Strategies To Mitigate Muscle Loss While Using Weight Loss Drugs Like Ozempic

Obesity is a chronic disease and global public health challenge⁽¹⁾. Obesity leads to insulin resistance, hypertension, and dyslipidemia and is associated with complications such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease and reduces life expectancy⁽²⁾.

Lifestyle interventions (diet and exercise) are the cornerstone of weight management, but sustaining weight loss over time is very challenging.  Clinical guidelines suggest adjunctive pharmacotherapy, however available medications remain limited by modest efficacy, safety concerns, and cost⁽³⁾. 

Although Ozempic is only FDA approved for treating type 2 diabetes, its off-label use for weight loss has been utilized by clinicians as a management strategy for overweight and obese patients. Another medication called Wegovy contains higher amounts of semaglutide than Ozempic and is FDA approved for chronic weight management.

What is Ozempic and How Does It Work?

Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1mg administered subcutaneously once weekly, for treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in individuals with type 2 diabetes and cardiovascular disease⁽⁴⁾.

Evidence indicates that the actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans. The well-defined mechanisms of GLP-1 action along with the extensive safety database in people with type 2 diabetes provide reassurance surrounding long-term use of these agents in people with obesity and multiple co-morbidities⁽⁵⁾.

Figure. Representative targets for GLP-1 action and sites of GLP1R expression within the nervous system, and consequences of GLP-1 therapy in people with obesity⁽⁵⁾.

Evidence indicates weight loss with semaglutide stems from a reduction in energy intake due to decreased appetite, which is thought to result from direct and indirect effects on the brain⁽⁶⁾.  

Although a recent study demonstrated 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight in overweight and obesity; analysis on a subgroup of 140 participants showed an average loss of 15 lbs of lean muscle during the 68-week trial⁽⁷⁾.

In addition, a recent meta-analysis of randomized controlled trials was conducted to comparatively examine the effects of GLP-1 receptor agonists on fat-free mass.  Eighteen randomized controlled trials showed a significant decrease in fat-free mass compared with the placebo⁽⁸⁾.

Study authors concluded that although semaglutide has a large weight loss effect, it is important to pay attention to muscle loss because a decrease in fat-free mass was observed.

Problems Associated With Muscle Loss

The issue that can potentially occur with Ozempic and GLP-1 is that over time it can cause sarcopenic obesity. For instance, recent evidence as mentioned above showed that patients receiving Ozempic lost about 8 kg of fat and about 5 kg of muscle. It seems that this is a good thing because they lost more fat than muscle and their lean mass relative to fat mass increased by 3%.

The problem is that this doesn’t hold up when weight rebounds.

If someone lost 8 kg of fat and 5 kg of lean mass, but regained 5 kg of fat a year later with no gain in muscle mass, they would have lost more lean mass than fat over that period. Although they are lighter than they were originally, they have a higher percentage of body fat; thus leading to sarcopenic obesity.

Sarcopenia is a disorder characterized by a fast deterioration of muscle mass that affects metabolic rate and general function.

Type II fibers are rapidly lost during sarcopenia which can lead to falls, especially in the elderly population. Another problem that occurs is that bones become weaker, thus exacerbating the problem.

Another concern with losing muscle is the increase in prevalence of metabolic disorders. Skeletal muscle is a crucial tissue for maintaining blood glucose control and energy balance.  Muscle uses both glucose and fatty acids as fuel and serves as a source of amino acids for fuel utilization by other tissues during starvation⁽⁹⁾.  

Skeletal muscle is the main organ for glucose disposal and losing skeletal muscle tissue can lead to insulin resistance and type II diabetes.  In addition, muscle is a big metabolic driver for burning calories. Losing muscle tissue makes the undertaking of long-term weight loss much more difficult.

Strategies to maintain muscle while on Ozempic

In general, when people lose weight, one-quarter to one-third of that weight loss can be muscle and the faster we lose weight, the more likely we are to lose muscle tissue. The problem is the length of time that this muscle loss occurs with faster loss of weight being correlated with greater muscle loss. This seems to be the issue with GLP-1s like Ozempic, the weight loss process is relatively fast so people need to be extra vigilant on their nutrition, specifically increasing protein to avoid sarcopenic obesity.

Protein and Amino Acids

One way is to make sure you are eating enough protein, which can be difficult to do while using weight loss drugs. Protein is the building block of muscle; without enough of it, muscles are not able to build and repair themselves.

A recent systematic review assessed the effects of protein intake (<25% vs ≥25% of energy intake) on energy restriction-induced changes in body mass, lean mass, and fat mass in adults age 50 or older.  One important note from this research is that the acceptable macronutrient distribution range for protein (10%-35% of total energy intake) is only applicable to states of energy balance.

In energy restriction states, crudely the percentage of energy consumed as protein should be increased by about 5% to retain the same quantity of protein in the diet. This review strengthens the scientific foundation for older overweight and obese adults to consume protein intakes ≥1.0 g/kg/day to help preserve lean mass as part of a successful weight-loss intervention⁽¹⁰⁾.  

Another way to ensure you are getting adequate protein is to utilize high quality protein supplements (e.g. WHEY-ISO, VEG-PRO, EAAs, BCAAs).  The protein quality of the supplement is important. The essential amino acid leucine is key to optimal stimulation of muscle protein synthesis which is key during a weight loss, sub-optimal calorie situation⁽¹¹⁾.

• Leucine: The increase in essential amino acids (EAAs) with leucine being the most important has independently shown to stimulate muscle protein synthesis, and protein sources higher in leucine content typically produce a greater stimulation of muscle protein synthesis. To maximally stimulate muscle protein synthesis; additional leucine confers no significant benefit when a sufficient bolus of protein is provided (>35 g) ^(7),(12).  Leucine is important for stimulating muscle protein synthesis and particularly in older persons where anabolic resistance of muscle appears can be overcome to some degree by leucine supplementation.
• Omega-3 Polyunsaturated Fatty Acids: Omega-3 polyunsaturated fatty acids (n3-PUFA), commonly referred to as fish oil, contains two or more double bonds and performs an important role in normal metabolic function. The most biologically active n3-PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are considered conditionally essential fatty acids, due to the low conversion rate from Alpha-linolenic acid (ALA); therefore, increasing dietary (e.g., oily fish) and/or supplemental (e.g., fish oil) intake is recommended⁽¹³⁾.  EPA and DHA possess anti-inflammatory properties and serve as critical components of phospholipids in cellular membranes, therefore increasing n3-PUFA consumption may theoretically, benefit any bodily tissue – skeletal muscle included.
• Vitamin D: Vitamin D is a fat-soluble nutrient that plays an important role in the maintenance of skeletal muscle health and function. It seems that vitamin D and the vitamin D receptor may play a role in modulating satellite cell activity, protein synthesis, mitochondrial metabolism, as well as energy production through various protein pathways that play a role in maintaining skeletal muscle mass and function⁽¹⁴⁾.
• Creatine: There is a substantial amount of evidence documenting the benefits of creatine supplementation in a young, healthy, population. Specifically, creatine has been shown to augment performance in repetitive, explosive tasks, such as sprinting and resistance exercise and facilitates increased lean body mass. Therefore, creatine supplementation may confer a meaningful benefit on skeletal muscle mass and function in an older population. Creatine supplementation in an older population has been shown to elicit improvements in body composition. Creatine and resistance training may act synergistically to promote improvements in body composition and performance, therefore the benefits of supplementation in the absence of resistance training may be limited⁽¹⁵⁾.
• Carbohydrates: Due to their ability to cause rapid loss of bodyweight, low-carb diets have grown in popularity in recent years. Although these diets sound promising in that they decrease fat mass, they also increase reliance on protein for energy⁽¹⁶⁾.

The issue with relying on dietary protein for energy production is that it restricts the availability of essential amino acids, namely the BCAA leucine, isoleucine, and valine to preserve optimal protein synthesis⁽¹⁷⁾. 

The failure to support muscle anabolism following a low carbohydrate intake may limit muscle growth and jeopardize muscle remodeling and repair⁽¹⁸⁾ potentially contributing to blunted hypertrophic responses to resistance exercise training. New evidence indicates that low carbohydrate diets increase the concentrations of BCAA and muscle protein breakdown metabolites, due to increased reliance on essential amino acids for oxidation. As a general guideline, research indicates that individuals looking to lose weight and maintain muscle mass consume 1.0-1.4 grams of carbohydrates per kilogram of body weight per day, or 45-65% of their total daily calorie intake⁽¹⁹⁾.

Exercise Strategies

Exercise, specifically resistance training, is also a critical part of maintaining muscle mass during weight loss. Evidence is clear that resistance training mitigates all muscle loss that occurs during caloric restriction. It is crucial to incorporate some sort of individualized resistance training when undergoing therapeutic weight loss interventions.

A recent systematic review demonstrated that resistance training while in a caloric deficit completely prevented the loss of lean body mass while resulting in similar fat mass and body mass loss as seen with caloric restriction alone⁽²⁰⁾.  

Prioritize Quality Sleep

Quality sleep is vital to both enhancing muscle or preventing muscle loss and to preventing weight gain.

Here are 6 ways in which quality sleep will improve your weight loss efforts:

• Avoid weight gain associated with short sleep
• Help moderate your appetite
• Help with making better food choices
• Sleeping early can prevent late-night snacking
• Benefits for your metabolism

Enhance Your Physical Activity

Healthy, restorative, and consistent sleep patterns impact various hormones involved in body weight regulation and muscle strength, such as cortisol, growth hormone, melatonin, leptin, and ghrelin⁽²¹⁾. Optimal circadian patterns of these hormones can contribute to a healthier body composition.  On the other hand, sleep deprivation can lead to increased levels of your hunger hormone, causing more food cravings.

Ensure you have a medical team when on weight loss medication.

Due to the risk of muscle loss and sarcopenic obesity while taking GLP-1s like Ozempic; it is recommended to be under the supervision of a medical expert and nutrition expert.  Clinicians should embrace the potential adverse effects of some lean mass loss when they are treating people with obesity and help mitigate that with resistance training and protein optimization.

In addition to monitoring muscle loss, people should monitor kidney function, salt and electrolytes, which can be thrown off by dramatic weight loss.

Summary

There are currently no guidelines for clinicians counseling patients on weight loss drugs. Clinicians base their recommendations on guidelines for bariatric surgery patients, since the weight loss effects of surgery are comparable to those seen with the new weight loss drugs. 

Since these GLP-1 analogue drugs can cause dramatic weight loss, clinicians need research-backed recommendations about whether they should tell people on the drugs to take extra vitamins or other nutrients. It is also unclear how these recommendations may be different for older people.

I think given the current body of knowledge and research to date on sarcopenia and muscle loss during caloric deficits; the strategic use of nutritional strategies such as high quality protein, high quality protein supplements, EAAs, creatine, omega-3, vitamin D can be extremely in the mitigation of skeletal muscle loss while using GLP-1 analogue drugs like Ozempic.

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