Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are considered by many to be the most significant advancement in diabetes treatment since the discovery of insulin in 1921. The scientific journey leading to this point began in the early 1900s with the identification of gut hormones. In the 1960s, the "incretin effect" was described, demonstrating that an oral glucose challenge produces a greater insulin response than an intravenous glucose challenge. In 1996 a compound called exendin-4 was isolated from the venom of the Gila monster, a discovery that ultimately led to the development of exenatide by Amylin Pharmaceuticals and the FDA approval of Byetta (exenatide) in 2005. Twenty years later here we are with single agonists (GLP-1), a dual agonist (GLP-1/GIP), and soon a triple agonist (GLP-1/GIP/glucagon). The original and subsequent follow up studies related to approval and marketing continue to give us more information on the use of these medications. New information on their benefits appears regularly and treatment recommendations will continue to change as ongoing study results become available.

Benefits in diabetes

The incretin therapies have unique mechanisms of action related to common defects in type 2 diabetes and have beneficial effects on common comorbidities.

• Enhances glucose-dependent insulin secretion, resulting in superior A1c reduction with a low risk of hypoglycemia when used alone.
• Suppresses glucagon and reduces hepatic glucose output.
• Slows gastric emptying.
• Activates central satiety pathways to suppress appetite and promote weight loss.
• Reduces risk and progression of atherosclerotic cardiovascular disease (ASCVD).
• Slows progression of chronic kidney disease (CKD).

Benefits in overweight and obesity with or without diabetes

The two most effective agents, semaglutide and tirzepatide are approved for obesity in people without diabetes. Studies are showing positive effects on other obesity related conditions, some of which are listed here.

• Heart failure with preserved ejection fraction (HFpEF).
• MASH (metabolic dysfunction associated steatohepatitis) and MASLD (metabolic dysfunction associated steatotic liver disease)
• Obstructive sleep apnea
• Osteoarthritis pain (due to joint stress and inflammation).
• Diabetes prevention: reduced progression from prediabetes to diabetes

Opportunities for pharmacists and staff members to promote successful outcomes with GLP-1 and GLP-1/GIP therapies

Because of the prevalence of diabetes, overweight and obesity, atherosclerotic cardiovascular disease, and chronic kidney disease it is estimated that 50% of the adult population in the United States is eligible for GLP-1 type therapy.  Ideally these medications are used on a long-term basis, but the discontinuation rate is high (up to 50% after 1 year). The demand will increase exponentially, and we need to be prepared to help navigate coverage issues, formulary changes, and drug shortages.

Pharmacists can help prepare the patient for success by counselling at therapy initiation in areas such avoiding the common GI side effects, referring to a dietitian for nutrition planning, and following titration recommendations. Pharmacists can examine the patient’s current diabetes medications when starting incretin therapy and make recommendations for a dose reduction if insulin or a secretagogue is in use to avoid hypoglycemia. We can dispel myths by being familiar with evidence-based guidelines and answer questions about discontinuing or interrupting therapy.