Association between atorvastatin exposure and low folate status: A case–Control study



   Table of Contents   BRIEF COMMUNICATION Year : 2022  |  Volume : 11  |  Issue : 3  |  Page : 124-126

Association between atorvastatin exposure and low folate status: A case–Control study

Roberto Lozano1, Irati Apesteguía2, Alejandro Martínez3
1 Department of Pharmacy, University Clinical Hospital, “Lozano Blesa,” Zaragoza, Spain
2 Department of Health Emergencies o61, Servicio Aragones de Salud, Zaragoza, Spain
3 Department of Pharmacy, Psychosocial Rehabilitation Center of Ntra, Zaragoza, Spain

Date of Submission22-Aug-2022Date of Acceptance11-Nov-2022Date of Web Publication24-Mar-2023

Correspondence Address:
Dr. Roberto Lozano
Department of Pharmacy, University Clinical Hospital, “Lozano Blesa,” Zaragoza
Spain
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Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jrpp.jrpp_66_22

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Objective: The objective of this study is to assess the association between exposure to atorvastatin (ATV) and low-plasma folate (PF) status. Methods: The sample consisted of patients admitted to the internal medicine service of a basic general hospital, located in Zaragoza (Spain). We adopted a pharmacoepidemiological case–control study design. For this, the number of treatment days (TDs) of all the drugs part of their treatment during the study period was obtained from each patient in the sample. The cases were comprised by the number of patient's TDs for which PF ≤3 mg/dl and the controls by the number of patient's TDs for which PF >3 mg/dl. To measure the strength of the association, the odds ratios (ORs) were calculated. The Chi-square test, using the Bonferroni correction, was used to calculate the statistical significance. Findings: The sample consisted of 640 polymedicated patients. The mean PF obtained were 8.0 ± 4.6 mg/dl and 2.1 ± 0.6 mg/dl, for the cases and controls, respectively; the total number of TDs for the cases and controls were 7615 and 57899, respectively. We obtained a U-shaped curve when representing the dose of ATV against the corresponding ORs when comparing cases with control. Conclusion: Exposure to ATV at 10 or 80 mg is associated with an augmented risk of low folate status. We recommend implementing guidelines for mandatory folic acid fortification in patients exposed to ATV doses of 10 or 80 mg.

Keywords: Atorvastatin, case–control, folate


How to cite this article:
Lozano R, Apesteguía I, Martínez A. Association between atorvastatin exposure and low folate status: A case–Control study. J Res Pharm Pract 2022;11:124-6
How to cite this URL:
Lozano R, Apesteguía I, Martínez A. Association between atorvastatin exposure and low folate status: A case–Control study. J Res Pharm Pract [serial online] 2022 [cited 2023 Mar 25];11:124-6. Available from: https://www.jrpp.net/text.asp?2022/11/3/124/372495   Introduction Top

We know that a deficiency of folic acid may result in an elevated risk of cardiovascular diseases,[1] stroke,[2] and/or depression.[3] Furthermore, folate status can be altered in patients with statin treatment, for example, atorvastatin (ATV) compared with the patients not receiving statin therapy. However, current conclusions, based on data obtained by different authors, do not always agree.[4],[5] Therefore, complementary studies are necessary to clarify the influence of statins on folate homeostasis. Based on the above, we assessed the association between exposure to ATV and low folate status.

  Methods Top

The sample consisted of patients admitted to the internal medicine service of a basic general hospital. Those patients were in previous or current treatment with medications that altered plasma folate (PF) values (e.g., folate, phenytoin, sulfasalazine, or trimethoprim with sulfamethoxazole) and/or with diseases that occur with variations in the level (e.g., celiac disease, Crohn's disease, excessive alcohol consumption, hemolytic anemia, and/or kidney dialysis), were excluded. The main variable was PF, as a marker of folate status. We adopted a pharmacoepidemiological case–control study design. As the study took place in a Spanish public hospital, no ethics committee review was required. However, this study did meet the ethical standards of the Helsinki Declaration of 1975, as revised in 2013. For this, the number of treatment days (TDs) of all the drugs part of their treatment during the study period was obtained from each patient in the sample. The cases were comprised by the number of patient's TDs for which PF ≤3 mg/dl and the controls by the number of patient's TDs for which PF >3 mg/dl. The data, collected during 2018 and 2019 (pre-COVID-19), were obtained from the assisted electronic prescription system and laboratory records of the hospital. Finally, to measure the strength of the association between exposure to ATV and PF level, the odds (ATV exposed vs. ATV not exposed) were calculated in both groups of cases and controls, and finally, the odds ratio (OR) was calculated between both groups, cases versus controls, for each of the doses of ATV used (10, 20, 40, and 80 mg) and for all of them. The Chi-square test, using the Bonferroni correction, was used to calculate the statistical significance of the differences, taking into account that the number of drugs tested was 14 (n = 14; P < 0.05/14 = 0.0036).

  Results Top

The sample consisted of 640 (age = 87 ± 6 years; body mass index = 31.3 ± 2.9 kg/m2; height = 159 ± 12 cm; weight = 81 ± 18 kg; women 47%) patients, polymedicated (drugs/patient ≥5), in treatment with doses of ATV at doses of 10, 20, 40, or 80 mg, and admitted to the internal medicine service (average stay = 7.5 days) of a basic hospital with fewer than 200 beds. The mean PF obtained was 8.0 ± 4.6 mg/dl and 2.1 ± 0.6 mg/dl, for the cases and controls, respectively; the total number of TDs for the cases and controls were 7615 and 57,899, respectively.

The second and third columns of [Table 1] contain the data on the number of TDs of the cases and controls, both exposed and not exposed to ATV, for the four doses (total) of ATV used and for each of them (10, 20, 40, and 80 mg). Finally, the last column shows the OR data between the cases and controls, both for the total dose of ATV and each of them.

Table 1: Data on the number of patient's treatment days corresponding to cases and controls, exposed and not exposed to atorvastatin

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[Figure 1] illustrates the resulting U-shaped curve when representing the dose of ATV (10, 20, 40, and 80 mg) used (X-axis) against the corresponding OR obtained when comparing cases with controls (Y-axis).

Figure 1: Curve representing the DATV used (10, 20, 40, and 80 mg; X-axis) against corresponding OR between cases and controls (Y-axis), and best-fitting curve line through the points of a data set. OR: Odds ratio, ATV: Atorvastatin, DATV: Dose of atorvastatin

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  Discussion Top

This U-shaped curve, suggests that intermediate doses of ATV (20 and 40 mg) are not associated with interferences in folate homeostasis, whereas very low (10 mg) or very high (80 mg) doses are associated with interferences in folate homeostasis.

Indeed, this U-shaped association, as observed for vitamins, at low doses of ATV occurs such as a deficiency of folate to maintain homeostasis. As the dose is increased, homeostasis is achieved and the trough of the U-shaped curve is reached. Finally, as the dose of ATV exceeds the amount required to maintain homeostasis, overdose toxicity may occur. Therefore, adverse effects are seen at both low and high levels.

This nonlinear bidirectional relation deduced from these results could explain the contradictory observations described by different authors depending on the dose and statin used (e.g., deficiency,[6] increase,[4] no effect of statins on folate status[7] and/or slight increase in PF concentration).[8] On the contrary, the alteration of folate homeostasis, and therefore, its status, associated with exposure to ATV constitutes an example of a drug-associated increased risk for some diseases. Indeed, folate deficiency has been associated with additional risk for cardiovascular diseases[1] and depressive disorders.[9] Nonlinear associations between PF with a risk of cardiovascular disease mortality and all-cause mortality[10] have also been described. Finally, some studies have shown that PF significantly reduces the risk of stroke.[11] By the way of a limitation, many researchers warn about the high risk of introducing biases when using secondary databases such as clinical and therapeutic data extracted from medical records. However, studies based on data drawn from secondary databases do reflect routine clinical practice. Moreover, despite not being used to test hypotheses, they are used to generate them. Further, because we did not assess the influence of age, although all the patients were older than 65 years, the presence of polymorphisms in cytochrome P450, previous outpatient treatments and cotreatments, and other possible hidden covariates could have had an influence.

In short, based on electronic medical and prescription records and administrative databases using a pharmacoepidemiological case–control study, we assessed the influence of ATV exposure and folate status. The results indicated that exposure to ATV at low doses (10 mg) or very high doses (80 mg) is associated with a high risk of the alteration of folic acid homeostasis, and consequently, increased risk of cardiovascular diseases, stroke, and/or depression. We, therefore, recommend implementing or creating guidelines for mandatory folic acid fortification in these cases.

  Authors' Contribution Top

All authors have contributed equally.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

  References Top
1.Liu Y, Geng T, Wan Z, Lu Q, Zhang X, Qiu Z, et al. Associations of serum folate and vitamin B12 levels with cardiovascular disease mortality among patients with type 2 diabetes. JAMA Netw Open 2022;5:e2146124.  Back to cited text no. 1
    2.Qin X, Spence JD, Li J, Zhang Y, Li Y, Sun N, et al. Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke. Neurology 2020;94:e1126-36.  Back to cited text no. 2
    3.Bender A, Hagan KE, Kingston N. The association of folate and depression: A meta-analysis. J Psychiatr Res 2017;95:9-18.  Back to cited text no. 3
    4.Palabiyik S, Girgin G, Asci A, Demirelli S, Uslu A, Karakelleoglu S, et al. Folate, neopterin and kynurenine pathway in patients with statin therapy. Pteridines 2016;27:7-12.  Back to cited text no. 4
    5.van der Loo B, Spring S, Koppensteiner R. High-dose atorvastatin treatment in patients with peripheral arterial disease: Effects on platelet aggregation, blood rheology and plasma homocysteine. Clin Hemorheol Microcirc 2011;47:241-51.  Back to cited text no. 5
    6.Yi F, Li PL. Mechanisms of homocysteine-induced glomerular injury and sclerosis. Am J Nephrol 2008;28:254-64.  Back to cited text no. 6
    7.Milionis HJ, Papakostas J, Kakafika A, Chasiotis G, Seferiadis K, Elisaf MS. Comparative effects of atorvastatin, simvastatin, and fenofibrate on serum homocysteine levels in patients with primary hyperlipidemia. J Clin Pharmacol 2003;43:825-30.  Back to cited text no. 7
    8.Lüftjohann D, Sigit JI, Locatelli S, von Bergmann K, Schmidt HH. High-dose simvastin (80 mg/day) decreases plasma concentrations of total homocyst(e) ine in patients with hypercholesteromia. Atherosclerosis 2001;155:265-6.  Back to cited text no. 8
    9.Molero Y, Cipriani A, Larsson H, Lichtenstein P, D'Onofrio BM, Fazel S. Associations between statin use and suicidality, depression, anxiety, and seizures: A Swedish total-population cohort study. Lancet Psychiatry 2020;7:982-90.  Back to cited text no. 9
    10.Dong Z, Liang X, Zhang Q, Luo S, Liu H, Wang X, et al. Folic acid deficiency enhances the Tyr705 and Ser727 phosphorylation of mitochondrial STAT3 in in vivo and in vitro models of ischemic stroke. Transl Stroke Res 2021;12:829-43.  Back to cited text no. 10
    11.Preeti K, Saini RP, Saluja S, Kabi BC. A clinical study to determine levels of vitamin B12, folic acid and homocysteine in patients of ischemic stroke. J Assoc Physicians India 2020;68:66.  Back to cited text no. 11
    
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