The results of this prospective study show that the incidences of CHD, CHD plus CI, and CVD are reduced in patients with HDL-C 60–90 mg/dL (i.e. mild hyper-HDL cholesterolemia). This finding is consistent with the results of a previous prospective study on Japanese-American men in Hawaii  and an observational prevalence study on the population of Western Japan . Elderly Japanese-American men in Hawaii with heterozygous CETP deficiency and intermediate HDL-C (41–60 mg/dL) have an increased prevalence of CHD . However, the present study shows that patients with increased HDL-C (>60 mg/dL) have a low risk of CHD regardless of the presence of CETP abnormality.
The incidence of stroke and total death in this study did not differ significantly between patients with HDL-C ≤ 60 mg/dL and those with HDL-C > 60 mg/dL.
A recent study showed that some genetic mechanisms that increase HDL-C do not seem uniformly to lower the risk of myocardial infarction . The authors tested for an SNP in endothelial lipase. In most patients, the presence of this SNP did not increase HDL-C to > 60 mg/dL. Neither the mass nor activity of CETP was available in this study. Plasma CETP activity was measured in 1,978 participants of the Framingham Heart Study, and lower CETP activity was found to be associated with greater risk of CVD . However, there seems to be no association between CETP activity and HDL-C level, which remained to be at < 60 mg/dL.
Further investigations of the association between three CETP genotypes and the incidence of CHD have shown higher HDL-C to have a weakly inverse association with coronary risk . Also, CETP-deficient families, including heterozygous persons, have increased levels of HDL-C (>60 mg/dL) and no evidence of premature atherosclerosis .
A higher HDL-C level (>60 mg/dL) seems to be the threshold for preventing CHD. However, two patients in the diet-alone group developed CHD despite having HDL-C > 90 mg/dL. One of these patients had hypertension and the other had HDL-C > 120 mg/dL, and both developed spastic angina confirmed by coronary angiography, which was relieved by the coadministration of nitrate and statin.
High-density lipoprotein plays several roles, including reverse cholesterol transport and endothelial, antioxidative, and immunological functions. CETP inhibitors increase HDL by promoting reverse cholesterol transport , with small HDL remaining . Therefore patients with spastic angina may have had endothelial dysfunction. No cases of angina were found in the diet-plus-pravastatin group in the present analysis. Therefore the precise mechanism should be clarified under further experimental conditions.
These findings suggest that the target threshold HDL-C for patients not receiving statin therapy should be between 60 and 90 mg/dL for them to achieve a significant reduction in CHD without the occurrence of adverse events.
Regarding the incidence of cancer, there were no significant differences in the incidence of cancer at any site according to HDL-C level. Cancer-related mortality was reduced with statin use in previous studies [14, 15].
To exclude selection bias, we separated the diet-alone group from the diet-plus-pravastatin group. There were no significant differences in the total incidence of cancer or the incidence of cancer at different sites according to HDL-C level.
The limitations of this study include the relatively short follow-up period and the small number of participants. However, the study included participants from all over Japan (from Hokkaido in the north to Okinawa in the south) approximately in proportion to the population in different areas.
Three percent of patients with mild hypercholesterolemia (total cholesterol ≥ 220 mg/dL) had hyper-HDL-C cholesterolemia (HDL-C > 90 mg/dL) and 38% had mildly increased HDL-C (>60 mg/dL). These figures are considered to be representative for Japanese. Furthermore, figures for the incidence of cardiovascular events and cancer were reliable because of the high follow-up rate (99.4%) .
Another limitation to this study is the lack of information on the markers or mechanisms for the increase in HDL-C. However, this was not a purpose of the original investigation. Also, a previous study has confirmed the reduction in cardiovascular events in patients with high HDL-C irrespective of the presence or absence of CETP deficiency .