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COMMENT

Despite best evidence-based management, including well controlled low-density lipoprotein cholesterol (LDL-C) levels, patients at high cardiovascular (CV) risk continue to experience (recurrent) events. A proportion of this residual CV risk is indisputably due to a lipid/lipoproteins risk component (1). There are a number of lines of thought as to the best approach to reduce this risk. Recent studies have focused on reducing LDL-C levels below the recommended goal, given that LDL-C is the primary lipid priority for therapeutic intervention. Results from the GLAGOV study (2), discussed in this month’s Landmark study, showed that greater LDL-C lowering with the addition of a PCSK9 inhibitor to background statin therapy is associated with greater regression of atherosclerotic plaque. Whether this translates to reduction in cardiovascular events is so far unknown. The first outcomes trial with PCSK9 inhibitor evolocumab (FOURIER) (3), is due to report in the first quarter of 2017. Despite the indisputable efficacy of these agents in lowering LDL-C levels by >50%, we perhaps need to be cautious in our expectations about the results, as highlighted by a recent report.

Ference and colleagues used a Mendelian randomization design, a type of ‘natural’ randomized trial, to compare the effect of LDL-C–lowering variants in PCSK9 or 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR; the target of statins) on the risk of cardiovascular events (and also the risk of diabetes) (4). They used genetic scores based on independently inherited variants in these genes to randomly assign 112,772 subjects from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to compare the effects of lower LDL-C levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events.  Surprisingly, they showed that variants in either PCSK9 or HMGCR had the same effect on the risk of cardiovascular events per unit decrease in LDL-C level (decrease in coronary heart disease events by 19% with each type of variant per 10 mg/dl [0.26 mmol/L] decrease in LDL-C). The effect was additive in combination. Incidentally, PCSK9 variants and HMGCR variants also had similar effects on the risk of incident diabetes (increasing this risk by 11% and 13%, respectively). Based on these findings, the authors concluded that it is reasonable to anticipate that PCSK9 inhibitors and statins are likely to have therapeutically equivalent effects on the risk of cardiovascular events. Thus, exuberant expectations that PCSK9 inhibitors will reduce cardiovascular events by more than 50% against a background of (relatively) short-term statin treatment in major ongoing outcomes studies are unlikely. 

 This scenario therefore poses a key challenge: what other strategies can be used to target lipid-related residual cardiovascular risk beyond LDL-C lowering? Targeting atherogenic dyslipidaemia, the combination of elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), has been on the horizon for some time as a potential therapeutic approach. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) tested this in statin-treated type 2 diabetes patients, but failed to show benefit overall given that a substantial proportion of patients enrolled in the study did not have sufficiently elevated triglycerides according to the study protocol, and as a result did not suffer from atherogenic dyslipidaemia (5). Additionally, the therapeutic agent, fenofibrate, had relatively low potency and selectivity for peroxisome proliferator-activated receptor alpha (PPARα). However, it is noteworthy that in a post hoc subgroup analysis, patients with elevated triglycerides (>200 mg/dl) and low HDL-C at baseline did show significant reduction in cardiovascular events by about 40% compared with those without this dyslipidaemia (6).

Modulating the unique receptor–cofactor binding profile to identify the most potent molecules that induce PPARα-mediated beneficial effects, while at the same time avoiding unwanted side effects, may offer distinct advantages. This concept has led to the development of the first SPPARMα, pemafibrate. In a phase II trial in patients with type 2 diabetes mellitus (7), pemafibrate substantially reduced elevated triglycerides, as well as remnant cholesterol and apolipoprotein CIII, both associated with increased cardiovascular risk (8-10). Pemafibrate was also shown to decrease inflammation and atherosclerosis in an animal model (11).

 Thus, the stage is set for a landmark study to evaluate whether targeting atherogenic dyslipidaemia that persists in high-risk statin-treated patients with type 2 diabetes reduces residual cardiovascular risk. PROMINENT, using pemafibrate, will be a true test of this hypothesis