Do Positive Cardiovascular Outcomes Trials With New Glucose-Lowering Agents Overestimate Both Efficacy and Safety?

Abstract

HomeCirculation ResearchVol. 123, No. 4Do Positive Cardiovascular Outcomes Trials With New Glucose-Lowering Agents Overestimate Both Efficacy and Safety? Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBDo Positive Cardiovascular Outcomes Trials With New Glucose-Lowering Agents Overestimate Both Efficacy and Safety? André J. Scheen André J. ScheenAndré J. Scheen Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium Search for more papers by this author Originally published2 Aug 2018https://doi.org/10.1161/CIRCRESAHA.118.313485Circulation Research. 2018;123:e3–e4In Response:Our invited review1 focused on oral glucose-lowering agents, DPP-4 (dipeptidyl peptidase-4) inhibitors and SGLT-2 (sodium-glucose cotransporter type 2) inhibitors. The letter by Tampaki et al rather analyzes cardiovascular outcome trials that reported cardiovascular protection, either with GLP-1RAs (glucagon-like peptide-1 receptor agonists; liraglutide in LEADER [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results], semaglutide in SUSTAIN-6 [Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes]) or SGLT-2 inhibitors (focusing on EMPA-REG OUTCOME [Empagliflozin Cardiovascular Outcome Events in Type 2 Diabetes Mellitus Patients] with empagliflozin), and in fact mainly debates results with GLP-1RAs. Overall, the main message of the letter is that these 3 positive cardiovascular outcome trials2 may have overestimated efficacy and underestimated some safety concerns.Overestimation of efficacy may result from methodological issues. Because the protocol permitted hypoglycemic agents in both groups if the glycated hemoglobin level remained above targets, an unbalance treatment distribution between the placebo arm and the active arm was observed. In agreement with the Food and Drug Administration 2008 guidance document, all patients should continue to be treated to standard of care and glycated hemoglobin targets, according to a design searching glycemic equipoise.3 Tampaki et al hypothesize that the higher use of insulin and sulfonylureas in the placebo arm may lead to unwanted cardiovascular effects that would result in an overestimation of the benefits of the GLP-1RAs or the SGLT-2 inhibitors. However, this interference could not have markedly influence the results4 and what so ever in practice the difference versus standard of care is of major clinical relevance. Furthermore, in the 3 cardiovascular outcome trials having evaluated DPP-4 inhibitors, a similar increased use of sulfonylureas or insulin in the placebo arms did not lead to an increased CV risk compared with the DPP-4 arms.1 The results of SUSTAIN-6 were also criticized because of a rather high rate of premature discontinuation with semaglutide compared with placebo. SUSTAIN-6 was a preapproval trial designed to prove safety rather than efficacy of semaglutide. If we can agree with some limitations of SUSTAIN-6, our review was devoted to new oral glucose-lowering agents, emphasizing the positive results with SGLT-2 inhibitors, rather than GLP-1RAs.1The main criticism raised by Tampaki et al on EMPA-REG OUTCOME concerns the quotation of cardiovascular events and deaths, a remark raised by the Food and Drug Administration and already discussed.2 Although cardiovascular death was not explicitly part of the confirmatory testing hierarchy, the reduction seems to be robust because of consistency across doses and subgroups, and a clinically relevant effect size. All categories of cardiovascular death remained significant in a sensitivity analysis excluding presumed cardiovascular death.5 We agree that heart failure was poorly assessed. Nevertheless, the positive effects on cardiovascular outcomes were observed in patients with or without heart failure at baseline. Furthermore, the reduction in hospitalization for heart failure and all-cause mortality reported in EMPA-REG OUTCOME with empagliflozin was confirmed in CANVAS (Canagliflozin Cardiovascular Assessment Study) with canagliflozin and in 3 large observational studies (CVD-REAL 1 [Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors], CVD-REAL2, EASEL [Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World]) including dapagliflozin, thus providing strong external validity.1 Ongoing trials specifically devoted to heart failure, with reduced or preserved ejection fraction, will better delineate the role of SGLT-2 inhibitors in heart failure patients with or without diabetes mellitus.3On safety concern, Tampaki et al mainly focused on cancer risk, especially for GLP-1RAs but also for empagliflozin. Thyroid cancer potentially associated with incretin-based therapies is not considered as an issue in humans.6 The trend for an increased risk of pancreatic cancer in LEADER was not confirmed in 3 other trials with GLP-1RAs.7 LEADER was not primarily designed to assess neoplasm risk, and firm conclusions cannot be made on numeric imbalances observed for individual neoplasm types.6 Similarly, current evidence did not indicate a significantly increased risk of overall cancer among patients using SGLT-2 inhibitors.8 Given the uncertainty of evidence because of a low incidence rate in rather short-term trials, future long-term prospective studies and postmarketing surveillance studies are still warranted.There is no doubt that current cardiovascular outcome trials have some limitations, well discussed by a recent expert forum,3 but obviously they have opened a new paradigm in the management of type 2 diabetes mellitus, especially in patients with cardiovascular disease.André J. ScheenDivision of Diabetes, Nutrition and Metabolic DisordersDepartment of MedicineCHU LiègeLiège, BelgiumDisclosuresA.J. Scheen has received lecturer/advisor/investigator fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi, and Servier. A.J. Scheen worked as clinical investigator in the TECOS, EMPA-REG OUTCOME, CANVAS-R, and DECLARE trials.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment.