Muscle Matters: The Lean-Mass Problem with Appetite-Based Weight Loss

GLP-1 receptor agonists have revolutionized obesity treatment, making significant weight loss pharmacologically achievable for millions of patients. However, these medications come with notable trade-offs. From a clinical perspective, one of the most concerning is the simultaneous loss of muscle mass. Studies show that when patients lose weight on GLP-1 medications, more than 30% of the lost weight comes from lean mass, including muscle, rather than fat. [1]

Why Muscle Loss Matters

Preserving skeletal muscle during weight loss is critical for several key reasons:

• Metabolic Rate: Muscle tissue burns significantly more energy than fat tissue, even while the body is at rest. [2] Losing muscle lowers an individual's Resting Metabolic Rate (RMR), reducing the number of daily calories burned naturally.
• Blood Sugar Control: Skeletal muscle is the body’s primary sink for glucose, absorbing up to 80% of the sugar that enters the bloodstream after eating. [3,4]
• Physical Function and Mobility: Muscle loss compromises physical strength, joint stability, and balance - muscle loss is a particular hazard for older adults who already have lower baseline muscle mass.
• Bone Health: The mechanical tension exerted on bones by muscle contractions stimulates bone density, helping protect against osteoporosis and fractures.
• The Weight-Regain Trap ("Sarcopenic Obesity"): If a patient stops taking a GLP-1, weight regain is common. During this phase, the body naturally prioritizes storing fat over rebuilding muscle. A person can easily regain all their lost weight - or more - while ending up with a higher body fat percentage and a lower metabolic rate than when they started. This shift toward low muscle mass and high body fat is known as sarcopenic obesity. [5-7]

A Different Approach: Boosting Energy Expenditure

It is worth noting that muscle loss is not unique to GLP-1 drugs; it occurs with almost any form of caloric restriction, whether through traditional dieting, fasting, or other appetite suppressants.

Because GLP-1 medications are now so widely prescribed, preserving muscle has become a central focus for the next generation of anti-obesity therapies. Researchers are exploring strategies to curb muscle loss, and one approach stands out: enhancing energy expenditure. Unlike appetite suppressants - which cause weight loss by cutting calories in - therapies that increase calorie burning (calories out) appear to drive weight loss almost exclusively from fat stores while leaving muscle intact.

At Energesis, we believe that targeting energy expenditure could become an essential component of future weight management protocols.

Looking Ahead: Early Research at Energesis

A Preclinical Disclaimer: EGS-2632, Energesis’ most advanced investigational candidate, is currently pre-clinical. It has been evaluated only in animal models of obesity and has not yet been tested in humans. It is not approved by any regulatory authority, and preclinical results may not predict human safety or efficacy.

In animal models of obesity, EGS-2632 induced significant weight loss while completely sparing muscle mass. All the weight loss comes from fat.

Furthermore, EGS-2632 demonstrated a powerful synergistic effect when combined with GLP-1 therapy:

1. Enhanced Efficacy: Combined treatment produced total weight loss greater than the sum of either therapy used alone.
2. GLP-1 Dose Reduction: Because EGS-2632 amplified GLP-1 efficacy in these models, it could allow GLP-1s to be administered at significantly lower doses, mitigating muscle loss without sacrificing weight-loss results.
3. Muscle Preservation: In our preclinical studies, pairing a low-dose GLP-1 with EGS-2632 produced robust weight loss without detectable muscle loss.

We therefore believe that combination regimens - pairing appetite suppressants with energy-expenditure enhancers like EGS-2632 - may offer a promising path toward healthier, muscle-sparing, and more sustainable weight loss. This vision drives our ongoing research.

Sources

1. Beavers KM, Cortes TM, Foy CM, et al. GLP1Ra-based therapies and DXA-acquired musculoskeletal health outcomes: a focused meta-analysis of placebo-controlled trials. Obesity (Silver Spring). 2025;33(2):225-237.
2. MedlinePlus. Resting Metabolic Rate and Body Composition. U.S. National Library of Medicine.
3. Jensen J, Rustad PI, Kolnes AJ, Lai YC. The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise. Front Physiol. 2011;2:112.
4. Merz KE, Thurmond DC. Role of skeletal muscle in insulin resistance and glucose uptake. Compr Physiol. 2020;10(3):785-809.
5. Donini LM, Busetto L, Bischoff SC, et al. Definition and diagnostic criteria for sarcopenic obesity: ESPEN and EASO consensus statement. Clin Nutr. 2022;41(4):990-1000.
6. Roh E, Choi KM. Health consequences of sarcopenic obesity: A narrative review. Front Endocrinol. 2020;11:332.
7. Stenholm S, Harris TB, Rantanen T, et al. Sarcopenic obesity: Definition, cause and consequences. Curr Opin Clin Nutr Metab Care. 2008;11(6):693-700.