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Harmony Outcomes - Harmony Outcomes
Contribution To Literature:
The Harmony Outcomes trial showed that albiglutide is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and high CV risk.
Description:
The goal of the trial was to assess the cardiovascular (CV) safety of albiglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, in patients with type 2 diabetes at high risk for CV events.
Study Design
Patients were randomized in a 1:1 fashion to either albiglutide once weekly (n = 4,731) or matching placebo (n = 4,732). Both medications were administered as a subcutaneous injection. The starting dose of study medication was 30 mg in 0.5 ml once a week. If, after ≥5 weeks of study treatment, the investigator determined that a trial participant required intensification of glucose-lowering therapy, the dose of study treatment could be increased to 50 mg.
- Total screened: 10,793
- Total number of enrollees: 9,463
- Duration of follow-up: 1.6 years
- Mean patient age: 64.2 years
- Percentage female: 31%
Inclusion criteria:
- Type 2 diabetes
- Age ≥40 years
- Established disease of the coronary (myocardial infarction [MI], ≥50% stenosis in ≥1 coronary artery, or previous coronary revascularization), cerebrovascular (ischemic stroke, ≥50% carotid artery stenosis, or a previous carotid vascular procedure), or peripheral arterial circulation (intermittent claudication and an ankle to brachial index <0.9, nontraumatic amputation, or a previous peripheral vascular procedure)
- Hemoglobin A1c (HbA1c) ≥7.0%
Exclusion criteria:
- Type 1 diabetes
- Estimated glomerular filtration rate <30
- Severe gastroparesis, previous pancreatitis or substantial risk factors for pancreatitis,
- Personal or family history of medullary carcinoma of the thyroid or multiple endocrine neoplasia type 2
- History of pancreatic neuroendocrine tumors
- Current use of a GLP-1 receptor agonist
Other salient features/characteristics:
- White 70%, Asian 5%
- Established coronary artery disease: 71%; stroke: 18%
- HbA1c: 8.7%
- Duration of diabetes: 14.2 years
- Diabetes medications: biguanide: 74%, sulfonylurea: 29%, insulin: 59%
Principal Findings:
The primary outcome, CV death, nonfatal MI, or stroke, for albiglutide vs. placebo: 7.0% vs. 9%, hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.68-0.90, p < 0.0001 for noninferiority; p = 0.0006 for superiority; CV death: 3% vs. 3%, p = 0.58; all MI: 4% vs. 5%, p = 0.003; all stroke: 2% vs. 2%, p = 0.30.
Secondary outcomes for albiglutide vs. placebo:
- All-cause mortality: 4% vs. 4%, p = 0.64
- Severe hypoglycemia: 1% vs. 1%, p < 0.05
- Acute pancreatitis: <1% vs. <1%, p > 0.05; pancreatic carcinoma: <1% vs. <1%, p > 0.05
Mean HbA1c decreased more in patients in the albiglutide group than in those in the placebo group (difference from placebo at 8 months: –0.63%, 95% CI –0.69 to –0.58; at 16 months: –0.52%, 95% CI –0.58 to –0.45). Body weight decreased more in patients in the albiglutide group than the placebo group (difference from placebo at 8 months: –0.66 kg, 95% CI –0.83 to –0.49; at 16 months –0.83 kg, 95% CI –1.06 to –0.60.
Interpretation:
The results of this trial indicate that albiglutide is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and established atherosclerotic disease. This appeared to be driven by a reduction in MI; rates of CV death and stroke were similar. Approximately 75% of these patients were on background metformin and 60% on insulin. Similar salutary effects on CV outcomes have been reported for two other GLP-1 agonists in their respective trials: liraglutide in LEADER, and semaglutide in SUSTAIN-6. On the other hand, two other trials of GLP-1 agonists, ELIXA (lixisenatide) and EXSCEL (exenatide) did not show superiority for CV outcomes compared with placebo, suggesting that this may not necessarily be a class effect.
These are important findings and suggest that certain GLP-1 agonists may need to be considered as first- or second-line therapy in high-risk patients with type 2 diabetes going forward. Overall, these drugs reduce hyperglycemia in patients with type 2 diabetes and are also known to cause slight reductions in weight and blood pressure. One down side is that they have to be injected rather than taken orally (for example, sodium-glucose co-transporter-2 [SGLT-2] inhibitors). However, one benefit of albiglutide and semaglutide is that they are both once weekly medications, which may help with medication adherence.
Following the much-publicized CV safety concerns with rosiglitazone, the FDA mandated that all new diabetes drugs conduct studies demonstrating CV safety. The upper limit of the 95% CI for the HR had to be <1.8 for premarketing studies and <1.3 for postmarketing studies. This trial thus establishes the CV safety profile of albiglutide for use in patients with type 2 diabetes, and is in fact, one of the few large-scale type 2 diabetes trials to show an improvement in hard CV outcomes with simultaneous improvements in glycemic control in a high-risk population. The mechanisms for this benefit will need to be established in future trials.
References:
Hernandez AF, Green JB, Janmohamed S, et al., on behalf of the Harmony Outcomes Committees and Investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519-29.
Keywords: Amputation, Blood Pressure, Body Weight, Brain Ischemia, Carcinoma, Pancreatic Ductal, Carotid Stenosis, Coronary Artery Disease, Diabetes Mellitus, Type 2, Glucagon-Like Peptide 1, Glucose, Glycated Hemoglobin A, Hyperglycemia, Hypoglycemia, Insulin, Intermittent Claudication, Metformin, Myocardial Infarction, Myocardial Revascularization, Pancreatic Neoplasms, Primary Prevention, Stroke, Vascular Diseases
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