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Randomized controlled trial

ACHIEVE-4: heart safety of orforglipron vs insulin glargine

Over a median follow-up of 2 years, a major adverse cardiovascular event (MACE-4) occurred in 4.2% on orforglipron and 5.0% on insulin glargine (hazard ratio, 0.84; 95% CI, 0.59 to 1.20), which showed noninferiority, not a reduction in risk.

Klein KR et al. Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial. The Lancet, 2026. DOI: 10.1016/S0140-6736(26)01865-9

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Key facts

Drug
orforglipron
Design
Randomized controlled trial
Participants
2,749
Duration
Event-driven (follow-up is given in the results)
Funding
Eli Lilly
Registry
NCT05803421
Population
2,749 adults with type 2 diabetes (HbA1c of 7.0 to 10.5%), a BMI of 25 or more and established cardiovascular disease or chronic kidney disease, treated with up to three glucose-lowering drugs (metformin, a sulfonylurea or an SGLT2 inhibitor), at 317 sites in 16 countries and territories, including Spain, Mexico and Argentina per the registry; 38% women, mean age 63.1 years, mean HbA1c 8.2% and mean BMI 33. Of them, 85.9% had established cardiovascular disease and 37.6% had chronic kidney disease.
Primary outcome
Time to the first four-component major adverse cardiovascular event (MACE-4: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina) with once-daily orforglipron at the maximum tolerated dose (up to 36 mg as a capsule, equivalent to the 17.2 mg tablet) versus titrated insulin glargine, in an open-label, event-driven design; noninferiority was declared if the upper limit of the 95% CI of the hazard ratio was below 1.8.

What it found

Over a median follow-up of 2 years, a major adverse cardiovascular event (MACE-4) occurred in 4.2% on orforglipron and 5.0% on insulin glargine (hazard ratio, 0.84; 95% CI, 0.59 to 1.20), which showed noninferiority, not a reduction in risk. Digestive adverse effects affected 62.1% on orforglipron, compared with 14.2% on insulin glargine, and were the most common reason for stopping orforglipron. Clinically significant or severe hypoglycemia (glucose below 54 mg/dL) was less frequent on orforglipron: 6.8% versus 19.2%. There were 19 deaths (1.4%) on orforglipron and 43 (3.2%) on insulin glargine, and all deaths but one, in the insulin glargine group, were judged unrelated to treatment.

Limitations

Funded by Eli Lilly, the maker of orforglipron. Open-label design, with insulin glargine rather than placebo as the comparator, built to rule out an increase in cardiovascular risk, not to show a reduction; death was not the primary outcome. The published abstract does not give the changes in HbA1c or weight. As of the review date, orforglipron was not approved for type 2 diabetes in the United States.

What it means for you

ACHIEVE-4 set out to rule out that orforglipron raises cardiovascular risk in people with type 2 diabetes and heart or kidney disease, and it did so against insulin glargine: a major cardiovascular event occurred in 4.2% versus 5.0% over a median of 2 years. It does not show that the drug protects the heart, and it caused more digestive side effects but less hypoglycemia. In the US, orforglipron (Foundayo) is approved for weight management only; if you have diabetes and a history of heart disease, it is a finding to discuss with your doctor.

Further reading

Related trials

  • orforglipron40 weeks

    ACHIEVE-2

    At 40 weeks, HbA1c fell by 1.23, 1.50 and 1.56 points with orforglipron 3, 12 and 36 mg, compared with 0.81 on dapagliflozin.

  • orforglipron and semaglutide52 weeks

    ACHIEVE-3

    HbA1c fell by 1.71 and 1.91 points with orforglipron 12 and 36 mg, and by 1.23 and 1.47 points with oral semaglutide 7 and 14 mg.

  • orforglipron40 weeks

    ACHIEVE-5

    At 40 weeks, HbA1c fell by 1.58, 1.88 and 1.82 points with orforglipron 3, 12 and 36 mg, compared with 0.79 on placebo.

  • orforglipron52 weeks

    ACHIEVE-J

    Over 52 weeks, 85% of participants had at least one adverse event (81%, 84% and 88% on 3, 12 and 36 mg), mostly mild (67%) or moderate (16%).

Sources

The original paper and the records consulted for this summary, with the date they were accessed.

  1. The Lancet.Klein KR, et al. Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4). Lancet. Published online September 30, 2026.accessed .
  2. National Library of Medicine (PubMed).PubMed record PMID 42815506 (abstract).accessed .
  3. ClinicalTrials.gov (National Library of Medicine).ClinicalTrials.gov record NCT05803421 (ACHIEVE-4: registration and participating countries).accessed .