The Impact of Obesity on the Efficacy of Simvastatin for Lowering Low-Density Lipoprotein Cholesterol in a Veteran Population

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Rachel A. Sharpton, PharmD, BCACP; Paul J. Laucka, PharmD, CGP; Robyn N. McKeller, PharmD, MPH; Marsha A. Dangler, PharmD, BCACP; Julie S. Horne, PharmD, BCPS; and Jeremiah Y. Dangler

A retrospective review found that obesity did not impact the lipid- lowering effectiveness of simvastatin therapy.

ore than one-third of 18% of subjects in the Long-Term without obesity were not compared.9 Americans and > 20% of Intervention with Pravastatin in Studies that have examined statin veterans have obesity with Ischaemic Disease (LIPID) trial were efficacy in those with and without a body mass index (BMI) classified as having obesity, and sub- obesity include the Heart Protection M 2 1,2 ≥ 30 kg/m . It is well documented jects in the Scandinavian Simvastatin Study (HPS), a post hoc analysis of that patients with obesity have al- Survival Study (4S) trial had a mean the West of Scotland Coronary Pre- tered lipid metabolism, drug dis- BMI of only 26 kg/m2.7,8 Though vention Study (WOSCOPS), and a tribution, and drug clearance.3-5 As statins decreased mortality in both of meta-analysis by Blassetto and col- many as 8.2 million Americans may these studies, it is unknown whether leagues. The HPS examined the event receive statin (3-hydroxymethylglu- the lipid-lowering effects were the rate of vascular events with simvas- taryl coenzyme A reductase inhibi- same for participants with and with- tatin 40 mg daily in patients with dia- tors) prescriptions if the American out obesity. The Primary preven- betes mellitus (DM).10 Though these College of Cardiology/American tion of cardiovascular disease with subgroups were compared in HPS, Heart Association 2013 Cholesterol atorvastatin in type 2 diabetes in no statistical difference was demon- Guidelines are followed; therefore, the Collaborative Atorvastatin Dia- strated between these groups for the it is important to examine how the betes Study (CARDS) demonstrated rate of vascular events among those efficacy of these drugs is altered in a decrease in major cardiovascular with and without DM.10 However, patients with obesity.6 events and all-cause mortality with the obesity subgroup’s event rate ra- Multiple studies have examined atorvastatin 10 mg daily therapy in tios were consistently higher than the benefits of statin therapy through a sample where more than one-third were those for the nonobese group.10 lowering low-density lipoprotein of subjects had obesity.9 However, A post hoc analysis of WOSCOPS cholesterol (LDL-C); however, few the mean baseline BMI of subjects in examined obesity as a factor for have examined the impact of obesity both study groups was only 28 kg/ change in LDL-C with pravastatin on statin efficacy. For example, only m2, and outcomes for those with and 40 mg therapy.11 Though the authors found that no significant difference At the time this study was written, Dr. Sharpton was a PGY1 pharmacy resident; Dr. Laucka, Dr. McKeller, and was present between those with Dr. Dangler were clinical pharmacy specialists; Dr. Horne was a management and program analyst at the VA and those without obesity, the data Office of Informatics and Analytics; all at James H. Quillen VAMC in Mountain Home, Tennessee. Mr. Dangler supporting this claim were not dis- was a lecturer/manager at East Tennessee State University, College of Computing in Johnson City. Currently Dr. Sharpton holds a faculty position at the Ben and Maytee Fisch College of Pharmacy, University of Texas at closed, which makes drawing clini- Tyler. Dr. Dangler now is lead pharmacist at the University of Washington Medical Center Ambulatory Pharmacy, cal conclusions from this analysis and Mr. Dangler is a solution principle at Slalom Consulting, both in Seattle, Washington.

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follow-up lipid panel were excluded, Table. Baseline Characteristics as were those who had not filled a Characteristics BMI < 30 BMI ≥ 30 simvastatin prescription within 30 days of their baseline lipid panel. Simvastatin 20 mg N = 661 N = 1,122 Also excluded were patients who a Age, y 60.5 56.6 were newly established at the VA, Male, % 93.6 93.5 pregnant, or receiving concomitant BMI, kg/m2 26.2 35.0a antihyperlipidemia agents, dialy- AST/ALT 30/30 32/36 SCr, mg/dL 1.03 1.03 sis, or interacting medications (ta- crolimus, cyclosporine, atazanavir, Hemaglobin A1c 6.3 6.7 Baseline LDL-C, mg/dL 145 141a darunavir, nelfinavir, saquinavir, ritonavir, indinavir, lopinavir, tip- Simvastatin 40 mg N = 259 N = 219 ranavir, fosamprenavir, fluconazole, Age, y 61.7 55.4a voriconazole, itraconazole, voricon- Male, % 97.4 97.9 azole, posaconazole, amiodarone, BMI, kg/m2 26 34.7a or colchicine). Patients with a BMI AST/ALT 30/30 32/37 2 SCr, mg/dL 1.03 1.01 < 18 kg/m , hepatic failure as mea- sured by an aspartate transaminase/ Hemaglobin A1c 6.4 6.7 Baseline LDL-C, mg/dL 145 138 alanine transaminase (AST/ALT) ratio > 3 times the upper limit of Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; SCr, serum creatinine. normal, hepatitis, a history of alco- aP < .05. holism, any change in statin dose prior to follow-up cholesterol val- difficult.11 A meta-analysis by Blas- This network services more than ues, or no follow-up LDL-C values setto and colleagues examined the 350,000 patients each year in Ten- also were excluded. association between rosuvastatin’s nessee, Kentucky, and West Virginia. The baseline data collected in- efficacy in lowering LDL-C among Data were gathered and analyzed on cluded age, sex, weight, height, BMI, the subgroups of hypertension, ath- the VA Informatics and Computing hemoglobin A1c, LDL-C, ALT/AST, erosclerosis, type 2 DM, and obe- Infrastructure (VINCI) servers. Pa- and serum creatinine (SCr). All other sity.12 Though these subgroups were tients were included in this study if laboratory results were required to be not compared statistically, the obe- they were aged ≥ 18 years with a new within 270 days of the time the lipid sity subgroup had the lowest mean filled prescription for simvastatin panel was obtained. The index date percent change in lowering LDL-C. 20 mg or simvastatin 40 mg daily. was set as the date the initial pre- Moreover, patients without obesity Simvastatin was chosen because it scription was filled between February were not examined as a subgroup.12 was the formulary statin during 1, 2009 and April 1, 2014. Follow-up With the expected increase in the study period. This study was levels for LDL-C were obtained 40 to statin therapy and a significant por- approved by the James H. Quillen 95 days after the index date. Direct tion of the U.S. population having VAMC/East Tennessee State Univer- LDL-C values were preferred unless obesity, it is necessary to determine sity Institutional Review Board. only calculated values were available. if obesity alters the efficacy of statins. Patients were excluded if they Calculated LDL-C values were deter- This study was conducted to de- had received treatment for hyper- mined by using the Friedewald equa- termine the effect of obesity on the lipidemia (niacin, colestyramine, tion. An audit of 150 patient charts percent change in LDL-C with statin colestipol, colesevelam, other was conducted to ensure the integrity therapy within a veteran population. statins, gemfibrozil, fenofibrate, of data pulled from the database. omega-3 ethyl esters, ezetimibe) The percent changes in LDL-C METHODS during the 6 weeks prior to the ini- were calculated for those with and This study was a retrospective review tial fill date of the statin prescrip- without obesity for both simvastatin examining follow-up data from Janu- tion. Patients whose simvastatin 20 mg daily and simvastatin 40 mg ary 1, 2009 to July 1, 2014 from the therapy did not span the follow-up daily. The primary outcome was VA Midsouth Healthcare Network. period from the time of filling to the the percent change in LDL-C from

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baseline. All laboratory values were compared using independent 2-tailed Figure. Mean Change in LDL-C From Baseline t tests with α set to .05. To have an 35 80% chance of detecting a 5% difference in percent change in LDL-C be- 30.38 30 tween the experimental and control 27.84 28.07 26.74 groups, 129 patients were required. To determine whether an association 25 was present, a correlation between BMI and percent change in LDL-C 20 was conducted. All statistics were conducted using SAS software (Cary, North Carolina). 15 LDL-C Change, % LDL-C Change, RESULTS 10 From January 2009 through July 2014, 35,216 patients were initially 5 screened. The majority of patients did not have a baseline LDL-C value and were excluded. A total of 1,183 pa- 0 tients with simvastatin 20 mg daily Body Mass Index ≥ 30 Body Mass Index<30 (BMI < 30 = 661; BMI ≥ 30 = 1,122) ■ Simvastatin 20 mg ■ Simvastatin 40 mg and 478 patients with simvastatin Abbreviation: LDL-C, low-density lipoprotein cholesterol. 40 mg daily (BMI < 30 = 259; BMI ≥ 30 = 219) met the inclusion criteria. Baseline characteristics were vastatin dosage (r2 = 0.0016 and with those below the median BMI similar between groups except 0.0028, respectively). for patients on pravastatin therapy. for a slightly higher age in both However, the authors did find a dif- groups without obesity (Table). DISCUSSION ference in percent change LDL-C Hepatic and renal serum markers In this retrospective chart review, it with atorvastatin therapy.13 No dif- indicated a baseline of adequate was determined that obesity did not ference in percent change LDL-C organ function for drug clearance affect the percent change in LDL-C was present with simvastatin ther- for all groups. The mean baseline from baseline with statin therapy. The apy in this study. As simvastatin is BMI of those without obesity was HPS found similar results as a sec- more lipophilic than is atorvastatin, about 26 kg/m2, which is consid- ondary endpoint, although that study lipophilicity remains an area for fur- ered overweight. Baseline LDL-C was underpowered.10 In this study, all ther study for statin therapy in pa- values were clinically similar groups met power, and there was still tients with obesity. for those with and without obe- no difference between those with and The surrogate marker of percent sity, though statistically different without obesity. change in LDL-C was used for the (145 mg/dL for the nonobese group Nicholls and colleagues ex- primary outcome in this study. The and 141 mg/dL for the obese group, amined REVERSAL study data ACC/AHA 2013 guidelines and the P < .05). The percent change in to determine whether BMI National Lipid Association 2014 LDL-C was not statistically signifi- greater than the median BMI im- guidelines recommend an alterna- cant for those with and without pacted inflammatory markers tive goal of 30% to 50% change in obesity for simvastatin 20 mg daily or lipid levels with atorvastatin LDL-C from baseline.14,15 Using (P = .293) or simvastatin 40 mg 80 mg daily or pravastatin 40 mg this clinically relevant marker com- daily (P = .2773) (Figure). No cor- daily. The REVERSAL study au- pensated for differences in base- relation was found between the con- thors found no difference in per- line LDL-C and limited the effect tinuous percent change in LDL-C cent change LDL-C between those of these differences on the primary and continuous BMI for either sim- above the median BMI compared outcome of this study.

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Limitations Disclaimer 8. Pedersen TR, Kjekshus J, Berg K, et al; Scandinavian Simvastatin Survival Study Group. Randomised This study did not include pa- The opinions expressed herein are those trial of cholesterol lowering in 4444 patients with tients who were underweight (BMI of the authors and do not necessarily coronary heart disease: the Scandinavian Simvas- 2 tatin Survival Study (4S). 1994. Atheroscler Suppl. < 18 kg/m ), as these patients have reflect those of Federal Practitioner, 2004;5(3):81-87. previously demonstrated decreased Frontline Medical Communications 9. Colhoun HM, Betteridge DJ, Durrington PN, 16 et al; CARDS investigators. Primary preven- outcomes with statin therapy. Inc., the U.S. Government, or any of its tion of cardiovascular disease with atorvastatin However, this limits these data to agencies. This article may discuss un- in type 2 diabetes in the Collaborative Atorv- astatin Diabetes Study (CARDS): multicentre only those patients that have a BMI labeled or investigational use of certain randomised placebo-controlled trial. Lancet. of at least 18 kg/m2. Limitations of drugs. Please review the complete pre- 2004;364(9435):685-696. 10. Collins R, Armitage J, Parish S, Sleigh P, Peto R; this study also included the inability scribing information for specific drugs Heart Protection Study Collaborative Group. MRC/ to consider adherence and lifestyle or drug combinations—including indi- BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabe- changes. These limitations were un- cations, contraindications, warnings, tes: a randomised placebo-controlled trial. Lancet. avoidable due to the nature of a ret- and adverse effects—before administer- 2003;361(9374):2005-2016. 11. Streja L, Packard CJ, Shepherd J, Cobbe S, Ford I; rospective chart review. ing pharmacologic therapy to patients. WOSCOPS Group. Factors affecting low-density lipoprotein and high-density lipoprotein cholesterol response to pravastatin in the West Of Scotland CONCLUSION REFERENCES Coronary Prevention Study (WOSCOPS). Am J Car- The prevalence of obesity is increas- 1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Preva- diol. 2002;90(7):731-736. lence of childhood and adult obesity in the United 12. Blasetto JW, Stein EA, Brown WV, Chitra R, Raza A. ing, and it is a disease that alters phar- States, 2011-2012. JAMA. 2014;311(8):806-814. Efficacy of rosuvastatin compared with other statins macokinetics and lipid metabolism. 2. Shen Y, Sambamoorthi U, Rajan M, Miller D, Ba- at selected starting doses in hypercholesterolemic nerjea R, Pogach L. Obesity and expenditures patients and in special population groups. Am J Car- Though this study did not find a dif- among elderly Veterans Health Administra- diol. 2003;91(5A):3C-10C; discussion 10C ference between the LDL-C-lowering tion users with diabetes. Popul Health Manag. 13. Nicholls SJ. Tuzcu EM, Sipahi I, et al. Effect of 2009;12(5):255-264. obesity on lipid-lowering, anti-inflammatory, efficacy of simvastatin in those with 3. Chan DC, Watts GF, Wang J, Hegele RA, van Bock- and antiatherosclerotic benefits of atorvastatin or and without obesity, continued study xmeer FM, Barrett PH. Variation in Niemann-Pick pravastatin in patients with coronary artery dis- C1-like 1 gene as a determinant of apolipopro- ease (from the REVERSAL Study). Am J Cardiol. of the effect of obesity on the efficacy tein B-100 kinetics and response to statin therapy 2006;97(11):1553-1557. of medications is vital. in centrally obese men. Clin Endocrinol (Oxf). 14. Stone NJ, Robinson JG, Lichtenstein AH, et al; 2008;69(1):45-51. American College of Cardiology/American Heart 4. Cheymol G. Effects of obesity on pharmacokinetics Association Task Force on Practice Guidelines. Acknowledgments implications for drug therapy. Clin Pharmacokinet. 2013 ACC/AHA Guideline on the treatment of 2000;39(3):215-231. blood cholesterol to reduce atherosclerotic cardio- This material is the result of work sup- 5. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect vascular risk on adults: a report of the American ported with resources and the use of of obesity on the pharmacokinetics of drugs in hu- College of Cardiology/American Heart Association mans. Clin Pharmacokinet. 2010;49(2):71-87 Task Force on Practice Guidelines. J Am Coll Car- facilities at the James H. Qullen VAMC 6. Pencina MJ, Navar-Boggan AM, D’Agostino RB diol. 2014;63(25, pt B):2889-2934. in Mountain Home, Tennessee. Sr, et al. Application of new cholesterol guide- 15. Jacobson T, Ito M, Maki K, et al. National Lipid lines to a population-based sample. N Engl J Med. Association recommendation for patient-centered 2014;370(15):1422-1431. management of dyslipidemia: part 1-full report. J Author disclosures 7. Prevention of cardiovascular events and death with Clin Lipidol. 2015;9(2):129-169. pravastatin in patients with coronary heart disease 16. Nylén ES, Faselis C, Kheirbek R, Myers J, Pan- The authors report no actual or poten- and a broad range of initial cholesterol levels. The agiotakos D, Kokkinos P. Statins modulate the tial conflicts of interest with regard to Long-Term Intervention with Pravastatin in Isch- mortality risk associated with obesity and cardio- aemic Disease (LIPID) Study Group. N Engl J Med. respiratory fitness in diabetics. J Clin Endocrinol this article. 1998;339(19):1349-1357. Metab. 2013;98(8):33940-3401.

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