You’re probably seen at least one headline heralding the remarkable successes of Novo Nordisk’s drug Wegovy (Semaglutide, 2.4 mg) and Eli Lily’s tirzepatide (currently only approved for type 2 diabetes – likely to be approved for weight loss later this year), for the treatment of obesity.
Recent clinical studies demonstrate that in trial participants with general obesity, tirzepatide results in an average body weight loss of 21% after 18 months as compared to 3% for subjects receiving placebo. Likewise, semaglutide, 2.4 mg, prompted body weight loss of 14.9% as compared to 2.4% after 16 months of treatment. [side note: Ozempic and Wegovy are the brand names of semaglutide - named differently depending on dose and indication: Ozempic is for type 2 diabetes and can be given up to a 2 mg dose, while Wegovy is for obesity at a 2.4 mg dose]
As a PWS researcher that has focused on understanding PWS hyperphagia, I am ecstatic to see this type of progress in anti-obesity pharmaceutical development. For decades this level of efficacy could only be achieved with highly invasive bariatric surgeries that forever alter stomach and GI tract anatomy.
Semaglutide, 2.4 mg, and tirzepatide both work by mimicking the effects of GLP-1, an incretin hormone produced by the gut that regulates satiety and blood sugar levels. Tirzepatide additionally mimics the effects of GIP, another gut incretin hormone that also regulates blood sugar levels – especially after a meal.
For a long time, pharmacological interventions for obesity were only able to offer modest weight loss – typically in the single digits. Only a small minority of patients are able achieve and maintain >10% weight loss at tolerable doses of older anti-obesity medications. These results pale in comparison to the amount of weight loss that can be achieved with bariatric surgery – typically about 28% weight loss at 12 months. To be clear, the motivation for weight loss in obesity is not cosmetic. The goal is an improved metabolic profile: reduced risk or reversal of type 2 diabetes, reduction in fatty liver disease, reduction in cardiovascular disease, and reduced risk of other co-morbidities of obesity including certain cancers.
Given the dramatically superior efficacy of bariatric surgery (roux-en-y, gastric sleeve), scientists began to study the hormonal changes that followed surgery. One hormone that appeared to dramatically increase after bariatric surgery was GLP1. Further scientific studies have identified GLP1 as a key player in the gut-brain regulatory axis, acting in the brain to dampen appetite-stimulating and food-related reward circuity, and in the periphery to heighten insulin secretion and sensitivity, reduce fat in the liver, and decrease gastric emptying and mobility.
The natural next question is if these treatments can help people with PWS and their families in the treatment of hyperphagia, obesity, and obesity-associated complications.
To date, semaglutide and tirzepatide have not been systematically studied for their safety and efficacy in people with PWS. However, liraglutide, a GLP1 receptor agonist that is structurally similar to semaglutide has. A multicenter, 16-week, double-blind, placebo-controlled study in children and adolescents with PWS and obesity found that liraglutide had no impact on BMI in children or adolescents after 16 weeks of treatment, nor was weight improved after 52 weeks on the drug compared to placebo. However, a subgroup analysis showed a small reduction in hyperphagia scores in the adolescents with PWS. Importantly, liraglutide was found to be generally well tolerated in children and adolescents with PWS. The most common treatment-related adverse events were gastrointestinal-related; and most were mild to moderate in severity. The study authors note that relatively few events led to study discontinuation or dose reduction.
To put these results into context, it is important to keep in mind that Liraglutide, 3 mg, branded as Saxenda for weight loss, prompts a mean body weight decrease of 8% compared to 2.6% for placebo – about half of what 2.4 mg semaglutide (Wegovy) achieved in the general obese population. Liraglutide’s half-life is shorter than semaglutide and so it is administered as a once-daily subcutaneous injection, whereas semaglutide is injected once-weekly.
Thus, it's possible that better efficacy could be achieved with either semaglutide, 2.4 mg, or tirzepatide in PWS – but it will be critical to also understand the safety and tolerance for individuals with PWS. In particular, it's important to note that GLP-1's action on the stomach - decreasing stomach emptying - is one of the reasons it makes people in the general population feel less hungry. However, this aspect of its action is potentially problematic in PWS, since many individuals with PWS already have decreased stomach emptying rates and generally slow GI transit (which does not seem to reduce their appetite). Thus, the impact of these drugs on the functioning of the GI tract will need to be carefully monitored if GLP1 receptor agonists are to be applied in PWS.
Ultimately, incretin-mimicking compounds are unlikely to completely eliminate PWS-associated hyperphagia. However, given their newly emerging and unprecedented efficacy profile in the treatment of common obesity, they may represent an important addition to the pharmacological toolbox to help manage PWS symptomatology.
Well-controlled studies to understand the efficacy and tolerability of these two drugs in people PWS are needed ASAP.
Stay tuned for more information on this front!
