A clinical trial to evaluate the effect of statin use on lowering aldosterone levels

Abstract

Background: Statins are the first-line pharmaceutical agent in the management of hypercholesterolemia and cardiovascular (CV) risk reduction, and the most commonly prescribed class of drugs worldwide. Studies describing CV risk reduction independent of LDL-cholesterol lowering have evoked an interest in the pleiotropic mechanisms of statins' benefits. We recently demonstrated that administration of statins in animal models lowers aldosterone levels and observed an association between statin use and reduced aldosterone levels in two human cohorts, with lipophilic statins displaying a greater effect than hydrophilic statins. Therefore, we designed a randomized, placebo-controlled, double-blinded intervention study to assess whether statin treatment lowers aldosterone in a type-dependent manner in humans, with simvastatin (lipophilic) showing a greater effect than pravastatin (hydrophilic).

Methods/design: One hundred five healthy participants will be recruited from the general population to enroll in a 12-week, randomized, placebo-controlled, double-blinded, 3-arm clinical trial. Ninety participants are anticipated to complete the protocol. After baseline assessment of aldosterone levels, participants will be randomized to daily simvastatin, pravastatin, or placebo. Aldosterone levels will be assessed after 2 days on study drug and again after 6 weeks and 12 weeks on study drug. Prior to each aldosterone assessment, participants will consume an isocaloric sodium and potassium-controlled run-in diet for 5 days. Assessments will occur on an inpatient research unit to control for diurnal, fasting, and posture conditions. The primary outcome will compare 12-week angiotensin II-stimulated serum aldosterone by study drug. Secondary outcomes will compare baseline and 12-week 24-h urine aldosterone by study drug.

Discussion: Results from this rigorous study design should provide strong support that statins lower aldosterone levels in humans. These results may explain some of the beneficial effects of statins that are not attributed to the LDL-lowering effect of this important class of medications. Results would demonstrate that statin lipophilicity is an important attribute in lowering aldosterone levels. The outcomes of this program will have implications for the design of studies involving statin medications, as well as for the differential use of classes of statins.

Trial registration: ClinicalTrials.gov; NCT02871687 ; First Posted August 18, 2016.

Keywords: Aldosterone; Cardiovascular health; Hyperlipidemia; Hypertension; Metabolic health; Mineralocorticoid; Pravastatin; Simvastatin; Statins.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Aldosterone and its effects on cardiovascular risk factors. In addition to its primary function as a blood pressure and volume regulator, aldosterone influences several factors related to cardiovascular risk; insulin resistance [9, 10, 12], hypertension [–11], and obesity [10, 11]. Additionally, increased aldosterone secretion is associated with metabolic syndrome [10, 11] and higher degrees of inflammation in the kidneys, liver, vasculature, and systemically [–11]. Thus, aldosterone excess or excess mineralocorticoid activity exacerbates cardiovascular risk and mitigation should be of benefit

Fig. 2

Study schema. Participants will be enrolled in the study after completing screening visits. At Study Visit 1, aldosterone levels before and after angiotensin II stimulation will be assessed at baseline before participants are randomized to either simvastatin 20 mg, pravastatin 40 mg, or placebo. Aldosterone secretion will then be assessed 1 day after initiation of study drug in order to determine the acute effects of statin use. Aldosterone secretion will be assessed after 6 weeks at Study Visit 2 and after 12 weeks at Study Visit 3 in order to determine the chronic effects of statin use. Approximately 5 days before Study Visit 2, participants will have their lipid levels checked. If their LDL-cholesterol has decreased by less than 35% since screening, study drug dose will be doubled for the final 6 weeks of the study starting after Study Visit 2. A 5-day low-sodium diet will precede each study assessment. The primary endpoint is comparison of 12-week angiotensin II-stimulated aldosterone secretion between the simvastatin and placebo groups

Fig. 3

Beneficial pleiotropic effects of statin medications. Data from the past decade have shown that in addition to their classic LDL-cholesterol lowering effects, statins also function to improve cardiovascular health by mitigating oxidative stress, improving endothelial dysfunction through increased NO function, and decreasing high-sensitivity C-Reactive Protein levels. We propose that statins’ aldosterone-lowering effect represents another mechanism by which statins reduce cardiovascular risk apart from their influence on LDL-cholesterol