TL;DR
Get workout gear delivered free — and shop member deals
- Fast, free delivery on millions of items
- Access to Prime Big Deal Days deals on October 6–7
- Prime Video, Amazon Music and more included
The once-daily oral GLP-1 drug orforglipron met the ACHIEVE-4 trial’s 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 problems; a separate outcomes trial is expected to test that question. Gastrointestinal side effects were more frequent with orforglipron.
Orforglipron, a once-daily oral GLP-1 drug, met a trial standard for cardiovascular safety compared with insulin glargine in adults with type 2 diabetes and elevated heart risk, researchers reported. The ACHIEVE-4 results do not show that the drug protects against heart events; that benefit remains to be tested in a separate trial.
In ACHIEVE-4, a phase III study, 2,749 adults were assigned to take oral orforglipron or injectable insulin glargine once daily. Over a median two years, major adverse cardiovascular events occurred in 4.2% of participants in the orforglipron group and 5.0% in the insulin group. 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.
The trial included adults with type 2 diabetes, a body mass index of at least 25, and increased cardiovascular risk. They were already taking one to three glucose-lowering medicines. About 86% had established cardiovascular disease and 38% had chronic kidney disease at the start of the study. The MACE measure included cardiovascular death, non-fatal heart attack, non-fatal stroke, and hospitalization for unstable angina.
Researchers also reported sustained improvements in blood sugar control and body weight with orforglipron over 104 weeks. Clinically significant or severe low blood sugar was reported in 6.8% of the orforglipron group and 19.2% of the insulin group. Gastrointestinal adverse events were more common with orforglipron, at 62.1% versus 14.2%, and were the most common reason participants stopped taking it.
A Convenient Pill, With Limits
The findings add evidence about the cardiovascular safety of an oral GLP-1 treatment for people with type 2 diabetes who face elevated heart risk. Orforglipron is a non-peptide GLP-1 receptor agonist, and the source report says it can be taken without fasting or water restrictions. That may offer a different routine from some existing oral GLP-1 medicines.
Safety and prevention are distinct questions. ACHIEVE-4 tested whether cardiovascular events with orforglipron were not unacceptably worse than with insulin glargine; it was not designed to prove the drug reduces those events. Some established GLP-1 medicines have evidence of cardiovascular benefit and regulatory approval for cardiovascular risk reduction, according to the report. The new results do not establish the same benefit for orforglipron.
How ACHIEVE-4 Was Designed
The trial was conducted in 16 countries from 2023 to 2024. Participants had type 2 diabetes with HbA1c levels from 7.0% to 10.5%, and had been taking glucose-lowering medication for at least three months before enrollment. The average age was 63, and the average body mass index was 33.
Study investigator Klara Klein of the University of North Carolina School of Medicine presented the results at the European Association for the Study of Diabetes meeting in Milan. The trial manuscript appeared in The Lancet at the same time. The study was open-label, meaning participants and investigators knew which treatment was assigned; the investigators also noted that several small subgroup analyses were not adjusted for multiple comparisons.
“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.”
— The ACHIEVE-4 study authors
Heart Protection Still Untested
ACHIEVE-4 was not statistically powered to show cardiovascular superiority, so its results cannot establish that orforglipron prevents heart attacks, strokes, or cardiovascular deaths. The event rates were numerically lower with orforglipron, but the study’s main conclusion was that it met a noninferiority threshold against insulin glargine.
The open-label design and unadjusted subgroup analyses also limit how confidently some secondary comparisons can be interpreted. The report noted a mean pulse increase of 4.0 beats per minute with orforglipron at week 104, compared with a slight decrease with insulin glargine. The clinical implications of that difference were not settled by the reported trial results.
A Larger Outcomes Test Ahead
The ongoing ATTAIN-Outcomes trial is intended to test whether orforglipron can reduce cardiovascular events compared with placebo. It is enrolling people with established atherosclerotic cardiovascular disease or chronic kidney disease, with or without type 2 diabetes, and is scheduled for completion in 2031.
Until those results are available, ACHIEVE-4 supports a cardiovascular safety conclusion against insulin glargine in the studied population. Whether orforglipron provides heart protection, and how its benefits and side effects compare with other treatment options over longer periods, remain open questions.
Key Questions
What did ACHIEVE-4 find about orforglipron and heart safety?
Major cardiovascular events occurred in 4.2% of participants taking orforglipron and 5.0% taking insulin glargine over a median of two years. The trial met its criterion for noninferiority, meaning it supported cardiovascular safety relative to the comparator within the trial’s design.
Did the study prove that orforglipron prevents heart attacks or strokes?
No. ACHIEVE-4 was not powered to prove cardiovascular benefit. The ongoing ATTAIN-Outcomes trial is intended to test whether the drug reduces cardiovascular events compared with placebo.
What side effects were reported?
Gastrointestinal adverse events were reported in 62.1% of people taking orforglipron, compared with 14.2% taking insulin glargine. These events were the most common reason for stopping orforglipron in the trial.
How is orforglipron taken?
The source report describes it as a once-daily oral, non-peptide GLP-1 receptor agonist that can be taken without fasting or water restrictions. The trial studied adults with type 2 diabetes and elevated cardiovascular risk who were already using glucose-lowering medicines.
Source: rss
Fall Picks
fall essentials
As an affiliate, we earn on qualifying purchases.
