Original Research

A Conversion Protocol for Simvastatin and Gemfibrozil

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

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.

14. Lindenstrøm E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: The Copenhagen City Heart Study. BMJ. 1994;309(6946):11-15.

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.

18. Nofer JR. Hyperlipidemia and cardiovascular disease: Triglycerides—a revival of cardiovascular risk factor? Curr Opin Lipidol. 2011;22(4):319-321.

19. ACCORD Study Group; Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Eng J Med. 2010;362(17):1563-1574.

20. Keech A, Simes RJ, Barter P, et al; FIELD Study Investigators. Effects of long term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): Randomised controlled trial. Lancet. 2005;366(9500):1849-1861.

21. Mayo Clinic. Liver function tests. Mayo Clinic Website. http://www.mayoclinic.org/tests-procedures/liver-function-tests/basics/results/prc-20012602. Accessed May 30, 2014.

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.

A meta-analysis of 17 prospective studies of Western subjects found TGs to be an independent risk factor for cardiovascular disease (CVD) endpoints; RR was 1.14 in men (95% CI, 1.05 – 1.28) and 1.37 in women (95% CI, 1.13 – 1.66) per 88.6 mg/dL increase in TGs.¹⁵ The association of increased TG concentrations with increased risk of stroke has been validated in 2 other meta-analyses.^16,17 Based on these data, there is a correlation between elevated TGs and CVD; however, as Dr. Jerzy-Roch Nofer discusses in an editorial published in 2011 in Current Opinion in Lipidology, the importance of a risk factor is contingent on finding benefit with treatment.¹⁸

Two large interventional studies, ACCORD (Action to Control Cardiovascular Risk in Diabetes trial) and FIELDS (Fenofibrate Intervention and Event Lowering in Diabetes trial), did not show a beneficial effect on cardiovascular morbidity and mortality after a clear TG reduction.^19,20 The ACCORD and FIELDS studies suggest that although elevated TGs may be associated with elevated cardiovascular risk, no clear protective relationship exists when TGs are reduced to the goal level. Patients in this study who had gemfibrozil discontinued exhibited an increase in TG concentrations; however, the clinical significance of the change is minimal.

Additionally, none of the patients in this study had a TG concentration ≥ 500 mg/dL after the intervention; only 1 of 89 had a TG ≥ 300 mg/dL. This information indicates that most of the patients who were receiving both gemfibrozil and simvastatin likely did not need medical management of their TG levels to begin with. As mentioned earlier, numerous studies did not find a direct causal relationship between the reduction of cardiovascular risk after treating TG concentrations and the NCEP ATP III goal < 150 mg/dL.

There was a small yet significant increase in average ALT in the group of patients who met both LDL-C and TG goals at baseline at follow-up. The increase in ALT met criteria for statistical significance, but both values were maintained within the range of normal values (defined as 7 to 55 units/L by the Mayo Clinic).²¹ Additionally, the FDA no longer recommends routine monitoring of LF tests during statin therapy in patients with no history of abnormal results.²² The authors concluded that the change in ALT was an incidental finding and did not require further investigation.

The retrospective study design and small patient population limit the external validity of the study. Additionally, the authors did not assess patient compliance with therapy before or after the intervention, which may have skewed the results. Future studies may be designed in a randomized, controlled fashion and would ideally include a broader patient population.

This study provides evidence that can be used in future clinical decisions. Patients in this study may have had slightly elevated TG levels when gemfibrozil was initiated; however, all patients with a history of TG ≥ 500 mg/dL were excluded in this study. None of the patients reached the critical threshold at study follow-up despite a history of TG ≥150 mg/dL (but ≤ 500 mg/dL). This study provides further compelling information that practitioners should aggressively focus on reaching LDL-C and non−HDL-C goals before addressing TG concentrations.

Conclusions

Implementation of an automatic conversion protocol in patients prescribed both simvastatin and gemfibrozil with a baseline TG ≤ 150 mg/dL did not adversely affect lipid control. Patients whose LDL-C met goal preintervention maintained their LDL-C goal at follow-up. Additionally, patients who were not meeting LDL-C goals did not have an increase in LDL-C after the intervention, although there was not a significant improvement in LDL-C either. Both groups demonstrated a statistically significant increase in TG levels after discontinuation of gemfibrozil; however, the clinical significance of the TG change was limited. The results of this study support eliminating gemfibrozil from a statin-containing regimen in patients with low TG who are prescribed the combination.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.