Next-Generation GLP-1 Medications Explained: What’s Coming Next

GLP-1s are everywhere right now—from doctors’ offices to dinner-party conversations—but most of the attention has focused on just a few familiar names. Behind the scenes, however, a new generation of GLP-1 medications is moving through clinical trials, with oral options, combination therapies and strong early results.

Ahead, we’re breaking down the GLP-1 agonists being studied for weight-loss treatment that you’re likely to hear more about next, how they work in the body and what sets each one apart, drawing from a guide originally published by Pharmacy Times.

Orforglipron (Eli Lilly)

Orforglipron is a first-in-class, nonpeptide oral GLP-1 receptor agonist. It differs from injectable GLP-1 agents in its composition. Unlike peptide-based formulations made of amino acid chains, orforglipron is a small-molecule compound, allowing it to remain stable and effective in the acidic environment of the stomach. Orforglipron is taken orally once daily and there is no requirement for fasting.

In the ATTAIN-1 phase 3 trial (NCT05869903), adults with obesity who received orforglipron 36 mg once daily achieved a mean body weight reduction of 12.4% (approximately 27.3 lb) from baseline at 72 weeks, compared with 0.9% in the placebo group. These findings demonstrate clinically meaningful weight loss and confirm orforglipron’s potential as an effective oral alternative to injectable GLP-1 therapies.4

Unlike semaglutide, orforglipron is a small-molecule compound and can be easier to absorb through the stomach lining, allowing for less restriction with food timing. Direct head-to-head data versus oral semaglutide 50 mg is not yet available.

Cagrilintide-Semaglutide (CagriSema; Novo Nordisk)

CagriSema is a combination treatment that combines 2 injectable medications (cagrilintide and semaglutide) into 1. Cagrilintide is a newer long-acting amylin analogue. Amylin is co-secreted with insulin from the β-cells of the pancreas and plays a key role in postprandial satiety regulation. Amylin acts on amylin receptors in the brainstem to reduce food intake and improve glucose metabolism by delaying gastric emptying and inhibiting glucagon secretion.

CagriSema is an injectable medication that is administered subcutaneously weekly. In the REDEFINE 1 phase 3 trial (NCT05567796), which enrolled adults with overweight or obesity (BMI ≥ 27 kg/m²) and at least 1 weight-related comorbidity but without type 2 diabetes, participants receiving CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) achieved a mean body weight reduction of 22.7% from baseline after 68 weeks among adherent participants, compared with approximately 3% in the placebo group.5 These results establish CagriSema as one of the most potent antiobesity therapies investigated to date.

A large cardiovascular outcomes trial (REDEFINE-3; NCT05669755) is ongoing to evaluate the effects of CagriSema on major adverse cardiovascular events in individuals with established atherosclerotic cardiovascular disease. Until those results are available, cardiovascular benefit remains unconfirmed. Additionally, the combination of a GLP-1 receptor agonist and amylin analogue may increase the incidence or severity of nausea, early satiety or delayed gastric emptying, particularly during dose escalation.

Retatrutide (Eli Lilly and Co.)

Retatrutide is a novel triple-hormone receptor agonist that simultaneously activates the GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. It works for promoting weight loss in 3 ways: suppressing appetite, improving insulin sensitivity and increasing metabolism. Retatrutide is an injectable medication that is administered subcutaneously once weekly.

In a phase 2, randomized, double-blind, placebo-controlled trial (NCT04881760) involving adults with obesity without type 2 diabetes, retatrutide (1 mg–12 mg weekly) produced dose-dependent weight loss of up to 24.2% from baseline at 48 weeks, compared with 2.1% with placebo. These results represent the greatest mean body-weight reduction reported to date for any incretin-based investigational therapy in a clinical trial of this duration.6

Although the triple-agonist mechanism offers substantial promise, glucagon receptor activation introduces theoretical safety concerns, including transient hyperglycemia, increased heart rate and potential hepatic effects.

Maridebart Cafraglutide (MariTide; Amgen)

Maridebart cafraglutide is a dual-acting incretin modulator that functions as both a GLP-1 receptor agonist and a GIP receptor antagonist. It represents a novel peptide–antibody conjugate, which prolongs systemic exposure and allows for extended dosing intervals compared with conventional GLP-1 receptor agonists. Maridebart cafraglutide is injected subcutaneously every month.

In a phase 2, randomized, double-blind, placebo-controlled trial (NCT05669599) of adults with obesity (with and without type 2 diabetes), once-monthly MariTide produced dose-dependent reductions in body weight of up to 16% at 52 weeks, compared with approximately 2% to 3% with placebo. Weight loss continued through 52 weeks without plateau, suggesting potential for further reduction with longer treatment duration.7

Maridebart cafraglutide’s peptide–antibody conjugate design confers a long pharmacokinetic half-life, allowing for monthly dosing, which may significantly improve treatment adherence and convenience compared with weekly injectable regimens.

Conclusion

The emerging generation of phase 3 anti-obesity pharmacotherapies demonstrates substantially greater weight loss efficacy than earlier agents currently available in clinical practice. Agents such as oral semaglutide, orforglipron, CagriSema, retatrutide and maridebart cafraglutide have achieved unprecedented mean weight reductions, often exceeding 15% to 20% of baseline body weight in clinical trials.3–7

Clinicians must keep in mind that pharmacotherapy alone is not a cure for obesity. Sustained success requires integration with comprehensive lifestyle modification, including individualized nutrition plans, regular physical activity, behavioral counseling and ongoing clinician support. Continued evaluation of cardiovascular outcomes, safety profiles and real-world adherence will be essential to determine the long-term clinical impact of these therapies.