Since its debut in 2017 for the treatment of type 2 diabetes, Ozempic has sparked a race between pharmaceutical giants Novo Nordisk and Eli Lilly to develop superior GLP-1 receptor agonist medications. These drugs aim to enhance outcomes for diabetes and weight management. In their quest for weight loss solutions, Novo Nordisk's latest offering, a combined therapy named CagriSema, has shown results comparable to Lilly's Zepbound, yet it did not significantly outperform it in recent late-stage clinical trial data released on Friday.

The experimental CagriSema therapy combines semaglutide, found in both Ozempic and the weight loss medication Wegovy, with another drug, cagrilintide. The 68-week clinical trial indicated that individuals on CagriSema experienced an average weight reduction of approximately 23%, in contrast to 12% for those on cagrilintide alone, 16% for those on semaglutide, and 2.3% for those on a placebo. This outcome met the study's primary objective; however, expectations within the industry had been set higher, with many anticipating an average weight loss of at least 25% for CagriSema, which would have reset the benchmark in a field already transformed by GLP-1 drugs.

Lilly's Zepbound, which gained approval in November 2023 as a response to Novo Nordisk's Wegovy, demonstrated an average weight loss of 21% over 72 weeks at its highest dosage during Phase 3 trials. Furthermore, a mid-stage study of another experimental Lilly drug, retatrutide, showed a 24% weight loss after just 48 weeks. Martin Holst Lange, Executive Vice President for Development at Novo Nordisk, expressed optimism about CagriSema's weight loss results in a company statement on Friday, noting the drug's superiority over both semaglutide and cagrilintide as monotherapies. He mentioned that Novo Nordisk would leverage insights from the trial to further investigate CagriSema's potential for additional weight loss.

The news caused Novo Nordisk's stock to plummet by approximately 19% in early trading on Friday, erasing billions of dollars from the Danish pharmaceutical company's market capitalization. CagriSema's side effects were found to be similar to other GLP-1 class drugs, with the most common being gastrointestinal issues, which were predominantly mild to moderate and resolved over time. However, only slightly more than half of the participants reached the highest dose of the medication, raising concerns about its tolerability at higher dosages.

Novo Nordisk anticipates results from a second Phase 3 trial of CagriSema, this time involving individuals with type 2 diabetes, to be released in the first half of 2025. The study, known as REDEFINE 1, enrolled participants who were either obese or overweight with at least one additional health condition—the same demographic for which Wegovy and Zepbound are approved for weight loss. The average starting body weight of the participants was 106.9 kilograms, or approximately 236 pounds.

Novo Nordisk's Ozempic and Wegovy are based on semaglutide, a hormone that mimics GLP-1, which plays a crucial role in insulin secretion, digestion, and appetite regulation. Wegovy received FDA approval in 2021 after demonstrating an average body weight loss of about 15% over a 68-week clinical trial. Lilly countered with Mounjaro and Zepbound, approved in 2022 and 2023 for diabetes and weight loss, respectively. These drugs use tirzepatide, a hormone that not only mimics GLP-1 but also GIP, to amplify their effects.

A head-to-head trial sponsored by Lilly in December reinforced previous findings that Zepbound outperformed Wegovy in terms of average weight loss over 72 weeks, with 20% compared to approximately 14%. Dr. Daniel Skovronsky, Lilly's Chief Scientific Officer, described the competition as a "health race" in a November interview, emphasizing the development of better medicines for the benefit of patients.

The rivalry has also benefited the companies and their investors, with Lilly's market value now exceeding $700 billion, a fivefold increase over the past five years as GLP-1 drugs generate billions in annual revenue. Novo Nordisk's stock has tripled during the same period, reaching over $300 billion.

Practitioners have noted the rapid pace of advancement in the field. "I can still recall when a 5% weight loss was our target, and we were content with that," said Dr. Eduardo Grunvald, Medical Director of the Center for Advanced Weight Management at the UCSD Bariatric and Metabolic Institute, in an interview prior to the release of CagriSema's results. Previous weight loss drugs, such as Qsymia and liraglutide (sold under the brand name Saxenda), achieved maximum weight loss of 8 to 11% on average.

Semaglutide's average weight loss of about 15% in 2021 was a game-changer, shifting the clinical benefit from "improvement to remission of conditions like hypertension, hyperlipidemia, and diabetes," according to Dr. Jorge Moreno from Yale School of Medicine. A 25% weight loss would match the outcomes of bariatric surgery, and in Novo Nordisk's CagriSema trial, 40% of participants did achieve this milestone, although not enough to surpass the trial's overall average.

Dr. Daniel Drucker, a pioneer in GLP-1 research at the University of Toronto and a consultant for companies developing these medications, emphasized that the health benefits demonstrated by GLP-1 drugs in studies, including reductions in metabolic liver disease, sleep apnea, osteoarthritis, heart disease, and strokes, are not strictly dependent on weight loss. He pointed out that it takes several years for trials to confirm benefits on these other outcomes, which may be more significant to patients and physicians.

With CagriSema, Novo Nordisk is targeting an additional hormone, amylin, in addition to GLP-1. Lilly's retatrutide expands on tirzepatide's GLP-1 and GIP by adding glucagon, earning it the nickname "Triple G." Amgen has taken a different approach by blocking GIP instead of activating it with its drug MariTide, which resulted in an average weight loss of about 20% over a year in mid-stage trial results reported in November. This drug is designed for less frequent administration than Wegovy and Zepbound, with injections once a month or less, compared to the current weekly injections.

Dr. Clayton Runfalo, a family medicine practitioner at Ochsner Health in Louisiana, reflected on the transformation in understanding weight management over the past few decades. He now views GLP-1 drugs as tools, alongside behavioral changes, that have been "extremely beneficial in helping people become healthier."