Orforglipron Shows Promise as Weight Loss, Diabetes Agent in Phase 2 Trials

Sean Wharton, MD, PharmD
Credit: Wharton Medical Clinic

Data from a pair of trials presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023) introduced the medical community to orforglipron—an oral GLP-1 receptor agonist from Eli Lilly and Company showing promise as a both weight loss and an antihyperglycemic agent.

Eli Lilly and Company’s first nonpeptide oral glucagon-like peptide-1 receptor agonist being studied for chronic weight management, results of the phase 2 trials indicate use was associated with a mean reduction in body weight up to 14.7% and mean reduction in HbA1c with up to 2.1% at 26 weeks.^1,2

"We recognize that obesity is a global epidemic and there is a need for a variety of effective medications and administration routes," said Sean Wharton, MD, PharmD, medical director at Wharton Medical Clinic.³ "We are working to address these needs by researching different options, including a daily oral pill called orforglipron. In a phase 2 study, orforglipron demonstrated an average of up to 14.7% weight reduction. These exciting results indicate that orforglipron may be an effective, once-daily oral that can be taken without food or water restrictions."

The phase 2 weight management trial was designed as a randomized, double-blind trial and enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. For inclusion in the trial, patients need to be 18 to 75 years of age with a BMI or 30 kg/m2 or more or a BMI of at least 27 with at least one weight-related conditions, such as hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea.¹

The 272 patients who were enrolled and underwent randomization in a 5:5:3:3:3:3:5 ratio 12, 24, 36, or 45 mg or placebo once daily for 36 weeks. Investigators pointed out the 36 mg and 45 mg cohorts were divided into a pair of subcohorts with different starting doses and escalating schemes. At baseline, the study cohort had a mean body weight of 108.7 and a mean BMI of 37.9 kg/m2.¹

Per study protocol, the trial consisted of a 2-week screening and lead-in period followed by a 36-week treatment period, and a 2-week follow-up period, with the dose-escalation phase lasting no more than 16 weeks. The primary outcome of interest for the trial was percentage change from baseline in body weight at week 26. The secondary outcome of interest was the percent change from baseline in body weight at week 36.¹

Upon analysis, results suggested the mean change in body weight observed with orforglipron ranged from -8.6% to -12.6% at week 26 compared to just -2.0% with placebo therapy. Investigators highlighted weight loss of at least 10% by week 36 occurred in 46% to 75% of the participants who received orforglipron compared to 9% who received placebo.¹

The study examining use of orforglipron in type 2 diabetes was a 26-week, double-blind, randomized trial launched with the intent of assessing the efficacy and safety of orforglipron in 3 mg, 12 mg, 24 mg, 36 mg or 45 mg compared to placebo and dulaglutide in adults with type 2 diabetes. Conducted at 45 sites in the US and Europe, the trial enrolled and 383 patients and randomized them in a 5:5:5:5:5:3:3:3:3 to placebo, dulaglutide 1.5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg, 36 mg, 45 mg, or 45 mg once per day with no food or water restrictions. Investigators noted 2 different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts.²

For inclusion in the trial, patients were required to be aged 18 years or older with type 2 diabetes treated with diet and exercise, with an HbA1c of 7.0 to 10.5%, and a stable BMI of 23 kg/m2 or more. At baseline, the overall study cohort had a mean age of 58.9 years, the mean HbA1c was 8.1%, the mean BMI was 35.2 kg/m2, and 59% were male.²

Upon analysis, the mean change in HbA1c among those using orforglipron was -2.10% (placebo-adjusted, -1.67%) compared to -0.43% with placebo and -1.10% with dulaglutide. Further analysis demonstrated the HbA1c reduction observed with orforglipron was statistically significant relative to reductions observed with placebo therapy (estimated treatment difference -0.8% to -1.7%). When examining body weight, results suggested there was a mean body weight reduction of -10.1 kg (95% CI, -11.5 to -8.7; placebo-adjusted, -7.9 kg [95% CI, -9.9 to -5.9) with orforglipron compared to -2.2 kg (-3.6 to -0.7) for placebo and -3.9 kg (-5.3 to -2.4) for dulaglutide.²

"People living with chronic diseases such as type 2 diabetes and obesity deserve options – including oral treatments – to meet their treatment needs. In two phase 2 studies, orforglipron demonstrated the ability to lower weight and A1C in both patient populations," said Jeff Emmick, MD, PhD, senior vice president of product development with Eli Lilly and Company.³ "These study results support the continued development of orforglipron in phase 3. We look forward to those results and the continued development of our pipeline assets that explore novel treatments for type 2 diabetes and obesity."

In their release, Eli Lilly and Company pointed out orforglipron is being evaluated for chronic weight management in the ATTAIN phase 3 clinical program and for type 2 diabetes in the ACHIEVE phase 3 clinical program.³

1. Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity [published online ahead of print, 2023 Jun 23]. N Engl J Med. 2023;10.1056/NEJMoa2302392. doi:10.1056/NEJMoa2302392
2. Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study [Published: June 23, 2023]. The Lancet. DOI: 10.1016/S0140-6736(23)01302-8
3. Lilly’s Phase 2 results published in the New England Journal of Medicine Show Orforglipron, a once-daily oral nonpeptide GLP-1 receptor agonist, achieved up to 14.7% mean weight reduction at 36 weeks in adults with obesity or overweight. Eli Lilly and Company. June 23, 2023. Accessed June 24, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-phase-2-results-published-new-england-journal-medicine.