Pharmacologic Treatment of Obesity
Transcription
Hi, I'm Katherine Bakewell. I'm a rheumatologist out of Salt Lake City, Utah. And I have a particular interest in my practice on immunometabolic disease. And so it's my privilege and pleasure to talk to you today about the pharmacologic treatment of obesity.
The ACR has given us guidance that for individuals living with overweight or obesity and rheumatic disease that we should be addressing this, and they have said that weight management should be pursued through diet and physical activity which can complement but not replace pharmacologic therapy. We need to remember in rheumatology that obesity is a causal contributor for multiple of our rheumatic diseases including psoriatic arthritis, osteoarthritis and gout, and that it can portend worse outcomes and poorer response to our therapies in all of these diseases including rheumatoid arthritis.
Fortunately, we also have data that weight loss can improve outcomes and that individuals, for example, who can lose 5 to 10% of their body weight or more if they are at baseline living with overweight or obesity, they are more likely to attain low disease activity or remission.
So, without further ado, let's talk about the pharmacotherapies available at current. I am going to spend most of the time talking about incretin therapy since they have truly swept the market. So a recent New York Times article estimated that one in eight Americans either is on or has taken in the past the GLP-1 receptor agonist therapy. These or any pharmacologic therapy is indicated for individuals with a BMI of at least 27 with weight-related comorbidities or a BMI of 30 or higher regardless of comorbidity status.
So first I want us to talk about semaglutide which is a GLP-1 monoagonist. This is given as a once-weekly subcutaneous injection and in the initial phase 3 clinical trial program individuals lost an average of 15% of their body weight. This is not counting the recent 2026 approval of a high dose so up to 7.2 milligrams subcutaneous weekly in which individuals did lose up to 20% of their body weight in that clinical trial program.
Tirzepatide I'll mention next. This is a dual agonist for both GLP-1 and GIP with individuals losing up to 21% of their body weight in that clinical trial program. And I want to just touch on briefly a triple agonist which is currently under development that goes by the name of retatrutide. So this is a GLP-1, GIP, and glucagon triple agonist. And in the phase 3 clinical trials individuals have lost up to an astounding 28% of their
body weight, an astounding 28% of their body weight. This is approaching bariatric surgery levels of weight loss. We will hope to see this approved sometime in 2027. But by no means is this the only agent currently under investigation. There are multiple agents currently being looked at. For example, amylin analogues, which may have a more favorable GI side effect profile, or myostatin inhibitors, which can be used in combination with GLP-1 or amylin therapies to reduce some of the sarcopenia that individuals on these therapies have experienced.
There were two oral agents approved. The first was semaglutide at a dose of 25 milligrams once daily in 2025. This is a peptide and so is more delicate, if you will. It has to be taken with a sip of water and not have anything to eat or drink for a half hour afterwards. Orforglipron, which was approved in 2026, is the first small molecule GLP-1 non-peptide. So there are no food or water restrictions with dosing, which may be a therapeutic advantage.
When you have a patient in front of you that you're thinking about one of these therapies, you need to make sure that they don't have a personal or family history of multiple endocrine neoplasia type two or medullary thyroid cancer. Those would be considered contraindications. You would want to have caution in individuals with a history of pancreatitis. And you would not give it to anyone who is pregnant or lactating.
Most common side effects are going to be gastrointestinal — what you would expect: nausea, vomiting, diarrhea, or constipation. You can treat these things symptomatically. And bear in mind, this is why we start low, go slow with your uptitration. Generally speaking, uptitrating only after about 4 weeks at any one given dose.
Things to bear in mind are that any of your weight-related comorbidities like hypertension, diabetes, hyperlipidemia — as the individual loses weight, you're going to want to peel back those therapies to avoid hypoglycemia and hypotension. Some individuals have had acute kidney injury if they got too hypotensive and were not drinking enough water.
I'll also mention that sarcopenia. You need to absolutely advise your patients to be getting adequate protein in their diet — anywhere from 1 to 1.2 grams per kilogram per day. So in general, think about at least 30 to 40 grams of protein per meal on average. Depends on the weight of the individual, but it's a lot. And they also need to be weight-bearing exercising at least two
two times per week. Again, I'd be remiss if I didn't mention uh the TOGETHER PSA in a talk on obesity-related pharmacotherapy. These were patients with psoriatic arthritis who were randomized to receive either ixekizumab or ixekizumab plus tirzepatide with a primary endpoint of simultaneous achievement of an ACR50 and at least a 10% body weight loss.
Needless to say, there this was a statistically significant difference between the combination versus monotherapy. Ixekizumab is not a weight loss drug, uh but of interest to us in rheumatology is that there was a 64% relative increase in the percentage of patients who were able to attain that ACR50. They're showing a significant difference in our pure rheumatologic outcomes for in this case addition of incretin therapy to our standard of care.
So I'll leave you with three basic thoughts. Number one, obesity is a causal contributor to multiple of our rheumatic diseases and it can portend worse outcomes for these patients. Number two, fortunately, this is something that we can reverse with weight loss. And so, my hope is that addressing overweight and obesity will be a part of all of our systematic approaches to individuals with rheumatologic disease. Thank you for your time and attention.
The ACR has given us guidance that for individuals living with overweight or obesity and rheumatic disease that we should be addressing this, and they have said that weight management should be pursued through diet and physical activity which can complement but not replace pharmacologic therapy. We need to remember in rheumatology that obesity is a causal contributor for multiple of our rheumatic diseases including psoriatic arthritis, osteoarthritis and gout, and that it can portend worse outcomes and poorer response to our therapies in all of these diseases including rheumatoid arthritis.
Fortunately, we also have data that weight loss can improve outcomes and that individuals, for example, who can lose 5 to 10% of their body weight or more if they are at baseline living with overweight or obesity, they are more likely to attain low disease activity or remission.
So, without further ado, let's talk about the pharmacotherapies available at current. I am going to spend most of the time talking about incretin therapy since they have truly swept the market. So a recent New York Times article estimated that one in eight Americans either is on or has taken in the past the GLP-1 receptor agonist therapy. These or any pharmacologic therapy is indicated for individuals with a BMI of at least 27 with weight-related comorbidities or a BMI of 30 or higher regardless of comorbidity status.
So first I want us to talk about semaglutide which is a GLP-1 monoagonist. This is given as a once-weekly subcutaneous injection and in the initial phase 3 clinical trial program individuals lost an average of 15% of their body weight. This is not counting the recent 2026 approval of a high dose so up to 7.2 milligrams subcutaneous weekly in which individuals did lose up to 20% of their body weight in that clinical trial program.
Tirzepatide I'll mention next. This is a dual agonist for both GLP-1 and GIP with individuals losing up to 21% of their body weight in that clinical trial program. And I want to just touch on briefly a triple agonist which is currently under development that goes by the name of retatrutide. So this is a GLP-1, GIP, and glucagon triple agonist. And in the phase 3 clinical trials individuals have lost up to an astounding 28% of their
body weight, an astounding 28% of their body weight. This is approaching bariatric surgery levels of weight loss. We will hope to see this approved sometime in 2027. But by no means is this the only agent currently under investigation. There are multiple agents currently being looked at. For example, amylin analogues, which may have a more favorable GI side effect profile, or myostatin inhibitors, which can be used in combination with GLP-1 or amylin therapies to reduce some of the sarcopenia that individuals on these therapies have experienced.
There were two oral agents approved. The first was semaglutide at a dose of 25 milligrams once daily in 2025. This is a peptide and so is more delicate, if you will. It has to be taken with a sip of water and not have anything to eat or drink for a half hour afterwards. Orforglipron, which was approved in 2026, is the first small molecule GLP-1 non-peptide. So there are no food or water restrictions with dosing, which may be a therapeutic advantage.
When you have a patient in front of you that you're thinking about one of these therapies, you need to make sure that they don't have a personal or family history of multiple endocrine neoplasia type two or medullary thyroid cancer. Those would be considered contraindications. You would want to have caution in individuals with a history of pancreatitis. And you would not give it to anyone who is pregnant or lactating.
Most common side effects are going to be gastrointestinal — what you would expect: nausea, vomiting, diarrhea, or constipation. You can treat these things symptomatically. And bear in mind, this is why we start low, go slow with your uptitration. Generally speaking, uptitrating only after about 4 weeks at any one given dose.
Things to bear in mind are that any of your weight-related comorbidities like hypertension, diabetes, hyperlipidemia — as the individual loses weight, you're going to want to peel back those therapies to avoid hypoglycemia and hypotension. Some individuals have had acute kidney injury if they got too hypotensive and were not drinking enough water.
I'll also mention that sarcopenia. You need to absolutely advise your patients to be getting adequate protein in their diet — anywhere from 1 to 1.2 grams per kilogram per day. So in general, think about at least 30 to 40 grams of protein per meal on average. Depends on the weight of the individual, but it's a lot. And they also need to be weight-bearing exercising at least two
two times per week. Again, I'd be remiss if I didn't mention uh the TOGETHER PSA in a talk on obesity-related pharmacotherapy. These were patients with psoriatic arthritis who were randomized to receive either ixekizumab or ixekizumab plus tirzepatide with a primary endpoint of simultaneous achievement of an ACR50 and at least a 10% body weight loss.
Needless to say, there this was a statistically significant difference between the combination versus monotherapy. Ixekizumab is not a weight loss drug, uh but of interest to us in rheumatology is that there was a 64% relative increase in the percentage of patients who were able to attain that ACR50. They're showing a significant difference in our pure rheumatologic outcomes for in this case addition of incretin therapy to our standard of care.
So I'll leave you with three basic thoughts. Number one, obesity is a causal contributor to multiple of our rheumatic diseases and it can portend worse outcomes for these patients. Number two, fortunately, this is something that we can reverse with weight loss. And so, my hope is that addressing overweight and obesity will be a part of all of our systematic approaches to individuals with rheumatologic disease. Thank you for your time and attention.
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