Other cholesterol-lowering drugs
Other organisations tested other drugs. The World Health Organisation sponsored its own trial — World Health Organization Cooperative Trial on Primary Prevention of Ischaemic Heart Disease — using a fibrate, Clofibrate (Atromid). Clofibrate too was targeted against cholesterol and was confidently expected to lower blood cholesterol levels by 30%.
Clofibrate increases lipoprotein lipase activity to promote the conversion of VLDL to LDL, and hence reduce the level of VLDL. It as also been shown to increase the level of HDL. As with cholestyramine, the levels were lowered by much less than the expected amount. Nevertheless, on the face of it, clofibrate looked to be a useful drug to have in the armory
But, despite successful cholesterol lowering, it soon became clear that there were many more deaths in the clofibrate-treated group (47% more deaths during treatment with clofibrate and 5% after treatment with clofibrate) than the non-treated high cholesterol group, as can be seen in the Table below. These deaths were due to a wide variety of causes other than heart disease — notably from gallstones, and cancer of the liver and digestive system — a finding which has remained "unexplained".[1]
and at the end of the trial it became clear that there had been many more deaths in the group taking clofibrate than in the control group
To put this all in a nutshell: In the WHO clofibrate trial, clofibrate killed more than it saved.
| Cause of death |
Clofibrate
5,331 men |
Placebo
5,296 men |
| CHD | 157 | 138 |
| Stroke | 30 | 19 |
| Other cardiovascular diseases | 21 | 16 |
| Cancers | 125 | 99 |
| Other medical | 30 | 13 |
| Accidents | 31 | 30 |
| Unknown | 2 | 2 |
| All causes | 396 | 317 |
This result was pretty much the same with other drugs to be tested:
- The female hormone Estrogen on the theory that if premenopausal women did not get heart disease, perhaps estrogen would protect men. But the hormone caused heart attacks rather than preventing them.
- The hormone Dextrothyroxine, which lowers cholesterol levels, abandoned quickly when an increase in mortality was noticed in the treatment group.
- The vitamin Niacin, which looked promising, but although there appeared to be a reduction in non-fatal heart attacks, there were marked side effects: skin disorders such as darkening, itches and rashes, as well as digestive problems and gout.
- Gemfibrozil (Lopid) was tested and again an increase in deaths was noticed in the treatment group although this time the numbers did not reach statistical significance.
- Compactin which worked in a similar way to triparanol was withdrawn hurriedly and in some secrecy. The reason this time appears to be connected with cancer in dogs.
- Lastly, despite the previous experiences with triparanol and compactin, yet another inhibitor, Lovastatin, was approved for lifetime use on the general public after tests of very short duration only. Lovastatin was the first of the statins
A study of all trials into cholesterol lowering by drugs up to 1987 showed a 13.6% increased mortality in those treated with drugs
In 1993 a meta-analysis of all randomised controlled trials of cholesterol-lowering treatments showed that only those with very high risk showed any evidence of benefit. In all others mortality was increased. Its authors conclude that:
"Currently evaluated cholesterol-lowering drugs seem to produce mortality benefits in only a small proportion of patients at very high risk of death from coronary heart disease . . . a cautious approach to the use of cholesterol lowering drugs should be advocated".
Despite this, nearly eight times as many prescriptions for cholesterol-lowering drugs were being issued just 6 years later!
References
1. M H Frick, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle aged men with dyslipidemia. New Eng J Med. 1987; 317: 1237.
2. Coronary Drug Project Research Group: Gall bladder disease as a side effect of drugs influencing lipid metabolism. New Eng J Med. 1977; 296: 1185.
3. M N G Dukes. Drugs affecting lipid metabolism. in: Meyler's Side Effects of Drugs, Ninth Edition. M N G Dukes ed. Excerpta Medica, Amsterdam, 1980.
4. S Yusuf, J Cutler. Single factor trials: drug studies. in A G Olsson, ed. Atherosclerosis. Edinburgh: Churchill-Livingstone, 1987: 389.
5. G Davey Smith, F Song, TA Sheldon. Cholesterol lowering and mortality: the importance of considering initial level of risk. BMJ 1993; 306: 1367.
