Apitegromab helps tirzepatide users lose fat while preserving lean mass

By Pooja Toshniwal PahariaReviewed by Susha Cheriyedath, M.Sc.Jun 9 2026

A phase 2 trial suggests that blocking myostatin activation may help people taking tirzepatide retain more lean body mass without blunting weight loss.

Study: Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial. Image Credit: New Africa / Shutterstock

A recent phase II randomized clinical trial (RCT) published in the journal Nature Medicine showed that apitegromab, a monoclonal antibody, when administered along with tirzepatide, could help preserve lean body mass while supporting overall weight loss.

Such combination treatments, if validated in further studies, could help individuals improve their body composition by retaining more lean mass while continuing to lose fat. This could address a growing concern about modern weight-loss therapies: how to maximize fat loss while minimizing lean body mass loss, which is important for physical function and long-term health.

People are often prescribed tirzepatide, an incretin mimetic drug, for diabetes management and weight loss. These drugs can also reduce lean mass during weight loss, raising concerns about potential effects on strength, mobility, and metabolic health.

Scientists are therefore exploring treatments that can help preserve lean body mass during weight loss. They believe that apitegromab, an investigational antibody, could improve lean mass by binding to precursors of myostatin, a protein that regulates skeletal muscle catabolism, inhibiting its activation. While early results are promising, further trials are required to validate the findings and support its use in clinical practice.

About the Study

In this double-blind, placebo-controlled EMBRAZE trial, which enrolled participants between June and September 2024, researchers investigated whether apitegromab could preserve lean mass in tirzepatide users. They randomized 102 participants with overweight or obesity in a 1:1 ratio to receive either 10 mg/kg apitegromab every four weeks or placebo, alongside up to 15 mg tirzepatide weekly.

The sample population comprised individuals aged between 18 and 65 years. The participants either had a body mass index (BMI) of at least 27 and below 30 kg/m² with a weight-related health condition, or a BMI of 30–45 kg/m². Their body weight remained stable over the three months before screening despite weight-loss efforts through dietary adjustments.

The study included generally healthy adults with overweight or obesity. The team excluded people with diabetes, heart disease, stroke, blood vessel disorders, or active cancer. They also considered individuals who received chemotherapy, radiation therapy, or immunosuppressive medications in the previous year, or antiobesity and antidiabetic medications in the preceding three months, ineligible.

The team also measured levels of apitegromab and a related protein, latent myostatin, in the blood. Secondary endpoints included measurements of trunk, subcutaneous, and visceral fat. Vital signs, electrocardiographic (ECG) parameters, and clinical laboratory findings were assessed for all participants at multiple time points during the study period.

At week 24, the researchers performed efficacy analyses based on dual-energy X-ray absorptiometry (DEXA) scans of 43 apitegromab recipients and 44 placebo recipients. Eight weeks after discontinuation of the interventions, they conducted exploratory analyses to evaluate the durability of the treatment effects.

They used linear regression models adjusting for baseline characteristics such as age, sex, body weight, and lean mass for statistical analysis. The authors noted that DEXA cannot fully distinguish muscle from other lean compartments and may be affected by hydration levels.

Results

The study predominantly comprised obese women in their early 40s with average body weight ranging from 93 to 99 kg across the two groups. After 24 weeks of treatment, apitegromab recipients lost less lean mass than placebo recipients. On average, apitegromab-treated individuals maintained nearly 2 kg more lean mass than placebo-treated individuals.

Supporting these observations, the researchers found that 85% (about 8.5 kg) of the total weight loss in apitegromab recipients was fat. Compared with placebo recipients, those receiving the active treatment lost 70% (about 8.0 kg) of their weight as fat.

These findings suggest that although both groups demonstrated comparable overall weight loss, apitegromab users were better able to retain lean body mass during weight loss. Compared to the placebo group, these individuals had a 54.9% relative retention of lean mass.

Trunk, subcutaneous, and visceral fat changes were largely similar between the groups. The lean mass differences remained significant even after eight weeks of discontinuing the interventions, although this durability analysis was exploratory.

Vital signs, ECG parameters, laboratory tests, and post hoc efficacy analyses were consistent with the overall findings. However, the trial did not show notable between-group differences in exploratory physical function or cardiometabolic measures.

Serum apitegromab and latent myostatin levels gradually increased after treatment and then stabilized by about 16 weeks. Regardless of individual variations, the 10 mg/kg dose engaged its biological target and inhibited myostatin activation, suggesting durable target engagement. Apitegromab was also tolerated well by the participants.

While more than 70% of participants in both groups experienced adverse events (AEs), only about 2% in each group experienced a serious adverse event (SAE). No SAE was considered related to apitegromab, and nausea, fatigue, and headache were among the events reported more often with apitegromab than placebo.

Conclusions

The findings demonstrate that apitegromab may help preserve lean body mass during tirzepatide treatment. If confirmed in larger trials, this antibody could be an adjunct to pharmacologic weight-loss therapies to preserve lean mass during treatment without compromising overall weight loss.

Future studies should include larger sample sizes, longer follow-up periods, and diverse populations with obesity-related conditions, such as diabetes and cardiovascular disease, to confirm the applicability of the findings in real-world settings.

Researchers should also incorporate objective measures of physical activity and other advanced imaging techniques to help clarify the role of myostatin inhibition as a potential strategy for preserving lean mass during obesity treatment.

Because this was a small phase II trial based primarily on completers and using 80% confidence intervals without multiplicity adjustment, the findings should be interpreted as proof of concept rather than definitive evidence of clinical benefit.

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