The obesity treatment landscape is rapidly evolving beyond the blockbuster success of GLP-1 receptor agonists, with pharmaceutical companies developing next-generation therapies that promise enhanced efficacy while addressing key limitations of current treatments, particularly muscle mass preservation.
Amylin Pathway Shows Promise for Better Tolerability
Zealand Pharma's investigational amylin analog petrelintide demonstrated strong weight reduction and favorable tolerability in recent Phase Ib trial results. The drug achieved an average 8.6% body weight reduction at 16 weeks, positioning itself as a direct competitor to GLP-1 receptor agonists with potentially superior patient experience.
"These data further support the potential of this long-acting amylin analog to deliver weight loss comparable to GLP-1 receptor agonists with a better patient experience," stated David Kendall, Zealand's Chief Medical Officer. The company is specifically targeting better tolerability and higher-quality weight loss with preserved lean mass compared to existing GLP-1 therapies.
David Lau, professor emeritus of medicine at the University of Calgary, noted that drugs working along the amylin and calcitonin receptor agonist pathway "are associated with less GI side effects than those caused by GLP-1 receptor agonist drugs."
Dual Hormone Approaches Target Muscle Preservation
Altimmune's pemvidutide, combining GLP-1 and glucagon hormones, showed significant promise in Phase II trials involving 391 adults with obesity. Patients receiving the highest dose achieved 15.6% body weight loss after 48 weeks, compared to 2.2% in the placebo group.
Critically, pemvidutide demonstrated superior muscle preservation, with patients losing only 21% of lean body mass compared to the typical 25% loss seen with diet and exercise alone. "If people take the drugs long term, what's going to be their long-term health? What's going to be the long-term effects on their body composition, their muscle, their ability to function?" questioned Dr. Scott Harris, Altimmune's Chief Medical Officer.
The glucagon component is particularly significant as it mimics exercise effects and represents a key differentiator from first-generation appetite suppression mechanisms. "We are adding another component," explained Altimmune President and CEO Vipin Garg, describing their approach as "the next wave of obesity drugs."
Mitochondrial Uncoupling Offers Alternative Mechanism
Rivus Pharmaceuticals is pursuing an entirely different approach through mitochondrial uncoupling with their lead candidate HU6. Rather than reducing caloric input like GLP-1s, this mechanism targets energy expenditure, potentially offering more sustainable weight loss while supporting muscle mass.
"GLP-1s are tantamount to starvation," explained Shaharyar Khan, Rivus's Chief Scientific Officer. "You're reducing caloric input. Your body is now becoming more stingy with its resources. It starts stealing from muscle to feed itself."
HU6 increases resting energy consumption by approximately 30% at its highest dose, operating continuously to burn an additional 3,600 to 4,000 calories weekly. Trial participants have consistently lost three to four pounds per month without plateauing, according to CEO Jayson Dallas.
The drug is currently being investigated in Phase IIa studies for obese patients with heart failure with preserved ejection fraction and Phase IIb studies for metabolic dysfunction-associated steatohepatitis.
Triple Hormone Combinations Show Enhanced Efficacy
Eli Lilly's retatrutide represents the most advanced triple hormone approach, combining GLP-1, glucagon, and GIP (glucose-dependent insulinotropic polypeptide). Earlier trials demonstrated approximately 24% average weight loss, equivalent to about 58 pounds—exceeding any currently marketed obesity drug.
New data presented at the American Diabetes Association conference showed retatrutide also significantly reduced blood sugar levels in Type 2 diabetes patients, suggesting broader metabolic benefits beyond weight loss.
Market Dynamics and Patient Access
The obesity drug market is projected to exceed $110 billion by 2033, with current leaders Novo Nordisk's Wegovy generating $1.35 billion and Eli Lilly's Zepbound earning over $517 million in the first quarter of 2024 alone. However, monthly costs exceeding $1,000 for existing treatments remain financially prohibitive for many patients.
Increased competition from diverse mechanisms could drive down costs while addressing supply shortages that have plagued current GLP-1 therapies. "Different GLP-1 drugs may have varying levels of efficacy and potency," noted Dr. Fatima Cody Stanford from Harvard Medical School. "Some patients may respond better to one drug over another, depending on how their body metabolizes and responds to the medication."
Addressing Metabolic Comorbidities
Beyond weight loss, next-generation drugs are targeting associated metabolic conditions. Boehringer Ingelheim's survodutide, combining GLP-1 and glucagon, achieved 19% weight loss at 46 weeks while showing 83% improvement in metabolic dysfunction-associated steatohepatitis (MASH) among participants with fibrosis.
An estimated 75% of people with obesity have nonalcoholic fatty liver disease, with 34% progressing to MASH, making these dual benefits particularly significant for comprehensive metabolic health management.
The treatment paradigm is shifting toward expectations of 15% to 30% weight loss, according to Lau, representing a dramatic evolution from historical obesity interventions. With 27 GLP-1 and alternative mechanism drugs currently in development pipelines, the next few years promise unprecedented therapeutic options for patients struggling with obesity and related metabolic disorders.
