ORIGINAL ARTICLE

Hippokratia 2015, 19(4):332-337

Barkas F1, Elisaf M1, Rizos CV1, Klouras E1, Kostapanos MS2, Liberopoulos E1
1Department of Internal Medicine, School of Medicine, University Hospital of Ioannina, Ioannina, Greece, 2Clinical Pharmacology Unit, Addenbrooke’s Hospital Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Abstract

Background: Proton pump inhibitors (PPIs) might influence the metabolism of cholesterol and statins in the liver. Aim: The impact of PPIs on low-density lipoprotein cholesterol (LDL-C) levels in statin-treated patients. Methods: Retrospective observational study including consecutive statin-treated individuals followed for ≥3 years in a university hospital lipid clinic. Demographic characteristics as well as clinical and laboratory data were recorded at baseline and the most recent visit. High, moderate and low-intensity statin therapy was defined according to the expected LDL-C reduction (≥50%, 30-50%, and <30%, respectively). We compared the LDL-C reduction in subjects receiving statin + PPI with those on statin alone and assessed the overall effect of PPI administration on LDL-C lowering. Results: Of 648 statin-treated subjects, 7% were also taking a PPI. There was no difference between PPI vs. non-PPI group regarding baseline characteristics and intensity of lipid-lowering therapy. Stepwise linear regression analysis showed that PPI use was significantly associated with LDL-C reduction (b =0.104, p =0.005) along with baseline LDL-C levels (b =0.482, p <0.001), treatment with ezetimibe (b =0.198, p <0.001), presence of diabetes (b =0.168, p <0.001), compliance with treatment (b =0.205, p <0.001), intensity of statin treatment (b =0.101, p =0.005) and cardiovascular risk (b =0.082, p =0.049). Subjects receiving statin + PPI had a higher LDL-C reduction by 6.4% compared with those taking a statin alone (fully adjusted p =0.005). Conclusions: PPIs may modestly boost the statin-mediated LDL-C reduction. This effect should be confirmed by prospective clinical studies. Hippokratia 2015; 19 (4): 332-337.

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Key words: cholesterol, cytochrome, interaction, proton pump inhibitors, statin

Corresponding author: Dr Evangelos N Liberopoulos MD FASA FRSH, Assistant Professor in Internal Medicine, University of Ioannina Medical School, 45110 Ioannina, Greece, tel: +302651007502, fax: +302651007016, e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.  

Introduction

Statins and proton pump inhibitors (PPIs) are among the most commonly prescribed drugs1. In 2013, 24.4 and 15.3 million patients in the US received lipid-lowering drugs and PPIs, respectively1. Statins remain the cornerstone therapy for cardiovascular (CV) disease prevention while PPIs are frequently co-administered with clopidogrel or aspirin in clinical practice in high-risk patients for gastroprotection2,3. PPIs have recently been associated with clinically relevant side effects as well as interactions with other drugs2,4-8. Moreover, it has been reported that PPIs might interfere with cholesterol metabolism9-11. Indeed, PPIs may increase statin action since both drugs are metabolized by the same P450 cytochromes (CYP3A4, CYP2C19)10. Lansoprazole may act as an agonist for liver X receptor (LXR), which is associated with cholesterol metabolism9. However, there are no studies on the effect of chronic PPI use on statin-mediated low-density lipoprotein cholesterol (LDL-C) reduction in clinical practice.

The present study assessed the possible effect of chronic PPI use on LDL-C reduction in statin-treated individuals in a lipid clinic.

Subjects and methods

Design and conduct

This was a retrospective (from 1999 to 2013) observational study as previously described12,13. Briefly, consecutive adults followed up for ≥3 years for the treatment of dyslipidemia in the Outpatient Lipid Clinic of the University Hospital of Ioannina, in Greece were included. For all study participants, a complete assessment of their lipid-lowering and concomitant treatments was obtained. The study protocol was approved by the institutional Ethics Committee of School of Medicine, University of Ioannina (No 3231, 7/5/2012).

Demographic characteristics as well as clinical and laboratory data were recorded at the baseline and most recent visit. These included age, gender, smoking status, body mass index (BMI), blood pressure (BP) readings, liver and muscle enzymes together with history of CV risk factors and concomitant diseases. The rates of adverse events related to statin therapy were also recorded: myalgias, an increase of creatine phosphokinase (CK) >10 times the upper limit of normal values (ULN) and an increase of liver enzymes >3 times the ULN. Subjects were classified into three CV risk groups (‘very high’, ‘high’ and ‘moderate’) and treated for dyslipidemia according to the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines3. The intensity of statin therapy was defined according to the expected LDL-C reduction (≥50, 30-50 and <30%)14. Patients were classified according to their compliance with treatment as ‘good’ and ‘poor’ compliers if they took ≥ and <80% of the prescribed tablets, respectively. All subjects received hypolipidemic dietary instructions during their follow-up.

Exposure status and case – control definition

For the primary analysis, exposed patients were defined as those who received, at least, a 2-year supply of PPIs up to the last visit. We included only subjects receiving PPIs as gastroprophylaxis in case of treatment with aspirin and/or clopidogrel. Active ulcer, gastritis, and gastroesophageal reflux disease (GERD) were considered as exclusion criteria. The most commonly used PPIs were omeprazole, esomeprazole, lansoprazole or pantoprazole.

After excluding those taking lipid-lowering therapy at the baseline visit, individuals on statin + PPI during follow-up were considered as case subjects, while those receiving a statin without a PPI as controls.

We investigated whether the use of PPIs together with other factors (i.e. CV risk, concomitant lipid-lowering therapy, BMI change and baseline lipid levels) contributed to the changes of LDL-C and we compared the degree of LDL-C reduction between case and control subjects. Additionally, we assessed the safety of PPI + statins combination by comparing the changes in liver or muscle enzymes and the rates of statin-associated adverse events.

Statistical analyses

Continuous variables were tested for normality by the Kolmogorov-Smirnov test, and logarithmic transformations were applied accordingly. Parametric and non-parametric data are presented as mean ± standard deviation (SD) and median [interquartile range (IQR)], respectively. The differences of continuous numeric values between the two groups are expressed as mean (95% confidence interval [CI]). For categorical values, frequency counts and percentages were applied. Chi-square tests were performed for interactions between categorical values. Pearson’s and Spearman’s correlation coefficients (r) were used to investigate the relationship of the changes in LDL-C with other parametric and nonparametric variables, respectively. The independent contribution of variables being significantly associated with LDL-C changes in univariate analysis was assessed with stepwise linear regression analysis. These variables were used as covariates in the multivariate analysis of covariance (MANCOVA) to assess the difference in LDL-C reduction between case and control subjects. Two-tailed significance was defined as p <0.05. Data analysis was performed using the Statistical Package for Social Sciences (SPSS) 21.0 software (SPSS IBM Corp., Armonk, New York, USA).

Results

Of 1,000 consecutive patients being assessed, 648 subjects were eligible for inclusion in the present analysis after excluding those taking lipid-lowering treatment at the baseline visit and those with active gastrointestinal disease. Of those, 607 individuals (93%) were on a statin and 41 (7%) on a statin + chronic PPI during follow-up. Mean age was 56 ± 11 years; 45% were males and the study participants were followed-up for seven years (median). Baseline demographic and clinical characteristics of study subjects are shown in Table 1. Patients taking statin + PPI were older, had higher CV risk, higher prevalence of hypertension and CV disease, higher high-density lipoprotein cholesterol (HDL-C) levels and were more likely to receive clopidogrel compared with those on statin alone (Table 1). No difference was noticed between the two groups regarding their lipid-lowering therapy and compliance with treatment (Table 1).

The changes in metabolic and safety profile of study subjects from baseline to most recent visit are shown in Table 2. No significant differences were found between the two groups regarding the changes in these parameters except for the reductions noticed in diastolic blood pressure and levels of total cholesterol (TCHOL) and LDL-C (Table 2).

No differences were found regarding statin-induced adverse events between subjects taking statin + PPI and those on statin alone. The corresponding rates for myalgias and increase of liver enzymes >3 times the ULN were 0.5% vs. 2.4% (p =0.231) and 0.2% vs. 2.4% (p =0.123), respectively for the two groups. Neither of the two groups exhibited increase of CK >10 times the ULN.

Correlation coefficient analyses indicated that baseline LDL-C levels (r = 0.495, p <0.001), follow-up duration (r = 0.133, p =0.001), treatment with aspirin (r = 0.126, p =0.001), clopidogrel (r =0.098, p =0.013), ezetimibe (r =0.384, p <0.001), PPIs (r =0.121, p <0.001), along with the intensity of statin therapy (r =0.241, p <0.001), compliance with lipid-lowering treatment (r =0.161, p <0.001), diabetes (r = 0.156, p <0.001) and CV risk (r =0.169, p <0.001) were significantly associated with LDL-C reduction.

Stepwise linear regression analysis taking account all the above parameters indicated that chronic PPI treatment remained an independent predictor for LDL-C reduction (beta =0.104, p =0.005) (Table 3). Specifically, a higher LDL-C reduction by 6.4% was found in individuals on statin + PPI compared with controls (95% CI: 1.9-10.9%, p =0.005, after adjusting for the effect of the baseline LDL-C levels, presence of diabetes, ezetimibe use, compliance with treatment, intensity of statin treatment, CV risk). In sub-group analysis, this difference remained significant in individuals receiving rosuvastatin (10.8%, 95% CI: 3.3-18.4%, p =0.005, after adjusting for the same covariates). Despite not being significant, a similar trend towards a higher LDL-C reduction between case and control subjects was noticed among those taking atorvastatin (3.9%, 95% CI: -3.2-11.2%, p =0.280) and simvastatin (2.9%, 95% CI: -6.5-12.4%, p =0.535).

Discussion

The present study suggests, for the first time to our knowledge, that treatment with PPIs may modestly increase statin-mediated LDL-C reduction without increasing the risk of liver and muscle toxicity.

It has been reported that PPIs may be involved in cholesterol metabolism9,11. A study investigating whether helicobacter pylori infection was associated with changes in serum lipid levels indicated that its eradication significantly increased HDL-C after taking amoxicillin, clarithromycin, and omeprazole15. Despite not being significant, a trend towards a reduction in TCHOL and LDL-C levels was noticed in that study15. PPIs can decrease the intra-lysosomal acidity through the inhibition of the lysosomal membrane H+/K+ ATPase11. Therefore, these drugs could inhibit the intra-lysosomal oxidation of LDL-C11. In addition, lansoprazole and other PPIs with structure similarities might act as LXR agonists9. Lansoprazole can activate endogenous LXR in a concentration-dependent manner, followed-up by transcriptional up-regulation of LXR related genes leading to the increase of their proteins9. These proteins are involved in cholesterol metabolism and various steps of atherosclerosis9. Indeed, a synthetic LXR ligand reduced LDL-C in nonhuman primates with normal lipid levels16.

Furthermore, the possible cholesterol-lowering effect of PPIs on statin-treated individuals could be attributed to the liver metabolism of both drugs (CYP450)10,17. It is known that atorvastatin and simvastatin are metabolized by the cytochromes CYP3A4 and CYP2C8 while rosuvastatin is metabolized by CYP2C9 and CYP2C1917. PPIs also undergo similar hepatic metabolism, involving the cytochromes CYP3A4, and CYP2C1910. Most PPIs are weak inhibitors of CYP3A4, while omeprazole and esomeprazole are the most potent CYP2C19 inhibitors10. By competing with such isoforms, PPIs may reduce the metabolism of statins resulting in an increase of their LDL-C-lowering efficacy17,18. In a similar way, esomeprazole and omeprazole have been suggested to reduce the antiplatelet effect of clopidogrel by competing for the same cytochrome2. Nevertheless, PPIs have not been considered yet to interact with statins7,8.

In our study, a high proportion of the participants taking statin + PPI were also receiving clopidogrel (Table 1). Despite the fact that few reports have demonstrated a statin-clopidogrel interaction, posthoc analyses from randomized clinical trials have not associated the co-administration of statins and clopidogrel with an increased cardiovascular risk19. In addition, the effect of clopidogrel on LDL-C reduction did not remain significant in our multivariate regression analysis. Thus, the use of clopidogrel may not account for the higher LDL-C reduction noticed in the subjects taking statin + PPI in our study. 

Inhibitors of CYP450 are associated with skeletal muscle or liver toxicity by increasing the plasma concentrations of statins18,20. In this context, PPIs have been related to myopathy including polymyositis in statin-treated individuals21-24.  Nevertheless, no differences were found regarding the changes in liver or muscle enzymes and the rates of statin-induced adverse events between cases and controls in this study.

A higher proportion of individuals taking statin + PPI were on antihypertensive therapy compared with the control group (Table 1). This may explain the greater reduction in diastolic, and systolic BP noticed in the former group (Table 2).

Study limitations

This was a retrospective observational study not specifically designed to investigate the effect of PPIs on statin-induced LDL-C lowering. Unfortunately, there were no data available on the specific PPIs used. Therefore, we were not able to assess possible differences among various PPIs. Also, the number of patients on statin + PPIs was small. Despite careful adjustment, residual confounding may still be present. Diet could account for the noticed difference in LDL-C reduction between the two groups. Indeed, individuals taking PPIs due to gastrointestinal disorders usually follow a fatless diet. In order to avoid this bias, subjects diagnosed with an active ulcer, gastritis or GERD were excluded. Adherence to a healthy diet confers to a significant CV risk reduction, even in statin-treated individuals25,26. Thus, individuals at very high CV risk, such as the majority of those taking PPIs in our cohort, might have followed a stricter diet leading to greater cholesterol reduction. On the other hand, a less strict diet followed by those not receiving a PPI could explain the increase in markers of metabolic syndrome and non-alcoholic fatty liver disease (i.e. glucose, BMI, uric acid and liver enzymes, as shown in Table 2) although there was no significant difference between the two groups. Unfortunately, we have no data on participant diet. Another residual factor could be the lower estimated glomerular filtration rate (eGFR) in the group of statin + PPI27. Nevertheless, no association between eGFR and LDL-C reduction was evident.

Conclusion

Chronic PPI use may be associated with a modest enhancement in LDL-C lowering efficacy of statins. This possible effect should be documented in prospective clinical studies.

Conflict of Interest

ME and EL have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies. ME has disclosed that he is an Editorial Board member of JCPT. FB, CR, EK and MK have no conflict of interest to report.

References

1. Medicine use and shifting costs of healthcare. A review of the use of medicines in the United States in 2013. IMS Health Website. Availiable at: http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/IMS%20Health%20Institute/Reports/Secure/IIHI_US_Use_of_Meds_for_2013.pdf, last accessed: 14/4/2014
2. D’Ugo E, Rossi S, De Caterina R. Proton pump inhibitors and clopidogrel: an association to avoid? Intern Emerg Med. 2014; 9: 11-22.
3. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, et al; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011; 32: 1769-1818.
4. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013; 310: 2435-2442.
5. Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW. Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review. Heart. 2013; 99: 520-527.
6. Broeren MA, Geerdink EA, Vader HL, van den Wall Bake AW. Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med. 2009; 151: 755-756.
7. Abraham NS. Proton pump inhibitors: potential adverse effects. Curr Opin Gastroenterol. 2012; 28: 615-620.
8. Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf. 2014; 37: 201-211.
9. Cronican AA, Fitz NF, Pham T, Fogg A, Kifer B, Koldamova R, et al. Proton pump inhibitor lansoprazole is a nuclear liver X receptor agonist. Biochem Pharmacol. 2010; 79: 1310-1316.
10. Zvyaga T, Chang SY, Chen C, Yang Z, Vuppugalla R, Hurley J, et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos. 2012; 40: 1698-1711.
11. Namazi MR, Sharifian M. The potential anti-xanthoma and anti-atherosclerotic effects of proton pump inhibitors. J Clin Pharm Ther. 2008; 33: 579-580.
12. Barkas F, Milionis H, Kostapanos MS, Mikhailidis DP, Elisaf M, Liberopoulos E. How effective are the ESC/EAS and 2013 ACC/AHA guidelines in treating dyslipidemia? Lessons from a lipid clinic. Curr Med Res Opin. 2015; 31: 221-228.
13. Barkas F, Liberopoulos EN, Kostapanos MS, Liamis G, Tziallas D, Elisaf M. Lipid target achievement among patients with very high and high cardiovascular risk in a lipid clinic. Angiology. 2015; 66: 346-353.
14. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63: 2889-2934.
15. Kanbay M, Gür G, Yücel M, Yilmaz U, Boyacioğlu S. Does eradication of Helicobacter pylori infection help normalize serum lipid and CRP levels? Dig Dis Sci. 2005; 50: 1228-1231.
16. Quinet EM, Basso MD, Halpern AR, Yates DW, Steffan RJ, Clerin V, et al. LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse. J Lipid Res. 2009; 50: 2358-2370.
17. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006; 80: 565-581.
18. Kostapanos MS, Milionis HJ, Elisaf MS. Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia. Am J Cardiovasc Drugs. 2010; 10: 11-28.
19. Cuisset T, Quilici J. CYP-mediated pharmacologic interference with optimal platelet inhibition. J Cardiovasc Transl Res. 2013; 6: 404-410.
20. Neuvonen PJ. Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics. Curr Opin Investig Drugs. 2010; 11: 323-332.
21. Marusic S, Lisicic A, Horvatic I, Bacic-Vrca V, Bozina N. Atorvastatin-related rhabdomyolysis and acute renal failure in a genetically predisposed patient with potential drug-drug interaction. Int J Clin Pharm. 2012; 34: 825-827.
22. Sipe BE, Jones RJ, Bokhart GH. Rhabdomyolysis causing AV blockade due to possible atorvastatin, esomeprazole, and clarithromycin interaction. Ann Pharmacother. 2003; 37: 808-811.
23. Kanth R, Shah MS, Flores RM. Statin-associated polymyositis following omeprazole treatment. Clin Med Res. 2013; 11: 91-95.
24. Clark DW, Strandell J. Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Eur J Clin Pharmacol. 2006; 62: 473-479.
25. Panagiotakos DB, Georgousopoulou EN, Georgiopoulos GA, Pitsavos C, Chrysohoou C, Skoumas I, et al; ATTICA Study Group. Adherence to Mediterranean Diet Offers an Additive Protection Over the Use of Statin Therapy: Results from the ATTICA study (2002-2012). Curr Vasc Pharmacol. 2015; 13: 778-787.
26. Panagiotakos DB, Georgousopoulou EN, Pitsavos C, Chrysohoou C, Skoumas I, Pitaraki E, et al; ATTICA Study Group. Exploring the path of Mediterranean diet on 10-year incidence of cardiovascular disease: the ATTICA study (2002-2012). Nutr Metab Cardiovasc Dis. 2015; 25: 327-335.
27. Olyaei A, Greer E, Delos Santos R, Rueda J. The efficacy and safety of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in chronic kidney disease, dialysis, and transplant patients. Clin J Am Soc Nephrol. 2011; 6: 664-678.