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The development of glucagon-like peptide-1 (GLP-1) drugs, such as Wegovy and Zepbound, has ushered in a new era in weight management. While these drugs can lead to significant weight loss, researchers and medical professionals have raised concerns about the accompanying loss of muscle tissue. This Special Feature discusses the challenges associated with assessing changes in muscle mass that accompany GLP-1 drug-induced weight loss, the potential impact of muscle mass loss, and how to preserve muscle mass.
Lifestyle changes can lead to successful weight loss, but many find it challenging to achieve and maintain a healthy weight in the long term.
Bariatric surgery can cause substantial and sustained weight loss but is generally recommended in cases of severe obesity. In contrast, drugs such as Wegovy and Zepbound have shown an ability to produce weight loss almost to a similar extent as bariatric surgery.
Drugs such as Wegovy mimic the actions of glucagon-like peptide-1 (GLP-1), a hormone secreted by the gastrointestinal tract, and are referred to as GLP-1 agonists.
How do drugs like Wegovy and Zepbound lead to weight loss?
GLP-1 agonists facilitate weight loss by stimulating insulin secretion, delaying the emptying of the stomach contents, and reducing hunger.
The glucose-dependent insulinotropic polypeptide (GIP), another gastrointestinal hormone, plays a similar role to the GLP-1 hormone, and GIP receptors are another target for weight-loss drugs.
For instance, tirzepatide, sold under the brand name Zepbound, binds to both GLP-1 and GIP receptors.
While these drugs are effective in inducing weight loss, whether this approach to weight management is healthy remains controversial. Specifically, there are concerns that GLP-1 agonists may cause a loss of muscle mass and function.
Such a loss of muscle mass and function is common in old age and is termed sarcopenia. The loss of muscle mass and function in sarcopenia is associated with impaired physical function, reduced quality of life, and an increased risk of falls, illness, and death.
Christopher McGowan, MD, a gastroenterologist and obesity medicine specialist, told Medical News Today that:
“Losing weight at the expense of lean muscle can lead to future problems, including reduced basal metabolic rate, decreased strength, fitness, and tone, reduced bone density, and an increased risk of weight recurrence. For these reasons, it is essential to prioritize muscle preservation.”
Why is weight loss associated with muscle loss?
Muscle loss as a result of weight reduction in individuals with overweight or obesity is a normal phenomenon. Individuals with obesity and overweight tend to have more muscle mass than those with a healthy weight.
In individuals with obesity, the muscle tissue shows an accumulation of fat and changes in muscle fiber composition, resulting in reduced mobility and performance.
Notably, higher levels of infiltration of fat into muscles are associated with decreased muscle strength and deficits in function.
Weight loss induced by lower calorie intake is generally accompanied by muscle loss and lower fat levels in the muscle tissue. In other words, weight loss results in an improvement in muscle composition but a decline in muscle volume.
Besides facilitating movement, muscles help absorb glucose (sugar) in response to insulin secreted after a meal. Obesity is characterized by impaired glucose uptake by the muscles and the liver.
This reduced sensitivity of muscles to insulin in obesity results in an increased breakdown of muscle protein and, subsequently, muscle loss. In contrast, weight loss improves muscle insulin sensitivity, which, in turn, helps prevent muscle protein breakdown.
Since weight loss is typically associated with muscle loss, the concern with GLP-1 drugs is whether these medications induce excessive muscle loss than expected for the achieved decline in weight.
How do we know if muscle loss on GLP-1 drugs is unhealthy?
One of the obstacles in determining the impact of GLP-1 agonists on muscle health has been the dearth of direct measurements of muscle volume and composition.
Studies examining the efficacy of GLP-1 drugs used for weight loss have generally quantified changes in fat and lean mass, with changes in lean mass serving as a surrogate for muscle mass.
Lean mass consists of fat-free tissue, which includes muscles, organs, bones, water, and fluids. Even 15% of adipose (fat) tissue is estimated to be made up of lean mass. Consequently, a considerable loss of adipose tissue is expected to be accompanied by a significant loss of fat-free mass.
Lean mass is thus unlikely to reflect changes in muscle mass accurately. Moreover, studies examining the impact of GLP-1 drugs on weight loss have reported considerable variation in the proportion of lean mass lost due to the same GLP-1 drug.
Magnetic resonance imaging (MRI) can directly assess changes in muscle mass and composition, including fat infiltration. However, the Food and Drug Administration (FDA) guidelines do not require the assessment of muscle quality or volume in clinical trials assessing the efficacy of GLP-1 drugs for weight loss.
Additionally, the threshold to define unhealthy muscle mass has been debated. For instance, muscle mass is influenced by an individual’s biological sex, body weight, height, and body mass index (BMI).
To address this issue, researchers have devised a method to assess healthy muscle volume by quantifying the magnitude by which an individual’s muscle mass differs from that of a standard group belonging to the same sex and with a similar body type.
Who should worry about unhealthy muscle loss on GLP-1 drugs?
Studies using MRI showed that liraglutide (Victoza), a GLP-1 agonist used for diabetes, and tirzepatide (Zepbound) led to muscle loss that was expected with the observed magnitude of weight loss after accounting for age and the presence of other conditions.
Both liraglutide and tirzepatide effectively reduced muscle fat levels, thus improving muscle composition. In other words, evidence from a few studies suggests that GLP-1-agonist-induced weight loss may lead to expected levels of muscle loss while improving muscle quality, but further research is needed.
Muscles also play other vital roles, including secreting signaling molecules called myokines that modulate metabolism and inflammation and supporting protein synthesis in a starved state or during illness. Whether these functions of muscle tissue are affected by GLP-1-induced weight loss is unknown.
Individuals with a sedentary lifestyle, poor nutrition, co-occurring conditions, or at an advanced age are more likely to be at risk of experiencing the adverse effects of muscle loss associated with GLP-1-induced weight loss.
According to McGowan:
“Anyone with baseline reduced muscle mass should be cautious when starting a GLP-1 medication. For example, older adults with sarcopenia may be at the highest risk, as a further reduction in lean mass could jeopardize overall health and mobility. The use of GLP-1 medications in older adults has yet to be thoroughly studied in prospective clinical trials.”
“Likewise, anyone with baseline osteopenia or osteoporosis may be at risk of a further decrease in bone density and an increased risk of falls and fractures,” he added. ”Other at-risk populations include individuals on chronic steroids, which cause muscle wasting, patients unable to engage in strength and resistance training, or patients with muscle-wasting conditions like chronic kidney disease.”
McGowan also noted that even healthy individuals should expect some muscle loss. Although the muscle loss observed after GLP-1 treatments seem to be in line with the levels of expected weight loss, maintaining or increasing muscle mass can also prevent or retard weight regain in all individuals using these medications.
Individuals who rapidly lose a large amount of weight commonly regain most of the weight in the subsequent 5 years.
Since muscles contribute to energy expenditure at more than twice the rate of fat tissue, the reduction in muscle and other lean mass accompanying fat loss results in lower energy expenditure after weight reduction. Thus, preventing muscle loss during weight reduction can help maintain higher levels of energy expenditure and avoid weight regain.
How can you preserve muscle mass on GLP-1 drugs?
Researchers have yet to examine strategies to preserve or increase muscle mass during weight loss induced by GLP-1 drugs. However, considerable evidence exists on approaches to prevent muscle loss due to aging or weight loss induced by calorie restriction or bariatric surgery.
Muscle loss associated with the use of GLP-1 drugs can be mitigated by consuming a protein-rich diet and regular exercise. A moderate increase in protein consumption can help preserve muscle mass during weight loss.
Meghan Garcia-Webb, MD, a board-certified physician in internal medicine, lifestyle medicine, and obesity medicine, told MNT that: “A good goal is to aim for 1.0-1.2 grams of protein per kilogram, which is the ideal protein intake per body weight daily. So for someone who wanted to weigh 150 lbs [pounds], getting around 70-80 grams of protein daily would be a good goal.”
McGowan further advised that “working closely with a registered dietitian can provide valuable insight and a customized nutrition plan while tracking intake can ensure one meets these recommended goals.“
“GLP-1 medications can make you feel sick,“ he cautioned. “If you are nauseous, bloated, or uncomfortable, you are more likely to choose less nutritious, easier-to-digest foods, often low in protein. If medication side effects prevent you from reaching your nutrition goals, the dosage may need to be adjusted.”
Supplementation with whey protein and essential amino acids can also help meet the desired daily protein intake and facilitate muscle protein synthesis.
Endurance and resistance or weight training are effective in slowing down muscle loss accompanying weight loss. Moreover, resistance training can also increase muscle strength and improve physical function. Resistance training results in increased protein synthesis in the muscles and their composition and function.
Meghan Garcia-Webb said that:
“Strength training is very important to anyone starting a GLP-1 agonist medication. I advise training at least twice per week for 30 minutes. If a patient is brand new to resistance training, I always recommend meeting with a trainer once or twice to make sure they know how heavy they should lift and that they are maintaining proper form.“
‘Staying consistent’ most important aspect of GLP-1 treatment
Beverly Tchang, MD, an assistant professor of Clinical Medicine at Weill Cornell Medicine, also noted to MNT that “people who are at risk of frailty or sarcopenia (e.g., elderly) and taking a GLP-1 [drug] should be more mindful of incorporating resistance training to mitigate lean mass loss.”
Data from the United States suggest that some patients discontinue GLP-1 drugs within the first year, with one of the reasons being the cost of drugs. Weight regain is common after the discontinuation of these medications.
McGowan emphasized that: “The key to healthy, sustainable weight loss is maintaining protein intake and nutrition, performing regular resistance exercise, and staying consistent. Starting and stopping a medication can be detrimental and will all but guarantee weight regain and future difficulty losing weight.”
“Monitoring body composition during treatment can provide critical information. Options include bioelectrical impedance scales, DEXA scans, or a simple tape measure to assess nonscale changes. This knowledge can help guide treatment and provide essential reassurance during times of minimal weight loss,” he added.
Besides lifestyle changes, drugs that help prevent muscle loss may also be used in combination with GLP-1. Growth hormone and drugs that stimulate the release of growth hormone are used to slow down muscle loss after bariatric surgery and could be potentially used in combination with GLP-1 drugs.
However, growth hormone treatment is expensive and associated with adverse effects, including muscle and joint pain and risk of diabetes.
Currently, preclinical and clinical studies are also assessing drugs that prevent muscle loss by blocking the action of hormones, such as activin and myostatin, that inhibit muscle growth. One such treatment being investigated in clinical trials is the monoclonal antibody Bimagrumab, which blocks the receptor for the hormone activin II.
