Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Abstract

Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

ADVANCE in context: The benefits, risks and feasibility of providing intensive glycaemic control based on gliclazide modified release

“…The emergence of new approaches to glucose lowering with proven cardiovascular and renal benefits (ie, sodium‐glucose co‐transporter‐2 [SGLT‐2] inhibitors and glucagon‐like peptide‐1 [GLP‐1] agonists) has created further uncertainty as to the value of aiming for near normal glycaemic targets without consideration of the agents used. Indeed, the growing body of trial evidence would suggest that the agents used, at least over the short term (2‐5 years), may be even more important (especially in high‐risk patients with clinically apparent cardiovascular or renal disease) . The EMPA‐Reg, CANVAS, DECLARE‐TIMI and CREDENCE trials all reported the superiority of the introduction of SGLT‐2 inhibitors compared with placebo and standard care among patients with type 2 diabetes .…”

Challenges to hemoglobin A1c as a therapeutic target for type 2 diabetes mellitus

“…All the test drugs showed their noninferiority to placebo with regard to their primary endpoint. In five of the twelve CVOTs, the Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (HARMONY), the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER), the Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN‐6), the Canagliflozin Cardiovascular Assessment Study (CANVAS), and the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA‐REG OUTCOME), the primary CV endpoint was significantly lower in the test drug than the placebo group. The CV efficacy shown in the five CVOTs was achieved alongside moderate glycemic control, with HbA1c values not less than 6.8% (Table ), as recommended by the ACP guidance …”

Heart failure in the patient with diabetes: Epidemiology, aetiology, prognosis, therapy and the effect of glucose‐lowering medications

“…nary syndrome, the rate of HAHF was 4.0% with lixisenatide and 4.2% with placebo (HR 0.96, 95% CI 0.75-1.23; P = 0.75) 160. HAHF combined with cardiac death was 4% in the albiglutide group and 5% in the placebo group (HR 0.85, 95% CI 0.7-1.04; P = 0.113) 161. HAHF combined with cardiac death was 4% in the albiglutide group and 5% in the placebo group (HR 0.85, 95% CI 0.7-1.04; P = 0.113) 161.…”