GLP-1 analogs: Magic bullet against obesity or risky venture?

Traditional weight management programs often prescribe low-calorie diets and increased exercise, supplemented by cognitive behavioral therapy to support long-term lifestyle changes.

For more severe cases, pharmacotherapy options were limited and typically involved drugs like orlistat, which inhibits fat absorption, sibutramine, or phentermine, two drugs able to suppress appetite. However, these treatments often offered modest weight loss and were associated with undesirable side effects. In addition, it is essential to note that phentermine is a controlled substance due to its potential for abuse and dependence and is used under the close supervision of a healthcare professional. It's also not suitable for everyone, particularly those with a history of cardiovascular disease, hyperthyroidism, glaucoma, or a history of drug or alcohol abuse. On the other hand, sibutramine was withdrawn from the market in many countries in 2010 because of its association with increased cardiovascular events and strokes.

Bariatric surgery was, and remains, the most effective treatment for severe obesity, but due to its invasive nature and potential complications, it's generally reserved for individuals with a Body Mass Index (BMI) of 40 or above or those with serious weight-related health conditions.

In this scenario, the advent of GLP-1 agonists marked a significant shift in the obesity treatment landscape, offering a new pharmacological avenue for weight loss with a more favorable side effect profile. The concept of body weight reduction by 5 to 10% is invariably associated with noteworthy and prolonged enhancements in metabolic intricacies related to obesity. GLP-1, an incretin and satiety hormone secreted from the L cells of the gut post-food consumption, holds transformative properties that have been streamlined into the creation of GLP-1 analogs. These analogs have been influential in treating type 2 diabetes and obesity.

Harnessing the potential of GLP-1 analogs in the strategic clinical management of obesity unveils a realm of new possibilities. Diving deeper into the anti-obesity pharmacopeia reveals the involvement of Glucagon-like peptide one (GLP-1) agonists, specifically liraglutide and semaglutide, as promising tools in combating obesity.

Not surprisingly, the Danish pharmaceutical company Novo Nordisk, a powerhouse in diabetes and obesity care, experienced a banner year in 2021, reporting an 11% sales surge to reach 140 billion DKK. The company's financial windfall has primarily been driven by sales within diabetes and obesity care market, where GLP-1 products Ozempic and Rybelsus have carved a solid niche.

Several pharmaceutical giants, including Pfizer Inc, Amgen Inc, and smaller players like Altimmune Inc, are all vying for a slice of the lucrative weight-loss therapy pie. As competition heats up, companies are working on developing therapies that offer additional health benefits or greater convenience, aware that even a small market share could be worth billions.

Despite this encouraging progress, the growing GLP-1 market isn't without its challenges. The European Medicines Agency (EMA) and other global health authorities have ramped up scrutiny of GLP-1 treatments, raising safety signals concerning potential cancer risks associated with these drugs. Alongside Novo Nordisk, other manufacturers, including Eli Lilly, AstraZeneca, and Sanofi, have had their GLP-1 products flagged for further investigation. This regulatory scrutiny comes at a time of skyrocketing demand for such treatments. For instance, Novo Nordisk's Ozempic and Wegovy sales are projected to hit a combined total of $15.3 billion this year alone. Similarly, Lilly's Mounjaro, a treatment for type 2 diabetes soon to be authorized for obesity, is expected to see sales reach $3 billion this year.

To better understand how liraglutide and semaglutide earned their final approval as obesity treatments, let's delve into the foundational research supporting their use. We'll explore the scientific evidence behind these two drugs, examining their effectiveness, safety, and tolerability in depth.

Liraglutide: A Therapeutic Powerhouse for Obesity

Liraglutide, a GLP-1 analog showcasing 97% structural similarity to human native GLP-1, offers an extended half-life of around 13 hours after subcutaneous administration. This extended duration paves the way for once-daily dosing, making liraglutide a well-established agent in managing type 2 diabetes.

A pivotal study on liraglutide showcased significant, dose-dependent weight loss, outpacing the results of placebo or Orlistat by week 20. This clinical endeavor marked the start of an extended two-year trial, where the 3-milligram liraglutide dosage exhibited the most profound weight loss.

The SCALE program's subsequent series of randomized trials highlighted the efficacy of liraglutide in chronic weight management when combined with lifestyle alterations. This program further substantiated liraglutide's capacity to induce and sustain substantial weight loss while improving several cardiometabolic risk factors.

Despite rare but serious adverse effects, such as cholelithiasis, cholecystitis, and pancreatitis, liraglutide's safety and tolerability profile remained favorable. Furthermore, its cardiovascular safety benefits were demonstrated in patients with type 2 diabetes.

Semaglutide: Unraveling Therapeutic Efficacy in Obesity

Semaglutide, another GLP-1 analog with 94% structural homology to human native GLP-1, boasts an impressive half-life of 183 hours after subcutaneous administration. It has earned a reputation as an effective management tool for type 2 diabetes and is currently in clinical trials for obesity treatment.

Investigative studies on semaglutide presented promising results for obesity management. The STEP development program aimed to evaluate the efficacy, safety, and tolerability profile of semaglutide and successfully reported significant weight loss and improved cardiometabolic risk factors.

The SCALE and STEP trials consistently demonstrated that liraglutide and semaglutide could generate clinically meaningful and persistent weight loss, especially when paired with a lifestyle intervention program. Semaglutide, in particular, has emerged as a potential alternative to metabolic surgery, offering hope to patients requiring over 10% weight loss to mitigate obesity-related complications.

A New Dawn in Obesity Treatment?

A multitude of anti-obesity drugs involving the combination of GLP-1 agonists with other gut peptides are in developmental stages. Such combination therapies or co-receptor agonism promise enhanced pharmacological efficacy with lower drug doses.

The emergence of GLP-1 as a potent physiological signal in appetite and body weight regulation has led to the development and licensing of effective and safe GLP-1 agonists. Semaglutide, in particular, is the first anti-obesity agent to attain double-digit percentage weight loss in clinical trials. The advent of GLP-1 gut hormone combination therapies will indeed enrich the pharmacological repertoire available for obesity treatment in the future.

The coming years will undoubtedly be pivotal in shaping the landscape of the lucrative yet contentious GLP-1 market. The message for companies operating within this space is clear: Stay competitive, but never lose sight of patient safety and drug efficacy.