Muscle Preservation on GLP-1s: What UCN2, Amylin, and GIP Add for Body Recomp

Body recomposition, or 'body recomp,' means losing fat while keeping or gaining muscle. It is the goal most people actually have when they say they want to lose weight, even if the scale number is what they track.

GLP-1 monotherapy (semaglutide as Wegovy or Ozempic) is not designed for body recomp on its own. Published clinical trial data on semaglutide 2.4 mg shows that roughly 25% of total weight lost is lean mass, based on DEXA scan measurements. Some patients lose 30-40% of weight as lean mass depending on age, sex, protein intake, and activity level. That is not muscle-preservation. That is muscle loss along with fat loss.

The obesity drug field has been moving toward mechanisms that either reduce muscle loss during weight loss or actively increase muscle mass. The next-generation drugs each add something different:

• GIP (tirzepatide as Zepbound or Mounjaro): Adipose tissue effects that appear to shift the fat-vs-muscle loss ratio modestly in favor of fat.
• Amylin (cagrilintide in CagriSema): Some preclinical evidence for proportional fat-mass preference over lean mass.
• Glucagon (retatrutide, expected 2027-2028): Energy expenditure and thermogenesis that push fat burning while sparing muscle.
• UCN2 / CRFR2 (Hanmi's HM17321 licensed to Roche August 24, 2026 for up to $2.3 billion): Direct anabolic effects on skeletal muscle that could actually add muscle during weight loss.

This piece walks through why muscle-loss on GLP-1s matters for body recomp, what each mechanism adds, and what a practical protocol looks like for someone who wants to actually recomp on these drugs. The protocol side is where most of the outcome lives; the drug choice matters less than the protein-and-lifting-and-adequate-calories part.

The STEP-1 trial that supported Wegovy's approval measured body composition changes with DEXA scans in a subset of participants. Results at 68 weeks on semaglutide 2.4 mg:

• Total weight loss: 14.9% of body weight (average)
• Fat mass loss: roughly 34-38% of starting fat mass
• Lean mass loss: roughly 10-12% of starting lean mass
• Ratio of lean mass to total weight lost: approximately 25-30%

A STEP-1 participant losing 40 pounds total would lose roughly 30 pounds of fat and 10 pounds of lean mass. Ten pounds of lean mass is a lot of muscle. On someone with a starting lean mass of 130 pounds, that is nearly 8% of their entire lean mass compartment.

Several factors make lean mass loss on GLP-1s worse than it needs to be:

Reduced total food intake plus reduced protein intake. Appetite suppression cuts total calories, but it usually cuts protein along with everything else. Body recomp requires 1.2 to 1.6 g of protein per kg of bodyweight per day. On a 200-pound person, that is 110 to 145 grams of protein. Most patients on GLP-1s report protein intake closer to 40-60 grams per day because their appetite is reduced across all foods equally.

Reduced physical activity. Some patients on GLP-1s reduce activity because of nausea, fatigue, or the general 'I don't need to move as much when I'm not hungry' effect. Reduced movement plus reduced protein is a muscle-loss recipe.

Rapid weight loss rate. Losing 1-2 pounds per week gives your body time to preserve muscle. Losing 3-4 pounds per week does not. GLP-1 titration schedules often push weight loss rates faster than the body-recomp-friendly range.

Age matters. Adults over 50 lose muscle mass at a higher rate than younger adults on the same drug at the same dose. Sarcopenia (age-related muscle loss) plus GLP-1-driven weight loss compounds the problem.

Sex matters. Men tend to lose slightly more lean mass proportionally than women on semaglutide, though the difference is modest.

All of that is what makes GLP-1 monotherapy a poor tool for body recomp on its own. The good news: the newer drugs and the practical protocol (protein plus resistance training plus reasonable weight-loss rate) can substantially close the gap.

For someone doing body recomp, the muscle question is more than aesthetic. Four practical reasons muscle mass matters during and after weight loss:

Metabolic rate. Muscle tissue burns roughly 10-13 kcal per kg per day at rest. Fat tissue burns roughly 4-5 kcal per kg per day. Losing 10 pounds of muscle mass drops resting metabolic rate by roughly 50 kcal per day. Over a year, that is roughly 5 pounds of fat regain from the metabolic-rate change alone if food intake stays flat. That is a substantial part of the weight-regain problem after stopping GLP-1s.

Insulin sensitivity. Muscle tissue is the largest sink for postprandial glucose. Losing muscle reduces glucose disposal capacity, worsens insulin sensitivity, and makes long-term metabolic health harder. This matters a lot for patients using GLP-1s for type 2 diabetes.

Functional performance. Being able to carry groceries, get up from the floor, catch yourself when you trip. Loss of grip strength, leg strength, and balance in the 12-18 months of aggressive weight loss on GLP-1s has been documented in real-world case series. Aging patients are particularly affected.

Aesthetics and body composition. The 'Ozempic face' and 'Ozempic body' phenomena reflect facial and body fat loss with proportional loss of underlying muscle definition. Someone who is 190 pounds with 25% body fat is a different-looking person than someone at 190 pounds with 15% body fat, and muscle mass is the difference.

Tirzepatide (Zepbound for obesity, Mounjaro for diabetes) is a dual GIP + GLP-1 receptor agonist. The GIP component appears to shift the fat-vs-muscle loss ratio modestly in favor of fat.

SURMOUNT-1 body composition data at 72 weeks on tirzepatide 15 mg:

• Total weight loss: approximately 21% of body weight
• Fat mass loss: approximately 33% of starting fat mass
• Lean mass loss: approximately 10% of starting lean mass
• Ratio of lean mass to total weight lost: approximately 22-25%

That is a modestly better ratio than semaglutide (22-25% versus 25-30%), but the improvement is not dramatic. Tirzepatide is still losing a substantial fraction of total weight as muscle mass.

The GIP receptor is expressed on adipose tissue directly, which contributes to the improved fat-mass reduction. GIP does not have a strong direct effect on muscle preservation in most published work. The muscle-preservation benefit of tirzepatide over semaglutide appears to come mostly from the higher total weight loss (which makes protein and training benefits easier to achieve) and the somewhat better GI tolerability (which lets patients eat more protein). The GIP mechanism itself is not a muscle-preserving mechanism.

For body-recomp goals, tirzepatide is a moderate improvement over semaglutide but is not a solved problem. The same protein-and-lifting protocol still applies.

Cagrilintide (part of Novo Nordisk's CagriSema combination with semaglutide) is a long-acting amylin analog. Amylin acts on the brainstem to reduce appetite through a different pathway than GLP-1's hypothalamic action, and it also slows gastric emptying.

CagriSema body composition data from REDEFINE 1 at 68 weeks:

• Total weight loss: approximately 20.4% of body weight
• Fat mass loss: proportionally higher than semaglutide monotherapy on a percentage basis
• Lean mass loss: proportionally lower than semaglutide monotherapy on a percentage basis

Some preclinical amylin work has suggested that amylin agonists may reduce fat mass proportionally more than lean mass compared to GLP-1 monotherapy. Whether that preclinical signal holds up in humans is not fully settled from the published trial data yet. The CagriSema body-composition benefit over semaglutide alone appears real but modest.

CagriSema missed its non-inferiority endpoint against tirzepatide in REDEFINE 4 (23.0% weight loss versus tirzepatide 25.5% at 84 weeks). The head-to-head miss shifts the amylin-plus-GLP-1 story: cagrilintide adds real muscle-preservation help, but the total weight-loss efficacy still lags tirzepatide. For patients where muscle preservation matters more than absolute weight loss magnitude, CagriSema (once approved) may be a reasonable choice; for patients who want the largest weight loss with acceptable muscle preservation, tirzepatide-plus-protocol may remain the better tool.

Retatrutide (Eli Lilly, expected FDA approval 2027-2028) is a triple GLP-1 + GIP + glucagon receptor agonist. The glucagon component is the new addition, and it changes the muscle-preservation picture in an interesting way.

Retatrutide TRIUMPH-1 body composition data at 68 weeks on the 12 mg dose:

• Total weight loss: 28.7% of body weight
• Fat mass loss: approximately 48% of starting fat mass
• Lean mass loss: approximately 8-10% of starting lean mass
• Ratio of lean mass to total weight lost: approximately 15-18%

That is a substantially better ratio than semaglutide (15-18% versus 25-30%). Retatrutide is losing more absolute weight than any other approved obesity drug, but the proportion coming from muscle is smaller.

The mechanism: glucagon activation increases thermogenesis in brown adipose tissue and drives hepatic fat breakdown. Both effects push energy expenditure up, which means the body can meet energy needs by burning fat rather than by cannibalizing muscle protein. The higher energy expenditure also means calorie deficit at the tissue level is met from fat stores rather than lean mass breakdown, which is the same protective mechanism that endurance-trained athletes maintain during periods of low food intake.

Retatrutide is not yet FDA-approved. Realistic prescribing availability is late 2027 or early 2028. For body-recomp-motivated patients, retatrutide will likely be the best approved-medicine choice when it launches. Until then, tirzepatide plus protocol is the practical near-term tool.

The Hanmi Pharm and Genentech HM17321 licensing deal announced August 24, 2026 ($190 million upfront, up to $2.3 billion in milestones, tiered royalties) puts a substantially different mechanism into the obesity pipeline.

HM17321 is a urocortin-2 (UCN2) analog peptide. Urocortin-2 is a natural 38-amino-acid peptide of the corticotropin-releasing factor (CRF) family. It binds the corticotropin-releasing factor 2 receptor (CRFR2), which is expressed on skeletal muscle, adipose tissue, and parts of the central nervous system involved in appetite regulation.

What is different about UCN2 for body recomp: CRFR2 activation has direct effects on skeletal muscle. Preclinical studies have documented that CRFR2 agonism can drive skeletal muscle hypertrophy (muscle growth) and reduce muscle atrophy during periods of reduced food intake. This is the opposite of what GLP-1 monotherapy does to muscle. UCN2 also drives lipolysis (fat breakdown) in adipose tissue directly.

Positioning: Hanmi has framed HM17321 as designed to simultaneously promote weight loss and preserve lean body mass. This is a stronger claim than muscle-preservation as a side effect. In principle, HM17321 could be a genuine body-recomp drug: fat loss plus muscle gain in the same treatment period.

Caveats: HM17321 is in Phase 1 clinical development. Hanmi received FDA IND clearance in November 2025. Preclinical mouse data does not always translate to humans in obesity drug development. The muscle-preservation claim will need to be validated in Phase 2 human body composition data. Realistic FDA approval timeline is 2029-2030 at the earliest.

For body-recomp-motivated patients, HM17321 is a story about the future rather than a near-term option. But it is the first obesity drug that has been designed from the mechanism up to preserve or add muscle during weight loss, which is a substantial shift from the appetite-suppression paradigm that has dominated the last decade.

Drug choice matters for body recomp. Protocol matters more. Three non-drug factors determine most of the muscle-preservation outcome on any current GLP-1:

Protein intake. Body recomp requires 1.2 to 1.6 g of protein per kg of bodyweight per day. Older adults and those doing intensive resistance training should target the higher end. For someone at 200 pounds (90 kg), that means 110-145 grams of protein per day. That is substantial when appetite is suppressed. Practical strategies: high-protein breakfast (eggs, Greek yogurt, cottage cheese) before the drug's peak effect kicks in; protein shakes when solid food is unappealing; leucine-rich protein sources (whey, meat, fish) which trigger muscle protein synthesis more effectively than plant protein.

Resistance training. Progressive resistance training 2-4 times per week is the strongest signal for muscle preservation during weight loss. Compound movements (squat, deadlift, bench press, overhead press, pull-up) target the largest muscle groups. Training near failure (RPE 8-9 out of 10) with adequate volume (10-20 sets per muscle group per week) is the standard evidence-based recommendation. Cardio does not preserve muscle; it can worsen the muscle-loss problem if it replaces resistance training in the schedule.

Weight-loss rate. Losing 0.5-1% of bodyweight per week is the body-recomp-friendly range. On a 200-pound person, that is 1-2 pounds per week. Losing 3-4 pounds per week (which some GLP-1 patients achieve at higher doses) shifts the fat-vs-muscle loss ratio toward more muscle loss. If muscle preservation matters, the practical response is to either titrate the dose down, extend time between doses to reduce steady-state exposure, or eat more calories (higher food intake with the same drug produces slower but more muscle-friendly weight loss).

All three factors compound. A patient at 200 pounds on Wegovy who eats 130g protein per day, trains resistance 3 times per week, and loses 1.5 pounds per week will have substantially better body composition outcomes at 12 months than a patient at the same weight on the same drug who eats 60g protein per day, does no training, and loses 3 pounds per week. The drug is the same; the outcome is dramatically different.

Some patients and clinics stack additional peptides with their GLP-1 in an attempt to preserve or add muscle. The evidence base for these stacks in humans is limited; most of the underlying biology is well-characterized in isolation but not specifically studied in combination with GLP-1s during aggressive weight loss.

Sermorelin, ipamorelin, CJC-1295. These are growth-hormone-releasing peptides (GHRH analogs or ghrelin mimetics). They stimulate the pituitary to release growth hormone in a more physiologic pulsatile pattern than exogenous growth hormone would. GH drives IGF-1 production, which has muscle-preserving and mildly anabolic effects. Compounded through 503A pharmacies, these peptides have been used off-label for years for anti-aging, recovery, and muscle-preservation goals. Evidence base for combination with GLP-1s is anecdotal.

MK-677 (ibutamoren). Non-peptide small molecule that stimulates GH release. Similar effect profile to the GHRH peptides. Not FDA-approved for any indication. Available gray-market as a research chemical.

Testosterone replacement therapy (for eligible men). Men with clinically low testosterone (total T below approximately 300 ng/dL with symptoms) may benefit from testosterone replacement combined with a GLP-1. TRT has strong evidence for muscle preservation and fat loss when medically indicated. This is standard endocrinology care, not experimental peptide stacking.

BPC-157 and TB-500 (thymosin beta-4 fragment). Sometimes stacked for recovery and injury prevention during resistance training. No specific evidence that they help muscle preservation during GLP-1 weight loss.

Practical framing: these stacks may help at the margins for motivated patients working with a knowledgeable prescriber. They are not a substitute for the protein-training-rate protocol. And gray-market sources for these peptides carry the usual quality-control and safety risks. For consumers considering these stacks, working with a licensed prescriber and a legitimate 503A compounding pharmacy is the safer approach than online research-chemical vendors.

For a consumer wanting to actually do body recomp on a current GLP-1 (semaglutide or tirzepatide) rather than pure weight loss, here is a defensible protocol based on published evidence and clinical experience:

Phase 1: Titration (weeks 1-16 for semaglutide, 1-20 for tirzepatide).

• Follow the standard titration schedule to reach the target dose (2.4 mg semaglutide or 10-15 mg tirzepatide).
• Start protein tracking now. Target 1.2-1.6 g/kg/day. Use a food-tracking app for the first 4 weeks to calibrate.
• Start resistance training 3x per week if not already training. Full-body sessions, compound movements, progressive overload. If already training, keep it.
• Weight loss during titration will be relatively slow; that is fine. Focus on building the habit stack.

Phase 2: Maintenance dose (months 4-12).

• Continue at target dose.
• Weekly weight loss target: 0.5-1% of current bodyweight per week (0.75-1.5 pounds per week for a 200-pound person).
• If weight loss is faster than that range, increase food intake modestly (add 100-200 kcal per day from protein and complex carbs).
• Track body composition every 3 months with a DEXA scan alongside scale weight. DEXA measures lean mass and fat mass separately. Bodpod or InBody are cheaper alternatives; both are less accurate but useful for tracking trends.
• Progressive resistance training continues 3-4x per week. Add sets and weight over time as recovery allows.

Phase 3: Plateau or goal (month 12+).

• Body recomp goals are typically defined in body-fat-percentage or specific lean-mass targets, not scale weight.
• Decide whether to continue at maintenance dose, taper to a lower maintenance dose, or discontinue.
• Muscle preservation post-discontinuation depends on maintaining protein intake and training. Weight regain of 60-70% is common if protein and training stop; regain is closer to 20-30% if protein and training continue.

What to ask your prescriber:

• DEXA scan baseline before starting and every 3-6 months during therapy.
• Discuss whether tirzepatide (better body-recomp ratio) makes more sense than semaglutide for your specific case.
• If retatrutide becomes available (2027-2028), discuss whether switching makes sense.
• If you have low testosterone symptoms, get labs and discuss TRT eligibility.

What NOT to do:

• Do not try to lose 3-4 pounds per week on a GLP-1. That rate is not compatible with muscle preservation.
• Do not skip protein because you are not hungry. Force it. Protein shakes exist for exactly this problem.
• Do not add cardio at the expense of resistance training. Prioritize lifting.
• Do not stack gray-market growth hormone peptides without a licensed prescriber overseeing. The safety math changes at that point.

GLP-1 monotherapy is not a body-recomp tool on its own. Semaglutide loses roughly 25-30% of total weight as lean mass; tirzepatide is modestly better at 22-25%; retatrutide (when approved) will likely be substantially better at 15-18% because glucagon activation drives energy expenditure through fat burning rather than muscle breakdown.

The muscle-preservation mechanism landscape looks like this:

• GLP-1 alone: baseline muscle loss during weight loss
• GIP add-on (tirzepatide): modest improvement, mostly through better efficacy and tolerability
• Amylin add-on (CagriSema): modest improvement, more preclinical than confirmed
• Glucagon add-on (retatrutide): substantial improvement, glucagon drives energy expenditure rather than protein breakdown
• UCN2 / CRFR2 (Roche's HM17321 in Phase 1): potentially direct muscle-anabolic effect, but 3-5 years from availability

For patients doing body recomp on currently-approved drugs, the drug choice matters less than the protocol. Protein at 1.2-1.6 g/kg per day, resistance training 3-4 times per week with progressive overload, and weight-loss rate held to 0.5-1% of bodyweight per week produce substantially better body composition outcomes than any drug on its own. Tirzepatide plus protocol is the current best combination for most patients wanting real body recomp. Retatrutide plus protocol will be the upgrade when it launches. HM17321 or other UCN2-class candidates could reshape the picture again in 2029-2030 if the mechanism holds up in humans.

One last consumer note: the difference between a GLP-1 patient who ends up 40 pounds lighter with 15% body fat and one who ends up 40 pounds lighter with 25% body fat is not their drug. It is what they did with protein, training, and calorie deficit rate during those 12 months. That is the practical takeaway.