Ezetimibe/simvastatin

Ezetimibe/simvastatin

Combination of
Ezetimibe	via Niemann-Pick C1-Like 1 protein
Simvastatin	Statin HMG-CoA reductase inhibitor
Clinical data
Routes of administration	Oral
ATC code	C10BA02 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
CompTox Dashboard (EPA)	DTXSID80196177

Ezetimibe/simvastatin (Template:PronEng) is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe (best known as Zetia in the United States) and the statin drug simvastatin (best known as Zocor in the U.S.). The combination preparation is marketed by Merck & Co./Schering-Plough Pharmaceuticals (joint venture) under the trade names Vytorin and Inegy.

Ezetimibe reduces blood cholesterol by inhibiting absorption of cholesterol by the small intestine by acting at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver.

Simvastatin is an HMG-CoA reductase inhibitor or statin. It works by blocking an enzyme that is necessary for the body to make cholesterol.

Pharmacology

The combination of Ezetimibe and Simvastatin is the only product to treat both sources of cholesterol; absorption in the intestine of both biliary and dietary cholesterol, and production in the liver and peripheral tissues. It is thought that the treatment of high cholestrol from both sources is likely to result in lower cholesterol levels, particularly LDL cholesterol. In a clinical study, it was shown that the combination of Ezetimibe and Simvastatin was superior to Lipitor in lowering LDL cholestrol.

Clinical trials

ENHANCE trial data

The two year ENHANCE Study, released by the manufacturer as an abstract, recently failed to provide evidence that ezetimibe/simvastatin was better than simvastatin (a generic medication) in terms of achieving a lower change from baseline in carotid intima-media thickness despite lower LDL levels in a population of patients with heterozygous familial hypercholesterolemia (a form of high cholesterol that affects less than 1% of patients). Clinical events such as heart attack and stroke were not measured as primary or secondary endpoints of the study making it impossible to determine Vytorin's effect on these events. Data from studies specifically designed to answer this question are expected within the next few years.

Subsequent debate and enquiries

The American College of Cardiology released a statement suggesting that "major clinical decisions not be made on the basis of the ENHANCE study alone", given the small and unique patient population, 720 patients in an Amsterdam hospital with heterozygous familial hypercholesterolemia.

Merck and Schering Plough have reported that they have three trials underway to focus on outcomes, measuring the drug's effect on heart attacks and strokes in patients.

The results of the ENHANCE study have been long anticipated. These results were presented in full at the American College of Cardiology meeting on 30 March 2008. The House Committee on Energy and Commerce has started an inquiry into the delayed disclosure of the study data; In addition there is an ongoing investigation into Carrie Smith Cox, Schering-Plough’s president, who sold 900,000 shares of company stock in April and May of 2007 worth an estimated $28 million. This massive sell off comes after the ENHANCE trial was complete.

Finally there is an inquiry into the popular Vytorin brand, direct-to-consumer (DTC) ads. The companies continued spending at least $155 million a year on TV ads that heralded Vytorin’s supposed superiority over statins alone, while withholding the ENHANCE results.

IMPROVE-IT trial

Vytorin is currently undergoing another randomized control trial (IMPROVE-IT). This trial will measure the effects of Vytorin vs. simvastatin alone in determining primary outcomes of cardiovascular and cerebrovascular events in 18,000 patients who have been hospitalized for an acute coronary syndrome. The patients will be followed for a minimum of 2.5 years. The trial is expected to end in 2012.

Advertising campaign

In the United States, the Vytorin brand has become rather well known for its television advertising campaign showing a series of split-screen images of a person and a food item to make the point that cholesterol comes from two sources and can be absorbed from food or manufactured by the body, and that heredity plays a role in the latter. This point is a departure from the commonly held belief that high cholestrol only comes from the food that you eat. In each commercial, the person is dressed, and the food plated, to emphasize the resemblance between the person and the food. For example, in one advertisement a woman wearing a yellow shirt with a red and green pin is intended to look like a taco.

Contraindications

• Acute liver disease
• Pregnancy and breast feeding

Side effects

• Myopathy
• Rhabdomyolysis
• Myalgia
• Pain in extremities, abdomen,
• Angioedema
• Hepatitis
• Eczema
• Fatigue
• Headache
• Influenza, Pharyngitis, sinusitis and upper respiratory tract infection
• Depression.

In July 2008, the drug was linked to an increase in risk of cancer. A major clinical trial has also found that the medication had failed to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process, researchers in Norway detected a significant blip in cancers in the 1,800 subjects they followed.[1] FDA is investigating the possible association.[2]

Interactions

• Cyclosporine
• Danazol
• Protease inhibitors
• Verapamil
• Amiodarone
• Large amounts of niacin (nicotinic acid), grapefruit juice
• Erythromycin, telithromycin, clarithromycin
• Nefazodone

External links

• Vytorin's Official Site
• Vytorin Information Sheet
• [3]