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Abstract

Objective

To conduct a systematic review and meta-analysis to compare the effects of statins and placebo on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with hypertension.

Methods

We used different databases such as MEDLINE and the Cochrane Library Central Register of Controlled Trials (CENTRAL) to search for randomized controlled trials published from 1 January 2000 to 1 January 2022 to retrieve relevant studies and full-text articles evaluating statins versus placebo in patients with hypertension. Data were taken from eligible studies. The included articles also performed Cochran’s Q statistics, forest plots, funnel plots, Egger’s test, and sensitivity analyses.

Results

This study included 8 studies with a total of 3086 patients. We sought to assess patients' SBP and DBP. The results were expressed as mean differences (MD) with 95% confidence intervals. There was no difference in DBP between the statin and placebo groups (MD = 2.48, 95% CI [−2.00, 6.96], p = .28, random effects model). In terms of SBP, the statin group was superior to the placebo group (MD = 4.37, 95% CI [0.72, 8.02], p = .02, random-effects model). Sensitivity analyses and funnel plots showed that our study was robust, with low publication bias.

Conclusion

The results show that statins could be clinically more effective than placebo in patients with hypertension.

Keywords

Statins hypertension blood pressure clinical outcomes meta-analysis

Introduction

Essential hypertension is a common and frequent disease in cardiovascular medicine.¹ It is easily overlooked by patients because of its insidious onset and mild symptoms. However, hypertension causes dangerous complications in vital organs such as the heart, brain and kidneys,² and as such it has attracted increasing attention in the medical field.

Statins (HMG-CoA reductase inhibitors) are the most widely used and effective lipid-lowering drugs in clinical practice. With intensive clinical and basic research on statins, it has been found in recent years that statins have anti-hypertensive effects in addition to lipid-lowering effects.^3,4 Studies have found that statins also significantly lower blood pressure in hypertensive patients without dyslipidemia compared with the placebo group and other lipid-lowering drugs.

Some studies have shown that statins lower blood pressure, while others do not.^5,6 A recent meta-analysis of a number of trials relating to the effect of statins on blood pressure showed that patients using statins had significantly lower systolic (but not diastolic) blood pressure.⁴ A large randomised sample study of individuals in the community confirmed that statins significantly lowered both systolic and diastolic blood pressure. Statins lowered diastolic blood pressure by similar amounts in patients taking and not taking anti-hypertensive drugs. In addition, the antihypertensive effect of statins increased with increasing diastolic blood pressure in non-antihypertensive drug users.⁷

In this study, several newly published randomised controlled trials compared the clinical effects of statins and placebo in patients with hypertension. Relevant articles are included in this meta-analysis in order to fully understand the role of statins and placebo in patients with hypertension.

Methods

This research is based on PICO process: In patients with hypertension (Population), does the administration of statins (Intervention) compared to placebo result in SBP and DBP (Outcomes).

Literature search strategy

We searched MEDLINE and the Cochrane Library Central Register of Controlled Trials (CENTRAL) for randomised controlled trials published between 1 January 2000 and 1 January 2022, using the search terms. Our search strategy varied by database, but covered the search term ‘statins and hypertension’. We conducted a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings, with no restrictions on language of publication or publication status. To achieve maximum sensitivity of the search strategy and to identify all studies, we manually screened the reference lists of all retrieved articles to further identify potentially relevant studies.

Study selection

To be included in the analysis, the original research articles had to meet the following criteria. (1) articles published in peer-reviewed journals and (2) journal articles with outcome measures related to hypertension. Exclusion criteria were.

(1) A research paper not written in English.

(2) No full-text studies were provided.

(3) Not an original research report.

(4) A summary or presentation of the conference.

(5) Not a hypertensive patient.

(6) The study did not measure blood pressure.

In addition, if there are multiple publications from the same queue, we extract the data from the largest or most recent dataset.

Data extraction and quality assessment

The following data were extracted: study characteristics, number of patients, clinical outcome results including SBP and DBP. Where available, the following details were extracted: first author, study title, country, year of publication, study design, study characteristics, sample size, mean age of patients and male/female ratio.

For the quality assessment, we considered the following domains: random sequence generation, allocation concealment, blinding (self-reporting), blinding (objective results), incomplete and selective reporting of results, and the presence of other biases. We assessed each domain separately and critically, and our score system is based on GRADE (Grading of Recommendations, Assessment, Development and Evaluations), which is a transparent framework for developing and presenting summaries of evidence and provides a systematic approach for making clinical practice recommendations. We classified them as low risk of bias, unclear risk or high risk of bias according to the criteria set out in the Cochrane Handbook.⁸

Statistical analysis

Initially, we analysed all studies separately, replicating the originally reported findings using the methods described in the respective publications. Any inconsistencies were resolved with the authors of the original studies. To optimise the interpretability of our findings for continuous outcomes, we used network estimates of treatment effects to model the odds ratio (OR) of achieving a mean difference (MD), i.e. the smallest change in patient-reported outcomes that patients considered important. The broad Cochran’s Q statistic was used to assess homogeneity in multivariate meta-analyses. In detail, an I²value of 0% indicates no heterogeneity, 25% indicates low heterogeneity, 25–50% indicates moderate heterogeneity and 50% indicates high heterogeneity. In addition, a random effects model was used when heterogeneity was observed and a fixed effects model was used when no heterogeneity was modelled. Potential publication bias was assessed by visual inspection of funnel plots and Egger’s test for small study effects. Further sensitivity analyses were conducted to assess the robustness of the results via exponential skewing.

Results

Search process

A total of 780 titles and abstracts were identified through the screening electronic search strategy, of which 8 were eligible for assessment. Eight studies describing 16 study groups met the inclusion criteria and were included in the meta-analysis.

After title and abstract review, 372 studies were excluded due to duplication and 400 studies were excluded because they did not meet inclusion criteria based on article type, study design, study population or relevant outcomes. After exclusion, eight articles were included in our meta-analysis. In total, we retrieved 8 studies that met all inclusion criteria (Figure 1).^9–16

Figure 1.

Flowchart of study selection.

Characteristics of included studies

The sample sizes for the various studies ranged from 41 to 1946 people. A total of 3086 patients were included, of whom 1553 were treated with statins and 1533 were in the placebo group. The primary outcomes included SBP and DBP. Table 1 represents the detailed characteristics of the eight included studies.^9–16

Table 1.

Baseline characteristics of included studies.

Study	Year	Type of study	Country	Ethnicity	Intervention	Mean age (years)	n
9	2012	RCT	Turkey	Caucasian	Placebo	62.80 ± 6.80	24
9	2012	RCT	Turkey	Caucasian	Statin	61.80 ± 7.67	38
10	2008	RCT	USA	Caucasian	Placebo	57.7	973
10	2008	RCT	USA	Caucasian	Statin	56.8	973
11	2010	RCT	Italia	Caucasian	Placebo	58.3 (6.5)	254
11	2010	RCT	Italia	Caucasian	Statin	58.3 (6.5)	253
12	2011	RCT	China	Mongoloid	Placebo	—	20
12	2011	RCT	China	Mongoloid	Statin	—	21
13	2012	RCT	China	Mongoloid	Placebo	58 ± 6.5	37
13	2012	RCT	China	Mongoloid	Statin	59 ± 7.7	43
14	2014	RCT	China	Mongoloid	Placebo	48.1 ± 7.0	102
14	2014	RCT	China	Mongoloid	Statin	48.6 ± 7.2	102
15	2012	RCT	China	Mongoloid	Placebo	59 ± 7.7	59
15	2012	RCT	China	Mongoloid	Statin	60 ± 18	59
16	2020	RCT	China	Mongoloid	Placebo	20.16 ± 4.4	64
16	2020	RCT	China	Mongoloid	Statin	20.19 ± 4.46	64

Results of quality assessment

A qualitative assessment was conducted by using the Cochrane Risk of Bias tool to assess various indicators for each study (Figure S1). Scores ranged from 7 to 8, with nine studies scoring above 7. Given the bias summary, selection bias, detection bias and other biases were not an issue. Two trials were at risk of bias and seven were not (Figure S2).

Results of heterogeneity test

In eight studies involving 3086 patients, a comparison of systolic blood pressure (SBP) between the statin and placebo groups was reported. A meta-analysis showed a difference between the two groups (MD = 4.37, 95% CI [0.72, 8.02], p = .02, random effects model) (Figure 2).

Figure 2.

Forest plot: comparison of SBP between the statin and placebo groups, experimental = statin, control = placebo.

A meta-analysis was also performed on the diastolic blood pressure (DBP) of patients in the statin and placebo groups. The results showed no significant difference in DBP between the two groups (MD = 2.48, 95% CI [−2.00, 6.96], p = .28, random effects model) (Figure 3).

Figure 3.

Forest plot: comparison of DBP between the statin and placebo groups, experimental = statin, control = placebo.

Results of Sensitivity Analysis and Publication Bias

A total of eight studies reported SBP. The forest plots showed that the statin group was superior to the placebo group (MD = 4.37, 95% CI [0.72, 8.02], p = .02, p = .02, I² = 99%). We performed a sensitivity analysis by removing Beatrice’s 2008 study and the results were little changed, with I² = 92% from 99% (Figure 4), indicating that the results of the included articles were robust.

Figure 4.

Sensitivity analysis forest plots: comparison of SBP between the statin and placebo groups, experimental = statin, control = placebo.

We also drew a funnel plot to assess the publication bias of SBP between the statin and placebo groups; the plot shows its shape to be symmetrical. This result indicates that there was little publication bias in this meta-analysis (Figure S3).

Results of meta regression

From the results of meta regression, we found the main causes of high heterogeneity in SBP between the statin and placebo were age, gender and sample size (Table 2).

Table 2.

Meta regression of included studies.

	Estimate	se	zval	pval	ci.lb	ci.ub
Country	0.3746	0.1951	1.9205	0.0548	−0.0077	0.7569
Age	−0.2389	0.0544	−4.3916	<.0001	−0.3455	−0.1323
Gender	3.2209	0.6701	4.8063	<.0001	1.9074	4.5343
Size	−0.0016	0.0003	−4.5833	<.0001	−0.0023	−0.0009

Discussion

Eight studies met the inclusion criteria to assess the effect of statins on hypertension. Meta-analysis of these studies showed that statins were more effective than placebo for SBP. However, there was no difference in DBP between the statin and placebo groups, suggesting that the two treatments have similar clinical effects on DBP.

There are two main mechanisms by which statins provide protection against cardiovascular disease. Firstly, statins reduce the incidence of disease and fatal cardiovascular events by lowering total serum cholesterol and, more generally, lipid composition. Second, statins may have multiple effects (e.g. anti-inflammatory and anti-proliferative) in addition to causing changes in lipid composition, directly protecting tissues and organs from cardiovascular risk factors.¹⁷ In the past few years, a third mechanism for the cardiovascular protective effects of statins has been proposed - that statins also lower blood pressure, thereby reducing blood pressure-related risks.¹⁸ The effect of statins on cardiovascular disease has been described in the included studies.

One study reported that the addition of pravastatin to antihypertensive therapy resulted in a significant and sustained reduction in total serum cholesterol and LDL cholesterol compared with the placebo group. However, this increase did not result in further reductions in systolic or diastolic blood pressure values, either with regular measurements in the physician’s office or with repeated outpatient measurements over 24 h^19,20 This provides evidence for a substantial antihypertensive effect of statins in patients with hypertension, suggesting that the protective effect of these drugs on the cardiovascular system is not dependent on reducing the risk of blood pressure-related cardiovascular disease.

In addition, one study reported significant improvement in systolic left ventricular hypertrophy and left ventricular systolic function in patients with essential hypertension after one year of treatment with simvastatin.²¹ The trend of decreasing left ventricular diastolic function was the same as before treatment, but without significant changes. Simvastatin reversed left ventricular hypertrophy and improved left ventricular systolic function in patients with essential hypertension.²² A large body of data shows that statins, in addition to lowering plasma cholesterol, reduce morbidity and mortality from coronary artery disease; this beneficial effect is independent of their cholesterol-lowering effect.²³

Limitation

This study also had some limitations. Firstly, dynamic changes in blood pressure were not analysed in this study. Secondly, due to the limited raw data, no further stratified comparisons of complications were made.

Conclusions

In a systematic meta-analysis, we found that statin might be clinically more effective than placebo in the treatment of hypertension. It might be more effective in controlling systolic blood pressure (SBP) and reducing the conversion to hypertension, which could help clinician making a good choice for hypertension. The limited number of included studies reduces the reliability of the conclusions. However, a large number of relevant studies should be included in the future to validate the conclusions.

Supplemental Material

Supplemental Material - Effects of statin on hypertension patients: A systematic review and meta-analysis

Supplemental Material for Effects of statin on hypertension patients: A systematic review and meta-analysis by Jianwei Wan and Min Chen in European Journal of Inflammation

Footnotes

Acknowledgements

Sincere gratitude is extended to the Copenhagen Nordic Cochran Center for granting us permission to utilize the Cochrane bias risk assessment tool.

Author contribution

JW and MC participated in the conception and design of the study, library searches and assembling relevant literature, critical review of the paper, supervising the writing of the paper, and database management and participated in data collection, library searches and assembling relevant literature, writing the paper, and critical review of the paper.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Important Weak Discipline Construction Project of the Pudong New Area Health System (PWZbr2022-11).

ORCID iD

Min Chen

Supplemental Material

Supplemental material for this article is available online.

References

Lorenzen

Neunhöffer

David

, et al. Angiotensin II receptor blocker and statins lower elevated levels of osteopontin in essential hypertension-results from the EUTOPIA trial. Atherosclerosis 2010; 209(1): 184–188.

Koh

Quon

Waclawiw

. Are statins effective for simultaneously treating dyslipidemias and hypertension? Atherosclerosis 2008; 196(1): 1–8.

Deng

Xia

. Effects of statins on hypertension. J Pract Med Tech 2004; 10: 1303–1305.

Zhang

Zeng

Cheng

, et al. Efficacy and safety of statins for pulmonary hypertension: a meta-analysis of randomised controlled trials. Heart Lung Circ 2017; 26(5): 425–432.

Sang-Eun

Ji Min

In-Jeong

, et al. Risk of new-onset diabetes among patients treated with statins according to hypertension and gender: results from a nationwide health-screening cohort. Plos One 2018; 13(4): e0195459.

Cifkova

Nilsson

. Statins and hypertension. J Hypertension 2009; 27(3): 662–665.

Alves-Cabratosa

García-Gil

Comas-Cufí

, et al. Statins and new-onset atrial fibrillation in a cohort of patients with hypertension. Analysis of electronic health records. Plos One 2017; 12(10): e0186972.

Calderone

Bel-Hadj

Drapeau

, et al Scar myofibroblasts of the infarcted rat heart express natriuretic peptides. J Cel Physiol 2006; 207: 165–173.

Kamberi

Bakalli

Budima

, et al. Pleiotropic and lipid lowering effects of statins in hypertension. Materi a Socio Med 2012; 24(2): 84.

10.

Golomb

Dimsdale

White

, et al. Reduction in blood pressure with statins: results from the UCSD statin study, a randomized trial. Arch Internal Medicine 2008; 168(7): 721–727.

11.

Mancia

Parati

Revera

, et al. Statins, antihypertensive treatment, and blood pressure control in clinic and over 24 hours: evidence from PHYLLIS randomised double blind trial. BMJ 2010; 340: c1197.

12.

Pan

Zeng

Liang

, et al. The effects of simvastatin on left ventricular hypertrophy and left ventricular function in patients with essential hypertension. Clin Exp Hypertens 2011; 33(8): 558–564.

13.

Zhang

. Effect of atorvastatin on blood pressure variability in patients with hypertension. Hebei Medicine 2012; 34(10): 1492–1494.

14.

Guang

Huang

. Effects of atorvastatin on blood pressure and blood pressure variability in patients with normotensive hypertension. Chin J Modern Medicine 2014; 24(24): 102–106.

15.

Zhou

. Effect of atorvastatin calcium on blood pressure variability in patients with hypertension. Sichuan Med 2012; 33(05): 754–757.

16.

Yan

. Effect of statins on adolescent hypertension and its effect on serum indexes and blood pressure variability. J Cardiovascular Rehabilitation Medicine 2020; 29(01): 33–38.

17.

Zhou

Jaimes

Raij

. Statins lower blood pressure and end organ injury in salt sensitive hypertension: Role of cNOS and oxidative stress. In: 57th Annual Fall Conference on Hypertension, September 2003; 42.

18.

Vargas

Arrese

Shah

, et al. Use of statins in patients with chronic liver disease and cirrhosis: current views and prospects. Curr Gastroenterol Rep 2017; 19(9): 43.

19.

Trebicka

Schierwagen

. Statins, Rho GTPases and KLF2: new mechanistic insight into liver fibrosis and portal hypertension. Gut 2015; 69: 1349–1350.

20.

Drapala

Sikora

Ufnal

. Statins, the renin-angiotensin-aldosterone system and hypertension - a tale of another beneficial effect of statins. J Renin Angiotensin Aldosterone Syst 2014; 15(3): 250–258.

21.

Kiaie

Gorabi

Reiner

, et al. Effects of statins on renin-angiotensin system. J Cardiovasc Dev Dis 2021; 8(7): 80.

22.

Arab

Shah

. Statins and portal hypertension: a tale of two models. Hepatology 2016; 63(6): 2044–2047.

23.

Bjrck M, Gottster A, Bergqvist D, Wanhainen A . The importance of statins, smoking, hypertension and life style control. 34th Symposium Book. London: BIBA Publishing, 2012: 291–297.

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