Statins As Anti-Hypertensive Therapy: A Systematic Review and Meta-Analysis

Hypertension is the most prevalent condition in clinical practice. Hypertension, diabetes, and hypercholesterolaemia are major contributing factors to cardiovascular diseases. They commonly coexist in a single patient. Statins have been used as prominent medicines for the reduction of cardiovascular events. Statins have been shown to reduce blood pressure in patients with hypertension and have lipid-lowering properties in recent articles. Statins reduce blood pressure because of their impact on endothelial function, their interactions with the renin-angiotensin system, and their influence on major artery compliance. This meta-analysis aimed to ascertain the effectiveness and efficacy of statins for managing hypertension in patients with hypertension. Systematic searches were conducted on PubMed, Science Direct, Embase, Cochrane Library, and Google Scholar. Randomized controlled trials, systematic trials, and cohort studies were retrieved using keywords on statins and their use in patients with hypertension. Exclusion criteria included studies that were not in the English language, studies that did not include patients on statins with hypertension, studies that did not provide enough information, technical reports, opinions, or editorials, and studies involving patients < 18 years old. The inclusion criteria were randomized controlled trials, meta-analyses, adult patients aged > 18 years old, and studies that were freely available or through institutional login. This meta-analysis scrutinized 9361 randomized controlled trials, clinical trials, meta-analyses, and systematic reviews, of which 32 articles including 25 randomized controlled trials and seven meta-analyses were included in the final analysis. This meta-analysis of the role of statins in hypertensive patients aimed to determine the outcome of hypertension control along with antihypertensive medication. Our study showed that statins are useful in reducing both systolic and diastolic blood pressure. We used a heterogeneous model for analysis due to variations in the study characteristics. The I2 value was 0.33 (0.76, 0.10) for systolic blood pressure and 0/88 (0.86, 0.90) for diastolic blood pressure. The I2 value for the seven meta-analyses included in the study was 1.79 (2.88, 0.69).


Introduction And Background
Essential hypertension, also known as high blood pressure (BP), is the most common disease in adults and the leading cause of death globally [1].In the past few years, the prevalence of hypertension has surged significantly in low-and middle-income countries [1,2].In 2008, approximately 40% of adults aged ≥ 25 years had hypertension [3].Furthermore, hypertension is a major causative factor for at least 45% of deaths due to heart disease and 51% of deaths due to stroke worldwide [3][4][5].Large cohort studies have provided evidence that hypertension is an imperative risk factor for heart valve disease, stroke, heart failure, myocardial infarction, kidney disease, atrial fibrillation, aortic disease, and dementia [1,6].According to the guidelines of the European Society of Cardiology, hypertension is defined as systolic BP (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg [7].However, hypertension is further categorized as normal, highnormal, or grades 1-3 BP readings per office BP.Hypertension rarely occurs in isolation and is often accompanied by glucose intolerance and dyslipidaemia which are the major risk factors for cardiovascular diseases (CVDs) [7].In addition to lifestyle modifications and non-pharmacological measures, including the DASH (dietary approach to stop hypertension) diet to control BP, the majority of patients also require pharmacological treatment.There are five major drug classes for lowering BP: angiotensin-converting enzyme inhibitors (ACEI), beta-blockers, calcium channel blockers, angiotensin receptor blockers, and diuretics [7,8].However, there are some cases in which BP would be difficult to control despite all the medications or triple therapy [7,9].
Statins lower the amount of cholesterol synthesized in the liver by competitively inhibiting the enzyme 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is the rate-limiting step in cholesterol synthesis.Lower plasma concentrations of low-density lipoprotein (LDL) and other apolipoprotein B (ApoB)-containing lipoproteins, such as triglyceride (TG)-rich particles, are the results of the reduction in intracellular cholesterol, which also increases the expression of the LDL receptor (LDLR) on the surface of hepatocytes [10].Statins reduce blood cholesterol levels and enhance endothelial function by preserving endothelial nitric oxide synthase, which causes vasodilation and prevents arterial disease development [11].A previous study demonstrated that statins can prevent the progression of arterial stiffness and lower BP when combined with recommended antihypertensive treatment [11,12].Multiple studies have supported a reduction in BP in hypertensive patients treated with statins and antihypertensive medication [13].
A recent meta-analysis studied the positive effects of combination statin use on cardiovascular risk in hypertensive patients [1, 14,15], and our meta-analysis examined the impact of statin therapy (alone or in combination with other antihypertensive medications) on various outcomes associated with hypertension.Hypertension is one of the most important risk factors for endovascular atherosclerotic disease, and it increases the risk of cardiovascular atherosclerosis when combined with other risk factors.The combined use of statins and antihypertensive therapy has synergistic effects on the prevention of CVD progression.There is a lack of evidence supporting the use of statins with antihypertensive therapy in patients with grade 1 hypertension and normal cholesterol levels [16].Several randomised controlled trials (RCTs) have demonstrated the positive effects of statins on BP; however, other studies have shown neutral or no effects .This meta-analysis aimed to analyse previous RCTs and meta-analyses on the role of statins in patients with hypertension.

Search Strategy
This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) and the National Institute for Health and Care Research (NIHR) under the registration number CRD42023493395.A meta-analysis was conducted using multiple search engines to determine the role of statins in patients with hypertension.The literature search was performed on Cochrane Library, PubMed, Science Direct, Embase, and Google Scholar.Medical Subject Headings (MeSH) terms used for the search were "statin", "hypertension", "statins in hypertension", "the role of statins in hypertensive patients ', "statins in high blood pressure', " Statins in various grade of hypertension', "hypertension and statins, and "statin and blood pressure lowering effect", " atorvastatin", "rosuvastatin", "pravastatin", and "simvastatin", "statins as antihypertensive therapy", "combined statin and antihypertensive therapy".A combination of these MeSH terms was used in the literature search.A total of 9361 articles were identified.After removing duplicates and articles that did not meet the inclusion and exclusion criteria, 25 RCTs and seven metaanalyses were included in the final review.Two independent reviewers performed a literature search using the above search engines and agreed on the inclusion and exclusion of articles.In case of disagreement between the two reviewers, a third independent reviewer's opinion was sought, and a decision about the inclusion or exclusion of the articles was made through a majority consensus .
The study was performed by following the PICO (patient/population, intervention, comparison and outcomes) model (Table 1).Population: Studies such as RCTs, systematic reviews, and meta-analyses involving patients with hypertension, aged > 18 years, and any gender were included in this study.

Study characteristic Inclusion criteria Exclusion criteria
Intervention: Studies such as RCTs, systematic reviews, and meta-analyses involving patients with hypertension, aged > 18, and who received statin therapy alone or in combination with anti-hypertensive medications were included in this study.
Comparison: Studies such as RCTs, systematic reviews, and meta-analyses involving patients with hypertension, aged > 18, and who received placebo therapy alone or in combination with anti-hypertensive medications were included in this study.
Outcome: The primary outcome of interest in this study was the effect of statin on SBP and DBP.Secondary outcomes included endothelial function, inflammatory response and lipid level response.

Timeline of the Study
A literature search was carried out to identify studies conducted from 21 December 2023 to 31 January 2024.

Criteria for Selection
We included studies that were systematic reviews, meta-analyses, or RCTs.Articles were included only if the intervention was either statin as a solo treatment or a combination therapy of statin and antihypertensive, focusing on the role of statins in lowering SBP and DBP in patients with hypertension.Articles were selected based on pre-specified inclusion and exclusion criteria.The inclusion criteria were studies written in English only, studies providing sufficient information to calculate the odds ratio, relative risk, or mean difference for participants, studies including adults aged > 18 years, and studies from the year 2000 onwards.We included only RCTs, systematic reviews, and meta-analyses in this study.Studies that were not readily available freely or through institutional logins, that included patients aged < 18 years, and were not written in English were excluded.Case reports, editorials, opinion articles, cohort studies, cross-sectional studies, and case series were excluded.We also excluded studies that focused on the use of statins in pulmonary hypertension and portal hypertension with liver cirrhosis.Statin studies, including RCTs and meta-analyses, that did not provide sufficient data about hypertension and missing data were also excluded from the final analysis.

Data Extraction
Data extraction was performed by two independent reviewers and included relevant demographic information, such as first author and year of publication, study design, study period, sample size, mean age or years, patient female/male, experimental intervention, and outcome, that were collected from eligible studies.The data were cross-checked by a third independent reviewer and any differences were resolved through discussion.

Risk of Bias Assessment
The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) classification system was used to assess the overall certainty of the body of evidence for each outcome across both the systematic reviews and RCTs [18].The risk of bias in the included studies was assessed using the revised Cochrane Collaboration Risk of Bias (RoB 2) tool.The evaluations included (i) random sequence generation, (ii) allocation concealment, (iii) blinding of subjects and researchers, (iv) blinding of outcome measurements, (v) incomplete outcome data, (vi) selective outcome reporting, and (vii) other prejudices [16].

Quality of Evidence Assessment
The quality of evidence for the primary outcome was determined using the Risk of Bias in Systematic Reviews (ROBIS) assessment tool for systematic reviews and the RoB 2 assessment tool in RCTs (Figures 1-4) [17].This framework includes five downgrade factors: limitations, inconsistency, indirectness, imprecision, and publication bias [18].Most studies included in this meta-analysis were at a low risk of selection and reporting bias except a few studies where some concerns about the randomization and selection process were present.The funnel plots for both meta-analyses and RCTs included in this study showed a very low risk of publication bias as shown by funnel plots (Figure 5, 6).

Results
Our literature search yielded 9361 studies in total and 8719 were excluded after screening the titles of these studies as the aims and objectives of these studies were different.Of the 642 studies, 127 examined other variables and did not examine the efficacy of statins for hypertension; hence, they were excluded from the meta-analysis.A total of 515 studies with preexisting hypertension were evaluated for inclusion in our meta-analysis by reading the full studies.The details of the studies included in this meta-analysis are presented in Tables 2, 3. Numerous articles have been published on the role of statins in hypertension and dyslipidaemia .Table 2 provides demographic and outcome data for the 25 RCTs included in the current meta-analysis and Table 3 provides the data for the seven meta-analyses included in the current meta-analysis.The minimum follow-up duration for participants in these trials was two weeks [14] and the maximum follow-up duration was 60 months [40].The number of participants in the RCTs' statin and placebo groups was 9678 and 9652, respectively.The minimum number of participants in a single RCT statin group was 13 [27] and the maximum number was 4126 [40].The minimum number of participants in a single RCT placebo group was 13 [27] and the maximum number was 4159 [40].A significant reduction in mean systolic blood pressure from baseline (30.6 mmHg ± 18.7 vs. 25.24mmHg ± 13.9, P = 0.001) and mean DBP reduction (20.4 mmHg ± 11.3 vs. 17.2 ± 9.0, P = 0.002) were observed in the statin group compared to the non-statin group at the end of 3 months.This difference was even higher at the end of 6 months in the statin group compared to the control group (32.9 mmHg ± 18.7 vs. 27.7 ± 14.0, P = 0.001 and 21.2 mmHg ± 11.0 vs. 18.1 ± 9.1, P = 0.002).The study enrolled 120 hypertensive patients, and the mean systolic blood pressure and diastolic blood pressure were significantly lower in the combination therapy (Amlodipine and atorvastatin) group compared to amlodipine group only after two weeks of therapy(p≤0.05).

Beck et al., 2012 [20] RCT 20 weeks 26 28
There was no difference in the baseline measurements and no change in BMI during the experimental period in either group.The statin group had significantly reduced LDL cholesterol and triglyceride levels at the end of weeks 8 and 20.Both groups experienced a reduction in both systolic and diastolic blood pressure (P < 0.05); however, the blood pressure in the combination therapy group was markedly lower than that in the amlodipine therapy group after treatment (P < 0.05).The left ventricular mass index (LVMI) decreased in both groups (P < 0.05); however, the reduction was greater in the combination therapy group (P < 0.05).Higher doses of atorvastatin were associated with a reduction in systolic and diastolic blood pressure reduction and muscle sympathetic nervous system activity compared to placebo.There was no significant change in blood pressure control between statin and placebo groups and the mean absolute systolic blood pressure and diastolic blood pressure changes in the atorvastatin group were −3.9 mm Hg (95% CI, −8.2-0.In this trial, women taking atorvastatin showed a reduction in systolic and diastolic blood pressure from baseline over 6 months, whereas this effect was not observed in men taking atorvastatin.These sex-dependent blood pressure effects of atorvastatin were not different from those of the placebo.The meta-analysis showed that statin reduced systolic BP by -1.6 mmHg (95% CI: -2.50 to -0.60), and diastolic BP by -0.96 mmHg (95% CI: -1.36 to -0.56).This effect was independent of the dose or type of statin used (p > 0.05).The mean difference for systolic blood pressure was -1.42 (95% CI: -2.38, -0.46; p = .004)and diastolic blood pressure was 0.82 (95% CI: − 1.28, − 0.36; p = .0005).The observed decreases in both SBP and DBP in both groups were not large enough to be considered significant.

Wan et al., 2023 [46]
Metaanalysis NA 1553 1533 The study results showed that the statin group was superior to the placebo group in terms of systolic blood pressure, with a mean difference (MD) of 4.37, 95% CI [0.72, 8.02], p = .02,p = .02,I2 = 99%.However, there was no difference in diastolic blood pressure between the statin and placebo groups (MD = 2.48, 95% CI [−2.00,The combination therapy of amlodipine and statins resulted in a significantly greater percentage reduction in systolic blood pressure in patients (MD= −2.22%, 95% confidence intervals: [−3.82 to −0.62]).Combination therapy also resulted in a significant reduction in low-density lipoprotein cholesterol levels.Most studies demonstrated a positive effect of statins in hypertensive patients, either alone or as a combination therapy, and this effect was evident both during the day and night.Statins were effective in reducing both SBP and DBP in patients, although the exact effects varied between studies.It is important to mention that a lot of variation was observed in the methodology of the included studies.Additional benefits of statin therapy observed in these studies include improved endothelial function and reduction in inflammatory response and LDL cholesterol (LDL-c) levels.Studies using a combination therapy of statins with antihypertensive medications showed better BP control than antihypertensive therapy alone.The number of patients included in the RCTs measuring DBP in the statin and control groups was 8713 and 8874, respectively.
The total number of patients in the meta-analyses' statin and control groups was 145,958 and 66,485, respectively.Individual study demographics and results are presented in Tables 2 and Table 3 decline in SBP in the statin and ACEI groups compared to 20% in patients on ACEI and placebo only [23].
A random-effects model was used for the meta-analysis due to heterogeneity in the studies.The mean difference (MD) for RCTs measuring SBP was -0.33.There was a significant variation in the true effect size across the studies, as shown by a Tau2 value of 1.17, and significant heterogeneity was observed across the studies, with an I2 value of 99% (Figure 8).Similarly, the MD for RCTs measuring diastolic blood pressure was -0.60, there was a significant between-study variance Tau2 value of 6.76 and I2 for heterogeneity was 98%, demonstrating considerable heterogeneity (Figure 9).The MD for the included meta-analyses was -1.79 and the true effect size variation between studies was Tau2 1.87.Considerable heterogeneity was observed across the studies, with an I2 value of 100% (Figure 10).A meta-analysis based on RCTs demonstrated a synergistic effect of statins on both SBP and DBP.A meta-analysis showed that statins were more effective in reducing BP in patients with higher baseline BP [49].The effects of statins on SBP and DBP in this study when restricted to studies with baseline SBP > 130 mmHg and DBP > 80 mmHg were -4.0 mmHg and -1.2 mmHg, respectively.This effect was negligible when only trials with baseline SBP < 130 mmHg and DBP < 80 mmHg were included in the meta-analysis.Metaregression analysis did not show any effects of variables such as age, diabetes, use of antihypertensive therapy, cholesterol level, and duration of the trial [49].
There are several possible mechanisms through which statins may affect BP.Experimental studies have shown that statins increase endothelial production of nitric oxide which is correlated with the upregulation of endothelial nitric oxide synthase expression, resulting in the simultaneous inhibition of G proteins.This leads to reduced endothelial nitric oxide synthase messenger ribonucleic acid (mRNA) degradation and increased nitric oxide bioavailability.Another possible mechanism by which statins affect BP is reduced arterial stiffness and improved systemic arterial compliance.This in turn leads to alterations in the relative content of arterial vascular smooth muscle cells and the restoration of endothelial function restoration [49,50].A further possible explanation for this mechanism could be the downregulation of angiotensin IItype 1 receptor by statins, which is overexpressed in hypercholesterolaemic patients.This alteration is corrected by statins which markedly reduce the vasoconstrictor response to angiotensin II infusion [49,51].
Statins are known to have cardioprotective effects by reducing the incidence of CVD through their cholesterol-lowering mechanism, anti-inflammatory role, and BP-lowering effects [46].
The studies included in the current meta-analysis were mainly RCTs, and the included meta-analyses were also based on RCTs only.Our study also confirmed the findings of previous studies that statins alone or in combination have a BP-lowering effect.The risk of publication bias was also very low in these studies, as shown by the funnel plots.A previous meta-analysis that included 40 studies and 45,113 patients showed a small but significant reduction in SBP and DBP [52].The antihypertensive effect of statins was noted to be independent of age, trial length, or changes in serum cholesterol levels [49].A major drawback of most of these trials is that they failed to investigate the clinical endpoints after long-term statin therapy [19].
Another meta-analysis based on 12 RCTs showed that patients receiving statins had reduced cardiovascular morbidity and mortality, and this association was independent of the patient's BP status [47].A metaanalysis of 65,000 patients on the use of statins in primary prevention found that statins were effective in reducing mortality and morbidity irrespective of age and sex [53].To date, there is no evidence that one class or group of statins is more effective than the other, and the only trials that performed head-to-head trials on statins were the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) and Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trials that did not show any difference between individual statins [54,55].One meta-analysis did not find any difference between individual statins among placebo trials, but differences were noted between individual statins when combined with usual care controls [56].
A meta-analysis by Sundström et al. suggested that statins and antihypertensive therapy provided multiple benefits in terms of cardiovascular outcomes; however, this study did not directly compare the cardiovascular outcomes between combination therapy and antihypertensive therapy alone [57].Our metaanalysis also showed similar cardioprotective and BP-lowering effects of statins alone and in combination therapy.

Conclusions
This meta-analysis supports the findings of previous studies demonstrating the BP-lowering effect of statins, along with other cardiovascular benefits.Statins also improve endothelial function and have antiinflammatory roles in addition to lipid-lowering effects.It is unclear whether statins lower BP in patients with hypercholesterolaemia and normotension, and further research in this direction would be useful.Statins play a clear role in both the primary and secondary prevention of cardiovascular events, depending on the individual risk.A large-scale multicentre RCT focusing on the type and intensity of statins for the prevention of major cardiovascular events is recommended.

FIGURE 1 :FIGURE 2 :FIGURE 3 :
FIGURE 1: RoB 2 tool for the randomized controlled trials included in the systematic review

FIGURE 4 :
FIGURE 4: ROBIS tool for risk of bias assessment in sytematic reviews and meta-analyses included in the study ROBIS: Risk of Bias in Systematic Reviews

FIGURE 5 :
FIGURE 5: Funnel plot for meta-analyses included in the study

FIGURE 6 :
FIGURE 6: Funnel plot for the randomized controlled trials included in the study Only 32 studies consisting of 25 RCTs and seven meta-analyses met the inclusion and exclusion criteria and were included in the final analysis.The literature search and selection of studies are shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram (Figure 7).

FIGURE 9 :
FIGURE 9: Diastolic blood pressure forest plot for the randomized controlled trials included in the meta-analysisReferences:

TABLE 1 : Inclusion and exclusion criteria for eligible studies based on the PICO model
Patients who received amlodipine and atorvastatin showed a greater reduction in both systolic and diastolic blood pressure at 8 weeks during this double control trial compared to the placebo group (P < 0.0001).Hypertensive, obese, and normocholesterolemic patients in this trial showed a significant reduction in inflammatory markers, insulin resistance, and a decrease in systolic and diastolic blood pressure.The combination therapy with amlodipineatorvastatin reduced systolic blood pressure by 22.5 mmHg and diastolic blood pressure by 17.7 mmHg as compared to placebo and amlodipine therapy alone.
Pravastatin was not associated with any significant blood pressure reduction, however, pravastatin resulted in significantly lower heart attacks and cerebrovascular accidents and it also reduced the burden of cardiovascular disease in patients with mild hypertension and hypercholesterolaemia.
Statins significantly reduced diastolic and systolic blood pressures in the treatment group compared to those in the placebo group.Statins showed a reduction in blood pressure during both the daytime and nighttime.Simvastatin combined with losartan improved endothelial function and reduced inflammatory markers to a greater extent than monotherapy with either drug alone in hypercholesterolaemic or hypertensive patients.

TABLE 3 : Demographic findings for the meta-analyses included in this study
[13]spectively.Studies have shown that statins effectively reduce both SBP and DBP in patients when used alone or combined with antihypertensive therapy.Abebe et al. reported a mean difference of 5 mmHg in SBP and 3 mmHg in DBP in the statin group after six months of therapy[13].Similarly, Danaoğlu et al. reported a 23%