The future of weight-loss drugs: can we lose fat without losing muscle?

For twenty years we judged obesity treatment by a single number: how much weight came off. That question is now being replaced by a better one — what kind of tissue was lost?

Direct answer

Incretin medicines such as semaglutide and tirzepatide produce large weight loss, but a meaningful share of that loss is lean body mass rather than fat. A new class of investigational drugs targeting the myostatin/activin pathway is being tested alongside them, aiming to shift the loss toward fat while preserving muscle. None of these muscle-targeting agents is approved for obesity today.

Why muscle matters

Skeletal muscle is not simply for strength. It is the body's largest site of glucose disposal, a major determinant of resting metabolic rate, and the tissue that most reliably predicts independence in later life. Losing it during weight loss is not a cosmetic issue — it affects glucose control, the ease of maintaining the loss, and physical function with age.

In the phase 2 COURAGE trial, roughly 35% of semaglutide-induced weight loss was lean mass. That is the figure driving this entire field.

A note on terminology that is often blurred: lean body mass is everything that is not fat — muscle, organs, bone, body water. Skeletal muscle mass is a subset of it. Most trials measure lean body mass by DXA, so "lean mass preserved" is not identical to "muscle preserved," and neither automatically means "stronger."

The emerging strategy: anorectic plus anabolic

The concept pairs two mechanisms:

1. An incretin therapy (GLP-1, or GLP-1/GIP) to suppress appetite and drive fat loss.
2. A myostatin or activin-pathway blocker to reduce the muscle loss that accompanies rapid weight reduction.

Myostatin is a natural brake on muscle growth. Blocking it — or blocking the activin type II receptors it signals through — releases that brake.

Three candidates are furthest along:

• Apitegromab — selectively inhibits activation of latent myostatin; studied with tirzepatide in the phase 2 EMBRAZE trial.
• Bimagrumab — blocks activin type II receptors; studied with semaglutide in the phase 2b BELIEVE trial.
• Trevogrumab — an anti-myostatin antibody studied with semaglutide in the phase 2 COURAGE trial, which prevented about half of semaglutide-induced lean-mass loss.

All three remain investigational for obesity. None is approved, and none should be sought outside a clinical trial.

What trials will measure next

Expect endpoints to broaden well beyond the scale:

• Total body weight
• Fat mass and visceral adipose tissue
• Lean body mass — and, increasingly, skeletal muscle mass specifically
• Muscle strength and physical function
• Cardiorespiratory fitness
• Metabolic markers

That shift matters clinically. A 20% weight loss that is 90% fat is a different outcome from a 20% loss that is 70% fat, even though the scale reads the same.

What this means for you today

None of this changes current practice. The approved medications work, and the proven way to protect muscle during weight loss remains unglamorous and effective: adequate protein and resistance training two to three times weekly, whether you are losing weight through medication or surgery. I have written separately on sarcopenia and why this matters with age.

Frequently asked questions

Do GLP-1 drugs cause muscle loss?

Some lean mass is lost with any substantial weight loss. In the COURAGE trial about 35% of semaglutide-induced weight loss was lean mass. Protein intake and resistance training reduce this considerably.

Can weight-loss drugs preserve muscle?

Investigational drugs targeting myostatin and activin receptors have reduced lean-mass loss in phase 2 trials when combined with incretin therapy. None is approved for this use yet.

What is "quality of weight loss"?

It describes the composition of the weight lost — how much is fat versus lean tissue — rather than the total on the scale. It is becoming a primary consideration in obesity trials.

What are myostatin inhibitors?

Drugs that block myostatin, a protein limiting muscle growth. Blocking it may preserve or increase muscle mass. They are investigational in obesity.

Are muscle-preserving obesity drugs approved?

No. Apitegromab, bimagrumab and trevogrumab are all investigational for obesity as of August 2026.

Can you lose fat without losing any muscle?

Not entirely, but the proportion can be shifted substantially through protein, resistance training, and — in trials — these new agents.

This article is educational and does not replace personalized medical advice. Contact Professor Jamal's clinic on WhatsApp +965 60621662.

References: Pratley RE et al., Nature Medicine, 2026 (EMBRAZE); Heymsfield SB et al., Nature Medicine, 2026 (BELIEVE); Regeneron COURAGE phase 2 interim results, EASD 2025.