Triple Agonist Therapy: A New Frontier in Treating Type 2 Diabetes and Obesity

Type 2 diabetes, obesity, cardiovascular disease, and liver disease are significant global health challenges with common pathological risk factors related to insulin sensitivity, glucose, and lipid homeostasis. Incretin receptor agonists are novel therapeutic options for these diseases. Glucagon-like peptide 1 (GLP-1) receptor agonists enhance glycemic control and weight loss, and some reduce major adverse cardiovascular events (MACE) and provide kidney protection (1). The first dual-acting incretin receptor agonist, tirzepatide, activates both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, showing greater impacts on glucose and weight control compared with GLP-1 receptor agonists alone (2). New research is investigating the benefits of triple agonist therapy.

Indications

No triagonist is currently approved for use, although several are under investigation for glycemic control in type 2 diabetes, weight loss in obesity, and treatment of metabolic dysfunction–associated steatohepatitis (MASH). A retatrutide cardiovascular outcomes trial, needed to attain U.S. Food and Drug Administration (FDA) approval for the treatment of type 2 diabetes, is currently underway (3).

Mechanism of Action

Triagonism involves the simultaneous activation of GLP-1, GIP, and glucagon (GCG) receptors. GLP-1 receptor agonism lowers blood glucose by enhancing insulin secretion, inhibiting glucagon release, slowing gut motility, and suppressing appetite. GIP receptor activation further stimulates insulin secretion and augments weight loss by promoting satiety and enhancing thermogenesis. Unlike GLP-1 receptor agonism, GIP receptor activation stimulates glucagon secretion. GCG receptor agonism promotes hepatic glucose production but contributes to weight loss by facilitating lipid catabolism and augmenting energy expenditure.

The ideal receptor activity ratio is crucial for optimized therapeutic outcomes (4–6). Proportionally adequate GCG receptor agonism is advantageous to augment weight loss; however, excessive GCG receptor agonism could produce undesired hyperglycemia. Dual GLP-1/GIP receptor agonism appears required to combat the risk of hyperglycemia from unopposed GCG receptor agonism (7).

Potential Advantages

The triagonism approach offers several potential advantages over single- or dual-agonist therapies, including:

1. Glycemic control and weight loss. Activation of GLP-1, GIP, and GCG receptors promotes weight loss and glucose control, making triagonism effective for the treatment of both obesity and type 2 diabetes.

2. Cardiorenal-metabolic benefits. Improved glycemic control and weight loss may improve lipid profiles and reduce cardiovascular risk factors. Some GLP-1 receptor agonists have demonstrated reductions in MACE (1) or improved kidney outcomes (8), which triagonism may also support.

3. MASH treatment. Triagonists reduce hepatic fat and improve steatosis, which outpaces benefits observed with single- and dual-agonist agents, presumably from weight loss and possibly from hepatic GCG receptor activation (9).

Potential Disadvantages

Despite its promising benefits, triagonism may have some drawbacks, including:

1. Adverse effects. Gastrointestinal (GI) disturbances are common and occur at rates similar to those with other incretin agonists. However, the addition of GIP agonism may mitigate nausea, attributing to greater glucose and weight loss compared to single and dual agonists, with equivalent rates of nausea (5). As with single and dual agonists, nausea and vomiting with triagonists are most likely to present upon initiation or dose escalation, are typically mild to moderate in intensity, and are transient with continued use. For these reasons, slow dose titration is advised (4,10,11). Another concern with triagonism is the risk of tachycardia because agonism at each receptor increases the heart rate. Thus, a potential concern looms for negative impacts on cardiovascular hemodynamics (7).

2. Subcutaneous administration. Oral administration produces inadequate bioavailability because of degradation by GI enzymes. Thus, as with other incretin receptor agonists, triagonists are administered via subcutaneous injection, which could limit adherence in some patients. However, the frequency of subcutaneous administration ranges from once daily to once weekly based on the half-life of the product (4,7,10).

3. Complexity and cost. Like single- and dual-incretin agonists, triagonists are polypeptides, which are manufactured through delicate processes to maintain product integrity. The production of triagonists is therefore more complex and costly compared to other medications used to treat diabetes or obesity, but may be comparable to production of single and dual agonists. Higher costs may limit accessibility for some patients.

Current Developments

Various combinations of single-, dual-, and triagonists are under development, with each evaluating impacts on obesity and type 2 diabetes and, in some cases, MASH. The most promising triagonist is retatrutide (Eli Lilly), a once-weekly subcutaneous injection. Preclinical studies resulted in greater weight loss and improved glucose control compared with the dual GLP-1/GIP receptor agonist tirzepatide, the GLP-1 receptor agonist dulaglutide, or placebo. The phase 3 program, TRIUMPH-3, is ongoing to evaluate the safety and efficacy of retatrutide in a variety of populations, including individuals with type 2 diabetes, obesity, obstructive sleep apnea, osteoarthritis, and cardiovascular disease (6,11).

Efocipegtrutide (Hanmi Pharmaceuticals) is earlier in the developmental process but has shown promising initial results. Phase 1 trials evaluating its safety and tolerability in individuals with obesity and MASH demonstrated reductions in hepatic fat and body weight with once-weekly injections compared with placebo. Phase 2b studies are underway in individuals with biopsy-confirmed MASH fibrosis. The FDA granted a fast-tracked designation for the treatment of MASH with efocipegtrutide (12).

Commentary

Triagonist therapy represents a significant advancement for the treatment of type 2 diabetes, obesity, and possibly MASH. Simultaneous activation of GLP-1, GIP, and GCG receptors offers a multifaceted approach potentially surpassing the benefits of single- or dual-agonist therapies. All triagonists must proportionally balance the agonist activity among the three receptors for optimal benefit. Retatrutide is the most promising triagonist in development to date.

The development of triagonists such as retatrutide and efocipegtrutide highlights the potential for enhanced glycemic control and substantial weight loss by activating multiple incretin receptors. Clinical trials have demonstrated that these agents can yield greater weight reduction and improved metabolic outcomes than existing therapies.

The journey toward widespread clinical use of triagonists remains challenged by GI side effects, potential tachycardia, high cost, and subcutaneous administration. Further research is needed to articulate the long-term benefits and safety profiles of triagonist agents, including their contraindications, drug interactions, and use in special populations such as pediatrics. Phase 3 studies will clarify these issues and guide the placement of these treatments within the growing class of pharmacotherapy for metabolic diseases.

Bottom Line

Triagonism represents a novel and promising approach for treating type 2 diabetes and obesity that is unmet by current therapeutic options. By simultaneously targeting GLP-1, GIP, and GCG receptors, triagonists facilitate glycemic control and provide weight management benefits beyond those observed with single and dual agonists.