Weight Loss Drugs Face New Scrutiny Over Efficacy, Safety, and Access Concerns

Recent clinical trial results for retatrutide, a compound Eli Lilly is developing, found that people with obesity and knee osteoarthritis lost an average of 28.7 percent of their body weight after 68 weeks on the highest dose. Between 12 and 18 percent of participants dropped out of the trial because of side effects, a higher percentage than is typical in trials of existing weight loss drugs. The company said that at least some of those people dropped out because they thought they were losing too much weight, alarming some outside researchers.

The trial included 445 participants and was sponsored by Eli Lilly. The full data has not been published yet, so it's difficult to make definitive conclusions about why patients dropped out. Currently available weight-loss drugs have helped people lose around 20 percent of their body weight over the same time period.

The chief medical officer at Eli Lilly said that retatrutide will be aimed at patients who need to lose more weight than they could on other medications. "We're not of the belief that the most potent weight loss medicine is required for everybody, or that that's even the goal," he said.

According to a November poll of 1,350 Americans, around one in four people taking GLP-1s were getting these medications from online providers, websites, medical spas or aesthetic medical centers — rather than from their primary care doctors or specialists. Often, these outlets sell low-cost copycats of obesity medications — compounded versions made by pharmacies that measure and dissolve drug ingredients, creating their own injectable product.

Earlier this month, Hims & Hers, a major online provider of obesity medications, announced that it would be selling a compounded version of the Wegovy pill for about $100 a month less than the official version sold by Novo Nordisk. Hims pulled this product from the market two days later, after federal regulators raised concerns.

Federal law allows compounding when there's a drug shortage or when a patient needs a special formulation. However, after several years of limited supply, the Food and Drug Administration says that the GLP-1 shortages are over. Since then, many medical spas and telehealth companies have continued to sell compounded drugs, relying on providers who say these personalized versions are necessary.

These companies tend to sell slightly altered versions (for example, mixing in ingredients like Vitamin B12 or the molecule N.A.D.+) or custom doses that pharmaceutical companies don't sell. Compounded GLP-1 drugs can be cheaper and easier to obtain, since many insurance companies balk at covering the more expensive brand-name versions. But these copycat drugs also come with more uncertainty, said an obesity medicine physician at University of Florida Health, since they are not approved by the F.D.A. While regulators do oversee the compounding process, the scrutiny is generally lighter than for approved drugs.

Gastrointestinal adverse effects are the most commonly reported side effects of GLP-1RAs. A systematic review of 39 randomized controlled trials found increased risks of vomiting, nausea, constipation, and diarrhea with GLP-1RAs in non-diabetic individuals compared to placebo. Another review of 38 RCTs involving type 2 diabetes patients observed nausea in 19% of participants treated with GLP-1RAs and vomiting in 7.6%. In a phase II trial of subcutaneous semaglutide, rapid dose escalation led to greater weight loss but more adverse events.

Tirzepatide is a co-agonist of the GIP receptor and GLP-1R and demonstrates greater efficacy for weight loss and glucose lowering than selective GLP-1RAs, with a broadly similar adverse event profile. In one clinical trial, 5 mg per week tirzepatide was slightly more effective than 1 mg per week semaglutide in reducing body weight and glycated hemoglobin (HbA1c). However, a systematic review reported that tirzepatide conferred the highest risk of vomiting. A large cardiovascular outcomes trial found that higher proportions of tirzepatide recipients reported vomiting, diarrhea, and nausea compared to those taking a selective GLP-1RA.

Delayed gastric emptying associated with GLP-1RAs may increase the volume of retained gastric contents before endoscopic or surgical procedures, although evidence directly linking this to aspiration pneumonia remains limited and sometimes conflicting. Some analyses also suggest an increased risk of biliary disease, particularly cholelithiasis, with GLP-1RA therapy.

Earlier concerns regarding acute pancreatitis and pancreatic cancer have largely been alleviated by long-term randomized trials that have not confirmed a causal association, although reporting biases and diagnostic complexity remain considerations, and continued pharmacovigilance is recommended.

Concerns about medullary thyroid carcinoma emerged from rodent studies showing increased calcitonin secretion and C-cell growth after liraglutide treatment. While GLP-1R expression has been demonstrated in rodent thyroid C cells, the receptor has generally not been detected in healthy human or primate thyroid C cells, or has been detected only in small subsets. In contrast, many hyperplastic C cells and medullary thyroid carcinomas in humans express GLP-1R. Data from France suggest a higher risk of medullary thyroid carcinoma in people treated with GLP-1RAs compared to other glucose-lowering agents. However, absolute event numbers remain low.