Original Research

A Conversion Protocol for Simvastatin and Gemfibrozil

Fed Pract. 2014 July;31(7):22-27

Author(s):

Eliminating gemfibrozil from a statin-containing regimen may be safe and effective for patients with low triglyceride levels.

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References

1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22.

2. 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(8934):1383-1389.

3. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. 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 (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497.

4. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high density lipoprotein cholesterol level: A meta-analysis of population based prospective studies. J Cardiovasc Risk. 1996;3(2):213-219.

5 Gotto AM Jr. High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. Am Heart J. 2002;144(suppl 6):S33-S42.

6 Pedersen TR, Tobert JA. Benefits and risks of HMG-CoA reductase inhibitors in the prevention of coronary heart disease: A reappraisal. Drug Saf. 1996;14(1):11-24.

7. Zocor [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2014.

8. Rubins HB, Robins SJ, Collins D, et al; for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341(6):410-418.

9. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317(20):1237-1245.

10. Backman JT, Kyrklund C, Kivistö KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68(2):122-129.

11. U.S. Food and Drug Administration. FDA Drug Safety Communication: High Dose Simvastatin. U.S. Food and Drug Administration Website. http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Updated January 3, 2013. Accessed June 13, 2014.

12. SEARCH Collaborative Group, Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: A double-blind, randomised trial. Lancet. 2010;376(9753):1658-1669.

13. Gaist D, Rodríguez LA, Huerta C, Hallas J, Sindrup SH. Lipid-lowering drugs and risk of myopathy: A population based follow-up study. Epidemiology. 2001;12(1):565-569.

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15. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: A meta-analysis of population-based prospective studies.J Cardiovasc Risk. 1996;3(2):213-219.

16. Labreuche J, Deplanque D, Touboul PJ, Bruckert E, Amarenco P. Association between change in plasma triglyceride levels and risk of stroke and carotid atherosclerosis: Systematic review and meta-regression analysis. Atherosclerosis. 2010;212(1):9-15.

17. De Caterina R, Scarano M, Marfisi R, et al. Cholesterol-lowering interventions and stroke: Insights from a meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2010;55(3):198-211.

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22. U.S. Food and Drug Administration. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. U.S. Food and Drug Administration Website. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm#sa. Update July 7, 2012. Accessed May 30, 2014.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for the development of coronary artery disease (CAD). For the past decade, lowering LDL-C has been the main focus in the treatment of dyslipidemia.1-3 Significant evidence also exists that hypertriglyceridemia is related to complications, including pancreatitis, and may also be independently linked to cardiovascular risk.4,5

Current treatment guidelines, published by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), establish LDL-C reduction as the primary goal and triglyceride (TG) reduction as the secondary goal. If TG levels are significantly elevated (> 500 mg/dL), then TG becomes the primary goal due to increased risk of pancreatitis.³

Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor, has long been the drug of choice in the VA system for the treatment of dyslipidemia, despite its risks, which include myalgias, myopathy, and rhabdomyolysis.⁶ Incidence of true statin-induced myopathy or rhabdomyolysis is very low, estimated to occur in < 1% of high-dose simvastatin users; the benefits of statin use are often thought to outweigh the risks of therapy.^6,7

In the Helsinki Heart Study and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), gemfibrozil reduced TG concentrations by 20% to 50%. Gemfibrozil was shown to be useful in both the primary and secondary prevention of CAD and demonstrated mortality reduction in patients with CAD.^8,9 The combination of gemfibrozil with simvastatin has been discouraged due to the increased risk of muscle-related complications; however, in practice, the medications are often prescribed concomitantly. A pharmacokinetic study reported that gemfibrozil increased the measured area under the curve concentration of simvastatin 2-fold, likely the reason that rates of myopathy and rhabdomyolysis are 6 times greater when simvastatin is used in combination with gemfibrozil.¹⁰

In June 2011, the FDA released new recommendations on the use of simvastatin, which included a dose limit of 40 mg (previously the maximum simvastatin dose was 80 mg) and new drug combination contraindications.¹¹ These recommendations were made in light of the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial, a large, randomized, placebo-controlled trial that revealed a significantly higher rate of myopathy and rhabdomyolysis with simvastatin than had other previous studies.¹² Medications cited to increase risk of simvastatin-induced muscle injury included gemfibrozil, and combination therapy is now considered a contraindicated treatment option.^10-13

In August 2011, the Pharmacy and Therapeutics (P&T) Committee at the Ralph H. Johnson VA Medical Center in Charleston, South Carolina, reviewed the FDA warning and approved an automatic conversion protocol to be applied to patients prescribed both gemfibrozil and simvastatin. First, the primary goal of therapy (either TG or LDL-C reduction) was determined. TG reduction was considered the primary goal if patients had a history of TG level of > 500 mg/dL or TG-induced pancreatitis; LDL-C was the primary goal in all other patients.

Once the goal of therapy was determined, options for intervention included discontinuation of gemfibrozil, statin dose escalation, and/or addition of niacin or fish oil. In patients whose TG concentration met NCEP goal < 150 mg/dL, gemfibrozil was discontinued. Statin dose was escalated if needed for further LDL-C reduction. Per P&T recommendations, a clinical pharmacist evaluated each patient, made an intervention based on the P&T approved protocol, and sent a letter, which described the intervention and the reason for the action, to each patient.

This study evaluated the outcome of the P&T committee-approved automatic conversion protocol in subgroups of patients prescribed simvastatin and gemfibrozil with a TG serum concentration ≤ 150 mg/dL at baseline (Figure 1).

Methods

A retrospective chart review was conducted on all patients who had prescriptions for gemfibrozil and simvastatin, prescribed in the 52 weeks before August 15, 2011; patient records were reviewed between September 1, 2011, and April 30, 2012. Patients were included for study analysis if they underwent a P&T committee-approved conversion algorithm between September 1, 2011, and December 31, 2011, were aged 18 to 88 years, and their most recent TG measurement was ≤ 150 mg/dL.

Only those patients who had a fasting lipid panel documented in the 56 weeks preceding the study intervention and who returned for a follow-up lipid panel within 6 to 24 weeks following the intervention were included in the study analysis. Patients were excluded from the analysis if they received prescriptions for simvastatin or gemfibrozil from pharmacies outside the VA system, if their cholesterol medications were adjusted during the observation period outside of the initial intervention, if they had any lifetime history of TG > 500 mg/dL or pancreatitis, or if the subjects were incarcerated or pregnant at any time during the study period.