HARMONY OUTCOMES deep-dive: albiglutide MACE result for a shelved GLP-1 (Hernandez 2018)

Name: HARMONY OUTCOMES deep-dive: albiglutide MACE result for a shelved GLP-1 (Hernandez 2018)
Creator: Eli Marsden
Published: 2026-05-28

Last verified 2026-05-28 · Phase 3 (registered as Phase 4 on ClinicalTrials.gov; conducted as a post-approval cardiovascular outcomes trial) · Completed (results published October 2018; albiglutide withdrawn from the global market by GSK in July 2018 for commercial reasons before the read-out) · NCT02465515 ↗

By Eli Marsden · Founding Editor

Editorially reviewed (not clinically reviewed) · How we verify contentLast reviewed May 28, 2026

HARMONY OUTCOMES (Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus) was a multicenter, double-blind, placebo-controlled trial sponsored by GlaxoSmithKline at 610 sites in 28 countries. It enrolled 9,463 adults aged 40 years or older with type 2 diabetes and pre-existing cardiovascular, cerebrovascular, or peripheral arterial disease, and randomized them 1:1 to once-weekly subcutaneous albiglutide (starting at 30 mg, titratable to 50 mg by glycemic response and tolerability) or matching placebo, both on top of standard care. The primary endpoint was time to first occurrence of a three-point major adverse cardiovascular event composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, tested first for non-inferiority and then for superiority. GSK announced the commercial withdrawal of albiglutide in July 2017, citing limited prescriber uptake rather than any safety concern, but completed the trial under contractual commitments to enrolled participants. Hernandez and colleagues published the results in The Lancet on October 27, 2018, after the drug had already been pulled from global markets.

Enrollment: 9,463
Duration: Median follow-up 1.6 years (median 1.65 person-years for the CV follow-up period); final patient visit March 12, 2018. The trial ran shorter than other GLP-1 cardiovascular outcomes trials because GSK declared the pre-specified event threshold met (611 primary endpoints with at least 1.5 years median follow-up) on November 8, 2017, after the July 2017 announcement that albiglutide would be withdrawn from the market.
Drug: Albiglutide 30-50 mg weekly (subcutaneous)
Population: Adults aged 40 years or older with type 2 diabetes and established cardiovascular disease, defined as a prior coronary, cerebrovascular, or peripheral arterial event or relevant revascularization. HbA1c at least 7.0% on stable background diabetes therapy. Mean age 64.1 years, 30.7% female, mean BMI 32.3 kg/m², mean HbA1c 8.7%, mean diabetes duration 13.8 years. About 70% had a prior myocardial infarction or coronary revascularization, about 18% had a prior stroke, and most participants were on metformin, statins, antiplatelets, and antihypertensives at baseline. The cohort was a true secondary-prevention population rather than a mixed primary-and-secondary group.

Primary endpoint

Three-point MACE: first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (time-to-first-event, albiglutide vs placebo, intention-to-treat)

Treatment arm

338 of 4,731 (7%) — incidence rate 4.6 events per 100 person-years

Comparator

428 of 4,732 (9%) — incidence rate 5.9 events per 100 person-years

Treatment difference: Hazard ratio 0.78 (95% CI 0.68–0.90); P<0.0001 for non-inferiority; P=0.0006 for superiority

22% relative reduction in three-point MACE with albiglutide vs placebo over a median 1.6 years. Absolute risk reduction roughly 2 percentage points; number needed to treat over the trial duration is in the same range (≈75) as LEADER and SUSTAIN-6 once adjusted for the shorter follow-up. The trial passed pre-specified non-inferiority and then demonstrated formal superiority on the primary endpoint.

Secondary endpoints

Endpoint	Treatment	Comparator	Difference
Cardiovascular death (component of MACE) Cardiovascular mortality was numerically lower but not statistically reduced. Unlike LEADER, HARMONY OUTCOMES did not show a CV-death benefit at 1.6 years — a result consistent with its shorter follow-up.	Incidence rate 1.61 events per 100 person-years on albiglutide	Incidence rate 1.72 events per 100 person-years on placebo	Hazard ratio approximately 0.93 (95% CI crossed 1.0); no significant reduction
Nonfatal myocardial infarction (component of MACE) 25% relative reduction in adjudicated myocardial infarction. MI was the single largest component contributor to the MACE win — the opposite direction-of-effect from SUSTAIN-6, where stroke dominated.	Incidence rate 2.43 events per 100 person-years on albiglutide	Incidence rate 3.26 events per 100 person-years on placebo	Hazard ratio 0.75 (95% CI 0.61–0.90); statistically significant
Nonfatal stroke (component of MACE) Directional but not statistically significant reduction in stroke. The pattern is the inverse of semaglutide's SUSTAIN-6 result and is part of the argument that individual GLP-1 receptor agonists have different cardiovascular component-level signatures.	Incidence rate 1.25 events per 100 person-years on albiglutide	Incidence rate 1.45 events per 100 person-years on placebo	Hazard ratio approximately 0.86; confidence interval crossed 1.0
MACE or urgent revascularization for unstable angina (expanded cardiovascular composite) The expanded composite tracked the primary result closely, suggesting the MI-driven benefit also affected revascularization for unstable angina.	Incidence rate 5.06 events per 100 person-years on albiglutide	Incidence rate 6.45 events per 100 person-years on placebo	Hazard ratio 0.78 (95% CI 0.69–0.89); statistically significant
Cardiovascular death or hospitalization for heart failure Directional but not statistically significant. Heart-failure hospitalization on GLP-1 receptor agonists has been a recurring null finding across the class.	Incidence rate 2.49 events per 100 person-years on albiglutide	Incidence rate 2.92 events per 100 person-years on placebo	Hazard ratio approximately 0.85; confidence interval crossed 1.0
Time to a clinically important microvascular event (composite of need for renal transplant or dialysis, new diabetes-related blindness, or photocoagulation or anti-VEGF procedures) Numerically fewer microvascular events on albiglutide; the trial was not powered to demonstrate microvascular benefit but the direction matches the renal signals seen with semaglutide and dulaglutide.	Incidence rate 0.46 events per 100 person-years on albiglutide	Incidence rate 0.69 events per 100 person-years on placebo	Hazard ratio approximately 0.66; confidence interval crossed 1.0
HbA1c change from baseline at month 16 Modest glycemic effect from a mean baseline HbA1c of 8.7%, in line with albiglutide's reputation as a less potent GLP-1 receptor agonist than liraglutide, semaglutide, or dulaglutide. The cardiovascular benefit was disproportionately large relative to the HbA1c effect, reinforcing the class argument that GLP-1 cardiovascular benefit is not driven primarily by glucose lowering.	−0.83 percentage points (least-squares mean) on albiglutide	−0.31 percentage points (least-squares mean) on placebo	Estimated treatment difference approximately −0.5 percentage points vs placebo
Body weight change from baseline at month 16 Small weight reduction, much less than the 4-15 kg seen with semaglutide and tirzepatide. Albiglutide is a long-acting GLP-1-albumin fusion that crosses the blood-brain barrier poorly, which most likely explains both the modest weight effect and the weaker satiety profile.	−1.36 kg (least-squares mean) on albiglutide	−0.53 kg (least-squares mean) on placebo	Estimated treatment difference approximately −0.8 kg vs placebo
Time to initiation of insulin of more than three months duration among participants not on insulin at baseline More than half of placebo-arm patients who would have escalated to insulin avoided it on albiglutide. A clinically meaningful glycemic-treatment-burden endpoint that did not get the spotlight at publication because the cardiovascular result dominated the headlines.	Incidence rate 3.56 events per 100 person-years on albiglutide	Incidence rate 8.58 events per 100 person-years on placebo	Hazard ratio approximately 0.42; statistically significant
Composite metabolic endpoint (HbA1c ≤7% with no severe hypoglycemia and no weight gain) at final assessment Roughly 11 percentage points more patients hit a clean composite of glycemic target without hypoglycemia or weight gain on albiglutide — the diabetes-management piece of the case for GLP-1 receptor agonists in this population, separate from the MACE story.	26.0% of participants on albiglutide	15.1% of participants on placebo	Treatment difference approximately +11 percentage points; statistically significant

Adverse events

Event	Treatment rate	Comparator rate
Acute pancreatitis (adjudicated) No statistically significant excess; absolute numbers low. Consistent with the class-level pancreatitis profile seen in LEADER and SUSTAIN-6.	0.2% (10/4,731)	0.1% (7/4,732)
Pancreatic cancer No imbalance between arms over the trial period.	0.1% (6/4,731)	0.1% (5/4,732)
Medullary thyroid carcinoma No cases in either arm. The black-box warning on the GLP-1 class derives from rodent C-cell tumors, not human trial signals.	0 of 4,731	0 of 4,732
Injection-site reactions Albiglutide was the GLP-1 receptor agonist most commonly associated with injection-site reactions in head-to-head comparisons, which prescribing experience cited as a reason for slow uptake.	Higher on albiglutide than on placebo (numerically the most common drug-attributable adverse event)	Lower on placebo
Treatment-related deaths (investigator-assessed, blinded) Numerically fewer on albiglutide. Investigators were masked to treatment when assigning relatedness.	2 of 4,731 (<1%)	3 of 4,732 (<1%)
Discontinuation due to adverse events Discontinuation rates in HARMONY OUTCOMES were not meaningfully elevated on albiglutide — a softer GI profile than semaglutide or liraglutide, consistent with the drug's weaker pharmacodynamic potency.	Comparable to placebo overall	Comparable to albiglutide overall

Subgroup analyses

Prior myocardial infarction at baseline (about 70% of cohort): MACE hazard ratio consistent with the overall result of 0.78
The dominant subgroup. Benefit was observed in the secondary-prevention majority that defines the trial population.
Prior stroke at baseline (about 18% of cohort): MACE hazard ratio consistent with the overall result, with wider confidence intervals because of smaller numbers
Direction-of-effect matched the overall result; the trial was not powered for a definitive stroke-subgroup conclusion.
Age 65 years and older: MACE hazard ratio similar to the overall result
No interaction by age across the pre-specified cut points; benefit appeared consistent in older patients, who made up roughly half of the cohort.
Baseline HbA1c above and below 8.7% (median): MACE hazard ratio similar in both glycemic subgroups
Cardiovascular benefit did not appear to depend on baseline glycemic burden, reinforcing that the effect is not explained by glucose lowering alone.

Clinical significance

HARMONY OUTCOMES is the trial that should have launched a commercial franchise and instead serves as the cardiovascular pillar of a shelved drug. The 22% MACE reduction over a median 1.6 years sits inside the same effect-size envelope as LEADER (liraglutide, HR 0.87 over 3.8 years), SUSTAIN-6 (semaglutide, HR 0.74 over 2.1 years), REWIND (dulaglutide, HR 0.88 over 5.4 years), and AMPLITUDE-O (efpeglenatide, HR 0.73 over 1.8 years). The class-level conclusion that GLP-1 receptor agonism reduces major adverse cardiovascular events in adults with type 2 diabetes and high cardiovascular risk now rests on five positive trials, and HARMONY OUTCOMES contributes the largest single MI signal. The clinical lesson for prescribers is two-pronged: the cardiovascular benefit is broad across the class even when the parent drug is no longer available, and a drug can be pulled from the market for commercial reasons without that decision telling clinicians anything about its underlying efficacy or safety. The trial also stands as the cleanest published example of why a GLP-1 receptor agonist's potency on weight and HbA1c is not a tight proxy for its cardiovascular effect size.

Frequently asked questions

Why was albiglutide withdrawn from the market?

GlaxoSmithKline announced on July 25, 2017 that it would discontinue albiglutide for commercial reasons. The drug had launched as Tanzeum in the United States in 2014 and as Eperzan in Europe in 2014 but never captured meaningful market share against liraglutide, exenatide, dulaglutide, and the emerging semaglutide program. Reasons cited in industry coverage and analyst notes included a weaker HbA1c and weight-loss profile than competitors, higher injection-site reaction rates, and the once-weekly market increasingly being defined by Trulicity and the pipeline toward Ozempic. GSK clarified at the time that the decision was not driven by any new safety finding. Global market withdrawal was completed in July 2018, three months before HARMONY OUTCOMES read out at the European Association for the Study of Diabetes meeting.

Does HARMONY OUTCOMES still inform GLP-1 cardiovascular class data?

Yes. Every major meta-analysis and guideline review of GLP-1 receptor agonist cardiovascular benefit published since 2018 — including the American Diabetes Association Standards of Care, the American College of Cardiology and American Heart Association cardiometabolic syndrome guidance, and pooled analyses such as the Sattar 2021 Lancet Diabetes & Endocrinology meta-analysis — includes HARMONY OUTCOMES alongside LEADER, SUSTAIN-6, REWIND, and AMPLITUDE-O as one of the trials that establishes the class effect. The reasoning is that the result was generated under a rigorous, double-blind, event-adjudicated design and that the molecular target (the GLP-1 receptor) is the same regardless of which agonist activates it. A drug being unavailable does not retroactively remove its trial data from the class-level evidence base.

Could albiglutide ever return to the market?

It is not impossible, but as of 2026 there is no public indication that GSK or a successor company plans to relaunch albiglutide. The Biologics License Application (BLA 125431) remains on the FDA's Drugs@FDA database in a discontinued status rather than a withdrawn-for-safety status, which means the regulatory record itself does not stand in the way of a future relaunch. A relaunch would still require GSK or a licensee to restart manufacturing, address device and packaging supply, and decide that the commercial case had improved — historically a high bar for a drug that lost its niche to more potent competitors. For practical purposes prescribers should treat albiglutide as unavailable and treat HARMONY OUTCOMES as evidence about the class rather than guidance about a prescribable agent.

How does the HARMONY OUTCOMES MACE effect size compare to LEADER and SUSTAIN-6?

HARMONY OUTCOMES reported a primary MACE hazard ratio of 0.78 (95% CI 0.68-0.90) over a median 1.6 years. LEADER (liraglutide, Marso 2016, PMID 27295427) reported 0.87 (95% CI 0.78-0.97) over a median 3.8 years. SUSTAIN-6 (semaglutide 0.5 mg and 1.0 mg, Marso 2016, PMID 27633186) reported 0.74 (95% CI 0.58-0.95) over a median 2.1 years. The point estimates land in the same range and the confidence intervals overlap; differences in follow-up duration and event rates explain most of the apparent spread. The component-level signatures differ — HARMONY OUTCOMES was MI-driven, SUSTAIN-6 was stroke-driven, LEADER was CV-death-driven — but the headline class effect is the same: roughly a 12-26% relative reduction in three-point MACE in adults with type 2 diabetes and elevated cardiovascular risk.

Why did HARMONY OUTCOMES stop after only 1.6 years of follow-up?

The trial was event-driven, meaning it was designed to keep enrolling and following participants until a pre-specified number of primary cardiovascular endpoints had accrued. On November 8, 2017 the executive committee determined that 611 primary endpoints had occurred and that the median follow-up had reached at least 1.5 years, triggering trial close-out. Investigators called participants back for a final visit and the last patient visit was March 12, 2018. The decision to declare the threshold met arrived four months after GSK's July 2017 announcement that albiglutide would be withdrawn from the market. GSK has stated that the trial was completed under contractual obligations to enrolled participants and that the early close-out reflected pre-specified statistical criteria rather than the commercial decision. The shorter follow-up (1.6 years versus 2-5 years for LEADER, SUSTAIN-6, REWIND, and AMPLITUDE-O) is the most-cited methodological note in the published trial and one reason the cardiovascular-death component did not reach significance.

References

1.Hernandez AF, Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MC, Thorpe KM, McMurray JJV, Del Prato S; 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. PMID: 30291013.
2.GlaxoSmithKline. Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus (HARMONY OUTCOMES) — Study Results. ClinicalTrials.gov, NCT02465515. 2019. https://clinicaltrials.gov/study/NCT02465515
3.U.S. Food and Drug Administration. Drugs@FDA: Tanzeum (albiglutide) for injection — BLA 125431, status discontinued. FDA Drugs@FDA database. 2018. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125431
4.Marso SP, Daniels GH, Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016. PMID: 27295427.
5.Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016. PMID: 27633186.
6.Gerstein HC, Colhoun HM, Dagenais GR, et al.; REWIND Investigators. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019. PMID: 31189511.
7.Gerstein HC, Sattar N, Rosenstock J, et al.; AMPLITUDE-O Trial Investigators. Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes. N Engl J Med. 2021. PMID: 34215025.