In addition to the established gastrointestinal side effects common with the highly effective anti-obesity drugs, there is growing discussion around their potential to contribute to the loss of lean mass, necessary to keep the metabolic engine running full-steam.
And although measures should be recommended to prevent those effects, experts also want to remind clinicians that the loss of lean mass is indeed expected with most weight loss interventions — when they're successful.
"The bottom line is if you're successful with weight loss, it's a normal process that you're going to lose some lean mass," said Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center in Boston, during a presentation on the issue at Obesity Medicine 2024.
"It's what we would expect to see if you successfully lost weight with bariatric surgery or with an intense lifestyle intervention," said Fitch, who is the past president of the Obesity Medicine Association.
"The difference is, there haven't been nearly as many people being successful with weight loss with those other interventions," she noted. "But with the popularity of the glucagon-like peptide 1 (GLP-1) medications, people are hearing this for the first time and saying, 'Oh my gosh, 30% of the weight loss is muscle mass — that's horrible.' "
An underlying goal in the treatment of obesity is the reduction of fat mass, and significant fat mass reduction can provide benefits exceeding the drawbacks resulting from lean mass loss, which have been reported in clinical trials of the GLP-1s semaglutide and the dual glucose-dependent insulinotropic polypeptide tirzepatide to range from about 25% to 40%, respectively, of weight loss.
"Excess adiposity is what makes us sick — not our weight," Fitch underscored. "The amount of fat that people are losing [with anti-obesity medications] is far more beneficial than maybe the potential that they've lost a little bit of lean mass," she said.
She cited research suggesting that significant weight loss from bariatric surgery is linked to increases in life expectancy, cardiovascular risk reduction, cancer risk reduction, and a wide array of other positive effects — despite the loss of lean mass that occurs with the weight loss.
Opportunity for Awareness
The increased attention on issues of body composition accompanying weight loss importantly provides clinicians the chance to underscore to patients the importance of offsetting the loss of lean mass through strength training, nutritional choices, and other measures.
However, patients should be prepared that achieving these goals can be more challenging than expected, said Fitch.
"It can be very hard to be in an energy deficit (due to a weight loss regimen) and gain muscle mass," she said. "When athletes are trying to gain muscle mass, they're increasing their intake to do so. It doesn't come naturally in today's world."
Nevertheless, patients can be reassured that the losses can be reversed with some effort, Fitch noted.
She cautioned that for those who succeed in building or rebuilding lean mass, the evidence may be reflected on the scale, with numbers going up, not down — something they may not wish to see.
"Patients tend to freak out when they see the scale going up after losing all of that weight, but you can reassure them that it's okay — this is healthier weight gain."
Special Considerations in Older Patients
Efforts at staving off lean mass loss are particularly important in older patients, who are already most vulnerable to experiencing it naturally with age, even if not on a weight loss regimen.
But Fitch offered that age does not necessarily have to be a barrier in tackling those effects.
She described two cases of treating patients in their mid-70s, a male and female, with GLP-1s for obesity. Not only were they able to achieve substantial reductions in body mass index over nearly a year on treatment, but they were also able to avoid skeletal muscle mass loss during a period when it would have likely naturally occurred.
She noted the need to augment strength training with protein intake to help build muscle, citing recommendations including consuming 1.4-2.0 g of protein per kg of body weight for building muscle and maintaining muscle mass.
Importantly, "make sure patients aren't too appetite suppressed so they can keep up with their nutrition," Fitch said.
A key condition to watch for in these patients is sarcopenia. Definitions of sarcopenia vary, but it is distinguished by low skeletal muscle mass and either low muscle strength — measured, for instance, with hand grip — or low muscle performance, such as reduced walking speed or muscle power, Fitch said.
In such cases, patients may need special considerations, including avoiding significant caloric deficits and whether the risks of medication outweigh the benefits.
'Super-Responders', Other Lean Mass Loss
Further addressing the issues of body composition and weight loss at the meeting, Robert F. Kushner, MD, a professor of medicine and medicine education at Northwestern University in Chicago, noted that one area of concern regarding lean mass loss is "super-responders" — patients who have exceptionally high weight loss on GLP-1s.
Speaking with Medscape Medical News, Kushner elaborated that, "we are concerned about individuals who experience very high weight loss responses to medication, [specifically] 25% or more weight loss, as well as individuals at higher risk of losing lean body mass [muscle mass], specifically people in their 50s, 60s, and 70s."
"Lifestyle counseling, particularly regarding safety and body composition, is recommended in these patients," he said, adding that in managing these patients, "the approach is to use close patient monitoring, dose reduction if needed, and emphasizing a high-protein diet accompanied by aerobic and resistance physical activity."
Potentially dramatic lean mass loss can occur in obesity whether or not patients are on obesity medications. As evidence of this, Kushner cited a sub-analysis of the Look AHEAD trial of 1019 overweight or obese patients who had a mean age of 58 years at baseline. Patients were randomized to either a physical activity and reduced calorie intervention group or simply education.
Although the results showed that fat losses in the intervention group were generally regained over 8 years, a striking, steady decline was observed in lean mass in both the intervention and control groups, including men and women.
Fitch's disclosures include consulting and/or advisory relationships with Eli Lilly, Novo Nordisk, Currax, Vivus, SideKick Health, Jenny Craig, Carmot, and Seca. Kushner is on the advisory boards of Novo Nordisk, Weight Watchers, Lilly, Boehringer Ingelheim, and Altimmune.
https://www.medscape.com/viewarticle/tackling-lean-mass-loss-when-weight-loss-successful-2024a100099q
