Recent advances in treatments for overweight and obesity---such as gastrointestinal (GI) peptide analogs and expanded access to bariatric surgery---have revolutionized weight management by delivering unprecedented weight reductions in clinical practice. These agents include glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the "twincretin" GLP-1 RA/ glucose-dependent insulinotropic polypeptide receptor agonist (GIP RA) agent tirzepatide, the triple agonist retatrutide (targeting GLP-1, GIP, and glucagon receptors), and very recently, a non-peptide GLP-1 RA (orforglipron). These medications produce unprecedented levels of weight loss at accelerated rates. However, they affect not only fat mass, but also skeletal muscle loss, raising concerns about metabolic adaptation, sarcopenic obesity, and long-term weight regain among patients. Understanding and addressing muscle mass preservation is therefore essential to optimize sustained cardiometabolic outcomes beyond initial weight reduction.
Background
Multiple studies have demonstrated that reductions in fat mass are also associated with a decrease in fat free mass (FFM, which includes skeletal muscle), regardless of the method used to lose weight.1,2 Nevertheless, there are differences in the proportion of FFM lost, which do vary by which approach is taken (Figures 1A, B and C). Amongst those on very low-calorie diets (<900 kcal/day), muscle mass loss was similar whether or not the individuals had type 2 diabetes mellitus (T2DM) or not.2 Interestingly, in that analysis, non-diabetics restricted to 400-600 kcal/day had significantly less reduction in both body weight and fat mass than diets of 600-900 kcal/day.2 Another analysis demonstrated that the greater the calorie restriction and the faster the rate of weight loss, the greater the proportion of FFM lost.3 In pivotal studies for recent weight loss medications, the FFM is even greater, reflecting both the amount and accelerated rate of weight loss that they produce.3-7 Figure 1C compares the pivotal weight loss studies for newer weight loss medications: the injectable GLP-1 RA semaglutide (STEP 1),4 tirzepatide (SURMOUNT-1)5, retatrutide (TRIUMPH-4)6,7, and orforglipron (ATTAIN-1).8
Difficulties Comparing Body Composition
Any discussion about the proportion of weight loss that can be attributed to non-fat mass must include reference to the nomenclature and methods of measurement used, as well as the body tissue analyzed. For example, there has been confusion in the past as to whether fat-free mass (FFM) and lean mass (LM) reflect the same body compartments; according to an analysis by Heysmfeld et al, they are.9 The various body components relevant to weight loss are represented in Figure 2, and include the assumption that adipose tissue itself contains fat-free elements (estimated to be 15% of adipose tissue).10 It's important to note that FFM/LM does not accurately reflect skeletal muscle mass.10
Various methods have been used to gauge fat percentages and other body components. Dual energy X-ray absorptiometry (DEXA) is considered the gold standard for measurements of fat, muscle, and bone, though MRI is more useful for determining intramuscular fat infiltration (myosteatosis) and may be more accurate than DEXA for LM.11 The latest multi-frequency versions of bioelectric impedance analysis (BIA) devices have moderate-high accuracy, are easy to use, and are especially useful for measuring changes over time; models include the InBody and Evolt scanners. The InBody demonstrates high retest reliability in healthy people, though tends to underreport body fat percentage by ~3%.12 However, with increasing BMI, the InBody BIAs' deviation from DEXA analyses reduces.13
Another issue that arises when evaluating the effect of weight loss interventions on muscle mass is that while overweight and obese people have increased fat mass, they also have increased skeletal muscle mass (as a consequence of their greater weight-bearing load), albeit with relatively decreased strength, mobility and function.14 Therefore, it's been argued that the decrease in FFM is to be expected as they lose weight, and may not be problematic if the muscle changes reflect an adaptive (rather than maladaptive) or even enhanced response to weight loss.14 (Adverse effects on muscle health or function are maladaptive changes, while minimal effects are adaptive and improvements in health or function are enhanced changes.)14 In addition, most researchers measure FFM/LM rather than skeletal muscle mass, so the decrease seen includes non-muscle elements of FFM (including the non-fat components of adipose tissue, which -- as noted earlier -- has been estimated to be ~15% of it).
It's therefore been argued that a more accurate reflection of the effects on muscle mass of weight loss interventions can be obtained by comparing changes in muscle volume MRI measurements as weight changes. Z-scores (the numbers of standard deviations from the mean for a matched group) are used to determine whether a change in muscle volume is as expected for an individual's weight, height, gender and age.14 A Z-score of 0 indicates that the change in muscle volume does not deviate from the expected mean, a score >0 shows an increased value above the expected mean, and a score <0 reflects a greater loss than expected. A recent evaluation of the thigh muscle volume Z-scores in overweight and obese people with T2DM demonstrated that the participants all had reduced muscle volume at baseline (Z-score -0.48), which was further significantly reduced by tirzepatide (pooled tirzepatide result --0.22, p<0.00001).15 Z-scores reduced more as the dose of tirzepatide increased, and those aged ≥60 had a significantly greater reduction in Z-score than younger individuals (moving from -1.0 to -1.27, p=0.016 vs. the younger age group).15
Whichever measure is used, nevertheless, the importance of analyzing body composition remains, with the aim to preserve FFM/LM while losing fat mass.1
Consequences of Reduced Skeletal Mass
Sarcopenia -- a reduction in skeletal muscle mass, strength, and function -- is associated with multiple adverse effects that may be present even if the Z-score for muscle volume remains constant (i.e., the loss is commensurate for an individual's new weight). Muscle is metabolically active: it's responsible for 70% of post-prandial glucose absorption and is important in whole-body protein metabolism, especially during physiological stress.16 Sarcopenia seen in heart failure- and cancer-related cachexia is an important determinant of survival, and burn victims who have lower LBM mass have reduced survival rates.16 Adequate muscle mass, strength and function are necessary to maintain metabolic health, insulin sensitivity, physical function, and cardiovascular health.16 The effects of reduced muscle mass can be grouped as follows.
Physical function
- Reduced strength2,14
- increased frailty with reduced ability to perform activities of daily living.
- reduced ability to exercise.
- Higher risk of falls.17
- Decreased quality of life.
A meta-analysis in overweight and obese individuals with diet-induced weight loss suggested a negative effect on muscle strength, with a significant reduction in leg extensor strength.18 Similarly, a meta-analysis of the effects of bariatric surgery on post-operative muscle strength showed significant reductions in muscle strength as BMI decreased.19
Metabolic effects
- Reduced energy expenditure (REE)/decreased basal metabolic rate: each 1kg of muscle lost reduces REE by ~10-13 kcal/day (vs. ~4 kcal/day for each kg of fat lost), which would produce an increase in fat of ~4.7 kg/year.14,16
- The "fat overshoot": if the weight loss intervention ceases, rebound weight gain is common. With a lower REE, the gain is likely to be in fat rather than muscle, with consequent worse glycemic control, leaving the individual metabolically worse off.1,2
Osteoporosis
- The direct mechanical effect of body weight and exercise on bone's strength and mass is reported to be less than that from muscle contractions, because more force/unit area is required to move heavier bodies.16
- If muscle strength is not maintained, there is a parallel loss of bone strength and density.16
Cardiovascular health
- Impairment of myokines with decreased muscle mass may lead to endothelial dysfunction and arterial stiffness.20
- There is a proven association between endothelial dysfunction and sarcopenia/reduced hand grip strength.21
Muscle Preserving Strategies
There are several suggestions for mitigating the effects of weight loss on muscle mass, including the use of exercise programs, adequate (or increased) protein intake, certain supplements, and investigational agents.
Exercise
Muscle mass is preserved during weight loss by endurance and resistance training, though only the latter also helps improve muscle strength.14 In addition, exercise improves insulin sensitivity.16 However, exercise is better at preventing loss of muscle than of restoring lost muscle mass.16 Consequently, resistance training should be recommended as part of a weight loss program (in addition to aerobic exercise), but it's often neglected in lifestyle "prescriptions".22 Moreover, fatigue associated with weight loss may impair patients' ability to undertake physical activity during weight loss programs.14
Protein intake
Protein intake directly affects muscle protein.14 Amino acid supplementation improves insulin sensitivity and muscle function and strength in older people, and improves metabolic control in T2 diabetics.14 While a daily intake of 0.8 g/kg/day or 10-35% of daily calorie intake has been typically recommended as the recommended daily allowance, this figure is based on nitrogen balance studies in healthy young adults and is the minimum amount required to prevent deficiency in healthy, weight-stable adults. It does not reflect the amount needed to counter FFM loss during caloric restriction. Indeed, figures of 1.2-≥2 g/kg/day have been recommended during weight loss programs, especially with the degree of FFM lost with newer medications.1,14 A specific guide to protein requirements can be found in our Optimizing Protein Intake for Muscle Preservation clinical guide.
Muscle-preserving supplementation
Figure 1B compares FFM loss with the use of a variety of weight loss supplements purported to help reduce BMI.1 Although the results with using chromium picolinate look promising, subsequent studies have not replicated these. However, this year a study assessing the effects of Amarasate, a nutraceutical derived from bitter hop flowers, has shown encouraging results. Previous clinical research determined that Amarasate increased GLP-1, cholecystokinin (CKK) and peptide tyrosine tyrosine (PYY) by 6.4, 6, and 1.7 times, respectively, with a subsequent 18% reduction in calories consumed, after a single 500 mg dose.23 In a 24-week double-blind, randomized comparison of Amarasate 250 mg (an hour before two meals a day) and placebo, average weight loss in those receiving the nutraceutical was 3.8 kg (-4.3%) -- significantly more than the placebo group (-0.4 kg / - 0.5%).24 . However, this weight loss was achieved with preservation of muscle mass (determined by InBody multi-frequency BIA scanning): those taking Amarasate showed a 0.9 kg increase, so that the muscle-mass adjusted weight loss increased to -5.3% (Figure 3).24 While not significant versus baseline, the preservation of muscle mass reflects a distinct departure from most other weight loss interventions.
As noted earlier, Amarasate not only increases GLP-1, but also CCK and PYY, which occurs following activation of bitter taste receptors on enteroendocrine L-cells. PYY receptors exist in skeletal muscle and human muscle progenitor cells (satellite cells), and these tissues may also be a source of PYY.25 PYY is thought to have a role in skeletal muscle regeneration,26 so it's possible that increased levels associated with Amarasate use helped preserve muscle mass in the recent trial.
Investigational agents
Muscle growth is negatively affected by the peptides activin A and myostatin that attach to the activin type II receptor.14 A study evaluating the use of bimagrumab, a monoclonal antibody that binds to the receptor (blocking activin A and myostatin), led to a modest weight loss of 6.5% after 48 weeks in obese T2 diabetics, but a reduction in fat mass of 20.5% and an increase in lean mass of 3.6%.27 Other monoclonal antibodies against these peptides have shown promising results in animal studies.14
Conclusion
Preservation of skeletal muscle mass during deliberate weight loss is a critical clinical element, as disproportionate FFM loss is associated with multiple unwanted effects, including the risk of a worse metabolic state once the weight loss intervention ceases. Loss of FFM occurs with almost all methods used for weight loss, though is greater with those that cause more profound and faster effects. The widespread use of medications like semaglutide and tirzepatide with associated FFM losses of 25-40% has caused concern that we will be facing an epidemic of sarcopenia (in those who remain on them) and sarcopenic obesity (in those who stop using them). Incorporating exercise programs that include resistance training and nutritional advice to increase protein intake well beyond typical recommendations are necessary parts of any weight loss program. The use of Amarasate (available as Calocurb capsules), may help preserve muscle mass in addition to aiding weight loss. In addition, concurrent use of Amarasate with GLP-1 RAs allows for reduced dosing of the medication (with a reduction in adverse events), likely helps preserve endogenous production of GLP-1 (which is blunted by the peptide analogs) and may be beneficial in reducing FFM loss due to its effect on PYY.
