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The phase III ACHIEVE-4 trial found the once-daily oral GLP-1 pill orforglipron (Foundayo) was noninferior to insulin glargine for major adverse cardiovascular events in adults with type 2 diabetes at high cardiovascular risk. Heart benefit itself remains unproven; the superiority-powered ATTAIN-Outcomes trial is due in 2031.
The oral GLP-1 pill orforglipron (Foundayo) met noninferiority criteria against insulin glargine for major adverse cardiovascular events in adults with type 2 diabetes at increased cardiovascular risk, according to the phase III ACHIEVE-4 trial reported by Klara Klein, MD, PhD, of the University of North Carolina School of Medicine, at the European Association for the Study of Diabetes meeting in Milan and published simultaneously in The Lancet. The findings establish cardiovascular safety for the easier-to-manufacture pill, though actual heart benefit remains unproven.
Among 2,749 adults with type 2 diabetes and overweight or obesity already taking glucose-lowering medications, orforglipron was noninferior to once-daily injectable insulin glargine on major adverse cardiovascular events (MACE) over a median of 2 years (4.2% vs 5.0%; HR 0.84, 95% CI 0.59-1.20, P<0.0001 for noninferiority). MACE included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina.
Secondary outcomes favored orforglipron on several measures. Participants had sustained improvements in glycemic control and body weight over 104 weeks, a drop in albuminuria at week 52 (median change in urinary albumin-to-creatinine ratio -24.2% vs 0%), slower decline in kidney function measured by cystatin C (estimated treatment difference 2.8 mL/min/1.73 m²), and lower rates of clinically significant or severe hypoglycemia (6.8% vs 19.2%). Deaths were 1.4% versus 3.2%, and investigators deemed all deaths except one in the insulin glargine group unrelated to treatment.
Gastrointestinal adverse events were markedly more common with orforglipron (62.1% vs 14.2%) and were the most common reason for discontinuing the drug. Pulse rate rose with orforglipron and stayed elevated at week 104 (+4.0 beats per minute on average) versus essentially no change with insulin glargine. Supraventricular tachyarrhythmia-related events occurred in 3.2% versus 2.7%.
What the Safety Result Means for Patients
The study allows orforglipron’s label to carry established cardiovascular safety — a meaningful benchmark, because injectable GLP-1 drugs have been linked to heart protection and this oral option now clears the initial bar. Unlike semaglutide (Ozempic, Wegovy), orforglipron is a non-peptide small molecule, making it easier to manufacture at scale, shelf-stable, and free of restrictions on time of day, fasting, or water intake. Those properties, Klein argued, could expand global access to GLP-1 therapy.
The caveat is equally important: the trial was not powered to prove cardiovascular benefit, only to rule out excess risk. Established peptide GLP-1 receptor agonists remain ahead, with proven heart benefit and FDA approval for cardiovascular protection. Whether orforglipron matches them will depend on future trials.
Orforglipron’s Path Through the ACHIEVE Program
: “Orforglipron is FDA approved for the treatment of obesity and is being developed for diabetes. This summer, the ACHIEVE-5 trial showed once-daily orforglipron improved outcomes in adults with type 2 diabetes and inadequate glycemic control, and prior ACHIEVE and ATTAIN studies established its glycemic and weight-management safety profiles.
ACHIEVE-4 ran from 2023 to 2024 in 16 countries. Participants averaged 63.1 years of age, 62.5% were men, 85.9% had established cardiovascular disease, 37.6% had chronic kidney disease, and mean HbA1c was 8.2% with a mean BMI of 33 kg/m². Most were on metformin (88.0%), an SGLT-2 inhibitor (53.3%), or a sulfonylurea (36.2%). The drug is also being studied for obstructive sleep apnea, osteoarthritis knee pain, hypertension, peripheral artery disease, and stress urinary incontinence.
“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, in The Lancet
Heart Benefit Still Unproven for the Pill
ACHIEVE-4 was not statistically powered for superiority on cardiovascular outcomes, so the numerical edge in MACE cannot be read as proven heart protection. Investigators also acknowledged the trial’s open-label design and its multiple small subgroup analyses without adjustment for multiplicity. The long-term significance of the sustained rise in pulse rate with orforglipron was not established by this study.
ATTAIN-Outcomes Trial Due in 2031
The ATTAIN-Outcomes trial is underway and is powered for superiority, comparing orforglipron against 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. Meanwhile, development continues for diabetes — building on ACHIEVE-5 — and for additional indications including sleep apnea, hypertension, and osteoarthritis knee pain.
Key Questions
Is orforglipron proven to protect the heart?
No. ACHIEVE-4 showed the drug was noninferior to insulin glargine on cardiovascular events, meaning it did not carry excess heart risk. Whether it provides heart benefit like injectable GLP-1 drugs will be tested in the ATTAIN-Outcomes trial, due in 2031.
How is orforglipron different from Ozempic or Wegovy?
Orforglipron is a non-peptide small molecule taken as a once-daily pill. That makes it easier and cheaper to manufacture, shelf-stable, and free of fasting, water, or timing restrictions, unlike oral semaglutide.
What were the main side effects?
Gastrointestinal adverse events occurred in 62.1% of orforglipron patients versus 14.2% on insulin glargine and were the leading cause of discontinuation. Pulse rate also rose by an average of 4 beats per minute and stayed elevated through week 104.
Is orforglipron FDA approved?
It is FDA approved for obesity. It is still in development for type 2 diabetes, with the ACHIEVE-5 trial supporting that use.
Who was studied in the trial?
Adults with type 2 diabetes, a BMI of 25 or more, and increased cardiovascular risk — most already had cardiovascular disease — already taking one to three glucose-lowering medications. The 2,749 participants were randomized in 16 countries between 2023 and 2024.
Source: rss
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