Response by Watts et al to Letter Regarding Article, "Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism".


Circulation. 2017;136:120–121. DOI: 10.1161/CIRCULATIONAHA.117.028790 120 Gerald F. Watts, DSc, PhD, DM Dick C. Chan, PhD Ransi Somaratne, MD, MBA Scott M. Wasserman, MD Marc S. Sabatine, MD, MPH In Response: The FLOREY trial (Effects on Lipoprotein Metabolism From PCSK9 Inhibition Utilizing a Monoclonal Antibody) uniquely demonstrated that evolocumab increases catabolism and lowers production of low-density lipoprotein (LDL) particles.1 The evolocumab dose was chosen to elucidate how maximal inhibition of proprotein convertase subtilisin/kexin type 9 regulates lipoprotein metabolism. Given the comparable ranges of plasma LDL-cholesterol,1,2 it is likely that a similar mode of action of evolocumab applies to changes in atherogenic lipoproteins in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Another investigation with a lower dose of alirocumab suggested a similar mechanism in a smaller number of subjects of mixed sex and race.3 Given the primacy of the LDL receptor pathway in controlling LDL-cholesterol, the mechanism described in FLOREY is likely to apply to individuals with diverse characteristics and ethnicity. No specific adverse events occurred with the higher dose evolocumab.1 Although data from FLOREY provide new mechanistic insights for the clinical observations in the FOURIER cardiovascular outcomes trial, data from the latter were not part of our article. Nevertheless, in response to Dr Koh’s comments, one must note that it takes time for LDL-cholesterol lowering to translate into a reduction in atherosclerotic events. The CTTC (Cholesterol Treatment Trialists’ Collaboration) analyzed 26 statin trials with a median duration of 5 years. The relative risk reduction of cardiovascular events in year 1 was ≈50% to 75% of subsequent years owing to delayed effects of treatment. A landmark analysis in FOURIER (Figure VI in the online-only Data Supplement),2 which had a median duration of 2.2 years, demonstrated that per 1 mmol/L reduction in LDL-cholesterol, the risk reductions with evolocumab in years 1 and 2 were consistent with the risk reductions with statins in years 1 and 2 in the CTTC.2 Dr Koh posits that more prolonged exposure to extremely low LDL-cholesterol could lead to neurocognitive dysfunction, cataract, and new-onset diabetes mellitus. In FOURIER, the rate of these adverse events was similar with evolocumab versus placebo across a wide range of LDL-cholesterol concentrations. The detailed Ebbinghaus study (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) also showed no impact of either evolocumab or low LDL-cholesterol on neurocognitive function. The long-term safety of evolocumab over 44 months is supported by a recent report.4 There is also no biological basis to implicate LDL-cholesterol lowering with evolocumab in neurocognitive dysfunction or cataracts. Nevertheless, to consolidate the long-term safely of evolocumab, open-label extensions involving ≥6000 patients from FOURIER are underway (NCT02867813, NCT03080935). The emergent risk of diabetes mellitus in subjects with preexisting glucose intolerance in Mendelian randomization studies is noteworthy. However, inferences from Mendelian randomization studies are not absolute because of Response by Watts et al to Letter Regarding Article, “Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism”

DOI: 10.1161/CIRCULATIONAHA.117.028790

Cite this paper

@article{Watts2017ResponseBW, title={Response by Watts et al to Letter Regarding Article, "Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism".}, author={Gerald F . Watts and Dick C. Chan and Ransi Somaratne and Scott M . Wasserman and Marc S. Sabatine}, journal={Circulation}, year={2017}, volume={136 1}, pages={120-121} }