The Skinny on Weight Loss Drugs

By now you’ve probably heard that there’s a new way lose weight. Marketed under the names Wegovy, Mounjaro, and Ozempic, the class of injectable drugs called GLP-1 agonists are taking the weight loss space by storm. Here’s what you need to know about them: what they are, how they work, who they’re for, who they’re not for, their benefits, and their risks.

GLP-1 agonists have been used since 2005 for the treatment of type 2 diabetes. Over time, doctors noticed that patients on these drugs tended to lose weight, which is why they’re now being prescribed for weight loss. In 2021, Wegovy (semaglutide) became the first – and is so far the only – drug to get FDA approval for the treatment of obesity.

Before we get too far into the weeds, I wanted to clear up the confusion about drug terminology and share with you what these drugs really are. Every drug has a brand name (like Tylenol) as well as a generic name (like acetaminophen). Ozempic and Wegovy are actually the same drug, semaglutide. The difference is in the dose, and in what the Food and Drug Administration (FDA) has approved them for. Ozempic is packaged as a lower-dose formula (2 mg/week max) and is only FDA-approved to treat diabetes. Wegovy contains a higher dose (2.4 mg/week max) and is FDA-approved to treat obesity. Mounjaro (tirzepatide) is the same class of drugs as Ozempic and Wegovy, but it’s only FDA approved for diabetes at the moment. It’s likely that Mounjaro will soon receive FDA approval for weight loss because a recent trial showed promising results (1).

Lack of FDA approval hasn’t stopped people from using Ozempic and Mounjaro for weight loss because they can be prescribed “off-label.” Prescribing drugs off-label is not uncommon nor illegal, it just means that the prescribing doctor is taking a risk by going outside of the FDA approval guidelines. It also means that insurance isn’t likely to cover the cost of the drugs, which can be upwards of $1,200 per month. But doctors can prescribe Ozempic, for instance, even if the patient is not diabetic, and Wegovy can be prescribed for weight loss in patients who aren’t obese. This is how all these drugs have become over-prescribed to the point of drug shortages, limiting their availability.

So now that you know the landscape, let’s jump into what these drugs do. GLP-1 stands for glucagon-like peptide 1, which is a hormone we naturally produce in our intestines (and – fun fact – has been isolated in the venom of Gila monsters). “Agonist” means that the drug stimulates our body’s receptors for GLP-1. GLP-1 agonists help your body manage glucose after a meal by secreting the hormone insulin, which is why it’s helpful for diabetics. They have also been shown to decrease the risk of cardiovascular disease in diabetics by lowering blood pressure and improving vascular function.

As far as weight loss is concerned, the major role of GLP-1 agonists is to work directly on brain receptors in the hypothalamus to reduce hunger cues. Food just doesn’t seem as appealing, cravings decrease, and people eat less. These drugs also slow down the rate that food passes through your stomach, so you feel fuller for longer.

So who should these drugs be used for? The FDA approval for Wegovy is specific for people who have a BMI over 30, or who have a BMI over 27 plus one weight-related complication, such as diabetes or high blood pressure. The philosophy behind this is that these drugs can help lower the risk of heart disease, hypertension, diabetes, obstructive sleep apnea, fatty liver disease, and other weight-related health conditions in patients who are obese.

These drugs have become so popular for weight loss simply because they work. In the largest controlled trial of obese adults without diabetes, patients who took 2.4 mg of Wegovy per week lost an average of 14.9% of their initial body weight over 68 weeks, which was approximately 33.7 pounds (2). In the recent SURMOUNT-2 trial, patients taking 15 mg per week of Mounjaro lost 15.7% of their body weight, or approximately 34.4 pounds, over 72 weeks (1).

GLP-1 agonists are not without risk. The most common side effect is nausea, which can be severe and lead to dehydration. There is also a risk of pancreatitis, gallstones, C-cell thyroid tumors, depression, and suicidality, and they should not be used on anyone with a family history of medullary thyroid cancer. People taking these drugs must also be cautious about their bone density and muscle mass. Protein intake and resistance training can minimize muscle loss, but patients should be tracked with body composition analysis metrics along the way.

Dose titration, image from Wegovy

It’s also important to point out who should NOT take these drugs. There is absolutely zero data on how GLP-1 agonists affect patients with normal BMIs who do not have diabetes. In other words, if your BMI is below 27, you are flying blind with respect to side effects and long-term risks. Short-term weight loss is also not an indication for these drugs. Since the dose must be titrated up over 16-20 weeks, you won’t see immediate weight loss. Also, the weight will come back once you stop the drug (3), so the weight reduction benefits will not persist after the drug is discontinued without diet and lifestyle changes.

Finally, although these drugs have been studied in adolescents with obesity, there has never been a study that has lasted longer than two years. If patients are expected to be on these drugs for the rest of their lives, we’ll need longer studies than that. There is also no data on the effect that GLP-1 agonists may have on the developing body, such as on bone density and hormonal development. It’s still too early to say.

So that’s the skinny on GLP-1 agonists. I think there will be a lot more to come on these drugs in the future. Stay tuned!

In good health,

Gina

(1)   A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1) ClinicalTrials.gov ID: NCT04184622

SURMOUNT-2 Trial: ClinicalTrials.gov ID: NCT04657003

(2)   Wilding et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Eng J Med 2021; 384:989-1002. DOI: 10.1056/JEJMoa2032183

(3)   Wilding et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obesity and Metabolism 2022; 24(8): 1553-1564