Glucagon-like peptide (GLP-1) medications are highly effective at helping patients lose 15% or more of their weight. But they are expensive, generally costing employers $7,500-$9,000 annually, even after rebates and discounts. Some employer plans find that these two medications, semaglutide (Wegovy) and tirzepatide (Zepbound), represent as much as 10% of their total outpatient pharmacy spending, and an outsized portion of pharmacy inflation. These drugs are available directly from pharmaceutical companies for about $6,000 per year for those without insurance coverage.
GLP-1 drugs have been used for about two decades to treat diabetes. Their safety and side effect profiles are well understood.
The Food and Drug Administration (FDA) has approved Wegovy (semaglutide) and Zepbound (tirzepatide) to treat those with obesity or those who are overweight with metabolic complications (such as heart disease, hypertension or hypercholesterolemia). An older drug, Saxenda (liraglutide), was approved in 2014 but requires daily injections and results in only ~5% average weight loss. About 42% of the adult population could be eligible for these medications. Most long-term studies of GLP-1 drugs are in people with diabetes, as semaglutide was only approved for obesity in June 2021, and tirzepatide was only approved for obesity in November 2023.
The diabetes versions of the obesity-labeled GLP-1 drugs are the same drug. Maximum doses available for semaglutide for diabetes (Ozempic) are lower than those labeled for obesity (Wegovy). Doses available for Zepbound and Mounjaro are identical. Drugs labeled for diabetes are generally about 20% less expensive than drugs labeled for obesity.
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These drugs are highly effective at helping patients achieve a medically desirable weight. Semaglutide generally leads to 10–15% weight loss, and tirzepatide generally leads to 15–20% weight loss. Weight reduction has been associated with improvements in mental health and improved employment prospects. Here’s a recent Reuters article on the impact of weight loss on obese adolescents.
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A randomized trial published in the New England Journal of Medicine in 2023 showed that the risk of major adverse cardiovascular events was 20% lower in those with previous heart disease and without diabetes who were treated with semaglutide compared to those treated with placebo. The trial was discontinued early based on positive results. Wegovy is approved for this indication.
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Zepbound (tirzepatide) was associated with a 93% relative risk reduction in the onset of diabetes over a 4-year study period in those with “prediabetes” in a randomized trial published in the New England Journal of Medicine in late 2024. An earlier trial showed a 73% lower incidence of HbA1C >=6.5% in those treated with semaglutide for obesity compared to those treated with placebo.
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A 2024 study in the New England Journal of Medicine showed that people on tirzepatide had dramatic improvements in their sleep apnea compared to those on placebo. Zepbound is approved for this indication, and it's likely that Wegovy is also effective.
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In 2024, a study published in JAMA Network Open showed a decrease in the risk of multiple cancers in those treated with GLP-1 medications for diabetes. This included a decrease in the risk of breast, colorectal and endometrial cancers. All the decreases below are statistically significant.
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Research published in JAMA Internal Medicine in 2024 showed that those with obesity who took GLP-1 medications were less likely to have MASH (metabolic associated steatohepatitis) than those who took a placebo. This study also showed a lower risk of liver cancer and death. The New England Journal published research in late April that showed those on Wegovy were more likely than those on placebo to experience resolution of steatohepatitis (63% vs. 34%), representing an 83% relative improvement. Novo Nordisk is seeking FDA approval of Wegovy for MASH.
Rezdiffra (resmiterom), currently the only approved drug for MASH, has a list price of about $47,000 annually. Recent research has suggested that an effective drug for this indication could be cost-effective at $5,600-$10,600.
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A randomized controlled trial published in the New England Journal of Medicine in 2024 showed that among people with diabetes and preexisting kidney disease, 24% fewer on semaglutide had an adverse kidney outcome (including kidney failure requiring dialysis, transplantation, death, or significant decline in renal function).
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A randomized trial published in the New England Journal of Medicine in 2024 showed a decrease in standardized pain scores and improved physical function in those with moderate to severe arthritis treated with semaglutide.
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A randomized trial presented at the Obesity Society meeting in 2024 showed an 11% decrease in hospitalizations in those on semaglutide.
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This category of drugs could be effective in the treatment of substance use disorder and compulsive gambling. Neither drug has been approved by the FDA for this indication.
There are certainly adverse effects of GLP-1 medications, especially adverse gastrointestinal effects in the first months of use as doses are titrated up. Here's a summary of well-documented adverse effects, and adverse effects that are either less well-documented, general to weight loss, or not likely related to GLP-1 use.
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Nausea, vomiting and constipation are common and are generally worse in the early months of therapy while dosing is ramped up.
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The GLP-1s slow food passage through the stomach, and in some cases, paralysis of the stomach can require urgent intervention.
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The GLP-1 medications have been linked with a statistically significant increase in non-arteritic anterior ischemic optic neuropathy (NAION). NAION is a rare condition that can lead to vision loss. They have also been associated with an increased risk of age-related macular degeneration in people with diabetes.
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Many people who lose a substantial amount of weight (through GLP-1s, bariatric surgery, or diet) have gallbladder attacks.
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Those who lose substantial amounts of weight lose both fat and lean body mass. Loss of muscle doesn't appear to be worse with GLP-1 use than with other weight loss mechanisms. Exercise and diet can reduce muscle loss, and the clinical implications of loss of lean body mass aren't clear.
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There are reports of pancreatic inflammation with GLP-1 medications, although causality isn't confirmed, and this hasn't been observed in large observational studies. Clinical trials generally excluded those with a history of acute pancreatitis. At least one large claims review showed lower rates of pancreatitis with the use of GLP-1 drugs than with other drugs used to treat diabetes.
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The GLP-1 drugs have an FDA “black box” warning of the risk of a rare type of thyroid cancer. But there's no convincing observational evidence that this risk is being seen in clinical use. The warning was based on rodent experimental evidence.
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Early reports suggested that GLP-1 medications might increase depression and suicidal ideation. More recent population studies show a statistically significant decrease in suicidal ideation and suicides in those on GLP-1 medications. Here are studies (1) (2) that show lower rates of depression and suicide in those treated with GLP-1 medications.
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Observational studies (see above) show that GLP-1 use is associated with a decrease in cancer incidence. Given that this drug class has been used widely for two decades, it's unlikely that these drugs will be found to increase the risk of future cancers.
GLP-1 drugs clearly offer substantial health benefits for members with obesity and can prevent serious future disease. However, the cost of the drugs is far higher than savings from preventing these bad outcomes. Demand for these drugs is high and could increase when oral versions become available. The high price of these drugs places coverage out of reach for some employers. Some pharmacy benefit managers say they have achieved better net prices by restricting their formulary to either Zepbound (tirzepatide) or Wegovy (semaglutide). Future new market entrants could help lower the acquisition price for these medications.
Glucagon-like peptides:
GLP-1 drugs like semaglutide (Wegovy and Ozempic) and tirzepatide (Zepbound and Mounjaro) were developed to treat type 2 diabetes, but they’ve gained media attention in the past couple of years for their ability to help people lose weight. These drugs are expensive and mostly given as a self-injection. The drugs to treat obesity and to treat diabetes are the same, although the obesity medications are more expensive and sometimes come in higher doses.
In addition to weight loss and better diabetes control, these drugs have been shown to decrease onset of diabetes in those with prediabetes, decrease progression to kidney failure, and decrease heart attacks in those at high risk. They are also approved for obstructive sleep apnea (Zepbound), metabolic liver disease (MASH, Wegovy), and heart disease prevention (Wegovy). Studies have shown lower risk of obesity-related cancers, too.
Jeff is an internal medicine physician and has led WTW’s clinical response to COVID-19 and other health-related topics. He has served in leadership roles in provider organizations and a health plan and is an Assistant Professor at Harvard Chan School of Public Health.
