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The oral GLP-1 drug orforglipron met the ACHIEVE-4 trial’s criteria for cardiovascular safety compared with insulin glargine in adults with type 2 diabetes and elevated cardiovascular risk. The study did not establish that the drug prevents heart events; a separate trial is intended to test that question.
Oral GLP-1 drug orforglipron met cardiovascular safety criteria compared with insulin glargine in a phase III trial of adults with type 2 diabetes and elevated cardiovascular risk, according to results presented at the European Association for the Study of Diabetes meeting. The findings support safety in the studied population, but do not show that orforglipron prevents heart attacks, strokes or cardiovascular deaths.
In ACHIEVE-4, 2,749 participants were randomly assigned to once-daily orforglipron or once-daily insulin glargine. Over a median of two years, major adverse cardiovascular events occurred in 4.2% of the orforglipron group and 5.0% of 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 test for noninferiority.
The trial counted cardiovascular death, nonfatal heart attack, nonfatal stroke and hospitalization for unstable angina in its major-event measure. Orforglipron was also associated with sustained improvements in blood sugar and body weight through 104 weeks. At week 52, the median change in urinary albumin-to-creatinine ratio was -24.2% with orforglipron and 0% with insulin glargine. Researchers also reported a slower decline in estimated kidney function, measured using cystatin C, in the orforglipron group.
Gastrointestinal adverse events were more common with orforglipron: 62.1% compared with 14.2% for insulin glargine. They were the most common reason participants stopped orforglipron treatment. Clinically significant or severe low blood sugar was reported in 6.8% of participants taking orforglipron and 19.2% taking insulin. Mean pulse increased by 4 beats per minute with orforglipron at week 104, compared with a 0.2-beat decrease with insulin.
Safety Findings Without Proof of Benefit
The results address whether orforglipron’s use was associated with an unacceptable increase in major cardiovascular events compared with insulin glargine in the population studied. That is a safety finding, not evidence that the drug reduces those events. The study team said ACHIEVE-4 was not statistically powered to show cardiovascular superiority.
The distinction matters because some established GLP-1 receptor agonist medicines have demonstrated cardiovascular benefits and have received U.S. regulatory approval for cardiovascular risk reduction. ACHIEVE-4 does not establish the same benefit for orforglipron. Its reported changes in blood sugar, weight and kidney-related measures are relevant trial findings, but they do not substitute for a trial designed to test whether the medicine prevents cardiovascular events.
How ACHIEVE-4 Was Designed
ACHIEVE-4 was 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 the trial. Their average age was 63.1; 85.9% had established cardiovascular disease and 37.6% had chronic kidney disease.
Orforglipron is a once-daily, oral, non-peptide GLP-1 receptor agonist. The source report describes it as FDA-approved for obesity treatment and says its formulation can be taken without fasting or water restrictions. The trial compared it with injectable insulin glargine, with both treatments taken once daily. The study was open-label, meaning participants and researchers knew which treatment was assigned; the investigators also reported testing several small subgroups without adjusting 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
Whether the Drug Prevents Heart Events
Cardiovascular benefit remains unproven for orforglipron. Klein said the drug’s status as a small-molecule GLP-1 treatment means researchers cannot assume that cardiovascular benefits seen with other drugs in the class apply to it. ACHIEVE-4’s noninferiority result does not settle that question.
The trial’s open-label design and unadjusted testing of small subgroups are also limitations identified by investigators. The reported pulse increase and differences in adverse events add to the safety profile described in this trial, but the supplied results do not establish what those findings mean over longer periods or in populations unlike the participants enrolled.
The Outcomes Trial Due in 2031
The ongoing ATTAIN-Outcomes trial is designed to test whether orforglipron can demonstrate cardiovascular benefit. It is comparing the drug with placebo in people with established atherosclerotic cardiovascular disease or chronic kidney disease, with or without type 2 diabetes. The trial is scheduled for completion in 2031.
Until results from that study are available, ACHIEVE-4 supports a conclusion about cardiovascular safety versus insulin glargine under the trial conditions. Whether orforglipron lowers the chance of heart-related events, and how its benefits and risks compare with other treatment options, remain open questions.
Key Questions
Did ACHIEVE-4 show that orforglipron prevents heart attacks or strokes?
No. It met criteria for cardiovascular safety compared with insulin glargine, but was not designed or powered to prove that orforglipron prevents major cardiovascular events.
How many participants had major cardiovascular events?
Over a median of two years, the trial reported major adverse cardiovascular events in 4.2% of participants taking orforglipron and 5.0% taking insulin glargine.
What side effects were more common with orforglipron?
Gastrointestinal adverse events were reported in 62.1% of the orforglipron group, compared with 14.2% of the insulin group. These events were the most common reason for stopping orforglipron.
When could evidence on cardiovascular benefit be available?
The separate ATTAIN-Outcomes trial is scheduled for completion in 2031. It is designed to evaluate cardiovascular outcomes against placebo.
Source: rss
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