The Ethics of Conducting Clinical Trials With Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure
Authors: Javed Butler, Stefan D. Anker
Journal: Circulation (2017)

everal randomized clinical trials have recently started enrolling patients or are in the planning stages to assess the impact of treatment with various sodiumglucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure, many of whom will have comorbid diabetes mellitus.The impetus for these trials comes from the EMPA-REG OUTCOME trial (Empaglifozin-Reducing Excess Glucose CV Outcomes), in which treatment with empagliflozin in patients with type II diabetes mellitus with a known history of cardiovascular diseases was shown to lower the risk of cardiovascular death by 38%. 1 This led to the US Food and Drug Administration approval of a new indication for empagliflozin, ie, "to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease."Also, the 2016 European Society of Cardiology heart failure guidelines issued a IIa-B recommendation stating that "empagliflozin should be considered in patients with type 2 diabetes mellitus in order to prevent or delay the onset of heart failure or prolong life."No recommendation was made for treatment in patients with established heart failure.Recently, the CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) assessing the impact of 3 different SGLT2 inhibitors in real-life clinical practice from 6 different countries also showed mortality benefit with these agents in patients with diabetes mellitus. 2Although the results of the cardiovascular outcomes trials with several other SGLT2 inhibitors will be presented in the future, the aforementioned data provide a strong rationale for the use of these agents in patients with diabetes mellitus.While encouraging for the treatment of diabetes mellitus, these data have also raised concerns about whether patients with comorbid diabetes mellitus and heart failure, who may be perceived as fulfilling the new US Food and Drug Administration indication for the use of empagliflozin in patients with diabetes mellitus with established cardiovascular disease, can be ethically randomized to the placebo arm in future trials testing these agents in such patients.This concern is further accentuated by the fact that in the EMPA-REG OUTCOMES trial, both patients with and without heart failure derived similar mortality benefit. 3The type of outcomes that improved in this trial included adverse events commonly seen in heart failure patients, ie, heart failure hospitalizations, heart failure death, and sudden cardiac death.Also, a large proportion of deaths in the EMPA-REG OUTCOMES trial were presumed to be cardiovascular deaths, many of which were likely sudden deaths.Thus, randomizing such patients to the placebo arm with these existing data and the new US Food and Drug Administration indication has raised understandable concerns.Herein we describe why conducting trials with SGLT2 inhibitors in patients with comorbid heart failure and diabetes mellitus is both ethically justified and important. The Ethics of Conducting ClinicalTrials With Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure Is Placebo Assignment Justified in Patients With Comorbid Diabetes Mellitus and Heart Failure?