Statin's role on blood pressure levels: Meta‐analysis based on randomized controlled trials

Abstract

Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to their significance and their use as a potential anti‐hypertensive. Using a meta‐analysis approach, the aim of this study was to explore whether certain statins have the potential to lower blood pressure (BP). For the period 2002–2022, Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched for the studies that examined the effect of statins on blood pressure in normotensive or hypertensive individuals. Randomized controlled clinical trials that investigated this effect were included based on our inclusion criteria. Our primary outcomes were changes in systolic and diastolic blood pressure (DBP). The final analysis of the study included 49 RCTs involving 45 173 participants randomized to receive either statins or placebo. Among the two groups, the total weighted mean difference (WMD) for systolic blood pressure (ΔSBP) was –1.42 (95% CI: –2.38, –0.46; p = .004) and diastolic blood pressure (ΔDBP) was 0.82 (95% CI: –1.28, –0.36; p = .0005). Despite various studies suggesting the efficacy of statins in blood pressure lowering to be significant and non‐significant both, we observed a decrease in SBP and DBP both, although the change was not as large and could be considered significant. A large multicenter, multi‐ethnic, large sample pool size, and a long period follow‐up study is still required to assert these claims.

1. INTRODUCTION

Statins reduce plasma cholesterol as well as blood pressure (BP), another potential mechanism in which other antihypertensive medications can reduce cardiovascular risk. ¹ Additionally, statins have been shown to lower BP in experimental and clinical studies. ² Several studies have shown that statins are beneficial in lowering BP in patients with hypertension because they inhibit 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase. ³ , ⁴ , ⁵ While statins are primarily known for their cholesterol‐lowering properties, their antihypertensive properties have increasingly gained attention. ⁶ Statins show pleiotropic effects, yet are still controversial. ⁷ The effects include enhancement of endothelial function, influence the inflammatory response, stabilize plaques, and reduce the risk of blood clots. ⁷ There are several pharmacological effects of endothelial NOS (eNOS and NOS III) on blood vessels, including dilation, control of BP, and anti‐atherosclerosis. ⁸ Statins have also been studied in relation to hypertension and BP, but the evidence is ambiguous about whether statin use affects BP dramatically. ¹ , ⁹ , ¹⁰ Statistically, statins are effective in reducing inflammation, preventing blood clots, and lowering BP. ¹¹ In addition to their effects on stiffness, statins and antidiabetic medications are also expected to reduce BP. ¹² In most published reports, statins are not shown to significantly lower BP in patients with normotensive hypercholesterolemia, or in patients with hypertension under control. ¹³ , ¹⁴ Statins also appear to be useful in lowering BP in hypertensive patients with high cholesterol, uncontrolled hypertension without high cholesterol, and hypertensive patients without high serum cholesterol. They can be added as a secondary prevention tool to counter elevated BP even in the presence of other cardiovascular risk factors. ¹⁵ Furthermore statins can also effect the functioning of autonomic circulatory system which in turn can also has implications on BP control. ¹⁶ A number of pathological determinants of essential hypertension include endothelial dysfunction, decreased arterial compliance, and activation of inflammatory and fibrotic pathways. It is possible that statins may also lower BP as a result of their ability to reverse these abnormalities, thus making them potentially useful in simultaneously treating dyslipidemias as well as hypertension. ¹⁷ Patients with hypertension may benefit from statins by preventing hypertension or controlling their BP more effectively. ¹⁸ Therefore, we conducted this study to explore whether certain statins have the potential to lower blood pressure (BP).

2. MATERIALS AND METHODS

2.1. Search strategy

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐analyses) guidelines for meta‐analyses of interventional studies were followed in this systematic review and meta‐analysis. ¹⁹ A systematic search was conducted in the electronic databases MEDLINE, PubMed, EMBASE, and the Cochrane Library for the Central Register of Clinical Trials using the MESH terms statins, hypertension, BP, and the names of individual statin agents (Table S1). Our search focused on peer‐reviewed journals in English language from 2002 to 2022. Additional clinical studies were retrieved by manual review of all relevant references in screened articles and reviews on statins.

2.2. Inclusion criteria and exclusion criteria

The study included only prospective randomized, controlled trials published as original articles in peer‐reviewed scientific journals in English. Criteria for inclusion in this meta‐analysis included (1) randomized intervention of statin; (2) presence of placebo population; (3) Statins as a mode of intervention; (4) blind studies (single or double‐blind); (5) minimum follow up of at least 2 months; (6) data about change in blood pressure levels available; (7) Studies where if concomitant therapy was present had a fixed regimen and was not modifiable throughout the trial. Only studies that met these criteria were included and it has to be noted that presence or absence of hypercholesterolemia was not objected as inclusion criteria since our study primarily focuses on changes in blood pressure levels due to statin administration. The criteria for exclusion exercised in this meta‐analysis are: (1) absence of report baseline and follow‐up BP levels; (2) absence of data about net changes in BP levels before and after treatment; (3) studies with missing variables such as sample size of the groups, duration of follow‐up, type of statin, dose of statin, type of study population, sex, age, and concomitant medications; (4) concomitant interventions such as antihypertensive treatment medication or dose titration could be modified during the trial period; (5) if concomitant therapy was given but was not explicitly specified; (6) study population in trials with critically ill patients or organ transplant recipients, as well as short‐term studies (less than 10 days).

2.3. Data extraction and quality

Two authors independently extracted the data using a standardized protocol and reporting form (Figure 1). We considered all clinical trials that investigated the effect of statins on BP. We also considered studies and abstracts presented at meetings. In some of these studies, BP did not serve as the primary outcome, and in others it was measured as a secondary outcome. The key outcomes of interest were changes in SBP and DBP. To eliminate duplicates, reviews, case studies, trials without institutional review board approval, trials without the desired outcomes, and trials published in languages other than English, two reviewers independently examined the title and abstract of each article. Each of these reviewers independently extracted data regarding the characteristics of the patients, the therapeutic regimens, the dosages, the durations of the trials, and the outcomes of the trials. Consensus was reached to resolve disagreements. The GRADE (Grading of Recommendation, Assessment, Development and Evaluation) ²⁰ was used to evaluate the certainty of evidence of this study. GradePro GDT ²¹ web application was used to carry out the GRADE evaluation. The study's assessment criteria included study design, risk of bias, inconsistency, indirectness, imprecision and other considerations (Publication bias, large scale, plausible confounding and dose response gradient).

FIGURE 1.

Flow diagram of the study selection process.

2.4. Outcomes assessed

In the meta‐analysis, the primary outcomes were changes in SBP and DBP (mmHg) values between baseline and final visit for statins and for the control group.

2.5. Statistical method

We conducted an intention‐to‐treat meta‐analysis according to the Cochrane Collaboration's recommendations and PRISMA. The random‐effects model was chosen a priori to estimate outcome differences, as different baseline characteristics, statin type and dose, and follow‐up duration are expected to differ between studies. Heterogeneity was assessed with the I² statistic, with I² < 25% considered low and I² > 75% considered high. Small study effect, including publication bias, was tested using funnel plot and Egger tests. In cases where publication bias was found, the nonparametric trim and fill method of Duvall and Tweedie was employed to add any studies that appeared to be missing. A separate analysis was conducted for each group of statins. Specifically, we examined whether the results of studies involving an up‐titration of antihypertensive agents during the study differed from those involving stable doses of antihypertensive drugs. All analyses were performed by Review Manager (RevMan) 5.4.

3. RESULTS

Overall, we screened 3766 abstracts, of which 49 were eligible for full‐text review (Figure 1). The GRADE evaluation revealed the certainty of the evidence and the quality of the study, shown in Figure 2. Table 1 lists the statin type, dosage, and duration of treatment for each study. In addition, basic characteristics data has also been illustrated in Table S2. In these studies, 22 856 controls and 22 867 patients taking statins were included, with treatment durations ranging from 2 to 72 months. In total, eight studies with long‐term follow‐up (more than 30 months) were included, whereas all other included studies had a follow‐up of 12 months or less. It was found that atorvastatin was the most commonly used intervention among the 19 comparison groups, ¹³ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ followed by rosuvastatin (10 groups), ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ simvastatin (9 groups), ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ pravastatin (7 groups), ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ and fluvastatin (4 groups). ⁵⁹ , ⁶⁵ , ⁶⁶ , ⁶⁷

FIGURE 2.

GRADE Evaluation of RCTs included in the study.

TABLE 1.

Reported BP differential characteristics.

Statin Group						Control Group
Author	Year	Type of statin	Duration of Follow‐up	Baseline SBP/DBP, mmHg	Follow‐up SBP/DBP, mmHg	Baseline SBP/DBP, mmHg	Follow‐Up SBP/DBP, mmHg
Beck	2012	Simvastatin, 80 mg	3	130 (3)/73 (2)	127 (3)/76 (2)	125 (2)/73 (2)	124 (2)/71 (1)
Choi	2021	Rosuvastatin, 20 mg	4	135.80 (14.22)/82.37 (9.50)	130.69 (13.23)/79.87 (10.76)	134.37 (12.50)/82.85 (8.75)	133.75 (12.30)/83.04 (11.82)
Cohn	2009	Atorvastatin, 10 mg	2	146.7 (11.1)/91.8 (7.2)	–7 (2)/–4.2 (1) a	147 (11)/93 (5.3)	–5 (2)/–3.4 (0.8) a
Collins	2004	Simvastatin, 40 mg	56	–7.6 (27.5)/–4.5 (15.1) a	NA	–7.1 (28.9)/–4.6 (14.1) a	NA
Correa	2014	Simvastatin, 40 mg	2	135.6 (16.7)/82.6 (11.3)	127.2 (14.4)/77 (9.7)	138.8 (13.8)/86.5 (10.3)	123.5 (12.3)/77.1 (9)
Danaoglu	2003	Simvastatin, 20 mg	3	160 (11)/99 (9)	122 (9)/76 (6)	158 (14)/104 (10)	126 (19)/82 (8)
Derosa	2003	Fluvastatin, 80 mg	12	133 (4)/86 (5)	127 (5)/82 (3)	132 (5)/84 (3)	128 (3)/82 (2)
Fassett	2010	Atorvastatin, 10 mg	12	147.6 (20.2)/75.8 (9.1)	–4.18 (8.35)/–1.24 (5.22) a	148.3 (22.1)/79.3 (6.7)	–4.63 (8.98)/–1.98 (3.51) a
Fogari	2006	Atorvastatin, 20 mg	3	160 (11)/98 (5)	137 (8)/80 (4)	160 (11)/68 (5)	143 (8)/84 (4)
Fu	2022	Rosuvastatin, 20 mg	3	161.87 (12.82)/104.21 (10.28)	114.29 (9.64)/77.59 (9.87)	162.47 (12.34)/103.32 (10.35)	131.86 (10.85)/86.64 (10.47)
Ge	2008	Atorvastatin, 20 mg	4	164.3 (14.8)/106.4 (9.2)	123.2 (12.4)/82.5 (7.8)	162.8 (13.4)/105.2 (8.6)	136.7 (11.2)/91 (7.32)
Grimm	2010	Atorvastatin, 20 mg	1.5	132.3 (11.3)/81 (9.5)	–4 (1)/–1.7 (0.8) a	132.9 (12.3)/81.9 (8.2)	–1 (1.17)/–1.1 (0.7) a
Hjelstuen	2007	Fluvastatin, 40 mg	12	141.8 (12.3)/90.5 (7.4)	–1.7 (14.25)/0.1 (9.1) a	140.4 (15.3)/88.6 (9)	–1.5 (7.68)/‐1.1 (7.68) a
Hosomi	2005	Pravastatin, 10 mg	60	137.3 (17.6)/79.3 (11.6)	134.1 (0.38)/76.8 (0.25)	136.9 (18)/79.4 (10.9)	134.4 (0.38)/77.4 (0.25)
Ichihara	2005	Pravastatin, 10 mg	12	142 (7)/84 (3)	140 (5)/86 (2)	142 (6)/89 (4)	138 (10)/90 (3)
Ichihara	2005	Fluvastatin, 20 mg	12	142 (6)/84 (3)	141 (4)/85 (2) a	142 (6)/89 (4)	138 (10)/90 (3)
Jin	2020	Rosuvastatin, 20 mg	2	155.40 (12.12)/87.60 (8.61)	135.16 (13.72)/73.3 (22.18)	155 (12.09)/89.49 (9.99)	141.87 (14.74)/154.77 (36.94)
Joyeux‐Faure	2014	Atorvastatin, 40 mg	3	127.78 (15.07)/79.16 (11.6)	121.23 (9.68)/76.8 (8.55)	127.67 (15.27)/79.02 (11.61)	127.46 (12.77)/80.64 (12.33)
Kanaki	2013	Atorvastatin, 10 mg	6.5	146.7 (7.2)/92.2 (10.3)	141.6 (7.3)/89.6 (9.2)	147.5 (6.7)/91.2 (8.5)	147.8 (6.8)/90.6 (8.6)
Kanbay	2005	Atorvastatin, 20 mg	2	133 (16)/76 (10)	120 (11)/70 (6)	134 (15)/75 (9)	117 (8)/70 (4)
Kim	2016	Atorvastatin, 40 mg	2	148.7 (9.6)/94.7 (6)	NA	145.7 (7.6)/91.4 (5.2)	NA
Kim	2019	Rosuvastatin, 20 mg	2	155.46 (10.56)/92.45 (7.25)	−22.82 (12.99)/−15.89 (11.50) a	151.58 (10.46)/88.82 (9.73)	−5.80 (17.37)/–3.9 (2.1) a
Koh	2011	Atorvastatin, 20 mg	2	157 (1)/96 (1)	138 (2)/85 (1)	156 (2)/95 (1)	139 (1)/85 (1)
Koh	2004	Simvastatin, 20 mg	2	145 (2)/90 (1)	142 (2)/87 (2)	145 (2)/89 (1)	128 (2)/79 (2)
Kuklińska	2010	Atorvastatin, 80 mg	3	129 (11)/76 (9)	123.3 (8.9)/72.1 (8.6)	129.5 (13)/74 (7.6)	128.5 (9.7)/74 (7.6)
Kushiro	2009	Pravastatin.40 mg	60	140.9 (16)/82.9 (10)	138.6 (16)/80.3 (10)	141 (15)/83 (10)	139.1 (15)/81.3 (10)
Lavallee	2009	Atorvastatin, 80 mg	3	132.7 (14.6)/78 (8.3)	–3.9 (2.1)/–2.8 (1.4) a	133.7 (12.8)/78.1 (7.7)	–0.8 (2.24)/–1.4 (1.5) a
Lee	2002	Pravastatin, 20 mg	6	121 (10)/70 (4)	120 (11)/70 (6)	117 (10)/69 (5)	117 (8)/70 (4)
Lee	2009	Pravastatin, 40 mg	6	133 (16)/76 (10)	130 (18)/79 (8)	134 (15)/75 (9)	132 (14)/79 (8)
Lee	2017	Rosuvastatin, 20 mg	2	142.74 (13.64)/94.24 (6.95)	NA	143.54 (14.39)/95.18 (7.14)	NA
Lewandowski	2010	Simvastatin, 40 mg	2	142 (11.8)/91 (10.8)	136 (9.5)/84 (9.8)	136 (9.5)/86 (11)	131 (12.4)/82 (7.5)
Magen	2004	Atorvastatin, 10 mg	2	153 (4.8)/87.1 (6.7)	136.9 (6.1)/78.3 (4.2)	151.2 (7.4)/84.7 (5.9)	150.9 (6.8)/83.2 (5.7)
Mancia	2010	Pravastatin, 40 mg	31	159.6 (8.9)/98.3 (4.1)	–19.2 (1.94)/–12.4 (1.55) a	160 (9.1)/98.3 (4.4)	–18.1 (1.94)/–12.8 (1.55) a
Manisty	2009	Atorvastatin, 10 mg	39	158 (20)/93 (10)	141 (11)/81 (8)	164 (20)/94 (10)	142 (12)/81 (7)
Mok	2009	Simvastatin, 20 mg	24	147.7 (25)/80 (18)	148.1 (24.4)/78.5 (11)	146.6 (21)/80 (14)	149.6 (21.7)/78.8 (10.7)
Mondillo	2003	Simvastatin, 40 mg	6	148 (7)/81 (6)	149 (7)/78 (6)	146 (6)/83 (5)	144 (7)/81 (5)
Oh	2018	Rosuvastatin, 20 mg	2	151.8 (11.4)/91.2 (10.1)	NA	150.1 (12)/89 (7.9)	NA
Olkinuora	2006	Simvastatin, 10 mg	3	156 (12)/93 (9)	142 (10)/86 (8)	161 (12)/95 (9)	147 (15)/80 (9)
Orr	2009	Atorvastatin, 80 mg	3	129 (4)/74 (2)	124 (4)/73 (3)	127 (4)/75 (2)	124 (4)/75 (2)
Ott	2012	Rosuvastatin, 10 mg	2	129 (18)/79 (10)	NA	130 (20)/78 (12)	NA
Park	2016	Rosuvastatin, 20 mg	2	148.9 (13.3)/92.9 (6.5)	153.4 (19.1)/93 (9.2)	152.2 (14.5)/92.5 (7)	154.2 (21)/92.9 (8.7)
Puurunen	2013	Atorvastatin, 20 mg	6	128.7 (13.3)/81.3 (7.7)	124.6 (9.7)/80.1 (10.7)	123.5 (13.2)/76.1 (7.2)	117.7 (11.5)/73.9 (7.7)
Raison	2002	Atorvastatin, 10 mg	3	147.8 (17.8)/87.7 (8.5)	NA	135.1 (16)/82.7 (9.4)	NA
Rhee	2020	Rosuvastatin, 20 mg	2	153.19 (10.28)/93.23 (8.58)	140.86 (16.07)/85.04 (9.33)	153.94 (9.66)/93.40 (7.63)	139.62 (16.26)/84.72 (9.94)
Sever	2009	Atorvastatin, 10 mg	36	164.3 (17.8)/95.1 (10.2)	137.5 (17)/80.5 (9.5)	165.7 (18.3)/95.1 (10.4)	137.5 (16.8)/80.8 (9)
Teixeira	2011	Fluvastatin, 20 mg	12	139 (14)/87 (11)	126 (12)/80 (7)	138 (12)/86 (9)	131 (11)/82 (8)
Teramoto	2014	Atorvastatin, 10 mg	3	120 (9.8)/75 (7.6)	122 (12)/77 (8.2)	119 (12)/75 (7.3)	118 (10)/75 (6.4)
Tonelli	2006	Pravastatin, 40 mg	3	128.7 (18.4)/78.5 (10.2)	NA	129 (17.8)/78.6 (10.1)	NA
Williams	2009	Atorvastatin, 10 mg	40	159.6 (16.7)/92.5 (9.7)	133.9 (0.6)/79.1 (0.4)	160.3 (17.5)/92.9 (9.2)	133.8 (0.6)/79 (0.4)
Yusuf	2016	Rosuvastatin, 10 mg	72	137.9 (15)/81.8 (9.3)	NA	137.9 (14.6)/81.8 (9.2)	NA

Abbreviations: DBP: diastolic blood pressure; SBP, systolic blood pressure.

^a In the follow‐up column (Statins and Control), some values are reported in negative since they were represented on this table as they were illustrated in the original publication. The negative values indicate blood pressure level decrease due to administration of statins or placebo in statin and control group respectively.

3.1. Effect of statin therapy on SBP

The summary for effect size (weighted mean difference) on SBP from 49 trials for statin therapy was –1.42 mmHg (95% CI: –2.38 to –0.46; p < .05). It shows that throughout the analysis on an average, the statins intervention was able to reduce SBP by –1.42 mmHg and this reduction was significant. The Cochrane Q test p value for heterogeneity was <.05 suggesting significant heterogeneity across studies (Figure 3). The funnel plot showed no evidence of publication bias asymmetry among studies (Egger's test p < .05, Figure 4).

FIGURE 3.

Meta‐analysis of the impact of statins on SBP, studies were sub‐grouped based on concomitant BP‐lowering medications.

FIGURE 4.

Funnel Plots for publication bias assessment for SBP.

3.2. Effect of statin therapy on DBP

The random‐effects model showed a significant reduction in diastolic BP by statins of –0.82 mmHg (95% CI: –1.28 to –0.36; p < .05). In addition, it has to be noted that statins use aided in reduction of DBP by 0.82 mmHg and this reduction was significant as well. The Cochrane Q test p value for heterogeneity was (p < .05, Figure 5) suggesting significant heterogeneity across studies. The funnel plot showed no evidence of publication bias asymmetry among studies (Egger's test p < .05, Figure 6).

FIGURE 5.

Meta‐analysis of the impact of statins on DBP, studies were sub‐grouped based on concomitant BP‐lowering medications.

FIGURE 6.

Funnel Plots for publication bias assessment for DBP.

3.3. Subgroup analysis

As shown in Figures 3 and 5, different types of statins have different effects on SBP and DBP. The effects of atorvastatin and simvastatin on BP were greater (atorvastatin: SBP –2.82; 95% CI, –4.87 to –0.77; DBP –1.26; 95% CI, –2.27 to –0.25), simvastatin: SBP –1.80; 95% CI, –5.38 to 1.78; DBP –0.06; 95% CI, –0.42 to 0.31) compared with pravastatin (SBP –0.21; 95% CI, –1.58 to 1.15; DBP 0.21; 95% CI, –0.19 to 0.60). Moreover, 17 studies were included in the sensitivity analysis of larger studies (study arms with more than 50 patients). It was observed that statins had an attenuated effect on SBP and DBP, with SBP decreasing by 0.34 (95% CI, –0.81 to 1.49; p < .05) and DBP decreasing by –0.09 (95% CI, –0.50 to 0.32; p < .05). Despite the significant overall heterogeneity and heterogeneity in the atorvastatin and pravastatin groups, exclusion of these trials was not sufficient to eliminate some of the heterogeneity present in the trials. The grouping of trials by statin type is one explanation for some of the heterogeneity observed between trials in the conducted analyses. There are several factors that can contribute to the total heterogeneity we identified, including design, participants, interventions, and outcomes.

The study by Fu and colleagues ⁴¹ showed a significant effect on BP, whereas the remaining studies showed small effects. In a sensitivity analysis excluding the study by Fu and colleagues ⁴¹ it was found that SBP decreased by 2.30 (95% CI, –2.36 to 6.96; p > .05) and DBP decreased by 1.80 (95% CI, –3.04 to 0.55; p > .05).

4. DISCUSSION

This meta‐analysis included approximately 45 723 participants from 49 placebo‐controlled random trials. It was observed that SBP and DBP significantly decreased. There was no difference in the effect regardless of whether antihypertensive therapy was concurrently administered. Several RCTs investigated the relationship between hypertension and lipid lowering drugs or statins, however in most of those studies no significant change was observed in BP regardless of whether concurrent antihypertensive medications were administered or not. In a 2011 study by Kanaki and colleagues, atorvastatin was observed to reduce DBP within 24 h period of administration in patients with mild hypertension and was suggested to be cardioprotective. ⁶⁸ This was also confirmed by our findings, where we observed a –1.26‐mmHg reduction in DBP; p < .05 (Figure 5). In addition, similar findings were observed by Costa and colleagues, they demonstrated that atorvastatin was significant in BP reduction independent of LDL profiles. ⁶⁹ This BP lowering effect of atorvastatin was observed in our study, and atorvastatin was able to significantly reduce the levels of SBP and DBP (p < .05) (Figures 3 and 5). Along with other known statins, our analysis also studies rosuvastatin, which has been shown to significantly improve BP in patients with hypertension. To the best of our knowledge, this metanalysis also studies rosuvastatin's effect on BP variability based on newer randomized control trials which were not included in previously studied metanalyses. ⁴⁰ , ⁴² , ⁴⁷ , ⁷⁰ Heterogeneity in our studies was found to be significant in terms of efficacy of statins on variability of SBP (I² = 93%; p < .00001) and DBP (I² = 81%; p < .00001). The possible reasons for this heterogeneity can be explained by the methodological differences of the different studies; the existence of a large number of studies; a large population size, where it was also observed that the population belonged to different ethnic backgrounds; and comorbidities such as diabetes, COPD, and so forth, were found in limited studies as well as in concomitant therapies involving other medications. As these heterogenous events were not present evenly in all the studies and occurred in a limited number of studies, and their analysis was considered to be out of intention of this study. Despite the heterogeneity, it is understood that it does not affect the possible outcome of blood pressure levels, based on the fact that a number of studies indicated in their conclusion that these heterogenous events were not significantly affecting the changes in blood pressure levels, and that the affect was a result of statin administration. In addition, from the analysis of various studies, there was not a significant difference when only statin was administered while a combination of statin and an anti‐hypertensive drug aided in the reduction of BP safely in most cases while some studies also showed no significant changes as well. Since this study comprises RCTs investigating the effects of statins on BP, some studies have concluded that the combination of antihypertensive drugs with statins (such as rosuvastatin) is believed to contribute to the BP lowering effect of antihypertensive drugs. ⁴⁰ , ⁴² , ⁴⁷ , ⁷⁰ Furthermore, some of the study's subjects in the statin group also received some form of antihypertensive drugs since they were hypertensive patients. It was found that patients treated with statins between 6 weeks and 18 months had significantly lower BP levels than those who received placebos in the ASCOT‐LLA study. As a result, the differences between placebo and control groups were minimized due to the fact that patients on placebo received slightly more antihypertensive study drugs (significantly and increasingly) as well as antihypertensive non‐study drugs. ⁷¹ Large RCT studies like Sever and colleagues ⁷² for (Atorvastatin), Yusuf and colleagues ⁴⁸ (Rosuvastatin), Collins and colleagues ⁵⁰ (Simvastatin), and Kushiro and colleagues ⁶⁰ ; Tonelli and colleagues ⁶⁴ (Pravastatin) showed significant SBP lowering effect of statins (Figure 3) while newer studies such as Fu and colleagues, ⁴¹ Jin and colleagues, ⁷⁰ Kim and colleagues showed significant SBP lowering effect of Rosuvastatin. A metanalysis study by Lee and colleagues ⁷³ from 2021 which included 507 patients stated that Rosuvastatin could be beneficial to control hypertension and, consequently, contribute toward reducing the risk of cardiovascular events in patients with hypertension and dyslipidemia. In the same study an average decrease of 2.12 mmHg in DBP and an average decrease of 2.27 mmHg in SBP was observed with rosuvastatin use. A 2021 study by BP Lowering Treatment Trialists' Collaboration ⁷⁴ indicated improvement in survival and lower mortality from CVD related diseases if BP is reduced by only 5 mmHg over a period of 4 years. This implies the importance that statins may have on BP lowering as well as relative mortality. It has been asserted in a study that there is evidence that statins lower BP by cholesterol‐independent mechanisms, with a greater reduction in BP in those with higher BP and low HDL‐C, and that statins may be beneficial in preventing hypertension and may contribute to better BP control among hypertensive patients. ¹⁸ For six months, 973 patients were randomly assigned simvastatin (20 mg), pravastatin (40 mg), or placebo in the University of California San Diego (UCSD) Statin Study. With both statins, BP was modestly but significantly reduced (2.4–2.8 mmHg for both SBP and DBP). ⁷⁵ This is in line with our analysis where a similar level of BP reduction was observed in one or both SBP and DBP levels (Figures 3 and 5). Strazullo and colleagues ⁷⁶ in his 2007 study cited various mechanisms that maybe responsible for the BP lowering effect of statins which include statins inhibition of reactive oxygen reactive species thus contributing to vasodilation leading to reduction in BP or the statins effect on reduction of arterial stiffness by correcting the endothelial function and the downregulation of angiotensin II type‐1 receptor. A newer study by Drapala and colleagues ⁷⁷ mentioned that statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial BP. According to a 2013 meta‐analysis of 40 studies and 51 comparison groups (22 511 controls and 22 602 patients), mean SBP decreased by 2.62 mmHg and DBP decreased by 0.94 mmHg in the statin group (95 % CI –1.31 to –0.57; p < .001) while hypertensive patients experienced a higher reduction in BP with statin treatment (SBP ‐3.07 mmHg, 95 % CI –4 to 2.15, and DBP 1.04 mmHg, 95% CI –1.47 to –0.61). ⁷⁸ A similar level of the overall reduction in SBP and DBP was observed in our analysis. Figures 3 and 5 in our study point to the fact that statins are instrumental in lowering SBP and DBP respectively in patients with high BP and show a less significant effect on the normotensive group. In addition, the results favor statins use but the results do not overwhelmingly demonstrate that a positive outcome may be expected due to limited change in SBP and DBP. More in‐depth research with a large sample size and longer follow up are still required. Also, heterogeneity is a factor that should not be forsaken and a common unified methodology along the lines of multicenter and multi‐ethnic sample pool must be subjected to more trials.

4.1. Strengths and limitations

The strengths of this study include a large number of RCTs and a large observational population. In addition, this study included all age groups, sex, and all possible ethnicities. Moreover, all RCTs included statins as a mode of therapy, the included studies were randomized, and most were double‐blind, and these studies did not include alcoholics or drug users. In terms of limitations of this study, not all studies were double‐blinded studies and some studies had normotensive patients included in the statin‐administered group; heterogeneity was also observed in our study; comorbidities such as diabetes, COPD, and so forth, were present in a limited number of RCTs; patients who were undergoing statin administration also simultaneously had been administered other BP‐lowering drugs as well. In addition, the lipid profile was not analyzed as it was not in line with the purpose of this study.

5. CONCLUSIONS

This study demonstrated that statins have a favorable effect on reducing both SBP and DBP. In addition, the BP‐lowering effects of statins were found to be independent of their ability to reduce LDL‐C. Overall, the small antihypertensive effect may contribute to the reduction in cardiovascular risk conferred by statin therapy. This may be clinically significant in patients with intermediate to high cardiovascular risk. Although, experimental evidence suggests that statins reduce BP in a variety of ways; nevertheless, the evidence from clinical studies is inconclusive. As a matter of fact, in many of these studies, the sample size was too small, the study design was limited, BP measurement techniques were different, the patient populations were different, and the antihypertensive drugs used in many trials may have confounding effects too.

AUTHOR CONTRIBUTIONS

Zhisheng Jiang did the conceptualization and designed this review. Nianhua Deng, Zefan Wu, Zhanyang Zhou did the literature search and study selection. Huiting Liu wrote the manuscript, Zhen Tian, Xiyan Liu, Yanxia Wang, Hongyu Zheng, Yangshao Ou revised the manuscript, which was then read and approved by all authors.

CONFLICT OF INTEREST STATEMENT

The author declares that there is no conflict of interest.

Supporting information

Supporting Information

Supporting Information

Liu HT, Deng NH, Wu ZF, et al. Statin's role on blood pressure levels: Meta‐analysis based on randomized controlled trials. J Clin Hypertens. 2023;25:238–250. 10.1111/jch.14645