Review of GLP-1 side effects

April 30, 2024

GLP-1 drugs are very effective at treating obesity and are only approved for people with BMIs of over 30 (or 27 with metabolic diseases such as diabetes or hypertension) in conjunction with calorie restriction and increased exercise. The FDA requires that GLP-1s prescribed for weight loss are used in conjunction with calorie restriction and increased exercise, but does not require prescription of a ‘behavioral modification program.’ 

This class of drugs has been used since 2005 for diabetes, so a large new category of adverse events is less likely to become evident. Here is a brief review of the side effects and concerns for this set of medications.

Well established adverse effects:

• Gastrointestinal side effects. Most patients start at a low dose of semaglutide or tirzepatide, which is gradually increased over 3-5 months. They will often initially have nausea and constipation; these symptoms tend to get better over time.

• Lean body mass weight (sarcopenia). Those who lose a substantial amount of weight generally lose a lot of lean muscle mass, too. This could be altered somewhat by regular weight bearing exercise. People have also reported “Ozempic face” where wrinkles and lines appear with weight loss. Again, this is similar to what to expect with large amounts of weight loss.

• Gallbladder attacks. Substantial weight loss is associated with gallbladder attacks, where the gallbladder goes into spasm or a gallstone gets stuck in the bile duct. Gallbladder attacks are often painful and can require surgical intervention. This is also a well-known complication of bariatric surgery.

• Slow transit of food through the stomach. This is part of how these drugs work to decrease appetite; an empty stomach leads to release of gut hormones that influence hunger in the brain. Sometimes this is severe enough that the stomach is paralyzed, and in rare cases people need to have a nasogastric tube to drain the stomach and must stop the GLP-1 medication. This large study in JAMA last week showed no higher rate of complication from emergency surgery in those on GLP-1 medications.

Uncommon or less common potential adverse effects

• Thyroid cancer. Early mice studies suggested that thyroid cancers may be higher with the use of GLP-1s. As a result, the drugs have a boxed warning about the risk of these cancers. Since then, human studies have been mixed. A French study found a 1.8 times higher rate of medullary thyroid cancers and a 1.6 times higher rate of all thyroid cancers. A large Scandinavian cohort study did not find any increased risk of thyroid cancers in GLP-1 users. Medullary thyroid cancers are quite rare, so even a statistically significant increase in the rate of such cancers will mean relatively few such cancers.

• Increased fertility. There are reports of unexpected pregnancies in those on GLP-1 drugs. These drugs delay absorption of oral contraceptives, and losing weight increases fertility. Some physicians are prescribing these drugs off-label to treat polycystic ovary syndrome (PCOS), which is often associated with obesity, high blood pressure, and infertility. These drugs are not recommended during pregnancy, so women considering pregnancy should use effective contraception while taking them. GLP-1 drugs are not likely to impact effectiveness of long-acting contraception such as IUDs or progesterone implants.

Side effects that are reported but not likely to be related to GLP-1 medications

• Suicidality. An FDA report in 2023 suggested there might be an association between GLP-1 medications and suicidality, and Iceland recently reported three cases of suicidal ideation to the European Medicines Agency. However, a huge observational study (with 53,000 patients on Wegovy and 53,000 patients on non-GLP-1 anti-obesity medications showed only a quarter as much suicidal ideation in those on GLP-1 medications. There were 14 suicide attempts in the non-GLP-1 group, and none in the Wegovy group. In January, the FDA said that its preliminary evaluation did not suggest a causal link between these drugs and suicidality.

Implications for employers:

• GLP-1s have a host of known side effects (GI upset) and more serious gastrointestinal issues or concerns for cancer and altered fertility. Despite those risks, GLP-1s have a long safety record for the last 20+ years. Safety concerns, by themselves, should not stop an employer from covering these medications.

• Adherence to this class of drugs is important to avoid weight regain; benefit designs and formular decisions should minimize member disruption that can adversely affect adherence.

• There are some patients who cannot or do not want to take GLP-1s. Employers should review their pharmacy benefits to be sure they are also covering alternatives to this class of drug.

• Members should be fully aware of all the potential side effects of these medications, but these side effects are not likely to dissuade people who seek to lose weight and have unsuccessfully tried many other interventions.

Sources:

• Science Vs.  Transcript

• UptoDate  (electronic textbook)

• Harvard Health

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