ZETIA improves the effect of statins on cholesterol

[Guest guest]

Has anyone tried this drug yet? It does not seem to have any interaction problems and it further increases cholesterol reduction when taken with statins. It blocks the absorption of cholesterol accross the intestinal walls, while statins block the production of cholesterol in the liver. Most people with HIV who have high LDL cholesterol and taking statins can not achieve the target levels recommended by National Cholesterol Education Program (NCEP) Adult Treatment panel guidelines, so this drug seems to increase the chances for that to happen when used in combination with statins. Unlike fibrates and niacin combos, Zeta may not increase the changes of myopathy (muscle weakness) or rhabdomyolysis (destruction of muscle cells that can cause renal failure).

I also think that similar results can be achieved if someone exercises with statins.

FDA Approves ZETIAâ„¢ (ezetimibe) for Cholesterol Reduction

First New Class To Treat Cholesterol Since Statins Introduced 15 Years Ago; Studies Show Significant Reductions in LDL Cholesterol When Added to All Statins Tested

WHITEHOUSE STATION and KENILWORTH, N.J., Oct. 25, 2002 -- Following a 10-month review, the FDA has approved ZETIA™ (ezetimibe), the first in a new class of cholesterol-lowering agents that inhibits the intestinal absorption of cholesterol, Merck/Schering-Plough Pharmaceuticals announced today. The once-daily tablet of ZETIA 10 mg was approved for use either by itself or together with statins in patients with high cholesterol to reduce LDL “bad†cholesterol and total cholesterol. Cholesterol-lowering medicines should be used in addition to an appropriate diet when the response to diet and exercise has been inadequate.

In clinical trials, ZETIA was generally well tolerated with an overall side effect profile similar to placebo.

“Sixty percent of the estimated 13 million patients taking statins continue to have LDL cholesterol higher than recommended levels,†said H. Brewer, M.D., chief of the molecular disease branch, National Heart, Lung and Blood Institute, National Institutes of Health (NIH). “As the first breakthrough to treat cholesterol since statins were introduced 15 years ago, ZETIA provides physicians with a new option to get more of these patients to goal.

This is particularly important in view of last year’s changes to the NIH’s cholesterol guidelines, which substantially expand the number of Americans eligible for drug therapy and call for lower cholesterol goals for many patients,†he said.

“Discovered by Schering-Plough scientists and developed in partnership with Merck, ZETIA offers patients an important therapeutic advance in the treatment of high cholesterol,†said Jay Kogan, chairman and chief executive officer of Schering-Plough. “ZETIA is expected to be a major growth driver for Schering-Plough and an important new entry in the global cholesterol management market, now valued at $19 billion,†he added.

ZETIA has a unique, complementary mechanism of action

Cholesterol in the blood is controlled primarily by two organs: the liver, which produces cholesterol and bile acids (which are used in digestion), and the intestine, which absorbs cholesterol both from food and from the bile (made by the liver). ZETIA lowers cholesterol through a unique mechanism of action by inhibiting cholesterol absorption in the intestine. This mechanism of action makes ZETIA complementary to statins, which work in the liver. Therefore, patients who take ZETIA with a statin can achieve additional reductions in LDL and total cholesterol. The mechanism of ZETIA is also quite different from a currently available class of drugs known as “bile acid sequestrants,†which lower cholesterol by physically binding to bile acids in the small intestine.

ZETIA is administered as a once-daily tablet in a single 10 mg strength. It can be taken with or without food.

ZETIA is a prescription medicine and should not be taken by people who are allergic to any of its ingredients. When ZETIA is prescribed with a statin, it should not be taken by anyone with active liver disease or unexplained persistent liver enzyme elevations. All statins are contraindicated in such patients and in pregnant and nursing women. When ZETIA is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin.

ZETIA added to ongoing statin treatment provided 25 percent (36 mg/dL) additional LDL cholesterol reduction vs. 4 percent (6 mg/dL) with addition of placebo

In a pivotal, multi-center study known as the “Add-On†study, patients who had not reached their LDL cholesterol goal on a stable dose of a statin alone had ZETIA or placebo added to their statin regimen. The statin dose remained constant. The study showed that adding ZETIA to ongoing statin treatment provided a 25 percent (36 mg/dL) additional reduction in LDL cholesterol versus 4 percent (6 mg/dL) with the addition of placebo. Mean LDL cholesterol levels of patients on statin therapy dropped from 138 mg/dL to 102 mg/dL when ZETIA was added versus a drop from 139 mg/dL to 133 mg/dL when placebo was added. Most of the response in LDL cholesterol reduction was seen within two weeks of adding ZETIA and the additive reduction provided by ZETIA was generally consistent across all statins tested.

“The approval of ZETIA represents a major success of the U.S. joint venture between Merck and Schering-Plough and demonstrates the value of external collaboration and key strategic partnerships,†said V. Gilmartin, chairman, president and chief executive officer, Merck & Co., Inc. â€There is tremendous potential for ZETIA to positively impact the treatment of millions of statin-treated patients who need additional cholesterol reduction.â€

Seventy-two percent of statin-treated patients not at goal reached NCEP II goal when ZETIA was added to ongoing statin treatment vs. 19 percent with addition of placebo

Another important endpoint of the “Add-On†study was the percentage of patients who reached the National Cholesterol Education Program (NCEP) II target LDL cholesterol goal when either ZETIA or placebo was added to their ongoing statin therapy. The study showed that 72 percent of the patients who were not at goal on their statin dose at baseline reached goal when ZETIA was added, compared to 19 percent of patients with the addition of placebo.

Patients enrolled in the study had been taking any dose of a marketed statin for a minimum of six weeks and had not reached their LDL cholesterol goal. At the beginning of the study, mean baseline LDL cholesterol concentrations were 139 mg/dL for the statin plus placebo group versus 138 mg/dL for the group on statin plus ZETIA. Sixty-eight percent of these patients had LDL cholesterol goal <100 mg/dL, 23 percent had a goal of <130 mg/dL and 10 percent had a goal of <160 mg/dL.

ZETIA delivered significant reductions in LDL cholesterol when co-administered with all statins tested, including Lipitor and Zocor

The U.S. approval of ZETIA was also based on four placebo-controlled co-administration studies, in which ZETIA and either Lipitor (atorvastatin), Zocor (simvastatin), Pravachol (pravastatin) or Mevacor (lovastatin) were started together in previously untreated patients with high cholesterol levels.

“These studies showed that ZETIA, given with statins, provided impressive reductions in LDL cholesterol compared to statins alone and at all doses tested,†said son, M.D., director of preventive cardiology, Rush-Presbyterian-St. Luke’s Medical School, Chicago. “This includes the two most commonly used statins, Lipitor and Zocor, demonstrating consistent efficacy while also being generally well tolerated.â€

When ZETIA was initiated with Lipitor 10 mg, the most frequently prescribed starting dose, there was a 53 percent reduction in LDL cholesterol from the original untreated baseline. This was significantly more effective than the LDL cholesterol-lowering achieved by Lipitor 10 mg (37 percent), Lipitor 20 mg (42 percent), or 40 mg (45 percent) alone. ZETIA provided significant reductions across all doses of Lipitor.

A similar study with Zocor showed that administering ZETIA with Zocor 20 mg, the most frequently prescribed starting dose, resulted in a 46 percent reduction in LDL cholesterol. This was significantly more effective than reductions achieved with 20 mg (36 percent) or 40 mg (38 percent) of Zocor alone, and was similar to the LDL cholesterol reduction seen with Zocor 80 mg (45 percent) by itself. ZETIA provided significant reductions across all doses of Zocor.

Both of these studies were 12-week, double-blind studies in patients with high cholesterol (n=628 for the co-administration study with Lipitor; n=668 for the co-administration study with Zocor), evaluating the efficacy and safety of ZETIA on LDL cholesterol when given with either Lipitor or Zocor, compared to these statins taken alone. Mean baseline LDL cholesterol in these studies ranged from 176 mg/dL to 180 mg/dL across treatment groups.

ZETIA co-administered with Lipitor and Zocor further improved triglycerides and HDL “good†cholesterol

In patients with elevated LDL cholesterol, ZETIA, when used with statins, was also shown in the co-administration studies with Lipitor and Zocor to reduce triglycerides and increase HDL “good†cholesterol more than the statins alone.

In the co-administration study with Lipitor:

Triglycerides were reduced by 33 percent with ZETIA plus Lipitor compared to 24 percent for Lipitor alone.

HDL cholesterol was improved by 7 percent with ZETIA plus Lipitor versus 4 percent for Lipitor alone. The results from the co-administration study with Zocor showed:

Triglycerides were reduced by 29 percent with ZETIA plus Zocor compared to 20 percent for Zocor alone.

HDL cholesterol was improved by 9 percent with ZETIA plus Zocor versus 7 percent for Zocor alone.

These results were statistically significant and reflect average changes across all statin doses. The effect of ZETIA alone or in addition to a statin on the risk of cardiovascular morbidity and mortality has not been established.

ZETIA demonstrated an excellent safety and tolerability profile

ZETIA has been evaluated for safety in more than 4,700 patients in clinical trials. Clinical studies of ZETIA (administered alone or with a statin) demonstrated that ZETIA was generally well tolerated. The overall incidence of adverse events reported with ZETIA was similar to that reported with placebo, and the discontinuation rate due to adverse events was also similar for ZETIA and placebo.

For monotherapy, the most frequent adverse events reported with greater incidence than placebo, regardless of causality, were back pain (4.1 percent vs. 3.9 percent) and arthralgia (3.8 percent vs. 3.4 percent). In co-administration with a statin, the most frequent adverse events reported with greater incidence for ZETIA plus statin versus statin or placebo alone, regardless of causality, were back pain (4.3 percent vs. 3.7 percent vs. 3.5 percent, respectively) and abdominal pain (3.5 percent vs. 3.1 percent vs. 2.3 percent, respectively).

When ZETIA was co-administered with a statin, consecutive elevations in liver enzymes more than three times the upper limit of normal were slightly higher than those of statin alone (1.3 percent vs. 0.4 percent). These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment. ZETIA had no significant effect on drugs known to be metabolized by the cytochrome P450 system. Co-administration with cholestyramine has been shown to decrease the bioavailability of ZETIA while co-administration with gemfibrozil has been shown to increase the bioavailability. Because of significantly increased blood levels of ZETIA in one patient on multiple medications including cyclosporine, patients who take both ZETIA and cyclosporine should be carefully monitored.

Important information about ZETIA

When ZETIA is used with a statin, liver function tests should be performed at the start of therapy and after that in accordance with the label for that statin. Liver function tests are not required when ZETIA is used alone. Due to the unknown effects of the increased exposure to ZETIA in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients. In clinical trials, there was no increased incidence of myopathy or rhabdomyolysis associated with ZETIA. However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. There are no adequate and well-controlled studies of ZETIA in pregnant women. ZETIA should not be used in pregnant or nursing women unless the benefit outweighs the potential risks. The safety and effectiveness of ZETIA with fibrates have not been established; therefore, co-administration with fibrates is not recommended.

Other indications

The FDA also approved ZETIA for use in two rare genetic disorders: homozygous familial hypercholesterolemia and homozygous sitosterolemia. In homozygous familial hypercholesterolemia, ZETIA, administered with Lipitor or Zocor, is indicated for the reduction of elevated total cholesterol and LDL cholesterol as an adjunct to other lipid-lowering treatments.

In sitosterolemia, ZETIA is indicated as adjunctive therapy for the reduction of elevated sitosterol and campesterol levels in addition to diet. ZETIA is the only medicine approved for this serious condition.

Price and availability

The catalog price to all direct purchasers for ZETIA 10 mg is $57.90 for a 30-day supply. Prices at the retail level are independently established by pharmacies, not by Merck/Schering-Plough Pharmaceuticals. The 10 mg tablets of ZETIA should be widely available in pharmacies within two to three weeks.

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed in May 2000 to develop and market in the United States new prescription medicines in cholesterol management. The collaboration was expanded in December 2001 to include worldwide markets (excluding Japan).

MERCK FORWARD-LOOKING STATEMENT: This press release contains “forward-looking statements†as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties which may cause results to differ materially from those set forth in the statements. The forward-looking statements include statements regarding product development and product potential. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Additional detailed information concerning a number of factors that could cause actual results to differ materially is available in Item 1 of Merck’s Annual Report on Form 10-K for the year ended Dec. 31, 2001, in its periodic reports on Form 10-Q and in its reports on Form 8-K (if any). Copies of these forms are available on request to Merck’s Office of Stockholder Services.

SCHERING-PLOUGH FORWARD-LOOKING STATEMENT: The information in this press release includes certain “forward-looking†information including the size of the cholesterol treatment market, the market potential for ZETIA and its projected availability in the marketplace. The reader of this release should understand that the extent that ZETIA will be prescribed will be determined by market forces and the market viability of ZETIA is subject to substantial risks and uncertainties. In addition, the forward-looking statements may also be adversely affected by general market factors, competitive product development, product availability, the extent of market acceptance of new products, current and future branded, generic or over-the-counter competition, federal and state regulations and legislation, the regulatory process for new products and indications, manufacturing issues, trade buying patterns, patent positions, litigation and investigations. For further details and a discussion of these and other risks and uncertainties, see the company’s Securities and Exchange Commission filings, including the company's 2001 annual report on Form 10-K and subsequent quarterly reports on Form 10-Q and current reports on Form 8-K.

View the PDF of the physician Prescribing Information for ZETIA.

[Guest guest]

Thanks . This is a very encouraging report. Sounds like a good

alternative to combining statins and fibrates. My biggest concern

might be whether it could effect levels of HIV drugs. Although they

do say that Zetia had no significant effect on drugs known to be

metabolized by the cytochrome P450 system.

Glenn