The second-generation heart drug designed to deliver a one-two punch (with stat-ins) to cholesterol has been found to be ineffective-a discovery that its maker Schering-Plough has been accused of suppressing.
Ezetimibe (marketed as Zetia or Ezetrol), hailed as the new genera-tion of cholesterol-lowering drug, supposedly works by inhibiting chol-esterol uptake in the small intestine, unlike statins, which inhibit the absorption of cholesterol in the liver.
Schering-Plough received approv-al for the drug's release in 2002 and, in 2004 (with Merck), for Vytorin, a one-pill combo of Zocor (simvasta-tin) and Zetia, based on evidence that the two drugs reduced blood cholesterol 20 per cent more than did simvastatin by itself.
After S-P's $200 million direct-to-consumers advertising blitz, ezetim-ibe sales increased to more than 15 per cent of all cholesterol drug sales to the point where one in every five US prescriptions for cholesterol was being written out for Zetia (N Engl J Med, 2008; 358: 1819-28). The drug and combination drug soon managed to corner $5 billion in worldwide sales.
Most doctors believed that Zetia or Vytorin represented the most up-to-date approach to cholesterol management-as did the public.
But what had never been inves-tigated was whether the huge reduction in cholesterol would make a difference to disease progression.
The drugs don't work
Between 2002 and 2004, Schering-Plough funded a large, multicenter study (ENHANCE) to determine whether or not the combination regime had any real advantage over simvastatin alone.
In this double-blind, placebo-controlled study, 720 patients with inherited high cholesterol were given 80 mg of simvastatin with either a placebo or 10 mg of Vytorin to see if the drug combination could prevent the build up of arterial plaque. Ultrasound was then used to assess the thickness of the walls of the major carotid (neck) and femoral (thigh) arteries in all participants.
After two years, the researchers found that, although the combined therapy dramatically lowered LDL cholesterol, triglyceride fats in blood and C-reactive protein-a measure of arterial inflammation-more than simvastatin did on its own, there was no significant difference in the thick-ness of the arterial walls between the two groups (N Engl J Med, 2008; 358: 1431-43).
In other words, although it may well lower blood cholesterol, the drug was shown to be utterly useless in preventing atherosclerosis.
Although the study ended in April 2006, it was not published until April 2008-and then only after continu-ous pressure from the US Congress and prominent cardiologists. Three congressional committees have launched investigations to determine why it took the company so many years to release these data, particularly in light of the fact that the drug continued to be heavily advertised in the US and enjoyed such a huge sales boom during those years.
The Dutch scientist who led the ENHANCE study believes that Merck and Schering-Plough deliberately delayed the release of the results.
At the end of March, Chairman Herb Kohl, of the US Senate Special Committee on Aging, sent a letter to Schering-Plough to request docu-mentation on the company's so-called '49 Plan', an aggressive seven-week sales campaign aimed at convincing doctors to increase prescriptions of Zetia across the US, after word of the ENHANCE study findings began to leak out. One tactic mentioned in the 49 Plan encouraged S-P drug salesmen to offer doctors free meals and other perks.
Fatal liver disease
Schering-Plough has also been slow to come forward about dangerous and potentially fatal side-effects. According to Public Citizen, the Ralph Nader-founded drugs pressure group, as far back as 2004, the US Food and Drug Administration (FDA) Adverse Event Reporting System had evidence that Zetia on its own caused rhabdomyolysis, a serious and potentially fatal disease involving destruction or degeneration of skeletal muscle.
A year later, Merck Frosst/ Schering Pharmaceuticals was forced by Health Canada, the nation's drugs regulatory body, to write a 'Dear Doctor' letter advising health professionals that the drug had received post-marketing reports of rare but serious liver, muscle and pancreatic adverse events, including elevations of liver transaminases (a liver enzyme), liver failure and hepatitis.
In addition, within a warning box, the manufacturer admitted that the drug also caused rhabdomyolysis, acute pancreatitis and thrombo-cytopenia (a low blood-platelet count).
Nevertheless, S-P chose not to send this letter to American doctors and was never required by the US FDA to do so. The New York Times discovered that S-P chose not to publish several studies submitted to the FDA containing reports of liver damage.
S-P finally admitted that a number of patients in the ENHANCE trial were dropped when it was discovered that they had elevated liver enzymes, an early sign of organ damage.