A recent article in the BMJ highlighted concerns about the statin Crestor which in 2014 was the most prescribed brand name drug in the US, with 22.3 million prescriptions at a cost of $5.8bn. World-wide sales for 2013 were $8.2bn (1). The report is by Sidney Wolfe, who founded Public Citizen based in Washington DC and for many years was its director until he retired recently. The statin was approved for use as a cholesterol lowering drug in 2003, despite opposition from Public Citizen at the time.

In particular it was concerned because rhabdomolysis because Rosuvastatin is the only statin in which rhabdomyolysis was detected in randomized controlled clinical trials before the drug was approved. The objection pointed out that with cerivastatin which was eventually banned because of rhabdomyolysis, no cases had occurred in the clinical trials before its approval. Furthermore a recent study of 641?703 patients in the UK prescribed different statins, those taking rosuvastatin had a significantly higher risk of an abnormally raised creatine phosphokinase activity (which is a measure of muscle inflammation) than patients on large daily doses of other statins (simvastatin, pravastatin, or atorvastatin).

There was also serious concern seen during preapproval trials was renal problems. At the time, rosuvastatin was the only statin to have been associated with proteinuria and hematuria. According to FDA documents “in the subgroup of patients with dipstick [protein and blood] positive urine, the percentage of patients with an increase of serum creatinine of 30% over baseline was 14%, 16%, 24%, 33%, and 41% for 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of rosuvastatin, respectively. . . These data suggest that some patients with greater levels of proteinuria and hematuria may progress to clinically relevant renal disease.”

An editorial in The Lancet in October 2003 also expressed reservations and commented that:

“Physicians must tell their patients the truth about rosuvastatin—that compared with its competitors, rosuvastatin has an inferior [clinical] evidence base supporting its safe use. AstraZeneca has pushed its marketing machine too hard and too fast. It is time for McKillop to desist from this unprincipled campaign.”

In 2010 it was approved to reduce the cardiovascular risk. This was based on the results of the JUPITER Trial. However in a review of several key aspects, Michel de Lorgeril and colleagues concluded that the results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors (2). Sidney Wolfe points out that the JUPITER study, was restricted to patients with both low density lipoprotein (LDL) cholesterol <130 mg/dL (3.4 mmol/L) and C reactive protein ? 2 mg/L (19 nmol/L) which is quite a limited population and therefore does not provide a justification for general usage.

It is also crucial to recognise that the JUPITER Trial was stopped early. Invariably those trials which are stopped early consistently overestimate treatment effects. In a major study the results of 91 trials which were stopped early were compared with 424 trials which were completed in accordance with the original plan. It was found that those which stopped early systematically overestimate treatment effects. Large differences in treatment effect size between truncated and non-truncated trials (ratio of relative risks <0.75) occurred with truncated trials having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the non-truncated RCTs failed to demonstrate significant benefit (3).

In some trials, it has been found that the benefits observed with an early stop have not been confirmed in a full-length trial. If clinicians act on the results of shortened trials it is likely that they will be misled when trying to balance benefits, harms, inconvenience, and costs of a specific health care intervention.

The JUPITER trial also found that those treated with rosavustatin had an increased incidence of T2D, which is consistent with an increase in the glycated haemoglobin (HbA1c) and reduced insulin sensitivity. Both of these factors are associated with increased incidence of heart disease, obesity and various cancers. Hence it may well be that any benefit attributed to a decrease in the risks of heart disease by the effect of the statin are counterbalanced by deleterious effects linked to increase in blood sugar and reduced insulin sensitivity. According to NICE, 77 people who have heart disease have to be taking statins for 3 years in order that one person will benefit. Hence it follows that those who experience the increased risk of developing T2D are probably not the same individuals who benefit from the reduced risk of heart disease.

In addition, rosavustatin is associated with relatively high incidence of rhabdomolysis (muscle pain and damage) renal failure.

On top of all this, the behaviour of the company AstraZeneca in promoting the statin does not exactly inspire confidence. In late 2004 there was an advertisement in the Washington Post which stated that:

The scientists at the FDA who are responsible for the approval and ongoing review of CRESTOR have, as recently as last Friday, publicly confirmed that CRESTOR is safe and effective; and that the concerns that have been raised have no medical or scientific basis,” claiming this was information provided by the FDA website, which was not correct. As a consequence the FDA wrote to the company demanding that it immediately stop the advertising because it contained false and misleading information about Crestor’s risks. The letter also stated that:

“The ‘patient safety’ print ad makes false or misleading safety claims that minimize the risks associated with Crestor, thereby suggesting that Crestor is safer than has been demonstrated by substantial evidence or substantial clinical experience.”

The agency wrote to the company again the following year about “misleading superiority claims” for Crestor in other promotional materials.

This is just one more example of a drug being granted approval despite doubts about the adverse side-effects which may be associated with it. Subsequently there have been very many reports of statin users with muscle pain. Even so NICE continues to play down this damage to health. Then in February Sir Rory Collins of Oxford University which analyses data on statins for the pharmaceutical companies admitted to a Sunday newspaper that:

“his team had assessed the effects of statins on heart disease and cancer but not other side effects such as muscle pain”.

You just could not make it up!!

This information should be given to every individual before they agree to go on statins but I suspect it rarely happens.

REFERENCES

  1. http://www.bmj.com/content/350/bmj.h1388
  2. http://vernerwheelock.com/?p=670
  3. http://jama.jamanetwork.com/article.aspx?articleid=185591