A new oral GLP-1 receptor agonist, orforglipron (brand name Foundayo), has shown cardiovascular safety in a key study, according to results shared at the European Association for the Study of Diabetes conference. The medication, already approved for obesity management, satisfied noninferiority standards when compared to insulin glargine in reducing major adverse cardiovascular events (MACE) over a median follow-up of 2 years.
The event rate stood at 4.2% for orforglipron versus 5.0% with insulin glargine, yielding a hazard ratio of 0.84 (95% confidence interval: 0.59–1.20). This outcome met the predefined noninferiority threshold with statistical significance (P < 0.0001). The ACHIEVE-4 trial, a phase III study conducted across 16 countries from 2023 to 2024, enrolled participants who were already taking one to three glucose-lowering medications for at least three months prior.
The ACHIEVE-4 trial enrolled 2,749 adults with type 2 diabetes and obesity or excess weight alongside heightened cardiovascular risk. The average participant age was 63.1 years. Participants had an average baseline HbA1c of 8.2% and a BMI of 33 kg/m². Nearly two in three people were on two or more blood sugar-lowering drugs, namely metformin (88.0%), a SGLT-2 inhibitor (53.3%), and/or a sulfonylurea (36.2%).
Though orforglipron did not demonstrate cardiovascular benefit—only safety—it produced notable improvements in secondary outcomes. Over 104 weeks, it lowered urinary albumin-to-creatinine ratio by 24.2% (compared to no change with insulin glargine) and slowed kidney function decline by 2.8 mL/min/1.73 m² as measured by cystatin C. Blood sugar levels improved, with HbA1c decreasing from 8.2% at baseline, alongside weight loss. However, 62.1% of participants on orforglipron experienced gastrointestinal side effects, more than four times the 14.2% reported with insulin glargine, and it became the primary reason for treatment discontinuation.
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New study aims to prove heart benefits
Klara Klein, MD, PhD, from the University of North Carolina, noted that while ACHIEVE-4 confirmed safety, the trial was not designed to prove superiority in heart-related outcomes. That objective will be addressed by the ATTAIN-Outcomes study, scheduled for completion in 2031, which will compare orforglipron to a placebo in patients with atherosclerotic cardiovascular disease or chronic kidney disease. Klein expressed confidence the drug will align with the broader GLP-1 class, pointing to “very encouraging data” from ACHIEVE-4. The findings were simultaneously published in The Lancet alongside the conference presentation.
Investigations into orforglipron’s potential extend beyond diabetes management, with ongoing studies exploring its effects on obstructive sleep apnea, osteoarthritis knee pain, hypertension, peripheral artery disease, and stress urinary incontinence. This year’s ACHIEVE-5 trial further advanced its development by showing improved outcomes in adults with type 2 diabetes and poorly controlled blood sugar, reinforcing its efficacy in glycemic management. The study cohort in ACHIEVE-4 had already been on contemporary glucose-lowering therapies, demonstrating orforglipron’s potential as an add-on treatment option.
Beyond diabetes: exploring broader health impacts
The study’s open-label design and subgroup analyses lacking multiplicity adjustments were acknowledged as limitations. Nonetheless, the findings align with earlier trials (ACHIEVE and ATTAIN) that confirmed benefits in blood sugar regulation and weight management. Death rates were low in both groups, with 1.4% in the orforglipron cohort versus 3.2% for insulin glargine, though most were unrelated to treatment. The MACE endpoint included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina.
A key distinction emerged in heart rate changes: orforglipron increased pulse by an average of 4.0 beats per minute at week 104, while insulin glargine produced no change. Rates of clinically significant hypoglycemia were lower with orforglipron (6.8% versus 19.2%), though supraventricular tachyarrhythmias occurred in 3.2% of users compared to 2.7% for insulin. The pulse rate increase with orforglipron remained consistent throughout the study period, contrasting with the slight decrease observed in the insulin glargine group.
