Semaglutides and co.

Semaglutides (Ozempic, Wegovy, Rybelsus, etc.) are part of a new generation of medications that have changed how we approach two very common and often related diseases: type 2 diabetes and obesity. Initially, these treatments were designed to help control blood sugar. But within a few years, a clinical observation shifted their status: in many patients, they also led to significant weight loss, enough to become one of the most effective pharmacological tools available today against obesity.

Where do they come from?

The story begins with GLP-1 (glucagon-like peptide-1), a hormone released by the intestine after a meal. GLP-1 acts as a “post-prandial” signal: it stimulates insulin when glucose rises, suppresses glucagon, slows gastric emptying, and, via the brain, contributes to satiety. However, natural GLP-1 is rapidly degraded and its effects are very short-lived (its half-life in the body is only a few minutes), which makes it unusable as-is as a medication.

Researchers therefore sought to create GLP-1 analogues (GLP-1 receptor agonists) capable of resisting degradation and lasting long enough for practical use. Semaglutides are an emblematic example of this optimization: modifications make it possible to achieve a duration of action of about one week. This time window paved the way for a weekly injection, making use easier and reducing the burden of multiple high-frequency injections for patients.

How does it work?

Semaglutide is often presented as an “appetite suppressant,” but it is more nuanced than that: it is a medication that modifies hunger/satiety signals and the metabolic response to meals. It acts on several organs and systems, such as the pancreas (management of insulin and glucagon), the intestine and stomach (slightly slower digestion and emptying, earlier sensation of fullness), and the brain and appetite-regulation areas (less hunger, fewer food cravings).

Why use it?

Because this molecule has substantial effects on appetite regulation, its use mainly aims to influence energy balance. By facilitating prolonged exposure to an energy deficit through reduced energy intake, semaglutides indirectly affect weight and body composition. Combined with effects on blood glucose regulation, its use is particularly effective in combating type 2 diabetes and overweight/obesity.

Recently, a third axis has gained momentum: cardiovascular risk. The SELECT1 study showed, in people with overweight/obesity without diabetes but with established cardiovascular disease, a reduction in major cardiovascular events under semaglutide.

Side effects

Known adverse effects are mainly digestive: nausea, vomiting, diarrhea, constipation, abdominal discomfort. In several studies, they are often transient, appearing mainly during gradual dose escalation, but they can lead some patients to discontinue treatment. However, an important point must be considered: stopping the medication is frequently accompanied by weight regain, raising the question of treatment as a long-term strategy, in the same way as hypertension or hypercholesterolemia.

Effects on weight and body composition

Although semaglutides appear to demonstrate formidable effectiveness in inducing a prolonged energy deficit, what are the effects on body composition?

In the presence of severe “voluntary” caloric restriction, a major reduction is observed in both fat mass and lean mass compartments. While the decrease in fat mass is desirable, the decrease in lean mass, more specifically the muscle mass fraction, can lead to less desirable collateral effects, especially in people who do not have a large initial lean mass.

As shown in many classic studies by pioneers in the field2-6, the larger the energy deficit, the larger the effects on muscle mass. A massive reduction in nutritional intake then substantially alters fat mass and lean mass. When the decrease in lean mass, more specifically muscle mass, is very large, it is generally followed by a loss of functional capacity (decreased aerobic capacity and muscle strength, to name just those)5,6.

Weight loss: rapid kinetics at the beginning, then slowing

Data from randomized studies7-9 on semaglutides indicate non-linear weight loss: it is generally faster in the first months, then gradually slows as treatment continues (a partial plateau phenomenon). This kinetics is also observable in the presence of a prolonged “voluntary” energy deficit, where an initial so-called “rapid” phase is observed followed by a second, slower and progressive phase10 (there is also a third phase, but it is rarely observed because it leads to death2-4).

A meta-analysis of studies models the dynamics in two phases and estimates an average loss of about 0.04 kg per day under semaglutide, with a slowing as duration increases (a time “flattening” kinetics)7. Semaglutides and their effects on energy balance would therefore also be subject to the same limitations as weight loss induced by a voluntary energy deficit (decrease in cellular mass leading to lower energy expenditure, potential modification of energy expenditure associated with physical activity, and, less importantly, a potential slowing of resting metabolic rate).

In terms of magnitude, the STEP trials9 report average losses on the order of ~15–17% of initial body weight at 68 weeks in people without diabetes, with semaglutide 2.4 mg weekly (with counseling-type support). In people with type 2 diabetes (STEP 2), average weight loss is more moderate (for example ~9.6% at 68 weeks with 2.4 mg, versus ~7.0% with 1.0 mg). Another important timeline element comes from STEP 4: after an initial 20-week treatment phase (including dose escalation), participants who continue semaglutide keep losing weight on average, while those who switch to placebo regain weight, illustrating that treatment also acts as a maintenance tool for weight loss9.

The meta-analysis of randomized trials focused on body composition estimates that, on average, about 75% of mass loss under semaglutide is attributable to fat mass, suggesting a preferential effect on adipose tissue. Lean mass also decreases, but more slowly: the meta-analysis models a decrease of about 0.007 kg/day of FFM, with a rather linear trajectory (without a plateau as marked as total weight)7.

In the Minnesota study5,6 on the effects of caloric restriction and refeeding in humans, non-obese participants were exposed to substantial caloric restriction (50% of their energy needs were met) for 24 weeks. During this restriction phase, participants lost on average 24% of their initial weight, 69% of their initial fat mass, and 18% of their initial lean mass. Given the substantial restriction, the kinetics of “voluntary” weight loss was around 0.105 kg/day for total weight, 0.04 kg/day for fat mass, and 0.06 kg/day for lean mass (values relatively normal for non-obese individuals subjected to this type of caloric restriction).

Comparative timeline: fat mass vs lean mass

A similar timeline is observed between semaglutide use and a voluntary energy deficit in terms of the kinetics of changes in body composition: an initial rapid decrease in both compartments, followed by a progressive dissociation between fat mass loss and lean mass loss, with the latter tending to decrease less than fat mass.

In the prospective SEMALEAN study8 (semaglutide 2.4 mg; DXA measurements), average weight loss is about ~10% at 7 months and then ~13% at 12 months. Fat mass decreases markedly (~14% at 7 months; ~18% at 12 months). In contrast, lean mass decreases initially (≈ 3 kg at 7 months) and then stabilizes between 7 and 12 months.

A systematic review11 focused on lean mass highlights that the share of lean mass in total loss can range from nearly 0% to ~40% depending on the studies, while noting that the relative proportion of lean mass can nonetheless improve (because fat mass decreases more).

Do semaglutides change energy expenditure?

Semaglutides mainly cause weight loss by decreasing energy intake (appetite, food intake, “control of eating”). But beyond reducing calories eaten, do these treatments also modify the different components of total energy expenditure (i.e., resting metabolism, diet-induced thermogenesis, and energy expenditure linked to physical activity)?

Resting metabolism

Resting metabolism (or resting energy expenditure) is strongly determined by lean mass (mainly organs and muscle mass). During weight loss, it is therefore common to observe a decrease in total energy expenditure and resting metabolism, simply because the body and the cellular mass to maintain are smaller12.

This aspect is clearly visible: under semaglutides, obese mice lose a lot of fat mass as well as lean mass (about 9–10% in this model at 1–3 weeks), which can mechanically help reduce energy expenditure13.

However, the magnitude of the reduction in energy expenditure associated with metabolism seems mainly caused by changes in body composition. When energy expenditure is corrected for lean mass (which makes it possible to assess whether the body “spends less at equal size”), the results do not suggest a durable collapse in energy expenditure induced by the drug. In obese mice, energy expenditure decreases transiently at the beginning of treatment, then returns to levels comparable to control; and an analysis adjusted for lean mass finds no difference between semaglutides and control14. Similar effects tend to be observed under “voluntary” caloric restriction in humans, where any potential slowing of resting metabolism might amount to a few percent, if it exists at all15.

Dietary thermogenesis

Dietary thermogenesis (or the thermic effect of food) corresponds to the energy spent to digest, absorb, and metabolize nutrients. In humans, it depends largely on the quantity and composition of meals. Consequently, a treatment that strongly reduces energy intake can lower dietary thermogenesis simply because there is less food and fewer macronutrients to process.

Recent clinical trials on semaglutides mainly highlight a clear reduction in energy intake and hunger sensations. For example, in a 20-week controlled trial with oral semaglutide 50 mg/day, ad libitum energy intake decreases sharply (−39%) and weight drops by about 9.8%16. This roughly 39% decrease in energy intake mechanically implies an expected decrease in dietary thermogenesis.

By contrast, direct and “compartmentalized” measurements of dietary thermogenesis under semaglutide do not appear to be present in the scientific literature at the time of writing this article. The main takeaway is therefore that the most robust and best-established effect is indirect: less energy ingested, therefore less dietary thermogenesis, which can contribute slightly to the decrease in total energy expenditure during weight loss12,16.

24h physical activity

Data on physical activity and semaglutide use are scarce. In rodents, locomotor activity is maintained under semaglutides14. But a more recent result nuances the story: even if the animal moves as much, the energetic cost of movement could decrease if muscles become more efficient. In a murine model, semaglutide-induced weight loss increases oxidative phosphorylation efficiency in skeletal muscle, resulting in lower oxygen consumption in permeabilized muscle fibers13. Permeabilized muscle fibers (often called skinned fibers, saponin-permeabilized) are bundles of fibers or small portions of muscle whose plasma membrane (the sarcolemma) has been made permeable in order to control the intracellular environment, while keeping the architecture and mitochondria nearly intact. This “improvement” in oxidative capacity or muscle efficiency is also observable in humans and manifests as a slight reduction in resting energy expenditure during caloric restriction after correction for body size. However, this improvement in muscle oxidative function does not seem to translate into an improvement in aerobic capacity or mechanical efficiency. In the Minnesota study5,6, participants’ fitness was assessed before and after the 24 weeks of caloric restriction (~50% of energy needs met). The results are unequivocal: a marked decrease in aerobic capacity of about 70% is observed after 24 weeks of caloric restriction. If the muscle seems more economical in using oxygen, this improvement does not seem to carry over to exertion.

The conclusion that each movement “costs” less remains to be measured, and any speculation would therefore be hazardous regarding a decrease in physical-activity-related energy expenditure induced by increased muscle efficiency. If we consider the 70% reduction in aerobic capacity, what we risk observing is a reduction in moderate-intensity physical activity or higher. In individuals whose daily physical activity pre–weight loss is very low, this decrease in aerobic capacity and functional capacity following caloric restriction may have little or no impact on physical-activity-related energy expenditure. However, a marked decrease in aerobic capacity is associated with a significant risk of premature death from all causes17 and could restrict participants to a sedentary lifestyle, their aerobic capacity making moderate- or vigorous-intensity physical activity exhausting and arduous.

Muscle strength is another component of physical activity that is affected by caloric restriction. With substantial caloric restriction, a notable decline in grip strength (an indicator of overall strength) of about 25% is observed after 24 weeks5,6. Interventions using semaglutides report maintenance18 or even an increase in grip strength8 when total weight loss is about 10% of initial body weight. The average baseline grip strength of participants in the two previous studies is around 27 to 32 kg for the dominant hand. The results of these two studies combine the values of men and women. The baseline values are relatively low considering that the clinical weakness threshold in women is 16 kg and in men 26 kg19. It will be interesting to see the results of the Cortez study once data are available in order to get a better idea of the effects of an energy deficit induced with semaglutides on two pillars of physical fitness that have an important influence on health20.

Semaglutides illustrate a turning point in the management of type 2 diabetes and obesity: by durably mimicking GLP-1, they act simultaneously on glycemic regulation, satiety, digestion, and brain appetite circuits, enabling a marked and relatively durable reduction in energy intake and therefore weight. Clinical results (the STEP program) and the emergence of a cardiovascular benefit (SELECT) reinforce their relevance beyond the simple “weight-loss drug.” In return, their use is accompanied by sometimes limiting digestive side effects, a frequent risk of weight regain upon discontinuation, and a central issue of the quality of weight loss (preserving lean mass, function, and physical fitness). This is a powerful tool, but it ideally fits within a structured, long-term monitored strategy, where the goal is not only to lose weight, but to lose “better” and maintain the benefits. Improving physical fitness and reducing sedentary behavior should be inseparable collateral objectives of semaglutide use.

Recommendations

  • Ensure you have a 24-hour measure of physical activity level before starting the medication
  • Ensure you have a measure of your aerobic capacity before starting the medication
  • Ensure you have a measure of your muscle strength (lower limbs, upper limbs)
  • Ensure you have a measure of your body composition that allows quantifying lean mass and fat mass
  • Reassess the above elements at regular and reasonable time intervals (6 to 8 weeks) in order to determine the nature of the changes
  • Try to monitor the magnitude of the energy deficit
  • Always consult a competent healthcare professional when using this type of medication, ideally a multidisciplinary team (physician, pharmacist, dietitian, kinesiologist)

References

  1. Lincoff, A.M., et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 389, 2221–2232 (2023).
  2. Benedict, F.G. The Influence of Inanition on Metabolism, (Carnegie Institution of Washington, 1907).
  3. Benedict, F.G., et al. A Study of Prolonged Fasting, (Carnegie Institution of Washington, 1915).
  4. Benedict, F.G., Miles, W.R., Roth, P. & Monmouth Smith, H. Human Vitality and Efficiency Under Prolonged Restricted Diet, (Carnegie Institution pf Washington, 1919).
  5. Keys, A., et al. The Biology of Human Starvation Volume I, (University of Minnesota Press, 1950).
  6. Keys, A., et al. The Biology of Human Starvation Volume II, (University of Minnesota Press, 1950).
  7. Giorelli, G., et al. Body Composition Changes with Semaglutide: A Systematic Review and Meta-Analysis. (Cold Spring Harbor Laboratory, 2025).
  8. Alissou, M., et al. Impact of Semaglutide on fat mass, lean mass and muscle function in patients with obesity: The SEMALEAN study. Diabetes, Obesity and Metabolism 28, 112–121 (2026).
  9. Bergmann, N.C., Davies, M.J., Lingvay, I. & Knop, F.K. Semaglutide for the treatment of overweight and obesity: A review. Diabetes, Obesity and Metabolism 25, 18–35 (2023).
  10. Heymsfield, S.B., et al. Voluntary weight loss: systematic review of early phase body composition changes. Obesity Reviews 12, e348–e361 (2011).
  11. Bikou, A., Dermiki-Gkana, F., Penteris, M., Constantinides, T.K. & Kontogiorgis, C. A systematic review of the effect of semaglutide on lean mass: insights from clinical trials. Expert Opinion on Pharmacotherapy 25, 611–619 (2024).
  12. Christoffersen, B.Ø., et al. Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss. Obesity 30, 841–857 (2022).
  13. Choi, R.H., et al. Semaglutide‐induced weight loss improves mitochondrial energy efficiency in skeletal muscle. Obesity 33, 974–985 (2025).
  14. Gabery, S., et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 5(2020).
  15. Nunes, C.L., et al. Does adaptive thermogenesis occur after weight loss in adults? A systematic review. British Journal of Nutrition 127, 451–469 (2022).
  16. Gabe, M.B.N., et al. Effect of oral semaglutide on energy intake, appetite, control of eating and gastric emptying in adults living with obesity: A randomized controlled trial. Diabetes 26, 4480 – 4489 (2024).
  17. Kodama, S., et al. Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality and Cardiovascular Events in Healthy Men and Women: A Meta-analysis. JAMA : the journal of the American Medical Association 301, 2024–2035 (2009).
  18. Xiang, J., et al. Clinical effectiveness of semaglutide on weight loss, body composition, and muscle strength in Chinese adults. European Review for Medical & Pharmacological Sciences 27(2023).
  19. Cruz-Jentoft, A.J., et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48, 16–31 (2019).
  20. Cortes, T.M., et al. Effect of Semaglutide on Physical Function, Body Composition, and Biomarkers of Aging in Older Adults With Overweight and Insulin Resistance: Protocol for an Open-Labeled Randomized Controlled Trial. JMIR Research Protocols 13, e62667 (2024).