Cholesterol Lowering and Stroke: No Longer Room for Pleiotropic Effects of Statins - Confirmation from PCSK9 Inhibitor Studies.

BACKGROUND:The relationship between cholesterol levels and stroke has been much less clear than the relationship between cholesterol levels and coronary heart disease. This is likely mostly due to the inadequate power of older studies and the low intensity of cholesterol-lowering interventions available at the time. Because a reduction in stroke has been, conversely, clearly observed in trials with statins, for long "pleiotropic" effects of such drugs, unrelated to cholesterol lowering, have been invoked. In a previous analysis of all randomized trials of cholesterol-lowering treatments reporting on stroke we had, however, reached the conclusion that any cholesterol lowering is related to a significant reduction of stroke, in a relationship that appeared to exist for both statin and nonstatin cholesterol-lowering interventions. Outcome results of the FOURIER trial with evolocumab, SPIRE-1 and -2 with bococizumab, and ODYSSEY OUTCOMES trial with alirocumab now offer the opportunity of clearly confirming or confuting this concept. METHODS:We here report on an updated meta-regression of the relationship of total cholesterol changes that occur with various drugs or treatments and changes in the risk of stroke compared with control. RESULTS:Relative risk (RR) figure found in FOURIER, SPIRE-1/2, and ODYSSEY OUTCOMES (0.79, 0.60, and 0.79) are extremely close to the RRs of 0.79, 0.79, and 0.84, respectively, predicted by our new meta-regression. CONCLUSIONS:These findings offer definitive proof that the pure total (and low-density lipoprotein) cholesterol lowering, with any available lipid-lowering intervention, reduces stroke risk proportional to the extent of cholesterol reduction, without the need of invoking "pleiotropic" effects of any such treatment.