• Patients with mental Health dx are excluded....many are getting approved and using this med now for this indication w severe MH conditions.
The authors try to convince that the benefit is a direct drug effect. You must achieve a 10% weight loss in our group before you could compare VA outcomes with SELECT.
Perhaps most concerning is that the trial includes smokers (16% in each arm) but this is not even in Table 1. We received information directly from Novo. How can a CVD outcomes trial get away with not even reporting smoking status?
and on the subgroup outcomes see chart p 35 appendix. The conclusions in the published article pool the data to include a much larger group:
• no benefit age <55 or >75 (approval happens now for people age 45 and over based on pooled analysis)
• the only pts w benefit were BMI 27 to 35 (higher BMIs did not benefit yet people are being approved now with higher BMIs)
• No benefit for only PAD or only stroke (our approval happens if they have any one of the CVD dx)
• no benefit in North America (yes that is correct)
• no benefit African Americans
And here is a similar paradigm from New England Journal last week with the med and OA.
Obesity Drug Shows Promise in Easing Knee Osteoarthritis Pain
A large trial showed that semaglutide, sold as Ozempic for diabetes and as Wegovy for obesity, was better than any current medications in alleviating symptoms.
We know the weight loss is super powerful for osteoarthritis in itself. Yes these medications help weight loss but we do not know if it is a direct drug effect or just they lose the weight.
This article shows the power of weight loss for osteoarthritis
40% of the weight lost using glp1 inhibitors is lean body weight, not just fat. Many people can not sustain glp1 indefinitely and eventually gain back the weight they lost. Unfortunately, the weight they regain in almost entirely fat.
Both TSC and your posts (and I assume the study referenced) describe "obesity" as BMI over 27. But the definition of obesity is BMI 30+.
Many obese people losing 8% of their body weight will still be obese. I don't think the draw of semaglutide is an 8% weight loss, but the idea of being lean. Both the patients and the doctors are unlikely to call an obese person (after 8% weight loss) a success.
Obesity is not a disease. We have to get away from that model.
The real killer is that you are treating people with drugs and nothing else. There are hundreds of safer, more natural and less costly and much more effective ways to treat most ailments and diseases. But using those would make people 1,000% healthier and put you on the streets selling pencils.
How about DMSO? It's an credible drug that can be used for many ills yet you guys let the FDA keep it out of use. How about herbs that have been used for thousands of years? How about diet? You guys completely ignore it. It is a fact that is inescapable that 99% of disease and illness have direct causes due to mistreatment of the body and yet you guys refuse to find the sources. Despicable.
Thanks for the note. Write a piece for us on DMSO with the data supporting its use.
I’ve spent decades counseling people on the importance of diet and exercise. People have the entire world working against them to be able to achieve a healthy diet and get reasonable exercise. Even for those with the means, it’s incredibly difficult. I totally get the hypocrisy of using meds to treat what our society has wrought, but that’s where we are.
I’m with ASC here. I’ve spent years educating people about diet, weight loss, physical exercise, and medication compliance and can confirm that success is low. Occasionally some embrace the advice but most will not or cannot for reasons beyond my control and often theirs- like the bus driver who is working 2 jobs, or the statin skeptic, or the islander who thinks vegetables are too costly to waste stomach space on. We have to work with our patients or we fail to help them. The great thing about semaglutide is that people are highly motivated to take it, and I have not seen forbidding side effects so far. And yes, after a few years they will probably be normotensive and have lower IR just because of the almost inevitable weight loss. I think we have greatly underestimated how damaging the last half century of upward trending BMI has been. I think that if semaglutide hits this mysterious obesity pandemic - as it seems to - it deserves a place in the formulary for people like those in SELECT.
The obesity pandemic would not be a mystery at this late date if obesity researchers had familiarized themselves with endocannabinoid system research findings when they first became available. (1996) "Excessive signaling of arachidonic acid (AA) metabolites has been associated with various chronic degenerative or autoimmune diseases, and intervention with the metabolism of AA is widely employed therapeutically in these afflictions. In essence, AA is the most biologically active unsaturated fatty acid in higher animals. Its concentration in membranes and its magnitude of effects depend on its amount, or that of its precursors and analogues, in the diet. The tendency of the field of nutrition to ignore the role of dietary AA will optimistically be reversed in the future." The article also said, "The underlying rationale for this symposium is that dietary AA is perhaps the single most important nutritional determinant in regulating AA levels in Americans. This may ultimately account in part for the striking differences in chronic diseases between strict vegetarians and the bulk of the omnivorous population." (web search - Biological Effects of Arachidonic Acid: Introduction)
(2013) 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. As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid based endocannabinoids being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production. Similarly, oleoyl ethanolamide, a product of oleic acid, induces satiety, decreases circulating fatty acid concentrations, increases the capacity for β-oxidation, and is capable of inhibiting the action of AEA and 2-AG in adipose tissue. Thus, understanding how dietary fats alter endocannabinoid system activity is a pertinent area of research due to public health messages promoting a shift towards plant-derived fats, which are rich sources of AEA and 2-AG precursor fatty acids, possibly encouraging excessive energy intake and weight gain." (web search -fatty acid modulation of the endocannabinoid system)
Note that the authors of the above narrative made a mistake. The sentence should read, "As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production."
This narrative from a 2010 article accurately explains the displacement principle. "Because arachidonic acid (AA) competes with EPA and DHA as well as with LA, ALA and oleic acid for incorporation in membrane lipids at the same positions, all these fatty acids are important for controlling the AA concentration in membrane lipids, which in turn determines how much AA can be liberated and become available for prostaglandin biosynthesis following phospholipase activation. Thus, the best strategy for dampening prostanoid overproduction in disease situations would be to reduce the intake of AA, or reduce the intake of AA at the same time as the total intake of competing fatty acids (including oleic acid) is enhanced, rather than enhancing intakes of EPA and DHA only. Enhancement of membrane concentrations of EPA and DHA will not be as efficient as a similar decrease in the AA concentration for avoiding prostanoid overproduction." (web search - Anna Haug Individual Variation)
(2011) In this next comment, the authors take note of indifference to this body of research. "Eicosanoids are major players in the pathogenesis of several common diseases, with either overproduction or imbalance (e.g. between thromboxanes and prostacyclins) often leading to worsening of disease symptoms. Both the total rate of eicosanoid production and the balance between eicosanoids with opposite effects are strongly dependent on dietary factors, such as the daily intakes of various eicosanoid precursor fatty acids, and also on the intakes of several antioxidant nutrients including selenium and sulphur amino acids. Even though the underlying biochemical mechanisms have been thoroughly studied for more than 30 years, neither the agricultural sector nor medical practitioners have shown much interest in making practical use of the abundant high-quality research data now available." (web search - Anna Haug Animal Products)
(2024) "Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway–mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors." (web search - Xiao-Jing Zhang Emerging Roles)
Steve Blechman explains why the Mediterranean style diet consistently produces favorable results. "The Mediterranean diet is low in arachidonic acid and rich in healthy fats such as monounsaturated fats found in extra-virgin olive oil (EVOO), nuts and omega-3 fatty acids from fish, which has been shown to lower the risk of inflammation, heart disease, cancer, diabetes and obesity, and other degenerative diseases." (web search - Steve Blechman New red meat study)
The Norwegian animal science researchers quoted above also said, “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.” (web search - Anna Haug Individual Variation)
In 2023 Perdue University researchers wrote, “Poultry meats, in particular chicken, have high rates of consumption globally. Poultry is the most consumed type of meat in the United States (US), with chicken being the most common type of poultry consumed. The amounts of chicken and total poultry consumed in the US have more than tripled over the last six decades… Limited evidence from randomized controlled trials indicates the consumption of lean unprocessed chicken as a primary dietary protein source has either beneficial or neutral effects on body weight and body composition and risk factors for CVD and T2DM. Apparently, zero randomized controlled feeding trials have specifically assessed the effects of consuming processed chicken/poultry on these health outcomes.” (web search - Poultry consumption and human cardiometabolic health)
Excerpt from Page 56 of 'Omega Balance' by Australian zoologist Anthony Hulbert, PhD (2023) "The contribution of 'pork and poultry' to animal-sourced foods was 20 percent in 1961 and 41 percent in 2018…Between 1961 and 2018 there was a dramatic worldwide increase in the supply of fats from sources that have very low omega balances. Fat from 'pork and poultry' was greatest in North America for the entire 1961-2018 period, while for Australia and South America, the contribution from 'pork and poultry' was the World average level in 1961 and showed the greatest absolute increases (about 16 g) over this period to be similar to North America and Europe in 2018. There was negligible change in Africa over this period."
I agree with this. TSC made compelling points, but the ARR in Improve-It (for ezetrol) was very small; the benefit with PCSK-9 is with soft endpoints, and they aren’t cheap; and the very recent but largest trial of colchicine (Clear Synergy Oasis 9) was impressively negative (paper not yet published to my knowledge, so just based on TCT presentation). Nonetheless, I think there is a role in residual risk with ezetrol and PCSK-9; no longer so sure about colchicine.
But I love 2-fers. And Semaglutide provides a new pathway for secondary prevention that offers additional benefit in obesity for someone with a BMI >27. I don’t think it will be for everyone, and not even everyone merely based on BMI, but I think there will be a place for it. Likewise, it offers a 2-fer for diabetics in secondary prevention (based on Sustain-6), not unlike empagliflozin in that particular cohort.
Something is off w semulglutidde. I can't prove it. I'm glad the other methodology minded folk I turn to like it, so far - but I do not like miracle drugs. I'm happy to have the option to just add whichever drug, if we are adding a drug anyway. I guess it may as well be the unproven new favorite - bc Christ only knows the real research Hx of the "standard of care" itself, beyond one's own practice. Ever pt has a medical record, the number of answers we should just have is infuriating.
Institutions. Enforcement. The warped structures that exist between university, hospital, researcher and journal/pharma are so broken. And so life long term, that we just shrug at "oh, yeah, they will target that market, with research or no" as if that is science. It is not. May be the way it is, it may even be wi squinting distance of science on a good day, w the right team (they know x is probably in the ballpark, so why do the work? What could go wrong?). I feel for individuals who have a career of decent work, but had to maybe jiggle a few things on some less influential papers between grant approvals or to meet other deadlines. But it all feels very mucky to me. But it isnt really. We arent fixing the things we know are wrong, and until then it is all pretend. Like sports.
& yes, so they are grabbing (prematurelly) at marketshare: Well, frankly, I'm not sure we should just be shrugging at even that. Amyway.
Loved it, as always, Adam. In a bit of a mood, as I read some blatant things in this morning's retraction watch re universities I've had a bit to do with, attended, been on comtes etal. All items done by researchers - potentially actual misconduct prper in some cases - and you know what: I *still* blame the journals, grant comtes and other super structures. There are such bigger fish. & also (vinay will hate this too, but...) image duplication of mainstream nonclaims to keep your lab running so they can feed their family is at the lower end of fraud. It is not clear to me these papers should even be retracted rather than corrected. (But it is not clear to me we need journals at all. Or editors, so.)
Have to have coffee. Seeing family. I have a really fat couzzin who i want on semulglutide. That's what started all this. I betr run. Fine entry. _JC
I have a concern about "weight loss." I have heard discussion that a significant amount of weight loss from semaglutide is muscle loss, which I believe we would largely agree is a bad thing. Is this tracked in any of the studies being referenced? For context, I am a cancer survivor, and during chemo, I gained 22 lbs of edema on top of what had been an athletic body (active duty military). All of the information I was given about "weight gain during chemo" was actually about fat gain, and it was completely unhelpful. "Weight" can be gained or lost as fat, muscle, or fluids (at the least) and there needs to be distinctions made for healthy weight loss.
You're right that some of the weight loss while on semaglutide is lean muscle mass, but it's not from the drug, but rather from the calorie restriction that occurs. You also lose muscle when you're on an "old fashioned" calorie restriction diet (link below). I recently heard a researcher on a podcast say that a recent study demonstrated that the amount of lean mass loss was equivalent between the two groups, but I couldn't find a reference in a quick search. If somebody restricts calories, whether via the new drugs or not, the way to prevent muscle loss is exercising and ensuring protein intake is adequate. An area that interests me but which I haven't heard anything about is what is the quality of the diets of people on semaglutide? Yes, they are consuming fewer calories, but are they eating more healthfully?
I have a different take than both TSC and Adam. The SELECT trail provides some insight regarding the effect of diagnosing and treating IR on outcomes, even with it's significant limitations. IR is the root cause of the modern day abnormal lipid profile (elevated LDL-p, low HDL and high TG). In the cohort studied, 67% had a A1c greater than 5.7% but less than 6.5% (not diabetic, technically but lots of IR). Unfortunately, nearly all pharma research continues to rely on a very poor metric of IR, A1c. I am quite confident that this population is universally and profoundly suffering from IR. The elevated LDL, hs-CRP and BP are confirmational. This is a massive confounder in all lipid lowering trials including statin trials that is largely ignored. The totality of evidence accusing LDL for ASCVD is contaminated. Prospective cohort studies, RCT's are contaminated by the undiagnosed, and therefore unadjusted for, presence of IR. MR studies have serious limitations due to incorrect assumptions.
Despite these limitation in this trial, markers of IR were reduced (at least by A1c). This strikes as a powerful testament to the role of IR — even populations already offered standard of care for lipid lowering therapies. Not surprisingly, LDL-c was not altered. In Framingham Offspring Study analysis, LDL-c was independent of Metabolic Syndrome factors, which is why LDL-c is of little value in CHD. LDL-P INCREASES with Metabolic Syndrome factors, so each LDL is smaller, more dense (cholesterol depleted). Unfortunately, appropriately measures of IR and LDL-p were not measured in the semaglutide trial so we don't know the relative contributions of each to the benefit in MACE and CV mortality.
Will LDL lowering meds or GLP-1's take us to the promised land – I am doubtful, as a cardiologist with skepticism in the right place.
Whenever data on IR or Metabolic Syndrome is available it is always more in the driving seat for CVD.
Why not instead target the root causal factor, IR?
Imagine if we had lifestyle protocols that when applied with precision, put IR in complete remission.
How can you say RCT’s were confounded or contaminated by IR? It’s the whole point of randomization….to evenly distribute variables (known and unknown) into both the treatment and control arms, such that the only difference at baseline btw the two groups is the intervention being studied. To suggest any residual confounding would require a failure of randomization.
Much has been said of IR/metabolic syndrome. What is required is an RCT showing that some intervention targeting some metric for IR (separate from LDL lowering) results in CV outcome benefits.
Isn't this just another pharmaceutical con job? As a skeptical cardiologist myself, one of my firm rules is to never give figures of relative risk reduction. They are only used to sell drugs or other treatments that show such small real risk reductions that no one with any common sense would take them seriously. Granted that is logistically difficult (if not impossible) to determine risk in a disorder such as atherosclerosis that is gradually progressive with age but punctuated by acute complications (infarctions). Few drugs or studies of risk factor reduction modalities show any significant effect beyond that shown for baby aspirin (also not of any practical significance). In my opinion, we have no idea how to prevent complications of this ubiquitous process of atherosclerosis and should concentrate on improvements in treating them when they arise. There is no harm in recommending changes in "lifestyle" factors that one believes may be helpful but I draw the line at giving medications which are not only expensive but may be harmful.
"Let’s just hope she has a doctor who will talk her through all the possibilities." Touched by your inclusion but as a she, I have to smile as I don't see myself adequately represented in this 70+% male cohort. (Or did I read the table wrong?) Thank you for highlighting this study. I will go look for ASC's piece. I would have liked to see one or the other of you provide your opinion/perspective on the problem of side effects we are hearing so much about from folks like the Means siblings.
sorry but something is completely fishy in this entire study, just by looking at 2 pairs of numbers: BLOOD PRESSURE. Normal healthy people, which should be the placebos, DO NOT have 130/80 values, that's NOT NORMAL. The normal blood pressure, in average, is 110/70. And here both groups have HIGHER BLOOD PRESSURE to even start with. It is almost like the new EKG values for pilots, only to allow them to continue to work, with damaged hearts! Apparently CDC changed also the 'normal' blood pressure values to higher 'new normal'.
It ALMOST looks like this discussed here study equals the fraud studies of covid genetically modifying injections, in which both study groups, must have gotten something similar, and at the end, officially the entire placebo group received the covid injections too. Based on such criminal fraud, people were told, gene therapies are safe end effective. All actually ILLEGAL, because without human consent.
These are obese patients with heart disease. Nobody said they were normal. Also the placebo group and the intervention group are supposed to have the same values, that is the result of randomization and how you can do a downstream comparison at the end of the study.
I will be discussing with my obese ASCVD patients (most of whom don't have LDL/BP/CRP #s as high as the SELECT enrollees) the risks and CV benefits of semaglutide for their particular situation. I'll also make it clear that the weight loss it provides adds additional holistic benefits beyond my particular specialty.
If it's so simple, why are so many people obese? And why can't people maintain weight loss once they achieve it? If you're going to say they lack "willpower," then how did the massive change in willpower happen? (After all, if lack of willpower is the cause of the large increase in obesity, then logic dictates that willpower decreased as weight increased). We live in an environment of constantly available hyperpalatable ultraprocessed food, and research has demonstrated that this leads to overconsumption (first link, Kevin Hall is the researcher to follow if you want to know more). Also, we now know that some people become addicted to this type of food (link #2). Do we all become addicted to it when exposed? No, just like we don't all get addicted to alcohol, drugs, etc. when exposed. We are all unique genetically, not to mention other contributing factors. Some people live in food deserts where whole foods are less available, some cannot afford to make most of their diets unprocessed (ultraprocessed foods are much cheaper than whole foods), and some folks experience greater life stress which leads to more eating of "comfort foods." My BMI is 23 so I'm not being defensive here, but I think it's high time we stop blaming victims. Yes, I believe in agency, but it's not as simple as you claim. It's like telling somebody with alcohol use disorder: "It's simple! Just stop drinking!"
I think you have answered your question. It might help if fat people knew that what they choose to eat is the reason they are fat (and usually sick). Why they choose to eat that way is, as you rightly say, a complex and multi-faceted problem. Out of interest, the only way to stop drinking is to stop drinking. How an individual gets there can vary of course - drugs, cold turkey, AA, rehab, hypnotism - but the objective is to stop consuming the things that cause the damage. Just the same as being fat. And no one ever recommends just drinking less to an alcoholic who has managed to stop, unlike with food addictions.
Thoughtful article thank you .
a few other highlights from SELECT:
• Patients with mental Health dx are excluded....many are getting approved and using this med now for this indication w severe MH conditions.
The authors try to convince that the benefit is a direct drug effect. You must achieve a 10% weight loss in our group before you could compare VA outcomes with SELECT.
Perhaps most concerning is that the trial includes smokers (16% in each arm) but this is not even in Table 1. We received information directly from Novo. How can a CVD outcomes trial get away with not even reporting smoking status?
and on the subgroup outcomes see chart p 35 appendix. The conclusions in the published article pool the data to include a much larger group:
• no benefit age <55 or >75 (approval happens now for people age 45 and over based on pooled analysis)
• the only pts w benefit were BMI 27 to 35 (higher BMIs did not benefit yet people are being approved now with higher BMIs)
• No benefit for only PAD or only stroke (our approval happens if they have any one of the CVD dx)
• no benefit in North America (yes that is correct)
• no benefit African Americans
And here is a similar paradigm from New England Journal last week with the med and OA.
https://www.nejm.org/doi/full/10.1056/NEJMoa2403664
and the NYT headline
Obesity Drug Shows Promise in Easing Knee Osteoarthritis Pain
A large trial showed that semaglutide, sold as Ozempic for diabetes and as Wegovy for obesity, was better than any current medications in alleviating symptoms.
https://www.nytimes.com/2024/10/30/health/ozempic-wegovy-knee-pain-osteoarthritis.html
but yet they lost 16% of their body weight
We know the weight loss is super powerful for osteoarthritis in itself. Yes these medications help weight loss but we do not know if it is a direct drug effect or just they lose the weight.
This article shows the power of weight loss for osteoarthritis
https://pubmed.ncbi.nlm.nih.gov/15986358/
Conclusion. Our results indicate that each pound
of weight lost will result in a 4-fold reduction in the load
exerted on the knee per step during daily activities.
Accumulated over thousands of steps per day, a reduction
of this magnitude would appear to be clinically
meaningful.
so a lot to unpack before SELECT is definitive evidence for anything
Mark Cucuzzella MD
40% of the weight lost using glp1 inhibitors is lean body weight, not just fat. Many people can not sustain glp1 indefinitely and eventually gain back the weight they lost. Unfortunately, the weight they regain in almost entirely fat.
Both TSC and your posts (and I assume the study referenced) describe "obesity" as BMI over 27. But the definition of obesity is BMI 30+.
Many obese people losing 8% of their body weight will still be obese. I don't think the draw of semaglutide is an 8% weight loss, but the idea of being lean. Both the patients and the doctors are unlikely to call an obese person (after 8% weight loss) a success.
Obesity is not a disease. We have to get away from that model.
I am developing a remedial 5th-grade math class in understanding percentages. It will be mandatory for doctors and reporters!
There was not a 1.5% reduction in MACE between the control group and the active group. It was an 18.8% reduction. Or a 1.5 percentage point reduction.
Percentages are a ratio. You calculate ratios by division not subtraction!
The real killer is that you are treating people with drugs and nothing else. There are hundreds of safer, more natural and less costly and much more effective ways to treat most ailments and diseases. But using those would make people 1,000% healthier and put you on the streets selling pencils.
How about DMSO? It's an credible drug that can be used for many ills yet you guys let the FDA keep it out of use. How about herbs that have been used for thousands of years? How about diet? You guys completely ignore it. It is a fact that is inescapable that 99% of disease and illness have direct causes due to mistreatment of the body and yet you guys refuse to find the sources. Despicable.
Thanks for the note. Write a piece for us on DMSO with the data supporting its use.
I’ve spent decades counseling people on the importance of diet and exercise. People have the entire world working against them to be able to achieve a healthy diet and get reasonable exercise. Even for those with the means, it’s incredibly difficult. I totally get the hypocrisy of using meds to treat what our society has wrought, but that’s where we are.
I’m with ASC here. I’ve spent years educating people about diet, weight loss, physical exercise, and medication compliance and can confirm that success is low. Occasionally some embrace the advice but most will not or cannot for reasons beyond my control and often theirs- like the bus driver who is working 2 jobs, or the statin skeptic, or the islander who thinks vegetables are too costly to waste stomach space on. We have to work with our patients or we fail to help them. The great thing about semaglutide is that people are highly motivated to take it, and I have not seen forbidding side effects so far. And yes, after a few years they will probably be normotensive and have lower IR just because of the almost inevitable weight loss. I think we have greatly underestimated how damaging the last half century of upward trending BMI has been. I think that if semaglutide hits this mysterious obesity pandemic - as it seems to - it deserves a place in the formulary for people like those in SELECT.
The obesity pandemic would not be a mystery at this late date if obesity researchers had familiarized themselves with endocannabinoid system research findings when they first became available. (1996) "Excessive signaling of arachidonic acid (AA) metabolites has been associated with various chronic degenerative or autoimmune diseases, and intervention with the metabolism of AA is widely employed therapeutically in these afflictions. In essence, AA is the most biologically active unsaturated fatty acid in higher animals. Its concentration in membranes and its magnitude of effects depend on its amount, or that of its precursors and analogues, in the diet. The tendency of the field of nutrition to ignore the role of dietary AA will optimistically be reversed in the future." The article also said, "The underlying rationale for this symposium is that dietary AA is perhaps the single most important nutritional determinant in regulating AA levels in Americans. This may ultimately account in part for the striking differences in chronic diseases between strict vegetarians and the bulk of the omnivorous population." (web search - Biological Effects of Arachidonic Acid: Introduction)
(2013) 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. As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid based endocannabinoids being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production. Similarly, oleoyl ethanolamide, a product of oleic acid, induces satiety, decreases circulating fatty acid concentrations, increases the capacity for β-oxidation, and is capable of inhibiting the action of AEA and 2-AG in adipose tissue. Thus, understanding how dietary fats alter endocannabinoid system activity is a pertinent area of research due to public health messages promoting a shift towards plant-derived fats, which are rich sources of AEA and 2-AG precursor fatty acids, possibly encouraging excessive energy intake and weight gain." (web search -fatty acid modulation of the endocannabinoid system)
Note that the authors of the above narrative made a mistake. The sentence should read, "As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production."
This narrative from a 2010 article accurately explains the displacement principle. "Because arachidonic acid (AA) competes with EPA and DHA as well as with LA, ALA and oleic acid for incorporation in membrane lipids at the same positions, all these fatty acids are important for controlling the AA concentration in membrane lipids, which in turn determines how much AA can be liberated and become available for prostaglandin biosynthesis following phospholipase activation. Thus, the best strategy for dampening prostanoid overproduction in disease situations would be to reduce the intake of AA, or reduce the intake of AA at the same time as the total intake of competing fatty acids (including oleic acid) is enhanced, rather than enhancing intakes of EPA and DHA only. Enhancement of membrane concentrations of EPA and DHA will not be as efficient as a similar decrease in the AA concentration for avoiding prostanoid overproduction." (web search - Anna Haug Individual Variation)
(2011) In this next comment, the authors take note of indifference to this body of research. "Eicosanoids are major players in the pathogenesis of several common diseases, with either overproduction or imbalance (e.g. between thromboxanes and prostacyclins) often leading to worsening of disease symptoms. Both the total rate of eicosanoid production and the balance between eicosanoids with opposite effects are strongly dependent on dietary factors, such as the daily intakes of various eicosanoid precursor fatty acids, and also on the intakes of several antioxidant nutrients including selenium and sulphur amino acids. Even though the underlying biochemical mechanisms have been thoroughly studied for more than 30 years, neither the agricultural sector nor medical practitioners have shown much interest in making practical use of the abundant high-quality research data now available." (web search - Anna Haug Animal Products)
(2024) "Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway–mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors." (web search - Xiao-Jing Zhang Emerging Roles)
Steve Blechman explains why the Mediterranean style diet consistently produces favorable results. "The Mediterranean diet is low in arachidonic acid and rich in healthy fats such as monounsaturated fats found in extra-virgin olive oil (EVOO), nuts and omega-3 fatty acids from fish, which has been shown to lower the risk of inflammation, heart disease, cancer, diabetes and obesity, and other degenerative diseases." (web search - Steve Blechman New red meat study)
The Norwegian animal science researchers quoted above also said, “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.” (web search - Anna Haug Individual Variation)
In 2023 Perdue University researchers wrote, “Poultry meats, in particular chicken, have high rates of consumption globally. Poultry is the most consumed type of meat in the United States (US), with chicken being the most common type of poultry consumed. The amounts of chicken and total poultry consumed in the US have more than tripled over the last six decades… Limited evidence from randomized controlled trials indicates the consumption of lean unprocessed chicken as a primary dietary protein source has either beneficial or neutral effects on body weight and body composition and risk factors for CVD and T2DM. Apparently, zero randomized controlled feeding trials have specifically assessed the effects of consuming processed chicken/poultry on these health outcomes.” (web search - Poultry consumption and human cardiometabolic health)
Excerpt from Page 56 of 'Omega Balance' by Australian zoologist Anthony Hulbert, PhD (2023) "The contribution of 'pork and poultry' to animal-sourced foods was 20 percent in 1961 and 41 percent in 2018…Between 1961 and 2018 there was a dramatic worldwide increase in the supply of fats from sources that have very low omega balances. Fat from 'pork and poultry' was greatest in North America for the entire 1961-2018 period, while for Australia and South America, the contribution from 'pork and poultry' was the World average level in 1961 and showed the greatest absolute increases (about 16 g) over this period to be similar to North America and Europe in 2018. There was negligible change in Africa over this period."
Anyone care to connect the dots?
Well said.
I agree with this. TSC made compelling points, but the ARR in Improve-It (for ezetrol) was very small; the benefit with PCSK-9 is with soft endpoints, and they aren’t cheap; and the very recent but largest trial of colchicine (Clear Synergy Oasis 9) was impressively negative (paper not yet published to my knowledge, so just based on TCT presentation). Nonetheless, I think there is a role in residual risk with ezetrol and PCSK-9; no longer so sure about colchicine.
But I love 2-fers. And Semaglutide provides a new pathway for secondary prevention that offers additional benefit in obesity for someone with a BMI >27. I don’t think it will be for everyone, and not even everyone merely based on BMI, but I think there will be a place for it. Likewise, it offers a 2-fer for diabetics in secondary prevention (based on Sustain-6), not unlike empagliflozin in that particular cohort.
Something is off w semulglutidde. I can't prove it. I'm glad the other methodology minded folk I turn to like it, so far - but I do not like miracle drugs. I'm happy to have the option to just add whichever drug, if we are adding a drug anyway. I guess it may as well be the unproven new favorite - bc Christ only knows the real research Hx of the "standard of care" itself, beyond one's own practice. Ever pt has a medical record, the number of answers we should just have is infuriating.
Institutions. Enforcement. The warped structures that exist between university, hospital, researcher and journal/pharma are so broken. And so life long term, that we just shrug at "oh, yeah, they will target that market, with research or no" as if that is science. It is not. May be the way it is, it may even be wi squinting distance of science on a good day, w the right team (they know x is probably in the ballpark, so why do the work? What could go wrong?). I feel for individuals who have a career of decent work, but had to maybe jiggle a few things on some less influential papers between grant approvals or to meet other deadlines. But it all feels very mucky to me. But it isnt really. We arent fixing the things we know are wrong, and until then it is all pretend. Like sports.
& yes, so they are grabbing (prematurelly) at marketshare: Well, frankly, I'm not sure we should just be shrugging at even that. Amyway.
Loved it, as always, Adam. In a bit of a mood, as I read some blatant things in this morning's retraction watch re universities I've had a bit to do with, attended, been on comtes etal. All items done by researchers - potentially actual misconduct prper in some cases - and you know what: I *still* blame the journals, grant comtes and other super structures. There are such bigger fish. & also (vinay will hate this too, but...) image duplication of mainstream nonclaims to keep your lab running so they can feed their family is at the lower end of fraud. It is not clear to me these papers should even be retracted rather than corrected. (But it is not clear to me we need journals at all. Or editors, so.)
Have to have coffee. Seeing family. I have a really fat couzzin who i want on semulglutide. That's what started all this. I betr run. Fine entry. _JC
I have a concern about "weight loss." I have heard discussion that a significant amount of weight loss from semaglutide is muscle loss, which I believe we would largely agree is a bad thing. Is this tracked in any of the studies being referenced? For context, I am a cancer survivor, and during chemo, I gained 22 lbs of edema on top of what had been an athletic body (active duty military). All of the information I was given about "weight gain during chemo" was actually about fat gain, and it was completely unhelpful. "Weight" can be gained or lost as fat, muscle, or fluids (at the least) and there needs to be distinctions made for healthy weight loss.
You're right that some of the weight loss while on semaglutide is lean muscle mass, but it's not from the drug, but rather from the calorie restriction that occurs. You also lose muscle when you're on an "old fashioned" calorie restriction diet (link below). I recently heard a researcher on a podcast say that a recent study demonstrated that the amount of lean mass loss was equivalent between the two groups, but I couldn't find a reference in a quick search. If somebody restricts calories, whether via the new drugs or not, the way to prevent muscle loss is exercising and ensuring protein intake is adequate. An area that interests me but which I haven't heard anything about is what is the quality of the diets of people on semaglutide? Yes, they are consuming fewer calories, but are they eating more healthfully?
https://www.scientificamerican.com/article/weight-loss-why-you-dont-just-lose-fat-when-youre-on-a-diet/#:~:text=Muscle loss,rates of muscle when dieting.
I have a different take than both TSC and Adam. The SELECT trail provides some insight regarding the effect of diagnosing and treating IR on outcomes, even with it's significant limitations. IR is the root cause of the modern day abnormal lipid profile (elevated LDL-p, low HDL and high TG). In the cohort studied, 67% had a A1c greater than 5.7% but less than 6.5% (not diabetic, technically but lots of IR). Unfortunately, nearly all pharma research continues to rely on a very poor metric of IR, A1c. I am quite confident that this population is universally and profoundly suffering from IR. The elevated LDL, hs-CRP and BP are confirmational. This is a massive confounder in all lipid lowering trials including statin trials that is largely ignored. The totality of evidence accusing LDL for ASCVD is contaminated. Prospective cohort studies, RCT's are contaminated by the undiagnosed, and therefore unadjusted for, presence of IR. MR studies have serious limitations due to incorrect assumptions.
Despite these limitation in this trial, markers of IR were reduced (at least by A1c). This strikes as a powerful testament to the role of IR — even populations already offered standard of care for lipid lowering therapies. Not surprisingly, LDL-c was not altered. In Framingham Offspring Study analysis, LDL-c was independent of Metabolic Syndrome factors, which is why LDL-c is of little value in CHD. LDL-P INCREASES with Metabolic Syndrome factors, so each LDL is smaller, more dense (cholesterol depleted). Unfortunately, appropriately measures of IR and LDL-p were not measured in the semaglutide trial so we don't know the relative contributions of each to the benefit in MACE and CV mortality.
Will LDL lowering meds or GLP-1's take us to the promised land – I am doubtful, as a cardiologist with skepticism in the right place.
Whenever data on IR or Metabolic Syndrome is available it is always more in the driving seat for CVD.
Why not instead target the root causal factor, IR?
Imagine if we had lifestyle protocols that when applied with precision, put IR in complete remission.
How can you say RCT’s were confounded or contaminated by IR? It’s the whole point of randomization….to evenly distribute variables (known and unknown) into both the treatment and control arms, such that the only difference at baseline btw the two groups is the intervention being studied. To suggest any residual confounding would require a failure of randomization.
Much has been said of IR/metabolic syndrome. What is required is an RCT showing that some intervention targeting some metric for IR (separate from LDL lowering) results in CV outcome benefits.
👏👏👏
Isn't this just another pharmaceutical con job? As a skeptical cardiologist myself, one of my firm rules is to never give figures of relative risk reduction. They are only used to sell drugs or other treatments that show such small real risk reductions that no one with any common sense would take them seriously. Granted that is logistically difficult (if not impossible) to determine risk in a disorder such as atherosclerosis that is gradually progressive with age but punctuated by acute complications (infarctions). Few drugs or studies of risk factor reduction modalities show any significant effect beyond that shown for baby aspirin (also not of any practical significance). In my opinion, we have no idea how to prevent complications of this ubiquitous process of atherosclerosis and should concentrate on improvements in treating them when they arise. There is no harm in recommending changes in "lifestyle" factors that one believes may be helpful but I draw the line at giving medications which are not only expensive but may be harmful.
"Let’s just hope she has a doctor who will talk her through all the possibilities." Touched by your inclusion but as a she, I have to smile as I don't see myself adequately represented in this 70+% male cohort. (Or did I read the table wrong?) Thank you for highlighting this study. I will go look for ASC's piece. I would have liked to see one or the other of you provide your opinion/perspective on the problem of side effects we are hearing so much about from folks like the Means siblings.
Sorry. I meant TSC's post. So confusing. :-(
sorry but something is completely fishy in this entire study, just by looking at 2 pairs of numbers: BLOOD PRESSURE. Normal healthy people, which should be the placebos, DO NOT have 130/80 values, that's NOT NORMAL. The normal blood pressure, in average, is 110/70. And here both groups have HIGHER BLOOD PRESSURE to even start with. It is almost like the new EKG values for pilots, only to allow them to continue to work, with damaged hearts! Apparently CDC changed also the 'normal' blood pressure values to higher 'new normal'.
It ALMOST looks like this discussed here study equals the fraud studies of covid genetically modifying injections, in which both study groups, must have gotten something similar, and at the end, officially the entire placebo group received the covid injections too. Based on such criminal fraud, people were told, gene therapies are safe end effective. All actually ILLEGAL, because without human consent.
These are obese patients with heart disease. Nobody said they were normal. Also the placebo group and the intervention group are supposed to have the same values, that is the result of randomization and how you can do a downstream comparison at the end of the study.
I loved TSC article and this follow up as well.
Excellent thought process and analysis!
ASC makes some powerful points here.
I will be discussing with my obese ASCVD patients (most of whom don't have LDL/BP/CRP #s as high as the SELECT enrollees) the risks and CV benefits of semaglutide for their particular situation. I'll also make it clear that the weight loss it provides adds additional holistic benefits beyond my particular specialty.
TSC
🙏
No such thing as a free lunch. Do the work to eat healthy and exercise.
That’s a simplistic answer.
It’s not free. 10K/month and it works better than anything I’ve tried, including recommending lifestyle interventions, in 30 years.
It's a simple problem. Too fat.
If it's so simple, why are so many people obese? And why can't people maintain weight loss once they achieve it? If you're going to say they lack "willpower," then how did the massive change in willpower happen? (After all, if lack of willpower is the cause of the large increase in obesity, then logic dictates that willpower decreased as weight increased). We live in an environment of constantly available hyperpalatable ultraprocessed food, and research has demonstrated that this leads to overconsumption (first link, Kevin Hall is the researcher to follow if you want to know more). Also, we now know that some people become addicted to this type of food (link #2). Do we all become addicted to it when exposed? No, just like we don't all get addicted to alcohol, drugs, etc. when exposed. We are all unique genetically, not to mention other contributing factors. Some people live in food deserts where whole foods are less available, some cannot afford to make most of their diets unprocessed (ultraprocessed foods are much cheaper than whole foods), and some folks experience greater life stress which leads to more eating of "comfort foods." My BMI is 23 so I'm not being defensive here, but I think it's high time we stop blaming victims. Yes, I believe in agency, but it's not as simple as you claim. It's like telling somebody with alcohol use disorder: "It's simple! Just stop drinking!"
https://news.harvard.edu/gazette/story/2023/12/why-are-americans-so-sick-researchers-point-to-middle-grocery-aisles/
https://www.apa.org/gradpsych/2011/11/food-addiction
I think you have answered your question. It might help if fat people knew that what they choose to eat is the reason they are fat (and usually sick). Why they choose to eat that way is, as you rightly say, a complex and multi-faceted problem. Out of interest, the only way to stop drinking is to stop drinking. How an individual gets there can vary of course - drugs, cold turkey, AA, rehab, hypnotism - but the objective is to stop consuming the things that cause the damage. Just the same as being fat. And no one ever recommends just drinking less to an alcoholic who has managed to stop, unlike with food addictions.