GLP-1 RAs, though generally safe, do have some risks.

Although GLP-1s were first introduced more than 19 years ago, there is still limited information available regarding their long-term safety.¹ Research into the safety of GLP-1 receptor agonists is ongoing.² Though generally considered safe, like all medications, GLP-1 RAs are not completely risk free.

The Efficacy of GLP-1 Receptor Agonists

GLP-1 receptor agonists effects on cardiovascular risk reduction have been replicated across several studies. Several cardiovascular outcome trials invested the safety of GLP-1 RAs in samples of patients with type 2 diabetes.^1,2 Across trials, nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular death with long-acting GLP-1 RAs (e.g. exenatide, albiglutide, duaglutide) was reduced.

Once weekly 2.4 mg of semaglutide was assessed in 17,604 adults with a BMI ≥27 kg/m²  and a history of atherosclerotic cardiovascular disease without a known type 2 diabetes diagnosis. Semaglutide resulted in a 20 percent reduction in nonfatal MI, nonfatal stroke, and cardiovascular death. This was driven primarily by a reduction in MI. ^1,3

The SURMOUNT^1,4 trial investigated tirzepatide in adults with a BMI ≥ 27 kg/m² and one or more complications or obesity BMI ≥ 30 kg/m². Participants were dosed at 5 – 15 mg once weekly. Substantial placebo-subtracted weight loss (20 percent) was observed in participants with obesity without diabetes. Sixty percent of participants taking the 15 mg weekly dose achieved weight loss of ≥20 percent.

In a meta-analysis of 21 studies and almost 3,400 participants with random assignment to a GLP-1 compared with 3,016 participants in control groups, all trials resulted in weight ranging from -0.2 to -7.2 kg for the GLP-1 RA groups.^5,6

The Safety of GLP-1 Receptor Agonists

• Gastrointestinal effects. Common adverse effects have been reported in patients using a GLP-1 RA, the most frequent of which is gastrointestinal related. GI effects include diarrhea, nausea, and vomiting. ² During clinical trials, > 5 percent of participants discontinue the GLP-1, though in clinical practice the discontinuation rate is reported to be 5 – 10 percent.
• Cardiovascular safety. Regarding cardiovascular safety, research has shown that GLP-1s have a positive effect on cardiovascular health. A meta-analysis of 33 trials did not find any increase in major CV events, including MI, stroke, and all-cause mortality.⁷
• Acute pancreatitis. Acute pancreatitis has been reported in patients in clinical trials; retrospective observational studies found almost no increase in pancreatitis cases when incretin-based therapy was used.⁸ Although histologies taken from the organs of type 2 diabetes patients on incretin did have some pancreatic abnormalities, not enough information is available to determine if there may be cofounding. The researchers caution it’s too early to know if there is any link.
• GLP-1 and medullary thyroid cancer. A 2023 study⁹ nested case-control analysis that included adults with type 2 diabetes, found that GLP-1 RA use for 1 – 3 years was correlated with an increased risk in thyroid cancer adjusted hazard ratio ([HR] 1.58, 95% CI 1.27-1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04-3.05). Case subjects were matched with control subjects based on age, sex, and duration of diabetes. Risk sampling procedure was used.

Implications for Clinical Practice

As noted above, GLP-1 RAs are effective at managing type 2 diabetes and facilitating weight loss, though they are not without risks. Because GLP-1 RAs are still relatively new, more long-term data regarding their safety is needed. When prescribing GLP-1 RAs, health care professionals should monitor their patients for side effects and work with their patients to build a sustainable weight loss and weight management plan to minimize the use long-term use of GLP-1 RAs.

Health care providers should consider working collaboratively with patients to implement sustainable lifestyle changes can help them achieve long-term, sustainable weight loss. Part of this treatment program could include Low Calorie (LCD) or Very Low Calorie Diets (VLCD) supported with scientifically formulated meal replacements to ensure nutritional needs are being met.

Source(s):
1 Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity
2 Drugs in context
3 Semaglutide and cardiovascular outcomes in obesity without diabetes
4 Tirzepatide once weekly for the treatment of obesity
5 Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomized trial
6 Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomized trial
7 Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials
8 Beyond metformin: Safety consideration in the decision making process for selecting a second medication for type 2 diabetes management. Reflections from a diabetes care editors’ expert forum
9 GLP-1 receptor agonists and the risk of thyroid cancer

About the Author: Dr. Dawn M. Sweet has over 20 years of experience in the field of communication. Dr. Sweet has given several invited talks to and workshops for academic and private sector audiences on the role of nonverbal and verbal communication in achieving positive outcomes and mitigating bias. Her research has been published in several top ranked peer-review journals, and it has been featured on NPR’s River to River / All Things Considered, Buzzfeed, and Science Daily. Her research has also been used to inform expert testimony.

About Robard: Robard Corporation’s medical obesity treatment programs and scientifically-designed nutrition products have been utilized by physicians, surgeons and hospitals across the United States to successfully treat patients living with obesity. To learn more about us and how we can help your practice and patients, visit us online at www.Robard.com, email us at info@robard.com, or call (800) 222-9201.