738 Diabetes Care Volume 39, May 2016 Robert J. Smith,1 Allison B. Goldfine,2 and Evaluating the Cardiovascular William R. Hiatt3 Safety of New Medications for CARDIOVASCULAR DISEASE AND DIABETES Type 2 Diabetes: Time to Reassess? Diabetes Care 2016;39:738–742 | DOI: 10.2337/dc15-2237 The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstra- tion of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 140,000 subjects thus far have been completed or are ongoing in accordance with this guidance. All five of the completed trials, involving three different drug classes, have met their primary objective to exclude an unacceptable level of ischemic cardiovascular risk as defined in the FDA guidance. Additionally, one trial found an increased risk of hospitalization for heart failure, and another demonstrated decreases in cardio- vascular mortality and hospitalization for heart failure. Given that a heightened risk of cardiovascular ischemic events has not been demonstrated across several classes of new diabetes drugs, we believe it is time for the scientificcommunityand the FDA to consider a more targeted approach to what is, in effect, a global cardiovascular safety trial requirement for all new type 2 diabetes medications in development. Multiple new medications for glycemic management of type 2 diabetes have re- cently been approved by the U.S. Food and Drug Administration (FDA), with addi- tional drugs in development. In the regulatory process, all agents for treatment of hyperglycemia in diabetes are evaluated for efficacy in lowering blood glucose levels 1Department of Medicine, Alpert Medical School and overall safety and are subjected to particularly rigorous screening for cardio- and Department of Health Services, Policy & vascular safety. The approach to these cardiovascular studies is largely directed by a Practice, School of Public Health, Brown Univer- sity, and Ocean State Research Institute, Provi- Guidance for Industry issued by the FDA in 2008 stating that all new type 2 diabetes dence VA Medical Center, Providence, RI drug development programs should rule out unacceptable cardiovascular risk by 2Research Division, Joslin Diabetes Center, demonstrating an upper bound of the two-sided 95% CI of the risk ratio ,1.8 Harvard Medical School, Boston, MA preapproval for a composite end point of major adverse cardiac events (MACE), 3Division of Cardiology, University of Colorado consisting of at least cardiovascular death, nonfatal myocardial infarction, and School of Medicine, and CPC Clinical Research, Aurora, CO stroke (1). For drugs in which the upper bound of the CI is between 1.3 and 1.8, the guidance states that subsequent postapproval trials of the same composite Corresponding author: Robert J. Smith, robert_ [email protected]. MACE end point should be conducted to continue marketing. These recommendations Received 13 October 2015 and accepted 23 were motivated by the high prevalence of cardiovascular disease in diabetes (accounting February 2016. for approximately 70% of deaths) and, in part, by concerns about a signal of potentially © 2016 by the American Diabetes Association. increased cardiovascular risk for the thiazolidinedione rosiglitazone (2) occurring on a Readers may use this article as long as the work is background of additional cardiac safety concerns with antihyperglycemic medications properly cited, the use is educational and not for for type 2 diabetes. The latter included evidence for increased deaths and major profit, and the work is not altered. cardiovascular events during the development program of the peroxisome proliferator– See accompanying articles, pp. 664, 668, activated receptor (PPAR) agonist muraglitazar (3), persistent uncertainty about cardio- 677, 686, 694, 701, 709, 717, 726, and vascular safety with sulfonylureas (4), increased mortality with intense glucose control 735. care.diabetesjournals.org Smith, Goldfine, and Hiatt 739 in the Action to Control Cardiovascular Sitagliptin [TECOS] trial) (10), the sodium– In addition to concerns about ischemic Risk in Diabetes (ACCORD) trial (5), and glucose cotransporter 2 (SGLT2) inhibitor cardiovascular events, as addressed by increased risk for congestive heart failure empagliflozin (BI 10773 [Empagliflozin] the recommendations for a composite with pioglitazone (6) and rosiglitazone (7). Cardiovascular Outcome Event Trial in MACE in the FDA guidance, there is an Seventeen large, randomized, controlled, Type 2 Diabetes Mellitus Patients increased risk of heart failure in patients multicenter postapproval trials involving [EMPA-REG OUTCOME] study) (11), and with diabetes (13). Increased heart failure more than 140,000 participants thus far the glucagon-like peptide 1 (GLP-1) recep- risk has previously been demonstrated have been initiated in accordance with tor agonist lixisenatide (Evaluation of Lix- with thiazolidinediones (6,7) but was not the FDA guidance (Tables 1 and 2). Results isenatide in Acute Coronary Syndrome apparent during the initial develop- from five of these trials now have been [ELIXA] study) (12). The sitagliptin and lix- ment of any of the agents for which reported, providing an opportunity to ex- isenatide studies demonstrated a hazard postmarketing safety trials were subse- amine the utility of this approach to eval- ratio for a composite MACE end point ap- quently performed under the 2008 FDA uate the safety of new antihyperglycemic proximating unity and an upper bound of guidance. Unexpectedly, exploratory medications for type 2 diabetes. the 95% CI ,1.30 for both drugs, while analysis of hospitalization for heart failure The FDA Endocrinologic and Metabolic the empagliflozin results provided evi- as an individual clinical end point revealed Drugs Advisory Committee was convened dence for cardiovascular benefit with a an elevated hazard ratio for saxagliptin at in April 2015 to review the results of hazard ratio of 0.86 and upper bound of 1.27 (95% CI 1.07–1.51) and a nonsignifi- postmarketing trials of the dipeptidyl the 95% CI 0.99 (Table 1). Thus, all five cant numerical increase in risk for peptidase 4 (DPP-4) inhibitors saxagliptin trials involving medications from three alogliptin with a hazard ratio of 1.19 (Saxagliptin Assessment of Vascular Out- different drug classes have excluded an (95% CI 0.90–1.58). The hazard ratios for comes Recorded in Patients with Diabetes unacceptable level of ischemic cardiovas- hospitalization for heart failure as a Mellitus–Thrombolysis in Myocardial In- cular risk (which was the primary analysis) prespecified, adjudicated individual end farction 53 [SAVOR-TIMI 53] trial) and as defined in the FDA 2008 guidance point approximated unity in the sitagliptin alogliptin (Examination of Cardiovascular document. and lixisenatide trials (Table 1), and in- Outcomes with Alogliptin versus Standard All-cause mortality, another important, creased risk for an expanded MACE end of Care [EXAMINE] trial) in type 2 diabe- prespecified secondary end point, raised point that included hospitalization for tes. The study data reviewed at those focused concerns by demonstrating in- heart failure was not evident with any of meetings demonstrated hazard ratios consistent findings across the DPP-4 in- these incretin-modulating drugs (10,12). for a composite MACE end point (cardio- hibitor trials. For saxagliptin, all-cause By contrast, the empagliflozin trial vascular death, nonfatal myocardial in- mortality in the intent-to-treat analysis showed a decreased hazard ratio for hos- farction, and nonfatal stroke) of 1.00 for population showed a hazard ratio of pitalization for heart failure as an individual saxagliptin and 0.96 for alogliptin. The up- 1.11 (95% CI 0.96–1.27), which increased end point at 0.65 (95% CI 0.50–0.85) and per bound of the 95% CI for the two drugs to 1.23 (95% CI 1.02–1.48) when evalu- as a component of an expanded MACE was 1.12 and 1.16, respectively, which ated in the on-treatment population. It is composite outcome combined with CV was below a threshold for concern based important to note that, consistent with death but excluding stroke at 0.66 (95% on the FDA guidance (Table 1) (8,9). The the lack of increased risk of MACE, the CI 0.55–0.79) (11). Thus, hospitalization advisory committee vote on whether ac- increased mortality risk was primarily for heart failure as a stand-alone explor- ceptable cardiovascular risk profiles were driven by noncardiovascular deaths, atory end point demonstrated inconsistent demonstrated was 13 “yes,” 1 “no,” and 1 with no specific identified causal con- results for the DPP-4 inhibitors, with a po- abstention for saxagliptin and was unan- cerns. By contrast, all-cause mortality tential concern observed for saxagliptin, a imous at 16 “yes” for alogliptin (note that was not numerically increased with less evident trend for alogliptin, and no there was not complete overlap in mem- alogliptin, sitagliptin, or lixisenatide, and numeric or statistical difference for bers attending each meeting). Results of all-cause mortality was significantly de- sitagliptin. Hospitalization for heart failure three additional cardiovascular outcome creased with empagliflozin (Table 1). It is risk was either neutral or decreased with trials conducted under the FDA guidance not possible to directly compare agents as the other two agents studied. On the basis