In type 2 diabetes, the effectiveness and side effects of GLP-1 RAs vary

A recent systematic review of the beneficial and harmful effects of 15 glucagon-like peptide-1 receptor agonists (GLP-1 RAs) should be helpful to clinicians and suggests which drugs are likely to dominate the market in the next few years, an ACP Journal Club commentary said.

A review of available glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for type 2 diabetes (T2DM) found that all lowered HbA1c and fasting plasma glucose levels but that tirzepatide had the greatest effect on both outcomes. Semaglutide with cagrilintide resulted in the greatest weight loss, followed by tirzepatide. Several of the drugs were significantly more likely to be discontinued due to adverse events than placebo, including lixisenatide, semaglutide, exenatide, tirzepatide, and liraglutide.

The study was published by The BMJ on Jan 29 and summarized in the February ACP Diabetes Monthly. The following commentary by Clare O'Brien, MB, and Sean F. Dinneen, MD, was published in the ACP Journal Club section of Annals of Internal Medicine on May 7.

The incretin effect, whereby ingested glucose leads to a greater insulin secretory response than isoglycemic administration of IV glucose, was first recognized 60 years ago. Gut peptides were identified as the most likely mediators of this effect. In the past 20 years, studies have shown that several gut peptides and their analogues not only help lower glucose in patients with T2DM but also have beneficial effects on appetite and satiety, leading to weight reduction. This has resulted in a plethora of new drugs being marketed for management of T2DM. Major advantages of these drugs (vs. insulin) include glucose-sensitive insulin secretion leading to glucose lowering without increased risk for hypoglycemia, once-weekly administration for many agents, and weight loss (vs. weight gain with insulin). It has become difficult for clinicians to keep up with the many new agents and vast literature in this area.

The systematic review and network meta-analysis by Yao and colleagues provide a detailed summary of the beneficial and harmful effects of the 15 GLP-1 RAs available globally as of August 2023. The ranking of agents based on their relative glucose-lowering effects, effects on weight, and association with (mainly gastrointestinal) side effects is helpful to clinicians and suggests which drugs are likely to dominate the market in the next few years. The willingness of patients to tolerate unpleasant side effects for degrees of weight loss not previously seen with pharmacotherapy is evident from the relative ranking of cagrilintide–semaglutide (marketed as CagriSema [NovoNordisk]) for efficacy and toxicity. CagriSema was ranked at the top for weight loss (with a mean reduction of 14 kg vs. placebo) and in the top 3 for glucose-lowering effect. Despite also ranking in the top 3 for causing diarrhea, nausea, and vomiting, the drug was the least likely to be discontinued by patients, outperforming semaglutide and tirzepatide.

The meta-analysis did not rank agents' effects on major adverse cardiovascular events, but trials with these end points take longer to report and should be underway based on requirements of the U.S. Food and Drug Administration. Cost and cost-effectiveness are also missing from the review and are important determinants of whether a drug gets to market in some health economies. Nevertheless, the increase in choice of incretin-related compounds augurs well for patients with T2DM and may see an offsetting of the current global shortage of drugs like semaglutide as persons with obesity compete for a limited supply of drugs.