Cardiovascular disease (CVD) is the leading cause of death in Italy and in the 28 countries of the European
Union. Low-density lipoprotein cholesterol (LDL-C) is a key CVD risk factor. Results from the
randomized intervention clinical trials with lipid-lowering agents strongly suggest that the reduction of
fatal and non-fatal CVD events is associated with the absolute LDL-C reduction, in mg/dl or mmol/L,
regardless of the lipid-lowering agent studied. Statins, by decreasing cholesterol synthesis in the liver,
are associated with a large LDL-C reduction and with robust and convincing evidence of a significant
reduction of all-cause, CVD and coronary heart disease (CHD) mortality. An LDL-C reduction by
39 mg/dl (1 mmol/L) on statin therapy is associated with a decrease by 10% (p<0.0001) in all-cause
mortality, by 20% (p<0.0001) in CHD deaths and by 24% (p<0.0001) in major cardiovascular events.
These results were often observed in secondary CVD prevention patients (4S, HPS and LIPID trials),
independently of patients\u2019 gender and age, in patients on primary CVD prevention at high CV risk and
in patients with type two diabetes. In patients with diabetes a 39 mg/dl (1 mmol/L) LDL-C reduction
is associated with a decrease by 9% (p=0.02) in all-cause mortality, by 12% (p=0.03) and 13% (p=0.008)
in deaths due to CHD and CVD causes respectively, and by 21% (p<0.0001) in major cardiovascular
events. Data on CVD and CHD mortality regarding ezetimibe, fibrates and PCSK9 inhibitors are not
nearly as robust as those with statin therapy: a significant reduction with these lipid-lowering agents
has been observed in combined clinical endpoints including fatal and non-fatal CVD events while no
significant reduction in all-cause, CVD or CHD mortality has been reported. This lack of positive
results on CVD and CHD mortality should be interpreted in the light of remarkable changes in the
background therapy to prevent CVD events seen in patients enrolled in the more recent trials where
aggressive antihypertensive, antiplatelet and lipid-lowering therapy are common enrollment criteria
for both control and active treatment groups