R3i Editorial

This editorial highlights the latest news on residual vascular risk, with a particular focus on news from the European Society of Cardiology Congress, held in Barcelona, Spain from 30 August to 3 September, 2014.

What have we learned about residual vascular risk?

It is clear that best evidence-based treatment, including statins, is insufficient to address the high level of lipid-related residual cardiovascular risk in at-risk patients. ODYSSEY COMBO II showed that treatment with alirocumab, a monoclonal antibody therapy targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), resulted in significant additional lowering of low-density lipoprotein cholesterol (LDL-C), on top of maximally tolerated statin therapy, compared with ezetimibe.(1) Furthermore, ODYSSEY LONG TERM offered the first hint that marked lowering of LDL-C levels with PCSK9 inhibition may offer the possibility of translating these lipid effects to reduction in residual cardiovascular risk.(2) As discussed in this month’s Focus article, a post hoc analysis of ODYSSEY LONG TERM including patients who completed at least 52 weeks on treatment, showed that alirocumab treatment reduced cardiovascular outcomes by 54% (from absolute events rates of 3% with statin alone to 1.4% with alirocumab plus statin). Of course, we need to bear in mind that this study was not powered for analysis of outcomes, as well as the usual caveats associated with post hoc analyses. Moreover, PCSK9 inhibition also reduces lipoprotein(a), a cardiovascular risk factor, by 25-30%.(3,4) Suffice to say that these interesting findings hint at a step in the right direction, pending the results from the prospective outcomes studies with this novel therapy. Incidentally, a post hoc analysis of the DEFINE study showed no difference in rates of major cardiovascular events with the combination of statin plus the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib versus statin alone over a 24 week treatment period.(5) In this case, however, the analysis was primarily for safety reasons, given the track record of previous CETP inhibitors. Taking both studies into consideration, it is clear that this is an exciting time for novel approaches to tackle residual cardiovascular risk, and we await the results of ongoing outcomes trials with much interest.

ESC Congress brought news of other possibilities for targeting residual cardiovascular risk, including an antisense inhibitor to apolipoprotein CIII,(6) and a selective peroxisome proliferator activated-receptor alpha agonist (albeit in an experimental model).(7) There was also evidence to suggest that incretin-based therapies to manage glycaemia in type 2 diabetes patients are also associated with improved cardiometabolic risk, specifically lowering triglycerides and raising high-density lipoprotein cholesterol (HDL-C).(8) Such developments are clearly welcome with the rise in prevalence of atherogenic dyslipidaemia, a consequence of the pandemic of diabetes. For example, in India which, after China has the most people with type 2 diabetes, 90% of people with diabetes have atherogenic dyslipidaemia, which translates to over 55 million people, according to Professor S. Guha, Calcutta School of Tropical Medicine, India speaking in the ESC session: Risk Factor Reduction in CAD: Do we require different strategies in developing countries?

Residual microvascular risk: what made the news?

Beyond ESC Congress, a recent study(9) has suggested that the use of statin therapy may reduce the risk of microvascular complications in diabetes patients. However, caution is needed in the interpretation of this study given the study design and the lack of data on important predictors of microvascular disease, as well as issues with the definition of the end points selected (see this month’s Landmark Trial). Moreover, it is important to note that despite statin therapy, microvascular disease still developed in 2-4% individuals in less than 3 years. The best evidence to date for targeting residual microvascular risk is for fenofibrate in early-stage diabetic retinopathy; however, it is likely that this beneficial effect is not mediated by lipid- or lipoprotein-modifying effects. Whether the new SPPARMs offer potential benefit in this respect clearly merits investigation.

The R3i believes that novel approaches targeting atherogenic lipoproteins, including LDL, fasting/postprandial triglycerides, lipoprotein remnants and lipoprotein(a), offer potential for reducing residual cardiovascular risk that persists despite best evidence-based treatment. However, we clearly need additional approaches to address the residual burden of diabetes-related microvascular complications.

References

1. Cannon CP, Cariou B, Blom D et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study. ESC Congress, Hotline II. 31 August, 2014 [Abstract 2123].
2. Robinson JG, Farnier M, Krempf M et al. Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: first results from the ODYSSEY LONG TERM study in 2,341 patients. Reported at ESC Congress Hotline 2, 31 August 2014.
3. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
4. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278-88.
5. Cannon CP, Shah S, Dansky HM et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15.
6. Alexander VJ, Gaudet D, Brisson D et al. Antisense inhibitor of apoC-III produces significant decreases in apoC-III and triglycerides and increases in HDL-C as a single agent or in combination with fibrates in hypertriglyceridemic patients. Eur Heart J 2014;35(Abstract Supplement):218-219. Abstract P1275.
7. Masuda D, Kobayashi T, Nakaoka H et al. A novel potent and selective PPARalpha agonist, K-877, ameriolates the atherogenic profile of fasting and postprandial hypertriglyceridemia in mice. Eur Heart J 2014;35( Abstract Supplement):904. Abstract: P5145.
8. Klepacka A, Nikfar S, Rizzo M et al. The effect of incretin-based therapies on metabolic and cardiovascular parameters in diabetic patients: A meta-analysis of 28 randomized control trials with 10171 patients. Eur Heart J 2014;35(Abstract Supplement): 740. [Abstract: P4239].
9. Nielsen SH, Nordestgaard BG. Statin use before diabetes diagnosis and risk of
microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol 2014; [Epub ahead of print, September 10, 2014]. http://dx.doi.org/10.1016/S2213-8587(14)70173-1.