In early T2D inadequately controlled with diet and exercise, once-daily orforglipron reduced HbA1c vs. placebo at 40 wk
An industry-funded trial showed that the new oral glucagon-like peptide-1 receptor agonist reduced HbA1c levels by a similar amount as oral semaglutide but less than higher-dose injectable drugs in the class, an ACP Journal Club commentary noted.
A phase 3 trial, ACHIEVE-1, compared orforglipron, a small-molecule, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist, to placebo. It tested three doses of the drug (3 mg, 12 mg, or 36 mg) in 559 patients who had type 2 diabetes (T2D) previously treated only with diet and exercise, an HbA1c level of 7.0% to 9.5%, and a body mass index of at least 23 kg/m2. All three doses were superior to placebo on the primary outcome of change in HbA1c level from baseline. The study was supported by Eli Lilly.
The study was published by the New England Journal of Medicine on June 21. A summary was published in the July ACP Diabetes Monthly. The following commentary by Maham Shahid, MD, and Gunjan Y. Gandhi, MD, MSc, was published in the ACP Journal Club section of Annals of Internal Medicine on Oct. 7.
Most glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are administered by injection, but 75% of patients with T2D prefer an oral vs. a weekly injectable medication. Orforglipron, a once-daily nonpeptide oral GLP-1 RA that can be taken any time of day without food or water restrictions, may soon be an option. Orforglipron differs from the only other oral GLP-1 RA on the market, semaglutide, which must be taken on an empty stomach followed by fasting for optimal absorption.
ACHIEVE-1 showed that orforglipron reduced HbA1c by 1.2 to 1.5 percentage points, depending on the dose. This reduction is similar to that of oral semaglutide but less than those of injectable GLP-1 RAs at higher doses.
Oral semaglutide and injectable GLP-1 RAs reduce major adverse cardiovascular (CV) events, heart failure hospitalizations, all-cause mortality, and albuminuria. Orforglipron improves surrogate markers of CV risk, such as blood pressure, lipid levels, pro-brain natriuretic peptide, and inflammatory markers. ACHIEVE-4 (NCT05803421) will compare the cardioprotective effects of orforglipron vs. insulin in patients with T2D and overweight or obesity.
Orforglipron is a reasonable oral alternative with convenient dosing and comparable efficacy to injectable GLP-1 RAs for patients with T2D and obesity, especially those who prefer oral medication. Its long-term effects will depend on affordability and sustained use, as weight regain is common after discontinuation of injectable GLP-1 RAs.