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|Objective||To test the hypothesis that increased triglycerides (TG) are associated with risk of recurrence of cardiovascular events in patients with stable coronary disease.|
7,232 patients from the IDEAL trial and 8,547 patients from the TNT trial
|Study design||Post-hoc analysis.|
Statistical analysis of the relationship between on-treatment plasma triglyceride levels at one year and risk of subsequent cardiovascular events (coronary death, non-fatal myocardial infarction, resuscitation after cardiac arrest, fatal or non-fatal stroke, coronary revascularization, hospitalization for unstable angina or a primary diagnosis of heart failure, and peripheral artery disease).
|Author's conclusion||Even slightly increased TG levels are associated with higher risk of recurrence of cardiovascular events in statin-treated patients and should be considered as a useful marker of risk.|
This study was conducted in the overall population of two landmark randomized clinical trials comparing conventional-dose and high-dose statin therapy in secondary cardiovascular prevention. Compared with the conventional-dose treatment, the high-dose treatment resulted in a non-significant 11% reduction of major coronary events but a significant 17% reduction in non-fatal myocardial infarction (p = 0.02) in IDEAL,1 and a significant 22% reduction of major cardiovascular events (major coronary events + stroke) in TNT.2 Although the conventional-dose regimens differed in the two trials, their inclusion criteria were similar as was duration of treatment (mean follow-up: 4.8 and 4.9 months in the IDEAL and TNT trial, respectively). This enabled the authors to pool patients’ data from the two trials. The primary analysis was performed on the whole population of patients, irrespective of their statin treatment regimen (conventional- or high-dose). However, a specific analysis was carried out in those patients reaching a LDL cholesterol level <100 mg/dL.
The occurrence of any cardiovascular event, used as outcome measurement for the present analysis, encompassed major coronary events and/or the development of heart failure. The authors acknowledge that the causes and mechanisms of these two types of events are different, but underline that heart failure accounted for less than 2% of reported events, and thus could not markedly impact the results.
The most striking result is the 63% difference in relative risk of cardiovascular events between patients in the highest and lowest quintiles of fasting plasma triglycerides (TG). Guidelines have defined 150 mg/dL as the threshold defining normal and elevated fasting TG. The difference in cardiovascular risk between these two categories was 30% in the present analysis. However, the difference in cardiovascular risk between the first and second TG quintiles was already significant, which suggests that the increased risk is present with plasma TG levels well below the conventional 150 mg/dL cutoff.
Results reported above are adjusted for age, gender, and trial (TNT or IDEAL). Entering HDL-cholesterol and the apoB/apoA1 ratio into the statistical model markedly attenuated the higher-to-lower triglycerides quintile difference (19% increase in risk of cardiovascular events; p=0.044). This may be explained by the permanent metabolic trade and exchanges (including mutual transfer of cholesterol and TG) between VLDL and HDL particles mediated by the cholesteryl ester transfer protein (CETP). Accordingly, the TG-rich VLDLs give away their TG to HDLs, from which they acquire cholesteryl esters in exchange. The rate of exchange increases when concentrations of VLDLs are high. As a result, HDL particles become depleted in cholesteryl esters, more sensitive to subsequent TG depletion by lipoprotein lipase and more subject to breakdown, which explains why HDL cholesterol level tend to be lowered when TG are elevated.
This analysis shows that even slightly elevated plasma TG levels are a marker of recurrent, and thus of residual cardiovascular risk, in patients with coronary heart disease treated with statins. Results were similar when only the group of patients with normalized LDL-cholesterol levels (< 100 mg/dL) was considered for analysis. In patients with elevated TG while being treated with a statin, lifestyle changes and/or triglyceride-lowering drugs with evidenced clinical benefit should be considered to further reduce this residual vascular risk.