Tirzepatide tops semaglutide for patient weight loss, study finds

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In the battle against obesity – and maybe for eventual market share – tirzepatide won a round over semaglutide in a recent study, said drug maker Eli Lilly and Company.

Meanwhile, the war over blended semaglutide continued as pharmaceutical giant Novo Nordisk Inc. has asked the U.S. Food and Drug Administration to plug the vials of compounding pharmacists, arguing they are making potentially unsafe versions of its antidiabetes and antiobesity bestseller. The druggists countered they are capable of mixing it safely for patients who can’t find it at pharmacies, or can’t afford it if they do.

In another study, researchers projected GLP-1 RA drugs have potential to help heart patients on a scale large enough to alter the global coronary stent market.

The developments were the latest in one of the hottest continuing issues in health care.

Head-to-head for weight loss

Tirzepatide led to a 47% greater reduction in weight compared with semaglutide in the first head-to-head trial between the antiobesity medications from Eli Lilly and Novo Nordisk, respectively.

Specifically, topline findings from the phase 3b SURMOUNT-5 trial revealed an average loss of 50.3 pounds (20.2%) among tirzepatide-treated participants vs 33.1 pounds (13.7%) among semaglutide-treated adults after 72 weeks, according to a news release from Lilly.

Study findings also showed superiority of tirzepatide across five secondary endpoints, the key result being body weight loss of at least 25% among 31.6% of participants who received tirzepatide compared with 16.1% of those who received semaglutide who reached the designated mark.

"Given the increased interest around obesity medications, we conducted this study to help health care providers and patients make informed decisions about treatment choice," Leonard C. Glass, MD, senior vice president of global medical affairs at Lilly Cardiometabolic Health, said in the news release.

The multicenter, randomized, open-label SURMOUNT-5 trial evaluated the efficacy and safety of Lilly’s tirzepatide, marketed as Zepbound, and Novo’s semaglutide, marketed as Wegovy, in adults with obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea (OSA) or cardiovascular disease, who did not have diabetes. Investigators randomly assigned 751 adults in the United States and Puerto Rico to receive maximum tolerated dose of tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg).

The safety profile of tirzepatide was similar to that observed in previously reported SURMOUNT program clinical trials. The most commonly reported adverse events in SURMOUNT-5 for both tirzepatide and semaglutide were gastrointestinal-related and were generally mild to moderate in severity.

Lilly will amend these topline findings pending further evaluation. Results will be published in a peer-reviewed journal and presented at a medical meeting next year, the company said.

Tirzepatide is a dual GIP glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 receptor agonist (GLP-1 RA), administered once-weekly by subcutaneous injection. Semaglutide acts solely at the GLP-1 receptor and is also administered once-weekly. Both incretin mimetics reduce hunger, increase satiety, and slow gastric emptying. Both are approved by the U.S. Food and Drug Administration for long-term weight management as an adjunct to lifestyle changes including increased physical activity and a reduced-calorie diet. The tirzepatide dual agonism is thought to be associated with the greater observed impact on body weight.

Difficult to compound?

Meanwhile, Novo Nordisk this fall asked FDA to place semaglutide on its Demonstrable Difficulties for Compounding Lists, known as DDC lists, with additional regulations on compounded versions to protect public health.

“Semaglutide products belong on these lists due to the complexities associated with their formulations, delivery mechanisms, dosage forms, achievement of bioavailability, compounding processes, and physicochemical and analytical testing,” said the company’s petition published on regulations.gov.

That move “would eliminate patients’ access to compounded semaglutide literally overnight, even as the commercially manufactured drug remains in shortage,” according to the Alliance for Pharmacy Compounding (APC).

That organization relied on chemistry, acknowledging the active pharmaceutical ingredient (API) in synthetic semaglutide made by compounders has a different impurity profile than the recombinant semaglutide API used in Novo Nordisk’s commercially made drugs. But the impurity characteristics of synthetic semaglutide remain safe and effective, and they do not create a danger for patients, according to the letter from APC legal counsel Stephen T. Snow, Esq.

Patients use vials with syringes or pre-filled syringes to administer compounded semaglutide. Novo Nordisk may claim that makes it difficult to compound the drug, but patients with diabetes have used the same form of administration for decades by, APC’s letter said.

As for extraordinary patient demand, Novo Nordisk created that problem with aggressive advertising. But semaglutide has been on FDA’s drug shortage list since March 31, 2022, and remains “currently in shortage” now, according to APC.

“The two and a half-year delay in the drugmaker’s nomination of semaglutide to the DDC Lists calls into question the veracity of its claim that its nomination is motivated by a concern for patient safety,” the APC letter said.

“Did it really take Novo Nordisk two-and-a-half years to suddenly determine that semaglutide is demonstrably difficult to compound? Or did Novo Nordisk simply decide to follow the lead of its competitor, Eli Lilly, by nominating compounded semaglutide for inclusion on the FDA’s DDC Lists in an opportunistic attempt to stifle what it improperly perceives to be competition from (compounding pharmacies)?” the letter said.

Good for heart patients

A number of studies have found potential health benefits of using the GLP-1 RA drugs. Added to those are findings from the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity, known as the SELECT trial.

If GLP-1 RA use became as common as use of statins, coronary stent use could drop an estimated minimum 6%, and possibly as much as 22%, depending on the cardiovascular risk profiles of patients. That could cut $600 million to $2 billion from the global stent market, now valued at $9 billion, with some hospital markets seeing reductions of more than 30%.

The report was presented in November’s American Heart Association (AHA) Scientific Sessions in Chicago, by Andrew Epstein, PhD, MPP, of Medicus Economics and Saif S. Rathore, MD, PhD, MPH, of Sandbar Life Sciences. An abstract was published in the AHA Journal Circulation, and additional data come from a news release about the results.

An earlier version of this article appeared on Patient Care Online.