Part 1 – From Type 2 Diabetes to Obesity
In this first of a two-part look at glucagon-like peptide receptor agonists (GLP-1RAs), we focus on their current applications in the treatment of Type 2 diabetes (T2D) and the growing interest in their use to treat obesity, a condition that is frequently associated with or is a harbinger of T2D onset. Our second post on GLP-1RAs,will focus on the potential for other applications beyond obesity, particularly NASH.
GLP-1RAs were first introduced as a new class of therapeutics for the treatment of T2D in 2005. Individuals with T2D often have insufficient levels of GLP-1, a protein that stimulates the production of a hormone called incretin. This hormone slows digestion, prevents the liver from making too much glucose, and helps the pancreas produce more insulin. GLP-1 RAs also affect the hypothalamus, the part of the brain that controls hunger signals, reducing food cravings.
That first GLP-1RA was exenatide, originally produced by Amylin and sold by AstraZeneca as Byetta. The drug, a twice-daily injection, lowered both post-meal and fasting blood glucose levels by stimulating insulin secretion only when blood sugar is high and by restoring the first-phase insulin response, an activity of insulin-producing cells in the pancreas that is lost in people with T2D. While the drug was efficacious and led to modest weight loss for many patients, it was associated with frequent unpleasant side effects of nausea and vomiting, and with rare cases of pancreatitis.
Exenatide’s launch spurred Novo Nordisk and Eli Lilly to develop their own GLP-1RAs, working to create better tolerated drugs that offered greater potency and only required once-weekly dosing. Liraglutide, Novo Nordisk’s Victoza, was approved for the treatment of T2D in Europe in 2009 and by the U.S. Food and Drug Administration (FDA) in 2010. Dulaglutide – Lilly’s Trulicity – was approved by the FDA for T2D in 2014. In 2017, Novo Nordisk’s semaglutide entered the market, approved by the FDA for T2D initially in 2017 as the injected drug Ozempic and then in 2019 in a daily oral version branded Rybelsus.
The weight loss associated with GLP-1 RAs has been equally or even more interesting to drug developers as their efficacy in T2D. In June 2021, the FDA approved a higher dose of Novo Nordisk’s semaglutide as Wegovy after that drug was shown to produce an average 15% weight loss over 68 weeks – significantly better than any previous drug developed for that purpose. This effect generated considerable interest from both physicians and patients in a drug that could truly treat obesity – thus perhaps preventing T2D as well as other obesity-related health and image issues.
As we have written previously, in November 2022, interest in the obesity market grew further when Eli Lilly presented weight loss data from advanced clinical trials of its own GLP-1 drug tirzepatide, approved by the FDA in May 2022 for T2D as Mounjaro. Tirzepatide also appeared to stimulate greater weight loss than had been reported for semaglutide, with patients on the highest dose losing around 22% of their weight at 72 weeks — a level that medical experts viewed as comparable to the weight loss achieved with bariatric surgery. Tirzepatide differs from semaglutide and other earlier GLP-1RAs in that it also stimulates a second target, gastric inhibitory polypeptide (GIP), which helps regulate insulin secretion and food intake. Experts widely expect the drug to be approved as an obesity treatment by early 2024. Lilly is also working on an oral GLP-1RA, orforglipron, which is currently in Phase 3 trials in T2D and obesity.
These successes in the weight loss and T2D space have created enough momentum for other drug developers to pursue their own GLP-1 and GLP-1/GIP drugs, aiming for treatments with oral or less frequent injectable dosing, greater weight loss, and/or fewer side effects. Pfizer is currently conducting Phase 2 trials of an oral GLP-1RA, danuglipron, for use in T2D where oral drugs are greatly preferred by patients over injectables. Amgen is developing a bi-specific drug that uses an antibody portion to block GIP (unlike tirzepatide, which has GIP agonist activity) and a peptide portion to stimulate GLP-1. The antibody component allows the drug to remain active in the body for a longer period than current GLP-1RAs, thus enabling a lower frequency dosing of once-monthly. In a small Phase 1 trial of this drug, participants who received the highest of four studied doses lost 14.5% of their weight in less than 3 months. Amgen is now preparing to start a large Phase 2 trial to understand the drug’s effects on both T2D and obesity over the course of a year.
The market for GLP-1 and GLP-1/GIP drugs in diabetes is already generating around $23 billion in annual sales. Some estimate that with the addition of obesity approvals, the market for these drugs could approach $100 billion in less than 10 years.
However, the obesity drug market is notoriously tough and littered with treatments that first generated much attention and then ultimately failed due to issues such as serious delayed-onset side effects, payer resistance to reimbursement, changes in drug ownership and failed marketing strategies, as well as the existing stigma surrounding obesity as a “character flaw” that affects the drugs’ use. Even now, GLP-1 RAs are facing issues regarding constraints on their reimbursement for obesity, as well as other issues like drug shortages, that have limited access for T2D and weight loss alike. And like other previous weight loss drugs, evidence is mounting that the current GLP-1s require consistent, long-term use, or in most cases, the lost weight relapses.