GLP-1 Weight Loss Drugs: Side Effects, Discontinuation Rates, and Industry Response

The pharmaceutical industry is grappling with the complex landscape of GLP-1-based obesity drugs, as recent studies reveal multifaceted challenges in patient adherence and treatment persistence. While these medications have garnered significant attention for their impressive weight loss efficacy, concerns about side effects and discontinuation rates are prompting drug developers and healthcare providers to seek innovative solutions.

Side Effect Profiles and Patient Experiences

GLP-1 receptor agonists, such as Novo Nordisk's Wegovy (semaglutide) and Eli Lilly's Zepbound (tirzepatide), have been associated with a range of gastrointestinal side effects. Real-world studies indicate that between 40-70% of patients treated with GLP-1 drugs experience adverse events including nausea, vomiting, diarrhea, constipation, and abdominal pain.

Dr. David Cummings, director of the weight management program for VA Puget Sound Health Care System, notes that these side effects are largely related to the drugs' mechanism of action. "For my patients, [the gastrointestinal side effects] are not a huge deal, but it's not a trivial deal either," Cummings told BioSpace. He explains that the slowing of GI motility, a key aspect of how GLP-1s induce satiety, can lead to nausea in the upper GI system and constipation in the lower intestine.

Discontinuation Rates and Contributing Factors

A real-world study published by Prime Therapeutics in July 2024 revealed that 85% of patients were no longer taking GLP-1 drugs two years after starting treatment. However, this high discontinuation rate is not solely attributed to side effects. Ben Urick, senior director of health outcomes at Prime Therapeutics, identified five common causes for discontinuation:

1. Side effects
2. Affordability
3. Availability
4. Physician drug switches
5. Achievement of weight loss goals

Interestingly, Urick noted that patients without type 2 diabetes discontinued treatment at a higher rate than those with the disease, suggesting that some patients may view these medications as short-term solutions rather than long-term treatments.

Industry Response and Future Directions

Pharmaceutical companies and researchers are actively working to address the challenges associated with GLP-1 drugs. Key strategies include:

1. Careful titration and dose adjustments
2. Development of combination formulations
3. Creation of drugs targeting specific side effects

Blai Coll, chief medical officer of Structure Therapeutics, emphasized the importance of titration in optimizing patient tolerability. "The starting dose and length of time to maintenance dose are critical," Coll told BioSpace.

Combination formulas are gaining traction, with the addition of gastric inhibitory polypeptide (GIP) or amylin receptor agonists showing promise in mitigating GI effects. Companies like Novo Nordisk, Structure Therapeutics, AstraZeneca, and Viking Therapeutics are actively pursuing amylin-based candidates for weight loss.

Some firms are taking a different approach by developing secondary drugs to manage GLP-1-associated side effects. For instance, Jaguar Health subsidiary Napo Pharmaceuticals has filed a patent application for Mytesi, a plant-based oral drug, to treat GI side effects common with GLP-1 and GIP treatments used for obesity.

Despite these efforts, industry experts like Coll acknowledge that completely eliminating GI events while maintaining the benefits of GLP-1s remains a challenge. "I don't think there's a silver bullet," he said, reiterating the focus on combination therapies as a path forward.

As the pharmaceutical industry continues to navigate the complexities of GLP-1-based obesity treatments, the emphasis on improving patient experiences and long-term adherence remains at the forefront of drug development and clinical practice.