Response to Statins in Cardiovascular Prevention: Hypo-Responders´ Evaluation

Walter Masson, Martín Lobo, Diego Manente, Laura Vitagliano, María Rostán, Daniel Siniawski, Melina Huerin, Mariano Giorgi

Abstract


Introduction: Numerous clinical trials have shown that statins reduce cardiovascular events, bothin primary and secondary prevention. There is, however, considerable individual variation in the expected response for each dose and type of statin; therefore, detectionof hypo responder patients would allow considering additional hypolipidemic treatment.

Objectives: The aims of this study were to evaluate the response to statins in cardiovascular prevention patients and to analyze the characteristics of hypo-responder subjects.

Methods: Consecutive outpatients receiving statins were included. The treating physician defined the type and dose of statin used. The lipid profile was assessed at baseline andpost-treatment (6-24 weeks). The distribution of LDL-C reduction for each type anddose of statin was analyzed and “low response” was defined according to two strategies: if the percent reduction was below the median or below the 25th percentile. Univariate and multivariate analyses were performed.

Results: A total of 446 patients (52% female, 25% diabetic, 80% primary prevention, age 58 ±11 years) were included in the study. Mean LDL-C reduction was 27%, 38% and 43%for simvastatin 10 mg, 20 mg and 40 mg, respectively, 36% and 43% for atorvastatin 10 mg and 20 mg, respectively, and 44% and 49% for rosuvastatin 10 mg and 20 mg, respectively. Hyporesponsiveness defined by both strategies (median and 25th percentile) showed that male gender (OR 2.54 and 2.31), diabetes (OR 2.0 and 3.85), age (every 5 years, OR 0.87 and 0.83) and baseline LDL-C (every 10 mg/dL, OR 0.78 and0.77) were independently associated with greater chance of being hypo-responder.

Conclusions: LDL-C reduction by different statins was similar to previous reports. Men, diabetics, younger subjects or with lower baseline LDL-C were more likely to show poorresponse to statins.


References


-Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013 Jan 31;1:CD004816.

-Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9.

-Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20.536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360:7-22.

-Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C; et al. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-78.

-Smith MEB, Lee NJ, Haney E, Carson S. Drug class review: HMG-CoA reductase inhibitors (statins) and fixed-dose combination products containing a statin: Final report update 5 [Internet]. Portland (OR): Oregon Health & Science University, 2009 Nov.

-Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003;93:152-160.

-Mangravite LM, Wilke RA, Zhang J, Krauss RM. Pharmacogenomics of statin response. Curr Opin Mol Ther. 2008;10:555-561.

-Deshmukh HA, Colhoun HM, Johnson T, McKeigue PM, Betteridge DJ, Durrington PN. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). J Lipid Res. 2012;53:1000-11.

-Shiffman D, Trompet S, Louie JZ, Rowland CM, Catanese JJ, Iakoubova OA, et al. Genome-Wide Study of Gene Variants Associated with Differential Cardiovascular Event Reduction by Pravastatin Therapy. PLoS ONE 2012;7:e38240.

-Bai JP. Ongoing challenges in drug interaction safety: from exposure to pharmacogenomics. Drug Metab Pharmacokinet 2010;25:62–71.

-Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci USA 2009;106:14728-33.

-Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, Nguyen UT, et al. Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS ONE 2011;6: e25482.

-Vaquero MP, Sanchez Muniz FJ, Jimenez Redondo S, Prats Olivan P, Higueras FJ, Bastida S. Major diet-drug interactions affecting the kinetic characteristics and hypolipidaemic properties of statins. Nutr Hosp 2010;25:193-206.

-Kaddurah-Daouk R, Kristal BS, Weinshilboum RM. Metabolomics: a global biochemical approach to drug response and disease. Annu Rev Pharmacol Toxicol 2008;48:653-83

-Ziajka PE, Reis M, Kreul S, King H. Initial low-density lipoprotein response to statin therapy predicts subsequent low-density lipoprotein response to the addition of ezetimibe Am J Cardiol 2004;93:779-80.

-Thompson G, O’Neill F, Seed M. Why some patients respond poorly to statins and how this might be remedied. Eur Heart J 2002;23:200-06.

-Senaratne J, Griffiths J, Macdonald K, Senaratne MP. Evidence for Cholesterol Hyperabsorbers and Hyperproducers Based on Comparative Low-Density Lipoprotein Reductions Achieved by Ezetimibe Versus Statins. J Cardiopulm Rehabil Prev 2012;32:250-4.

-Consenso de Prevención Cardiovascular. Sociedad Argentina de Cardiología - Área de normatizaciones y consensos. Rev Argent Cardiol 2012; 80, Sup. 2: 1-126.

-Adult Treatment Panel III, Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA. 2001;285:2486-97.

-Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WM, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012;33:1635-1701.

-Tattersall MC, Gangnon RE, Karmali KN, Cullen MW, Stein JH, Keevil JR. Trends in low-density lipoprotein cholesterol goal achievement in high risk United States adults: longitudinal findings from the 1999-2008 national health and nutrition examination surveys. Plos One. 2013;8:e59309.

-Navarro-Vidal B, Banegas JR, León-Muñoz LM, Rodríguez-Artalejo F, Graciani A. Achievement of Cardiometabolic Goals among Diabetic Patients in Spain. A Nationwide Population-Based Study. PLoS One. 2013;8:e61549.

-Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med. 2005;353:487-97.

-Pedan A, Varasteh L, Schneeweiss S. Analysis of factors associated with statin adherence in a hierarchical model considering physician, pharmacy, patient, and prescription characteristics. J Manag Care Pharm. 2007;13:487-96.

-Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet. 2012;5:257-64.

-Lally S, Tan CY, Owens D, Tomkin GH. Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: The role of Niemann-Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein. Diabetologia 2006;49:1008-16.

-Tomkin GH. The intestine as a regulator of cholesterol homeostasis in diabetes. Atheroscler Suppl 2008;9:27–32.

-Gylling H, Miettinen TA. Cholesterol absorption and lipoprotein metabolism in type II diabetes mellitus with and without coronary artery disease. Atherosclerosis 1996;126:325-32.

-Matthan NR, Pencina M, Larocque JM, Jacques PF, D’Agostino RB, Schaefer EJ, et al. Alterations in cholesterol absorption and synthesis characterize Framingham offspring study participants with coronary heart disease. J Lipid Res 2009;50:1927-35.

-Simonen P, Gylling H, Miettinen TA. The validity of serum squalene and non-cholesterol sterols as surrogate markers of cholesterol synthesis and absorption in type 2 diabetes. Atherosclerosis 2008;197:883-88.

-Abramson BL, Benlian P, Hanson ME, Lin J, Shah A, Tershakovec AM. Response by sex to statin plus ezetimibe or statin monotherapy: A pooled analysis of 22,231 hyperlipidemic patients. Lipids Health Dis. 2011;10:146

-Shigematsu E, Yamakawa T, Taguri M, Morita S, Tokui M, Miyamoto K, et al. Efficacy of ezetimibe is associated with gender and baseline lipid levels in patients with type 2 diabetes. J Atheroscler Thromb. 2012;19:846-53.

-C L Shear, F A Franklin, S Stinnett, D P Hurley, R H Bradford, A N Chremos, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins. Circulation. 1992;85:1293-1303

-Cone C, Murata G, Myers O. Demographic determinants of response to statin medications. Am J Health Syst Pharm. 2011;68:511-7.

-Naoumova RP, Marais AD, Mountney J, Firth JC, Rendell NB, Taylor GW, et al. Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia. Atherosclerosis. 1996;119:203-13.

-Leitersdorf E, Eisenberg S, Eliav O, Friedlander Y, Berkman N, Dann EJ, et al. Genetic determinants of responsiveness to the HMG-CoA reductase inhibitor fluvastatin in patients with molecularly defined heterozygous familial hypercholesterolemia. Circulation 1993;87(4 Suppl):III35-44.

-Farnier M, Averna M, Missault L, Vaverkova H, Viigimaa M, Massaad R, et al. Lipid-altering efficacy of ezetimibe⁄simvastatin 10⁄20 mg compared with rosuvastatin 10 mg in high-risk hypercholesterolaemic patients inadequately controlled with prior statin monotherapy. The IN-CROSS study. Int J Clin Pract 2009;63:534-5.

-Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46:1411-6.

-Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175-82.

-Miettinen TA, Gylling H, Strandberg T, Sarna S. Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ. 1998;316:1127-30.


Full Text

Refbacks

  • There are currently no refbacks.

Comments on this article

View all comments


Licencia Creative Commons
The documents published in this journal are under the licencia Creative Commons Atribución-NoComercial-Compartir-Igual 2.5 Argentina.

Revista argentina de cardiología. ISSN en línea 1850-3748. Argentine journal of cardiology (English ed. Online ISSN 2314-2286) Sociedad Argentina de Cardiología. Azcuénaga 980 (C1115AAD),Ciudad Autónoma de Buenos Aires, República Argentina. Tel. (54 11) 4961-6027/8/9 Fax: 4961-6020 www.sac.org.ar revista@sac.org.ar