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The phase III ACHIEVE-4 trial found that orforglipron, a once-daily oral GLP-1 medicine, met criteria for cardiovascular safety compared with insulin glargine over a median two years. The trial did not establish that the drug reduces heart events; a separate outcomes trial is intended to test that question.
Orforglipron, a once-daily oral GLP-1 medicine, met a trial benchmark for cardiovascular safety compared with insulin glargine in adults with type 2 diabetes and increased cardiovascular risk, according to results from the phase III ACHIEVE-4 trial. The findings do not show that orforglipron prevents heart attacks or other cardiovascular events: the study was designed to assess whether its risk was not unacceptably higher than insulin’s, not to prove a heart benefit.
Over a median of about two years, major adverse cardiovascular events occurred in 4.2% of participants assigned to orforglipron and 5.0% assigned to insulin glargine. The hazard ratio was 0.84, with a 95% confidence interval of 0.59 to 1.20; the study met its prespecified noninferiority criterion. That statistical result supports a safety comparison, but does not establish superiority or demonstrate that the drug lowers cardiovascular risk.
The trial randomized 2,749 adults in 16 countries to once-daily orforglipron or injectable insulin glargine. Participants had type 2 diabetes, an HbA1c of 7.0% to 10.5%, and a BMI of at least 25. Most already had cardiovascular disease: 85.9% of the study group had established disease, while 37.6% had chronic kidney disease. The results were presented by Klara Klein of the University of North Carolina School of Medicine at the European Association for the Study of Diabetes meeting in Milan and published in The Lancet.
Orforglipron was also associated with sustained improvements in blood sugar and weight through 104 weeks. Gastrointestinal adverse events were more common with the pill than with insulin glargine, at 62.1% versus 14.2%, and were the most common reason participants stopped orforglipron. Clinically significant or severe low blood sugar was reported in 6.8% of the orforglipron group and 19.2% of the insulin group. These are trial findings, not a guarantee of how an individual patient will respond.
Safety Does Not Prove Heart Protection
The distinction matters because some established GLP-1 medicines have shown cardiovascular benefits in dedicated outcomes trials and have received regulatory approval for cardiovascular risk reduction in specified patients. ACHIEVE-4 adds evidence about orforglipron’s safety in a group at elevated risk, but its results do not place the drug on the same evidentiary footing for heart protection.
The oral format could matter for patients who prefer a pill to an injection. Orforglipron is a non-peptide GLP-1 receptor agonist; the report says it is shelf-stable and can be taken without fasting or water restrictions. Those features may make use more convenient than some other oral GLP-1 medicines. They do not, by themselves, establish better health outcomes, wider access, or suitability for any particular person.
The safety comparison also needs to be weighed alongside tolerability. The high rate of gastrointestinal events in the orforglipron arm—and their role in treatment discontinuation—shows that a convenient route of administration does not eliminate treatment burdens. Patients should discuss medication choices and risks with a qualified health professional.
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How ACHIEVE-4 Tested Orforglipron
ACHIEVE-4 compared orforglipron at the maximum tolerated dose with once-daily insulin glargine in adults whose diabetes remained above target despite existing glucose-lowering treatment. Participants were already taking one to three such medicines; metformin was used by 88.0%, an SGLT-2 inhibitor by 53.3%, and a sulfonylurea by 36.2%. The trial’s major cardiovascular event measure included cardiovascular death, nonfatal heart attack, nonfatal stroke, and hospitalization for unstable angina.
Investigators also reported a 24.2% median reduction in urinary albumin-to-creatinine ratio at week 52 with orforglipron, compared with no median change with insulin, and a more favorable estimated change in kidney filtration. These were additional trial measures; they do not establish that orforglipron prevents kidney disease progression. The study was open-label, meaning participants and investigators knew which treatment was assigned, and the authors noted limitations in the analysis of small subgroups.
Orforglipron is FDA-approved for obesity treatment, according to the source report, and is also being developed for type 2 diabetes. The ACHIEVE-4 findings concern adults with diabetes and elevated cardiovascular risk; they should not be read as results for every population or every proposed use.
“These findings support orforglipron as a potential once-daily, oral treatment option with established cardiovascular safety in people with type 2 diabetes and increased cardiovascular risk.”
— ACHIEVE-4 study authors
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Heart Benefit Still Needs Testing
ACHIEVE-4 was not statistically powered to test superiority on cardiovascular outcomes. It therefore cannot determine whether orforglipron reduces heart attacks, strokes, or cardiovascular deaths compared with another treatment or placebo. The event figures are consistent with the trial’s safety conclusion, but do not prove a protective effect.
Other findings also need careful interpretation. The trial was open-label, and investigators tested several small subgroups without adjusting for multiple comparisons. The report gives an increase in pulse rate with orforglipron—an average change of 4.0 beats per minute at week 104, compared with a 0.2-beat decrease with insulin—while treatment-emergent supraventricular rhythm events were reported in 3.2% and 2.7%, respectively. The supplied results do not resolve the clinical significance of these observations over longer periods.
It also remains unclear how orforglipron’s cardiovascular profile will compare with GLP-1 medicines that already have dedicated evidence of cardiovascular benefit, or which patients may be best suited to the pill. The ongoing outcomes study is intended to address a key part of that evidence gap.
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Outcomes Trial Will Test Protection
The ongoing ATTAIN-Outcomes trial is designed to evaluate whether orforglipron can demonstrate cardiovascular benefit against placebo in people with established atherosclerotic cardiovascular disease or chronic kidney disease, with or without type 2 diabetes. According to the report, it is powered to test superiority and is scheduled for completion in 2031.
Until those results are available, ACHIEVE-4 supports a claim of cardiovascular safety in the studied population, not a claim of proven heart protection. Further reporting can clarify the outcomes trial’s progress, longer-term safety findings, and how regulators and clinicians assess the evidence for the medicine’s different uses.
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Key Questions
Did ACHIEVE-4 prove that orforglipron prevents heart attacks?
No. The trial met a noninferiority benchmark for cardiovascular safety against insulin glargine. It was not designed or powered to prove that orforglipron reduces heart events.
What were the cardiovascular event rates in the trial?
Over a median of about two years, major adverse cardiovascular events occurred in 4.2% of participants taking orforglipron and 5.0% taking insulin glargine. Those figures supported the safety comparison; they do not establish a protective benefit.
How is orforglipron taken?
The report describes it as a once-daily oral medicine that does not require fasting or water restrictions. The study compared it with once-daily injectable insulin glargine.
What side effects were reported?
Gastrointestinal adverse events were reported in 62.1% of the orforglipron group and 14.2% of the insulin glargine group. They were the most common reason participants stopped orforglipron. Individual treatment decisions should be discussed with a qualified health professional.
When could evidence of heart protection be available?
The ongoing ATTAIN-Outcomes trial is intended to test cardiovascular superiority and is scheduled for completion in 2031, according to the report. Its results are needed before a cardiovascular benefit can be established for orforglipron.
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