Design and progress of a factorial trial testing the effect of spironolactone and inorganic nitrate on arterial function in people at risk of or with type 2 diabetes

Govoni

et al. 2020

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Aims:To test if spironolactone or dietary nitrate from beetroot juice could reduce arterial stiffness as aortic pulse wave velocity (PWVart), a potential treatment target, independently of blood pressure. Methods:Daily spironolactone (≤50 mg) vs doxazosin (control ≤16 mg) and 70 mL beetroot juice (Beet-It ≤11 mmol nitrate) vs nitrate-depleted juice (placebo; 0 mmol nitrate) were tested in people at risk or with type-2 diabetes using a double-blind, 6-month factorial trial. Vascular indices (baseline, 12, 24 weeks) were cardiac-ankle vascular index (CAVI), a nominally pressure-independent stiffness measure (primary outcome), PWVart secondary, central systolic pressure and augmentation. Analysis was intention-to-treat, adjusted for systolic pressure differences between trial arms.Results: Spironolactone did not reduce stiffness, with evidence for reduced CAVI on doxazosin rather than spironolactone (mean difference [95% confidence interval]; 0.25 [−0.3, 0.5] units, P = .080), firmer for PWVart (0.37 [0.01, 0.7] m/s, P = .045). There was no difference in systolic pressure reduction between spironolactone and doxazosin (0.7 [−4.8, 3.3] mmHg, P = .7). Circulating nitrate and nitrite increased on active vs placebo juice, with central systolic pressure lowered −2.6 [−4.5, − 0.8] mmHg, P = .007 more on the active juice, but did not reduce CAVI, PWVart or peripheral pressure. Change in nitrate and nitrite concentrations were 1.5-fold [1.1-2.2] and 2.2-fold [1.3, 3.6] higher on spironolactone than on doxazosin respectively; both P < .05.Conclusion: Contrary to our hypothesis, in at-risk/type 2 diabetes patients, spironolactone did not reduce arterial stiffness, rather PWVart was lower on doxazosin.Dietary nitrate elevated plasma nitrite, selectively lowering central systolic pressure, observed previously for nitrite.PI statement: The authors confirm that the Principal Investigator for this paper is Professor J.K. Cruickshank and that he had direct clinical responsibility for patients.Clinical trial registration: ISRCTN registry: ISRCTN25003627

Section: Methodsmentioning

confidence: 99%

A randomised, factorial trial to reduce arterial stiffness independently of blood pressure: Proof of concept? The VaSera trial testing dietary nitrate and spironolactone

Govoni

et al. 2020

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“…A subsample of patients (with, or at risk of, T2DM) who were consented and randomized in our VaSera factorial RCT had serial transthoracic cardiac ultrasound performed during the course of the study. The study design and methods have previously been described in detail . Briefly, participants with or at risk of T2DM were recruited from Guy's and St Thomas' Hospitals, London, UK, and surrounding areas between 2013 and 2015.…”

Section: Methodsmentioning

confidence: 99%

“…(Clinical trial registration: ISRCTN25003627/DOI 10.1186/ISRCTN25003627). After initial consent and screening/familiarization, visit 1 (V1), and having met the inclusion criteria, patients were invited to return for double randomization (in blocks of six) at visit 2 (V2), with simultaneous allocation to both types of intervention for each patient – therefore into one of four groups ; see Figure for study flow diagram. After cardiac and vascular measurements, treatments comprised either spironolactone 12.5 mg once daily for 1 week titrated to twice daily, OR doxazosin 2 mg once daily for 1 week titrated to twice daily, AND either nitrate‐containing beetroot juice (BEET‐IT®, nitrate 4.5 mmol day –1 ) or placebo beetroot juice.…”

Section: Methodsmentioning

confidence: 99%

“…Given the potential for long‐term dietary nitrate, and spironolactone, to improve cardiac structure or function, alongside, or independently of, any changes in arterial haemodynamics, we prospectively performed echocardiograms in a subsample of patients participating in our VaSera factorial randomized controlled trial (RCT) , with the a priori intention of exploring these specific mechanisms independently of BP, following chronic, 6 months' treatment with dietary nitrate (‘Beet‐it®’ or ‘Beet‐it Sport®’ beetroot juice), and/or spironolactone.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double‐blind, randomized controlled VaSera trial

Govoni

et al. 2018

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Aims The aims of the present study were to explore whether a long‐term intervention with dietary nitrate [(NO3−), a potential tolerance‐free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). Methods A subsample of participants in our double‐blind, randomized, factorial‐design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent‐to‐treat. Results Nitrate‐containing juice (n = 40) decreased left ventricular (LV) end‐diastolic volume {−6.3 [95% confidence interval (CI) –11.1, –1.6] ml} and end‐systolic volume [−3.2 (95% CI −5.9, –0.5) ml], and increased end‐diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [−0.01 (95% CI −0.02, –0.00)]. Although spironolactone reduced LV mass index relative to baseline [−1.48 (95% CI −2.08, –0.88) g m–2.7], there was no difference vs. doxazosin [−0.85 (95% CI −1.76, 0.05) g m–2.7]. Spironolactone also decreased the E/A ratio [−0.12 (95% CI −0.19, –0.04)] and increased S′ (a tissue‐Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s–1. BP did not differ between the juices, or between the drugs. Conclusions Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP‐independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic–diastolic function, although confirmatory, were independent of BP.

“…The main trial was powered to detect a 20% (SD 8%) reduction in the primary outcome of PWVart with spironolactone, with minimum 80% power, at P < .05, requiring a sample size of 24 participants each arm, aiming for 30 to allow a 20% drop-out. 35 The sample size was achieved in…”

Section: Discussionmentioning

confidence: 99%

Dietary nitrate prevents progression of carotid subclinical atherosclerosis through blood pressure‐independent mechanisms in patients with or at risk of type 2 diabetes mellitus

Morselli

et al. 2021

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To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, vs. placebo/ doxazosin, to control for blood pressure (BP).Methods: A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3-and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph) and carotid lumen area. Data were analysed by modified intention to treat and using mixed-model effect, adjusted for confounders.Results: In total, 93 subjects had a baseline evaluation and 86% had follow-up data.No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing vs. placebo juice significantly lowered CIMT (À0.06 [95% confidence interval À0.12, À0.01], P = .034), an overall difference of $8% relative to baseline; but had no effect on CD or CS. Doxazosin appeared to reduce CS from baseline (À0.34 [À0.62, À0.06]) however, no difference was detected vs. spironolactone (À0.15 [À0.46, 0.16]). No differences were detected between spironolactone or doxazosin on CIMT and CD. Conclusions:Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.