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The phase III ACHIEVE-4 trial found that orforglipron, a once-daily oral GLP-1 medicine, met the standard for cardiovascular safety compared with insulin glargine in adults with type 2 diabetes and elevated cardiovascular risk. The trial did not establish that the drug prevents heart events; a separate study designed to test cardiovascular benefit is ongoing.
Orforglipron met the cardiovascular safety standard compared with insulin glargine in adults with type 2 diabetes and elevated cardiovascular risk, according to results from the phase III ACHIEVE-4 trial presented in Milan and published in The Lancet. The finding supports the drug as an oral treatment option, but does not show that it prevents heart attacks, strokes or other cardiovascular events.
Among 2,749 trial participants followed for a median of two years, the trial’s major adverse cardiovascular event endpoint occurred in 4.2% of people taking orforglipron and 5.0% of those taking insulin glargine. The hazard ratio was 0.84, with a 95% confidence interval of 0.59 to 1.20. The result met the prespecified criterion for noninferiority, meaning the data supported that orforglipron was not unacceptably worse than insulin glargine on this measure.
ACHIEVE-4 enrolled adults with type 2 diabetes, a body mass index of at least 25, and elevated cardiovascular risk. Participants were already taking one to three glucose-lowering medicines. About 86% had established cardiovascular disease and 38% had chronic kidney disease. The trial compared once-daily oral orforglipron with once-daily injectable insulin glargine, and researchers tracked cardiovascular death, nonfatal heart attack, nonfatal stroke and hospitalization for unstable angina.
Orforglipron was also associated with sustained improvements in blood sugar control and body weight over 104 weeks. Significant or severe hypoglycemia was reported in 6.8% of the orforglipron group, compared with 19.2% of the insulin group. Gastrointestinal side effects were more common with orforglipron: 62.1% versus 14.2%. They were the most common reason participants stopped taking it.
What Oral Dosing Could Change
The results add cardiovascular safety data for an oral GLP-1 receptor agonist in a group at elevated risk of heart problems. Orforglipron is a non-peptide GLP-1 drug; the report describes it as shelf-stable and not subject to the fasting, water or time-of-day restrictions associated with oral semaglutide. Those features could make daily use simpler for some patients, although the trial did not measure whether convenience improves access or long-term adherence.
Safety and cardiovascular protection are different findings. Some established GLP-1 medicines have evidence of reduced cardiovascular risk and regulatory approval for that use. ACHIEVE-4 was designed to test whether orforglipron was not worse than insulin glargine on cardiovascular events; it was not statistically powered to prove cardiovascular benefit. The event rates alone cannot establish that orforglipron lowers risk compared with insulin or placebo.
For clinicians and patients weighing treatment options, the trial also reports trade-offs beyond heart safety. Orforglipron participants had fewer episodes of clinically significant or severe low blood sugar, while gastrointestinal adverse events were substantially more frequent. The findings do not determine which treatment is appropriate for an individual.
How ACHIEVE-4 Tested Safety
ACHIEVE-4 was a phase III trial conducted across 16 countries from 2023 to 2024. Participants had type 2 diabetes with HbA1c levels from 7.0% to 10.5% and were taking existing glucose-lowering medicines. The average age was 63.1 years, and the average baseline HbA1c was 8.2%. Researchers randomly assigned participants to the two treatments and followed them for up to 104 weeks.
The study compared orforglipron with insulin glargine, a daily injectable insulin. Its primary cardiovascular question was whether orforglipron met a noninferiority threshold for major adverse cardiovascular events. The investigators also reported kidney measures: at week 52, the median change in urinary albumin-to-creatinine ratio was -24.2% with orforglipron and 0% with insulin glargine; estimated kidney filtration declined more slowly in the orforglipron group. These secondary findings do not establish long-term kidney protection.
The report notes study limitations, including its open-label design and multiple small subgroup analyses that were not adjusted for multiplicity. Participants and investigators knew which treatment was assigned. The trial authors also stressed that ACHIEVE-4 was not designed to show superiority on cardiovascular outcomes.
“We can’t say definitively until we have a trial that demonstrates this, and that’s coming.”
— Klara Klein, speaking at a press conference
Heart Benefit Still Unproven
ACHIEVE-4 does not answer whether orforglipron reduces cardiovascular events. Its noninferiority result compared the drug with insulin glargine and did not test whether it was superior. The confidence interval around the hazard ratio also spans values on either side of 1, and the study was not powered to resolve a cardiovascular benefit claim.
Other findings require caution as well. The trial reported a mean pulse increase of 4.0 beats per minute with orforglipron at week 104, compared with a 0.2-beat decrease with insulin. Supraventricular rhythm-related adverse events, including atrial fibrillation or flutter, were reported in 3.2% and 2.7%, respectively. The report does not establish the clinical significance of these differences. Longer-term outcomes and whether the findings apply to populations outside the trial remain uncertain.
A Larger Outcomes Test Ahead
The ongoing ATTAIN-Outcomes trial is designed to test whether orforglipron can reduce cardiovascular events compared with placebo in people with established atherosclerotic cardiovascular disease or chronic kidney disease, with or without type 2 diabetes. It is scheduled for completion in 2031. Until results from that study are available, ACHIEVE-4 supports a cardiovascular safety conclusion against insulin glargine, while the question of cardiovascular protection remains open.
Key Questions
What did the ACHIEVE-4 trial find?
It found that orforglipron met the prespecified cardiovascular noninferiority standard compared with insulin glargine over a median of two years in adults with type 2 diabetes and elevated cardiovascular risk.
Does the result mean orforglipron prevents heart attacks?
No. ACHIEVE-4 assessed cardiovascular safety against insulin glargine and was not designed or powered to prove that orforglipron prevents heart attacks, strokes or other cardiovascular events.
What side effects were reported?
Gastrointestinal adverse events were reported in 62.1% of participants taking orforglipron and 14.2% taking insulin glargine. They were the most common reason for stopping orforglipron. Significant or severe hypoglycemia was less frequent with orforglipron in this trial.
When will researchers test for cardiovascular benefit?
The ongoing ATTAIN-Outcomes trial is designed to test cardiovascular outcomes against placebo and is scheduled for completion in 2031.
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