Ezetimibe and Atorvastatin Tablets (Liptruzet™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A second ezetimbe/statin combination has been approved by the FDA for the treatment of hyperlipidemia. Ezetimibe is now combined with atorvastatin and is marketed by Merck & Co. as Liptruzet.
Ezetimibe and atorvastatin (EZT/ATO) is indicated as adjunctive therapy to diet to reduce elevated total cholesterol (total-C), LDL-cholesterol (LDL-C), Apo B, triglycerides (TG), and non-HDL-cholesterol (non HDL-C), and to increase HDL-cholesterol (HDL-C) in patients with primary hyperlipidemia or mixed hyperlipidemia.1 It is also indicated to reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments.
The recommended starting dose is 10/10 mg or 10/20 mg once daily. If a LDL-C reduction of > 55% is required, the recommended starting dose is 10/40 mg once daily. The tablets may be taken any time of the day without regard to meals.
EZT/ATO is available as 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg tablets.
The addition of EZT to a statin is more effective than doubling the statin dose in terms of LDL-C reduction.1,2
The addition of EZT does not appear to provide incremental benefit on cardiovascular morbidity and mortality.1
EZT/ATO is a new, potent lipid-lowering drug combination. EZT inhibits the absorption of cholesterol at the brush borders of the small intestines and ATO is a potent inhibitor of HMG-CoA reductase. The combination of EZT and ATO has the potential to achieve mean reductions in LDL-C of 61%, total-C 46%, Apo B 50%, TG 40%, and non-HDL-C 58%.1 The addition of EZT to ATO achieved greater reduction than doubling the dose of ATO. The benefit is greatest at the lower dose. LDL-C reduction achieved with 10/10 mg was 53% compared to 42% for 20 mg ATO. The reductions for 10/20 mg vs 40 mg were 54% and 45%, and 10/40 mg and 80 mg were 56% and 54%, respectively. There does not appear to be additional risk of myopathy or rhabdomyolysis with the addition of EZT.1 The benefit of EZT beyond lipid lowering is still unclear. A recent Japanese study (n = 243) reported that increasing the dose of ATO (10 mg to 20 mg) can improve endothelial function (assessed by logarithmic-scale reactive hyperemia index), but adding EZT (10/10 mg) resulted in additional LDL-C reduction but no change in endothelial function.3
The combination of EZT/ATO provides another option for patients with highly elevated plasma lipids to help them achieve target levels. The clinical benefit of the addition of EZT to a statin has been controversial and its routine clinical use questioned.4 The landmark ENHANCE study showed that the addition of EZT to simvastatin did not reduce the progression of intima-media thickness in the walls of the carotid and femoral arteries in patients with familial hypercholesterolemia compared to simvastatin alone.5 In contrast, in a population of patients with chronic kidney disease with no history of myocardial infarction or coronary revascularization (Study of Heart and Renal Protection; n = 9270), patients randomized to simvastatin 20 mg plus EZT 10 mg, compared to simvastatin 20 mg, had significant reductions in atherosclerotic events (11.3% vs 13.4%), non-hemorrhagic stroke (2.8% vs 3.8%), and arterial revascularization (6.1% vs 7.6%) during a median follow-up of 4.9 years.6 Numerically, the risk of non-fatal myocardial infarction or death from coronary heart disease favored EZT/ATO (4.6% vs 5.0%, P = 0.37). In a small pre-post observational study (n = 231), investigators reported a regression in carotid total plaque area 2 years after EZT was added.7 The definitive clinical benefit of adding EZT to ATO beyond lipid lowering still remains to be determined.
1. Liptruzet Prescribing Information. Whitehouse Station, NJ: Merck & Co.; May 2013.
2. Mikhailidis DP, et al. Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: Systematic review and meta-analysis. Curr Med Res Opin 2011;27:1191-1210.
3. Matsue Y, et al. Differences in action of atorvastatin and ezetimibe in lowering low-density lipoprotein cholesterol and effect on endothelial function. Circ J 2013; Apr 19. [Epub ahead of print.]
4. Doggrell SA. The ezetimibe controversy – Can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin Pharmacother 2012;13:1469-1480.
5. Kastelein JJ, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-1443.
6. Baigent C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): A randomised placebo-controlled trial. Lancet 2011;377:2181-2192.
7. Bogiatzi C, Spence JD. Ezetimibe and regression of carotid atherosclerosis: Importance of measuring plaque burden. Stroke 2012;43:1153-1155.