Semaglutide lowered cardic events but enrollees weren't treated with currently available generic medications to achieve appropriate cholesterol, blood pressure, and inflammation goals
Excellent post thank you. The cost is pretty wild for the niche absolute risk reduction. One comment about colchicine - I have very few patients taking this, and also most with ASCVD have seen/are seeing a cardiologist. HS-CRP levels are not commonly checked or acted upon. I’ll have to brush up the relevant consensus guidelines, but what percentage of your patients (estimated) are on colchicine?
i consider hs-CRP one of 4 essential blood tests in primary and secondary aSCVD risk estimation (along with apo B and LDL which i recheck on treatment and lipo (a) which I check usually once). If we accept that inflammation is a hallmark of ASCVD plaque development and progression it makes sense to have one simple parameter to monitor.
There was pretty good evidence prior to a few weeks ago that colchicine was beneficial in patients with ongoing inflammation and ASCVD.
However, the CLEAR trial was a large, high-quality RCT looking at colchicine added on to standard therapy after acute MI and at 3 years it was totally negative.
Only a small % of my patients are on colchicine. I had been reserving it for those with advanced subclinical ASCVD or post-MI with residual elevated hs-CRP despite optimized lipid-lowering therapy and aspirin.
I'm sure you have commented on this before. I had my Apo Lip A checked once by a cardiologist. It was normal. Can you discuss the Apo B. That was not checked. I saw a cardiologist last year at age 65 because I have a terrible family h/o early heart disease. He did a CT coronary calcium scan. It was about 100. I've been a long term vegetarian. My HDL & LDL are 47. Should I ask about apo B and CRP? Oh, I've never had any CV event. I'm due for a 1 year check up soon. Thanks!
As noted, the recent CLEAR presentation at TCT and paper in NEJM adds some uncertainty to the “inflammation” issue at least wrt efficacy of colchicine.
While I would also target a lower LDL, I would add that “targets” themselves are not evidence-based; those levels were simply the average attained levels in the high intensity statin arm of studies. In addition, Pegasus showed very small ARR with addition of ezetimibe. And PCSK9 outcome studies only showed CV revasc benefits.
Your point is well taken wrt BP control. And I still need to better understand the results of BPROAD study from recent AHA.
I think there are many practical limits to how SELECT is translated, esp from an economic standpoint. But I would consider it a substantiated addition to the armamentarium.
Have you had a chance to review the CLEAR trial, which was presented last month at TCT and published in the NEJM on Nov. 17, 2024? The trial found that colchicine did not reduce cardiovascular events in patients who had had an MI. DOI: 10.1056/NEJMoa2405922.
I'm aware of that trial and its findings. I wrote the SELECT piece prior to TCT and prior trials of colchicine had been favorable. Hopefully, we will get some critical analysis on the preponderance of evidence in light of the new trial and a better feel for which patients with established ASCVD or advanced subclinical ASCVD will benefit from colchicine.
This is just a simple 'Thank you' from a subscriber. But, it's a very appreciative thank you for this excellent, well-written article! I am a 63 y/o retired health care provider who is overweight and prediabetic (A1C 5.8). You just answered so many of my questions about Wegovy, and I am truly grateful to you. Thank you for addressing so many topics of interest and/or concerns throughout the years. I wish you good health and happiness for many years to come. Susan A.
You said "apo B/LDL-c down to levels where ASCVD regresses". Regress? I have never heard this before. About 6 months ago I switched my statin to 1mg pitavastain and added 10mg ezietimibe. I hope to drive my apoB downward from my present value of 65 mg/dL. So there is a possibility that my ASCVD will regress? ( I have not measured my apoB since I switched to the new medications) I assume the value will be lower.
which lowered LDL to 60 and raised HDL by 13% . Subsequent studies have shown that lowering LDL to 36 with combo PCSK9i + statin results in even more IVUS documented regression in plaque volume
My apoB 65 mg/dL was measured before I switched my statin to 1mg pitavasatin and added the 10 mg ezetimibe. I've now been on this combination for about 6 months. I'll be getting my new blood work in the first week of December. I'll post my new results.
A GLP-1 receptor agonist endocannabinoid system web search brings up an article that says, "The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels." https://pmc.ncbi.nlm.nih.gov/articles/PMC5625085/
What sort of food elevates endocannabinoid levels? "Chicken meat with reduced concentration of arachidonic acid (AA) and reduced ratio between omega-6 and omega-3 fatty acids has potential health benefits because a reduction in AA intake dampens prostanoid signaling, and the proportion between omega-6 and omega-3 fatty acids is too high in our diet." https://pmc.ncbi.nlm.nih.gov/articles/PMC2875212/
Note that prostanoids are endocannabinoids. Excerpt from another article: "Endocannabinoids and their G-protein coupled receptors (GPCR) are a current research focus in the area of obesity due to the system's role in food intake and glucose and lipid metabolism. Importantly, overweight and obese individuals often have higher circulating levels of the arachidonic acid-derived endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) and an altered pattern of receptor expression. Consequently, this leads to an increase in orexigenic stimuli, changes in fatty acid synthesis, insulin sensitivity, and glucose utilisation, with preferential energy storage in adipose tissue." https://pubmed.ncbi.nlm.nih.gov/23762050/
I find it peculiar that the endocannabinoid system is never mentioned in articles about the new generation of weight loss drugs.
"Death from CV cause, nonfatal MI or stroke occurred in 8% of the treatment group and 6.5 % of the placebo group so the absolute risk of events was reduced by 1.5%."
We do get a lot of US media so I have seen some and wanted to fact check myself. From the Canadian government “The Food and Drugs Act and its associated regulations do not apply to advertising of services.
However, advertising any prescription drugs to the general public for the treatment, prevention or cure of is prohibited.”
There are "experts" out there saying that a substantial amount of weight loss achieved with these meds comes from loss of muscle as well as fat. This is seen as bad.
Other "experts" point out that the loss of fat weight reduces one's body's need for the musculature it takes to simply carry that weight around. Musculature adjusts. This is seen as to be expected.
These are legitimate concerns. Patients starting on semaglutide should be counseled on the importance of resistance/strength training to maintain muscle mass. They should already have been counseled on the importance of 150 minutes of MVPA per week. I think measurement of visceral fat mass and lean mass by DEXA (available for 15$ in STL) in a great way to both educate individuals, motivate them, and assess changes in fat/lean mass with lifestyle changes and drugs.
Excellent post thank you. The cost is pretty wild for the niche absolute risk reduction. One comment about colchicine - I have very few patients taking this, and also most with ASCVD have seen/are seeing a cardiologist. HS-CRP levels are not commonly checked or acted upon. I’ll have to brush up the relevant consensus guidelines, but what percentage of your patients (estimated) are on colchicine?
Thanks for a helpful cardiology perspective
i consider hs-CRP one of 4 essential blood tests in primary and secondary aSCVD risk estimation (along with apo B and LDL which i recheck on treatment and lipo (a) which I check usually once). If we accept that inflammation is a hallmark of ASCVD plaque development and progression it makes sense to have one simple parameter to monitor.
There was pretty good evidence prior to a few weeks ago that colchicine was beneficial in patients with ongoing inflammation and ASCVD.
However, the CLEAR trial was a large, high-quality RCT looking at colchicine added on to standard therapy after acute MI and at 3 years it was totally negative.
Published in NEJM 2 weeks ago....https://www.nejm.org/doi/full/10.1056/NEJMoa2405922?query=cardiology
Only a small % of my patients are on colchicine. I had been reserving it for those with advanced subclinical ASCVD or post-MI with residual elevated hs-CRP despite optimized lipid-lowering therapy and aspirin.
Dr.,
I'm sure you have commented on this before. I had my Apo Lip A checked once by a cardiologist. It was normal. Can you discuss the Apo B. That was not checked. I saw a cardiologist last year at age 65 because I have a terrible family h/o early heart disease. He did a CT coronary calcium scan. It was about 100. I've been a long term vegetarian. My HDL & LDL are 47. Should I ask about apo B and CRP? Oh, I've never had any CV event. I'm due for a 1 year check up soon. Thanks!
As noted, the recent CLEAR presentation at TCT and paper in NEJM adds some uncertainty to the “inflammation” issue at least wrt efficacy of colchicine.
While I would also target a lower LDL, I would add that “targets” themselves are not evidence-based; those levels were simply the average attained levels in the high intensity statin arm of studies. In addition, Pegasus showed very small ARR with addition of ezetimibe. And PCSK9 outcome studies only showed CV revasc benefits.
Your point is well taken wrt BP control. And I still need to better understand the results of BPROAD study from recent AHA.
I think there are many practical limits to how SELECT is translated, esp from an economic standpoint. But I would consider it a substantiated addition to the armamentarium.
Have you had a chance to review the CLEAR trial, which was presented last month at TCT and published in the NEJM on Nov. 17, 2024? The trial found that colchicine did not reduce cardiovascular events in patients who had had an MI. DOI: 10.1056/NEJMoa2405922.
I'm aware of that trial and its findings. I wrote the SELECT piece prior to TCT and prior trials of colchicine had been favorable. Hopefully, we will get some critical analysis on the preponderance of evidence in light of the new trial and a better feel for which patients with established ASCVD or advanced subclinical ASCVD will benefit from colchicine.
Many thanks for all the education you provide us!!
Hello Dr. Skeptical,
This is just a simple 'Thank you' from a subscriber. But, it's a very appreciative thank you for this excellent, well-written article! I am a 63 y/o retired health care provider who is overweight and prediabetic (A1C 5.8). You just answered so many of my questions about Wegovy, and I am truly grateful to you. Thank you for addressing so many topics of interest and/or concerns throughout the years. I wish you good health and happiness for many years to come. Susan A.
Thanks Susan! You just made my day
You said "apo B/LDL-c down to levels where ASCVD regresses". Regress? I have never heard this before. About 6 months ago I switched my statin to 1mg pitavastain and added 10mg ezietimibe. I hope to drive my apoB downward from my present value of 65 mg/dL. So there is a possibility that my ASCVD will regress? ( I have not measured my apoB since I switched to the new medications) I assume the value will be lower.
Philip Thackray
Yes. We've had solid evidence of plaque regression measured by IVUS beginning about 20 years ago with this trial (https://jamanetwork.com/journals/jama/fullarticle/202629#:~:text=Conclusions%20Very%20high%2Dintensity%20statin,IVUS%20measures%20of%20disease%20burden.)
which lowered LDL to 60 and raised HDL by 13% . Subsequent studies have shown that lowering LDL to 36 with combo PCSK9i + statin results in even more IVUS documented regression in plaque volume
My apoB 65 mg/dL was measured before I switched my statin to 1mg pitavasatin and added the 10 mg ezetimibe. I've now been on this combination for about 6 months. I'll be getting my new blood work in the first week of December. I'll post my new results.
Thanks for all you do!
Philip Thackray.
A GLP-1 receptor agonist endocannabinoid system web search brings up an article that says, "The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels." https://pmc.ncbi.nlm.nih.gov/articles/PMC5625085/
What sort of food elevates endocannabinoid levels? "Chicken meat with reduced concentration of arachidonic acid (AA) and reduced ratio between omega-6 and omega-3 fatty acids has potential health benefits because a reduction in AA intake dampens prostanoid signaling, and the proportion between omega-6 and omega-3 fatty acids is too high in our diet." https://pmc.ncbi.nlm.nih.gov/articles/PMC2875212/
Note that prostanoids are endocannabinoids. Excerpt from another article: "Endocannabinoids and their G-protein coupled receptors (GPCR) are a current research focus in the area of obesity due to the system's role in food intake and glucose and lipid metabolism. Importantly, overweight and obese individuals often have higher circulating levels of the arachidonic acid-derived endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) and an altered pattern of receptor expression. Consequently, this leads to an increase in orexigenic stimuli, changes in fatty acid synthesis, insulin sensitivity, and glucose utilisation, with preferential energy storage in adipose tissue." https://pubmed.ncbi.nlm.nih.gov/23762050/
I find it peculiar that the endocannabinoid system is never mentioned in articles about the new generation of weight loss drugs.
"Death from CV cause, nonfatal MI or stroke occurred in 8% of the treatment group and 6.5 % of the placebo group so the absolute risk of events was reduced by 1.5%."
Are these percentages reversed?
yes.
We don't get the same drug comercials in Canada so I'm not going to look it up and ruin Magic for myself.
You are very lucky. Are there no direct to consumer drug adverts in Canada?
You can't watch the network nightly news or a network sporting event in the US without getting a barrage of these.
We do get a lot of US media so I have seen some and wanted to fact check myself. From the Canadian government “The Food and Drugs Act and its associated regulations do not apply to advertising of services.
However, advertising any prescription drugs to the general public for the treatment, prevention or cure of is prohibited.”
https://www.canada.ca/en/health-canada/services/drugs-health-products/marketing-drugs-devices/illegal-marketing/prescription-drugs.html
Dr. Skeptical,
There are "experts" out there saying that a substantial amount of weight loss achieved with these meds comes from loss of muscle as well as fat. This is seen as bad.
Other "experts" point out that the loss of fat weight reduces one's body's need for the musculature it takes to simply carry that weight around. Musculature adjusts. This is seen as to be expected.
Your thoughts?
These are legitimate concerns. Patients starting on semaglutide should be counseled on the importance of resistance/strength training to maintain muscle mass. They should already have been counseled on the importance of 150 minutes of MVPA per week. I think measurement of visceral fat mass and lean mass by DEXA (available for 15$ in STL) in a great way to both educate individuals, motivate them, and assess changes in fat/lean mass with lifestyle changes and drugs.