Unexpected Benefits, Unexpected Limits: The Changing Landscape of GLP-1 Research

Glucagon-like peptide-1 receptor agonists (GLP-1s, also known as incretin mimetics and GLP-1 analogs) have gained significant attention as patients use them for glucose control in type 2 diabetes (T2D) and weight management. It is known that these medications have activity in metabolism, inflammation, and some brain pathways, but many patients have reported surprising developments and adverse effects.¹ This has prompted researchers to examine them in conditions other than T2D, with some encouraging if not downright welcome results.

Another Drink? No, Thank You

As Americans began using GLP-1s for off-label weight loss, clinicians reported anecdotal evidence that patients had less interest in drinking alcohol. A leading modifiable cause of morbidity and mortality, alcohol contributes to 2.6 million deaths globally and 178,000 US deaths every year.^2-4 It also increases risks of cardiovascular disease, liver disease, and cancers.^2-4 Researchers interested in addressing this issue designed studies to investigate further.

One placebo-controlled study included 48 women with alcohol use disorder and serious difficulty controlling alcohol consumption.⁵ The researchers randomly assigned half the participants to low doses of injectable semaglutide (Wegovy; Novo Nordisk) and half to an injectable placebo. Participants were placed in a laboratory room where they could self-administer their preferred alcoholic beverages for 2 hours before they started the medications and one time after. Participants also reported how much they drank daily for 9 weeks.⁵

All participants consumed alcohol at about the same frequency, but at 8 weeks, people in the semaglutide arm drank approximately 30% less on the days they consumed alcohol compared with an average reduction of approximately 2% in the placebo arm. Participants in the semaglutide arm reported fewer days of heavy drinking and fewer alcohol cravings than those taking the placebo.⁵

A larger study used the US Department of Veterans Affairs (VA) databases and identified individuals with diabetes who initiated GLP-1s (n = 215,970), comparing them to 3 groups who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 inhibitors (n = 117,989), sodium-glucose cotransporter-2 inhibitors (n = 258,614), or a control group (n = 1.2 million).

Compared with usual care, patients taking GLP-1s were less likely to have substance use or psychotic disorders. However, they were more likely to experience arthritic disorders, drug-induced pancreatitis, gastrointestinal disorders, hypotension, interstitial nephritis, nephrolithiasis, and syncope.⁶ Most of these are well-known adverse effects related to GLP-1s.

Little Headway in Cognitive Disorders

The hope that GLP-1s could slow or alleviate cognitive disorders was based on 6 theories (mostly developed preclinically) listed in Table 1.^7,8 Data from the VA study also showed that individuals in the GLP-1 arm had fewer seizures and neurocognitive disorders (including Alzheimer disease and dementia). This has been an area of intense interest. Unfortunately, findings from large recent trials (N > 3800) showed no statistically significant reduction in disease progression among people with early Alzheimer disease treated with semaglutide.^9,10

Research into Parkinson disease (PD) is also underway. A study that randomly assigned 194 participants with PD to exenatide (Byetta; Amylin Pharmaceuticals, Inc) or placebo found no evidence that exenatide is disease-modifying.¹¹ A phase 2 study employing lixisenatide in patients with PD, however, found that it slowed motor disability progression compared with placebo at 12 months in patients with early-stage PD. Gastrointestinal adverse effects were common and concerning.^12,13 This underscores the possibility that different GLP-1s may exhibit distinct behaviors in various diseases.

Turning the Tide on PCOS

Finally, a meta-analysis of the use of GLP-1s in polycystic ovarian syndrome (PCOS) looked at data from placebo-controlled studies to determine whether they impact weight reduction and hormonal regulation in women with this condition.¹⁴ The answer was a definitive yes. Among 176 participants, GLP-1 use was linked to a significant reduction in waist circumference, body mass index, serum triglycerides, and total testosterone levels.¹⁴ A larger meta-analysis that included 1476 women had similar findings.¹⁵

Conclusion

Few drug classes influence this many biologic systems through a single receptor family. It is clear that GLP-1s are pleiotropic, as Table 2¹⁶ indicates. Several studies are currently underway, with some yielding promising results and others showing mixed or negative findings. We can look forward to accumulating data to find or eliminate new uses for the agents. In the meantime, everyone involved should remember that off-label use should be guided by a clinician only after careful risk-benefit assessment.

About the Author

Jeannette Y. Wick, RPh, MBA, FASCP, is director of the Office of Pharmacy Professional Development at the University of Connecticut School of Pharmacy in Storrs.

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