Letters

Beneficial effects of simvastatin may be due to non-lipid actions

According to Oliver and colleagues, the first principle of the lipid hypothesis is the association between a raised plasma cholesterol concentration and risk of coronary heart disease. This association, however, has been found mainly in people without previous disease. A strong, graded, positive correlation has been found in a few studies of patients with coronary heart disease, but in at least 17 studies the correlation has been weak, dichotomous, or absent. Also, several studies have found no association between changes in serum cholesterol concentration and the progress of angiographic signs of atherosclerosis; most studies have found no association between serum lipid concentrations and restenosis after angioplasty; and no trial has found a systematic association between the degree of cholesterol lowering and outcome.

Oliver and colleagues claim that angiographic trials have shown a decrease in cholesterol concentration to be associated with a lessening of atheromatous obstruction. To translate a microscopic widening or delay of angiographic stenosis to a lessening of atheromatosis, however, is premature, because early stages of atheromatosis are compensated for by an enlargement of the lumenal area,² indicating that a widening may be due to both an increase and a decrease in atherosclerosis. That the effect was due to cholesterol lowering is also questionable because a dose-response relation was not found in these angiographic trials.³

The Scandinavian simvastatin study is seemingly a good argument for cholesterol lowering, but simvastatin has other effects. At least two of them may be beneficial to cardiovascular disease independent of the cholesterol concentration.⁴ Such effects may have operated in the Scandinavian study, because the outcome was independent of baseline lipid concentrations⁴ and, according to the preliminary data presented at meetings arranged by Merck Sharpe and Dohme in Sweden, there was no dose-response relation with either total or low density lipoprotein cholesterol concentration.

Simvastatin may be of benefit in cardiovascular disease, but its effect seems unlikely to be due to the lowering of cholesterol concentration. It is also unlikely that its effect can be extrapolated to other treatments because one of the mechanisms mentioned above was studied after several cholesterol lowering drugs but found only after simvastatin; and, most importantly, four meta-analyses have found a significantly increased total or non-coronary mortality after drug treatment. The new trials do not verify the lipid hypothesis, and there is still much controversy about what to do.

Specialist in internal medicine Rabygatan 2, S-223 61 Lund, Sweden

Uffe Ravnskov 

1. Oliver M, Poole-Wilson P, Shepherd J, Tikkanen MJ. Lower patients' cholesterol now. BMJ 1995;310:1280-1. (20 May.) [Free Full Text]
2. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Koletis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:1371-5. [Abstract]
3. Ravnskov U. What do angiographic changes after cholesterol lowering mean? Lancet 1994;344:1297.
4. Ravnskov U. Implications of 4S evidence on baseline lipid levels. Lancet 1995;346:181.