Over the last several decades, the public has gained awareness about dyslipidemia (abnormal cholesterol levels) and has increased their usage of cholesterol-lowering medication. In 1988, 5% of the population used dyslipidemia medications. Though that percentage has increased to 23% today, 31% of men and 24% of women still have elevated LDL-C (low density lipoprotein cholesterol) levels. The unresolved prevalence of dyslipidemia invites another look at the current guidelines.
According to the 2013 guidelines set by the American College of Cardiology and the American Heart Association (ACC/AHA), the current first line therapy for decreasing elevated LDL-C levels is a statin. Statins also known as or HMG-COA reductases Inhibitors include:
If LDL-C goal is not met, the statin dose is increased or changed to a more potent one. If the patient is still uncontrolled, the addition of another agent is considered. An alternate treatment strategy that has shown promise is the addition of a drug called Zetia.
What is Zetia?
Zetia (ezetimibe) was developed by Merck and approved by the Food and Drug Administration on October 25, 2002. Approximately two years later on July 23, 2004, Vytorin, a fixed dose combination of ezetimibe and simvastatin was approved by the FDA. Zetia works in the digestive tract where it blocks the absorption of cholesterol from food. Zetia, when used in conjunction with a statin reduces LDL-C levels by an additional 15 to 20 percent. However, there has been no evidence that adding Zetia to a treatment regimen reduced a patient’s risk of experiencing heart attack or stroke. This recently changed when the results of a long time trial were revealed at the American Heart Association Scientific Sessions meeting on November 17, 2014.
Zetia and Vytorin are indicated as adjunctive therapies to diet for the reduction of elevated total cholesterol, LDL cholesterol, apolipoprotein B, and non-HDL cholesterol in patients with primary hyperlipidemia. Zetia is available as a 10 mg tablet. Vytorin is a fixed dose combination of ezetimibe (10 mg) with varying strengths of simvastatin (10, 20, 40 and 80 mg). Both medications can be taken once daily with or without food
Zetia and Vytorin are well tolerated with common adverse reactions such as the common cold, muscle pain, upper respiratory tract infections, joint pain and diarrhea. Patients should be counseled about skeletal muscle effects such as myopathy (muscle pain) and rhabdomyolysis (breakdown of muscle) that might increase relative to the dose of statin administered. With simvastatin 80 mg, a higher incidence of rhabdomyolysis has been observed. Patients who have been using Vytorin 10/80mg for more than twelve months without incident can continue treatment. However, new patients should not be be titrated up to this dosage.
Zetia and Vytorin should be avoided in patients with moderate to severe liver impairment. They should not be used in patients who are pregnant, who plan to become pregnant or who are breastfeeding. If the patient has a known allergy to any of the components in Zetia or Vytorin, they should not take these medications.
Until now, Zetia has been used in conjunction with a statin without knowing if it was truly beneficial to the patient. However, the results from the IMPROVE-IT trial show a clear benefit to adding Zetia to a statin regimen to further lower LDL-C levels.
Results of IMPROVE-IT TRIAL: Benefit of Vytorin (ezetimibe plus simvastatin) therapy in patients with acute coronary syndromes
High-risk patients currently treated with statins, including those with decreased LDL-C levels, are still at increased cardiovascular risk. The IMPROVE-IT trial enrolled 18,144 high-risk patients who presented with acute coronary syndromes. The purpose was to determine whether lowering LDL-C well under 70 mg/dL by adding ezetimibe to a statin would further reduce the incidence of cardiovascular events such as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, readmission into hospital for unstable angina, and coronary revascularization within 30 days of the initial event. Patients were randomized to treatment with Vytorin 10/40 mg or simvastatin 40 mg. They were followed for nine years with a median follow-up period of about six years. Initially, the average baseline LDL-C was approximately 95 mg/dL. Within one year, the average LDL-C level of patients on Vytorin decreased to 53 mg/dL versus 70 mg/dL for patients on simvastatin monotherapy. Throughout the duration of the study, 5,314 primary events were reported.
The primary composite endpoint was defined as death due to any cardiovascular event, non-fatal myocardial infarction (MI), non-fatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization (≥30 days postrandomization). At 7 years, 32.7% of patients on Vytorin experienced a primary endpoint versus 34.7% of patients on simvastatin alone. The difference was statistically significant.
Vytorin reduced the composite secondary endpoint of death due to all causes, major coronary events and non-fatal stroke. This endpoint was seen in 38.7% of patients on Vytorin compared to 40.3% of patients taking simvastatin alone. It also reduced the risk of death due to coronary heart disease, non-fatal MI, and coronary revascularization with a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) occurring within 30 days of the initial event. This endpoint was seen in 17.5 percent of patients on Vytorin compared to 18.9% of patients on monotherapy simvastatin. Vytorin reduced hospitalization within 30 days of an event that occurred as a result of cardiovascular death, non-fatal MI, and unstable angina. This endpoint was seen in 34.5% of patients on Vytorin compared to 36.2% of patients in the simvastatin group.
In the IMPROVE-IT trial, the addition of ezetimibe to a statin resulted in a greater reduction in cardiovascular events compared to monotherapy with a statin. This is the first time a non-statin cholesterol-lowering medication has directly shown these results in a study.
The results of the IMPROVE-IT trial show a significant decrease in the number of patients who experienced cardiovascular events when taking Zetia with a statin. However, Zetia is not indicated for acute coronary syndromes. Merck plans to submit data from the trial to the US Food and Drug Administration in mid-2015 to support a new indication for reduction of major cardiovascular events for Vytorin and Zetia.
The positive results from the IMPROVE-IT trial call for a change to the current ACC/AHA guidelines. The use of Zetia in conjunction with a statin may become a mainstay in therapy for patients with acute coronary syndromes. Additionally, the benefit seen from lowering LDL-C levels well under 70 mg/dL suggests that individuals with acute coronary syndromes and LDL-C under 70 mg/dL should be included as a statin benefit group in ACC/AHA guidelines. Hopefully, future studies will address the effect of Zetia and Vytorin on morbidity and mortality.
US National Institutes of Health. IMPROVE-IT: Examining Outcomes in Subjects with Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (P04103). ClinicalTrials.gov. From: http://www.clinicaltrials.gov/ct2/show/NCT00202878?term=IMPROVE-IT&rank=1.
Merck Newsroom: Vytorin (ezetimibe/simvastatin) Significantly Reduced Cardiovascular Events More than Simvastatin Alone in Patients Presenting with Acute Coronary Syndromes in the Investigational IMPROVE-IT Study.
Blazing, MA, Giugliano RP, Cannon CP et al. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18.144 patients after acute coronary syndromes: final baseline characteristics of the IMPROVE-IT study population. American Heart Journal. 2014 Aug: 168(2): 205-12.
Kuklina EV, Carroll MD, Shaw, KM et al. Trends in High LDL Cholesterol, Cholesterol-lowering Medication Use and Dietary Saturated-fat Intake: United States, 1976-2010. Centers for Disease Control and Prevention; NCHS Data Brief. Number 117, March 2013.
Vytorin Prescribing Information (Package Insert, Label)
Zetia Prescribing Information (Package Insert, Label)