A Michael Lincoff1, Jean-Claude Tardif2, Gregory G Schwartz3, Stephen J Nicholls4, Lars Rydén5, Bruce Neal6, Klas Malmberg7, Hans Wedel8, John B Buse9, Robert R Henry10, Arlette Weichert11, Ruth Cannata1, Anders Svensson11, Dietmar Volz11, Diederick E Grobbee12. 1. Department of Cardiovascular Medicine, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio. 2. Montreal Heart Institute Coordinating Center, Université de Montréal, Montreal, Canada. 3. Veterans Affairs Medical Center and University of Colorado School of Medicine, Denver. 4. South Australian Health and Medical Research Institute, University of Adelaide, Adelaide. 5. Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 6. George Institute for Global Health, University of Sydney, Sydney, Australia. 7. Department of Medicine, Karolinska Institutet, Stockholm, Sweden7F. Hoffman-La Roche Ltd, Basel, Switzerland. 8. Nordic School of Public Health, Frolunda, Sweden. 9. University of North Carolina School of Medicine, Chapel Hill. 10. University of California San Diego, San Diego. 11. F. Hoffman-La Roche Ltd, Basel, Switzerland. 12. Julius Center for Health Sciences and Primary Care and Julius Clinical, University Medical Center Utrecht, Utrecht, the Netherlands.
Abstract
IMPORTANCE: No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles. OBJECTIVE: To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS). DESIGN, SETTING, AND PARTICIPANTS: AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. INTERVENTIONS: Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function. RESULTS: The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased. CONCLUSIONS AND RELEVANCE: Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01042769.
RCT Entities:
IMPORTANCE: No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles. OBJECTIVE: To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS). DESIGN, SETTING, AND PARTICIPANTS: AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. INTERVENTIONS: Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function. RESULTS: The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased. CONCLUSIONS AND RELEVANCE: Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01042769.
Authors: Anastasia-Stefania Alexopoulos; Ali Qamar; Kathryn Hutchins; Matthew J Crowley; Bryan C Batch; John R Guyton Journal: Curr Diab Rep Date: 2019-02-26 Impact factor: 4.810