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My Approach to GLP-1s: Great Power, Great Responsibility

Op-Med is a collection of original articles contributed by Doximity members.

Modern medicine has been taken by storm with the latest breakthrough of “wonder drugs,” which are a class of medications that have changed the management of obesity not only from a practical standpoint, but also from a philosophical one. Up until these options became FDA approved and available to us, doctors essentially had two options for treating their obese patients: telling them patients to “work on lifestyle changes” or sending them for an invasive bariatric surgery, neither of which was desirable, cost effective, or readily practical for the more than 40% of Americans who are classified as obese.

These medications were initially studied as diabetic drugs, but it became apparent in the clinical trials that their mechanisms and benefits extended far beyond diabetes and included brisk weight loss, and, more recently, fewer heart attacks, strokes, and cardiovascular death in non-diabetic obese patients, as well as better functional capacity in heart failure and improved kidney outcomes. With these drugs, it became clear that obesity was no longer considered a personal failing or drawback but instead was a disease like any other – the first “domino,” in fact, in a series of diseases, including heart failure, kidney disease, hypertension, diabetes, metabolic syndrome, cancer, and even dementia, among others. And, if this domino could be prevented from falling or be uprighted, all the other downstream dominos would also stand straight.

Today, this class of medications, which can result in rapid weight loss within weeks to months (approximating the magnitude of weight loss which was previously only achievable with bariatric surgery), has provided an extremely appealing option for physicians of all specialties and obese patients alike. For perspective, the GLP-1s (semaglutide, liraglutide) can result in a ~15% of the body’s weight loss, and their newer iteration, the “dual agonist” GLP1RA and GIP receptor agonist (tirzepatide), can result in a weight loss of ~20% body weight. Currently under study and looming on the horizon is the even newer “triple agonist” GLP1RA, GIP, and glucagon agonist retatrutide, which results in a whopping ~25% body weight loss.

But … to quote Uncle Ben from Spider-Man, “With great power comes great responsibility” and with these drugs now being launched on a population level, we must take the responsibility for this class of drug just as seriously as the power that they hold. With an increasing number of indications and patients using these medications, signals for smaller adverse effects are now becoming more amplified. There are a number of adverse effects that need to be carefully assessed, monitored, and reviewed by the FDA in the post-marketing surveillance database.

Before initiation, screening for medullary thyroid cancer or familial history of multiple endocrine neoplasia is important. Although the majority of studies to suggest a signal for thyroid cancer has been detected in rodents (whose thyroid is biologically distinct from humans), there have been some observational studies in humans with medullary thyroid cancer. It is not clear that this class of medications is causal for this type of cancer; nonetheless, the FDA currently includes a warning on the drug that it has been linked to medullary thyroid cancer and should not be used in such patients.

In addition, it is becoming increasingly clear that clinic screening for gastric motility disorders and pancreatic inflammation before and during therapy is necessary. The mechanism of action of the drug is through delayed gastric emptying, therefore the higher risk of functional intestinal obstruction or gastroparesis as well as pancreatitis (pancreatic inflammation), as compared to prior obesity drugs, also naturally follows. In fact, for every 1,000 users of drugs with semaglutide, nearly five developed pancreatitis. For liraglutide, out of every 1,000, there were about eight cases. For gastroparesis, researchers found roughly nine cases among every 1,000 users of semaglutide and about seven in liraglutide patients. Checking liver function tests and pancreatic enzymes during dose titration, although not mandated by the FDA, is probably done commonly in clinical practice. In addition, nausea, vomiting, diarrhea, flatulence, and a feeling of fullness are common expected side effects due to slower gastric emptying, which, if significant, may mandate slower dose uptitration. However, they can easily mask the effects of significant motility disorders, so if they do not improve or resolve with lower doses, gastric emptying studies may be indicated.

In addition, both the FDA and the European Medicine Agency are investigating concerns for suicide and self-harm. Clinical trials in adults found that nine people on liraglutide, of more than 3,300, reported suicidal ideation, compared with two of more than 1,900 on a placebo. Suicidal thoughts are not listed as a side effect in the E.U. product information for either semaglutide or liraglutide. In the U.S., however, prescribing instructions for semaglutide for weight loss recommend that patients are monitored for suicidal thoughts or behavior. The FDA has received 265 reports of suicidal thoughts or behavior in patients taking these or similar medicines since 2010. The possible pathophysiologic mechanism of this association remains unclear; however, it is becoming increasingly clear that these drugs can blunt the “reward circuit” in the brain through modulation of dopamine. This may, in part, be the explanation for the off-target effects of these medications on addictive behaviors, including food addiction (a possible mechanism for obesity), as well as studies showing favorable effects on nicotine, alcohol, and other addictions. However, it may also explain a possible association with suicidal thoughts. So, assessing mood and suicidal ideation before and throughout the duration of therapy has also emerged as an important safety metric for anyone on therapy.

Given the rapid weight loss within a matter of weeks, there can be a substantial impact on a patient’s appearance, including loss of volume in the face and an older/more wrinkled facial and body appearance, which many TikTok trends have identified as “Ozempic face” – something we should be warning our patients about before initiation. These “wonder drugs” also have to be continued even after the weight loss has occurred as discontinuation may result in re-gaining of the weight.

How they will, with their hefty price tag, impact the cost of health care is a whole other discussion which will also determine access and clinical use.

These drugs have changed the landscape of obesity management in a way that is unprecedented. However, safe use as the indications and benefits expand will require clinicians and the FDA to be vigilant for established and emerging side effects.

What side effects are you on the lookout for with GLP-1s?

Payal Kohli, MD is a cardiologist and was a 2018–2019 Doximity Author.

Image by Alphavector / Shutterstock

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