Balancing Weight Loss and Muscle Health in the Age of Incretin-Mimetic Drugs

Obesity is a serious medical condition that significantly increases the risk of developing diet-related noncommunicable diseases, such as diabetes, cardiovascular disease, stroke and cancer – even leading to premature death. The stigma and biases surrounding obesity can also contribute to substantial social and mental health challenges, including anxiety and poor body image.

The World Health Organization (WHO) defines being overweight or obese as excessive fat accumulation posing health risks, often measured by body mass index (BMI). A BMI over 25 kg/m² indicates overweight, and over 30 kg/m² denotes obesity – though BMI is controversial for ignoring fat vs muscle composition.

Obesity rates have reached record highs globally. Data from the Centers for Disease Control and Prevention highlights that one in five children and two in five adults in the United States have obesity. By 2000, over 300 million individuals were thought to be obese, with women having higher rates of obesity than men.

To combat the disease, experts recommend a balanced, calorie-deficit diet combined with regular exercise. Weight loss surgeries, like gastric bypass, are options when lifestyle changes fail, but strict criteria often apply.

New pharmaceutical interventions, including glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide/Ozempic^TM and Wegovy^TM) and dual gastric inhibitory polypeptide and GLP-1 (GIP/GLP-1) receptor agonists (e.g., tirzepatide), demonstrate significant weight-loss efficacy. In 2017, the US Food and Drug Administration (FDA) first approved Ozempic as a treatment for type 2 diabetes to aid with regulating blood glucose levels and subsequent weight loss. Since then, the drug has been somewhat repurposed and can be bought over the counter; the FDA approved Wegovy in 2021 for treating obesity – the first weight loss drug approved since 2014.

While these drugs have led to dramatic weight loss in individuals, this does not solely mean fat loss. Skeletal muscle mass loss is commonly observed when using these drugs – an undesirable side-effect, as muscle is a vital organ for maintaining health.¹ Alarmingly, a recent review highlighted the amount of muscle lost from weight loss drugs was ~10% (6kg) – equivalent to a decade of aging.¹ In this article, we explore the impact of incretin-mimetic drugs on muscle health and what can be done to limit these severe side effects.

Firstly, how do these drugs work?

Incretins are intestinal hormones secreted in response to nutrient entry into the gut, inducing insulin secretion and inhibiting glucagon release.

While this response is diminished in individuals with type 2 diabetes and obesity, it is still partially maintained, allowing pharmacological activation of GLP-1 receptors to effectively lower plasma glucose levels and enhance glycemic control.² Consequently, GLP-1 has become the foundational compound for incretin-based therapies (e.g., GLP-1 receptor agonists), which also provide additional benefits of appetite suppression and reduced food intake, ultimately promoting long-term weight loss.

Indeed, the drugs can facilitate average body weight reductions of ~15–24%, losses similar to that previously seen only with intensive interventions such as bariatric surgery or very low-calorie diets.¹

Incretin-mimetic drugs have also been observed to improve cardiovascular risk factors, blood pressure and cholesterol levels – but it's not clear whether these benefits are from the drug or the weight loss.³ These drugs do, however, come with common side effects including nausea, diarrhea, vomiting, constipation, abdominal pain, headache and fatigue.

Growing concerns

The rapid and widespread adoption of these highly effective drugs for the treatment of obesity has outpaced the updating of clinical practice guidelines. Many patients may, therefore, be at risk of adverse effects and uncertain long-term outcomes.

Of emerging concern is the loss of skeletal muscle mass and function that can accompany rapid weight loss. Such losses can lead to reduced functional and metabolic health, weight cycling, compromised quality of life and other adverse outcomes.

Skeletal muscle health and function are vital for maintaining locomotion and whole-body metabolic health across a person’s lifespan.⁴ Importantly, the rate at which muscle declines as we age (i.e., sarcopenia) dictates levels of morbidity and even mortality.⁵ Therefore, the impact of incretin-mimetic drugs on the loss of skeletal muscle should not be overlooked. If individuals do choose to use such drugs, avenues to limit the loss of skeletal muscle need to be explored to help reduce lean tissue losses (i.e., skeletal muscle) and promote fat loss.

Consuming a high-quality protein diet

Dietary protein is essential for muscle health throughout life. It plays a crucial role in stimulating muscle protein synthesis, supporting the maintenance or growth of skeletal muscle mass. Insufficient protein intake can lead to excessive loss of lean body mass, weakness, edema, hair loss and skin changes. Although recommendations vary by population, the recommended daily allowance for protein for healthy adults of normal weight is 0.8 g/kg body weight/day.

Individuals treated with incretin-mimetic drugs generally experience reduced appetite, reduced hunger and increased satiety, leading to decreased food intake.³ The quality of an individual’s diet, therefore, becomes vitally important due to the nutritional needs that must be met in the context of reduced food intake, especially regarding dietary protein intake.

“Consumption of protein at higher-than-recommended levels has been theorized to have a number of potential advantages during weight loss, including a greater thermogenic effect upon consumption compared with carbohydrate and fat, a greater satiety response on consumption, and the potential for greater weight loss, fat loss and lean mass retention,” Dr. Stuart Phillips detailed in a review.⁶

This is somewhat echoed by a recent review by Almandoz and colleagues, which highlighted the importance of dietary protein in obese individuals undergoing weight loss treatments, including anti-obesity medications. “In patients with obesity, protein intakes of at least 60 to 75 g/day and up to 1.5 g/kg body weight/day have been recommended during weight reduction with various treatments, including very-low-calorie diets and bariatric surgery,” the authors detailed.³

They continued to state that meal-replacement products such as protein shakes, bars or other products – typically containing 15–25g protein – may also be used to formulate an individual's diet to meet protein needs, especially if appetite is reduced.³

“These considerations are even more important in older individuals seeking to lose weight because muscle mass decreases with age (potentially leading to sarcopenia); therefore, older individuals may be at higher risk of excessive muscle loss and risk of falls and fracture with weight loss.”³

Although further research is needed to fully understand the impact dietary protein consumption can have on maintaining skeletal muscle mass in those taking incretin-mimetic drugs, individuals should consume high-protein foods first at each meal to ensure adequate protein intake is met.

Resistance exercise training

The development of obesity is affected by the quantity and quality of muscle mass and its metabolic rate. Individuals with obesity possess lower relative levels of muscular strength and often have an increase in intramuscular fat, which in turn decreases muscle quality.⁷ This effect is more significant in older adults,⁸ but even young individuals experience impaired muscle recruitment and activation due to excess adipose tissue.⁹

Alongside dietary protein, physical activity and exercise are vital to maintain muscle mass and function throughout life. Intentional or unintentional weight loss is accompanied by a loss in skeletal muscle mass that can amount to up to ~40% of total weight loss – a factor that may have long-term implications for functional capacity, resting energy expenditure, bone strength, metabolic health and weight regain.¹⁰ Exercise training has the potential to increase muscle mass, thus preventing or mitigating adverse effects of weight loss interventions.

The American College of Sports Medicine endorses resistance exercise training (RET) over other exercise modalities for the gain or preservation of muscle mass, with RET occurring two-to-three days per week.¹¹ For example, in healthy untrained men, the quadriceps femoris muscle cross-sectional area increased by 6% following 21 weeks of RET, compared to 2% observed with endurance training.¹² Further, in older overweight and obese individuals undergoing a diet, despite similar body weight (~9%) and fat mass losses (~6.9%), RET resulted in less lean mass loss (−2%) compared to endurance exercise alone (–5%) or a combination of the two (–3%).¹³

While incretin-based pharmacotherapies are very effective for inducing weight loss, upon their cessation or ending energy intake restriction, weight is rapidly regained.¹⁴ Wilding et al highlighted that “one year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss.”¹⁵

Ongoing treatment for obesity is clearly necessary to sustain improvements in weight and overall health. Although definitive studies are lacking, given the well-documented effects of RET on muscle mass in conditions such as obesity, sarcopenia and type 2 diabetes, it is reasonable to suggest that RET could help reduce muscle loss, enhance fat mass reduction and potentially reduce fat regain after discontinuing treatment in individuals undergoing incretin-based weight loss therapy.

Repartitioning drugs – a controversial avenue

Could turning fat into muscle be an alternative to incretin-based drugs to avoid significant muscle loss?

Treatments that stimulate global muscle hypertrophy, such as hypertrophy-focused RET or drugs, have the potential to reduce fat mass and improve glucose homeostasis with the added benefit of increased muscle mass.¹⁶

Repartitioning drugs, such as growth hormone, anabolic steroids and B2-agonists (e.g., salbutamol), stimulate skeletal muscle hypertrophy and reduce fat mass. Although some of these drugs are approved in the United States, they have been banned in Europe since 1988.¹⁷

“A fat-to-muscle repartitioning through the stimulation of muscle hypertrophy is a desirable treatment outcome in patients with obesity and so it seems surprising that repartitioning has not been conceptualized as a therapy for obese patients,” Wackerhage and colleagues detail.¹⁶

Insights into the potential of such drugs are drawn from studies in mouse models. For instance, Izumiya et al. induced the expression of constitutively active AKT1 specifically in skeletal muscle. When these mice were fed a high-fat, high-sugar diet, AKT1 expression resulted in hypertrophy of “fast” type two muscle fibers, reductions in body weight and subcutaneous fat and normalization of blood glucose levels.¹⁸

In humans, bodybuilders achieve major fat-to-muscle repartitioning, but it is unclear whether this is due to their hypertrophy-focused resistance training, misuse of doping agents or a hypocaloric diet during the so-called “cutting phase”.

The discovery that global muscle hypertrophy has anti-obesity and anti-diabetic effects prompts critical research questions about the mechanisms driving these changes and which fat-to-muscle repartitioning strategies could be clinically effective for individuals with obesity – questions that remain unanswered.