Obesity has become a major global health crisis, affecting millions of adults and nearly a billion people worldwide. It is closely associated with chronic conditions such as type 2 diabetes, heart failure, kidney disease, and various cancers. According to the World Obesity Atlas 2025, the number of adults living with obesity is projected to more than double between 2010 and 2030, rising from 524 million to 1.13 billion worldwide. In the United States, nearly half of all adults are now classified as obese, highlighting the urgent need for effective strategies and interventions. DelveInsight’s obesity market report says that over 191 million adults in the 7MM had obesity, defined as a BMI of 30 or higher, in 2024, and this figure is expected to climb to 221 million by 2034.
The pharmaceutical industry is responding to this crisis with a surge of innovation and investment in the obesity drug sector, fueled by the rise of GLP-1 agonist molecules. In 2024, life sciences stocks surged by 4.2%, adding USD 386 billion in value to reach a staggering USD 9.6 trillion, much of it driven by obesity-focused pharma companies. The global GLP-1 receptor agonist market is projected to soar from USD 28.19 billion in 2025 to USD 63.54 billion by 2032, reflecting a compound annual growth rate of 12.3%.
The Rise of GLP-1 Agonists and Combination Therapies
Riding the wave of success from obesity drugs like WEGOVY and ZEPBOUND, which together generated USD 10.8 billion in sales and, according to DelveInsight, are forecasted to hit USD 22.5 billion by 2034, pharmaceutical companies are scrambling to expand their pipelines. More than 80 molecules are currently in development for obesity, with over 25 companies testing GLP-1s either as monotherapies or in combination with other agents. While four injectable GLP-1 receptor agonists have already secured regulatory approval, the market is hungry for more convenient oral alternatives. Oral GLP-1s promise to boost patient acceptance and adherence, addressing a critical barrier, as only 1-3% of eligible US adults currently receive pharmacologic treatment for obesity.
Next-generation obesity drugs are exploring combinations of GLP-1 with other entero-pancreatic hormones, such as GIP, glucagon, and amylin, to amplify weight loss and cardiometabolic benefits. Notably, dual and triple agonists like tirzepatide and retatrutide are showing early promise of weight loss results that rival bariatric surgery.
CagriSema: A Novel Combination Therapy
CagriSema, a novel obesity treatment developed by Novo Nordisk, combines semaglutide (2.4 mg) with cagrilintide (2.4 mg), a long-acting amylin analogue. This fixed-dose combination aims to enhance weight loss by reducing appetite, slowing gastric emptying, and lowering blood glucose levels. In the Phase III REDEFINE 1 trial, CagriSema demonstrated a 22.7% mean weight loss after 68 weeks, surpassing both monotherapies and placebo. Notably, 40.4% of participants achieved a ≥25% weight loss, indicating a robust therapeutic effect. In the subsequent REDEFINE 2 trial, which focused on adults with obesity or overweight and type 2 diabetes, CagriSema achieved a 15.7% mean weight loss after 68 weeks, compared to 3.1% with placebo. These results underscore the efficacy of CagriSema in a specific patient population, though the weight loss observed was lower than that in the REDEFINE 1 trial. The trial also reported that the most common adverse events were mild to moderate gastrointestinal issues, consistent with the GLP-1 receptor agonist class, and these diminished over time.
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Despite the promising efficacy and safety data, the market response has been cautious. Novo Nordisk’s stock experienced significant declines following the release of the REDEFINE 1 trial results, partly due to investor expectations not being met. The company now plans to file for regulatory approval in early 2026, slightly later than initially anticipated. This timeline adjustment is to ensure supply chain readiness, according to the company’s full-year report, and is conducting additional studies to further assess CagriSema’s efficacy and safety.
Amycretin: A Dual GLP-1 and Amylin Receptor Agonist
Amycretin is emerging as a promising new player in the obesity and type 2 diabetes treatment landscape. Developed by Novo Nordisk, amycretin is a novel, long-acting, unimolecular agonist targeting both GLP-1 and amylin receptors, designed for both oral and subcutaneous administration. In recent Phase Ib/IIa clinical trials, amycretin has demonstrated impressive weight loss outcomes. Participants receiving the highest dose (20 mg weekly) achieved an average body weight reduction of 22% over 36 weeks, while lower doses (1.25 mg and 5 mg) resulted in 9.7% and 16.2% weight loss over 20 and 28 weeks, respectively. The safety profile of amycretin has so far aligned with other incretin-based therapies. The most common side effects were gastrointestinal, with the majority being mild to moderate in severity.
While detailed safety data and long-term efficacy remain to be seen, amycretin’s early clinical results have reignited optimism for Novo Nordisk’s obesity franchise. These early results come at a critical time for Novo Nordisk, which is under pressure to reinforce its innovation pipeline following underwhelming results from its other next-generation candidate, CagriSema.
Orforglipron: An Oral GLP-1 Receptor Agonist
Orforglipron is an investigational, once-daily, small-molecule oral glucagon-like peptide-1 receptor agonist under development by Eli Lilly. Licensed from Chugai Pharmaceutical in 2018, orforglipron represents a significant advancement in the treatment of type 2 diabetes and obesity. Lilly’s Phase II clinical trial results, published in the New England Journal of Medicine, demonstrate that orforglipron achieved up to a 14.7% mean weight reduction at 36 weeks in adults with obesity or overweight. At the 26-week primary endpoint, the trial showed statistically significant dose-dependent body weight reductions for all doses ranging from 8.6% (19.8 lb. or 9.0 kg) to 12.6% (29.3 lb. or 13.3 kg), compared to 2.0% (4.6 lb. or 2.1 kg) for placebo. These weight reductions continued to improve at 36 weeks, with all doses achieving body weight reductions ranging from 9.4% (21.6 lb. or 9.8 kg) to 14.7% (34.0 lb. or 15.4 kg) compared to 2.3% (5.3 lb.).
Orforglipron has shown statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in a successful Phase III trial. Orforglipron is the first small molecule GLP-1 to complete a Phase III trial, lowering A1C by an average of 1.3% to 1.6% across doses. The investigational once-daily oral pill also reduced weight by an average of 16.0 lbs (7.9%) at the highest dose in a key secondary endpoint. Currently, Lilly is conducting Phase III studies to evaluate orforglipron for the treatment of type 2 diabetes and weight management in adults with obesity or overweight with at least one weight-related medical problem. The safety profile of orforglipron has been similar to other incretin-based therapies.
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Retatrutide: A Triple Agonist
Retatrutide (LY3437943), a novel investigational drug by Eli Lilly, is making waves in the obesity treatment landscape. Functioning as a triple agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors, retatrutide is poised to redefine weight management. Phase II clinical trials have showcased retatrutide’s impressive efficacy in reducing body weight. Participants in these trials experienced weight reductions of up to 24.2% over 48 weeks. In the Phase II trial, participants received varying doses of retatrutide (1 mg, 4 mg, 8 mg, or 12 mg) or a placebo. The most commonly reported adverse events in the retatrutide groups were gastrointestinal, including nausea, diarrhea, and vomiting. These events were generally dose-related, mostly mild to moderate in severity, and could be partially mitigated by using a lower starting dose.
While the Phase II results are undeniably exciting, it’s crucial to acknowledge that further research and clinical trials are necessary to fully elucidate the long-term safety and efficacy of retatrutide. While its long-term safety and efficacy are still under investigation, the Phase II results provide compelling evidence that this triple agonist could revolutionize the way we approach obesity and its associated health risks.
Survodutide: A Glucagon/GLP-1 Receptor Dual Agonist
Survodutide (BI 456906), co-invented by Boehringer Ingelheim and Zealand Pharma, is an investigational glucagon/GLP-1 receptor dual agonist. This innovative drug activates both the GLP-1 and glucagon receptors, which play pivotal roles in regulating metabolic functions. The Phase II trial data reveal impressive weight loss outcomes for survodutide, with participants achieving nearly 19% weight reduction in individuals with overweight or obesity. Survodutide’s novel mechanism of action, involving dual agonism of the GCG/GLP-1 receptors, sets it apart from other weight loss medications. This dual action may have direct effects on energy expenditure in the liver, in addition to reducing appetite.
Treatment with survodutide has not shown unexpected safety or tolerability issues. Serious adverse events were reported by 4.2% of participants on survodutide, compared to 6.5% of those on placebo. However, treatment discontinuation due to adverse events occurred in 24.6% and 3.9% of participants, respectively, mainly due to gastrointestinal adverse events. It’s worth noting that most treatment discontinuations occurred during the rapid dose-escalation phase, suggesting that a more gradual dose-escalation strategy could potentially mitigate these issues.
VK2735: Viking Therapeutics' Candidate
Viking Therapeutics is emerging as a significant player in the competitive obesity market with its drug candidate, VK2735. The company has reported positive results from its Phase II VENTURE study, demonstrating significant weight loss and an encouraging safety profile. The Phase II VENTURE trial successfully achieved its primary and secondary endpoints, with subjects receiving VK2735 demonstrating statistically significant reductions in body weight compared with placebo. 95% of gastrointestinal (GI) related adverse events were reported as mild or moderate. Viking completed an End-of-Phase II meeting with the FDA and received feedback on proposed Phase III study plans and the overall development program for VK2735.
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In addition to the subcutaneous formulation, Viking is also developing an oral tablet formulation of VK2735, which could represent an attractive treatment option for people who may prefer to initiate treatment with oral therapy or for those seeking to maintain the weight loss they have already achieved. A differentiating feature of the tablet formulation of VK2735 is that it offers the potential to transition subjects from the subcutaneous formulation to an oral formulation of the same molecule. Viking has entered into a broad, multi-year manufacturing agreement with CordenPharma, an industry-leading CDMO, covering both the active pharmaceutical ingredient (API) and final finished product supply for VK2735. The agreement secures dedicated capacity for the annual manufacture and supply of multiple metric tons of VK2735 API.
MariTide: Amgen's Novel Approach
Amgen’s MariTide is capturing the spotlight in the rapidly evolving obesity drug landscape, offering a groundbreaking approach that could rival, and potentially surpass, the efficacy of today’s leading therapies. In Phase II trials, MariTide demonstrated up to approximately 20% average weight loss at 52 weeks in people living with obesity or overweight, without evidence of a plateau, suggesting even greater results with longer treatment. Analysts are modeling up to 30% average weight loss in one year-a transformative outcome that rivals the benefits seen with bariatric surgery. Unlike other incretin-based drugs such as Eli Lilly’s ZEPBOUND (tirzepatide), which activates both GLP-1 and GIP receptors, MariTide activates GLP-1 while blocking GIP. MariTide is the first obesity treatment with monthly or less frequent dosing to demonstrate such robust efficacy in a Phase II study.
Beyond weight loss, MariTide delivered clinically meaningful improvements in cardiometabolic parameters, including reductions in blood pressure, triglycerides, and high-sensitivity C-reactive protein (hs-CRP), with no significant increases in free fatty acids. The most common side effects were mild to moderate gastrointestinal symptoms, such as nausea and vomiting, primarily associated with the first dose and substantially reduced with dose escalation. MariTide’s innovative design as a peptide-antibody conjugate, a monoclonal antibody linked to two peptides, sets it apart from other therapies. Amgen has launched the MARITIME Phase III clinical program to further evaluate MariTide in obesity and related conditions.
CT-388: Roche's Dual GLP-1/GIP Receptor Agonist
CT-388, a dual GLP-1/GIP receptor agonist under development by Roche, is emerging as a promising contender in the fight against obesity and type 2 diabetes (T2D). This novel therapeutic aims to regulate blood sugar and reduce appetite by selectively targeting and activating GLP-1 and GIP receptors, which play critical roles in nutrient-derived signaling to control food intake, energy absorption, and assimilation. Data from a Phase Ib clinical trial have revealed that a once-weekly subcutaneous injection of CT-388 produced statistically significant weight loss in healthy adults with obesity compared with placebo over 24 weeks.
CT-388 belongs to the class of incretin-based medicines that aim to regulate blood sugar and reduce appetite. A key differentiator of CT-388 lies in its design to produce potent activity on both the GLP-1 and GIP receptors, along with minimal-to-no β-arrestin recruitment on either receptor. CT-388 was found to be well tolerated, with no new or unexpected safety signals detected. The results of the Phase Ib trial are extremely encouraging, suggesting that CT-388 has the potential to be a highly effective therapy for both obesity.
Pemvidutide: Altimmune's Dual Receptor Agonist
Pemvidutide, a novel peptide-based GLP-1/glucagon dual receptor agonist developed by Altimmune, is garnering attention as a potential game-changer in the treatment of obesity and MASH (metabolic dysfunction-associated steatohepatitis). By simultaneously activating GLP-1 and glucagon receptors, pemvidutide mimics the complementary effects of diet and exercise, suppressing appetite and increasing energy expenditure. The MOMENTUM Phase II obesity trial demonstrated compelling weight loss and a favorable safety profile. Subjects receiving pemvidutide achieved mean weight losses of 10.3%, 11.2%, and 15.6% at the 1.2 mg, 1.8 mg, and 2.4 mg doses, respectively, compared to 2.2% for placebo. A key differentiator of pemvidutide is its ability to preserve lean mass during weight loss. MRI-based body composition analysis revealed that…
Teva's Entry into the Market: Generic Liraglutide
Amidst this flurry of innovation, Teva Pharmaceuticals has made a significant move by securing FDA approval for a generic version of Novo Nordisk’s Saxenda, which contains the active ingredient liraglutide. Teva’s Saxenda generic is indicated for chronic weight management in adults who are obese or overweight with at least one weight-related comorbidity, and in pediatric patients with obesity who are 12 years and older and have a body weight of at least 60 kg. Teva has also launched its liraglutide generic alongside its approval.
Liraglutide is a GLP-1 receptor agonist that, in many ways, is a predecessor to Novo’s blockbuster drug semaglutide. This forerunner therapy was first approved in 2010 for the treatment of type 2 diabetes, for which it carried the brand name Victoza. Saxenda, which is the same compound as Victoza, followed nearly five years later when the FDA in December 2014 cleared it for weight loss. In December 2024, Teva secured regulatory approval for a Victoza generic for type 2 diabetes.
Since its initial approval in 2010, Novo’s liraglutide franchise has been a consistent contributor to its earnings, with Saxenda and Victoza bringing in $1.08 billion and $860 million last year, respectively. But it has since been eclipsed by the semaglutide brands Ozempic for type 2 diabetes and Wegovy for obesity.
Teva’s generic approval could pose additional problems for Novo’s business, which so far this year has already been burdened by compounders eating into Wegovy sales. Year-to-date, the pharma’s shares have slid more than 40%, with both investors and analysts expressing skepticism regarding the company’s commercial execution for its semaglutide franchise. During Novo’s Q1 earnings call, for instance, BNP Paribas’ Peter Verdult questioned Novo’s insistence that compounders were the problem. “Is it really only about the compounders or do we have to consider your nearest branded competitor doing a better job?” he asked company executives, referring to Eli Lilly and its own weight loss drug Zepbound. Amid its shares slump, Novo in May ousted its long-time CEO Lars Fruergaard Jørgensen, citing “recent market challenges” that the pharma had been facing.
Semaglutide: A Closer Look
Semaglutide, the active ingredient in Ozempic and Wegovy, promotes satiety, which leads to a reduction in food intake. The bioavailability of semaglutide is 89% when injected subcutaneously. It is designed to be injected once weekly. Administration sites include the abdomen, thigh, and upper arm. Semaglutide is eliminated via the urine and feces. It can be administered subcutaneously without regard to meals.
The dosage escalation schedule involves starting at 0.25 mg weekly for the first four weeks, then escalating every four weeks to doses of 0.5 mg, 1 mg, and 1.7 mg, and the maintenance dose of 2.4 mg. A 4-week delay in dose escalation may be needed to improve tolerability. Lifestyle interventions were consistent with STEP 1, including a reduced-calorie diet, increased physical activity, and counseling sessions.
Semaglutide Clinical Trials: The STEP Program
The Semaglutide Treatment Effect in People with obesity (STEP) program included several clinical trials evaluating the efficacy and safety of semaglutide 2.4 mg for weight management. Details of these trials are shown in Table 1.
- STEP 1: This trial involved adults with overweight or obesity. Participants receiving semaglutide 2.4 mg experienced a significant reduction in weight when compared with either placebo or liraglutide. Mean weight change from baseline to week 68 was -14.9% with semaglutide 2.4 mg vs. -2.4% with placebo. 86.4% of patients treated with semaglutide 2.4 mg vs. 31.5% of patients treated with placebo achieved a weight loss of 5% or more at 68 weeks. Adverse events for semaglutide 2.4 mg vs. placebo included nausea (44.1% vs. 17.7%), diarrhea (29.7% vs. 16.3%), and vomiting (24.8% vs. 6.3%).
- STEP 2: This trial involved patients with type 2 diabetes and a BMI of 27 kg/m2 or greater. The mean weight change from baseline to week 68 was -9.6% with SQ semaglutide 2.4 mg vs. -3.4% with placebo.
- STEP 3: This trial involved intensive behavioral therapy plus semaglutide 2.4 mg vs. placebo. The mean weight change from baseline to week 68 was -16.0% with semaglutide vs. -5.7% with placebo. 86.6% of patients treated with semaglutide vs. 47.6% of patients treated with placebo achieved a weight loss of 5% or more at 68 weeks.
- STEP 4: This trial examined weight loss after discontinuation of semaglutide. Participants received a total of 20 weeks of semaglutide therapy. After 20 weeks, participants were randomized to either continue semaglutide therapy or replace therapy with placebo. Described lifestyle interventions appear similar to STEP 1. The mean change in body weight from week 20 to week 68, -7.9% with placebo vs. -2.5% with semaglutide.
- STEP 5: This trial compared semaglutide 2.4 mg weekly with liraglutide 3.0 mg daily or placebo.
- STEP Teens: This trial involved adolescents with obesity. The mean percentage change in BMI from baseline to week 68 was -16.1% with semaglutide vs. 0.6% with placebo.
These trials demonstrated that semaglutide 2.4 mg is effective for weight management in overweight or obese adults, including those with type 2 diabetes, when used in conjunction with lifestyle changes.
Considerations for Weight Management Medications
When considering pharmacotherapeutic options for chronic weight management, it is essential to evaluate the benefits and risks based upon the side effects, precautions, and contraindications of a medication. Factors such as the patient's medical history, concomitant medications, and potential drug interactions should be carefully assessed. Clinicians should also have a clear plan for dosage adjustments and discontinuation of the medication, as well as management of potential side effects or contraindications.
Lifestyle interventions, including a reduced-calorie diet and increased physical activity, are crucial components of any weight management program. Moderate-intensity exercise spread over 3 to 5 sessions per week is generally recommended.
Challenges and Future Directions
Despite the advances in obesity pharmacotherapy, significant challenges remain. High development costs, manufacturing complexities, and persistent supply constraints threaten to limit access and affordability, especially in emerging markets. Only 1-3% of eligible US adults currently receive pharmacologic treatment for obesity, highlighting the need for improved access and adherence.
The development of more convenient oral formulations, combination therapies, and personalized treatment strategies holds promise for improving outcomes in the fight against obesity. Next-generation obesity drugs are exploring combinations of GLP-1 with other entero-pancreatic hormones, such as GIP, glucagon, and amylin, to amplify weight loss and cardiometabolic benefits.