Understanding IMPROVE-IT and LDL-C Lowering in CVD
Understanding IMPROVE-IT and LDL-C Lowering in CVD
There has been, and still is, debate on whether statins exert beneficial effects on vascular function and inflammation in addition to LDL lowering, i.e. cholesterol independent 'pleiotropic' actions and these may not be replicated with ezetimibe therapy. Since the two treatment arms of IMPROVE-IT will have different achieved LDL-C levels the question of whether the two drug classes exert a further, differential impact on vascular disease per mg/dL LDL lowering will not be answered. The vascular/clinical effect could be less, equal or theoretically enhanced. Retrospective analyses of ENHANCE and SHARP suggest that the clinical benefits of ezetimibe therapy fall on the statin-LDL regression line, and therefore most likely are equal to statin-mediated LDL lowering.
The clinical impact of further LDL reduction in a population with a starting LDL-C <70 mg/dL is unknown. The epidemiological association of cholesterol with risk is not linear but flattens in the lower range, and the absolute risk reduction with statins depends not only on mg/dL reduction but importantly on the initial LDL-C concentrations (Figure 2) with sharply diminishing returns in the lower regions (for review, see Shepherd). In addition, the relative importance of LDL-C for CV risk appears to be significantly lower in statin-treated compared with statin-naive patients, especially when LDL-C concentrations are <100 mg/dL. The LDL-attributable risk diminishes in patients on statin treatment and with very low LDL-C concentrations. Thus the use the CTT regression line based on the effects in statin-naive patients to calculate the power of adjunct lipid-lowering drugs on-top of statins may be potentially misleading.
Effects in a Statin-Treated Population
There has been, and still is, debate on whether statins exert beneficial effects on vascular function and inflammation in addition to LDL lowering, i.e. cholesterol independent 'pleiotropic' actions and these may not be replicated with ezetimibe therapy. Since the two treatment arms of IMPROVE-IT will have different achieved LDL-C levels the question of whether the two drug classes exert a further, differential impact on vascular disease per mg/dL LDL lowering will not be answered. The vascular/clinical effect could be less, equal or theoretically enhanced. Retrospective analyses of ENHANCE and SHARP suggest that the clinical benefits of ezetimibe therapy fall on the statin-LDL regression line, and therefore most likely are equal to statin-mediated LDL lowering.
The clinical impact of further LDL reduction in a population with a starting LDL-C <70 mg/dL is unknown. The epidemiological association of cholesterol with risk is not linear but flattens in the lower range, and the absolute risk reduction with statins depends not only on mg/dL reduction but importantly on the initial LDL-C concentrations (Figure 2) with sharply diminishing returns in the lower regions (for review, see Shepherd). In addition, the relative importance of LDL-C for CV risk appears to be significantly lower in statin-treated compared with statin-naive patients, especially when LDL-C concentrations are <100 mg/dL. The LDL-attributable risk diminishes in patients on statin treatment and with very low LDL-C concentrations. Thus the use the CTT regression line based on the effects in statin-naive patients to calculate the power of adjunct lipid-lowering drugs on-top of statins may be potentially misleading.
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