Thank you Dr. Nadeem for the introduction. Thank you everyone for being here. It's a hot topic. Today I will be talking about muscles and obesity and weight loss. I have no financial disclosures to make. The burden of obesity is huge. Millions of people are affected by obesity. The prevalence of obesity is very high worldwide and the Middle East and North African region is not an exception to that. Obesity is associated with several obesity related comorbidities. There has been major advances in the efficacy of anti-obesity medications over the last few years. Anti-obesity medications are widely used to manage obesity, control metabolic risk factors and reduce the risk of cardiovascular events. Medications like semaglutide is FDA approved for obesity management and is also FDA approved to reduce MACE, to reduce major adverse cardiovascular events in patients with obesity and established cardiovascular disease. Concerns were raised about losses from muscles with these medications. In this presentation I will begin by talking about the impact of obesity on muscles to establish a baseline status in these patients. And then I'll move on to explore the impact of weight loss on muscle mass and physical function. And I will end by discussing strategies to preserve muscle mass. What's the impact of obesity on muscle? Most patients with obesity do not have lower absolute muscle mass. Most of them have normal or higher absolute muscle mass. But one thing to keep in mind is that having more muscles does not necessarily mean better quality and better function. Muscles in patients with obesity appear to be resistant to anabolic stimuli. Stimuli that increase protein synthesis in the muscles. In this study they recruited older adults 55 to 75 years. They had two groups. One group, older adults with obesity and elevated CRP. And the control group was healthier adults without obesity. They were interested in assessing muscle protein synthesis in response to anabolic stimuli. And the anabolic stimuli in this study were insulin and amino acid. The way they assessed muscle protein synthesis is by assessing myofibrillar FSR from muscle biopsy. And what they observed is that the response to anabolic stimuli in patients with obesity is blunted compared to patients who do not have obesity. Which suggests that people with obesity have lower protein synthesis rate than patients who are lean. Why is this the case? What explains it? It's thought to be secondary to chronic systematic inflammation that we see in patients with obesity. Intermuscular adipose tissue and alteration in gene expression. What is intermuscular adipose tissue? Intermuscular adipose tissue refers to fat deposits between muscle fibers. It's distinct from fat droplets within the muscle cells. Studies have linked intermuscular adipose tissue with insulin resistance that we see in people with metabolic syndrome and obesity. And this figure shows you the adipose tissue between muscle fibers. Let's now move on to discuss the impact of obesity on physical performance, which is something not new to any of you. Several studies have linked obesity with lower physical performance, increased risk of falls, and decline in quality of life. In fact, our goal when we're treating obesity is to improve physical performance and improve quality of life. Now that we've discussed the impact of obesity on muscles and we established the baseline status of patients with obesity, let's delve deeper into the most exciting part of this presentation, which is the impact of weight loss on muscles. I'd like to begin by discussing how muscle mass is measured. Fat-free mass refers to the mass of everything except fat. Skeletal muscle mass represents approximately 50% of fat-free mass. This may vary, but for the sake of simplicity, I'm saying 50% of fat-free mass. The remainder of fat-free mass is composed of fluids, organs, and body tissues. Most weight loss studies assess changes in fat-free mass or lean body mass, not muscle mass. And the way they do so is by doing a DEXA scan to estimate body composition or doing CT or MRI scans. What we do in practice is usually different. Most of us, when we assess body composition, we assess body composition by bioelectrical impedance analysis, by machines commonly known as TANITA and BODY. We use these machines because they're easy to do. They're not expensive. However, they have limitations to their use that I will discuss in the next slide. The reason most studies assess fat-free mass and lean body mass is because to measure skeletal muscle mass, you need more advanced techniques, such as whole body MRI or D3 creatine dilution technique. Let's move on to discuss the limitations of bioelectrical impedance analysis. The way these machines work is by sending an electrical impulse and measuring the body's impedance resistance to the electrical impulse. Fat mass has high impedance. Muscle mass has lower impedance. But it's important to keep in mind that there are other variables that affect fat-free mass. Such as hydration status and food intake. For example, in people who are over-hydrated, their fat-free mass will be overestimated. And in those who are dehydrated, their fat-free mass will be underestimated. Therefore, it's important to interpret the result of these machines with caution. Can we do anything to decrease variability? Yes, you can follow proper protocol standardization and do the test in standardized settings. All right, let's talk about changes to fat-free mass with weight loss. What happens to fat-free mass with weight loss? Intentional weight loss is a change in the fat-free mass. What happens to fat-free mass with weight loss? Intentional weight loss decreases both body fat and fat-free mass. Losses from fat-free mass generally represent between 20 to 30% of the total weight loss. Unfortunately, we see this with all obesity interventions. Here we see what you would expect with calorie restriction with adequate protein intake. 23% of the loss is coming from fat-free mass. This is similar to what we saw with terzepatide in the Sermon trial. However, we saw a higher loss from fat-free mass in the semaglutide study. It's important to keep in mind that DEXA scan was not done on everyone in the Step 1 trial. It was done on a select number of individuals. So I wonder if this result is a matter of selection bias. Other things to keep in mind are factors that affect fat-free mass that I will talk about in the next study. I cannot think of any reason why something is special with semaglutide compared to terzepatide that would lead to more fat-free mass loss than terzepatide. And we see around 30% loss from fat-free mass with bariatric surgery, maybe more with raw NY compared to sleeve gastrectomy. Alright, let's move on to discuss factors influencing fat-free mass. Is age a factor that influences fat-free mass? We know that as people age, they lose muscles. But do older patients who take medications to lose weight lose more muscle mass? They did a sub-analysis in the terzepatide trial and they looked at patients who were less than 50, patients who were less than 50, patients between 50 to 65, and patients who were 65. There was no increase in losses from fat-free mass as you get older, which was reassuring. How about the rapidity of weight loss? Do patients who lose weight more rapidly lose more from their fat-free mass compared to gradual weight loss? This is a meta-analysis that pooled data from different studies that assessed the impact of gradual versus rapid weight loss on fat-free mass. There was no difference between gradual versus rapid weight loss. It's important to note that there was significant heterogeneity between the studies. How about initial weight? Some studies suggest that people who are starting with higher fat-free mass, lower fat mass, are more likely to lose from their fat-free mass. And there are several studies linking inadequate protein intake with higher fat-free mass, and we'll discuss this more during the section on preservation of fat-free mass. And there are several studies linking physical inactivity with loss from fat-free mass. Now that we've discussed that we see fat-free mass loss with all interventions of anti-obesity, with all interventions for obesity management, let's move on to discuss the clinical significance of this. What happens to physical function? What happens to quality of life? All phase 3 randomized clinical trials assessed quality of life and physical function using questionnaire as a secondary outcome. And they found strong association between weight loss and improved physical function, strong association between weight loss and improved quality of life. Recently, the results of the Step 9 trial were published. The Step 9 trial was a randomized controlled trial that randomized patients with obesity and moderate to severe osteoarthritis to semaglutide versus placebo. And what they found is that the group that was randomized to semaglutide had significant improvement in symptoms, significant improvement in physical function. And we heard earlier about how the use of GLP-1 agonists like semaglutide in the flow trial was shown to improve renal outcomes in patients with diabetic kidney disease. And there are many other benefits for these medications that have been well established in randomized clinical trials. What's the concern? The concern is that changes in muscle mass and strength with anti-obesity medications are not sufficiently evaluated. Yes, we need more research. I'm not saying no. Older adults are underrepresented in phase 3 clinical trials. That's true. 10 to 15 percent of the study populations were older than 60. The remaining were less than 60. What I was surprised to see is that older adults are even underrepresented in real-life obesity clinics. When I looked at our data of patients who received draglutide, less than 5 percent were older than 60. It's important to distinguish between intentional medical weight loss and unintentional weight loss. Unintentional weight loss and muscle loss often caused by disease and poor health are associated with increased morbidity and mortality. I do not think we can extrapolate this to intentional medical weight loss. In fact, we're seeing the opposite with intentional medical weight loss. Another concern is that fat free mass loss is associated with a decrease in basal metabolic rate. We'll discuss ways to try to preserve fat free mass, but remember that we're seeing this at the expense of significant improvement in obesity-related medical conditions. We're seeing this at the expense of improvement in glycemic control. We're seeing this at the expense of improvement in heart failure symptoms in patients who have heart failure, at the expense of improving obstructive sleep apnea in people who have obstructive sleep apnea and many other conditions. So to summarize what I covered so far, there is no evidence to support that intentional weight loss induced by anti-obesity medications leads to frailty or sarcopenia. I cannot give a talk about obesity and muscles without talking about sarcopenic obesity. Sarcopenic obesity is having both obesity and sarcopenia at the same time. Sarcopenia is a muscle disorder characterized by loss of muscle mass and loss of muscle strength, leading to adverse clinical outcomes such as falls, fractures, morbidity and mortality. According to the European Working Group on Sarcopenia in Older People, the diagnosis of sarcopenia is confirmed if you have low muscle strength and low quantity. If you have low muscle strength and low quantity with impaired physical performance, then you have severe sarcopenia. And the diagnosis is probable if you only have low muscle strength. The guidelines suggested the SARC-F questionnaire as a way to assess muscle strength. This is the SARC-F questionnaire. The SARC-F questionnaire assesses patient's ability to carry 10 pounds, patient's ability to walk across a room, patient's ability to transfer from bed or a chair, patient's ability to climb a flight of 10 stairs and if there's any history of falls in the last year. So it's self-reported data. A score is calculated and if they have a score of 6, they consider to have a positive results for sarcopenia, for low strength. It's important to assess the diagnostic validity of this, the diagnostic accuracy of this test. So when you look at the negative predictive value of SARC-F, it's very decent, 93.2. So if the results are negative, they're likely to be true negative. However, this test has a very poor positive predictive value. If the results are positive, they could be false positive. Other ways to assess muscle strength include the hand grip strength. It's a surrogate of more complicated strength measurements. Studies have linked low hand grip strength with poor health outcomes, longer length of stay in patients who are sick and when they use the hand grip strength to assess for low strength in patients with obesity, they found that at baseline, 5.4 to 24 percent have sarcopenia based on the hand grip strength. What we don't know is what happens to hand grip strength with obesity medication induced weight loss. What's the worst outcome? What's the worst-case scenario? The worst-case scenario is that when you give these medications, hand grip strength will go down, right? Will that change the management? Is that gonna push me to stop a medication that helps with improving glycemic control, that helps improve heart failure symptoms in patients with heart failure, that help produce MEs in patients with established cardiovascular disease? Probably not. Will I use this tool to convince patients to engage in physical activity and make sure that they're meeting their protein intake? Maybe yes, although I'm not a big fan of fear-based interventions to change a behavior. I don't think it works for chronic conditions, but this is an area where you can use it. Another test to assess muscle strength is the chair stand test. My issue with this test is that if patients are not able to do it, are they not able to do it because they have low muscle strength or are they not able to do it because they have a lot of fat tissue on board? When they use this test to assess the prevalence of sarcopenia in patients with obesity, 3.2% had sarcopenia based on this test. For those of us who prescribe these medications to patients with obesity, this is one of the things that patients are proud of, that when they take these medications, they lose weight, their ability to change position is smoother and they're happy with this. So there are no studies on this, but this is something that I see in clinic, that their chair to stand test gets better. And there are other ways to measure strength that are mainly used in research settings such as the repetition maximum testing. So to summarize this section, the prevalence of sarcopenia is highly variable depending on the diagnostic tool used. There is limited data on strength and strength changes during weight loss and we need more data on this. All right, so now that we have talked about the changes of fat-free mass that happens during weight loss, let's now move on to discuss strategies to preserve muscle mass and talk about the positive side of this presentation. The backbone of interventions to preserve muscle mass is adequate protein intake and resistance exercises and I will share the evidence with you in a little bit. It's important that when you're seeing someone who loses significant fat-free mass to consider other conditions that are associated with accelerated muscle mass, such as endocrinopathies, as in Cushing, other diseases, patients with advanced kidney diseases, they are in a catabolic state, they lose muscle mass more rapidly, so keep these things in mind. All right, Lehman and his colleagues included individuals with obesity and they randomized them to one of the four calorie restricted groups. The first group is a group that received a high protein diet with light physical activity and what they meant by light is less than 100 minutes of walking per week. The second group received a high protein intake with an exercise program, five days a week, a combination of aerobic and resistance training. The third group was a low protein diet without an exercise program, only with light activity, walking less than 100 minutes per week. And the fourth group was a low carb diet with an exercise program, five sessions per week, a combination of aerobic and resistance training. At baseline, all four groups were meeting the recommended daily allowance of protein, 0.8 to 0.9 grams per day. The group that were randomized to higher protein diet increased their protein intake to 1.2 grams per day and the group that were not randomized to the high protein diet ended up reducing their protein intake to 0.6 to 0.7 gram per day. What did they find? All groups lost the same amount of weight. But when it comes to fat-free mass preservation, the best group is the group that consumed adequate protein intake with an exercise program. They only lost, fat-free mass represented 4% of the total weight loss. The second best group is the group that received an exercise program even with a little bit lower protein intake. The third group is the adequate protein intake with light physical activity but not a structured exercise program. And the worst is the group that had lower protein intake and no exercise program. That's not surprising. All right, so let's now move on to talk why we always stress resistant training, why do we always stress strength training. The type of training does not matter, does not affect the final weight loss that's achieved. However, those who engage in strength and resistance training preserve more lean mass compared to people who do aerobic exercises, for example, and their strength is higher compared to the group that does aerobic exercises. Exercise program is not easy. People are different. The patients that we see in clinic are very heterogeneous. It must be individualized. You may start with a patient who is very sedentary at baseline. When you look at their phone or their wearables, all they're doing is like 1,500 steps per day, which is very low to begin with. So the initial step in that case is to increase their physical activity, increase the number of steps, increase your activity at work, at home, maybe start carrying your shopping bags instead of having someone else carry your shopping bags, and then take it step by step. Some people are starting at an advanced step. Most of the physical activity guidelines for the public recommend moderate intensity exercise, 150 minutes per week. And what's considered moderate intensity exercise is brisk walking, swimming, or biking. So this might be a good place to start in someone who is more active at baseline. And then with time, we need to try to add resistance training, and resistance training is not easy to add. It requires machines, devices, bands, and it requires training. It's very hard to do strength training without proper supervision. To conclude, and I hope you agree with this with my conclusions, obesity is not associated with lower muscle mass, but is associated with impaired muscle quality and decreased muscle function. Intentional weight loss is associated with a reduction in fat-free mass, but better physical function and better cardiometabolic outcomes. Adequate protein intake and resistance exercises could medicate losses from fat-free mass. There is no evidence currently to suggest that intentional weight loss is associated with sarcopenia and frailty. I did not discuss what's in the pipeline, the medications that are being studied to preserve fat-free mass, but this is something that might be considered for a subset of the individuals that we take care of in clinic in the future. Thank you, everyone, for listening.

obesity

muscle mass

weight loss

anti-obesity medications

muscle quality

preservation strategies