The GLP-1 guide.

How GLP-1 medications work.

GLP-1 (glucagon-like peptide-1) is a hormone secreted by L-cells in the small intestine in response to food. It drives roughly 50% of the postprandial (after-meal) insulin response in healthy people, a phenomenon called the incretin effect. GLP-1 receptor agonists mimic this hormone but with dramatically extended half-lives: natural GLP-1 is degraded by the DPP-4 enzyme in about 7 minutes; semaglutide is engineered to last 7 days.

The drug landscape.

What the clinical trials actually show.

The STEP program (semaglutide) and SURMOUNT program (tirzepatide) are among the largest and most rigorously conducted obesity trials in history. The numbers below are averages from intent-to-treat analyses. Individual results vary, and effects depend on staying on therapy.

Side effects and safety.

GI side effects affect 70–80% of users, particularly in the first weeks of each dose escalation step. Nausea is the most common, followed by vomiting, diarrhoea, and constipation. These are largely transient and are the primary reason the titration is slow. Pushing through escalation steps faster increases the likelihood and severity of GI effects without necessarily improving efficacy.

Weight regain after stopping.

The STEP 4 and STEP 5 extension data make this clear: people who stopped semaglutide after 68 weeks regained approximately two-thirds of their lost weight within 12 months. By two years, most returned near baseline. The mechanism is straightforward: as the drug washes out, GLP-1R signalling returns to baseline, appetite-suppression resolves, and food intake and body weight trend back. This doesn't mean GLP-1 drugs don't work. They work while you take them. It means obesity is a chronic condition that appears to require long-term management for most people, just as hypertension requires long-term antihypertensives.

Oral vs injectable semaglutide.

Rybelsus is an oral semaglutide tablet, approved for type-2 diabetes (not for weight management). Its bioavailability is approximately 1% without the absorption enhancer SNAC and approximately 6% with it, compared to nearly 100% for subcutaneous injection. That lower and more variable bioavailability means lower dose ceilings, stricter requirements (taken fasting, with minimal water, upright for 30 minutes), and a higher GI side effect burden relative to absorbed dose. Most patients who need higher therapeutic exposures prefer the subcutaneous route. Oral semaglutide does provide a non-injection option for people with needle aversion or diabetes management goals at lower exposure.

The compounding controversy.

Supply shortages of Ozempic and Wegovy beginning in 2021 created a market for compounded semaglutide and tirzepatide. US compounding pharmacies (503A/503B) can legally produce compounds when brand-name drugs are on the FDA shortage list. When they were removed from the list (tirzepatide in 2024, semaglutide on a rolling basis), FDA moved to restrict compounding, triggering legal challenges.

Muscle loss: what the data says and what to do.

A consistent finding across GLP-1 trials is that approximately 25–35% of total weight lost is lean body mass (LBM), the muscle and non-fat tissue. This ratio is broadly similar to other methods of caloric restriction and is not unique to GLP-1 drugs. What mitigates it: resistance training (demonstrated in exercise + semaglutide trials to preferentially preserve LBM) and adequate protein intake (the current evidence supports ≥1.6 g/kg body weight/day during active weight loss). The combination of GLP-1 therapy + resistance training + sufficient protein represents the evidence-supported approach to body composition preservation, though the trials are not large enough to establish precise magnitudes.