New Easier-to-Use GLP-1 Pill Safe for the Heart, Study Says

Orforglipron (Foundayo) was able to claim cardiovascular safety based on the ACHIEVE-4 trial, though heart benefits remain unproven.

Among adults with type 2 diabetes and obesity or overweight at risk for increased cardiovascular risk who were already on contemporary glucose-lowering medications, orforglipron met noninferiority criteria against insulin glargine regarding major adverse cardiovascular events (MACE) over a median 2 years (4.2% vs 5.0%; HR 0.84, 95% CI 0.59-1.20, P<0.0001 for noninferiority).

Also favoring orforglipron were 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%), and slower decline in estimated glomerular filtration rate by cystatin C (estimated treatment difference 2.8 mL/min/1.73 m2) compared with insulin glargine. However, gastrointestinal adverse events were unsurprisingly more frequent (62.1% vs 14.2%) and the most common reason for orforglipron treatment discontinuation.

Klara Klein, MD, PhD, of the University of North Carolina School of Medicine in Chapel Hill, reported the ACHIEVE-4 trial results at the annual meeting of the European Association for the Study of Diabetes in Milan. The manuscript was simultaneously published in The Lancet.

“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,” study authors concluded. “The safety profile was consistent with that established for orforglipron in the previous ACHIEVE and ATTAIN studies for glycemic control and weight management, respectively.”

Orforglipron is an oral, non-peptide GLP-1 receptor agonist that is FDA approved for the treatment of obesity. In contrast with the more well-known oral GLP-1 drug semaglutide (Ozempic, Wegovy), orforglipron’s non-peptide makeup makes it easier to manufacture and is more convenient to use, with no restrictions on time of day for administration.

“The ACHIEVE-4 study reaffirmed the safety of orforglipron while demonstrating clinically meaningful improvements in blood sugar control and weight. Combined with the convenience of a shelf-stable, once-daily oral medication that can be taken without fasting or water restrictions, these results highlight the potential of orforglipron to expand access to effective diabetes treatment globally,” Klein said in a press release.

In any case, the more established peptide GLP-1 receptor agonist drugs are several steps ahead, having achieved proof of cardiovascular benefit and FDA approval for cardiovascular protection.

ACHIEVE-4 was not statistically powered for superiority on cardiovascular outcomes, Klein’s team stressed. ATTAIN-Outcomes is the ongoing trial that will be powered for superiority in evaluating orforglipron against placebo in people with established atherosclerotic cardiovascular disease or chronic kidney disease with or without type 2 diabetes. That trial is scheduled for completion in 2031.

Klein expressed optimism that the trial will ultimately favor orforglipron. “I personally believe that the cardiovascular benefit is largely a class effect. Now, this is a new small molecule … so we can’t say definitively until we have a trial that demonstrates this, and that’s coming. But I think these are very encouraging data [from ACHIEVE-4] that this will be in line with the [GLP-1] class,” she said during a press conference.

Orforglipron continues to be developed for diabetes, with a major boost having arrived this summer when ACHIEVE-5 showed that once-daily orforglipron improved outcomes in adults with type 2 diabetes and inadequate glycemic control. The GLP-1 agent is also being studied as a treatment for obstructive sleep apnea, osteoarthritis knee pain, hypertension, peripheral artery disease, and stress urinary incontinence.

ACHIEVE-4 was a phase III trial conducted in 16 countries from 2023 to 2024. Participants were adults with type 2 diabetes at increased cardiovascular risk with an HbA1c of 7.0%-10.5% and a body mass index (BMI) of 25 kg/m² or more. Enrollees also had to be on one to three glucose-lowering medications for at least 3 months before trial initiation.

Klein and team had 2,749 individuals randomized 1:1 to oral orforglipron at maximum tolerated dose or injectable titrated insulin glargine, both once daily.

The study cohort averaged 63.1 years of age, with 62.5% men. At baseline, 85.9% of participants had established cardiovascular disease and 37.6% had chronic kidney disease. HbA1c was 8.2% and BMI was 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%).

The trialists counted cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina in the MACE endpoint.

Among secondary endpoints, there was a lower rate of clinically significant or severe hypoglycemia (glucose <3 mmol/L) observed with orforglipron compared with insulin glargine (6.8% vs 19.2%). Treatment-emergent adverse events related to supraventricular tachyarrhythmias, including atrial fibrillation or atrial flutter, were reported in 3.2% versus 2.7%.

Deaths came out to 1.4% versus 3.2%, respectively, with all deaths except one in the insulin glargine group deemed unrelated to treatment.

Additionally, pulse rate rose with orforglipron and remained elevated at week 104 (mean change +4.0 beats per minute) versus no change with insulin glargine (mean change -0.2 beats per minute).

ACHIEVE-4 was limited by an open-label design, investigators acknowledged, and it had a number of small subgroups tested without adjusting for multiplicity.