The Rise of GLP-1 Drugs
Glucagon-like peptide-1(GLP-1) agonist drugs have emerged as one of the most significant breakthroughs in recent pharmaceutical history. Designed for managing Type 2 diabetes, these drugs have made news headlines and skyrocketed in popularity for their effectiveness in weight loss.
Transition from Diabetes to Weight Loss:
The GLP-1 hormone was first identified by researchers at Massachusetts General Hospital in 1986 as a glucagon precursor. This quickly found commercial applications for managing conditions such as diabetes with Novo Nordisk developing liraglutide in 1990s. This eventually led to the development of semaglutide in 2012, with a similar mechanism of action, but slower onset of effect and longer duration of action. Initially designed for diabetes treatment, the FDA approved Ozempic in 2017. Researchers noted in clinical trials that participants lost 10-15% of their body weight, prompting further applications for weight loss and obesity. Wegovy, another semaglutide-based formulation, uses a higher dose specifically for weight loss and achieved FDA approval in 2021. This class of drug has continued to develop. Eli Lilly recently conducted a test in a head-to-head comparison between Wegovy, and their drug Zepbound. They found that participants on average lost 20.2% of body weight compared to 13.7% for Wegovy participants.
How GLP-1 Differ from Traditional Weight Loss Medications:
GLP-1 is a naturally produced hormone made by the body, primarily after eating. The endogenous hormone has an extremely short half-life in the body of about 2 minutes. GLP-1 agonists mimic this hormone, prompting the body to increase insulin production, and decrease appetite in the hypothalamus. The presence of GLP-1s also inhibits glucagon release, thereby lowering post-prandial blood glucose levels. This effect is tied to an individual’s glycemic state, and diminishes with hypoglycemia – a critical, built-in safety valve that lowers the risk of developing life-threatening hypoglycemia, at least when taking GLP-1s alone.
Traditional weight loss drugs focus on appetite suppressants (phentermine), or stimulants that increase metabolic rate. Others like Orlistat work in the digestive system by blocking fat absorption. These have strictly focused on weight loss without addressing a more systemic view of health. These traditional drugs have more side effects on the patient, such as dependency or cardiovascular impacts not seen in GLP-1 agonist drugs. Many side effects of GLP-1 agonists are short-term, only observed while taking the drug, and dosage dependent.
Market and Competition:
This success has led to high competition in the obesity drug market, with reports estimating it to exceed $126 billion dollars by 2030. Industry leaders are working to advance oral drugs as a method of patient retention. The recent approval of oral semaglutide (Rybelsus) enables some patients to avoid injections. Companies are also working to use other hormones such as glucose-dependent insulinotropic polypeptides (GIPs) to improve efficacy. Similar to GLP-1, GIP promotes the secretion of insulin. However, GIP also prompts the production of glucagon regardless of an individual’s glycemic state, an important consideration that has hindered the development of GIP drugs until recently.
Areas for Future Development:
At last count, over 300 GLP-1 drugs were in development, and the number is growing quickly. According to an article by Daniel Drucker, GLP-1 drugs have shown potential in helping to treat conditions other than diabetes and obesity. Based on the mechanism of action and reduction of systemic inflammation, these drugs could have the potential to treat other conditions such as cardiovascular, kidney, and even neurodegenerative diseases. While not all of the mechanisms are fully understood at this time, GLP-1 drugs have great potential for expansion into novel therapeutic areas. Even more recently, GLP-1 drugs have been shown to mediate pain perception and addictive behaviors, underscoring the fact that some of their profound benefits are orthogonal to weight loss and metabolic regulation.
Another avenue for future development are drugs that not only focus on the GLP-1 hormone, but other related hormones like GIP. These dual sites of action have been shown to be effective, with Tirzepatide receiving approval from the European Medicines Agency. Finding multiple add-on drugs has proved challenging so far; BioAge discontinued Phase 2 clinical trials for a combination trial of azelaprag and tirzepatide due to patient safety concerns.
Similarly, the method of delivery is another arena where contenders seek to shine in this market.. Novo Nordisk’s Rybelsus has already received FDA approval as a Type 2 diabetes therapy, but numerous oral candidates are in development at other companies. Some of those candidates are worthy of mention: Viking Therapeutics’ oral GLP-1/GIP dual agonist VK2735 has recently released noteworthy results. Eli Lilly’s LY3502970 (Orforglipron) is another oral contender, unique in being a small molecule, and which has posted strong clinical results so far.
