A historical perspective on the discovery of statins

Cholesterol is essential for the functioning of all human organs, but it is nevertheless the cause of coronary heart disease. Over the course of nearly a century of investigation, scientists have developed several lines of evidence that establish the causal connection between blood cholesterol, atherosclerosis, and coronary heart disease. Building on that knowledge, scientists and the pharmaceutical industry have successfully developed a remarkably effective class of drugs—the statins—that lower cholesterol levels in blood and reduce the frequency of heart attacks

Plasma lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)

Background— Statins are important in vascular disease prevention in the elderly. However, the best method of selecting older patients for treatment is uncertain. We assessed the role of plasma lipoproteins as predictors of risk and of treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Method and Results— The association of LDLc and HDLc with risk was examined in the 5804 70- to 82-year-old subjects of PROSPER. Baseline LDLc showed no relation to risk of the primary end point in the placebo group (P=0.27), nor did on-treatment LDLc in the pravastatin group (P=0.12). HDLc was inversely associated with risk in subjects on placebo (P=0.0019) but not in those on pravastatin (P=0.24). Risk reduction on pravastatin treatment was unrelated to baseline LDLc (P=0.38) but exhibited a significant interaction with HDLc (P=0.012). Subjects in the lowest 2 quintiles of HDLc (<1.15 mmol/L) had a risk reduction of 33% (hazard ratio, 0.67; 95% confidence limits, 0.55, 0.81; P<0.0001), whereas those with higher HDLc showed no benefit (RR, 1.06; 95% confidence limits, 0.88, 1.27; P=0.53). During follow-up, there was no relation between achieved level of LDLc or HDLc and risk. However, the change in the LDLc/HDLc ratio on statin treatment appeared to account for the effects of therapy. Conclusions— In people >70 years old, HDLc appears to be a key predictor of risk and of treatment benefit. Findings in PROSPER suggest that statin therapy could usefully be targeted to those with HDLc <1.15 mmol/L or an LDLc/HDLc ratio >3.3

C-reactive protein and prediction of coronary heart disease and global vascular events in the prospective study of pravastatin in the elderly at risk (PROSPER)

<p><b><i>Background</i></b> - The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required.</p> <p><b><i>Methods and Results</i></b> - Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke; n = 865 events) and secondary (coronary heart disease events or stroke alone) and tertiary (stroke plus transient ischemic attack) end points in the Prospective Study of Pravastatin in the Elderly at Risk (n = 5804 men and women; age, 70 to 82 years). CRP levels were higher in subjects who had a subsequent primary end-point event compared with those who did not (geometric mean; 3.64 mg/L [SD, 3.08 mg/L] versus 3.01 mg/L [SD, 3.05 mg/L]; P < 0.0001). CRP correlated positively with body mass index and smoking status and negatively with high-density lipoprotein cholesterol. The unadjusted hazard ratio for the primary end point was 1.48 (95% CI, 1.26 to 1.74) in a comparison of top and bottom thirds for CRP, falling to 1.36 (95% CI, 1.15 to 1.61) with adjustment for established predictors and body mass index. Similar results were obtained for other end points or when results were examined separately by history of vascular disease. However, baseline CRP added minimally to risk prediction beyond conventional predictors and did not relate to the magnitude of pravastatin benefit.</p> <p><b><i>Conclusions</i></b> - Elevated CRP minimally enhances cardiovascular disease prediction beyond established vascular risk factors and does not predict response to statin therapy in elderly subjects at risk. These data suggest that CRP has limited clinical value in cardiovascular disease risk stratification or predicting response to statin therapy in elderly people.</p&gt

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies

<p><b>Background</b> <br>Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.</br></p> <p><b>Methods</b> <br>We assessed the −1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent differences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2·79 million person-years at risk). We analysed −1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy.</br></p> <p><b>Findings</b> <br>The minor allele frequency of −1131T>C was 8% (95% CI 7—9). −1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3·5% [95% CI 2·6—4·6]; 0·053 mmol/L [0·039—0·068]), lower apolipoprotein AI (1·3% [0·3—2·3]; 0·023 g/L [0·005—0·041]), and higher apolipoprotein B (3·2% [1·3—5·1]; 0·027 g/L [0·011—0·043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16·0% (95% CI 12·9—18·7), or 0·25 mmol/L (0·20—0·29), higher (p=4·4×10−24). The odds ratio for coronary heart disease was 1·18 (95% CI 1·11—1·26; p=2·6×10−7) per C allele, which was concordant with the hazard ratio of 1·10 (95% CI 1·08—1·12) per 16% higher triglyceride concentration recorded in prospective studies. −1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12·2 nmol/L [95% CI 7·7—16·7]; p=9·3×10−8) and smaller HDL particle size (0·14 nm [0·08—0·20]; p=7·0×10−5), factors that could mediate the effects of triglyceride.</br></p> <p><b>Interpretation</b> <br>These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease.</br></p> <p><b>Funding</b> <br>British Heart Foundation, UK Medical Research Council, Novartis.</br></p&gt