Retatrutide

The increasing worldwide prevalence of obesity has greatly affected care for people with type 2 diabetes. More precisely, >90% of people with diabetes have some degree of overweight or obesity (1). In addition to increased risk of cardiovascular and renal disease, obesity contributes to worsening of hyperglycemia and progression of prediabetes to type 2 diabetes.

The development of pharmacotherapy for the treatment of obesity has increased significantly in the past decade, especially with regard to incretin mimetics. This drug class has several advantages that make them highly desirable pharmacotherapy options for the treatment of obesity and diabetes, including high efficacy for weight loss, low risk of hypoglycemia, and reduction of cardiorenal disease risks. Until recently, drugs in this class focused on agonism of receptors for the single peptide hormone glucagon-like peptide 1 (GLP-1). The more recently developed drug tirzepatide combined GLP-1 receptor agonism with agonism of receptors for the other major incretin hormone—glucose-dependent insulinotropic polypeptide (GIP). Thus, tirzepatide has been dubbed a “dual agonist” and has been shown to produce greater weight loss and improvements in glycemic control than agonists of GLP-1 receptors alone. Success with this dual agonist led to the current development of “triple agonists,” which add agonism of glucagon (GCG) receptors. Retatrutide (LY3437943) is being investigated as a triple agonist of GLP-1, GIP, and GCG for treatment of type 2 diabetes and obesity. Another triple agonist was developed previously but was withdrawn, and yet another is in development for metabolic dysfunction–associated steatohepatitis (MASH) (2,3).

Several ongoing clinical trials (the TRIUMPH and TRANSCEND-T2D trials) are assessing the effect of retatrutide on weight loss and glycemic control in relation to varying outcomes. Although this drug has not yet gained U.S. Food and Drug Administration approval, it is expected to reach the market as early as 2026. Phase 1 and 2 trials published to date have demonstrated its superior effects for both weight loss and glycemic control (4–6).

Indications

Initial indications are expected to include the treatment of type 2 diabetes and the treatment of obesity. Similar to other medications in this class, however, approved indications secondary to the treatment of diabetes may eventually include primary or secondary risk reduction of atherosclerotic cardiovascular disease and reduction of complications from diabetic kidney disease. The other triple agonist that is currently in development for the treatment of MASH may also be studied with retatrutide eventually (3).

Mechanism of Action

Retatrutide has a unique mechanism of action in the increasingly popular class of incretin mimetics. As a novel triple agonist, it harnesses the action of the three peptide hormones GLP-1, GIP, and GCG. Like other incretin mimetics, it is structurally similar to GIP, with alterations in the peptide backbone to increase agonist activity at the GIP, GLP-1, and GCG receptors (6). Agonism of GLP-1 and GIP receptors has been shown to provide multifaceted actions leading to increased insulin secretion, increased glucose uptake, increased satiety, and decreased rate of gastric emptying. In addition to GLP-1 and GIP receptor agonism, agonism of GCG receptors increases energy expenditure and lipolysis, decreases lipogenesis, and increases insulin secretion (6–8). The addition of GCG receptor agonism augments weight loss primarily through increased energy expenditure, while the hyperglycemic effects of glucagon are balanced by agonism of GLP-1 and GIP receptors.

Potential Advantages

Thus far, retatrutide has made an impressive debut as a pharmacological option for the treatment of obesity and type 2 diabetes. In one trial involving people with obesity but without diabetes, retatrutide yielded weight loss as much as 24.2% compared with baseline at 48 weeks with similar safety profiles to other incretin mimetics. This degree of weight loss is similar to that achieved with some bariatric surgery procedures and one of the highest weight loss percentages of any pharmacological therapy (4). Another trial demonstrated that retatrutide improved glycemic control more than dulaglutide, with A1C reductions as great as 2.16% with retatrutide versus 1.36% with dulaglutide at 36 weeks (5). Retatrutide has the potential to become the most efficacious pharmacotherapy option for the treatment of obesity with comorbid type 2 diabetes.

Potential Disadvantages

Clinical trials thus far have reported adverse effects similar to those of other incretin mimetics, with the most common being gastrointestinal in nature and dose related (4,5). Two other disadvantages that may affect retatrutide are its potential cost and availability. As with other incretin mimetics, retatrutide, once approved, may be expensive and difficult to keep in stock at pharmacies because of high market demand.

Cost

Similar to other medications in this class, retatrutide is expected to have an average wholesale pricing ranging from $1,200 to $1,600 per month.

Commentary

Although not yet available on the market, retatrutide is thus far a promising new pharmacological option for the treatment of obesity and diabetes and may provide some of the greatest weight loss potential of all pharmacological agents available. More data are needed to effectively compare retatrutide to other incretin mimetics, especially tirzepatide, which is the most closely comparable incretin mimetic on the market. Trials to date have compared retatrutide only to dulaglutide and placebo but not to other incretin mimetics.

The novel action of retatrutide may provide a unique mechanism for weight loss, with its GCG receptor agonism leading to increased energy expenditure. Data from the TRANSCEND-T2D and TRIUMPH trials will reveal more about retatrutide and its place in the treatment of type 2 diabetes and obesity. Although retatrutide has opened the door to future medications that could take advantage of triple agonism, much remains to be learned about the long-term effects of agents in this drug class.

Bottom Line

Overall, retatrutide may serve as a viable option for the treatment of obesity and type 2 diabetes, similar to other incretin mimetics. Its eventual placement within the American Diabetes Association’s recommendations for the pharmacological management of type 2 diabetes (9) will be important, as it may be a good first-line treatment option for people with comorbid obesity and type 2 diabetes. Affordability and accessibility of retatrutide will likely play a factor in how helpful this medication proves to be for weight loss and glycemic control.