The consumption of a hypocaloric diet and consequent fat loss lead to alterations in circulating levels of hormones that regulate hunger and satiety, which signals nutrient deprivation to the brain and results in increased hunger and food cravings as well as decreased satiety.^[6] Alongside these physiological nudges to increase energy intake, total daily energy expenditure decreases with weight loss. This occurs for a variety of reasons, including reduced sympathetic nervous system activity, lower circulating levels of leptin and thyroid hormone, and increased skeletal muscle and mitochondrial efficiency. As a result of these changes, incremental decreases in energy intake are often needed over time to produce further fat loss.^[7]

Evidence from observational studies and randomized controlled trials suggests that losing weight quickly often leads to improved long-term weight and fat loss maintenance.^[8][9] However, losing weight quickly may increase the risk of muscle and bone mineral density loss,^[10][11][12] especially if weight loss occurs in the absence of a high-protein diet and resistance exercise. Therefore, athletes who need to maintain peak physical performance during a fat loss phase should pursue a slow rate of weight loss, whereas the average person can decide on their preferred rate of fat loss based on personal preferences.

Exercise is an advantageous adjunct to diet for achieving and maintaining weight loss, although exercise alone is an inefficient way to induce significant weight loss.^[14][15] An umbrella review published in 2021 reported that an exercise program (60–440 minutes of exercise per week, average of 150–200 minutes per week) induces an average weight loss of 1.5–3.5 kg, with aerobic exercise being much more effective than resistance exercise.^[16] Also, resistance exercise can reduce muscle loss associated with weight loss, which is important for preserving metabolic rate and aesthetic goals.

High volumes of exercise (225–400 minutes or 2,000 kcal per week) can induce clinically significant weight loss (at least 5% of initial body weight),^[15] but there are potential limitations to performing even higher volumes of exercise to induce further weight loss.

The traditional view assumes that increasing exercise leads to a corresponding increase in total energy expenditure, facilitating greater amounts of weight loss. However, more recent evidence suggests that there is a plateau in total energy expenditure at high levels of physical activity,^[17][18][19] meaning that exercising more leads to a corresponding increase in total energy expenditure up to a point. Beyond this threshold, each additional increment of exercise contributes less and less to total energy expenditure. This phenomenon, known as “energy compensation”, varies in magnitude between individuals, and seems to affect men and women of all ages similarly.^[18]

While the precise mechanisms are not entirely clear, energy compensation is a product of behavioral and physiological adaptations. Behavioral adaptations include decreases in nonexercise activity thermogenesis (e.g., less fidgeting, increased sitting), whereas physiological adaptations include downregulation of immune activity, hypothalamic-pituitary-adrenal axis and sympathetic nervous system activity and reactivity, and reproductive function.^[20]

The optimal strategy for promoting weight loss is a combination of a hypocaloric diet and adequate amounts of exercise (i.e., enough to facilitate the rate of weight loss the individual is pursuing while maintaining muscle mass). High volumes of exercise are also pivotal for maintaining weight loss.^[21]

Principal Study: A systematic review and meta-analysis of interval training versus moderate-intensity continuous training on body adiposity

Rarely do Study Deep Dives cover a study that does not involve a nutrition or supplementation component. However, there are exceptions for studies that provide valuable information on related topics. The study under review is one such exception because it addresses whether interval training is more effective than steady-state cardio training for fat loss.

Exercise combined with diet modifications has been shown to be more effective than either alone for promoting weight loss. Moreover, as seen in Figure 1, exercise has been identified as a key player in long-term weight loss maintenance. Therefore, establishing exercise habits during the weight loss phase can help prevent weight regain and yo-yo dieting down the road. Yet, roughly 80% of adults in the U.S. do not currently meet the recommended physical activity guidelines from the CDC, which are the same recommendations made by the American College of Sports Medicine (ACSM). One of the most common excuses for lack of exercise is a lack of time.

The ACSM recommends that most adults engage in moderate-intensity cardiorespiratory exercise training for a minimum of 150 minutes per week, preferably through performing at least 30 minutes per day on at least five days per week. However, they state an alternative means to obtaining sufficient physical activity is to engage in vigorous-intensity cardiorespiratory exercise training for at least 75 minutes per week, preferably through performing at least 20 minutes per day on at least three days per week. Interval endurance training satisfies the vigorous-intensity requirement and has therefore been suggested to be a time-efficient alternative to regular moderate-intensity steady-state cardio.

Numerous studies investigating the health effects of interval and steady-state cardiorespiratory training have been published, with some directly comparing the two. Previous meta-analyses have suggested that interval training might produce superior improvements in cardiorespiratory fitness compared to steady-state cardio, and one large systematic review suggested that higher training intensities, as would be observed with interval training, have a more favorable effect on body composition than lower training intensities common to steady-state. Yet, despite the time efficiency of interval training for promoting cardiorespiratory fitness, it remains unclear whether it is more efficient for fat loss.

The purpose of the study under review was to pool data from studies that have directly compared interval training to steady-state cardio training and use a meta-analysis to determine whether one method resulted in greater fat loss than the other.

About 80% of the U.S. population does not meet physical activity recommendations, with many people citing a perceived lack of time. However, exercise not only benefits changes in body composition when combined with a weight loss diet, but also plays a key role in long-term weight loss maintenance. Interval training has been proposed to be a time-efficient alternative to steady-state cardio for improving health and fitness. The study under review is a meta-analysis of studies directly comparing the two modalities for their ability to reduce fat mass.

Who and what was studied?

The study under review is a meta-analysis of controlled trials directly comparing high-intensity interval training (HIIT) or sprint interval training (SIT) with moderate-intensity continuous training (MICT) regarding their effect on changes in body fat percentage and total body fat mass (the two primary outcomes). Aside from providing data on these outcomes, the only other inclusion criteria were that studies had an intervention duration of at least four weeks and utilized an exercise protocol that fits the following definitions, outlined in Figure 2:

SIT was defined as “all-out” (greater than 100% of VO2max) bursts of activity lasting eight to 30 seconds interspersed with less intense recovery periods. HIIT was defined as submaximal (80-100% of VO2max) bursts of activity lasting 60-240 seconds interspersed with less intense recovery periods. MICT was defined as traditional steady-state cardio performed continuously for 20-60 minutes at a moderate intensity of 40-59% of VO2max or 55-69% of max heart rate.

After screening 402 articles, 28 studies providing 35 comparisons were included in the meta-analyses—25 for body fat percentage and 10 for total body fat mass. The studies contributed a combined sample size of 837 men and women, with only four studies involving more than 20 participants. Most studies were in healthy young adults (n=12) or overweight / obese adults (n=10), and the remainder involved children and adolescents (n=3), adults with metabolic syndrome (n=1), colorectal cancer survivors (n=1), and hypertensive women (n=1). The average age of the participants from each study ranged from 10.4 to 65 years.

The studies were roughly split between using HIIT (n=16) and SIT (n=12), with stationary bicycling (n=14) and running (n=11) being the most common modes of training. Studies lasted four to 16 weeks, averaging 12 weeks. Fat mass was assessed with DXA (n=15), densitometry (n=3), bioelectrical impedance (BIA; n=5), calipers (skinfolds; n=5), MRI (n=1), and tomography (n=1). Only seven studies monitored and reported the diet of the participants and only 11 monitored and reported physical activity outside of the intervention.

Study quality was assessed using a 21-point scale that judged numerous aspects of methodology and data reporting. Scores ranged from nine to 20, with an average of 13.7 points. All studies specified their primary outcomes and adequately reported their statistics. However, blinding of the researchers was present in only six studies and only 13 studies attempted to quantify the energy expenditure of the interventions.

A subgroup analysis was conducted to assess how energy expenditure influenced the results. Studies were grouped according to whether the HIIT or SIT intervention was matched to the MICT intervention for total energy expenditure. Additionally, subgroup analyses were performed according to the type of comparison group (HIIT vs. SIT), intervention duration (shorter than 12 vs. longer than 12 weeks), participant age (younger than 30 vs. older than 30 years), sex, and BMI. Finally, a sensitivity analysis was performed to investigate how study quality affected the results.

This was a meta-analysis of 28 studies comparing the effect of HIIT or SIT against that of MICT on changes in body fat percentage and total body fat mass. Most studies were conducted in healthy young or overweight and obese adults and used cycling and running as their mode of exercise. The average intervention duration was 12 weeks and few studies monitored participant diet and physical activity outside of the intervention.

What were the findings?

There were no significant differences between HIIT or SIT and MICT for changes in body fat percentage (-1.26 vs. -1.48 %, respectively) or total body fat mass (-1.38 vs. -0.91 kilograms, respectively). Heterogeneity was virtually non-existent for both outcomes. Subgroup analyses suggested that MICT might (p=0.09) be more effective than HIIT or SIT for reducing total body fat when HIIT or SIT resulted in a lower exercise-induced energy expenditure. However, when energy expenditure was matched between MICT and HIIT or SIT, there were no significant differences.

Other subgroup analyses showed no significant differences in body fat percentage or total body fat mass when comparing HIIT vs. SIT, men vs. women, studies lasting more vs. less than 12 weeks, normal-weight vs. overweight vs. obese participants, people younger vs. older than 30 years, or studies rated as low vs. moderate vs. high quality. There was no evidence of publication bias.

HIIT and SIT result in similar reductions in body fat percentage and total body fat mass as MICT, especially when matched for energy expenditure. However, MICT might be more effective for reducing total fat mass than HIIT or SIT, if it results in a greater exercise-induced energy expenditure.

What does this study really tell us?

The study under review tells us that when it comes to losing your gut, the intensity of exercise doesn’t matter so much. There was no significant difference between intervals and steady-state cardio for reductions in fat mass or body fat percentage, with both modalities resulting in marginal reductions. Rather, the caloric expenditure of the exercise session might be a more important variable. After all, the subgroup analysis found that steady-state cardio tends to produce greater body fat reductions than interval training if it burns more calories.

Overall, the study under review supports the notion that performing interval training for a shorter total workout time can be an effective alternative to regular steady-state cardio, provided caloric expenditure is matched. So, interval training might be a way to get more people to exercise, since a lack of time is cited as a primary barrier to exercising. Moreover, subgroup analyses found no difference between HIIT and SIT for fat loss, suggesting that personal preference, enjoyment, and physical capabilities should dictate what type of endurance training is used for fat loss.

Or rather, these should dictate what type of endurance training is used to complement a calorie-restricted diet, since this meta-analysis found marginal reductions in fat loss from exercise alone. Still, with 12 of the 28 studies using normal-weight participants, it’s reasonable to speculate that the reductions in fat mass were attenuated by the participants’ lean phenotype and that greater fat loss would be observed in people with overweight or obesity. However, subgroup analysis found no difference in fat loss between normal-weight, overweight, and obese people.

Another explanation for the marginal fat loss could be the lack of control over the participant’s habitual diet and physical activity levels, which can be seen in most of the included studies. One short-term study in people with prediabetes reported that a 10-day supervised HIIT intervention resulted in significantly greater levels of leisure-time physical activity during an unsupervised one-month follow-up, in addition to maintenance of the HIIT routine, compared to the same 10-day supervised intervention using MICT. Compensatory mechanisms regarding food intake are another issue. Some people might lose their appetite while others think they “earned” that slice of chocolate cake, thus erasing any exercise-induced energy deficit that would have resulted in fat loss.

The marginal fat loss reported in this meta-analysis helps emphasize why this meta-analysis is an important contribution to the topic investigated. Since only four of the included studies involved more than 20 people, and since the difference between interval and steady-state cardio was so small, it is possible that most studies out there may have lacked the statistical power to detect between-group differences. By pooling the data from these studies, this meta-analysis largely overcame this limitation of the individual studies and found no evidence to support the superiority of one exercise modality over the other regarding fat loss. The low heterogeneity of the meta-analyses further supports this notion, since it indicates that the studies are similar and that pooling them together is appropriate.

There was no evidence of publication bias, and subgroup analyses suggested that neither study quality, participant sex, nor age influenced the results. There are likely to be individual differences in fat loss from jogging or sprinting, perhaps not because of the exercise session per se, but because of the other lifestyle factors it affects, such as food intake and leisure-time physical activity. Studies are necessary to investigate how distinct types of exercise influence these variables and whether certain biochemical, psychological, or physiological parameters can predict someone’s response to the type of exercise in question.

Finally, this study did not consider the level of participant adherence among the included studies. This is problematic because it is unreasonable to expect fat loss to occur when the participants don’t show up for their morning run. Furthermore, there may be differences in the sustainability of interval vs. steady-state exercise programs, especially for people with lower levels of physical fitness. Similar to appetite and physical activity, the long-term viability of an exercise intervention will come down to personal preference.

These results show that the type of cardio performed for fat loss (intervals vs. steady-state) probably doesn’t matter as much as the number of calories burned in the exercise session. Moreover, the overall amount of fat loss is small. Rather, a focus should be placed on how the exercise session impacts other areas of life, such as appetite, food intake, and leisure-time physical activity. A focus should also be placed on whether you can see yourself sticking with your chosen exercise modality for the long-term.

The big picture

So, endurance exercise isn’t very helpful for fat loss on its own. However, it’s important to look at the big picture. There is little doubt that fat loss is a central component of improving health among people who have fat to lose, but it isn’t the only component. Exercise has many health benefits outside of fat loss that make its inclusion into daily life a sensible idea.

Several researchers have proposed that a person can be “fat-but-fit” or “healthy obese” based on the seemingly obvious concept that health is a function of both fitness and fatness factors. This concept is summarized in Figure 3. Although more fatness generally causes increases in chronic inflammation and downstream effects on metabolism, improving fitness through exercise causes an increased responsiveness to anabolic hormones that might become dysregulated from chronic inflammation and energy excess (such as insulin signaling) and increased release of anti-inflammatory signaling molecules. For example, both strength and endurance training have been shown to increase insulin sensitivity in overweight and obese adults by promoting glucose uptake via insulin-independent pathways and by increasing skeletal muscle antioxidant capacity. A systematic review of randomized controlled trials in at-risk populations reported that exercise interventions have moderate to strong favorable effects on triglycerides, total cholesterol, LDL, HDL, glucose, and insulin.

Importantly, not all types of exercise have the same effects on health. A systematic review of 66 studies and 162 study groups compared the effects of diet, endurance training, strength training, or their combinations on various health markers in overweight and obese adults. For example, strength training was significantly more effective than endurance training for increasing fat-free mass and high-intensity exercise (strength training with at least 75% of 1-rep-max or interval endurance training) was more effective than lower intensities (including steady-state cardio) for reducing insulin, blood lipids, and inflammatory markers. Accordingly, there may be a health advantage to performing interval endurance training relative to the classic steady-state, even if it doesn’t lead to more fat loss.

Exercise encompasses a diversity of modalities that have different effects on health. They may affect some areas similarly, such as fat loss, but evidence shows that they also have different effects on hormones, inflammation, and cardiometabolic risk factors. These differences cannot be overlooked when the goal is improving health.

Exercise may not be all that for fat loss, but it certainly impacts fitness and health improvement. As such, all forms of exercise should be encouraged despite their relatively minimal contribution to fat loss. Strength training is especially important for developing lean body mass. High-intensity training such as interval endurance training appears to be more effective at reducing inflammation and increasing insulin sensitivity than lower-intensity training such as steady-state cardio.

Frequently Asked Questions

Q. How can we encourage more people to be physically active?

Increasing physical activity at the population levels depends on numerous factors, including the efficacy of the chosen interventions that in turn are influenced by their policies, the environment in which they are enacted, the target population, and other important contexts like scalability and culture. In other words, there is no clear-cut answer to this question.

A review of this topic identified several strategies that do have some evidence to support their use. Individual-level policies that educate on behavioral skills such as goal setting, building social support, and problem solving appear to be effective in adults, whereas workplace interventions do not. Similarly, classroom- and college-based interventions do not have sufficient evidence supporting their use in children, adolescents, and young adults, but enforcing compliance via school-based physical education classes is highly effective at increasing physical activity levels.

Interestingly, interventions that use family-based social support appear to be relatively ineffective while those that build or strengthen non-family social support (e.g., walking groups or buddy systems) have strong evidence for use in Western nations. Moreover, community-wide campaigns that target social support and health education should be utilized over mass media campaigns. Finally, “point-of-decision” prompts such as motivational signs placed near stairwells or the base of elevators to encourage stair use are effective, as is changing the local environment to be more physically active friendly (e.g., walking trails and fitness centers).

What should I know?

Most people do not exercise regularly. A common excuse for the lack of exercise is a lack of time. Accordingly, interval training has been suggested to be a time-efficient alternative to the more classic steady-state endurance training that continues to be the poster child of aerobic exercise. The meta-analysis under review showed that both training modalities resulted in similar levels of fat loss, which was minor.

However, other evidence has shown that exercise has additional benefits on health that warrant its inclusion in daily life, such as reducing inflammation and increasing insulin sensitivity. Moreover, high-intensity exercise appears to be more effective than lower intensity exercise at inducing these beneficial changes, which might be one reason to prefer interval training over steady-state even if fat loss would be similar. Ultimately, though, adherence is key. Thus, enjoyment and personal preferences when it comes to exercise are what’s most important.

Resting Metabolic Rate

One study^[22] noted that one standard deviation of variance for resting metabolic rate (how many calories are burnt by living) was 5-8%; meaning 1 standard deviation of the population (68%) was within 6-8% of the average metabolic rate. Extending this, 2 standard deviations of the population (96%) was within 10-16% of the population average.^[22]

Extending this into practical terms and assuming an average expenditure of 2000kcal a day, 68% of the population falls into the range of 1840-2160kcal daily while 96% of the population is in the range of 1680-2320kcal daily. Comparing somebody at or below the 5^th percentile with somebody at or above the 95^th percentile would yield a difference of possibly 600kcal daily, and the chance of this occurring (comparing the self to a friend) is 0.50%, assuming two completely random persons.

To give a sense of calories, 200kcal (the difference in metabolic rate in approximately half the population) is approximately equivalent to 2 tablespoons of peanut butter, a single poptart (a package of two is 400kcal) or half of a large slice of pizza. An oreo is about 70kcal, and a chocolate bar in the range of 150-270kcal depending on brand.

Metabolic rate does vary, and technically there could be large variance. However, statistically speaking it is unlikely the variance would apply to you. The majority of the population exists in a range of 200-300kcal from each other and do not possess hugely different metabolic rates.

Metabolic Rate and Exercise

Exercise and physical activity reliably increase metabolic rate, and the aforementioned study notes that 1 standard deviation of variance in regards to this is 1-2%.^[22] Assuming somebody exercises 300kcal (on average), the true value of inherent caloric expenditure can vary from 294-306kcal (68% of the population) or 288-312kcal (96%).^[22] Although energy expenditure overall appears to be the strongest correlate predicting fat loss from exercise,^[23] it should be noted that alterations in lean mass (muscle) can further influence metabolic rate. Metabolic rate is highly correlated with lean mass (one increases when the other does)^[24] and the process of hypertrophying skeletal muscle (growing the muscles you can contract) has a high caloric cost to it.^[25]

This 'low' correlation seems to apply to aerobic exercise (cardio exercise that can be maintained at a constant speed for a prolonged period of time).^[22] Resistance training (weight lifting) or high intensity intermittent cardio exercise (sprinting, or any exercise which cannot be maintained for long and thus must be done intermittently) has something called EPOC, Post-Exercise Oxygen Consumption, which is an enhancement of the metabolic rate beyond working out.

Although a standard resistance training workout (in which participants were not forced to exhaustion) possesses a relatively low EPOC value, such as 19 extra calories the hour after exercise,^[26] higher intensity exercise such as the 'Tabata' protocol (170% VO2 max for 20 seconds, with 10 seconds break; repeat 8 times and lasting 4 minutes in total) are associated with greater EPOC and oxygen consumption.^[27][28] In these anaerobic exercises, the correlation noted above tends to break down and the 1-2% variance likely does not apply.

Exercise will induce increases in metabolic rate in all persons by the inherent nature of physical movement. There is a lower degree of variance for basic, aerobic movements like walking or jogging. The low variance may not hold for high-intensity exercises.

Active Living

A novel study investigating 11 Japanese men under living conditions, but in a metabolic chamber to measure metabolic rate via heat, found that after measuring all participants across 'low' intensity days, 'moderate' intensity and 'high' intensity, that the same persons who averaged a 2228+/-143kcal metabolic rate during low activity increased daily expenditure to 2816+/-197kcal (average increase of 588kcal) during moderate physical activity, and to 2813+/-163kcal during high activity.^[29] The increase in metabolic rate via moderately vigorous active living (basically, working 'hard' but barely breaking a sweat and not losing your breath) can negate the difference in metabolic rate found in the majority (68%+) of the population (using numbers from the first study cited).^[22]

Moderately active living may be sufficient to negate the inherent differences in metabolism for a good deal of persons not on the extremes of the metabolic bell curve (so, those that are unlikely to be diagnosed with hypothyroidism; a low metabolic rate)

Usually, in diet studies, weight loss differs little between diet groups but a lot within each group. In other words, individual results will vary. For example, in the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) RCT, 600 participants were randomly assigned to either a low-fat or low-carb (non-keto) diet for 1 year, with intensive support from dietitians and research staff.^[13]

Here were the reported weight-loss averages:

• 5.3 kg (11.7 lb) in the low-fat group
• 6.0 kg (13.2 lb) in the low-carb group As you can see in the figure below, in which each bar represents the weight change of a single participant, individual changes varied widely in both groups: they ranged from -32 to +11 kg (-70 to +24 lb).

12-month weight change for each DIETFITS participant

Adapted from Gardner et al. JAMA. 2018.^[13]

One reason for these differences is that some people stick to their diets while others don’t (a support network is very helpful for diet adherence), but another may be that some diets do work better for some people than for others, for reasons that aren’t yet completely understood.

If there’s one takeaway to keep in mind after looking at all the evidence, it is that no one diet is inherently superior. Different diets work differently for different people, but the best fat-loss diet for a specific person will have at least two qualities: it’ll be hypocaloric (it’ll make adherents eat less than they burn) and sustainable (it’ll fit food preferences and lifestyle well enough that adherence is possible).

Weight loss drugs like phentermine belong to a class of medications known as anorectics, which decrease appetite. The anticonvulsant topiramate is used to decrease appetite and cause feelings of fullness.The combination of drugs like naltrexone (an opiate antagonist) and bupropion (an antidepressant) act on the hunger and reward centers of the brain to reduce appetite and help control cravings.

Tirzepatide is a dual GIP and GLP-1 receptor agonist — it stimulates insulin release and increases levels of the hormone adiponectin, reducing blood glucose and appetite.^[31]

Another weight loss drug, orlistat, prevents the fat (and fat calories) from foods from being absorbed by the intestines — it is known as a lipase inhibitor.

Large-scale clinical trials have reported that 68 weeks of semaglutide (2.4 mg as a once-weekly injection) reduced body weight by 9.6%–17.4% (up to 12.5 kg or 27.5 lb) in adults with a BMI ≥30 or a BMI ≥27 and at least 1 weight-related comorbidity.^[32] Semaglutide appears to reduce weight to a larger degree compared to other anti-obesity medications (i.e., orlistat, naltrexone-bupropion, phentermine-topiramate, liraglutide), for which weight loss in the range of 2.6–8.8 kg (5.7–19.4 lb) has been reported.^[33] Semaglutide appears to be less effective than terzepatide, with a 9.2 kg/20.2 lb greater weight loss reported with once-weekly terzepatide vs. once-weekly or daily semaglutide.^[34]

In addition to their effect on weight, semaglutide and other GLP-1 agonists may also improve cardiovascular disease risk factors including waist circumference, systolic and diastolic blood pressure, HbA1c, fasting blood glucose, cholesterol, triglycerides, and inflammatory markers like C-reactive protein (CRP).^[32] Many of these effects are likely due to weight and/or fat loss, however.

When you lose weight, some of it will be fat loss, and some proportion (usually around 25%) will be lean mass and/or muscle mass. It should be noted that lean mass loss is not always muscle mass loss per se, as lean mass comprises muscle, but also bone, connective tissue, organs, and body water content. The goal of most fat loss programs is to improve body composition — in other words, to increase the body’s proportion of lean mass to fat mass.

Most clinical trials of weight loss drugs such as semaglutide and other GLP-1 agonists (e.g., tirzepatide) report weight loss as a secondary if not a primary outcome, and the results don’t seem to indicate a disproportionate loss of muscle mass. For example, in a 72-week study comparing once-weekly tirzepatide (5, 10, and 15 mg) to placebo, fat loss was 34% on average, and the ratio of total fat mass to lean mass decreased from 0.93 to 0.7 (indicating a favorable improvement in body composition).^[35] In adults with type 2 diabetes, semaglutide also reduced body fat mass by 10% and the proportion of fat mass by 1.4 percentage points. Although lean mass was also reduced by 4%, the proportion of lean mass increased by 1.2 percentage points, and the ratio of fat mass to lean mass decreased.^[36] Semaglutide also reduced visceral fat while preserving fat-free mass and skeletal muscle mass in adults with type 2 diabetes,^[37] and in a 24-week retrospective study of adults taking once-weekly semaglutide, body fat decreased while whole-body lean mass and appendicular skeletal muscle mass (ASMI, the total mass of arm and leg muscles) were preserved.^[38]

Thus, recent clinical data don’t seem alarming regarding the impact of weight-loss drugs on lean mass. However, being prudent about diet and exercise can quell any worries that may exist: sufficient protein intake and regular resistance exercise, when paired with weight loss, can help increase/maintain muscle mass and may even help promote fat loss.^[39][40]

The most common side effects of GLP-1 agonists tend to be gastrointestinal problems including nausea, diarrhea, vomiting, and constipation. These side effects tend to be mild to moderate in severity and transient, and tend to occur within the first 5 months of treatment during the dose-escalation phase. More serious side effects, while rare, include diabetic retinopathy, thyroid cancer, gallbladder-related events, kidney injury, hypoglycemia, and pancreas-related events, all of which have been reported in clinical trials.^[41]

The GLP-1 receptor agonists are also associated with an elevation in resting heart rate by 1–4 beats per minute.^[41] Physician and podcast host Peter Attia has reported that his clinic has observed an overnight heart rate elevation of 8–10 beats per minute in his patients, although this is an anecdotal report and not peer-reviewed research.^[42]

Glucagon-like peptide 1 (GLP-1) is a hormone that is released from cells in our intestines and colon when we eat food. When GLP-1 binds to its receptor, it stimulates the release of insulin and inhibits the release of glucagon by the pancreas. GLP-1 receptors are located throughout the body, and therefore, the binding of GLP-1 can have effects unrelated to blood glucose lowering, including increased feelings of fullness and satiety, reduced hunger, and decreased food intake.^[43]

Synthetic GLP-1 agonists such as liraglutide, semaglutide, and terzepatide mimic the effects of GLP-1 in the body. Furthermore, synthetic GLP-1 agonists have a longer half-life in the body than the native hormone, making for longer-lasting therapeutic effects. Specifically, while the half-life of native GLP-1 is 1–2 minutes, the half-life of GLP-1 analogs can range from 11–15 hours (liraglutide) to 155–184 hours (semaglutide), allowing semaglutide to be administered just once per week by subcutaneous injection.^[32]

Orlistat, liraglutide, and semaglutide are approved by the FDA for children ages 12 and older with a BMI at or above the 85th percentile. In a study involving 201 children between the ages of 12 and 18, semaglutide treatment for 68 weeks reduced weight and BMI by 14.7% and 16.1%, respectively.^[44]

The safety of GLP-1 receptor agonists and other weight loss drugs in children and adolescents remains to be determined. Adolescence is a period of rapid growth, sexual maturation, and neural development. It is unknown whether decades-long use of semaglutide or other drugs could impact metabolic regulation, brain circuitry, or long-term development in children or adolescents who start treatment at an early age.