A new era for weight loss?
Researchers in Denmark conducted a study testing the effects of four weight-loss strategies for persons with obesity, without diabetes, and with an average age of 42 years. The four strategies included 1) the GLP-1 drug liraglutide (Saxenda) plus usual activity, 2) liraglutide plus exercise, 3) placebo plus exercise, and 4) placebo plus usual activity. The main outcome was change in body weight. The four strategies followed an 8-week, low-calorie diet in which all participants consumed an 800-calorie meal replacement drink as their only daily food. At the end of 8 weeks, the average participant lost 13.1 kg (29 lbs) of body weight.
During the following 12 months, participants could meet individually with a dietician to support weight loss maintenance. During those 12 months, the liraglutide plus exercise group outperformed the other groups with an additional loss of 3.4 kg (7 lbs) of body weight. Members of the liraglutide plus exercise group also showed greater gains in cardiorespiratory fitness, insulin sensitivity, and general health perception than the other groups. While lean mass declined by about 5 kg (11 pounds) during the 8-week weight-loss period, participants in the liraglutide plus exercise group regained all of the lost lean mass and then some. The combination of liraglutide plus exercise led to substantial weight loss, no weight regain, and no loss of lean mass.
A more recent example of dramatic weight loss
Researchers at a medical center in France conducted a weight loss study using the GLP-1 agonist drug semaglutide (Wegovy). The 12-month study included 115 patients with an average age of 52 years and with grade 3 obesity (body mass index of 40 or more) and with at least one related comorbidity, such as obstructive sleep apnea. Patients at 7 and 12 months post-baseline lost 9.8 and 18.9 percent of their baseline body weight. Fat mass declined by 14 and 18 percent from baseline to 7 and 12 months, respectively. Fifty-nine percent of the patients lost 10 percent or more of their baseline body weight. From baseline to 7 months, lean mass (non-fat body mass) decline significantly by 3.0 kg (6.6 lbs), but it stabilized by 12 months. Handgrip strength increased significantly at 7 months by 3.4 kg and increased further to 4.1 kg at 12 months. The proportion of patients with sarcopenic obesity declined from 49 percent at baseline to 33 percent at 12 months. Curiously, the authors concluded that lean mass was preserved, even though it declined significantly.
Even more dramatic weight loss
GLP-1 receptor agonist drugs and the combination of a GLP-1 receptor drug and a glucagon-dependent insulinotropic polypeptide receptor agonist drug (got that?) produce major loss in body weight, especially body fat. These drugs can also induce substantial and disconcerting loss in lean mass and muscle mass. However, studies report wide variations in loss of body fat and lean mass. Part of the variation may arise from measurement-related errors. Most weight loss studies measure lean mass with DEXA (more available, relatively inexpensive, less time-consuming to use) but do not measure muscle mass with MRI (less available, relatively expensive, more time-consuming to use). Loss of lean mass (often measured in weight loss trials) does not equal loss of muscle mass, because lean mass includes non-muscle items, such as organs, bone, and water. Results of studies using MRI suggest that loss of muscle volume aligns with that which is expected considering patient age, sex, comorbid conditions, and the amount of weight loss.
Further complicating the situation, these weight loss drugs can improve insulin sensitivity and reduce fat infiltration into muscle cells, thereby improving muscle quality. In addition, combining new weight loss drugs with increased physical activity (aerobic, strength training) and increased protein intake may limit muscle loss. Older patients with obesity and at risk for sarcopenia (generalized muscle wasting) and with comorbid conditions need to carefully consider using GLP-1 drugs for weight loss.
Concerns about older people losing muscle mass, sarcopenia
The glucagon-like peptide 1 receptor (GLP-1) agonist drugs liraglutide and semaglutide produce major loss of body mass in adults with overweight and obesity. Fat accounts for most of the body mass loss, but lean mass can also account for a sizeable fraction. Loss of about 6 kg (13 lbs) of lean mass in some trials corresponds to a decade or more of aging. Newer weight-loss drugs that also contain glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (tirzepatide), and also glucagon receptor triple agonist (retatrutide) appear to induce even more loss of body fat and potentially lean mass. Lean mass includes muscle, bones, and connective tissue.
Older people who lose muscle mass may also lose strength, both of which predict increased risk of cardiovascular disease, sarcopenia, frailty, and death. Thus, loss of lean mass arising from weight-loss drugs may negate some of the drugs’ positive effects. On the positive side, long-term resistance training leads to increased lean mass and strength. The combination of semaglutide or liraglutide and resistance training could lead to substantial loss of fat mass, while limiting the loss of lean mass. Furthermore, retaining lean mass could limit the amount of weight regain after a weight-loss drug is terminated.
Strategic use of GLP-1 receptor agonist drugs
While GLP-1 agonist drugs are changing the face of weight loss, potential down sides merit close attention. A trio of researchers argue that weight loss using GLP-1 agonist drugs needs to consider potential muscle mass and muscle strength loss, along with increased risk of sarcopenia. In addition, muscle plays key roles in numerous metabolic processes that extend beyond strength, balance, posture, and movement. The researchers state that weight loss with GLP-1 agonist drugs must be used strategically with concurrent exercise and nutrition components. Regulatory agencies need to provide more comprehensive guidance for researchers to evaluate body composition using appropriate technology.
Benefits of skeletal muscle measurement
Researchers in Canada reviewed the importance of skeletal muscle in weight loss in persons with obesity. High-quality weight loss features a high proportion of fat loss and a low proportion of skeletal muscle loss. Skeletal muscle affects a range of bodily processes and states including glucose metabolism, metabolic flexibility, mobility, and strength. Loss of muscle mass leads to reduced basal metabolism, which promotes weight gain. In addition, greater muscle mass promotes greater insulin sensitivity, better blood sugar management, and greater glucose metabolism. More muscle mass also provides a wider pathway for blood sugar metabolism. Exercise leads to maintained or increased muscle mass and reduced fat inside muscle cells. Alas, measuring skeletal muscle accurately requires expensive equipment (MRI or CT) and considerable time. On top of that, researchers sometimes conflate muscle-related terms, such as lean mass and muscle mass, which are not the same.
Research suggests that patients undergoing weight loss need to take steps to reduce their risk of skeletal muscle loss. One step is to engage in a regular program of strength training. While the details vary among individuals, a typical program might include working out at a gym two or three times per week for an hour each time performing resistance exercises with weights and/or weight machines. Another step, especially for those doing weight training, is to increase daily protein intake above the standard recommendation of 0.8 grams of protein per kg of body weight by 50 percent to about 1.2 grams of protein per kg of body weight. This translates into 82 grams of protein per day, ideally consumed in three relatively equal portions, for a 150 pound person. Overall, persons undergoing rapid weight loss can improve their health and well-being by engaging in resistance training and eating enough protein.
More concerns
A new mini-review cautions that GLP-1 drugs may lead to substantial muscle loss along with substantial weight loss. In addition, cessation of GLP-1 drugs may lead to hefty weight regain (mostly fat), with little or no muscle regain. Weight cycling, arising from periods of GLP-1 drugs commencing then stopping may lead to sarcopenic obesity, an unhealthy combination of excess body fat and substandard muscle strength and/or function.
Exercise and adequate nutrition can limit downside risk of GLP-1 drugs
The burgeoning use of GLP-1 drugs to reduce obesity rapidly can induce unfavorable side-effects including loss of skeletal muscle mass and function. Recent evidence suggests that treatment of obesity with these drugs over 68-72 weeks can lead to 10 percent loss of muscle, equivalent to 20 years of age-related muscle loss. Two key factors, adequate nutrition, especially protein intake, and adequate physical activity, especially resistance training, can limit muscle loss during rapid weight loss. All patients using GLP-1 drugs for weight loss should participate in programs that promote adequate nutrition and physical activity.
What to do
If you’re contemplating asking your doctor to prescribe a GLP-1 drug so you can lose a lot of weight, make sure that you understand the potential risks and rewards. Are you willing to reduce your risk of muscle loss by participating in exercise training and increasing your protein intake?
