Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2)

Bogman, Katrijn; Schwab, Dietmar; Delporte, Marie‐Laure; Palermo, Giuseppe; Amrein, Kurt E.; Mohr, Susanne; Mudry, Maria Cristina De Vera; Brown, Morris J.; Ferber, Philippe

doi:10.1161/hypertensionaha.116.07716

Cited by 61 publications

(77 citation statements)

References 27 publications

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“…Acute changes in aldosterone concentrations can result in dramatic changes in urine sodium-to-potassium ratio. 30 At a steady state, these are less apparent, but they contribute to an index based on the SUSPPUP ratio that has only slightly lower accuracy than ARR itself in detecting patients with proven primary aldosteronism. 13 The correlation of blood pressure response to spironolactone but not to the other drugs in PATHWAY-2 offers some independent support for the sodium-to-potassium or SUSPPUP ratio as a diagnostic threshold.…”

Section: Discussionmentioning

confidence: 99%

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies

Williams

MacDonald

Morant

et al. 2018

The Lancet Diabetes & Endocrinology

214

132

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SummaryBackgroundIn the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.MethodsPATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25–50 mg, bisoprolol 5–10 mg, and doxazosin 4–8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10–20 mg once daily on clinic systolic blood pressure during an optional 6–12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008–007149–30, and ClinicalTrials.gov, number NCT02369081.FindingsOf the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17–33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3–22·5), compared with a reduction of 18·3 mm Hg (16·2–20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95–4·08) on placebo to 4·50 (4·44–4·57) on amiloride (p<0·0001).InterpretationOur results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension.FundingBritish Heart Foundation and UK National Institute for Health Resea...

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Section: Discussionmentioning

confidence: 99%

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies

Williams

MacDonald

Morant

et al. 2018

The Lancet Diabetes & Endocrinology

214

132

View full text Add to dashboard Cite

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“…There are a number of other new potential drug therapies for hypertension including, amongst others, inhibitors of aldosterone synthase, [86][87][88] soluble guanylate cyclase stimulators, [89][90][91][92] inhibitors of phosphodiesterase-5 [93][94][95][96] and xanthine oxidase, [93][94][95] and advanced glycation end-product breakers. 96,97 Details of these are given in Table 3 and Figure 3.…”

Section: Other Novel Pharmacological Approaches To Hypertensionmentioning

confidence: 99%

Hypertension: Current trends and future perspectives

Hunter

Chapman

Dhaun

2021

Brit J Clinical Pharma

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Hypertension is a significant and increasing global health issue. It is a leading cause of cardiovascular disease and premature death worldwide due to its effects on end organs, and through its associations with chronic kidney disease, diabetes mellitus and obesity. Despite current management strategies, many patients do not achieve adequate blood pressure (BP) control. Hypertension-related cardiovascular mortality rates are rising in tandem with the increasing global prevalence of chronic kidney disease, diabetes mellitus and obesity. Improving BP control must therefore be urgently prioritised. Strategies include utilising existing antihypertensive agents more effectively, and using treatments developed for co-existing conditions (such as sodium-glucose cotransporter 2 inhibitors for diabetes mellitus) that offer additional BP-lowering and cardiovascular benefits. Additionally, novel therapeutic agents that target alternative prohypertensive pathways and that offer broader cardiovascular protection are under development, including dual angiotensin receptor-neprilysin inhibitors. Nonpharmacological strategies such as immunotherapy are also being explored. Finally, advancing knowledge of the human genome and molecular modification technology may usher in an exciting new era of personalised medicine, with the potential to revolutionise the management of hypertension.

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“…Further studies are expected to develop more selective inhibitors of CYP11B2 with less effect on cortisol synthesis and appropriate profile of tolerability and safety. 99 , 100 …”

Section: Treatment Options and Updated Outcomesmentioning

confidence: 99%

Progress in the Management of Primary Aldosteronism

Morimoto

Omata

Ito

et al. 2018

American Journal of Hypertension

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Primary aldosteronism (PA) is now considered as one of leading causes of secondary hypertension, accounting for 5–10% of all hypertensive patients and more strikingly 20% of those with resistant hypertension. Importantly, those with the unilateral disease could be surgically cured when diagnosed appropriately. On the other hand, only a very limited portion of those suspected to have PA has been screened, diagnosed, or treated to date. With current advancement in medical technologies and genetic research, expanding knowledge of PA has been accumulated and recent achievements have also been documented in the care of those with PA. This review is aimed to have focused description on updated topics of the following; importance of PA screening both in the general and specialized settings and careful interpretation of screening data, recent achievements in hormone assays and sampling methods and their clinical relevance, and expanding knowledge on PA genetics. Improvement in workup processes and novel treatment options, as well as better understanding of the PA pathogenesis based on genetic research, might be expected to result in increased cure and better care of the patients.

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Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2)

Abstract: Supplemental Digital Content is available in the text.

Cited by 61 publications

References 27 publications

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies

Hypertension: Current trends and future perspectives

Progress in the Management of Primary Aldosteronism

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