Long-Acting GLP-1 Receptor Agonists vs. Short-Acting

Which GLP-1 is the most effective in getting patients to their goal? 

Are long-acting GLP-1 receptor agonists more beneficial than short-acting GLP-1 receptor agonists in the management of diabetes?  

Glucagon-like peptide-1 receptor agonists are now included in most guidelines for the treatment of type 2 diabetes. Even with GLP-1 receptor agonists‘ inclusion in most policies, only a few percent of patients with diabetes receive GLP-1 receptor agonists therapy. The reasoning behind the lack of usage of the medication is not understood, but may include factors such as pricing, the need for injections, and side effects. Clinical data have revealed that GLP-1 receptor agonist therapy improves glycemic control while reducing body weight and systolic blood pressure in patients with type 2 diabetes. GLP-1 has multiple physiological effects that make it an attractive candidate for type 2 diabetes therapy. It also increases insulin secretion while inhibiting glucagon release when glucose levels are elevated. This allows a GLP-1 receptor agonist to lower plasma glucose while reducing the likelihood of hypoglycemia.  

GLP-1 receptor agonists are available in different forms with remarkably varied characteristics. Short-acting GLP-1 receptor agonists consist of exenatide and lixisenatide, which have a duration of action of only a few hours after being subcutaneously injected. Long-acting agonists include liraglutide, exenatide, albiglutide, dulaglutide, and semaglutide. Each of these drugs is injected once weekly, except for liraglutide, which is injected once daily.  

The long-acting agonists can maintain an appropriate agonist level in plasma throughout the 24 hours of the day. Bullet inhibition of gastric emptying is one of the most noticeable actions of native GLP-1; the long-acting GLP-1 receptor agonists inhibit gastric emptying to some extent, which is another example of how this form of the GLP-1 receptor agonist is beneficial.  

Research from an analysis of 14 clinical trials supports these claims of long-acting GLP-1 receptor agonists being more beneficial than short-acting GLP-1 receptor agonists in the management of diabetes. Of the 14 clinical trials, eight trials reported short-acting GLP-1 receptor agonists, and six trials reported long-acting GLP-1 receptor agonists. Each study was required to report on baseline and endpoints for participants for a minimum duration of 6 weeks. The analysis results show that long-acting GLP-1 receptor agonist is beneficial in reducing HbA1c, fasting plasma glucose, BMI, and has fewer side effects such as nausea and vomiting compared to short-acting GLP-1 receptor agonist. Not only were participants able to reduce their HbA1c, but results also indicated long-acting GLP-1 receptor agonists’ use resulted in a more significant proportion of patients achieving a target HbA1c of less than 7%. The clinical trial results suggest that long-acting glucagon-like peptide one receptor agonists are more beneficial when combined with basal insulin, but short-acting GLP-1 receptor agonists were also helpful when combined with basal insulin. Concerning safety, there were fewer occurrences of hypoglycemia with long-acting GLP-1 receptor agonists. However, there were very few reports in each group. There were also more occasional reports of nausea and vomiting with the long-acting form. Nevertheless, long-acting GLP-1 receptor agonists were more effective with more advantages than short-acting GLP-1 receptor agonists.  

Practice Pearls: 

• Clinical trials suggest long-acting glucagon-like peptide one receptor agonists were more effective for managing diabetes than short-acting GLP-1 RAs among patients with type 2 diabetes on background basal insulin. 
• Investigators noted that the meta-analysis results indicated both short- and long-acting GLP-1 RAs improved HbA1c, fasting plasma glucose, and body weight when added to basal insulin regimens. 
• Long-acting GLP-1 RAs should preferentially be combined with basal insulin as they also have advantages regarding gastrointestinal adverse events. 

Davies MJ, D‘Alessio DA, Fradkin J, et al.  A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).  

American Diabetes Association. Standards of medical care in diabetes—2009. Diabetes Care 2009;32(Suppl. 1): S13–S61pmid:19118286.  

Destiny Funchess, PharmD Candidate, Tougaloo College, South College School of Pharmacy