Dr. Gofman’s research demonstrated that those in the cholesterol-rich LDL class were the most atherogenic and were highly predictive of cardiac risk. The triglyceride-rich VLDL class was also assigned a causal role in atherosclerosis. Subsequent studies by others definitively established HDL to be a strong inverse predictor of cardiovascular risk, hence the terminology identifying LDL as bad cholesterol and HDL as good cholesterol.
Bolstering the case implicating cholesterol in the pathogenesis of cardiovascular disease were two seminal epidemiological studies. The first, known as the Seven Countries Study, was an intensive compilation of the eating habits of middle-aged men in the U.S., Italy, Greece, Yugoslavia, the Netherlands, Finland and Japan.5 This long-term study confirmed that the rates of cardiovascular disease correlated with higher levels of LDL-C. Their observations led to the adoption of the Mediterranean diet among many dieters.
The second took place in Framingham, Mass., a tidy suburb of Boston situated about 20 miles west along the Massachusetts Turnpike from where I sit. With the ongoing support of the National Heart, Lung, and Blood Institute and Boston University, the Framingham Heart Study investigators have been meticulously collecting and analyzing the blood and the electrocardiograms of this town’s citizenry since 1948, and the results have helped shape our approach to cardiovascular disease. Notable findings include the confirmation of the adverse effects of smoking, and the role that diet, cholesterol and truncal obesity play in the development of cardiovascular disease.6
Lowering the LDL cholesterol has become a mainstay of cardiovascular risk management. … [But] when it comes to reducing LDL-C, how low is low enough?
Lowering the LDL cholesterol has become a mainstay of cardiovascular risk management. Statins are the most popular class of drug in the U.S., with approximately one of every four adults prescribed one. A recently published study confirmed the lifesaving benefits of lowering cholesterol levels even in patients with intermediate cardiac risk factors. In this double-blinded study of more than 12,000 male subjects over the age of 55, treatment with rosuvastatin resulted in a 24% reduction of cardiovascular events compared with placebo, whereas the addition of antihypertensive therapy to their regimen did not significantly reduce these events.7
These findings raise the question: When it comes to reducing LDL-C, how low is low enough? The identification of the PCSK9 protease and its role in LDL-C synthesis in hepatocytes sparked a race among several biopharmaceutical companies to identify those loss-of-function mutations in affected subjects that resulted in remarkable degrees of hypocholesterolemia.8 Would you consider an LDL-C measuring 15 mg/dL to be sufficiently low? Amazingly, these levels have been observed in family cohorts lacking functional PCSK9 proteases, and not surprisingly, their cardiovascular risks are fairly negligible. We will wait to see whether similarly slashed cholesterol levels will be achieved with the use of the new class of PCSK9-inhibiting drugs.
The Lipid Paradox
Of course, rheumatology would not be the wonderfully challenging discipline that it is by simply following the script. Sometimes, the rules of medicine don’t apply here. Consider the lipid paradox, the term used to describe what happens to patients with clinically active rheumatoid arthritis (RA) who may face heightened risks for cardiovascular morbidity and mortality at the time of maximal joint inflammation, even as they demonstrate reduced levels of total cholesterol, HDL-C and LDL-C. As their RA improves following immune suppressive treatment, these values begin to rise unexpectedly.9 This observation was confirmed by another great longitudinal study based in a single American county. The Rochester, Minn., Epidemiology Project measured and followed the lipid profiles of 577 patients with RA from five years before until five years after diagnosis. Despite having lower rates of statin use, the patients with RA displayed a greater mean reduction in total cholesterol (10%) and LDL-C (17%) during the five years preceding diagnosis compared with the control population, after adjustment for age, gender and calendar year.10 So can a rising LDL-C value be a sign of improving health? Another rheumatologic enigma to say the least!
