Is an Even Lower LDL-C Even Better, and Safe?

Since the first studies showing dramatic reductions in LDL-C by inhibiting PCSK9 with a monoclonal antibody, speculation has focused on their ability to further reduce atherosclerotic CVD events. Skeptics suggested further reductions in LDL-C achievable by high intensity statins, would have little additional CVD benefit as a plateau had been reached. They also expressed concern that very low LDL-C levels, such as ≤25 mg/dL, could be harmful, increasing the risk of hemorrhagic stroke, cognitive impairment, cataracts and diabetes. That CVD benefit continued to very low LDL-C started with data from IMPROVE-IT where patients achieving an LDL-C <30 mg/dL had a significantly (P<0.001) lower rate of CVD events. Additional evidence emanated from a post hoc analysis of CVD events in 10 phase 3 trials with alirocumab which showed CVD benefit continued down to a mean LDL-C of 25 mg/dL (i.e. half the patients had LDL-C <25 mg/dL) and reduction from 50 mg/dL to 25 mg/dL resulted in the same CVD benefit as reduction from 75 mg/dL to 50 mg/dL. The most unequivocal evidence was from FOURIER, where the median LDL-C in the evolocumab group was 30 mg/dL, 42% of subjects had LDL-C <25 mg/dL and 25% <20 mg/dL. CVD events were lower in the bottom two achieved LDL-C quartiles, between ~20 and ~25 mg/dL, compared to the highest two quartiles of ~35 to ~45 mg/dL, and led the FOURIER investigators to conclude ‘lower LDL-C is better’. FOURIER also provided evidence that there were none of the predicted untoward adverse effects.