Ozempic Requires Tradeoffs Between Efficacy and Safety

Novel obesity and type 2 diabetes drugs like Ozempic are highly effective but come with complex concerns, experts say.

Medications called glucagon-like peptide-1 receptor agonists (GLP-1RAs) are praised for their effectiveness in controlling insulin and blood glucose levels in type 2 diabetes patients.

As they promote feelings of satiety, drugs like Ozempic and Rybelsus are also increasingly used off-label for weight loss.

Despite high efficacy, these drugs may not be a universal cure for obesity, which affects about 40% of American adults. Experts say there are complex considerations such as dosages, costs, side effects, and comparisons between specific drugs.

“The current fervor for GLP-1RAs in the capital markets as well as in the general public, especially in terms of weight reduction, is probably going to result in overuse,” said Chun-Su Yuan, M.D., Ph.D., the Cyrus Tang Professor of Anesthesia and Critical Care at the University of Chicago. “This should raise a red flag.”

Yuan is a co-author of a recent study published in the BMJ comparing the effectiveness of 15 different GLP-1RAs. While different drugs performed better in different areas, all analyzed medications successfully lowered blood glucose and reduced weight. Semaglutide, the type of GLP-1RAs, also led to reductions in the LDL and overall cholesterol.

Another recent study, published in Nature Cardiovascular Research and led by Eric Polley, Ph.D., compared the effects of four different classes of diabetes medication in patients with moderate cardiovascular risk. These drugs included GLP-1RAs, SGLT2 inhibitors, DPP-4 inhibitors, and sulfonylureas.

The GLP-1RA drugs were found to be most effective not only in controlling blood glucose and weight but also in reducing the risk of major heart-related events and the risk of death overall.

Not suitable for everyone

However, experts warn that GLP-1RAs are not universally effective for all patients. They say physicians should consider multiple factors when selecting a specific drug and dosage, including comorbid conditions like hyperlipidemia, which is defined by elevated levels of cholesterol, triglycerides, and other lipids.

Polley pointed out that even patients with similar clinical profiles might prioritize different aspects of their health or quality of life.

If cardiovascular health is what you think is important for deciding between these drug classes, I think our most recent study provides some strong evidence. But if there are other outcomes that your patient is concerned about, then you have to consider the effect size for those other outcomes.

Polley

However, the emerging evidence links the drugs to side effects, which may range from mild to severe. The study published in the BMJ confirmed adverse effects related to gastrointestinal issues like nausea and vomiting.

Previous studies linked GLP-1RAs to pancreatitis, stomach paralysis, bowel obstruction, and rare psychiatric events. A more recent study, however, suggests that these medications can reduce the risk of acute pancreatitis.

Experts emphasize the need to consider tradeoffs between efficacy and side effects: while the higher doses can be more effective, they can also induce more severe side effects.

“It’s also important to note that the long-term side effects of these drugs are not yet well-studied. If large swathes of the general public start taking them off-label for weight loss and then we find out years later that there are bad side effects, it could be a real issue,” Yuan said.

Moreover, GLP-1RAs are expensive, and the recent spike in popularity has already led to shortages and increased hesitancy among insurance providers to cover these drugs.

“We know these drugs represent a massive breakthrough in our long fight against obesity-related clinical conditions, but their high cost has been the subject of substantial debate. It presents a key barrier to equitable access to this great innovation,” said David Kim, Ph.D., a UChicago health economist.

Some experts predict that competition will reduce the price of GLP-1RAs as new medications are being developed. Additionally, expanding Medicare’s coverage for these drugs would significantly raise the likelihood that private insurers will also start covering them.