Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action and their effects on clinical outcomes. The cardiovascular (CV) effects of once-weekly albiglutide in type 2 diabetes are not well characterised.

• The HARMONY study investigated the safety and efficacy of albiglutide in preventing CV death, myocardial infarction (MI), or stroke.

Type of study, patients, and inclusion criteria

• Double-blind, randomised, placebo-controlled trial at 610 sites across 28 countries.
• Patients with type 2 diabetes and CV disease were randomised (at a 1:1 ratio) to receive either subcutaneous injection of albiglutide (30-50 mg, based on glycaemic response and tolerability) or a matched volume of placebo once a week, in addition to standard care.
• Key inclusion criteria ensured a high rate of CV events: established disease of the coronary (MI, at least 50% stenosis in one coronary artery or more, or previous coronary revascularisation), cerebrovascular disease (ischaemic stroke, at least 50% carotid artery stenosis, or a previous carotid vascular procedure), or peripheral artery disease (intermittent claudication and an ankle to brachial index <0.9, non-traumatic amputation, or a previous peripheral vascular procedure) who had a HbA_1c level of more than 7.0% (53 mmol/mol).

Patient populations

• Total number of enrolees: 9463.
• Age: ≥40 years.
• Duration of follow-up: median of at least 1.6 years.

Primary outcome measure

• Composite of death from CV causes, MI, or stroke.

Secondary outcome measures

• Secondary CV outcomes: a four-component composite (the primary composite, with the addition of urgent revascularisation for unstable angina), the individual components of the primary endpoint, and the composite of CV death or hospital admission because of heart failure.
• Secondary metabolic outcomes: the time to initiation of chronic insulin therapy, the time to the first occurrence of an important microvascular event, changes in HbA_1c and bodyweight, and the proportion of participants who attained glycaemic control without severe hypoglycaemia and who gained less than 5% of their bodyweight by the end of the study.
• Safety outcomes: the change in blood pressure and heart rate, change in eGFR, and adverse events of special interest, which included the development of prespecified malignancies (medullary thyroid cancer, pancreatic cancer, and haematological malignancies), pancreatitis, severe hypoglycaemia, injection site reactions, immunological reactions, diabetic retinopathy, worsening renal function, and death from any cause.

Primary endpoints or outcomes

• The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4.6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5.9 events per 100 person-years in the placebo group (hazard ratio 0.78, 95% CI 0.68-0.90), which indicated that albiglutide was superior to placebo (p<0.0001 for noninferiority; p = 0.0006 for superiority) (Figure).

Secondary endpoints or outcomes

• The hazard ratios for each of the components of the composite primary endpoint were 0.93 (95% CI 0.73-1.19) for death from CV causes, 0.75 (0.61-0.90) for MI, and 0.86 (0.66-1.14) for stroke.
• The incidence of acute pancreatitis (10 patients in the albiglutide group and 7 patients in the placebo group), pancreatic cancer (6 patients in the albiglutide group and 5 patients in the placebo group), medullary thyroid carcinoma (no patients in either group), and other serious adverse events did not differ between the two groups.
• There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.

• In patients with type 2 diabetes and CV disease, albiglutide was superior to placebo with respect to major adverse CV events.