Tirzepatide (Mounjaro), perhaps with a new brand name, will likely join semaglutide (Wegovy) by year's end as an approved weight-loss treatment for people with obesity or overweight and at least one weight-related medical problem. Tirzepatide is currently only approved for diabetes but is prescribed off-label for weight loss. More potent than semaglutide, which is also approved for type 2 diabetes, tirzepatide causes an average 22.5% reduction in body-weight for people without diabetes. Tirzepatide's developer Eli Lilly will reportedly use a priority review voucher purchased for $110 million to shave 4 months off the approval timeline for a weight-loss indication.
Prescriptions for these incretin mimetics for weight loss -- on- or off-label -- have skyrocketed. While patients may be shedding pounds, it's far from certain whether these new drugs will actually improve health outcomes, and we're concerned that the prevailing narrative hasn't given enough air time to the potential drawbacks.
Incretin mimetics were originally developed to treat type 2 diabetes by stimulating insulin production. When diabetics lost weight, these drugs were repurposed for weight loss. Both semaglutide and tirzepatide act as agonists for glucagon-like peptide-1 (GLP-1), a hormone that slows gastric emptying and signals the brain to decrease appetite and reduce energy intake. With the addition of an agonist for another incretin (gastric inhibitory polypeptide [GIP]), tirzepatide causes greater weight reduction (although the role of GIP is uncertain).
The bottom line is that patients lose interest in eating, so they eat less. But incretin mimetics must be taken over a lifetime -- once the drugs are stopped, the weight returns. Given the adverse health consequences of weight cycling, any temporary benefit of weight loss could be offset by longer-term harms of weight regain when the drugs are stopped.
Weight Loss Doesn't Equal Better Health
These drugs may not improve health outcomes. In part that's because for obesity they are prescribed based only on body mass index (BMI) -- a measure solely defined by height and weight and developed using data only from white men. While a higher BMI may be associated with health risks in a population, BMI is a poor predictor of cardiometabolic health in individuals. What's more, a little extra weight may be protective. A meta-analysis found that, compared to normal weight, grade 1 obesity (BMI 30 to <35) was not associated with higher mortality, and overweight (BMI 25 to <30) was associated with significantly lower all-cause mortality.
Obesity is a risk factor for hypertension, hyperlipidemia, and diabetes, but is too often used as a surrogate for these conditions. Many thin people are hypertensive or diabetic, and many higher-weight people are normotensive and don't have diabetes or hypercholesterolemia.
Health outcomes can be improved without losing weight, and research supports a weight-neutral strategy for obesity treatment. Data show that, even in the absence of weight loss, exercise training can improve most cardiometabolic risk factors associated with obesity. And increases in cardiovascular fitness and physical activity, unlike weight loss, are consistently associated with lower mortality risks.
These Drugs Come With More Than Weight Loss
GLP-1 and GLP-1/GIP receptor agonists may benefit a few highly selected patients, but given known harms -- and the potential for unknown long-term harms -- BMI alone should never be the deciding factor. Certainly no one without medical problems should be using these drugs in an effort to improve health or to improve appearance. Nausea, vomiting, and diarrhea can be severe enough to send patients to the hospital. These drugs also increase risks of acute pancreatitis, gallbladder disease, kidney problems, and suicidal ideation, and may increase the risk of thyroid cancer.
Media are also reporting more adverse effects, including malnutrition caused by inadequate food intake, hair loss, and unusual, vivid dreams.
There's also concern about increased adverse effects in elders and populations of color, who were inadequately represented in clinical trials for both semaglutide and tirzepatide -- participants were primarily white (75%), middle-age (45 years) women (67%). Many older adults are sarcopenic, and incretin mimetics cause loss of lean body mass as well as fat mass. Moderate obesity may be protective against cardiovascular risks after age 65. Questions also remain about the effect of these drugs on Black Americans, three quarters of whom have a BMI classifying them as overweight or obese. At best, less than 8% of trial participants were Black in the tirzepatide trial.
Consider the Messenger
Hype is common with incretin drugs, and we understand these medications can be life-changing for select patients. But there needs to be more discussion of harms, the unknown effects of lifelong use, the dearth of information on Black patients, the value of BMI as a predictor of health risks, and whether these drugs actually benefit health. Even harder to find is discussion of the robust research available that supports a weight-neutral strategy for increasing health in higher-weight patients.
Certainly our weight-obsessed culture is one reason for this limited discourse, but omitting any unappealing facts or unknowns aligns with the interest of pharmaceutical companies. A legion of conflicted individuals and organizations funded by weight-loss drug manufacturers promote a one-sided perspective and actively advocate for broad insurance coverage, especially for Medicare recipients.
Pharmaceutical company-sponsored organizations and individuals may not believe this money influences their positions, but, if their positions didn't align with the industry view, they wouldn't be receiving that funding. Doctors paid by weight-loss drugmakers are training new residents and medical students, offering continuing medical education, providing interactive learning modules, and appearing on 60 Minutes. A slew of obesity care and advocacy organizations lobby for insurance coverage, run awareness campaigns, hold conventions, and offer advice for healthcare providers. Quotes from spokespeople to the media relay industry messages without mentioning ties with industry.
While advocates may believe they are providing unbiased evidence-based information, it's woefully incomplete and misleading. Billions of dollars are likely to be spent on these drugs. A dispassionate look at what taxpayers get for that money is the only way to assess that investment. That's not going to happen when industry is pulling the strings.
Judy Butler, MS, is a research fellow with PharmedOut, a Georgetown University Medical Center project that advances evidence-based prescribing and offers education on industry marketing practices. Adriane Fugh-Berman, MD, is the director of PharmedOut and a professor in the departments of pharmacology, physiology, and family medicine at Georgetown University Medical Center.
Disclosures
Fugh-Berman is a paid expert witness at the request of plaintiffs in litigation regarding pharmaceutical and medical device marketing practices.