Le Infezioni in Medicina, n. 2, 194-203, 2022

doi: 10.53854/liim-3002-4

REVIEWS

Further insights into to the role of statins against active tuberculosis: systematic review and meta-analysis

Edinson Dante Meregildo-Rodriguez1, Eleodoro Vladimir Chunga-Chévez1, Robles-Arce Luis Gianmarco1, Gustavo Adolfo Vásquez-Tirado2

1Universidad César Vallejo, Escuela de Medicina. Trujillo, Perú;

2Universidad Privada Antenor Orrego, Escuela de Medicina, Trujillo, Perú

Article received 25 April 2022, accepted 10 May 2022

Corresponding author

Edinson Dante Meregildo-Rodriguez

E-mail: dante_meregildo@hotmail.com

SummaRY

Objectives: Tuberculosis is a major cause of global morbidity and mortality. Statins could be associated with a lower risk of some infectious diseases, including tuberculosis. Statins could reduce the risk of latent tuberculosis infection and active tuberculosis, acting as an adjuvant in treating tuberculosis. This study aimed to determine if statins reduce the risk of active tuberculosis.

Methods: We systematically analyzed 8 databases from inception to December 2021. We included articles without language restriction if they met our inclusion and exclusion criteria and the PECO strategy (Population: adults without active pulmonary tuberculosis; Exposure: treatment with any statin; Comparator: no use of statins; Outcome: active tuberculosis). Odds Ratios (ORs) with 95% confidence intervals (CIs) were pooled using random-effects models regardless of heterogeneity quantified by Cochran’s Q and I2 statistics. We performed subgroup analyses according to the participants’ diabetic status and follow-up length (≤10 years or >10 years).

Results: Twelve articles reporting observational studies involving 3.038.043 participants, including at least 32.668 cases of active tuberculosis. Eight reported retrospective cohort studies, three nested case-control study, and one was a case control study.

According to our meta-analysis, statins may reduce the risk of active tuberculosis, in the general population (OR 0.66; 95% CI, 0.54-0.81), in non-diabetic (OR 0.66; 95% CI, 0.54-0.80) and in diabetic patients (OR 0.65; 95% CI, 0.49-0.87). This protective effect did not differ according to the participants’ diabetic status nor follow-up length (test for subgroup differences I2=0). We found significant clinical and methodological heterogeneity. Similarly, the forest plot, and the I2 and Chi2 statistics suggested considerable statistical heterogeneity (I2=95%, p<0.05, respectively). Of the 12 included studies, 9 were at low risk of bias and 3 were at high risk of bias. Similarly, according to the funnel plot, it is very likely that there are important publication biases.

Conclusion: Statin use may significantly reduce the risk of tuberculosis in the general population, diabetic and non-diabetic patients. Nevertheless, caution should be exercised when interpreting these conclusions, due to the quality of the evidence, the heterogeneity of the studies, the presence of bias, and the difficulty in extrapolating these results to populations of other races and ethnicities.

Keywords: tuberculosis, statins, hydroxymethylglutaryl-CoA reductase inhibitors, risk, systematic review.

INTRODUCTION

Tuberculosis is one of the most important causes of morbidity and mortality due to infectious diseases in the world [1, 2]. Globally in 2020, 10 million people became ill and 1.5 million people died due to tuberculosis [1].

Treatment against tuberculosis includes the prolonged use of several drugs, some of them with important adverse effects that can cause poor adherence [3, 4]. On the other hand, in 5% -25% of cases, Mycobacterium tuberculosis infection is resistant to drugs, so identifying new prevention and treatment strategies against this disease are public health priorities [1, 2].

Statins are lipid-lowering drugs widely used in the primary and secondary prevention of atherosclerotic disease that inhibit cholesterol synthesis [5-7]. Statins could also have an anti-inflammatory, anti-oxidative stress, immunomodulatory, and probably anti-infective effect [6, 7].

Evidence shows that statins could improve clinical outcomes in tuberculosis:

1) they could prevent or reduce the risk of developing active tuberculosis, both in diabetics, and in the general population;

2) reduce the probability of latent tuberculosis infection in diabetic patients;

3) act as an adjuvant in the treatment of tuberculosis since in murine models they significantly improved the bactericidal activity of first-line antituberculous drugs [5, 8-12].

On the contrary, some studies have reported that statin use among diabetic patients is not independently associated with a protective effect on the incidence of tuberculosis [13, 14]. Consequently, our aim was to synthesize the evidence regarding whether statin therapy can reduce the risk of active tuberculosis.

METHODS

To prepare this systematic review, the protocol was previously registered in PROSPERO (CRD42021286276) and we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15]. We conducted an exhaustive search for articles published up to the end of December 2021. We included clinical trials, observational studies (cohort, case-control, cross-sectional), systematic reviews, and meta-analyses from the databases Medline via Pubmed, Google Scholar, EBSCO, Scopus, Science Direct, Cochrane, EMBASE, and Web of Science. For the search we used controlled terms (MeSH) and free terms according to the PECO strategy (Population: adult patients without active pulmonary tuberculosis; Exposure: treatment with a statin for at least 7 days; Comparator: no use of statins; Outcome: active tuberculosis). Search strategy (keyword combinations in all the databases) can be found in Supplementary material.

We included only articles in full text. There was no limit per year of publication or language. Once the review protocol was established, electronic copies were distributed to the authors. For the peer review process, we use Rayyan™ software. Articles were assessed by three independent, blinded reviewers (CCEV, RALG, and VTGA) and discrepancies were resolved by a fourth reviewer (MRED). References from retrieved articles and narrative or systematic reviews were screened for additional articles. Figure 1 shows the study selection process.

Figure 1 - PRISMA flow chart of the selection of primary studies on the impact of statins on active tuberculosis.

The articles found were analyzed applying the terms of the PECO strategy, and the inclusion and exclusion criteria. Relevant data from each article were extracted and recorded in a Microsoft Excel™ sheet: name of authors, year and country of publication, type of study, number of patients, number of tuberculosis cases, study characteristics, measure of association, results of the association analysis and conclusion of the study. The measures of association that were considered were: odds ratio (OR), relative risk (RR), and hazard ratio (HR). The OR was considered to be equivalent to the RR if the frequency of the event of interest (active tuberculosis) was <10% [16]. For studies reporting OR or RR stratified into different subgroups, we considered each subgroup analysis as a separate study. Statistical heterogeneity was assessed using the forest plot, the p value of the Cochrane Q test, and the I2 statistic [17].

The risk of bias of the included primary observational studies was carried out using the Newcastle-Ottawa Scale (NOS) tool and to assess the quality and risk of bias of the systematic reviews we used the AMSTAR 2 tool (A Measurement Tool to Assess Systematic Reviews) [18-20].

RESULTS

We identified 135 articles, 114 in the primary search and 21 in the secondary search. After eliminating duplicates, 44 publications remained, which were evaluated in title and abstract. Subsequently, 16 articles remained that were analyzed in full text, of which 12 articles were selected for qualitative and quantitative assessment. These studies included a total of 3.038.043 participants and at least 32.668 cases of active tuberculosis (Figure 1). Of the total of 12 studies considered, 8 corresponded to retrospective cohorts, 1 was case controls and 3 nested case controls. All included studies were conducted in Asia (Taiwan and South Korea). The follow-up period was variable (from 1 to 14 years) (Table 1).

Almost all but one of the studies included in the meta-analysis reported a positive effect of statins on active tuberculosis [13].

According to the results of our meta-analysis, statins would reduce the risk of active TB, both in the general population (OR 0.66; 95% CI, 0.54-0.81) (Figure 2A), in non-diabetic (OR 0.66; 95% CI, 0.54-0.80) and diabetic participants (OR 0.65; 95% CI, 0.49-0.87) (Figure 2B). This protective effect does not differ among diabetic and non-diabetic participants (Figure 2B); nor, according to follow-up length (≤10 years or >10 years) (test for subgroup differences I2=0) (Figure 2C).

We found significant clinical and methodological heterogeneity (Table 1 and Table 2). Similarly, visual analysis of the forest plot and the I2 (I2=95%) and Chi2 statistics suggest considerable statistical heterogeneity (p<0.05, respectively) (Figure 2).

Of the 12 included studies, 9 were at low risk of bias and 3 were at high risk of bias (Table 2). Similarly, according to the funnel plot, it is very likely that there are important publication biases (Figure 3).

Figure 2A - Forest plot on the effect of statins on active tuberculosis in the general population.

Figure 2B - Forest plot on the effect of statins on active tuberculosis in diabetic and non-diabetic patients.

Figure 2C - Forest plot on the effect of statins on active tuberculosis according to follow-up length (≤10 years or >10 years) in in the general population.

Figure 3 - Funnel plot on the effect of statins on active tuberculosis in the general population.

DISCUSSION

According to the results of this systematic review and meta-analysis, statins would reduce the risk of active tuberculosis by approximately 34% in the general population (OR 0.66; 95% CI, 0.54-0.81) (Figure 2A), in non-diabetic patients (OR 0.66; 95% CI, 0.54-0.80), and in diabetic patients (OR 0.65; 95% CI, 0.49-0.87) (Figure 2B). Interestingly, this protective effect does not differ according to the participants’ diabetic status (Figure 2B); nor, according to follow-up length (≤10 years or >10 years) (test for subgroup differences I2=0) (Figure 2C). Our results are consistent with other primary studies and meta-analyses [8, 9, 21-31].

Duan et al. conducted a meta-analysis to define the impact of statins on the risk of tuberculosis in diabetic patients and the general population. The authors analyzed 6 observational studies of 2.073.968 patients. They reported that statins significantly reduced the risk of tuberculosis in diabetic patients by 22% (RR 0.78; 95% CI 0.63-0.95), although heterogeneity was significant (I2=76.1%). Similarly, the authors reported that statins also significantly reduced the risk of tuberculosis in the general population by 40% (RR 0.60; 95% CI 0.50-0.71) with significant heterogeneity (I2=57.7%). The authors associated using statins with a significantly lower risk of tuberculosis both in diabetic patients and the general population; however, the authors recommended to interpret these conclusions with caution due to the possibility of residual confounders [9].

Li et al. conducted a meta-analysis to evaluate the association between the use of statins and tuberculosis infection. They included 9 observational studies with significant heterogeneity (I2=93% and a p-value for the Cochrane Q test <0.001). They associated the use of statins with a lower risk of active tuberculosis (RR 0.60; 95% CI 0.45-0.75, p<0.001). According to the GRADE strategy, the evidence quality was generally low. Likewise, a significant publication bias was detected (p-value for the Egger regression test of 0.046). The researchers concluded that statins could be associated with a lower risk of active tuberculosis. However, they recommended controlled clinical trials to confirm this potential role of statins in active tuberculosis [31].

According to our results, statins would reduce the risk of tuberculosis by 35% in diabetic patients. However, some studies and subgroup analyses did not associate using statins with a protective effect on the incidence of active tuberculosis in diabetics [26,28]. Other investigators noted that the effect of statins on the risk of tuberculosis in patients with diabetes is uncertain. In fact, the risk of tuberculosis in diabetics is triple that of non-diabetics, but there are scarce prevention strategies for tuberculosis in diabetics [32].

Kang et al. aimed to assess whether using statins affected tuberculosis development in patients aged 20-99 years (mean 56.3±13.38) in South Korea. The authors analyzed 840,899 patients with newly diagnosed type 2 diabetes mellitus, of whom 281.842 (33.5%) used statins and 559.057 (66.5%) did not. During the study, 4 052 individuals were diagnosed with tuberculosis, with the incidence of tuberculosis being 251/100 000 patient-years (95% CI 243-258). Compared with patients who did not have tuberculosis, fewer patients with tuberculosis were statin users (19.2% vs. 33.6%). The authors concluded that, in patients with newly diagnosed type 2 diabetes, tuberculosis development was considerable. After adjusting for potential confounders, they did not associate statins with a protective effect on the incidence of tuberculosis (HR 0.98; 95% CI 0.89-1.07) [13]. Interestingly, in this study, statin users had a higher number of comorbidities than non-users (higher average Charlson index 2.62 vs. 2.50) associated with macro and microvascular diabetic complications. Similarly, the patients who developed tuberculosis, compared to those who did not develop the disease, were older on average (58.08±13.54 vs. 56.28±13.38), had greater comorbidity, and macro- and microvascular diabetic complications. Although the authors state that they adjusted for possible confounding factors, the only factor analyzed was gender. This might explain the apparent lack of protective effect of statins against tuberculosis development.

Multiple mechanisms have been proposed to explain the beneficial pleiotropic effects of statins against M. tuberculosis infection, such as inhibition of sterols, prenylation and isoprenoids, induction of proinflammatory cytokines, phagosome maturation and autophagy [32, 33]. Cholesterol is an important lipid for M. tuberculosis, mycobacteria use cholesterol in the membranes of macrophages to attach to and enter macrophages. Therefore, reducing membrane cholesterol inhibits the entry of mycobacteria into macrophages. Cholesterol is also essential for the phagocytosis of mycobacteria by macrophages [32]. Inhibiting cholesterol with statins is associated with phagosome containment of Mycobacterium and increased capacity of macrophages to kill M. tuberculosis. This could explain the bactericidal effect against Mycobacterium in macrophages. Furthermore, statins induce autophagy, a mechanism responsible largely for the attenuation of M. tuberculosis growth in human macrophages. Statin-mediated cholesterol inhibition increases maturation of M. tuberculosis-containing early endosome antigen 1 and lysosome-associated membrane glycoprotein 3 phagosomes, thereby reducing mycobacterial burdens in macrophages. The mechanism by which statins attenuate bacterial burdens is also associated with immunomodulatory functions. Statins exert different effects on the immune response following the phagocytosis of bacteria, which is due to their ability to inhibit the oxidative burst and protein prenylation [33].

In addition, statin as an adjunctive therapy increased the efficacy of a first-line tuberculosis regimen and reduced tuberculosis treatment in mice [11, 12]. Given these data, it is possible that statins could emerge as an adjunctive therapy for tuberculosis [33].

The main strength of this study is that it includes a larger number of studies than other previously published systematic reviews and meta-analyses. Likewise, we only included primary studies that specifically evaluated the effect of statins on active tuberculosis as a primary outcome. Some studies examined other results of using statins in tuberculosis. For example, Chen YT et al. evaluated the effect of statin treatment on the level of adherence (completion) of anti-tuberculosis treatment [14]. On the other hand, Magee MT et al. studied the effect of statins -combined with metformin- on the prevalence of latent tuberculosis infection [10]. Another strength is that we meta-analyze in 3 groups: general population, only diabetic population, only non-diabetic population, which allows us to more accurately examine the impact of diabetes on the effect size.

In this systematic review, we found some limitations that must be considered when interpreting the results. Firstly, the low quality of the available evidence, since all the included studies are retrospective, makes it difficult to analyze confounding factors. Although, most studies adjusted for confounding variables, these were mostly gender and/or age; other studies adjusted for other variables such as diabetes, type, dose and duration of statin therapy, but the number and severity of patient comorbidities were not adjusted for relevant factors. Second, we highlight the considerable heterogeneity of the studies. To address this heterogeneity, following the recommendations of the Cochrane manual, we carried out the following strategies: we verified the data, we performed the meta-analysis following a random-effects model, and we explored the heterogeneity by separating diabetics and nondiabetics into subgroups, and according to follow-up length (≤10 years or >10 years) [17]. We also included measures of association adjusted for the association between statin use and active tuberculosis infection, although we cannot rule out residual factors that may confound the association. Likewise, we performed a sensitivity analysis, with and without some “outlier” studies. However, the result of the effect measure and the heterogeneity statistics did not vary considerably, suggesting other study characteristics such as little control of confounders; differences in study size and design; type, dose and time of statins administration could have contributed to the heterogeneity. On the other hand, the funnel plot diagram warns of a publication bias. Third, all the included studies were conducted in Asia, which could affect the present study’s external validity. Therefore, the association between statin use and active tuberculosis infection should be evaluated in participants of other races, because genetic differences may affect response to statin treatment [34,35]. Besides, we did not examine whether the type, dose, and duration of a particular statin is associated with a greater or lesser protective effect against active tuberculosis.

Our results show that statins may have a protective effect against active tuberculosis, both in the general population and in diabetic patients. However, since this meta-analysis includes only observational studies with considerable heterogeneity and possible publication bias, we emphasize the need for further research including populations of other races to corroborate these findings.

Conflict of interest

None to declare

External grants and funding

None to declare

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