Losing weight on new drugs like GLP-1s – why medication alone isn’t enough

‍Management of chronic conditions like obesity is complex and requires a multifaceted approach, including a need to mitigate the loss of vital fat-free mass.

By Dr Louis Talay for Citro partner Juniper

Glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) have been generating a lot of media hype in the context of the current obesity epidemic. 

Clinical trials have consistently demonstrated that the medications induce significant weight loss in short periods for most patients living with obesity ^{[1] [2] [3]}. 

Another key conclusion drawn from these efficacy trials is that side effects are rare and can be effectively managed with appropriate support. 

However, these compelling discoveries have been tempered somewhat by the indication that a significant proportion of GLP-1-induced weight loss is attributable to a reduction of lean muscle mass and bone mineral density ^{[4] [5]}. 

These claims should be taken seriously by any prescriber of GLP-1 RAs. In this article, we are going to explain how holistic weight loss programs can address the risk of losing this vital fat-free mass. 

Why is lean muscle mass important? 

Lean muscle mass is essential for physical function, disease prevention and general quality of life. Inadequate muscle mass limits our ability to perform daily tasks such as carrying shopping bags, walking up stairs without difficulty, or maintaining a healthy sitting posture. 

For people whose hobbies include higher energy activities such as hiking, social sports or playing with their children, muscle mass deficiencies become even more of a hindrance to their well-being. 

Perhaps most concerningly, people with low relative muscle mass are both at a greater risk of developing critical illnesses and take longer to recover from acute conditions^[6]. 

This is largely due to the role of muscle mass in keeping the body’s vital tissues and organs healthy, enabling them to respond effectively to stress^[7]. 

Lean muscle mass is also highly important for long-term weight management. 

The higher the proportion of lean muscle to fat mass, the higher one’s basal metabolic rate becomes, meaning the higher the rate at which the body burns calories (even while resting)^[8]. 

A lot of us are aware of overweight and obesity’s association with type 2 diabetes (T2D). Again, the ratio of lean muscle to fat mass is important here, as it impacts the body’s insulin resistance. If there is too much fat relative to lean muscle, the body’s fat cells absorb more insulin than the pancreas can produce – a key driver of T2D^[9]. 

Once a person has T2D, the task of losing weight becomes more difficult, as their insulin resistance limits their body’s ability to convert blood sugar into energy. 

The role of GLP-1s and lean muscle loss 

It’s important to realise that the demonstrated link between GLP-1 RA-induced weight loss and lean muscle reduction has come from studies that have either treated patients with the medication in isolation or combined GLP-1 RA treatment with standardised behavioural therapy. 

Studies assessing non-pharmacological weight loss interventions have also observed significant reductions in lean muscle mass^{[10] [11]}. 

Critical omissions from all these studies are personalised resistance training programs and high protein diets, both of which have consistently been found to control and even improve lean muscle-to-fat mass ratios during weight loss interventions^{[12] [13]}. 

This is a key reason effective weight management programs shouldn’t offer GLP-1 RAs in isolation. 

Medication should constitute just one part of a program, combined with nutrition and exercise components to form a holistic intervention. 

The role of GLP-1s and bone mineral density

Bone mineral density is a key marker of bone health and a reliable predictor of fracture likelihood, osteopenia and osteoporosis^[14]. 

For this reason, maintaining healthy bone density is vital to longevity and quality of life. 

However, claims of a link between GLP-1 RA weight loss treatment and reductions in bone mineral density don’t appear to be well substantiated. 

In fact, several studies indicate that liraglutide can improve bone health in both diabetic and non-diabetic patients ^{15] [16] [17]}. One such investigation suggested that GLP-1 RAs may promote bone formation, and inhibit bone resorption^[18] – the process by which bones are broken down in the body.

There appears to be limited evidence of GLP-1 RAs contributing to a loss of bone density, however, it’s important to note that lean muscle mass and bone mineral density are often grouped together in the literature as fat-free mass, due to their close positive association.

Accordingly, rather than separating the two markers when monitoring patient health, clinicians providing weight services should focus on the ratio of fat-free mass as a whole, relative to fat mass. 

How to maintain lean muscle mass when losing weight 

As we have explored above, when undertaking weight loss interventions, an understanding of one’s overall body composition is key to successful weight management, general health and longevity.

Losing weight without maintaining muscle results in your body burning less energy overall, increasing the likelihood of weight regain when any given weight loss interventions are stopped. 

Moreover, the outcome will lead to other health risks and a lower quality of life. However, muscle wastage while losing weight is entirely avoidable. 

The key, as we emphasised earlier, lies in the degree to which diet and exercise are conducive to muscle building, not simply fat loss.

These are the factors that underpin the kind of holistic weight loss programs that should be followed in conjunction with any GLP RA use.

Exercise 

Resistance training in isolation has been shown to have a minimal effect on weight loss [19], while steady-state cardio tends to induce both fat loss and a significant reduction of fat-free mass^[20]. 

However, a combination of the two has proven to be very effective at generating fat loss without compromising vital muscle and bone strength^[21]. 

This knowledge has guided the exercise component of the services provided by Juniper’s health coaches. 

Our patients are typically encouraged to follow a progressive overload strength routine, in conjunction with at least two hours of Zone 2 cardio training per week, where the patient's heart rate sits at 60-70% of their maximum heart rate range. 

In designing these programs, our multidisciplinary team takes every patient’s health profile and preferences into account.

Nutrition

Resistance training, however, only represents half the equation in building and maintaining fat-free mass. 

Eating a protein-rich diet is essential to protein synthesis, the process required to build muscle fibres. 

Findings from a recent meta-analysis suggest that resistance training performed without adequate protein consumption results in insignificant gains in lean muscle mass [22].

Other studies have demonstrated the importance of protein intake to bone health^{[23] [24]}. Junipers’ health coaches and dieticians encourage their patients to eat 1.2g to 1.6g of protein per kilo of body weight, per day. 

This is intended to give their bodies adequate protein to maintain fat-free mass while losing weight. 

Management of chronic conditions like obesity is complex and requires a multifaceted approach.  

Comprehensive weight-loss programs can only be effectively delivered through the collaborative efforts of a multidisciplinary care team. 

By combining pharmacological treatments with holistic lifestyle coaching, it is possible for individuals to achieve their weight loss goals while mitigating the risk of losing fat-free mass.

Juniper believes a holistic approach to weight management also decreases the time it takes patients to obtain significant health benefits from their weight loss and enhances the degree to which these benefits are sustained.

Sources:

[1]  Pi-Sunyer, X., Astrup, A., Fujioka, K., et al. (2015) A randomised, controlled trial of 3.0mg of Liraglutide in weight management. N Engl J Med, 373:11-12

[2] Jastreboff, A., Aronne, L., Ahmad, N., et al. (2022) Tirzepatide once weekly for the treatment of obesity. N Engl J Med, 387: 205-216

[3]  Wilding, J., Batterham, R., Calanna, S., et al. (2021). Once-weekly Semaglutide in adults with overweight or obesity. N Engl J Med, 384: 989-1002

[4] Ibid

[5] Blundell, J., Finlayson, G., Axelsen, M., et al. (2017). Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes, Obesity and Metabolism, 19: 1242-1251

[6] Prado, C., Purcell, S., Alish, C., et al. (2018) Implications of low muscle mass across the continuum of care: a narrative review. Annals of Medicine, 50: 675-693. 

[7] Wolfe, R. (2006) The underappreciated role of muscle in health and disease. The American Journal of Clinical Nutrition. 84: 475-482

[8] Victoria State Government (2020) Better Health Channel: Metabolism. Retrieved from https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/metabolism

[9] Fukushima, Y., Kurose, S., Shinno, H., et al. (2016) Importance of lean muscle maintenance to improve insulin resistance by body weight reduction in female patients with obesity. Diabetes Metab J, 40: 147-153. 

[10] Varady, K. (2011) Intermittent versus daily calorie restriction: which diet regimen is more effective for weight loss. Obesity reviews, 7: e593-e601.

[11] Lowe, D., Wu, N., Rohdin-Bibby, L., et al. (2020). Effects of time-restricted eating on weight loss and other metabolic parameters in women and men with overweight and obesity: The TREAT randomised clinical trial. JAMA Intern Med, 180: 1491-1499.

[12] Varady, K. (2011) Intermittent versus daily calorie restriction: which diet regimen is more effective for weight loss. Obesity reviews, 7: e593-e601.

[13] Verreijen, A., Engberink, M., Memelink, R., et al. (2017). Effect of high protein diet and/or resistance exercise on the preservation of fat free mass during weight loss in overweight and obese older adults: a randomised controlled trial. Nutrition Journal, 16.

[14] Australian Government (2023). Health Direct: Bone density scan.

[15] Iepsen, E., Lundgren, J., Hartmann, B., et al. (2015). GLP-1 Receptor Agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women. J Clin Endocrinol Metab, 100: 2909-17. 

[16] Cai, T., Li, H., Jiang, L., et al. (2021). Effects of GLP-1 Receptor Agonists on bone mineral density in patients with type 2 diabetes mellitus: A 52-week clinical study. BioMed Research International.  

[17] Driessen, J., Henry, R., van Onzenoort, et al. (2015). Bone fracture risk is not associated with the use of glucagon-like peptide-1 receptor agonists: A population-based cohort analysis. Calcified tissue international, 97: 104-112. 

[18] Zhao, C., Liang, J., Yang, Y., et al. (2017). The impact of Glucagon-Like Peptide-1 on bone metabolism and its possible mechanisms. Front Endocrinol (Lausanne), 8.

[19] Willis, L., Slentz, C., Bateman, L., et al. (2012). Effects of aerobic and/or resistance training on body mass or obese adults. Journal of applied physiology, 113: 1831-1837

[20] Villareal, D., Aguirre, L., Gurney, B., et al. (2017). Aerobic or resistance exercise, or both, in dieting obese older adults. N Engl J Med, 376: 1943-1955

[21] Ibid

[22] Tagawa, R., Watanabe, D., Ito, K., et al. (2021). Dose-response relationship between protein intake and muscle mass increase: a systematic review and meta-analysis of randomised controlled trials. Nutrition reviews, 79: 66-75.

[23] Zittermann, A., Schimdt, A., Haardt, J. et al. (2023) Protein intake and bone health: an umbrella review of systematic reviews for the evidence-based guideline of the German nutrition society. Osteoporosis International, 34: 1335-1353. 

[24] Groenedijk, I., den Boeft, L., van Loon, L., et al. (2019). High versus low dietary protein intake and bone health in older adults: a systematic review and meta-analysis. Computational and Structural Biotechnology Journal, 17: 1101-1112.