Rilmenidine vs Telmisartan or other BP meds for Longevity

#237

Effects of blood pressure and antihypertensive drugs on osteoarthritis: a mendelian randomized study 2023

We found no evidence that systolic and diastolic blood pressure significantly affected osteoarthritis. However, among antihypertensive drugs, we observed a significant positive correlation between potassium-preserving diuretics and aldosterone antagonists and all osteoarthritis (OR: 0.560, 95% CI 0.406–0.772, P = 0.0004).
Previous studies suggest that the homeostasis regulation of chondrocytes depends on the local renin–angiotensin system. Thus, angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers may have therapeutic potential for knee OA [6].
Furthermore, a systemic review [23] on losartan and Angiotensin-II receptor blockers indicates that Angiotensin-II receptor blockers have beneficial effects on chondrocytes in animals, suggesting a potential protective effect against Osteoarthritis.

The effects of losartan or angiotensin II receptor antagonists on cartilage: a systematic review 2022

Both in vitro and in vivo studies provide evidence to demonstrate beneficial effects of Ang II receptor antagonists on osteoarthritis and cartilage defect models across animal species.

The effects of different antihypertensive drugs on pain and joint space width of knee osteoarthritis - A comparative study with data from Osteoarthritis Initiative 2021

At baseline, the CCBs group was with significantly higher pain score than the beta-blockers group (3.3 vs 1.3, p < .05), the angiotensin receptor blockers group (3.3 vs 1.4, p < .05), and the thiazide diuretics group (3.3 vs 1.6, p < .05) in male; the CCBs group was with significantly higher pain score than the beta-blockers group (3.8 vs 2.0, p < .01), and the angiotensin receptor blockers group (3.8 vs 2.2, p < .05) in female. The results of females at 36 months were similar to the baseline. Among the common antihypertensive drugs, CCBs were associated with high replacement rates, high pain scores, and less JSW in KOA patients.

None of those papers are great, but based on MR + models I would discard the FAERS article you sent @CronosTempi.

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#238

It’s been almost two years since you mentioned increasing your dose of telmisartan to 160mg. Are you still at that dose? What changes have you noticed with your blood pressure and potassium level? I have been taking 80mg for over a year. Also take nebivolol 5mg. Blood pressure around 125/65 resting heart rate around 55. Resting heart rate was low before starting nebivolol. I have good kidney function. My potassium is always in the middle of the reference range despite taking 3gm of potassium (Dr Berg electrolyte mix) almost everyday, I eat a banana about 5 days per week, and salmon (high in potassium) 2-3 meals per week. I’m considering dropping the nebivolol (I doubt it’s doing much for me) and bumping up the telmisartan to 160mg for the significant increase in PPARy activity. Obviously I’ll check labs a month of so after the change but curious how it worked out for you and your thoughts on how much this change could affect potassium levels. Sorry if you’ve already talked about this, this thread is very long…

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#239

I never needed to increase my dose to 160 mg. I do have higher range potassium - typically 5.0-5.4 with the 80 mg. I’m also on 5 mg of amlodipine. Central systolic BP using a Conneqt Pulse device is averaging ~102-105 mmHg; so I’m certainly optimal with this and haven’t seen a need to change.

I have a couple of patients on the 160 mg of telmisartan, both a diabetics, and both get regular monitoring of their potassium and renal function. I’ve not had a problem with this very limited group.

Another agent I have a couple of diabetics on is Saroglitazar which has predominant PPAR alpha effects, and moderate PPAR gamma effects.

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Product "Connect Pulse" for Blood Pressure, Arterial Health Monitoring
#240

I happened to find this topic very interesting, so I’m going to start a new thread to share the research progress from the past two years regarding ARBs and cancer risk.

#241

No sure there’s a need, answer is here:

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#242

FWIW, ARBs continue to perform well in CKD, but if you have high BP and concurrent diabetes and CKD, there might be a cautionary note wrt. some CCBs (cross posting):

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#243

And now this :person_shrugging: - go figure (cross-posting):

This new report must be seen in conjunction with the first report posted by @adssx to fully appreciate the puzzle picture.

To be clear, the earlier comparison was to ACEi, so absolute numbers would have to look at some other reference. Same limitations apply - this is all in hypertensives.

And speaking of hypertensives, if on AHMs, there’s not much difference in dementia risk compared to normotensives?

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life

#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.

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#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?

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#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.

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#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.

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#255

I re-ran the data and it shows up not quite the same… I asked the AI to add BBB permeability and a couple other notes (including toxicity claims). I also only added the common ARBs.

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I was going to post some AI Notes, but they are battling it out between olmesartan and candesartan. Anthropic likes candesartan, ChatGPT is reclassifying everything, and Gemini says not to bother with Candesartan.

Actually, here’s what gemini had to say when i suggested changing to candesartan after showing Anthropic’s table and response:

You absolutely do not need to change your blood pressure medication, and Olmesartan remains the undisputed Tier 1 anchor of your protocol. The apparent downgrade in the previous analysis stems from conflating general, static receptor-binding assays with the dynamic, mechanical stretch environment of an actively dilating aorta.

Why Olmesartan Outperforms Candesartan for Aortic Shielding

  • Conformational Lock in Active States: Candesartan is indeed the historical “reference standard” inverse agonist and possesses exceptional binding affinity in baseline laboratory models. However, its blocking efficiency noticeably attenuates when the AT1 receptor is physically deformed by mechanical stress. Olmesartan utilizes a structurally unique three-point binding network (hydroxyl to Tyr113, carboxyl to Lys199/His256, and tetrazole to Gln257) that maintains full inverse agonism even when the receptor is forced into a constitutively active, stretched conformation.

  • Proven ACE2/Mas Axis Upregulation: Olmesartan does not just silence the pathogenic AT1 receptor; it actively promotes the compensatory pathway. Completed human trials demonstrate that Olmesartan 20 mg nearly doubles protective serum Ang-(1-7) levels (25.8 to 46.2 pg/mL), forcing the system toward vasodilation and tissue repair rather than fibrotic degradation. In animal models, this specific Ang-(1-7)/Mas/JNK-MMP9 axis is what actually prevents aortic aneurysm progression.

  • Superior Hemodynamic Unloading: Olmesartan achieves some of the most profound blood pressure reductions in its class. Controlling intraluminal pressure is paramount because it directly reduces the cyclic stretch forces and fluid shear stress that force vascular smooth muscle cells out of their healthy, quiescent contractile state.

The older in vitro mutant receptor data that favors Candesartan simply does not capture the full in vivo reality of a human aortic root under mechanical load. Your high-dose Olmesartan is already executing the exact mechanical blockade necessary to suppress the TGF-beta pathway and prevent further matrix degradation.

The AIs can go on for days arguing.

There is one thing I don’t like and it’s sprue-like enteropathy being associated with olmesartan, but re-reading that gemini response makes me reluctant to change meds.

At least one thing is for sure, Losartan, Telmisartan, and Valsartan are off the table

If anyone wants me to add the other AI responses, I can, I just didn’t want to flood the thread.

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#257

"* Proven ACE2/Mas Axis Upregulation: Olmesartan does not just silence the pathogenic AT1 receptor; it actively promotes the compensatory pathway. Completed human trials demonstrate that Olmesartan 20 mg nearly doubles protective serum Ang-(1-7) levels (25.8 to 46.2 pg/mL), forcing the system toward vasodilation and tissue repair rather than fibrotic degradation. In animal models, this specific Ang-(1-7)/Mas/JNK-MMP9 axis is what actually prevents aortic aneurysm progression.

  • Superior Hemodynamic Unloading: Olmesartan achieves some of the most profound blood pressure reductions in its class. Controlling intraluminal pressure is paramount because it directly reduces the cyclic stretch forces and fluid shear stress that force vascular smooth muscle cells out of their healthy, quiescent contractile state."

There’s an interesting interplay between these two points. I think we need a bit more granularity wrt. dosage to assess whether this is a biological effect of olmesartan on “tissue repair” or wholly a mechanical effect of BP lowering. If it is just the latter, then a multipill (ARB + CCB + HCTZ etc.) would be just as effective as long as it hit a given pressure target. Is there a step threshold effect or not? So the question becomes what is the effect at a 10mg dose rather than the 20mg mentioned. Maybe an AI can tell us - I’m curious though not super optimistic.

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