Ongoing development of the proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors has re ignited debate about the preferred strategy for lowering residual vascular risk that persists beyond current standards of care. There is a conundrum: Should the focus be on lowering low-density lipoprotein cholesterol (LDL-C) beyond currently recommended levels or on targeting triglyceride-rich apolipoprotein (apo) B100/48-containing lipoproteins (TRL) and their remnants? The Residual Risk Reduction Initiative (R3i) strongly believes that there is evidence to support the latter approach, particularly relevant against the rising tide of obesity-related cardiometabolic disease.
Undoubtedly, LDL-C is the primary focus of dyslipidaemia management, as recognised by current international guidelines. However, there are two key questions: What evidence do we have that achieving very low LDL-C levels (<50 mg/dL or 1.25 mmol/L) provides further clinical benefits, against a background of current standards of care? And, is this approach safe in the long-term?
Transition from a hunter-gatherer to urban society with adoption of a Westernised diet is recognised as a major factor contributing to higher plasma LDL-C levels and escalation in the rates of cardiovascular disease in modern societies. For example, increasing urbanisation and adoption of a Westernised diet in China has dramatically increased cholesterol levels, and correspondingly, the prevalence of coronary heart disease, metabolic syndrome and type 2 diabetes.(1,2) Meta-analyses of LDL-lowering strategies indicate a linear relationship between reduction in LDL-C plasma levels and reduction in the risk of cardiovascular events, with no evidence of a threshold over the LDL-C range studied.(3,4) Ongoing studies with novel treatments targeting LDL-C will provide further insights. However, as a caveat we need to bear in mind that these treatments also lower other atherogenic lipoproteins. Notably, the PCSK9 inhibitors also lower triglycerides by 20-30% and lipoprotein(a).(5-7) A similar argument can be made for the cholesteryl ester transfer protein (CETP) inhibitors anacetrapib and evacetrapib, as well as mipomersen, the antisense oligonucleotide against apoB.(8.9) In respect of mipomersen, reducing the production of apoB-100 reduces hepatic production of very low-density lipoprotein, consequently decreasing circulating levels of atherogenic very low-density lipoprotein remnants, intermediate-density lipoproteins, LDL, and lipoprotein(a) particles.9 Therefore it is difficult to differentiate effects due to lowering LDL-C, triglycerides, LDL number, TRL and/or lipoprotein(a), on residual cardiovascular risk.
Safety is another consideration, especially in high-risk patients with or at risk of type 2 diabetes. High-dose statin therapy has been associated with a small increased risk of new-onset diabetes or worsening of glycaemic control of pre-existing diabetes,(10) although in the context of the high-risk patient, the reduction in the risk of cardiovascular events far outweighs this potential risk. Furthermore, high-dose statin therapy is also associated with an increased risk of myopathy, particularly in older persons with comorbid conditions and receiving polypharmacy.(11) However, we need to bear in mind the extensive safety database relating to statins, with huge long-term population exposure.
In respect of the new therapeutic agents, safety data are limited. While there has been no adverse signal in short-term trials with the PCSK9 monoclonal antibody inhibitors, long-term safety data are clearly needed. Indeed, safety is a particular issue for the CETP inhibitors in development, given the chequered history of this therapeutic class.
Targeting TRL in high-risk dyslipidaemic patients with cardiometabolic disease has been shown to confer clinical benefit. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study showed ∼30% reduction in cardiovascular events associated with fenofibrate treatment in statin-treated type 2 diabetes patients with marked atherogenic dyslipidaemia defined by baseline (on statin) triglycerides in the upper third of the population (≥204 mg/dL or 2.3 mmol/L) and baseline HDL cholesterol levels in the lower third (≤34 mg/dL or 0.9 mmol/L).(12) This finding was subsequently confirmed in a meta-analysis of subgroups with similar lipid criteria for atherogenic dyslipidaemia in the major fibrate trials.(13) However, the R3i acknowledges that this was a post hoc analysis, and recognises the need for an outcomes trial specifically in high-risk statin-treated patients with atherogenic dyslipidaemia to conclude this definitively. The next generation of highly potent and selective PPARα-modulators (SPPARMα), such as K-877, may offer greater benefit, given evidence of improved lipid-modifying efficacy. Furthermore, treatment with a fibrate (specifically fenofibrate) confers benefits on residual microvascular risk in patients with type 2 diabetes, irrespective of baseline atherogenic dyslipidaemia, with significant preventive effects on diabetic retinopathy, nephropathy and risk for lower-extremity distal amputations.(14-17) Evolving evidence also suggests that the pleiotropic effects of fibrates, including raising circulating plasma levels of adiponectin as discussed in this month’s Focus article (18) may potentially contribute to reductions in both macro- and microvascular residual risk.
Finally, the safety profile of fibrates appears to be well characterised. Although fenofbrate is associated with elevation in serum creatinine, this effect is generally considered functional, being transient and reversible usually within 6-8 weeks of stopping treatment, and is not associated with adverse effects on renal or CV outcomes.(19-21)
In conclusion, the R3i believes that the current evidence base supports a strategy targeting TRL associated with atherogenic dyslipidaemia to reduce the substantial residual cardiovascular risk that persists despite current standards of care, including targeting LDL-C. Consistent with this view, the recent International Atherosclerosis Society Position Paper(22) highlights the importance of targeting not only LDL-C but also very low-density lipoprotein cholesterol in individuals with elevated triglycerides, as associated with atherogenic dyslipidaemia.
Finally, it is relevant that fenofibrate has been shown to reduce the residual risk of microvascular complications, including diabetic retinopathy and nephropathy, in patients with type 2 diabetes. In the light of evidence that people with diabetes are living longer,23 this is at least as important given the increasing clinical, socioeconomic and disability burden associated with diabetic microvascular complications.
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