Angiotensin II receptor blocker (ARB) experiences?

[adssx]

Yes, that’s one of the reasons why telmisartan is the best ARB. Half-life matters because BP variability is as important, if not more, than mean BP for longevity. Guidelines recommend long-acting drugs to ensure efficient BP lowering over the whole day and night (and also in case you forget it one day or change the hour you take it). Besides telmisartan, the longest-acting dihydropyridine CCB is amlodipine and the longest-acting thiazide/thiazide-like is indapamide SR or chlortalidone.

[Tim]

Thank you the comprehensive answer. One more question. Would you say that idapamide is the most benign of the diuretics? I had a rough time with chlorthalidone.

[adssx]

This review indeed suggests that indapamide 1.5 mg SR has a better safety profile than other HCTZ and chlorthalidone (which themselves might have a better safety profile than other non-thiazide diuretics): Redefining diuretics use in hypertension: why select a thiazide-like diuretic? 2019

However, they cite old and/or small studies, so I’m not 100% convinced.

I find it more interesting that in many countries, such as Canada, the use of indapamide is slowly increasing: wisdom of the crowd? See: Prescription Trends of Thiazide Diuretics in a Canadian Primary Care Population from 2015-2021 2024:

Which chlorthalidone dose did you use? What is the dose equivalence between indapamide and chlorthalidone?

[Tim]

I took 25 mg of Chlothalidone, and my BP dropped like a rock. But it was hard to deal with. My GFR went down 6 points, my BUN went up 40, and I got a case of gout. Meanwhile, a mere 5 mg of amlodipine gave me pedema, a most unwelcome development for a runner.

I’m thinking of replacing the losartan with telmisartan, replacing the chlothalidone with1.25 mg or less of indapamide, and cutting the amlodipine from 5 to 2.5 mg.

I appreciate your extensive research into this subject. Have you delved so deeply because you struggle to control your own BP, or are you in the medical profession?

[Davin8r]

What about telmisartan along with an SGLT2 inhibitor such as empagliflozin or dapagliflozin instead of indapamide? You’d get a diuretic effect (mild and transient), but most importantly you’d get lasting effects of decreased glucose and blood pressure, possible modest body fat loss along with other potential health/longevity benefits. Might be worth considering with your medical provider (this is not meant to be medical advice).

[Tim]

Thanks for the suggestion @Davin8r. I’ll have to study the question further. I’ll read a little and then talk it over with my clinicians, although sometimes I make independent decisions. Rapamycin, for example.

[Ziegelhausen]

I’ve had good success with telmisartan 40mg and amlodipine 2.5 mg. I got pedema with amlodipine 5 mg, but it went away at 2.5. I also take empagiflozan 10 mg, but did not see an effect on BP from that. I’ve gotten my BP from low 120s systolic to my target of <115…

[adssx]

@Tim

Have you delved so deeply because you struggle to control your own BP, or are you in the medical profession?

I’m struggling to control my own. Usual disclaimer: I’m not a doctor and this is not medical advice. (In my case dapagliflozin 10 mg + telmisartan 40 mg + amlodipine 5 mg only reduced my 135 mmHg SBP by about 10 mmHg so I’m now considering indapamide 1.5 mg SR…)

I don’t think there’s any good reason to use losartan instead of telmisartan. Losartan does not reduce insulin resistance for instance. (I won’t cite sources because I’ve already posted them in this thread or the other one on telmisartan).

Amlodipine 5 mg combined with telmisartan has an edema risk barely higher than placebo: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172077/figure/f3-ibpc-4-027 So amlodipine 2.5 mg with telmisartan has probably a rate of edema lower than placebo. Another reason to ditch losartan for telmisartan.

SGLT2i such as empagliflozin or dapagliflozin can indeed decrease SBP but this is NOT a diuretic effect, stop saying this @Davin8r: SGLT2 Inhibition: Neither a Diuretic nor a Natriuretic and Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.

Regarding diuretics, I found this dose equivalence table: https://www.consultant360.com/articles/hydrochlorothiazide-hypertension-it-diuretic-choice

There hasn’t been large trials comparing indapamide to chlorthalidone so I think this table is mostly a guesstimate. It is still useful and it tells us that indapamide 2.5 mg won’t decrease BP more than the CTD 25 mg you tried. So you could try indapamide 1.5 mg SR (equivalent in BP reduction to 2.5 mg IR with lower side effects according to some paper). Please note that it takes three MONTHS for indapamide to reach its full effect on BP reduction.

You mentioned an eGFR dip: any drug that significantly decreases BP (including SGLT2i and ARBs that are renoprotective!) might cause an initial eGFR dip that normally bounces back to normal after a few weeks.

[adssx]

Just published in The Lancet: Antihypertensive medication classes and risk of incident dementia in primary care patients: a longitudinal cohort study in the Netherlands 2024

Compared to ACEi, ARBs [HR = 0.86 (95% CI = 0.80–0.92)], beta blockers [HR = 0.81 (95% CI = 0.75–0.87)], CCBs [HR = 0.77 (95% CI = 0.71–0.84)], and diuretics [HR = 0.65 (95% CI = 0.61–0.70)] were associated with significantly lower dementia risks. Regarding competing risk of death, beta blockers [HR = 1.21 (95% CI = 1.15–1.27)] and diuretics [HR = 1.69 (95% CI = 1.60–1.78)] were associated with higher, CCBs with similar, and ARBs with lower [HR = 0.83 (95% CI = 0.80–0.87)] mortality risk.
Moreover, a recent network meta-analysis suggested that specific AHM-classes, particularly angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs), reduce dementia risk beyond their BP lowering effects.
Dementia risk was similar within CCB subclasses (dihydropyridine/non-dihydropyridine), and within diuretic subclasses (thiazide/loop/K-sparing) versus ACEi.
Within diuretic subclasses, mortality risk was lower for thiazides (HR = 0.87; 95% CI = 0.83–0.93), and higher for loop (HR = 3.05; 95% CI = 2.89–3.22) and K-sparing (HR = 1.50; 95% CI = 1.42–1.59) diuretics versus ACEi
Among patients receiving AHM, ARBs, CCBs, and Ang-II-stimulating AHM were associated with lower dementia risk, without excess mortality explaining these results. Extensive subgroup and sensitivity analyses suggested that confounding by indication did not importantly influence our findings. Dementia risk may be influenced by AHM-classes’ angiotensin-II-receptor stimulating properties. An RCT comparing BP treatment with different AHM classes with dementia as outcome is warranted.
The lower dementia risks associated with ARBs and beta-blockers compared to ACEi slightly attenuated with increasing age. This may be a chance finding. Alternative explanations are speculative. Possibly, some classes, such as ARBs, rely more on neuroprotective properties that are particularly exerted before extensive neuropathological changes associated with late life dementia develop, thereby potentially extending their therapeutic benefits, especially in younger age groups. Alternatively, ARBs might particularly reduce the risk of dementia with (micro-)vascular origin, which could represent a larger proportion of dementia cases in younger patients.
Several hypotheses suggest how individual AHM-classes might reduce dementia risk beyond BP lowering effects. For example, dihydropyridine CCBs may prevent neuronal cell death and AD neuropathology by regulating cellular calcium influx, and ARBs may reduce inflammation, oxidative stress, and AD neuropathology by improving cerebral blood flow. The more recent “angiotensin hypothesis” suggests that several AHM-classes lower dementia risk by stimulating the angiotensin-II-receptors type (ATR) 2 and 4, involved in cerebral ischemia and memory function (Fig. 1). ARBs directly block ATR1, increasing ATR2 and ATR4 stimulation, and upregulating angiotensin-II production. Thiazide diuretics and dihydropyridine CCBs stimulate ATR2 and ATR4 by increasing renin and thereby angiotensin-II production. BBs and non-dihydropyridine CCBs decrease renin and thereby angiotensin-II production. Finally, ACEis inhibit angiotensin-II production, inhibiting ATR2 and ATR4, and may also decrease cerebral Amyloid-Beta degradation wherein ACE is involved. This would fit with ACEi generally being associated with the highest dementia risk, ARBs versus ACEi most consistently with lower dementia risk, and the consistent results of studies evaluating Ang-II-stimulating versus inhibiting medication, discussed above. Our results do not fully support the angiotensin hypothesis. This could be attributed to residual confounding within the observational data or to other, as-yet-unknown mechanisms that might also influence the differential associations between antihypertensive medication classes and the risk of dementia.
Moreover, a large meta-analysis reported that the association between blood pressure lowering with AHM and lower risk of dementia or cognitive decline was not affected by baseline blood pressure or cumulative systolic blood pressure change. Finally, in a different cohort with similar characteristics where BP values were available, we found no apparent differences in BP values between AHM-classes. Therefore, we expect that the differential associations in our study represent class-specific mechanisms affecting dementia risk beyond BP lowering effects.
ARBs, CCBs, and thiazide diuretics were associated with lower dementia incidence rates compared to ACEi-use, without excess mortality. Combined with previous studies, our study makes a compelling case for differential associations between AHM-classes and dementia risk, particularly for lower risks associated with ARBs versus ACEi and Ang-II-stimulating versus Ang-II-inhibiting AHM-classes.

The HRs are even better in those who started medication before age 60:

Quite an amazing paper!

Unfortunately, they did not address combinations well. So we don’t know if the effects are additive, and therefore the HR multiplicative, which, for example, would give, in the best-case scenario, for the combination of ARB + dihydropyridine CCB + Thiazide(like): 0.85x0.79x0.75 = 0.50 for dementia. If among each of these classes there is a best-in-class drug that reduces dementia risk even more and if the effects are still additive then we might have an HR for the combination as low as 0.3 (the proof is left as an exercise to the reader ).

[Davin8r]

@adssx

NOT a diuretic effect, stop saying this @Davin8r

It’s a diuretic for a short time, until counter-regulatory mechanisms kick in. It still lowers blood pressure. And there are ways to offer corrections/amendments without being patronizing.

[adssx]

@adssx

I dug more, almost all research papers on Aktiia are conducted by… Aktiia. One recent exception is Evaluation of the ability of a commercially available cuffless wearable device to track blood pressure changes. They found that the daytime average found by Aktiia was correct but that the night-time one was significantly off (+15.5 mmHg). They concluded: “This cuffless wearable device did not accurately track night-time BP decline and results suggested it was unable to track medication-induced BP changes.”

Aktiia answered: Inadequate study designs for the evaluation of blood pressure monitoring devices and their potential misleading conclusions - PMC

I find their answer unconvincing… They even “agree with the results showing that the nighttime dip measured by Aktiia was significantly smaller compared to ABPM”

A paper from this month by Aktiia themselves confirms that their device isn’t reliable during the night: COMPARATIVE EVALUATION OF THE AKTIIA CUFFLESS MONITOR AND STANDARD 24-H AMBULATORY BLOOD PRESSURE MONITOR

No significant differences were found between Aktiia and ABPM monitors in 24-h and daytime SBP readings (24-hour: mean ± SD [95% CI] 2.6±12.3 [-0.2, 5.4] mmHg, correlation r=0.57, P=0.06; daytime: 1.2±12.4 [-1.6, 4.0] mmHg, r=0.60, P=0.38). However, night-time SBP readings showed more pronounced differences (12.5±14.4 [9.3, 15.8] mmHg, r=0.39, P<0.001). DBP readings were significantly different but within clinical acceptance for 24-h and daytime (24-hour: -2.9±7.9 [-4.7, -1.1] mmHg, r=0.63, P=0.002; daytime: -3.1±8.2 [-5.0, -1.3] mmHg, r=0.64, P=0.001), with notable night-time differences (4.1±8.5 [2.2, 6.0] mmHg, r=0.57, P<0.001).
The findings reveal the Aktiia monitor’s promising performance in continuous, long-term BP monitoring, especially during daytime, while noting important differences at night. Further research is underway to investigate nocturnal measurements.

Another team (not Aktiia), published a paper in the same journal, this time comparing office measurements to the daytime average BP from Aktiia, and the figure doesn’t look great to me in terms of individual measures but it confirms that the average daily BP found is close to the office measurements:

Bland and Altman analysis revealed a difference of 0.015 (CI -0.734 to 0.763) in systolic BP and of 0.380 (CI -0.216 to 0.975) in diastolic BP (Figure 1). The agreement for the diagnosis of hypertension was 92.4% with a kappa of 0.61±0.04 for systolic BP and 94.7% with a kappa of 0.50±0.04.

---

This is really bad for 24h and night… But still reassuring for daytime measurements…

[adssx]

Efficacy of angiotensin receptor blockers for nocturnal blood pressure reduction: a systematic review and meta-analysis 2024

The overall analysis indicated that nocturnal BP drop varied considerably among different ARBs. Allisartan (13.04 [95% CI (−18.41, −7.68)] mmHg), olmesartan (11.67 [95% CI (−14.12, −9.21)] mmHg), telmisartan (11.11 [95% CI (−12.12, −10.11)] mmHg) were associated with greater reduction in nocturnal systolic BP.
This study demonstrates that for patients with mild to moderate hypertension, allisartan, olmesartan and telmisartan have more advantages in nocturnal BP reduction among the ARBs, while allisartan can reduce nighttime BP more than daytime BP and improve the dipping pattern.
To the best of our knowledge, this is the first systematic review and meta-analysis exploring the efficacy of ARBs on nocturnal BP reduction in patients with mild to moderate hypertension. Our results indicate that long-acting ARBs such as allisartan, olmesartan and telmisartan have similar efficacy in reducing nocturnal systolic BP as well as in 24-h systolic BP reduction. The efficacy of these drugs in lowering nocturnal systolic BP could be seen as the continuation of daytime antihypertensive effect.
Telmisartan, allisartan and olmesartan decreased systolic BP significantly in the last 4–6 h after daily dosing, which may be related to the longer half-lives. Due to the short half-lives (< 8 h) of valsartan and other ARBs, their blood concentration decreases significantly at night after routine morning administration, resulting in poor control of the last 4–6 h ambulatory BP. The results of this study suggest half-life may be one of the key factors affecting the nocturnal BP drop seen with ARBs.
Previous studies have shown long-acting ARBs exhibit a flat dose response curve, and although increasing the dose would appropriately prolong the drug action time, it does not enhance the antihypertensive effect. This observation is consistent with our subgroup finding that the efficacy of real long-acting ARBs, such as telmisartan, olmesartan and irbesartan are not affected by the dose. On the other hand, increasing the dose of valsartan and other drugs compensate for their relatively short half-lives and may increase the efficacy on nocturnal BP control.

(Allisartan only seems available in China, it’s not even on Indiamart)

[Jonas]

Gemini summary:

• Allisartan, Olmesartan, and Telmisartan showed the greatest reduction in nocturnal systolic blood pressure.
• Allisartan: 13.04 mmHg reduction
• Olmesartan: 11.67 mmHg reduction
• Telmisartan: 11.11 mmHg reduction
• The effect of Valsartan on nocturnal blood pressure is not specified in the given information.
• The study suggests that longer half-life ARBs (Allisartan, Olmesartan, Telmisartan) may be more effective due to sustained blood pressure control throughout the night. Shorter half-life ARBs (like Valsartan) may see their blood pressure control diminish at night, requiring dose adjustments.

[DeStrider]

This is why nocturnal BP control is so important.

Why do doctors still prescribe losartan and other ARBs that don’t provide 24-hour BP control???

Potential risk factors for nocturnal hypertension include sleep apnea, kidney disease, and diabetes. If a person does not treat nocturnal hypertension, they may be at higher risk of various health complications, including heart attack and stroke.

Nocturnal hypertension: Symptoms, causes, treatment, and more

[Tim]

I just read a paper on SLGT-2 and found the average reduction in BP is small, ranging from 2 to 7, depending on the type. Right now, on telmisartan 40 and amlodipine 5, my systolic BP is 135. So I think I’ll need something heftier.

[Tim]

The lab parameters you previously posted raise a concern for me, namely that indapamide SR has the same Increased + risk for uric acid, and thus the same risk for gout, as does chlorthalidone.

However, the dose-equivalence table you dug up may allay this concern. The table indicates that 2.5 mg of indapamide (or it’s near equivalent 1.5 mg SR) corresponds to 12.5 mg of chlorthalidone. Since I was taking 25 mg of chlothalidone at the time I stopped because of gout, I may be able to get away with either 12.5 mg of the same med or the 1.5 mg SR dose of indapamide.

The excerpt from a paper you posted today says that long-acting ARBs have a flat dose-response curve. Therefore, from a BP-lowering perspective, I couldn’t expect much of an effect by doubling my current 40-mg dose of telmisartan. On the other hand, lisinopril’s effectiveness does increase with dose. I’d rather have the famous “lisinopril cough” than a case of gout.

[adssx]

I was also at about 130 on telmisartan 40 mg + amlodipine 5 mg. I tried indapamide 1.5 mg SR for 2 weeks. I worked perfectly to lower my BP (without any hypotension symptoms). However, I didn’t like it as I felt like it messed up with my glucose levels (I used to have reactive hypoglycemia). I stopped it, and the unpleasant post-meal symptoms disappeared. I’m now on telmisartan 80 mg + amlodipine 5 mg. But as you said, going from 40 to 80 mg, telmisartan won’t probably do much to the BP lowering (but it might have other positive effects, and you never know, everyone has a different response, so it’s worth trying).

I’ve also just started taurine 1.5 mg as it seems to be able to reduce SBP by 5 mmHg (see the taurine thread). I’ll keep you posted if it works…

And @Tim, for gout risk, add an SGLT2 inhibitor (which can also reduce BP slightly).

[DrFraser]

If you are wanting PPAR effects, you’ll want your telmisartan up at 80-160 mg. Yes, that won’t make much impact on BP at all, but might as well get the unique benefit from Telmisartan if you are taking it.

@adssx funny we are on the same - I do Telmisartan 80 - might push it to 160 at some point for addl PPAR and amlodipine 5. I’m doing Taurine 4 grams all at once midday, gives a few hours of mTOR inhibition - and unaware on BP lowering as a bonus. Also 25 mg of Jardiance … and BP is actually good on all this!

[Barnabas]

@DrFraser

If you are wanting PPAR effects, you’ll want your telmisartan up at 80-160 mg.

If you were on 20mg of Telmisartan (and still running an SBP 125-135) how would you suggest to your doctor that it would make sense to ramp the Telmisartan dose so high? What would be the case for the PPARg effects? Just a generic “insulin sensitivity is good”?

[DrFraser]

First thing I’d inform my doctor that a SBP of 125-135 mmHg is doubling your cardiac mortality as compared to ideal BP - so if they are happy thinking that is okay … more power to them … but it isn’t what the data says. Additionally, going from 20 up to 80 mg of Telmisartan will do bugger all for changing your BP … so that might get you down another 5 points, but not where one would want to be ideally. So you’ll almost certainly require a second med. I have a nice blog on my website on Telmisartan that details it - take it to your doctor and the one I have on Hypertension … it’s an easy read and presents the evidence nicely.