerle HJ, Broedl U, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373: 2117-2128.
Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober 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;373:2247-2257.
Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. 3. Clinical implications of UGDP results. JAMA 1971;218:1400-1410.
Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 1970;19(Suppl.):830.
Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: A meta-Analysis of randomized clinical trials. Diabetes Obes Metab 2013;15:938-953.
Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-Analysis. Diabet Med 2013;30:1160-1171.
Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, Arima H, Monaghan H, Joshi R, Colagiuri S, Cooper ME, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Lisheng L, Mancia G, Marre M, Matthews DR, Mogensen CE, Perkovic V, Poulter N, Rodgers A, Williams B, MacMahon S, Patel A, Woodward M. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med 2014;371:1392-1406.
European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. http://www.ema.europa.eu/docs/en-GB/document-library/Scientific-guideline/2012/06/WC500129256.pdf (last updated: 14 May 2012; accessed: 24 March 2015).
Bethel MA, Sourij H. Impact of FDA guidance for developing diabetes drugs on trial design: from policy to practice. Curr Cardiol Rep 2012;14:59-69.
Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 2014;383:2008-2017.
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.
Marso SP, Lindsey JB, Stolker JM, House JA, Martinez RG, Kennedy KF, Jensen TM, Buse JB. Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2-3 liraglutide clinical development studies. Diab Vasc Dis Res 2011;8: 237-240.
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.
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;12:485-494.
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.
Patil HR, Al Badarin FJ, Al Shami HA, Bhatti SK, Lavie CJ, Bell DS, O'Keefe JH. Meta-Analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol 2012;110:826-833.
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;15:112-120.
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; 24:689-697.
Mahaffey KW, Hafley G, Dickerson S, Burns S, Tourt-Uhlig S, White J, Newby LK, Komajda M, McMurray J, Bigelow R, Home PD, Lopes RD. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 2013;166:240-249.
Hiatt WR, Goldfine AB, Kaul S. Cardiovascular risk assessment in the development of new drugs for obesity. JAMA 2012;308:1099-1100.
European Medicines Agency. Concept paper on the need for revision of the guidelines of medical products used in weight control. http://ema.europa.eu/docs/en-GB/document-library/scientific-guideline/2012/10/WC500133166.pdf (last updated: 2012; accessed: 24 July 2015).
White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J 2012;164:14-20.
O'Riordan M. LIGHT Stopped: Contrave CVD Safety Study Halted Following Premature Release of Data. http://www.medscape.com/viewarticle/844575#vp-1(last updated: 12 May 2015; accessed: 10 June 2015).
Mosenzon O, Raz I. Potential cardiovascular effects of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: current evidence and ongoing trials. Eur Heart J Suppl 2012;14:B22-B29.
Scheen AJ, Charbonnel B. Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: A critical reappraisal. Diabetes Metab 2014;40:176-185.
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: 1577-1589.
Holman RR, Bethel MA, George J, Sourij H, Doran Z, Keenan J, Khurmi NS, Mentz RJ, Oulhaj A, Buse JB, Chan JC, Iqbal N, Kundu S, Maggioni AP, Marso SP, Ohman P, Pencina MJ, Poulter N, Porter LE, Ramachandran A, Zinman B, Hernandez AF. Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. Am Heart J 2016;174:103-110.
Cleland JG, Atkin SL. Thiazolidinediones, deadly sins, surrogates, and elephants. Lancet 2007;370:1103-1104.
Sager PT, Seltzer J, Turner JR, Anderson JL, Hiatt WR, Kowey P, Prochaska JJ, Stockbridge N, White WB. Cardiovascular safety outcome trials: A meeting report from the Cardiac Safety Research Consortium. Am Heart J 2015;169:486-495.
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;130:1579-1588.
Standl E. Saxagliptin, alogliptin, and cardiovascular outcomes. N Engl J Med 2014; 370:483.
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: 2067-2076.
Khan MA, Deaton C, Rutter MK, Neyses L, Mamas MA. Incretins as a novel therapeutic strategy in patients with diabetes and heart failure. Heart Fail Rev 2013;18: 141-148.
Oyama J, Node K. Incretin therapy and heart failure. Circ J 2014;78:819-824.
Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res 2014;114:1788-1803.
Shannon RP, Angeli FS. Beyond glucose: cardiovascular effects of incretins and dipeptidyl peptidase-4 substrates. Eur Heart J Suppl 2012;14:B14-B21.
Boerrigter G, Costello-Boerrigter LC, Harty GJ, Lapp H, Burnett JC Jr. Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation. Am J Physiol Regul Integr Comp Physiol 2007;292:R897-R901.
U.S. Food and Drug Administration. FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. http://www.fda.gov/Drugs/DrugSafety/ucm486096.htm (last updated: 5 April 2016; accessed: 18 April 2016).
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; 2:843-851.
Vaur L, Gueret P, Lievre M, Chabaud S, Passa P. Development of congestive heart failure in type 2 diabetic patients with microalbuminuria or proteinuria: observations from the DIABHYCAR (type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril) study. Diabetes Care 2003;26:855-860.