To reduce the statin residual CVD risk, the following approaches should be needed: (1) the intensification of statin therapy with the aim to reach target values; (2) the improvement of lifestyle; (3) the incorporation of peroxisome proliferator-activated receptor alpha (PPARα) agonists and/or NPC1L1 inhibitor (ezetimibe), in particular in clinical scenarios such as high TG, low HDL-C, obesity, and metabolic syndrome. This evidence concerns the gene PPARA and obesity due to melanocortin 4 receptor deficiency.