GLP-1 Agonists

What are GLP-1 receptor agonists?

GLP-1 receptor agonists are medications that mimic glucagon-like peptide-1, an incretin hormone your gut releases after meals. By activating GLP-1 receptors across multiple organ systems, they trigger insulin secretion, suppress glucagon, slow gastric emptying, and reduce appetite through direct brain signaling. The drug class includes semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), and the dual GIP/GLP-1 agonist tirzepatide (Mounjaro, Zepbound). Originally developed for type 2 diabetes, these compounds now rank among the most studied medications in modern medicine, with effects that reach far beyond blood sugar and body weight ^[1].

Cardiovascular and organ protection

The SELECT trial enrolled over 17,600 adults with obesity and cardiovascular disease but no diabetes. Semaglutide cut major adverse cardiovascular events by 20%, and roughly two-thirds of that benefit was independent of waist circumference changes, pointing to direct vascular and anti-inflammatory mechanisms ^[2]. Heart failure hospitalizations and cardiovascular mortality also dropped significantly.

Kidney and liver data are equally strong. The FLOW trial showed semaglutide reduced major kidney disease events by 24% in people with type 2 diabetes and chronic kidney disease, prompting early trial termination for clear efficacy ^[5]. In the liver, the ESSENCE Phase 3 trial found that 62.9% of patients on semaglutide resolved metabolic dysfunction-associated steatohepatitis (MASH) versus 34.1% on placebo, with measurable improvement in fibrosis ^[6]. The FDA approved semaglutide for MASH with moderate to advanced fibrosis in 2025.

GLP-1 agonists and biological aging

A 2025 randomized controlled trial delivered the first clinical evidence that semaglutide slows biological aging at the epigenetic level. In adults with HIV-associated lipohypertrophy, semaglutide decreased epigenetic age by 3.1 years on PCGrimAge, 4.9 years on PhenoAge, and slowed the pace of aging by 9% on DunedinPACE ^[3]. Eleven organ-system clocks showed concordant decreases, most prominently in inflammation, brain, and cardiovascular markers. A 2025 mouse study using multi-omic analysis confirmed body-wide age-counteracting effects from low-dose GLP-1 receptor agonism, with benefits specific to aged animals. These findings position GLP-1 agonists as candidate geroprotective agents, though long-term human data outside specific disease populations remain an active area of research.

Brain health and neuroprotection

GLP-1 receptors are expressed throughout the brain. Preclinical work shows these agonists reduce neuroinflammation, clear toxic protein aggregates, and protect synaptic connections. In a Phase 2b trial, liraglutide reduced brain atrophy in memory-related regions by nearly 50% compared to placebo, while observational data links GLP-1 agonist use to up to 70% lower dementia risk ^[4]. Two Phase 3 trials (EVOKE and EVOKE+) are evaluating semaglutide in early Alzheimer's disease. Separate research also suggests GLP-1 receptor agonists may reduce addictive behavior: preclinical studies show they decrease alcohol intake and motivation to drink, and Phase 3 trials for alcohol use disorder are underway.

Weight loss and the rebound problem

Tirzepatide, the dual GIP/GLP-1 agonist, achieved up to 20.9% body weight reduction in the SURMOUNT-1 trial ^[7]. Semaglutide 2.4 mg produces roughly 15-17% weight loss. However, stopping these medications leads to substantial weight regain. A 2025 meta-analysis found average regain of 9.9 kg in the first year after discontinuation, with return to baseline weight by about 18 months. In the STEP-10 trial, over 40% of lost weight rebounded within 28 weeks. Metabolic improvements in blood sugar, lipids, and blood pressure also reversed. This pattern means most patients need ongoing treatment, which raises questions about cost, access, and long-term safety.

Practical considerations

GLP-1 receptor agonists are given as weekly subcutaneous injections, though oral semaglutide (daily pill) is also available, with the 25 mg Wegovy pill showing roughly 14-17% weight loss at 64 weeks. Common side effects are nausea, diarrhea, and constipation, which typically fade as doses are titrated up over weeks. Rare but serious risks include pancreatitis and gallbladder disease. A 2025 meta-analysis of cancer risk found no overall increase in cancer incidence and potential reductions in specific cancers like colorectal and liver cancer, though a signal for thyroid cancer requires further study. Muscle loss is a real concern: about 20% of total weight lost comes from lean mass, comparable to calorie-restricted diets. Resistance training 3+ times weekly and 1.2-1.6 g protein per kg body weight daily can largely offset this. Bone density appears preserved when GLP-1 therapy is combined with regular exercise.