Conclusions

PAUL SAMUEL, MD

Ii ypertension is now an eminently treatable disease. A major problem that has accompanied treatment, however, is the lack of convincing proof that the con- trol of high blood pressure will prevent the markedly increased risk of coronary artery disease (CAD), either in the young or the elderly. The suspicion that the long- term treatment of hypertension might slightly but sig- nificantly shift serum lipid levels toward a more ath- erogenic profile has yielded increasing concerns. Thus, this meeting of specialists in hypertension and experts in atherosclerosis and lipid metabolism repre- sents a symposium whose time has come.

Enormous progress has been made in the field of arteriosclerosis during the past few decades. The Lipid Research Clinics (LRC) Coronary Primary Prevention Trial clearly demonstrated that lowering total serum cholesterol and low-density lipoprotein cholesterol levels reduced CAD morbidity and mortality. It seems that a simple conclusion is emerging from the con- trolled clinical trials of the past 3 decades: when total serum cholesterol levels are reduced in a study popu- lation by an overall average of around 5% (i.e., clofi- brate in the Coronary Drug Project], there will be no change in morbidity or mortality from CAD. When the mean reduction of total cholesterol is around 9 to 10% (i.e., nicotinic acid in the Coronary Drug Project, and clofibrate in the World Health Organization Trial), morbidity will be reduced significantly but mortality from CAD will not change. When the overall reduction of total cholesterol reaches 13 to 15% [i.e., diet and cholestyramine in the LRC Trial) both morbidity and mortality from CAD will be significantly reduced. Can we achieve such reduction, and can it be done safely with little or no discomfort or side effects to patients?

Reduction of serum cholesterol can be achieved by any of the following processes:

1. Reduction in dietary cholesterol or its absorption. 2. A decrease in endogenous cholesterol synthesis. 3. An increase in fecal excretion of cholesterol end

products [fecal bile acids or neutral sterols). 4. An increase in the transfer of cholesterol from

the plasma to the tissues. It is, of course, of utmost importance to activate pro- cesses 1,2 or 3 or their combinations, so that cholester- ol transport will be reversed and will proceed from the tissues to hepatic receptors, from the hepatocyte to the bile and from there out in the stools. The important role of high-density lipoprotein (HDL) cholesterol in this reversed transport of cholesterol has been shown repeatedly, with almost unanimous agreement that de- creased HDL cholesterol levels markedly increase CAD risk.

How shall we proceed? It seems to me that with combined dietary and drug intervention we can easily achieve the 15% (or more) serum cholesterol reduction necessary to decrease mortality and morbidity from CAD. Interestingly, the molecular structures to accom- plish this goal are at hand: the neomycin molecule can reduce cholesterol absorption by about 50%; other compounds with almost similar effect are now being studied. Compactin, the original Japanese HMG-CoA reductase inhibitor, markedly decreases cholesterol synthesis: a number of compounds with similar or bet- ter activity are also under investigation. Cholestyra- mine increases fecal bile acid excretion and stimulates hepatic receptor activity. Many of these compounds may have unpleasant, undesirable and perhaps even toxic side effects: structures will have to be modified, and side effects will have to be eliminated. Neverthe- less, the basic fact remains: We have the molecules. I think that in theory and in principle the problem of the disease arteriosclerosis has been resolved. Practical application is only a question of time.

Why then should these benefits be denied to pa- tients treated for hypertension? Should we continue to treat patients with drugs that may increase serum cho- lesterol or triglycerides and decrease HDL cholester- ol? Obviously, the answer is not in, and prudence in choosing drugs remains sensible.

This symposium supplement should only be the be- ginning of the elucidation of these critical questions.

Paul Samuel, MD