Abstract
Objective To identify patients who may or may not benefit from use of new drugs for weight loss and to aid in minimizing loss of lean mass through proactive nutrition and exercise interventions.
Quality of evidence Choices and interventions are evaluated using the Grading of Recommendations Assessment, Development and Evaluation framework. Quality varies widely and is documented in multiple tables.
Main message Semaglutide and tirzepatide should be used in patients living with obesity or with overweight accompanied by weight-related comorbidity. Long-term use may be necessary. Use in children and adolescents has proven effective for weight reduction, but long-term consequences are unknown. Use in elderly patients may be harmful. Because weight loss by any means is accompanied by loss of lean mass, specifically muscle and bone, particular attention must be paid to nutrition and exercise. Protein supplementation is effective to preserve muscle mass. Resistance training is effective in mitigation of both muscle and bone loss. Both resistance and aerobic training are beneficial in preventing osteopenia in weight loss, which may contribute to premature mortality. There is observational evidence that weight cycling may be harmful in that weight regain can be composed primarily of fat, multiple cycles of which may actually increase obesity in individuals. This is of particular concern because of the cost and limited availability of new weight loss drugs leading to large rates of discontinuation. Similarly, patients using drugs for small amounts of weight loss are likely to regain or overshoot if they discontinue.
Conclusion Patient selection for use of new anti-obesity drugs should match those included in clinical trials and be paired with dietary and exercise interventions used in those trials. Use at the extremes of age is problematic because of lack of long-term data. Intermittent use for small amounts of weight loss may be harmful. More ongoing data are needed.
As of 2021 almost 2 in 3 Canadian adults were living with excessive body weight, characterized by a body mass index (BMI) greater than 25 kg/m2.1 In the same year, the fiscal burden of obesity, including income loss, forgone taxation, disability costs, and health care costs, totalled $23 billion, or $752 per taxpayer.2
Obesity is not a choice. It has a strong polygenetic component, with a 65% influence on BMI variation.3 Genetic randomization indicates a high association with mortality outcome, which is, in turn, modified epigenetically by lifestyle factors such as exercise, nutrition, smoking, alcohol, sleep quality, and psychosocial factors.4 Most monozygotic twin studies show high levels of concordance for weight.5 Genetics can determine susceptibility to obesity, but the nutritional and built environments determine gene expression. Weight stigmatization should never jeopardize effective treatment.
The default food environment in Western countries exposes individuals to increased portion size6 and to foods of high energy density—primarily added sugars, fats, and sodium, with high palatability.7 We now have effective tools in the form of glucagon-like peptide-1 agonists with or without glucose-dependent insulinotropic polypeptide agonists (GLP-1±GIPAs), which can enhance satiety and reduce energy intake. These drugs have been shown in sentinel randomized controlled trials (RCTs) to reduce body weight on average by 15% for semaglutide,8 and by 20% for tirzepatide9 under controlled conditions. Known modes of action include promotion of insulin secretion, inhibition of glucagon secretion, delayed gastric emptying, and promotion of early satiety.10 Because GLP-1±GIPAs are present in multiple body tissues, there are many known or anticipated pleiotropic effects beyond weight loss and glycemic control that promise health benefits.11
Weight loss by any means reflects not only loss of fat, but also reduction in muscle mass and bone mineral density (BMD).12 Long-term pharmacologic reduction in food intake requires attention to nutrients, which will maintain muscle mass and prevent accelerated loss of BMD. Similarly, exercise, particularly resistance training,13 must accompany weight loss to prevent sarcopenia (characterized by loss of muscle mass, strength, and function), which is associated with falls, fractures, loss of mobility, and premature death. While exercise interventions may minimally influence the quantity of weight loss, they will improve quality of body composition, leading to improvement in overall health.14
The prospect of successful weight loss warrants attention to use of GLP-1±GIPAs as they influence body composition in the long term. The objective of this review is to identify patients who may benefit from drug therapy for weight loss and to aid in minimizing loss of lean mass through proactive nutrition and exercise interventions.
Quality of evidence
Information was sourced from PubMed, Google Scholar, and Science Direct. Multiple search strategies were employed for this review, congruent with the range of information appropriate to generalist physicians. Reviews and meta-analyses were referenced when available, and signature randomized studies employing the new pharmaceuticals were prioritized. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework15 is used as outlined in Table 1.
Quality of evidence: GRADE classification adapted from the Canadian Task Force on Preventive Health Care.
Main message
Weight loss. Obesity is a chronic disease,16 but weight loss does not uniformly reduce mortality. There is little doubt that patients experiencing overweight and obesity are highly motivated to lose weight, whether it be for reasons of appearance, stigma, metabolic risk, or mechanical stress. Short-term subjective evidence suggests quality of life is improved with weight loss.17
Table 214-16,18-30 reveals that mortality benefit with weight loss can only be shown in individuals with obesity or those who are overweight with obesity-associated comorbidity. These indications happen to coincide with the populations included in sentinel studies of GLP-1±GIPAs.8,9 Also, as noted in Table 2,14-16,18-30 weight reduction in elderly individuals may be ineffective or actually increase mortality. Typically, mortality curves that follow BMI are U-shaped, with the nadir for mortality shifting toward overweight as the population ages. Excess adiposity reflecting superior energy reserves may indeed protect the elderly under conditions of illness or injury.31
Influence of body size and weight trajectory on mortality risk as compared to stable normal weight
While maintenance of weight loss is possible, regain, and even overshoot is common. In the Semaglutide Treatment Effect in People with Obesity (STEP-1) trial extension,32 using semaglutide for 68 weeks, a 17.8% weight reduction was achieved. In the following 52 weeks off the drug, two-thirds of this weight was regained, suggesting that continuing drug treatment may be necessary long term for maintenance of health benefits. Participants who lost the most weight tended to have the lowest relative regain. Those who lost less than 10% of body weight demonstrated either total weight regain or overshoot within a year. Those losing 20% or more regained only 50% of weight loss (Figure 1).32
Semaglutide treatment for 68 weeks and subsequent weight regain after 52 weeks off the drug: Comparing subsets of patients by percentage weight loss.
Body composition. Body composition as measured by dual-energy x-ray absorptiometry (DEXA) is the most practical way of measuring the body compartments (Figure 2). Fat mass is anhydrous and easily distinguished from fat-free mass, which is composed of bone, organs, and skeletal muscle. Skeletal muscle can contain water up to 75% of total mass.33 State of hydration is therefore a large factor in estimating lean body mass. Weight loss by any means has substantial influences on fat mass, skeletal muscle mass, and bone density.
Body mass components: Partitions usually reported on DEXA are indicated in red. Compartment sizes can vary and are not drawn to scale.
Fat mass is positively associated with mortality except in elderly individuals.34 Reduced skeletal muscle mass has been shown to be associated with increased mortality on meta-analysis,35 especially when coupled with obesity. Bone mass peaks in the 20s,36 suggesting that continuous use of weight loss drugs in children and adolescents may have major implications for sarcopenia in later life. Bone mass declines thereafter, accelerated by aging, inactivity, dietary restriction, menopausal status, chronic disease, and weight loss. The Look Action for Health in Diabetes (AHEAD) trial of intensive lifestyle intervention for weight loss in individuals with obesity and diabetes showed notable decrease in BMD and increase in fragility fractures at 4 years compared to placebo.37 This difference persisted at up to 16 years’ follow-up.37 Loss of bone mineral density is seldom recovered after a weight loss and regain cycle.38,39
There have been few good studies documenting the effects of GLP-1±GIPAs on muscle and bone mass in obesity. Trials using semaglutide have so far suggested lean body mass loss to comprise 40% of lost weight in participants with and without diabetes at 1 year.8,40 One tirzepatide trial suggested 24% of total loss was lean body mass,9 similar to the loss imposed by a very low-energy diet.41 Absolute percentage change in both the semaglutide42 and tirzepatide43 studies approximated 10% loss of total muscle mass.44
Secondary analysis of an RCT following considerable diet-induced weight loss compared the effects of liraglutide, vigorous exercise, or a combination on BMD.45 Bone loss with exercise was similar to placebo. BMD was substantially reduced by liraglutide, and only partially mitigated by combination with exercise. It seems important to include exercise training with these medications to preserve strength and mobility in later years and reduce risk for falls and fractures.
Weight cycling. In the past, weight cycling has typically been the result of repeated weight loss attempts using lifestyle interventions. Twenty percent of people who manage an intentional 10% weight reduction maintain this at 1 year,46 suggesting that the remainder may undergo several weight fluctuations in the course of a lifetime. Recent meta-analyses of epidemiologic studies indicate that weight fluctuation is associated with increased mortality across all weight categories23,24 (Table 2).14-16,18-30
Based on starvation experiments carried out many years ago in normal weight participants,47 it has been postulated that diet-induced weight loss can lead to selective regain of fat mass when the intervention is stopped. The model suggests that overfeeding persists past the original weight baseline because the drive to eat is not satisfied until lean body mass has been restored. Recovery of fat-free mass lags behind restoration of fat mass (Figure 3).48 This overshoot is more marked in lean than in obese dieters. Understandably, repeated weight loss and regain cycles can lead to excess fat accumulation, particularly in participants in lower weight categories.
Simplified model of weight recovery following significant diet-induced weight loss: Delayed recovery of fat-free mass results inaccumulation of fat mass above baseline values. Body mass index stabilizes above baseline.
The Look AHEAD study followed patients with obesity and diabetes over 8 years, aiming for a 7% weight loss using diet and moderate physical activity.37 At 1 year during initial weight reduction, both fat and lean tissue mass were lost. In the next 7 years with weight maintenance interventions, almost all regain represented fat mass.49 Rossi et al retrospectively evaluated a cohort with diabetes and obesity and found a direct association between the number of previous weight loss attempts and subsequent loss of muscle mass and strength.50
There have been no studies examining the effect on body composition of weight fluctuation as a result of use of GLP-1±GIPAs. From available evidence it would be reasonable to expect episodic muscle and bone loss and fat regain in people using these drugs intermittently, especially for small amounts of weight loss.
Diet and exercise. Lifestyle change becomes even more important with use of GLP-1±GIPAs.14 The nutrition and activity focus must change to promote optimal body composition, health, and longevity. The sentinel studies8,9 on these drugs were supported by a daily 500 calorie energy deficit and 150 minutes of moderate exercise per week.
Using the new medications, the present obesogenic food environment may be partially mitigated by increased satiety and reduced appetite, producing a 35% drop in energy intake51 and lower preference for energy-dense foods.52 However, reduced food volumes raise concern for nutrient deficiencies. There is evidence on meta-analysis to support protein supplementation, paired with resistance training, to sustain muscle mass.53,54 Elderly individuals may require particular attention to protein intake because of increased anabolic resistance.53 Some guidance to muscle and bone mass preservation can be derived from literature on metabolic or bariatric surgery.55,56 Recently there has been a review of dietary concerns specific to GLP-1±GIPAs.57 These and other recommendations, many based on expert opinion, are summarized in Table 3.53,54,57-59
Dietary recommendations for patients undergoing substantial weight loss (>5% to 10%) including those on anti-obesity medications
Sedentary behaviour is facilitated by modern labour-saving technologies. Exercise is a major component in maintaining the hallmarks of health,60 but it requires a commitment in time and energy, consuming fat stores, and augmenting muscle mass and skeletal integrity. Increased activity can mitigate lean tissue loss.61
When intensive exercise was added to semaglutide in the STEP-3 trial,62 there was no additional weight loss benefit as compared to the STEP-1 trial8 employing moderate exercise. Body composition was not considered. A more illustrative study using liraglutide45 following an 8-week weight loss on a very low-calorie diet demonstrated equal reductions in fat mass with vigorous exercise or liraglutide used alone and additive reduction if used together at 1 year. Considering lean mass maintenance, however, exercise alone was superior to both liraglutide alone and the combination, suggesting that liraglutide might actually interfere with the anabolic muscle benefits of exercise.
BMD falls gradually after the mid-20s and tends to accelerate during weight loss; moreover, there is no restoration of bone mass with weight regain.38 Exercise may mitigate this process somewhat by providing mechanical stress to bone via enhanced muscle mass and power. Resistance training has been shown on meta-analysis to be superior to aerobic training in maintaining bone mass,63 although both exercise modes are established on meta-analysis to extend lifespan.64 While elderly patients can benefit equally,65 the guidance of a certified exercise professional would be advisable for those who are frail.
Cost, availability, and persistence. GLP-1±GIPAs presently are prohibitively expensive, not always available or covered by insurance, and protected by a range of patents, which can last 20 years in Canada. While competition is said to reduce costs in a free market, there is scant evidence for this in pharmaceutical pricing.66 Considering the potential benefits of these drugs for both diabetes and obesity, and the numbers of patients standing to benefit, it is unlikely that the medical system or insurance organizations can absorb the cost of equitable access for those needing treatment.
Cohort studies using medical records have demonstrated 1-year persistence metrics of 17% for liraglutide,67 44% for tirzepatide, and 57.5% for semaglutide.67,68 Reasons for high discontinuation rates can include gastrointestinal side effects, high cost, loss of insurance coverage, inadequate drug supply, or failure to meet weight loss expectations. The result is another weight fluctuation cycle with fat regain and further loss of lean mass.
Conclusion
Concepts regarding patient selection, weight trajectory, and mitigation of undesirable weight partitioning are outlined in Table 4.69,70 Presently, use of GLP-1±GIPAs primarily in obesity or in overweight patients with weight-related comorbidity would seem prudent in primary care.
Summary of conclusions regarding GLP-1±GIPAs with quality of evidence
There is remarkable cognitive dissonance with use of GLP-1±GIPAs. These drugs, used as indicated, can be life-saving and life extending. While they facilitate weight loss, there is a risk of sarcopenia and BMD loss without considerable lifestyle intervention. They may require lifelong administration, yet are presently very costly and sometimes unavailable. Patients are motivated to use them, but many patients fail to persist with long-term use, risking fat overshoot with each weight cycle. They may not benefit the elderly, and longitudinal risk and benefit data are lacking in children and adolescent patients. Ongoing research and equitable access are needed before these drugs can achieve their potential in the at-risk population.
Notes
Editor’s key points
▸ The weight loss drugs semaglutide and tirzepatide have been shown to reduce body weight under controlled conditions.
▸ Concerns remain surrounding the risk of weight cycling and the loss of muscle mass and bone mineral density, which highlight the importance of diet and exercise used in conjunction with these drugs.
▸ While semaglutide and tirzepatide, used as indicated, can be lifesaving options for patients with obesity and obesity-related comorbidities, the above concerns, together with their high cost and challenges with both availability and the need for long-term adherence, mean that more research and attention is required for their use in at-risk populations.
Points de repère du rédacteur
▸ Il a été démontré que les médicaments sémaglutide et tirzépatide pour la perte pondérale réduisent le poids corporel dans des conditions contrôlées.
▸ Il persiste des préoccupations entourant le risque de perte et de retour cycliques du poids, de même que concernant la perte de masse musculaire et de densité minérale osseuse, ce qui met en évidence l’importance du régime alimentaire et du programme d’exercice suivis concurremment avec ces médicaments.
▸ Si le sémaglutide et le tirzépatide, pris tels qu’indiqués, peuvent être des options salutaires pour les patients obèses ou ayant des comorbidités liées à l’obésité, les préoccupations mentionnées plus haut, de même que leur coût élevé et les défis liés à leur disponibilité et à la nécessité d’une adhésion à long terme font en sorte qu’il faut plus de recherches et d’attention concernant leur utilisation dans les populations à risque.
Footnotes
↵* Appendix A is available from https://www.cfp.ca. Go to the full text of the article online and click on the CFPlus tab.
Competing interests
None declared
This article has been peer reviewed.
- Copyright © 2025 the College of Family Physicians of Canada
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