I think what you meant to say is unopposed estrogen is risky for all women.
Why on earth would we give testosterone to menopausal patients?
https://en.wikipedia.org/wiki/Estrogen_insensitivity_syndrom...
The point is to replace what’s missing and causing symptoms.
Menopause =/= estrogen insensitivity.
The discussion about estrogen in men is just for context. It's not unusual to talk about levels of any hormone in men or women. There's nothing "shocking" about testosterone in women, or estrogen in men.
I was fixating on semantics but it's not the point.
Not my area but for what it's worth UpToDate (KA Martin, RL Barbieri, JL Shifren @ MassGen Brigham) address it in expert opinion form:
> We do not suggest the routine use of androgen [testosterone] therapy for postmenopausal women. Levels of endogenous androgens do not predict sexual function for women; however, androgen therapy that increases serum concentrations to the upper limit or above the limit of normal for postmenopausal women has been shown to improve female sexual function in selected populations.
The linked out sexual dysfunction article (JL Shifren):
> In our practice, we rarely use testosterone, but will prescribe it when greatly desired by a peri- or postmenopausal patient with low libido associated with distress who has no contraindications to testosterone therapy or identifiable etiology for sexual dysfunction and is otherwise physically and psychologically healthy. Typically, the patient has already tried other safer interventions prior to the testosterone prescription, including low-dose vaginal estrogen, relationship interventions (eg, sex therapy, date nights, use of sexual aids such as vibrators, books), and adjustment of antidepressant medication (when indicated) [12]. At least one visit with a sex therapist is strongly advised prior to pharmacologic treatment, as this safe and effective intervention may make pharmacologic therapy unnecessary or enhance the response to treatment. Testosterone levels should not be used in determining the etiology of a sexual problem or in assessing efficacy of treatment, as no clear association between androgen levels and sexual function has been found in several large, well-designed studies.
Actually, it's probably a bad idea to combine them because the body's response to hormones is so variable. Keep them as separate pills so you can tweak the balance easier.
Testosterone is not the only (or first line) treatment for sexual dysfunction and is off-label/not FDA approved.
Separately, obesity causes higher system estrogen levels and carries the same risks.
What you may be referring to is the more recent WHI study which does have methodological flaws, but unopposed estrogen is a no-no for patients with a uterus.
- Absolute risk reduction in CVD-caused mortality is mild at best (<1-2% absolute risk reduction)
- Percentage of people that get side-effects is higher than the percentage of people that receive a benefit from statins; as well, the side-effects are rather serious in affecting QoL -- making them a poor choice as a long-term prophylactic
- Generic lipid panels that the vast majority of people take are generally worthless for estimating lipid health: LDL "large particle -- bad" cholesterol is not actually measured, but estimated. The current formula is: (total cholesterol - HDL - triglycerides)/5 which is liable to under-report true LDL levels. Estimation also has the drawback of being unable to tell how much of each "bad" particle is actually in your blood (chylomicrons vs VLDL vs LDL etc.) -- muddying your actual risk profile. Likewise, no LDL "content" tests are performed to measure how much cholesterol each LDL is actually carrying. So yes, statins will lower these numbers, but the methodology around these numbers is flawed, and only loosely correlated with cardiovascular health
> - Absolute risk reduction in CVD-caused mortality is mild at best (<1-2% absolute risk reduction)
It depends what your baseline risk is and what time point you're looking at.
> - Percentage of people that get side-effects is higher than the percentage of people that receive a benefit from statins; as well, the side-effects are rather serious in affecting QoL -- making them a poor choice as a long-term prophylactic
This is just completely false, even from 2013 data[0] (which overestimates diabetes) but is better addressed in a subsequent review [1].
The side effects, if they do happen, are also self-limiting and stop with cessation or changing agents.
> - Generic lipid panels that the vast majority of people take are generally worthless for estimating lipid health ... and only loosely correlated with cardiovascular health
See reference [1] and [2].
[0]https://thennt.com/nnt/statins-for-heart-disease-prevention-...
[1]https://www.thelancet.com/article/S0140-6736(16)31357-5/full...
[2]https://www.onlinecjc.ca/article/S0828-282X(21)00165-3/fullt...
Baseline risk is something like ~35% for men, and ~20% women. Time point is from 50 to 75 years of age.
Statins -- at most -- reduce your absolute risk from 35% to 33% (for men) and from 20% to 18% (for women).
If you do not smoke, your absolute risk drops by ~7%, from 35% to 28%. If you're diabetic, your risk jumps an absolute ~30% to 65%.
See: https://www.ahajournals.org/doi/full/10.1161/circulationaha.... (table 2 & table 3).
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Your article has this caveat: "Virtually all of the major statin studies were paid for and conducted by their respective pharmaceutical company. A long history of misrepresentation of data and occasionally fraudulent reporting of data suggests that these results are often much more optimistic than subsequent data produced by researchers and parties that do not have a financial stake in the results."
Ignoring that, 2% (absolute) of the population on statins develop diabetes and 10% (absolute) develop muscle pain/rhabdo (in one experiment). This is also ignoring all of the serious adverse events from gen-1 and gen-2 statins.
As a whole, they on average achieve a 1.2% reduction in absolute mortality (all-cause or only from heart disease?).
While I have just read it, I'm going to discount [1], because of what's inside "Declaration of interests."
And on principle, I'm not going to read [2], unless you quote the relevant sections (as is good form when referencing).
2% diabetes is overstated as in link 1 except you discount it because of declared disclosures despite the fact that it’s one of the most highly cited papers on the subject in the last 10 years and the study was a review.
You also discount a well respected guideline on lipids out of principle.
Then you cite unrelated data from 2006 as a good reference for an unknown reason?
Finally, you disregard the opinions of a Cochrane review in an unrelated patient population which directly contradicts your misinterpretation of the data (clearly have no concept of NNT/NNH as you just make capricious interpretations of ARR) yet cite yourself as more of an expert than the Cochrane authors.
For what it’s worth since you focus on conflicts it’s to my financial benefit if you don’t take your statins (and pharma pays me nothing), so by all means skip the statin at your own risk.
This really doesn’t seem like an open discussion so I’ll stop engaging. But you’re spreading misinformation for any reader, statins save lives.
However, I haven't seen any research that shows more than minor absolute risk changes, regardless of statin -- they're the wrong drugs for the job.
Page 11.
If you have an account at Cochrane: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...
If not, just get it from LibGen with: 10.1002/14651858.CD004816.pub5
And as haldujai mentioned this is explicitly regarding their use for primary prevention, not with regards to usage for secondary prevention which has strong supporting evidence.
Please provide me literature from a reputable publication (viz. the AHA, Cochrane, or the New England Journal of Medicine), that has not been funded by a pharmaceutical company — that demonstrates strong supporting evidence for the usage of statins in secondary prevention; wherein the experiment does not extrapolate from LDL values to determine mortality risk (I will concede defeat if you can find any paper that utilizes CAC scans and shows a reversal in atherosclerosis), and/or shows a greater than 2% absolute reduction all-cause or CVD-only mortality risk.
You will not find such a paper, because it does not exist. Most funding has gone towards primary prevention in young adults — while little more than weak associative studies have been published for secondary prevention (and countless others I no doubt have never seen the light of day).
Statins work amazingly not just for LDL reduction but plaque stabilization.
As an aside a 2% ARR is huge, it means the number needed to treat is 50 to save a life. For something with next to no serious side effects, rhabdo/diabetes is dramatically overstated.
Pertinently, the number needed to treat for MACE is 39. That’s hugely significant.
I don’t consider 2% ARR huge — especially when the risks of side-effects have been down-played. We can argue about this all we want, but it’s no longer a matter of fact, but of opinion and values.
I’ll use your 2% ARR for death although there are better numbers in different patient populations.
In other words: Statins will save 1 life for every 50 patients treated and prevent 1 in ~20-40 non-fatal cardiac events, a medically significant result period. The NNH is > 100, and the harm is a self-limiting myopathy (and a possible risk of accelerated diabetes-onset in observational studies, that is still outweighed by the reduction in all-cause mortality and MACE).
The evidence is unequivocal that the benefits far outweigh the harms.
Separately, you have a personal choice to take/not take any treatment, and you may personally feel treating 50 people to save 1 life is not worth it for you, because you subjectively feel the numbers don’t fit your personal risk/benefit model. This is where you are saying 2% ARR is insignificant to you but this says nothing about the evidence or rationale behind the treatment.
> risks of side-effects have been down-played.
Except every study looking at side-effects has shown they were overstated in the initial trial.
“The most severe complication of SI is discontinuation of effective cholesterol-lowering treatment in patients who, by virtue of their CVD risk and cholesterol level, might otherwise benefit.”
https://www.sciencedirect.com/science/article/abs/pii/S00219...
Linked study equivocating on the overstatement of statin side-effects has the first author as a pharmaceutical consultant (you do not see this as a problem, I do).
2% ARR is meager in relation to lifestyle changes that can account for 3x-15x the in ARR compared to statins (you do not see this as a problem, I do).
Those are the facts. How you interpret them is subjective.
All of the money and manpower thrown into statins, could have been thrown into smoking cessation programs or preventing onset of type 2 diabetes. This is an opinion.
Saving 1 life for every 50 patients, at the cost of untold resources, instead of saving 6-30 for every 50 is myopic. This is an opinion.
Medical significance is an opinion. The determination of significance is a subjective interpretation. This is not a "this idea concurs with my sentiments, so I will say it is so. Period." This is math. Statistical interpretation is an opinion. The difference in statin efficacy vs. lifestyle changes is a quantifiable fact. The difference is 3-15x. To take a statistical finding without incorporating it into the larger context is poor practice, bordering on deception (the former is a fact, the latter is an opinion).
Here are 50 people aged 50 y.o. from the general population:
OOOOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO
Here is the same group of people after 25 years (14 have died due to CVD-related mortality):
XXXXX_XXXXX | XXXXO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO
Here is the same group of people after 25 years, but they were on statins:
XXXXX_XXXXX | XXXOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO
Here is the same group of people after 25 years, but instead of statins, the smokers ceased smoking:
XXXXX_XXXXX | OOOOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO | OOOOO_OOOOO
Here is the same group of people after 25 years, but instead of a treatment, all of them developed diabetes:
XXXXX_XXXXX | XXXXX_XXXXX | XXXXX_XXXXX | XXXOO_OOOOO | OOOOO_OOOOO
Not going to argue the methodology but it seems like a starting point is $22,000-37000/QALY[0-1].
> instead of
This is a false dichotomy, guidelines all start with lifestyle modifications.
[0]https://jamanetwork.com/journals/jamacardiology/fullarticle/...
[1]https://jamanetwork.com/journals/jama/article-abstract/23964...
I'd say that generally it's advisable to take both into consideration given that in most cases the author of a paper likely has more domain expertise than you in that specific area. Not always, obviously, and not to the exclusion of an outside objective analysis of their data and results, but it's certainly more informative than referring someone to a page from a study with no additional context.
> that has not been funded by a pharmaceutical company
I get where you're coming from here, but it's kind of silly. And the question becomes where do you draw the line? Is a meta-analysis of a large group of studies each of which has been supported at least in part by funding from a pharmaceutical company guilty by association? That aside, the structure of research funding with regards to pharmaceuticals (at least in the US so far as I'm aware) makes the likelihood of conducting any long term, large scale study without receiving any funding from a pharmaceutical company vanishingly small. There have certainly been issues with studies funded and conducted by those companies, but that doesn't mean that all studies funded by them are instantly invalid. Nor does it mean that it's impossible to conduct a study that has received their funding without compromising its integrity. It is entirely possible to take sufficient measures to isolate those companies from the actual process and analysis of the research.
> wherein the experiment does not extrapolate from LDL values to determine mortality risk
As I made reference to earlier, I am not a subject domain expert here. That being said I did do a brief survey of the literature, reading fifteen papers published on either studies of statin efficacy or meta-analysis thereof. I may be misunderstanding what you're saying, but the studies I looked at assessed efficacy by looking at the actual number of cardiac events, strokes, et al suffered by those in the control and experimental groups. Their analysis was based on those numbers, not an extrapolation from LDL values.
> and/or shows a greater than 2% absolute reduction all-cause or CVD-only mortality risk.
Why that number? And why that number in two very different contexts? Regardless, statins have been show in numerous studies to be highly effective.
> while little more than weak associative studies have been published for secondary prevention
That's simply not true. There have been a number of large scale, long term studies on the efficacy of statins for secondary prevention and the preponderance of evidence is on the side of them being very effective.
Some of the studies I looked at:
Mega, J. L., Stitziel, N. O., Smith, J. G., Chasman, D. I., Caulfield, M. J., Devlin, J. J., … Sabatine, M. S. (2015). Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. The Lancet, 385(9984), 2264–2271. doi:10.1016/s0140-6736(14)6173
- The primary focus of this study was looking at the efficacy of statins with relations to genetic risk profiles, but as a component of that we can see the overall efficacy of the statins across those risk profiles as well.
- "The relative risk reductions were 34% in low, 32% in intermediate, and 50% in high genetic risk score categories in the primary prevention trials, and 3% in low, 28% in intermediate, and 47% in high genetic risk score categories in the secondary prevention trials. When the data were combined, the gradient of relative risk reductions with statin therapy across low, intermediate, and high genetic risk score categories were 13%, 29%, and 48%, respectively (p value for trend=0·0277, figure 2)."
- "With a focus on the primary prevention trials, in JUPITER, the number needed to treat to prevent one coronary event in 10 years was 66 for those individuals with a low genetic risk score, 42 for those with an intermediate score, and 25 for those with a high score. In ASCOT, the number needed to treat to prevent one coronary heart disease event in 10 years was 57, 47, and 20, respectively, across the three genetic risk score categories."
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebocontrolled trial. (2002). The Lancet, 360(9326), 7–22. doi:10.1016/s0140-6736(02)09327-3
- "All-cause mortality was significantly reduced (1328 [12·9%] deaths among 10 269 allocated simvastatin versus 1507 [14·7%] among 10 267 allocated placebo; p=0·0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5·7%] vs 707 [6·9%]; p=0·0005), a marginally significant reduction in other vascular deaths (194 [1·9%] vs 230 [2·2%]; p=0·07), and a non-significant reduction in non-vascular deaths (547 [5·3%] vs 570 [5·6%]; p=0·4). There were highly significant reductions of about one-quarter in the first event rate for non- fatal myocardial infarction or coronary death (898 [8·7%] vs 1212 [11·8%]; p<0·0001), for non-fatal or fatal stroke (444 [4·3%] vs 585 [5·7%]; p<0·0001), and for coronary or non- coronary revascularisation (939 [9·1%] vs 1205 [11·7%]; p<0·0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19–28) reduction in the event rate (2033 [19·8%] vs 2585 [25·2%] affected individuals; p<0·0001)."
Sever, P. S., Dahlöf, B., Poulter, N. R., Wedel, H., Beevers, G., Caulfield, M., … Östergren, J. (2003). Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. The Lancet, 361(9364), 1149–1158. doi:10.1016/s0140-6736(03)1294
- "The primary endpoint of non-fatal myocardial infarction, including silent myocardial infarction, and fatal CHD was significantly lower by 36% (hazard ratio 0·64 [95% CI 0·50–0·83], p=0·0005) in the atorvastatin group than in the placebo group (figure 2, table 3)."
- "There were also significant reductions in four of the seven secondary endpoints, some of which incorporated the primary endpoint: total cardiovascular events including revascularisation procedures (21%); total coronary events (29%); the primary endpoint excluding silent myocardial infarction (38%); and fatal and non-fatal stroke (27%, figures 3 and 4). All-cause mortality was non-significantly reduced by 13%, with non-significantly fewer cardiovascular deaths (figures 3 and 4) and no excess of deaths from cancer (81 assigned statin vs 87 assigned placebo) or from other non-cardiovascular causes (111 vs 130)."
It appears that the evidence in support of the use of statins is quite overwhelming.
I do not agree. I do not have the time to elaborate further.
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> I get where you're coming from here, but it's kind of silly. And the question becomes where do you draw the line? Is a meta-analysis of a large group of studies each of which has been supported at least in part by funding from a pharmaceutical company guilty by association? That aside, the structure of research funding with regards to pharmaceuticals (at least in the US so far as I'm aware) makes the likelihood of conducting any long term, large scale study without receiving any funding from a pharmaceutical company vanishingly small. There have certainly been issues with studies funded and conducted by those companies, but that doesn't mean that all studies funded by them are instantly invalid. Nor does it mean that it's impossible to conduct a study that has received their funding without compromising its integrity. It is entirely possible to take sufficient measures to isolate those companies from the actual process and analysis of the research.
Again, I do not agree. These are matters of values, and no arguments can be made for what we innately value. I draw a nuanced line based on my values, that I have tried to express here; but making it finer and finer will serve no purpose but as fuel for disagreement — because it is wholly subjective.
Possibility is not actuality. Most researchers are not a Platonic ideal: perfectly noble and virtuous and vigilant. They are real people: lazy, prone to error, requiring money to survive, self-interest at the very forefront.
I will not call your viewpoint naive, but it’s something that can only be formed when one’s exposure to this field is limited to papers and doctor’s visits.
> Why that number? And why that number in two very different contexts? Regardless, statins have been show in numerous studies to be highly effective.
Because 2% ARR is the highest change I’ve seen in any statin experiment — in either context. I do not consider one out of every fifty people being saved by a statin significant, or my definition of “highly effective.”
> It appears that the evidence in support of the use of statins is quite overwhelming.
My patience for reiterating this point is gone: relative changes are not absolute changes.
A starting risk profile of 2.25%, reduced to 1.25%, will have been reduced an absolute 1%, but a relative 44%.
This is why you read the methodology, and not the authors’ interpretation of their own data.
Seriously, if you're interested in this area then listen to the entire podcast that I linked above. It's packed with information from one of the leading researchers in the field and might change your mind about a few things.
You might be interested in Surgery, the Ultimate Placebo by orthopaedic surgeon Ian Harris.
Instead, all I can recommend is a collection of essays -- loosely -- related to the subject: Where's the Evidence?, Silverman
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On another note, someone who's gone down the pharmaceutical research rabbit hole and concluded a lot of it is "bunkum" (e.g. statins, anti-depressants, and so on), would do well to look into surgery next -- especially that of surgical implants.
Some of worth looking into: joint replacements, joint and spinal fusions, angioplasties.
Of note: spinal fusions were not brought about on any scientific or experimental bases, but on hunches from surgeons (damnable bunch). Many do result in a reduction in pain, but it does bring to question how much of it is simply "placebo." There were a few experiments in this realm of doing double blind (or single blind, it escapes me right now) studies on back surgeries, that showed evidence the placebo effect was involved. The simple act of being put under anaesthesia, and convinced one had gotten "treatment," resulted in reductions in pain for those who came in for spinal surgery.
I do wish more research would be done into the placebo effect, and doctors would stop faffing about in self-righteousness (though having an air of expertise and authority does impact the placebo effect positively). And I don't mean in a "the placebo effect exists and is usable as a treatment" way, but in a "the placebo effect exists, and here is how it works in the body." That would be very interesting. Long ago I read a few papers on the placebo effect in regulating blood pressure via regulation of a certain chemical (it could have been a hormone like renin, but I can't recall). At the time, I thought the autonomic nervous system would be a good avenue to research to better figure this out (it would be a convenient explanation for how the placebo effect works: activating the nerves in the kidneys via the cross-talk from the central nervous system to excrete certain hormones). If it can affect the kidneys, what other bodily systems can it impact? The possibilities are not endless, but rather exciting.
I believe the "placebo effect" is the reason chiropractors are so popular, in spite of there being no real physical evidence as to why their treatments help people.