TL;DR
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The phase III ACHIEVE-4 trial found that once-daily oral orforglipron met the criteria for cardiovascular safety compared with insulin glargine in adults with type 2 diabetes and elevated cardiovascular risk. The trial did not show that orforglipron prevents heart problems; a separate outcomes trial is expected to test for benefit.
In ACHIEVE-4, 2,749 adults were randomly assigned to once-daily orforglipron or injectable insulin glargine. Over a median of two years, major adverse cardiovascular events occurred in 4.2% of participants receiving orforglipron and 5.0% receiving glargine. The hazard ratio was 0.84, with a 95% confidence interval of 0.59 to 1.20; the result met the trial’s prespecified criterion for noninferiority.
The MACE measure included cardiovascular death, nonfatal heart attack, nonfatal stroke and hospitalization for unstable angina. The trial was not designed or powered to show cardiovascular superiority, the investigators said. The event rates therefore do not prove that orforglipron reduces cardiovascular risk compared with insulin glargine.
Orforglipron was also associated with sustained improvements in blood sugar control and body weight through 104 weeks. Gastrointestinal adverse events were more common with the pill than with 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% versus 19.2%, respectively.
A Safety Result, Not Heart Protection
For people with type 2 diabetes and cardiovascular risk, the findings address whether orforglipron performed within the trial’s accepted safety margin compared with insulin glargine. That evidence may inform its use as a once-daily oral treatment option, alongside its effects on blood sugar and weight.
The distinction matters because some established GLP-1 medicines have demonstrated cardiovascular benefit and received U.S. approval for cardiovascular risk reduction. ACHIEVE-4 did not test whether orforglipron provides that protection. Patients and clinicians should not read the similar event rates as proof that the drug prevents cardiovascular events or as a basis to replace treatments with established benefits.
The trade-offs in the trial also matter: gastrointestinal side effects were frequent, while low blood sugar was less common than with glargine. How those findings apply to individual treatment decisions depends on a patient’s health and other medications.
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How ACHIEVE-4 Was Designed
ACHIEVE-4 was a phase III trial conducted across 16 countries from 2023 to 2024. Participants had type 2 diabetes, an HbA1c between 7.0% and 10.5%, a body mass index of at least 25, and increased cardiovascular risk. They had been taking one to three glucose-lowering medicines before joining.
Participants had an average age of 63.1 years; 85.9% had established cardiovascular disease and 37.6% had chronic kidney disease. The study compared maximum-tolerated-dose orforglipron with titrated insulin glargine, both taken once daily. The trial was open label, meaning participants and investigators knew which treatment was assigned. The researchers also noted that several small subgroup analyses were not adjusted for multiple comparisons.
Orforglipron is a non-peptide GLP-1 receptor agonist. Its oral formulation can be taken without fasting or water restrictions, according to the report. The source describes it as FDA approved for obesity; ACHIEVE-4 itself studied cardiovascular safety in adults with type 2 diabetes and elevated risk.
““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
Heart Benefit Still Unproven
ACHIEVE-4 cannot establish whether orforglipron lowers the risk of heart attack, stroke or cardiovascular death. Its noninferiority result shows that the trial met its safety comparison threshold against glargine; it does not confirm a protective effect.
A separate trial, ATTAIN-Outcomes, is intended to test cardiovascular superiority against placebo in people with established atherosclerotic cardiovascular disease or chronic kidney disease, with or without type 2 diabetes. The report said it is scheduled for completion in 2031. Until results are available, the size and presence of any cardiovascular benefit remain unknown.
The ACHIEVE-4 report also noted a mean pulse-rate increase of 4.0 beats per minute with orforglipron at week 104, compared with a 0.2-beat decrease with glargine. Supraventricular tachyarrhythmias, including atrial fibrillation or flutter, were reported in 3.2% and 2.7%, respectively. The study does not settle the meaning of these differences for longer-term treatment.
The Outcomes Trial Ahead
Researchers are awaiting ATTAIN-Outcomes, the trial designed to assess whether orforglipron can demonstrate cardiovascular benefit. The reported target completion is 2031. Its results will address a question ACHIEVE-4 was not designed to answer.
Meanwhile, orforglipron continues to be studied for diabetes and other conditions. The current findings add cardiovascular safety data to evidence on blood sugar and weight, but treatment decisions should account for the trial population, gastrointestinal side effects and the absence of proven heart protection.
Key Questions
Did ACHIEVE-4 show that orforglipron prevents heart attacks or strokes?
No. It found that orforglipron met a noninferiority safety criterion compared with insulin glargine. The trial was not designed to prove that it prevents cardiovascular events.
What were the cardiovascular event rates?
Over a median of two years, major adverse cardiovascular events occurred in 4.2% of the orforglipron group and 5.0% of the insulin glargine group. The comparison met the trial’s noninferiority criterion, but did not establish superiority.
What side effects were reported most often?
Gastrointestinal adverse events were more frequent with orforglipron than with insulin glargine: 62.1% versus 14.2%. They were the most common reason for stopping orforglipron.
When will researchers know whether the drug protects the heart?
The separate ATTAIN-Outcomes trial is designed to test cardiovascular benefit. The report said it is scheduled to finish in 2031; its results are not yet available.
Source: rss
