What 2025 Holds for GLP-1s in Brain Health
It feels like every year is “the year of the GLP‑1,” but 2025 may really be the one where we crack how these drugs work in the brain—far beyond weight loss and diabetes.
This is the year where we are going to learn a lot about how GLP-1s work outside of cardiovascular and metabolic diseases. Back in August, I wrote about where GLP-1s are going next after Type 2 Diabetes and Obesity. As you could imagine, the densest trial activity for this class was in adjacent cardiovascular and metabolic indications, like renal disease, heart disease, and fatty liver disease. Basically, any indication where pressing the weight loss/appetite suppression button could confer a benefit, GLP-1s were already in advanced late-stage studies.
As we step into 2025, a defining storyline emerges: GLP‑1s, once relegated to metabolic care, now stand at the crossroads of neurology. Will the momentum built on weight‑centered benefits propel them into the brain, or will they retreat to their diabetic and obesity roots? This is the tension driving every Phase 2 pilot and Phase 3 mega trial: a class known for its “gas pedal” on metabolic health versus the unknown territory of cognition, motor function, and addiction. The forthcoming readouts constitute the climax—moments when hypotheses meet hard clinical data. And no matter the outcomes, we’ll gain the resolution to rewrite the GLP‑1 playbook: either cementing these drugs as truly neuro‑versatile or charting a refined focus on those indications where biology and pharmacology align most closely.
Since that newsletter, we’ve seen Eli Lilly’s ZEPBOUD (tirzepatide), a dual GLP-1/GIP agonist, become the first FDA-approved medication for moderate-to-severe obstructive sleep apnea in adults with obesity. The approval was based on results from the SURMOUNT-OSA Phase 3 trial, which demonstrated:
25–29 fewer breathing disruptions per hour vs. 5–6 with placebo
42–50% of participants achieved OSA remission (vs. 14–16% on placebo)
18–20% body weight reduction (45–50 lbs.) after one year
We heard from rival Novo Nordisk as well, with the company reporting positive Phase 3 data from the P3 ESSENCE study which examined semaglutide (aka OZEMPIC and WEGOVY) in metabolic dysfunction-associated steatohepatitis (MASH).
· 37% of patients treated with semaglutide (2.4 mg weekly) achieved improvement in liver fibrosis without worsening of steatohepatitis, compared to 22.5% on placebo.
62.9% of patients experienced resolution of steatohepatitis without worsening of liver fibrosis, versus 34.1% in the placebo group.
The next twelve months or so project to be rather interesting for this field, as we will start to see GLP-1 developers and investigator sponsored studies (of decent size) reporting on outcomes examining GLP-1s in multiple CNS indications. It’s less clear if, how, and why the weight loss button confers a benefit in this set of diseases. The results of these studies will give us tremendous insight into how GLP-1s work in the brain and potentially broaden and distinguish the therapeutic benefits of this class from the weight loss/appetite suppression mechanism, opening the addressable patient population for this class of medicines beyond comorbid T2D and Obesity conditions.
Let’s look at what readouts could potentially be on the horizon.