Effect of alirocumab dose increase on LDL-lowering and lipid goal attainment: is treatment to goal the way to go?

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In this issue, Kastelein and colleagues 1 present data on the effect of a standardized dose increase of alirocumab on LDL-cholesterol lowering, LDL goal attainment, and medication tolerability in patients participating in six early clinical trials that were designed primarily to assess efficacy at goal attainment 2–7. The patient profiles in these studies included individuals with heterozygous familial hyperlipidemia, individuals with coronary artery disease (CAD) or CAD equivalent, and individuals at very high risk of cardiovascular disease 2–7. Whereas most patients (73.7%) attained their LDL goal on the starting dose of 75 mg every 2 weeks, the present analysis focuses on the 26.3% of patients who required an alirocumab dose increase to attain protocol-driven LDL goals derived from then contemporary guideline-driven LDL goals. At the time that these studies were carried out, the LDL goal for individuals at high risk for CAD was less than 100 mg/day and less than 70 mg/dl for individuals with established CAD 8.
Since the time that these studies were designed, the 2013 US cholesterol-lowering guideline panel has redefined lipid lowering to be a class effect of statins aimed at maximizing statin dose, rather than treating to a specific LDL goal, with the primary outcome being the prevention of atherosclerotic events 9. At the time that these guidelines were published, proprotein convertase kexin type 9 (PCSK9) inhibitors were on the horizon; however, the guideline panel did not effectively address the use of nonstatin medications or the potential role of PCSK9 inhibitors as there were little to no data showing that adding an agent to a statin offered supplemental clinical benefits, even if a statin was considered to be inadequate. Indeed, simply defining when the statin effect was ‘inadequate’ was left open to interpretation.
In 2015, the IMPROVE-IT study assessed the value of adding ezetimibe to a standardized dose of simvastatin 40 mg in individuals who had recently experienced an acute coronary syndrome and had a baseline LDL of 50–100 mg/dl if they were receiving lipid-lowering therapy or 50–125 mg/dl if they were not on a lipid-lowering agent 10. The primary endpoint was a composite of cardiovascular events. The primary endpoint was achieved in 33% in the simvastatin-ezetimibe group compared with 35% in the simvastatin monotherapy group for an absolute reduction of 2% and a relative risk reduction of 6% (P=0.016). Thus, although the lipid-lowering effects of ezetimibe were modest (14 mg/dl beyond statin alone), clinical event reduction took place in the setting of statin therapy, although it too was modest. Nonetheless, this opens the possibility that other classes of lipid-lowering medications may supplement the powerful event-lowering effects of statins.
The primary finding of this present combined analysis of individuals in six separate clinical trials of alirocumab (N=2181) was that for those who needed a dose increase from 75 mg every 2 weeks to 150 mg every 2 weeks, the calculated LDL was reduced by an additional 14% or an absolute amount of 22 mg/dl. This information is potentially of great clinical importance if future studies show that the degree of LDL lowering with these agents correlates with the amount of prevention of clinical events particularly if the ‘curve flattens’ at LDL levels below a certain threshold. In such a case, a yet to be defined LDL goal would be the goal of therapy rather than, as with statins, where a class effect has been shown, particularly at high doses. A second possibility is that, as with statins, a benefit of PCSK9 inhibitors is a class effect and they should simply be used at a highest well-tolerated dose.

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