Weight Loss Drugs On the Horizon: What Pharmacists Should Know

Introduction

According to the CDC, the prevalence of obesity among adults was 40.3% during the period from August 2021 to August 2023.¹ The World Health Organization has estimated that in 2021, higher-than-optimal body mass index (BMI) caused an estimated 3.7 million deaths from noncommunicable diseases such as cardiovascular diseases, diabetes, cancers, neurological disorders, chronic respiratory diseases, and digestive disorders.² With obesity rates rising, weight loss drugs have been a fast and efficient way to help jump-start patients' healthy lifestyles.

Phase 3 clinical trials in pharma are the most crucial phase since they focus on the safety and efficacy of the drug prior to releasing it to the public. This article will review 5 key drugs currently in phase 3 trials.

Oral Semaglutide (Rybelsus; Novo Nordisk)

Oral semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist that mimics the effects of endogenous GLP-1, a gut-derived incretin hormone involved in glucose regulation, gastric emptying, and appetite suppression. The 50 mg tablet is taken once daily, preferably in the morning, after waking up. It should be taken at least 30 minutes before eating, drinking, or taking any other oral medications.

In the OASIS 1 phase 3 trial (NCT05035095), adults with overweight or obesity who received oral semaglutide 50 mg once daily achieved a mean weight reduction of up to 15% from baseline after 68 weeks of treatment. This degree of weight loss is comparable to that observed with injectable semaglutide 2.4 mg (Wegovy; Novo Nordisk).³

Because 50 mg is a relatively high dose, determining a safe titration schedule will be important to balance efficacy vs side effects. The requirement of strict fasting conditions may make adherence more burdensome, especially with higher doses if adverse effects increase.

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.

REFERENCES

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2. GBD 2021 Risk Factors Collaborators. Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403(10440):2162-2203. doi:10.1016/S0140-6736(24)00933-4

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