R3i Editorial

What contributes to residual cardiovascular risk? Certainly, lipid and lipoproteins risk factors are important. Much of the focus of the Residual Risk Reduction Initiative (R3i) has been on the management of elevated triglycerides, with or without low circulating levels of high-density lipoprotein cholesterol (HDL-C). In a key meta-analysis of the major fibrate trials, targeting atherogenic dyslipidaemia was associated with a 35% relative reduction in cardiovascular risk versus 6% in individuals without this dyslipidaemia. Reduction in coronary events was the major driver of this benefit ^1,2. In 2015, the focus has been elaborated. While accumulating evidence now presents a strong case for consideration of elevated triglyceride-rich lipoproteins and their remnants (for which plasma triglycerides are a marker) in guidelines, interest in targeting total HDL-C as conventional risk factor has waned. Indeed, while low HDL C plasma concentration is undoubtedly a marker of cardiovascular risk, as recognised by guidelines ³, the relevance of HDL-directed therapies has been disregarded to a large degree, especially non-selective approaches which did not specifically target atheroprotective HDL subtypes. Most recently, the outcomes trial involving the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib (ACCELERATE) has been terminated on the grounds of lack of efficacy ⁴. Yet this agent not only markedly raised HDL-C plasma concentration, but also reduced low-density lipoprotein cholesterol (LDL-C) by about 40% ⁵. Whether the lack of efficacy may be largely attributed to the patient population of ACCELERATE (acute coronary syndrome patients receiving standard of care treatment) is plausible, although we need to await full publication of the trial findings to discern the true causes. Indeed, it has been mooted that among high cardiovascular risk patients receiving best evidence-based medicine it is not feasible to attain further significant reduction in clinical outcomes, possibly due to the effect of long-term statin treatment on plaque morphology ⁶, although exploratory analyses with the PCSK9 monoclonal antibodies alirocumab and evolocumab counter this claim ^7,8. Once again, we need to await definitive results from ongoing outcomes studies with these agents.

Beyond lipid-related residual cardiovascular risk
Moving on, the results of the EMPA-REG OUTCOME study with empagliflozin, a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor, clearly indicate the relevance of non-lipid risk factors ⁹. This is the first time a glucose-lowering drug has shown superiority in a cardiovascular-outcomes trial, with reduction in the primary composite cardiovascular endpoint largely driven by a decrease in cardiovascular mortality (by 38%) in the absence of a benefit on myocardial infarction or unstable angina in patients with established CV disease. Importantly, this reduction was achieved against a background of standard care, including guideline-recommended management of blood pressure, glycaemia and dyslipidaemia. Thus, in 2015 we now have a positive trial showing the importance of considering non-lipid risk factors for residual cardiovascular risk.
Looking into a crystal ball, will these findings change guidelines? Undoubtedly for type 2 diabetes patients with CV disease, although questions remain as to the mechanism(s) of this benefit and whether it also exists in non-diabetic patients or in diabetic patients in primary CV prevention. In the absence of such insights from this trial, the R3i believes that the time is now right for a comprehensive approach to managing residual cardiovascular risk including both lipid and non-lipid contributors to risk in type 2 diabetes patients in the secondary prevention setting.

Residual microvascular risk beyond lipids
Finally, there is also accumulating evidence to implicate non-lipid risk factors in residual microvascular risk. Not only for diabetic retinopathy, as seen with fenofibrate, but there are also emerging data to suggest a potential renoprotective effect with SGLT2 inhibitors in animal models ^10,11. This is already being followed-up in clinical trials ^12,13.

The R3i believes that the concept of residual vascular risk is even more relevant in 2015 than in 2008 when the Foundation was established. For the future, therapeutic approaches targeting lipid and non-lipid risk factors will potentially become the norm for management of both cardiovascular and microvascular residual risk. Is elimination of residual vascular risk, the ‘holy grail’ for clinicians, really within our grasp?

References

1. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010,363:692-684.
2. Jun M, Foote C, Lv J et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010,375:1875-84.
3. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
4. Lilly to Discontinue Development of Evacetrapib for High-Risk Atherosclerotic Cardiovascular Disease. https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130
5. Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099-109.
6. Hikita H, Kuroda S, Oosaka Y et al. Impact of statin use before the onset of acute myocardial infarction on coronary plaque morphology of the culprit lesion. Angiology 2013;64:375-8.
7. Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
8. Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
9. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; DOI: 10.1056/NEJMoa1504720.
10. Kojima N, Williams JM, Slaughter TN et al. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats. Physiol Rep 2015;3(7). pii: e12436.
11. Kojima N, Williams JM, Takahashi T et al. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther 2013;345:464-72.