Super-duper weight loss drugs (originally they were designed to help those with Type 2 diabetes, or T2D) like Ozempic, Wegovy, Mounjaro, et al. have swamped the marketplace because of their unique pharmacologic actions compared to their predecessors. Earlier weight loss drugs and over-the-counter concoctions (like coffee and other caffeine-derivatives, as well as smoking cigarettes, for example) simply sped up metabolism and boost energy. These, then, provided (ab-)users an artificial mechanism by which to burn calories and even avoid consuming calories since energy levels didn’t require them.
What makes these modern drugs so unique is their effects on hunger and appetite hormones. Essentially, they alter or disrupt hormone signaling that tell the gut to stop demanding food and/or the brain to feel satisfied with the food you’ve consumed, presumably before you overeat. That is, those appetite and hunger messages lead people to eat less without – we hope – causing permanent and as-yet-unknown effects on the endocrine system as a whole.
Caveat: while some of these drugs have a relatively long history due to their use in managing diabetes, 5-10 years on the market may not be sufficient to declare with absolute certainty that long-term impacts are not going to crop up.
The past couple of decades have given scientists and pharmaceutical companies greater understanding about the gut-brain connection. Hormones, which are signaling proteins that course throughout the body, often have multiple outlets and receptors that allow one metabolic process to influence or be influenced by another part of the body. One of the most common hormones that most of us have some awareness and understanding of is insulin.
Insulin, cell receptors, and disease
Pumped out by the pancreas, insulin helps manage blood sugar, an essential substrate that feeds all of our organs, especially the brain. The digestive process breaks down carbohydrates into sugars that the blood stream then carries to organs for energy. Ever feel groggy or slower between meals? Well, that’s your brain saying ‘feed me…ideally, with sugars, or carbs’. Ever feel like your energy is waning on a long bike ride or hike? That’s your muscles demanding calories, especially sugar-based calories. The insulin signals drive both the sugar calories from those foods to their respective locales and even help pull stored glucose (a form of sugar) from glycogen stores (sugar formulations the body keeps around in case they’re needed like the liver) between feedings. When insulin is in short supply (as in Type 1 diabetes), sugar can’t enter cells.
However, without receptors on the surface and within the cells to allow insulin to do its job, it is neutered. These dysfunctional receptors are part of the process that leads to T2D: when insulin is unable to unlock the cells that have disabled receptors, the brain, heart, and other organs including muscles are deprived of energy.
A few digestive and appetite hormones have similar roles. Leptin, ghrelin, PYY, and the big kid on the block, glucagon-like peptide 1 (GLP-1) transmit signals of fullness, satiety, and hunger to and from the gut and brain. Without operative receptors, however, some of these signals get disrupted. Obesity itself, regardless of original causality, be it genetics, diet, or lifestyle, is one of those disruptors. With obesity, some of these hormones fail to signal when you are sated or over-signal that you continue to be hungry. GLP-1 works by messaging the digestive system that you are sated. Therefore, for those who cannot get that feeling, GLP-1 receptor agonists – these super-duper drugs – help reduce food intake by reducing appetite…and increasing weight loss.
All drugs have side effects
One of the oldest drugs which originally came from willow tree bark is aspirin. Well-known and long used to reduce fevers, manage headaches, and more recently thin blood for those folks at risk for potentially-fatal blood clots such as after lower-extremity surgery or certain cardiac conditions, can also lead to excessive bleeding in the event a closed-head injury or gastric ulcers due to its effect on the stomach lining.
Semaglutide and liraglutide, two of the main GLP-1 drugs out there, have been found to reduce food obsessions leading to calorie restriction but, oddly, have been correlated with reducing other addictive obsessions from gambling to sex to alcohol and other drugs. (1) Interestingly, in combination with bimagrumab, semaglutides “led to superior fat mass loss while simultaneously preserving lean mass despite reduced food intake”. (2)
However, a disconcerting unintended consequence of these weight loss meds is that “the potential health benefits of diet-induced weight loss are thought to be compromised by the weight-loss-associated loss of lean body mass, which could increase the risk of sarcopenia (low muscle mass and impaired muscle function)”. (3) Any time you diet, some of the weight you lose, after initial water weight, is lean tissue – muscle mass and, if rapid and extensive weight is lost, bone mass. A meta-analysis of 18 well-controlled studies that included over 1300 subjects confirmed that these kinds of drugs, which were originally designed to help those with T2D, contribute to loss of muscle mass; metformin, another T2D drug, on the other hand, does not. (4)
Some studies show that, “compared with persons with normal weight”, those with obesity have substantial muscle mass to support and transport their bodies, but poor muscle quality, that is more fatty infiltration generally from lack of a training stimuli. Somehow, though, the “diet-induced weight loss” reduction of muscle mass happens “without adversely affecting muscle strength”. This maintenance of muscle mass that accompanies weight loss improves overall physical function, likely due to the loss of fat mass which otherwise is a drag on performance. While it is recommended, and is very vogue, to encourage a high protein intake – of 1.2 – 2.0 grams/kg of body weight vs the RDA recommendation of 0.8 g/kg – to preserve lean body and muscle mass during weight loss, apparently this does not improve muscle strength; and it could have “adverse effects on metabolic function” if kidney problems are an issue or become one.
Finally, while both endurance exercise, if performed at pretty high intensities such as stair climbing or cycling with high resistances, and resistance training (RT) at moderate to heavy loads “help preserve” lean tissue during a weight loss regimen, only intensive and consistent RT improves muscle strength. This is why researchers are so heavily promoting RT as a way to prevent the inevitable loss of muscle and to restore the low-quality muscle that people with obesity have to a more functional variety. (3)
The mechanisms for these drugs’ effects on lean tissue are under investigation. One group of researchers has determined that the combination of these drugs actually protects against muscle atrophy. The biochemistry is irrelevant here. What might be more relevant is the customary fact that rarely are these drugs prescribed together. So, while they might prevent this adverse effect, it will require more study before they are co-prescribed. (5) There is evidence that shows that oral semaglutide, when prescribed for T2D patients, does help with weight loss and, even alone, does not lead to substantial loss of muscle mass. (6)
Weight loss vs Muscle loss: Inevitable or Preventable?
As we discussed above, any significant amount of weight loss is accompanied by muscle and even bone loss, especially if done quickly over a short period of time. This could be diet-related, disease- or medical treatment-related (think: during chemo or radiation for cancer), or even, shockingly, exercise-related. Yes, if someone engages in intensive and long-duration cardio training such as running or biking, and weight loss occurs, so, too, does muscle loss. (REAL News – Nov. 2024)
Why? It’s pretty simple: unless sufficient calories are consumed to compensate for the excess energy output, the body becomes very efficient by discarding muscles that are not used in the training (REAL News – Dec. 2024) or simply allowing unused muscle fibers, like the bigger, stronger, more powerful fast-twitch fibers, to atrophy since neural stimulation is withheld. Even young athletes on a hypo-caloric diet designed for weight loss lose muscle mass unless they’re on a significantly-elevated protein intake diet. (7) Sadly, too, weight loss of 5% or more is accompanied by bone density loss! (REAL News – December 2018; UC Berkeley Wellness Letter, Nov. 2018 (link unavailable))
With studies showing that GLP-1’s can lead to 15 – 24% weight loss, they can be accompanied by 10%, or ~6 kg, of muscle mass loss. (8) Sergeant et al (2019) found in over half of the studies included in their meta-analysis of the same year, the proportion of muscle loss was somewhere between 20% and an astounding 50% of the total weight lost! (9) A more recent study by Bikou et al. confirmed that, while extremely effective for fat loss, these meds can cause up to 40% of the weight lost being lean mass. (10)
All of these researchers concluded that, with intensive RT, not only can patients reduce the muscle loss, they can maintain muscle mass to reduce weight re-gain should they stop taking the medications.
Takahashi et al (11) demonstrated that vitamin D supplementation, and possibly vitamin B12, but not vitamins A, B6, C, and E, might correlate with with the loss of lean tissue in older adults with T2D. Thus, in addition to a vigorous RT program, getting in extra D could reduce the atrophy that accompanies weight loss.
Nunn et al., in a study of diet-induced mouse obesity, found that blocking a particular muscle cell receptor that is known to interfere with muscle growth – ActRII – while being treated with a semaglutide medication preserves muscle mass. It actually induced an almost 10% increase in lean mass! However, this is what you might call a proof of concept study and has not yet been approved for humans taking a GLP-1 drug. (12)
Some studies have found that muscle mass loss does not deteriorate as much in patients with T2D as one might expect. (6) The Japanese subjects experienced substantial health benefits over the 24 months they used a combination of liraglutide and semaglutide, affirming Klausen et al.’s (1) finding. Too, Gurjar et al. found that “drug repositioning” with liraglutide might be the answer to weight-loss-induced muscle loss, at least in mice. (13)
There is a new kid on the block in Phase 3 studies – a combination drug of Amylin + two GLP-1 drugs – semaglutide and cagrilintide – that offers comparable weight loss while helping to “preserve the reduction in energy expenditure” which could help maintain weight loss in the long run. (14) This could be the game-changer what with all these super-duper drugs that are helping people lose weight, especially for those who are older, more likely to have blood sugar control issues such as T2D, and may already have suffered age-related sarcopenia. However, for all patients who are taking these GLP-1’s, the basic prescription still holds, whether or not it totally reverses years of sedentary living or age-related muscle loss, and that’s RT using loads greater than body weight.
And that is the subject of Part 2 of these super-duper drugs.
Bibliography
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2. Nunn et al. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab. 2024 Feb:80:101880. doi: 10.1016/j.molmet.2024.101880. Epub 2024 Jan 11.
3. Cava et al. Preserving Healthy Muscle during Weight Loss. Adv Nutr. 2017 May 15;8(3):511-519. doi: 10.3945/an.116.014506. Print 2017 May.
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5. Xiang et al. GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway. Diabetes Metab Syndr Obes. 2023 Aug 15:16:2433-2446. doi: 10.2147/DMSO.S425642. eCollection 2023.
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7. Mettler et al., Increased Protein Intake Reduces Lean Body Mass Loss during Weight Loss in Athletes. Medicine & Science in Sports & Exercise 42(2):p 326-337, February 2010. DOI: 10.1249/MSS.0b013e3181b2ef8e
8. Locatelli et al. Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? Diabetes Care. 2024 Apr 30:dci230100. doi: 10.2337/dci23-0100.
9. Sergeant et al. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab (Seoul). 2019 Sep;34(3): 247-262. doi: 10.3803/EnM.2019.34.3.247.
10. Bikou et al. A systematic review of the effect of semaglutide on lean mass: insights from clinical trials. Expert Opin Pharmacother. 2024 Apr;25(5):611-619. doi: 10.1080/14656566.2024.2343092. Epub 2024 Apr 18.
11. Takahashi et al. Vitamin Intake and Loss of Muscle Mass in Older People with Type 2 Diabetes: A Prospective Study of the KAMOGAWA-DM Cohort. Nutrients. 2021 Jul 8;13(7):2335. doi: 10.3390/nu13072335
12. Nunn et al. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab. 2024 Feb:80:101880. doi: 10.1016/j.molmet.2024.101880. Epub 2024 Jan 11.
13. Gurjar et al. Long-acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents. Metabolism. 2020 Feb:103:154044. doi: 10.1016/j.metabol.2019.154044. Epub 2019 Dec 5.
14. From online lecture on Medscape: https://www.medscape.org/viewarticle/1001688_4
