The number that worries people, in context

About a quarter to 40% of the weight lost on semaglutide and tirzepatide is lean mass. In the STEP 1 semaglutide substudy, people lost roughly 13.6 kg on average: about 8.3 kg of fat (62%) and about 5.3 kg of lean mass (38%). Total lean mass fell around 10%, yet lean mass as a share of body weight actually rose by about 3 percentage points. Some analyses put the semaglutide lean fraction as high as roughly 45%, depending on the method and denominator used (Neeland et al., 2024; Mozaffarian et al., 2025). In the SURMOUNT-1 tirzepatide substudy, lean mass fell about 10.9% (roughly 5.7 kg), but fat mass fell about 33.9%. Around 25% of the weight lost was lean, nearly identical to the split seen with placebo (SURMOUNT-1 body-composition substudy, 2025). The gap between the two drugs reflects differences in method, not a proven difference between them.

Is that unusual? Not really. A 2026 meta-analysis of 20 randomized trials and 15,782 participants found the lean-mass share of weight loss with incretin drugs (25-39%) is in the same neighborhood as lifestyle interventions and bariatric surgery (roughly 20-30%) (Eisa & Barood, 2026). A JAMA review frames it as within the range of calorie restriction, while noting that faster, larger weight loss may cost somewhat more lean mass (Lieberman et al., 2026). These are comparisons across different trials, not head-to-head tests, so treat the ranges as context, not a scorecard.

Lean mass is not the same as muscle

Here's the part that gets lost in headlines. A DXA scan measures bone and fat directly and infers "lean" tissue by subtraction. That lean number includes organs, water and connective tissue, and skeletal muscle is only about half of it. In the SURPASS J-mono tirzepatide substudy, the drop in lean mass was largely explained by body-water reduction (Sun et al., 2026; Mozaffarian et al., 2025). So "lean mass lost" is a proxy, not a muscle measurement.

That doesn't mean there's nothing to protect. Whether the lean loss matters functionally is not settled, and almost none of the evidence is specific to adults over 40. Physical function and cardiometabolic markers generally improve, and strength is often preserved when weight loss is gradual and well fueled. The concern concentrates in older adults at risk of sarcopenia, who are underrepresented in the drug trials. Cardiorespiratory fitness has not clearly improved with these drugs despite the weight loss (Liu et al., 2025). And bone is a real signal: a 2026 NEJM review reports roughly 1% loss of bone mineral density at the hip and spine over 52 weeks with liraglutide, with fracture risk still undetermined, and greater bone loss when weight comes off quickly (Rosen & Ingelfinger, 2026).

What the trials show about lifting

The most direct evidence is the S-LITE trial. After a low-calorie diet, adults were randomized to exercise alone, liraglutide alone, both, or placebo for a year. The combination produced the largest fat loss, and in a secondary bone analysis it protected bone mineral density at clinically important sites, while liraglutide alone did not (Jensen et al., 2024). I want to be straight about the limits. S-LITE used liraglutide, not semaglutide or tirzepatide, and in the lean-mass figure the combination group did not clearly separate from liraglutide alone. So the case for lifting to preserve muscle rests mostly on the wider weight-loss literature.

That literature is encouraging. In calorie-restricted weight loss, resistance training reduces lean-mass loss by roughly 50-95% and helps preserve bone (Mehrtash et al., 2025). Lifestyle programs with structured resistance training show a lean share of about 17.5% of weight lost, the most favorable in the meta-analysis (Eisa & Barood, 2026). Supervised resistance training lasting more than 10 weeks has been reported to add about 3 kg of lean mass and roughly 25% more strength (Locatelli et al., 2024), and combined resistance and aerobic training improved muscle strength in people with obesity on tirzepatide (Mehrtash et al., 2025).

The honest gap: I could not find a high-quality trial of lifting plus semaglutide or tirzepatide with strength and physical-function outcomes in adults 40 and older. Trials are underway (Lieberman et al., 2026). And after stopping these drugs, regained weight is mostly fat, not muscle, which can worsen the fat-to-lean ratio over repeated cycles, though long-term human data are sparse (Ruder, 2024; Lieberman et al., 2026).

What this looks like in a week

Lift at least two days a week. That is the consistent minimum across the guidance, alongside roughly 150 minutes a week of moderate weight-bearing activity (Mehrtash et al., 2025; Mesinovic et al., 2025). Use progressive resistance training on the major muscle groups, favoring compound, weight-bearing moves plus some balance and mobility work. If you're deconditioned, start with machines or bands at modest loads, focus on movement quality, and build up gradually. Fatigue is common on these medications, so add activity in steps.

Protein matters, and the ranges differ by source. A 2025 practical guide recommends about 1.2-1.6 g per kg of body weight per day when exercise is included, with little added benefit above 1.6 g/kg and roughly 20-30 g of protein per meal across three or four meals. Aging blunts the muscle-building response, which is why intake above the standard 0.8 g/kg RDA makes sense (Mesinovic et al., 2025; Eglseer et al., 2026). Appetite suppression makes hitting those numbers hard, so anchor each meal around a protein source even when you're not hungry.

Then there are the rough weeks. Nausea and appetite suppression tend to peak at the start and around dose increases (France & Syed, 2024; Kunutsor & Seidu, 2026). On those weeks, trim training volume instead of skipping entirely, keep protein and hydration up, and don't push through nausea or lightheadedness. Aerobic work complements lifting, but it doesn't replace it for holding on to muscle.

Four claims worth retiring

"You'll lose muscle no matter what you do." Partly false. Some lean loss comes with nearly all substantial weight loss, but the amount is highly modifiable (Eisa & Barood, 2026).

"All the lean mass lost is muscle." False, for the DXA reasons above.

"Heavy lifting is unsafe on these drugs." Not supported as a blanket claim. The real cautions are dehydration from GI side effects and low blood sugar in people on insulin or similar drugs, not load itself (France & Syed, 2024).

"Protein shakes alone protect muscle." Protein without resistance training does worse than protein with it (Eglseer et al., 2026).

Where this needs a physician, dietitian or PT, not a newsletter

Everything above is general education drawn from published research, not a personalized prescription. As an ACE-certified trainer, I can program lifting, cardio, balance and mobility for an apparently healthy, cleared client, teach the movements, encourage adequate protein within public-health ranges, and watch for red flags. Starting, stopping, dosing or adjusting a medication is your prescriber's call. So is managing side effects and conditions like diabetes, kidney disease, osteoporosis or a history of pancreatitis. Individualized protein targets in clinical conditions such as kidney disease belong to a registered dietitian.

Stop and get medical input before continuing if you have persistent or severe vomiting or diarrhea or signs of dehydration, symptoms of low blood sugar (especially on insulin or sulfonylureas), severe or persistent abdominal pain, unexplained lightheadedness or fainting, chest pain or unusual shortness of breath, or a new injury or unexplained weakness.

The takeaway

The scale can't tell you what you're keeping. Lifting at least twice a week, eating protein at every meal, and adjusting on rough weeks is the best-supported way to give your muscle and bone a fighting chance while the weight comes off, even though the direct proof in this exact situation is still being built.

What I can't do in a newsletter is look at your training history, your appetite that week and your prescriber's plan, and tell you what to do with it. That's the part that needs a person.

Richard Skolasky is an ACE Certified Personal Trainer. This article is for general educational purposes only and does not constitute individualized exercise prescription. Consult a qualified healthcare provider before beginning or modifying a training program.

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