What is orforglipron?

Orforglipron is an oral experimental, once-daily weight loss/ type 2 diabetes medication that is easier to administer and may be less expensive than current injectable anti-obesity/type 2 GLP-1 drugs already on the market such as Ozempic or Trulicity, which are given by injection.

Lilly plans to submit the pill for FDA approval as a weight-loss treatment by the end of 2025 and for diabetes treatment in 2026.

How is orforglipron administered?

Orforglipron is administered orally, once daily as a pill.

How does orforglipron work?

Orforglipron is a nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist that works by binding to GLP-1 receptors and stimulating insulin release from the pancreas when it is needed. It also slows down how fast food travels through your digestive tract. This can help you feel fuller for longer, reduce how much you eat, and lead to weight loss.

Orforglipron differs from other GLP-1 drugs because of its small molecule structure, unlike the large molecules found in typical GLP-1 medications. This small size may help the body absorb it more easily.

What are the side effects of orforglipron?

The most common side effects were mild to moderate gastrointestinal events such as diarrhea, nausea, constipation, abdominal pain, or vomiting.

The side effect profile is similar to semaglutide but different with diarrhea leading the list. Vomiting is not as frequently reported as with semaglutide.

How effective is orforglipron?

In the ACHIEVE-1 phase 3 trial, 559 type 2 diabetes patients received orforglipron (3, 12, or 36 mg) or placebo for 40 weeks. The drug significantly reduced A1c levels (1.3-1.6 percentage points) compared to placebo (0.1). More than 65% of those taking the 36-mg dose achieved an A1c level of 6.5% or below.

Weight loss ranged from 4.7-7.9% with orforglipron versus 1.6% with placebo, with Lilly noting patients hadn't reached maximum weight reduction when the study ended.

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Previous studies

One phase 2 randomized, double-blind trial of 272 participants with an average baseline weight of 108.7kg (average BMI of 37.9 kg/m2) reported (Warton, et al. 2023):

• A weight change of at least 10% occurred in 46% to 75% of people who received orforglipron by week 36 compared to only 9% of those receiving placebo (an inactive tablet)
• The average change from the starting weight was a loss of 9.4% to 14.7% with orforglipron compared to a loss of 2.3% with placebo
• All prespecified improvements in weight and cardiometabolic measures were met by the trial
• The most common side effects were mild to moderate gastrointestinal events and led to discontinuation of orforglipron in 10% to 17% of participants.

A second phase 2 randomized, double-blind trial of 383 participants with an average BMI of 35.2 kg/m2 reported (Frias, et al. 2023):

• Dosages of orforglipron 12mg and greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide
• At week 26, there was a reduction in HbA1c of up to 2.1% with orforglipron, 0.43% with placebo, and 1.10% with dulaglutide.
• A reduction in body weight after 26 weeks of 10.1kg with orforglipron versus a loss of 2.2kg for placebo and a loss of 3.9kg for dulaglutide was also reported.
• Adverse events were reported in 61.8% to 88.9% of orforglipron treated patients, compared to 61.8% with placebo and 56% with dulaglutide. Most adverse events were mild to moderate gastrointestinal events. Clinically significant hypoglycemia was reported in 3 orforglipron patients and 1 dulaglutide patient. 80 patients did not complete 26 weeks of treatment.

Who makes orforglipron?

Orforglipron is made by Lilly.

Lilly also makes Mounjaro, an injectable dual GIP/GLP-1 receptor agonist which helps lower blood sugar levels in people with type 2 diabetes.

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