The Lancet OCTOBER 02, 2018

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes)

Adrian F. Hernandez, Jennifer B. Green, Salim Janmohamed, et al. on behalf of the Harmony Outcomes Committees and Investigators

Source: View publication →

Bottom Line

The HARMONY Outcomes trial demonstrated that the long-acting GLP-1 receptor agonist albiglutide significantly reduced the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes and established cardiovascular disease compared to placebo.

Key Findings

1. Albiglutide treatment significantly reduced the risk of the primary composite endpoint (cardiovascular death, myocardial infarction, or stroke) by 22% compared to placebo (hazard ratio 0.78; 95% CI 0.68–0.90; p=0.0006 for superiority).

2. The absolute event rate for the primary outcome was 7.1% (n=338) in the albiglutide group compared to 9.0% (n=428) in the placebo group over a median follow-up of 1.6 years.

3. The primary clinical benefit was largely driven by a reduction in myocardial infarction (hazard ratio 0.75; 95% CI 0.61–0.90).

4. No significant differences were observed between groups for individual outcomes of cardiovascular death (p=0.58) or stroke (p=0.30), nor for all-cause mortality (p=0.64).

5. Safety outcomes showed no significant increases in rates of acute pancreatitis, pancreatic cancer, or medullary thyroid carcinoma compared to placebo.

Study Design

Design

RCT

Double-Blind

Sample

9,463

Patients

Duration

1.6 yr

Median

Setting

Multicenter, International

Population Adults with type 2 diabetes and established cardiovascular disease.

Intervention Once-weekly subcutaneous albiglutide (30 mg or 50 mg).

Comparator Once-weekly subcutaneous matching placebo.

Outcome Time to first occurrence of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or stroke.

Study Limitations

• The median follow-up of 1.6 years was relatively short compared to other major cardiovascular outcomes trials, potentially limiting the ability to detect differences in mortality outcomes.

• The study was performed in patients with established cardiovascular disease, which may limit the generalizability of these findings to lower-risk populations.

• The manufacturer discontinued commercial production of albiglutide shortly after the study, which impacts its current clinical availability despite these positive trial results.

• Weight loss benefits observed were modest and decreased over time compared to some other agents in the GLP-1 receptor agonist class.

Clinical Significance

The results of HARMONY Outcomes strengthened the evidence base supporting the use of specific GLP-1 receptor agonists to improve cardiovascular outcomes in high-risk patients with type 2 diabetes, reinforcing their role in secondary prevention of atherosclerotic cardiovascular disease.

Historical Context

The trial was initiated during a period of uncertainty regarding the cardiovascular safety of glucose-lowering therapies, following regulatory mandates for cardiovascular outcomes trials. While early GLP-1 receptor agonist studies (like ELIXA) yielded neutral results, HARMONY Outcomes successfully added to the positive evidence established by trials such as LEADER (liraglutide) and SUSTAIN-6 (semaglutide), though the drug itself was commercially withdrawn for business reasons shortly before the study's completion.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Describe the physiological mechanism of action of GLP-1 receptor agonists like albiglutide and explain why they are specifically beneficial for patients with type 2 diabetes compared to DPP-4 inhibitors.

Key Response

GLP-1 receptor agonists (GLP-1 RAs) mimic the incretin hormone GLP-1, which stimulates insulin secretion, inhibits glucagon, slows gastric emptying, and promotes satiety. Unlike DPP-4 inhibitors, which only prevent the degradation of endogenous GLP-1 to achieve physiological levels, GLP-1 RAs provide pharmacological levels of GLP-1 that resist degradation. This leads to superior glucose lowering, significant weight loss, and, as shown in Harmony Outcomes, direct cardiovascular protection that is not typically observed with DPP-4 inhibitors.

Resident

In a patient with type 2 diabetes and a previous myocardial infarction, what was the primary cardiovascular benefit observed with albiglutide in the Harmony Outcomes trial, and how does this affect your choice of second-line therapy after metformin?

Key Response

The Harmony Outcomes trial demonstrated a 22% relative risk reduction in major adverse cardiovascular events (MACE), which was primarily driven by a reduction in myocardial infarction (HR 0.75). For a resident, this reinforces the clinical guideline to prioritize GLP-1 RAs with proven CV benefit as second-line agents (or even first-line in some contexts) for patients with established atherosclerotic cardiovascular disease (ASCVD), regardless of their current HbA1c.

Fellow

Contrast the components of the primary MACE endpoint in the Harmony Outcomes trial (albiglutide) with those of the LEADER trial (liraglutide) and SUSTAIN-6 (semaglutide). What do these differences suggest about the heterogeneity of GLP-1 receptor agonists?

Key Response

While all three trials were positive for MACE reduction, the drivers differed: albiglutide primarily reduced MI; liraglutide showed a significant reduction in cardiovascular death; and semaglutide showed a significant reduction in stroke. This suggests that while there is a 'class effect' for CV benefit, the specific organ-system protection (cardiac vs. cerebrovascular vs. mortality) may vary based on the molecule's structure, half-life, or dosing, requiring nuanced selection based on a patient's specific CV risk profile.

Attending

Albiglutide was withdrawn from the global market for commercial reasons shortly after the Harmony Outcomes results were published. How does the success of a now-unavailable drug influence your evidence-based approach to treating patients with high-risk ASCVD?

Key Response

The results remain practice-changing because they provide robust evidence for the class-wide efficacy of long-acting GLP-1 RAs in secondary prevention. It confirms that the CV benefit is likely a result of the GLP-1 receptor activation pathway rather than a fluke of a single molecule (like liraglutide). For an attending, this trial justifies the use of other available once-weekly GLP-1 RAs (like dulaglutide or semaglutide) to achieve similar cardioprotective outcomes seen in the albiglutide data.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The Harmony Outcomes trial utilized an 'enrichment' strategy for its study population. Critically evaluate how this design choice affects the external validity and the calculation of the absolute risk reduction (ARR) compared to a more heterogeneous 'real-world' diabetic population.

Key Response

By enrolling only patients with established CVD (100% of the cohort), the trial ensured a high event rate, which increases statistical power and shrinks the required sample size and follow-up time. However, this overestimates the ARR if applied to a general T2DM population (primary prevention). The Number Needed to Treat (NNT) of 50 over 1.6 years is highly impressive but only applicable to this high-risk subgroup; the NNT would be significantly higher in lower-risk populations, affecting cost-effectiveness models.

Journal Editor

The median follow-up in Harmony Outcomes was only 1.6 years, one of the shortest for a CVOT. As a reviewer, what concerns would you raise regarding the sustainability of the treatment effect and the detection of late-emerging safety signals?

Key Response

A short follow-up may capture early hemodynamic or anti-thrombotic benefits but fails to assess long-term 'legacy effects' or the progression of atherosclerosis. Furthermore, rare or slow-developing adverse events (such as thyroid C-cell hyperplasia, retinopathy progression, or certain malignancies) require much longer observation periods to reach a definitive safety conclusion, which a 1.6-year window cannot provide.

Guideline Committee

How does the evidence from Harmony Outcomes specifically refine the recommendations for GLP-1 receptor agonist use in the ADA Standards of Care and the ESC guidelines for patients with T2DM and ASCVD?

Key Response

Harmony Outcomes provided the 'Level A' evidence needed to strengthen the recommendation that GLP-1 RAs with proven CV benefit should be used in patients with established ASCVD independently of metformin or baseline HbA1c. Specifically, the ADA and ESC now recommend these agents to reduce the risk of MI and MACE, with Harmony Outcomes being a pillar study that helped move these drugs from 'glucose-lowering' to 'cardioprotective' therapies in clinical guidelines.

Clinical Landscape

Noteworthy Related Trials

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide 1.8mg daily

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Liraglutide significantly reduced the risk of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared to placebo.

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide 0.5mg or 1.0mg weekly

Population

T2DM patients with high CV risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Semaglutide demonstrated a significant reduction in the primary composite cardiovascular outcome, primarily driven by a reduction in nonfatal stroke.

2019

REWIND Trial

n = 9,901 · Lancet

Tested

Dulaglutide 1.5mg weekly

Population

T2DM patients with CV risk factors or established disease

Comparator

Placebo

Endpoint

3-point MACE

Key result: Dulaglutide reduced the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke among patients with T2DM.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis