Rilmenidine vs Telmisartan or other BP meds for Longevity

#244

Antihypertensive medications and risk of Alzheimer’s disease: Evidence for specific medication use

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70242

Risk of Dementia During Antihypertensive Drug Therapy in the Elderly

https://www.jacc.org/doi/10.1016/j.jacc.2024.01.030

Antihypertensive medications and risk for incident dementia and Alzheimer’s disease: a meta-analysis of individual participant data from prospective cohort studies

https://www.sciencedirect.com/science/article/abs/pii/S147444221930393X

#245

What’s the contradiction?

#246

Isn’t the contradiction that one study showed olmesartan to be superior to all other ARBs regarding HR for dementia and the other study showed BBB crossing ARBs to be superior. And of course, olmesartan is not a BBB crossing ARB.

I wonder but hard to do on phone - is the cluster of non BBB ARBs heavily weighted by other ARBs? Losartan is mixed but I think they classified as non crossing. Losartan being the most commonly used in the US.

Candesartan and telmisartan are the most common in Australia, fwiw. So AUS strongly favors the BBB crossing drugs and the US does not.

#247

From the first report, posted by you, we have:

“After controlling for major modifiable lifestyle factors such as diet and physical activity, ARB use was linked to a significantly reduced risk of dementia compared with ACEI use (hazard ratio [HR] = 0.72; 95% confidence interval [CI]: 0.65-0.80, p < 0.001). In exploratory agent-level analyses, compared with lisinopril, olmesartan (HR = 0.32 ; 95% CI: 0.16-0.62), candesartan (HR = 0.41 ; 95% CI: 0.24-0.69), telmisartan (HR = 0.42 ; 95% CI: 0.25-0.71), irbesartan (HR = 0.45; 95% CI: 0.27-0.75), and perindopril (HR = 0.52 ; 95% CI: 0.31-0.87) were associated with a significantly lower risk of dementia, while captopril showed a significantly increased risk (HR = 4.9 ; 95% CI: 1.04-23.4).”

And also, from the same report, for ACM, we have:

“All-cause mortality risk

Results indicated a significant reduction in the risk of death for ARB users compared to ACEI users (HR = 0.77; 95% CI: 0.73–0.82, p < 0.001). In exploratory agent-level analyses, olmesartan showed the greatest risk reduction (HR = 0.64; 95% CI: 0.56–0.74), followed by telmisartan (HR = 0.91; 95% CI: 0.85–0.97) and candesartan (HR = 0.92; 95% CI: 0.86–0.98) compared with irbesartan (Table S9 ).

ARBs showed varied mortality risk compared to lisinopril. Olmesartan was associated with the greatest reduction in mortality risk (HR = 0.34; 95% CI, 0.24–0.48) (Table S9 ). Perindopril was linked to the lowest risk of death among ACEIs (HR = 0.70; 95% CI: 0.50–0.86) compared with lisinopril (Table S9 ). After excluding patients whose hypertension diagnosis was based solely on AHM records, ARBs were significantly associated with the reduction of all-cause mortality compared with users of ACEIs (HR = 0.80; 95% CI: 0.75–0.85) (Table S9 ).”

So, here we have a comparison against a common reference (lisinopril), and for dementia, death, ACM, we see Olmesartan showing massively lower dementia, death, ACM compared to Telmisartan and Candesartan.

Now in the new report, we have a comparison between two ARB classes, on the one hand we have BBB crossing ARBs Telmisartan and Candesartan, and on the other hand we have the BBB non-crossing ARBs including Olmesartan, Irbesartan, Losartan.

In table 3 (download the pdf) we see that if we use the BBB non-crossing ARBs including Olmesartan as reference HR 1.00, then the BBB crossing ARBs (telmi, cande) have dementia adjusted HR (95% CI), p-value of <0.001 - 0.84 (0.80-0.88) representing a 16% lower hazard ratio for dementia favoring telmi and cande vs olme. For ACM, again if we use olme as reference HR 1.00, then telmi and cande show adjusted HR (95% CI) p-value <0.001 - 0.83 (0.82-0.86) representing 17% lower hazard ratio for ACM favoring telme and cande compared to olme. For death from dementia, again if we use olme as reference HR 1.00 then telmi and cande show adjusted HR (95% CI) p-value <0.001 - 0.85 (0.79-92) representing 15% lower hazard ratio for death from dementia favoring telmi and cande compared to olme.

In summary, the contradiction between the two reports is as follows: in the first report (which you originally posted - and on which I commented extensively) Olmesartan had a massively lower HR for dementia and ACM compared to Telmisartan and Candesartan, and in the second report (which I originally posted) Telmisartan and Candesartan had a massively lower HR for dementia, death from dementia and ACM compared to Olmesartan.

#248

Of course the thought occurred to me, but, well, in that first report irbesartan was marginally less protective against dementia compared to telmi and cande HR 0.45 for irbe, 0.41 for cande, 0.42 for telmi. I suppose theoretically losartan might be doing all the work, but that would have to be some epic level increase in dementia to overwhelm the massive protective effect of olme and non-significant irbe… we’d have panic clinical reports and withdrawal of the drug from the market as care facilities fill up with zombies on losartan.

And it would be a criminal level of misrepresentation by the research team to take the single best performer by many country miles - olmesartan - vs dementia, death, ACM compared to any ARB in the known universe and then lump it with such an epic malefactor as losartan would have to be in this scenario (irbe is statistically inert here), and then pronounce non-crossing ARBs as massively inferior in HR vs these maladies. I mean that’d be so egregious that the whole team would have to end up in handcuffs. I generously do not suspect them of such levels of prison bar gripping malfeasance. YMMV.

#249

At least as far as dementia, in the posted first study, the intervals all overlap. Did they do a head to head on dementia with statistical significance? They went around saying olmesartan was better it isn’t when you look at the intervals.

Now for ACM, olmesartan was better.

But it seems to me like for dementia, ARBs are better than acei but nothing can be said in that study about the various ARBs.

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#250

Ah OK your point was for olmesartan. I didn’t ascribe much value to that olme paper. Need to see many papers pointing to the same thing to reach a conclusion. Telmisartan still king?

#251

My take is olmesartan for ACM and telmisartan for dementia. But who really knows for sure. But there is a contradiction on ACM for sure.

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#252

All this can be quite frustrating, if someone wants to tease out the most optimal medication for longevity.

There will never be a gold standard RCT comparing different ARBs and their effect on ACM or dementia. And epidemiological data is often riddled with intricate con founders: apart from the obvious, it’s things like people having different insurance based on occupation/location and therefore different ARBs covered - e.g. in Germany the guidelines for public health insurers have Telmisartan as a secondary choice only, due to longer lasting patent protection. But you still got it routinely prescribed, if you’re a teacher, government clerk or other public sector official - due to special health insurance for those folks.

So if I’m reading analysis of cohort studies I wonder: is the effect size between different interventions very notable? A 10% difference in epidemiological data barely moves the needle - maybe it does for ACM. And if there is a large effect size - what it the plausible mechanism? If there is just no plausible mechanisms, it’s difficult to take it serious.

So if an observational study concludes Captopril got a factor 4,9 increased dementia risk… So it’s competing with APO4 carriers, really? What could possibly be the mechanism then?

Olmesartan reduced all-cause mortality by 36% vs. only 8% in Telmisartan? That’s huge, almost unheard of. That’s on the level of starting exercise + diet change combined. So I wonder what’s driving that? It can’t be differences in dementia, unless it’s completely curative for Alzheimers (it’s not, that would be known) in addition to notable cancer effects vs. Telmi. So what’s the mechanism? For that to be plausible, Olmesartan would need to be completely curable for either cancer or ASCVD (compared to Telmi) or jointly all_dementia+road_accidents.

I find this as confusing as anyone else.

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#253

Its mechanism of action intentionally lowers RHR by 10 points.

#254

In another recent thread Your Aorta Knows Your Real Age, and Surgeons Are Not Asking - #8 by trojanrapamycin there is an explanation for how Olmesartan may be the only ARB that not only lowers BP but also heals aortic stretching caused by past high BP: In that post there is also a link to another thread where trojanrapamycin provides more details and citations about why Olmesartan is mechanistically superior to other ARBs for this aortic healing effect. Perhaps this explains how Olmesartan might lower mortality from congestive heart failure and Aortic dilation more effectively than other ARBs.