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Letter to Lancet sent on September 4, 2002
Evidence from the simvastatin trials that cancer is a probable long-term side effect.  

Ravnskov U, Rosch PJ, Langsjoen PH, Kauffman JM, McCully KS

We are questioning the wisdom of recommending statin treatment for a large segment of the world’s population simply because they have elevated lipid levels or are assumed to be at increased risk for coronary events because of the presence of other risk markers. Even using the outcome in the Heart Protection Study (HPS)1 with the most optimistic figures (“Any major vascular event”), the number of individuals who benefited from treatment did not exceed 5.4 %, a figure that included many events with minor or no future health consequences. Such small treatment rewards demand a careful analysis of the potential risks.

It is already known that statins may induce fatal rhabdomyolysis, cardiac insufficiency, peripheral polyneuropathy, and mental disturbances. A much more momentous issue is that all statins have proven carcinogenic in laboratory animals using blood concentrations that approximated those achieved in clinical practice.2 While no significant increased incidence of cancer was reported in HPS, we believe that an important aspect of this potentially serious problem has been overlooked. 

The non-significant (p=0.06) increase of non-melanoma skin cancer seen after treatment with simvastatin in the Heart Protection Study seems to have been belittled. However, non-melanoma skin cancer was seen more often in the first simvastatin trial as well.3  If the results from both simvastatin trials are calculated together, non-melanoma skin cancer occurred significantly more often after simvastatin (p=0.028). Non-melanoma skin cancer is a benign cancer type because it is detected early

There is often a considerable lag between the time a cancer starts internally and its clinical diagnosis. Lung cancer for instance, is not commonly detected after five years of smoking. In contrast, skin cancers are diagnosed early in their development and might therefore be the first type of malignancy observed as a result of exposure to a carcinogenic drug. It is therefore troubling that in HPS, non-melanoma skin cancer was seen in 243 patients treated with simvastatin compared with 202 cases in the control group.1 This difference was not statistically significant (p=0.06), but non-melanoma skin cancer was seen more often in the first simvastatin trial as well (13 cases in the treatment group vs. six in the control group).3  If the results from both simvastatin trials are calculated together, non-melanoma skin cancer occurred significantly more often after simvastatin (p=0.028).

Also disquieting was the significant increase in the CARE trial of breast cancer, another readily detectable malignancy.4 These cases occurred in women who had been treated previously for breast cancer. Although breast cancer was not seen more frequently in HPS, subjects with a history of malignancy were excluded from the study, omitting those who would have been at greatest risk for statin-related cancers.

 

1.      Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet  2002; 360: 7-22.

2.      Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275: 55-60

3.      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9.

4.      Sacks FM, Pfeffer MA, Moye LA, et al. for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001-9.

The above letter was rejected. Here is the answer from the editor:

11 October 2002

Dear Dr Ravnskov

Thank you for the letter commenting on the Heart Protection study papers. We have dicided not to accept the letter for publication in The Lancet, but have forwarded your letter to the authors for their information.

Many thanks for taking the time to write.

Yours sincerely

Zöe Mullan

As we thought the letter may have been too long we sent a revised letter on November 11:

Evidence from HPS that cancer may be a long-term consequence of statin therapy
Sir-The authors of the Heart Protection Study state that its size provides "considerable reassurance" that long term simvastatin therapy to lower cholesterol is unlikely to induce cancer.1 However, we believe that an important aspect of this potentially serious problem has been overlooked. There is often a considerable lag between the time malignancy starts and its clinical diagnosis. Lung cancer is not commonly detected after five years of smoking. If statin therapy and or low cholesterol are associated with an increased incidence of malignancy, both of which have been reported, the first clinical evidence is likely to be from superficial skin lesions that are more readily detected than internal cancers. It is therefore somewhat alarming that in both simvastatin trials, non-melanoma skin cancer was seen more often in the treatment groups.1 2 While the increased incidence was not statistically significant in the HPS trial, when results from both simvastatin studies are combined, non-melanoma skin cancer was significantly higher (p=0.028) in patients receiving simvastatin. This could be due to medication, lipid alterations such as low cholesterol, or other factors.  A correlation with dosage, duration of therapy and degree of cholesterol lowering or changes in other lipids might shed further light on this disturbing association.  It would be helpful to learn if such analyses have been done. 

  1. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet  2002; 360: 7-22.

  2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9.

 Also this letter was rejected

 

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