Clinical Trials News

Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia Did Not Result In A Difference I In Intima–Media Thickness

2008-04-04T14:22:00.000-07:00

A reduction in levels of low-density lipoprotein (LDL) cholesterol constitutes one of the cornerstones in the prevention of cardiovascular disease. In recent trials comparing various statins or the same statin at various doses, aggressive therapy to lower LDL cholesterol levels was associated with a reduction in rates of cardiovascular events.1,2,3,4 However, administration of the highest approved statin dose offers only limited additional lowering of LDL cholesterol at the expense of an increased incidence of side effects.5 Therefore, novel compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. A recently introduced compound, ezetimibe, selectively inhibits cholesterol absorption by binding to the Niemann–Pick C1-like 1 (NPC1L1) protein. The latter is located at the brush-border membrane of the enterocyte, where it contributes substantially to the intestinal uptake and cellular transport of cholesterols and noncholesterol sterols.6,7 Combined therapy with ezetimibe and a statin provides an incremental reduction in LDL cholesterol levels of 12 to 19%.8,9

In this study, we sought to determine whether the daily administration of 10 mg of ezetimibe in combination with 80 mg of simvastatin could reduce the progression of atherosclerosis in patients with familial hypercholesterolemia, as assessed by measurement of arterial intima–media thickness. The rationale for studying patients with familial hypercholesterolemia is that such patients have a greatly increased risk of premature coronary artery disease10 and an increased rate of progression of intima–media thickness starting in childhood.11 In our study, called the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, we used B-mode ultrasonographic imaging of the intima–media thickness in the carotid and femoral arteries as a surrogate measure to assess the progression of atherosclerosis

The results of our study showed that the addition of ezetimibe to the highest recommended dose of simvastatin did not reduce the intima–media thickness of the carotid-artery wall in this cohort of patients with familial hypercholesterolemia, despite significant incremental reductions in levels of both LDL cholesterol and C-reactive protein. The primary outcome, the change in the mean intima–media thickness, did not differ significantly between the two study groups, nor did the secondary outcome measures.

There are at least three possible explanations for the absence of an incremental reduction in the intima–media thickness in patients receiving ezetimibe: the lack of vascular benefit conferred by ezetimibe despite the observed reduction in LDL cholesterol level, the inability of the measurement technique to accurately reflect changes in atherosclerotic burden, and the possibility that the study population had too low a risk, which would limit our ability to detect a differential response to the two interventions.

The first explanation to consider is that the lowering of LDL cholesterol levels by a drug other than a statin might be ineffective for slowing atherosclerosis. Thus, the fact that ezetimibe-induced lowering of LDL cholesterol levels was not associated with an incremental effect on carotid-artery intima–media thickness could be due to the different mechanisms of action of ezetimibe, as compared with those of statins. In addition to the capacity of statins to lower LDL cholesterol levels, the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase also leads to a plethora of lipid-independent effects involving antiinflammatory action and improvement in endothelial function.15 A direct comparison between ezetimibe and statins revealed differential effects on endothelial function favoring statin therapy despite similar reductions in LDL cholesterol,16,17 although this finding has not been consistent in all studies.18 Also, dose intensification of statins in patients with familial hypercholesterolemia resulted in a further reduction in the progression of intima–media thickness in the carotid artery.19 Thus, it can be argued that certain lipid-independent effects of statins that are not shared by ezetimibe are involved in the production of a vascular benefit.

However, several facts argue against the concept that ezetimibe-induced lowering of LDL cholesterol levels does not produce additional vascular benefit beyond that of statins. First, a recent regression meta-analysis showed that the lipid-independent effects of statins did not confer an additional risk reduction beyond that expected from the degree of the lowering of the LDL cholesterol level.20 Second, data from the Program on Surgical Control of the Hyperlipidemias (POSCH) trial showed that reductions in levels of LDL cholesterol after ileocecal bypass were associated with significant reductions in cardiovascular mortality and event rates similar to those observed in statin-prevention trials.21,22 In view of the controversy regarding the lipid-independent effects of statins, the results of ongoing clinical trials comparing statins with combined therapy with ezetimibe and a statin are eagerly awaited to resolve this issue.

Large epidemiologic studies have provided strong associations between intima–media thickness and stroke, angina pectoris, and myocardial infarction.10,11 In the Atherosclerosis Risk in Communities (ARIC) study involving 15,800 adults, an increase of 0.2 mm in the mean carotid-artery intima–media thickness was associated with an increase in relative risk for myocardial infarction and stroke of 33% and 28%, respectively.23 This close relationship between intima–media thickness and cardiovascular risk has subsequently been corroborated in several other studies.24

One of the principal determinants of atherosclerosis progression has proved to be LDL cholesterol levels, as confirmed by the linear relationship between the level of LDL cholesterol and intima–media thickness.25 This finding is further supported by the observation that progression in intima–media thickness is significantly attenuated in statin intervention studies in both adult and pediatric patients with familial hypercholesterolemia.11,19,26,27,28,29,30,31,32 On the basis of this information, the measurement of intima–media thickness can be considered as a validated surrogate marker for atherosclerotic vascular disease. Also, in view of the precision of the measurements in our study, as exemplified by the high intraclass correlation coefficient and the small standard deviations, it seems unlikely that we were unable to detect a truly significant change in arterial-wall measures using our measurement technique.

Patients with familial hypercholesterolemia are known to be at greatly increased risk for premature coronary artery disease,10 accompanied by accelerated progression of intima–media thickness starting in childhood.11 However, the treatment of patients with familial hypercholesterolemia has witnessed profound changes. Currently, the majority of patients with familial hypercholesterolemia are treated with high-dose statins starting at an early age. Such therapy can be expected to attenuate the progression of intima–media thickness, as was shown in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study.19 Thus, it is not unexpected that the baseline carotid intima–media thickness in our study was lower than that observed in earlier trials involving patients with familial hypercholesterolemia33 and in most other previous lipid-modifying trials,26,27,31 with the exception of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 1 (ARBITER-1) study.31 Among patients who received 80 mg of simvastatin only in our study, the progression of intima–media thickness was 0.0029 mm per year, as compared with 0.018 mm per year in patients with familial hypercholesterolemia who received 40 mg of simvastatin in the ASAP study — a reduction by a factor of 6 among patients receiving the higher dose. In further support of the influence of previous statin therapy, progression of intima–media thickness in the carotid artery decreased to 0.005 mm per year during long-term daily therapy with 80 mg of atorvastatin in the ASAP extension study,34 a finding that contrasts with the substantial reductions in intima–media thickness seen during the first 2 years of the trial. In the Rating Atherosclerotic Disease Change by Imaging with a New CETP [Cholesteryl Ester Transfer Protein] Inhibitor (RADIANCE 1) study,35 the most recent study involving a similar group of patients with familial hypercholesterolemia, the pattern of change in intima–media thickness after a mean daily dose of 57 mg of atorvastatin was very similar to that observed in both groups in our study. These data raise the possibility that there may be limits to the extent to which the lowering of LDL cholesterol levels can result in a further decrease in the progression of intima–media thickness in the context of previous statin therapy and a modest baseline intima–media thickness.

In conclusion, the reduction of LDL cholesterol by the addition of ezetimibe to simvastatin did not reduce intima–media thickness of the carotid-artery wall in patients with familial hypercholesterolemia in our study. The reason for the failure to observe an incremental effect on intima–media thickness despite a reduction in levels of LDL cholesterol remains unknown.

Supported by Merck and Schering-Plough.

Merck/Schering-Plough Pharmaceuticals Comments On Results Of The ENHANCE Study

2008-03-31T03:26:00.000-07:00

Results of ENHANCE (Ezetimibe aNd simvastatin in Hypercholesterolemia enhANces atherosClerosis rEgression), an imaging trial in 720 patients with heterozygous familial hypercholesterolemia (HeFH), a rare genetic condition that causes very high levels of LDL "bad" cholesterol and greatly increases the risk for premature coronary artery disease, were presented at the 57th annual scientific sessions of the American College of Cardiology and also were published on-line in The New England Journal of Medicine.i

As previously reported on Jan. 14, 2008, despite the fact that ezetimibe/simvastatin 10/80 mg (VYTORIN® *) significantly lowered LDL "bad" cholesterol more than simvastatin 80 mg alone, there was no significant difference between treatment with ezetimibe/simvastatin and simvastatin alone on the pre-specified primary endpoint, a change in the thickness of carotid artery walls over two years as measured by ultrasound. There also were no significant differences between treatment with ezetimibe/simvastatin and simvastatin on the four pre-specified key secondary endpoints: percent of patients manifesting regression in the average carotid artery intima-media thickness (CA IMT); proportion of patients developing new carotid artery plaques >1.3 mm; changes in the average maximum CA IMT; and changes in the average CA IMT plus in the average common femoral artery IMT.

In ENHANCE, when compared to simvastatin alone, ezetimibe/simvastatin significantly lowered LDL "bad" cholesterol, as well as triglycerides and C-reactive protein (CRP). Ezetimibe/simvastatin is not indicated for the reduction of CRP. In the ENHANCE study, as previously reported, the overall safety profile of ezetimibe/simvastatin in the study was generally consistent with the product label.

"LDL cholesterol remains the primary target of lipid-modifying therapy and physicians should continue to lower patients' elevated LDL cholesterol and get their patients to their goals based on guidelines," said Michael Davidson, M.D., professor, director of preventive cardiology, The University of Chicago, Pritzker School of Medicine.

In the ENHANCE publication, the authors provided three theoretical explanations why, despite ezetimibe/simvastatin significantly lowering LDL "bad" cholesterol more than simvastatin (56 percent vs. 39 percent, p<0.01), there was no significant difference between treatment groups on the primary endpoint and four key secondary endpoints: (1) lowering of LDL cholesterol with non-statin therapy, such as ezetimibe, might affect IMT differently than statin therapy, (2) the imaging technology selected was not sensitive enough to detect a difference, or (3) that these HeFH patients were extensively pretreated with lipid-lowering therapy, thereby limiting the amount that CA IMT could change with further LDL cholesterol-lowering therapy, consequently limiting the ability to detect a differential response to the two treatments. The authors concluded that the reason for the failure to observe an incremental effect on CA IMT thickness in spite of a reduction of level of LDL cholesterol remains unknown.

In the publication, the authors addressed the premise that the lack of a difference in change of mean CA IMT between ezetimibe/simvastatin and simvastatin despite greater LDL cholesterol-lowering could be attributed to lipid-independent effects of statins on arteries. The authors presented several facts that argued against this concept, including a discussion of clinical studies involving statin and non-statin therapeutic approaches that demonstrated that cardiovascular risk reductions were associated with the degree of LDL-cholesterol lowering. The authors suggested that clinical outcomes data are needed to answer this question.

As for the hypothesis that the results may reflect the imaging technology, the authors noted this seems unlikely given the precision of the imaging measurement results seen in the ENHANCE trial.

With respect to the hypothesis that the ENHANCE results were due to the characteristics of the patients studied, the authors pointed out that in an earlier imaging study (extension of ASAP or Atorvastatin vs. Simvastatin on Atherosclerosis Progression study) use of potent lipid-lowering therapy in HeFH patients produced "regression" or "thinning" of CA IMT during the first one to two years of therapy, but further decreases during the following two years on the same therapy were not seen. In ENHANCE, approximately 80 percent of the enrolled patients reported taking statin treatment at the time of screening for the study, and had a mean baseline CA IMT of 0.69 to 0.70 mm. In another recent IMT study in HeFH patients (RADIANCE 1 or Rating Atherosclerotic Disease Change by Imaging with A New CETP Inhibitor study), the baseline CA IMT was also lower than in the earlier IMT study and similar to ENHANCE and, importantly, the pattern of change in CA IMT in this IMT study was very similar to that observed in both treatment groups in the ENHANCE study.

The authors noted that "these data raise the possibility that there may be limits to the extent to which the lowering of LDL cholesterol levels can result in a further decrease in the progression of intima-media thickness in the context of previous statin therapy and a modest baseline intima-media thicknessii."

"Although a definitive explanation is never possible with a finding like this, we believe that the most likely explanation for the failure to see a significant difference between treatment groups in ENHANCE relates to the behavior of IMT in this population of HeFH patients," noted Thomas Musliner, M.D., executive director, Cardiovascular Disease, Clinical Research, Merck Research Laboratories. "The large majority of these patients were previously treated with LDL cholesterol-lowering therapy and presumably experienced an effect on CA IMT from that treatment, as reflected in the patients' relatively low CA IMT values when they began the study. The findings of the ASAP extension, RADIANCE 1 and ENHANCE suggest there are limits to how much IMT can be decreased in HeFH study cohorts in the context of the widespread and prolonged use of effective LDL cholesterol-lowering treatment starting at an earlier age, which is now the standard of care for these patients."

Endpoint data and cardiovascular events

ENHANCE investigators found no statistically significant difference between the two treatment groups on the primary endpoint, the change in the average CA IMT at three carotid artery locations. The change from baseline in the mean (average) CA IMT in the ezetimibe/simvastatin group was 0.0111 mm, which did not significantly differ from the simvastatin group's change of 0.0058 mm (P=0.29). The median data for the primary endpoint, which also showed no statistical difference between treatments, was 0.0058 mm in the ezetimibe/simvastatin group and 0.0095 mm for the simvastatin group. The treatment groups also did not have statistically significant differences for each of the three carotid artery locations that comprised the primary endpoint: the common carotid, the internal carotid and the carotid bulb. The data for these analyses, key secondary endpoints and cardiovascular events are included in the attachment.

The ENHANCE study was not designed nor powered to evaluate cardiovascular clinical events. IMPROVE-IT is underway and is designed to provide cardiovascular outcomes data for ezetimibe/simvastatin in patients with acute coronary syndrome. No incremental benefit of ezetimibe/simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

Lipid parameters of LDL cholesterol, triglycerides and HDL cholesterol; and C-reactive protein Over the two-year period of the ENHANCE study based upon the "last observation carried forward" endpoint approach, the group treated with ezetimibe/simvastatin had a 56 percent mean reduction of LDL cholesterol (from a baseline of 319 mg/dL) that was significantly greater than the 39 percent mean reduction of LDL cholesterol (from a baseline of 318 mg/dL) in the group treated with simvastatin alone (P<0.01). The LDL cholesterol-lowering observed in patients treated with ezetimibe/simvastatin in the ENHANCE trial was generally consistent with the LDL cholesterol-lowering of ezetimibe/simvastatin seen in separate head-to-head studies vs. simvastatin, vs. Crestor® and vs. Lipitor®.

In addition, by study completion, the ezetimibe/simvastatin group had a 30 percent median reduction in triglycerides (from baseline 157 mg/dL), significantly more than the 23 percent median reduction (from baseline 160 mg/dL) in the simvastatin group (P<0.01). Also, the ezetimibe/simvastatin group had a 49 percent median reduction in CRP (from baseline 1.70 mg/L), significantly more than the 24 percent median reduction in CRP (from baseline 1.70 mg/L) in the simvastatin group (P<0.01). The ezetimibe/simvastatin group had a 10 percent increase (from baseline 46.7 mg/dL) in HDL "good" cholesterol; the simvastatin group had an 8 percent increase from baseline 47.4 mg/dL (P=0.05, no statistical significance).

Safety data

As previously reported, the overall safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels. Both medicines were generally well tolerated. Also, the overall incidence rates of treatment-related adverse events were 34 percent for ezetimibe/simvastatin (122/357) and 29 percent (107/363) for simvastatin only; the incidence rates for discontinuations due to adverse events were 8.1 percent for ezetimibe/simvastatin (29/357) and 9.4 percent for simvastatin only (34/363). Additional adverse event data are included in the attachment.

About the study design and methodology

The ENHANCE study was an international two-year, randomized, double-blind, controlled trial in 720 HeFH patients between the ages of 30 to 75. All of the ENHANCE patients had HeFH, which affects approximately 0.2 percent of the population. The rationale for studying HeFH patients is that these patients are known to be at increased risk for premature coronary artery disease and, if untreated, exhibit increased IMT progression rates beginning in childhood. Prior LDL cholesterol-lowering therapy of any kind was not an exclusion criterion for ENHANCE, although such therapies were discontinued at the start of the study. Also, there wasn't a minimum value for CA IMT specified for inclusion in study. Following a six-week, single blind, placebo lead-in/drug "wash-out" period, patients were randomized to receive either daily ezetimibe/simvastatin 10/80 mg (N=357) or daily simvastatin 80 mg (N=363).

ENHANCE investigators took digitized single-frame CA IMT images at the three locations of the patients' right and left carotid arteries, the main arteries in the neck that provide blood to the brain. These images were taken at several time points: study baseline, 6, 12, 18 and 24 months.

"Examination of the CA IMT collected during ENHANCE proved to be a far more challenging process than originally anticipated when the study design was drawn up. Therefore, preparation of the images for entry into a database took significantly longer than expected, as the blinded investigators and CA IMT evaluators took numerous steps in 2006 and 2007 to address image quality control and finalize the analysis," said Enrico P. Veltri, M.D., co-author of the ENHANCE study publication and group vice president, Global Clinical Research, Cardiovascular and Metabolic Diseases, Schering-Plough Research Institute. "Our companies acted with integrity and good faith in connection with the trial," he said.

Important information about VYTORIN

Ezetimibe/simvastatin is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.

Ezetimibe/simvastatin is also indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.

Ezetimibe/simvastatin is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. Ezetimibe/simvastatin should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take ezetimibe/simvastatin.

Selected cautionary information for VYTORIN

Muscle pain, tenderness or weakness in people taking ezetimibe/simvastatin should be reported to a doctor promptly because these could be signs of a serious side effect. Ezetimibe/simvastatin should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking ezetimibe/simvastatin.

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (>3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with ezetimibe/simvastatin and 2.6 percent for patients treated with ezetimibe/simvastatin 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (>3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with ezetimibe/simvastatin 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with ezetimibe/simvastatin when clinically indicated to check for liver problems. People taking ezetimibe/simvastatin 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ezetimibe/simvastatin is not recommended in these patients. The safety and effectiveness of ezetimibe/simvastatin with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating ezetimibe/simvastatin in patients treated with cyclosporine and in patients with severe renal insufficiency.

Ezetimibe/simvastatin has been evaluated for safety in more than 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan). VYTORIN is also marketed as INEGY outside the U.S.

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 are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

Vytorin : Not Better Than Cheaper Generic

2008-03-24T16:50:00.000-07:00

The tough times for the cholesterol drugs Vytorin and Zetia may be just beginning.

Full results of a controversial artery-imaging study are due to be presented March 30 at the annual meeting of the American College of Cardiology (ACC), following an unusual 18-month delay in releasing the negative results of the study by drug makers Schering-Plough (nyse: SGP - news - people ) and Merck (nyse: MRK - news - people ). The resulting controversy drew a congressional investigation and caused prescriptions for both drugs to slump 17%.

Shares of Schering and Merck plunged as investors fretted over the threat to a $5.2 billion cholesterol franchise. Zetia is a unique drug for lowering cholesterol; Vytorin combines it in one pill with the generic drug Zocor.

The problem: The delayed study couldn't prove that Vytorin prevents artery disease that leads to heart attacks and strokes any better than Zocor does, although it costs four times as much. A trial actually measuring whether the Vytorin combo prevents heart attacks better than Zocor won't be out until 2011. In the meantime, the lack of clear data could leave the companies in a long, slow battle to hold on to their sales.

They argue the controversy is "media-driven," and Wall Street analysts have expressed hopes that a scientific discussion of data will convince doctors, quiet doubters and stabilize sales of Zetia and Vytorin. But critics will be on hand, including Harlan Krumholz of Yale University, who will be among the top cardiologists discussing the data at the ACC meeting.

Cardiologists are torn about what to think of the imaging study, called ENHANCE. Prediman K. Shah, at Cedars Sinai Medical Center, says the results are "inconclusive." But he cautions, "It's not an unimportant study. It certainly raises questions, but doesn't answer them."

If it turns out that Zetia doesn't prevent heart attacks in the 2011 study, Merck and Schering are conducting, "we have some explaining to do," Shah says.

William Boden, a top cardiologist at the University of Buffalo, still uses the Zetia in rare cases and expects the big trial due in 2011 may vindicate it. But he warns his patients, "We don't really know if putting you on this additional drug will do anything more than make your numbers look better." He says the companies have "gotten a long-overdue pass on marketing a drug where there was no outcomes data."

Zetia, approved in 2002, works completely differently from drugs like Lipitor, Zocor and Crestor. The other medicines, called statins, work in the liver to lower blood levels of LDL, the "bad cholesterol." They also seem to have other benefits. Zetia works by preventing the absorption of cholesterol in food. Adding it to the other pills gives them an added LDL-lowering wallop with few side effects.

But some prominent doctors have questioned whether they can be sure that Zetia confers the same benefit as statins. Now, the ENHANCE study has given doubters ammunition.
Mounting Evidence

The first real convincing trial came in 1984, a test of the cholesterol-lowering drug Questran. It took seven years to prove a benefit from lowering LDL 12%. Sales of cholesterol drugs remained pretty low. Lopid, a cholesterol drug from Warner-Lambert, generated only $200 million in 1988. Merck introduced the first statin, Mevacor, in mid-1987; it generated $260 million in its first full year on the market.

"People regarded cholesterol as a major risk factor," says Boden. "But we didn't have very good treatments to lower it."

It was giant studies of the statins that finally convinced many doctors that lowering cholesterol saved lives. Mevacor and other statins were developed from genetic insights gleaned from patients with familial hypercholesterolemia. In 1994 and 1995, studies of Merck's Zocor, a Mevacor replacement, and Bristol-Myers Squibb's (nyse: BMY - news - people ) new Pravachol showed a striking 30% reduction in the risk of death for patients with established heart disease.

In 1998, cholesterol drugs were reportedly a $5 billion market. By 2000, that had tripled, according to drug data company IMS Health (nyse: RX - news - people ), and by 2002 they were the best-selling drug class in the world. The top dog was Pfizer's (nyse: PFE - news - people ) Lipitor. It was approved in 1996, getting a fast review because of its unprecedented ability to lower cholesterol in patients with the FH disorder that causes cholesterol levels of 300 or more. Within two years, Pfizer already had presented data showing that Lipitor prevented heart attacks and strokes.

But big studies to prove a statin reduces heart attacks and deaths are expensive and can take half a decade. So drug companies also pursued the approach of using ultrasound to measure the thickness of the wall of the carotid artery in the neck. Mevacor, Pravachol and Novartis' (nyse: NVS - news - people ) Lescol all have such ultrasound data in their product labels. A 2005 analysis in Current Controlled Trials in Cardiovascular Medicine concluded these imaging studies predicted how well the drugs would prevent heart attacks, strokes and deaths.
"No Valid Evidence"

When Zetia was approved in October 2002, cardiologists were starting to think that the lower they could get cholesterol with statins, the better. The refrain in studies, in company press releases and at medical meetings was that lower cholesterol is better. Some cardiologists argued that LDL levels should be brought down to levels seen most often in rural China. But many doctors were statin-shy because patients didn't like the muscle achiness and liver testsrequired with Lipitor, Zocor, and Pravachol.

Zetia seemed to represent a solution. Added to a low dose of a statin, Zetia lowers LDL as much as the top dose, with fewer side effects. Vytorin, approved in 2004, provided such a combo in a single pill, allowing patients to get it for one insurance co-payment. Sales ramped up fast. Zetia had annual sales of $900 million in 2004; Vytorin hit the same mark in 2005.

But that year, Rodney Hayward, a clinical researcher at the University of Michigan's School of Public Health, wrote that cardiologists may have gone too far in assuming lower is actually better. Patients at high risk of heart attacks do better on high doses of statins, he wrote in a 2005 issue of Annals of Internal Medicine, but it hasn't been proved that how low their LDL goes predicts their risk of heart attacks or strokes.

He also warned, "There is no valid clinical evidence to suggest that using treatments other than statins to pursue proposed LDL cholesterol goals is safe or effective."

Pfizer conducted 12 big studies to prove Lipitor's benefit, and AstraZeneca (nyse: AZN - news - people ) started three imaging trials and three trials measuring hard outcomes like heart attack and stroke. Merck and Schering started only one imaging study and three outcomes trials. A second imaging trial, with Steven Nissen of the Cleveland Clinic, was planned but never begun.

The most important study, due in 2011, is a 12,500-person trial to show whether adding Zetia to Zocor predicts heart attacks, strokes and heart procedures. The study was announced two years after Zetia was approved and started one year after that.
The Problem With ENHANCE

ENHANCE, involving 720 patients, began immediately in June 2002 and was modeled on an imaging study that had worked for Pfizer, called ASAP, conducted by John Kastelein of the University of the Netherlands. The patients in ASAP had FH, the genetic cholesterol disease. LDL, the bad cholesterol, was cut 50% on Lipitor, compared with 41% on Zocor. But while artery thickness increased by 0.036 millimeters on Zocor, it actually decreased by 0.031 millimeters on Lipitor.

ENHANCE was supposed to repeat that success, this time comparing Zocor and Vytorin. But it didn't. After delaying the release of the results for more than 18 months, the companies finally revealed data showing no statistically significant benefit in using the more expensive Vytorin. One explanation is that the patients in ENHANCE had been better treated and had less atherosclerosis, making it harder to prevent plaque buildup. Another is that lowering cholesterol with Zetia in addition to Zocor didn't provide a benefit in terms of slowing atherosclerosis.

"The full data will hopefully put in full perspective that there weren't any harmful effects at all," says A. Michael Davidson, executive medical director at Radiant Research. "This was a population that was so well treated that there wasn't really any opportunity to see any difference."

He says that FH patients are no longer a good population to use in these studies. He points out that LDL lowering is a main driver of the benefit of these drugs.

The danger to Merck and Schering this week isn't simply that the full data from the study will cause doctors to decide Zetia doesn't work. More doctors may decide they don't have enough data and use other drugs instead while they wait for the big trial the companies are conducting. Zetia and Vytorin will remain blockbusters, almost certainly. But if a significant minority of doctors find the ENHANCE results unconvincing, the drug makers will face strong headwinds, and a fast-growing brand could not only stagnate but also shrink.

This is what was happening to Vioxx, because of safety concerns, before Merck yanked it. And it's what happened with the schizophrenia drug Zyprexa, from Eli Lilly (nyse: LLY - news - people ), as prescriptions in the U.S. dropped because of concerns about weight gain and high blood sugar. And the companies spent a lot of their time defending these franchises when they needed to look for new opportunities for growth.

One person who won't be convinced by ENHANCE: Eric Topol, the noted chief of translational medicine at Scripps Health in La Jolla, Calif. He still wants to see clear data on how Zetia affects heart attacks, strokes and deaths, and doesn't understand why it took so long to embark on a big study to prove it.

Doctors have been "hanging in suspense for years, unnecessarily," Topol says. "It's still conceivable there would be improvement in outcomes. Until we have that data, the jury is out."

FDA Approval For SIMCOR(R) (Niaspan(R) / Simvastatin), A Novel Combination Medicine For Comprehensive Cholesterol Management

2008-02-16T08:08:00.000-08:00

Abbott received U.S. Food and Drug Administration (FDA) approval for SIMCOR(R), the first fixed-dose combination of two widely prescribed cholesterol therapies, Niaspan(R) (Abbott's proprietary niacin extended-release) and simvastatin. SIMCOR is approved for use along with diet to lower levels of elevated total cholesterol, LDL "bad" cholesterol and triglycerides, and to raise HDL "good" cholesterol in patients with complex lipid disease when treatment with simvastatin or Niaspan monotherapies are not considered adequate.

"Managing cholesterol encompasses many factors, not just lowering LDL. There is a clear need for medicines that both raise good and comprehensively lower the bad components of cholesterol," said Christie Ballantyne, M.D., the Methodist DeBakey Heart and Vascular Center, Houston, and lead SIMCOR investigator. "SIMCOR represents an important new option to help patients reach healthy lipid levels."

An estimated 80 million Americans have high levels of the bad LDL cholesterol, and more than 44 million have low levels of the good HDL cholesterol, which the body uses to remove bad cholesterol from the bloodstream. Studies have shown that along with diet, SIMCOR can help patients with lipid disorders reach their treatment goals by addressing more than just bad cholesterol, targeting multiple lipids with one pill.

The FDA's approval was based on SIMCOR safety and efficacy trial data from more than 640 patients with mixed dyslipidemia and type II hyperlipidemia. In the SEACOAST clinical trial, patients receiving SIMCOR 1000/20mg achieved significant cholesterol improvements over and above what simvastatin 20mg alone provided. Patients treated with SIMCOR 1000/20mg had additional lipid improvements beyond simvastatin 20-mg treated baseline, with additional LDL reductions of 12 percent and an additional 21 percent HDL increase compared to a 7 percent decrease in LDL and an 8 percent increase in HDL with simvastatin 20mg alone. Furthermore, SIMCOR reduced triglycerides by an additional 27 percent compared to 15 percent with simvastatin 20mg alone.

SIMCOR was generally well tolerated by patients in clinical studies. Six percent of patients discontinued therapy due to flushing, the most commonly reported side effect of SIMCOR and niacin-based therapies. Flushing can be minimized by taking aspirin or an NSAID 30 minutes prior to taking the medication at bedtime. Flushing may subside over several weeks of consistent SIMCOR use.

"With SIMCOR, doctors now have a new option for helping patients reach their LDL and HDL cholesterol treatment goals with a combination of two proven therapies," said Eugene Sun, M.D., vice president of Global Clinical Development for Abbott. "Abbott is committed to bringing forward new cholesterol therapies, and SIMCOR represents a new treatment option for patients in Abbott's rapidly expanding portfolio of cholesterol treatments for lipid disorders."

The American Heart Association, National Cholesterol Education Program (NCEP) and American College of Cardiology recommend more aggressive treatment of HDL to reduce cardiovascular risk. Cholesterol and other lipids can build up in the bloodstream forming plaque and restricting blood flow, which can lead to heart disease. According to NCEP guidelines, a reduction in LDL of 1 percent is associated with a 1 percent reduction in heart disease risk. Additionally, raising HDL by 1 point is associated with a 2 percent heart disease risk reduction.

Abbott is committed to the continued research of its products and has sponsored the National Heart Lung and Blood Institute's AIM-HIGH outcomes study. The study is designed to evaluate the effects of niacin extended- release and simvastatin in reducing cardiovascular events in patients with existing heart disease. AIM-HIGH began enrolling patients in 2005 with final results expected to be reported in 2011.

SIMCOR Indications

SIMCOR is the combination of two cholesterol-lowering medications: niacin extended-release (Niaspan(R)) and simvastatin. SIMCOR is used along with diet to lower levels of total cholesterol, LDL "bad" cholesterol and triglycerides, and to increase HDL "good" cholesterol. SIMCOR is used when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate, and when diet and other non-drug measures alone have not been successful. Patients should stay on a diet low in saturated fat and cholesterol while taking this medicine. No additional benefit of SIMCOR on heart disease over and above that shown for niacin alone and simvastatin alone has been demonstrated.

Important Safety Information About SIMCOR

SIMCOR should not be used by people with liver problems, stomach ulcers, or serious bleeding problems; in women who are pregnant, may become pregnant, or nursing; and in people allergic to any product ingredient. Patients should contact their health care provider if symptoms of unexplained muscle pain, tenderness, or weakness occur, as this may be a sign of a serious but rare muscle disorder, from which rare cases of death have occurred. Health care provider should be informed about any other medications, vitamins, or nutritional supplements people are taking to avoid possible serious drug interactions. SIMCOR should not be substituted for equivalent doses of immediate-release niacin. Liver damage has been reported when substituting sustained-release niacin products with immediate-release niacin at equivalent doses. Always check with a health care provider before changing medication. SIMCOR should be used with caution by patients who consume large amounts of alcohol. Health care providers may do simple blood tests before and during treatment with SIMCOR to check for liver problems.

SIMCOR may cause an increase in blood sugar levels. Patients with diabetes should report any changes in blood sugar levels to their health care provider. Women of childbearing age should use an effective method of birth control to prevent pregnancy while using SIMCOR. Flushing (warmth, redness, itching, and/or tingling of the skin) is the most common side effect and may become less frequent over time. Additional symptoms may include rapid or pronounced heartbeat, shortness of breath, sweating, chills, dizziness, fainting, and/or swelling. Flushing may vary in severity and is more likely to occur when starting therapy or during dose increases. By taking SIMCOR at bedtime, flushing will most likely occur during sleep. If awakened by flushing, patients should take their time getting up, especially if feeling dizzy, faint, or taking blood pressure medications. Other common side effects may include headache, itching, nausea, back pain, and diarrhea.

About Niaspan

Available since 1997, Niaspan is the only FDA-approved, once-daily extended-release prescription formulation of niacin for treating abnormal cholesterol levels.

Niaspan Indications

Niaspan is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate, to reduce elevated total cholesterol, LDL- C, Apo B, and triglyceride levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia. In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to reduce the risk of recurrent non-fatal myocardial infarction. In patients with coronary artery disease and hypercholesterolemia, niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.

Important Safety Information About Niaspan

Niaspan is contraindicated in patients with allergies to any of its ingredients, active peptic ulcer disease, significant or unexplained persistent liver dysfunction, or arterial bleeding. Niaspan should not be substituted for equivalent doses of immediate-release niacin. Niaspan should be prescribed with caution in patients who consume substantial amounts of alcohol and/or have a past history of liver disease. Liver function tests should be performed on all patients during therapy with Niaspan. Use of Niaspan with other lipid-altering medications called statins may increase the risk of rhabdomyolysis, a rare condition that causes muscles to breakdown. The most common side effect with Niaspan is flushing of the skin. Patients with diabetes should carefully monitor their blood sugar and report changes to their doctor. Other commonly reported side effects include indigestion, headache, pain, abdominal pain, nausea, itching, diarrhea, runny nose, vomiting and rash.

Important Safety Information About Simvastatin

Simvastatin is a prescription tablet and isn't right for everyone, including women who are nursing or pregnant or who may become pregnant, and anyone with liver problems. Unexplained muscle pain or weakness could be a sign of rhabdomyolysis, a rare but serious side effect and should be reported to a doctor right away. Simvastatin may interact with certain foods or other medicines including lipid-lowering medications called fibrates or niacin, increasing the risk of getting this serious side effect. Patients should tell their doctor about any other medications they are taking. The most common side effects are headache, abdominal pain, and constipation.