Register now to R3i !
Your Login
Your Password
Confirm Password  
Your Email

R3i EDITORIAL

7 March 2013

Scope for multifocal approaches for reducing residual cardiovascular risk?

Prof. JC Fruchart, Prof. J. Davignon, Prof. M Hermans

An Editorial from the R3i Trustees
Prof. JC Fruchart, Prof. J. Davignon, Prof. M Hermans Despite current evidence-based therapeutic approaches, high-risk patients remain at excess risk of cardiovascular events. Clearly additional strategies are needed.

The Residual Risk Reduction Initiative (R3i) has already argued for improved management of atherogenic dyslipidaemia, the combination of elevated triglyceride-rich lipoproteins (TRL) and low plasma high-density lipoprotein cholesterol (HDL-C) concentration, a key contributor to this excess risk, especially in people with cardiometabolic disease.(1,2) Intestinal chylomicron production is upregulated in insulin resistant conditions; chylomicron remnants containing apolipoprotein B48 are also highly atherogenic. Thus, postprandial lipaemia (TRL and their remnants) is an important additional target to reduce residual cardiovascular risk. Indeed, evidence from the ACCORD Lipid study supports a role for peroxisome proliferator-activated receptorα (PPARα) agonists in reducing postprandial lipaemia in patients with atherogenic dyslipidaemia.(3) As highlighted in a recent State of the Art Review,(4) the next generation of highly potent and selective PPARα-modulators (SPPARMα), such as K-877, may offer improved efficacy in reducing postprandial lipaemia, given evidence of improved lipid-modifying efficacy.

Insights into the role of the intestine in TRL metabolism also suggest new therapeutic possibilities for reducing residual cardiovascular risk. Identification of the intestinally derived incretins, including glucagon-like peptide-1 (GLP-1), has led to the development of incretin-based therapies for type 2 diabetes mellitus. In addition to benefits on glycaemic control, these agents also reduce postprandial lipaemia (triglycerides and apoB48). Indeed, this month’s LANDMARK study highlights the efficacy of liraglutide, a GLP-1 analalogue, in substantially reducing postprandial excursions of triglyceride and apoB48.(5) These findings therefore provide support for evaluating liraglutide in a large prospective cardiovascular outcomes study in type 2 diabetes patients (LEADER).(6)

In addition, targeting the inflammatory process to prevent progression from stable to unstable plaque may offer a complementary strategy to reduce residual vascular risk. Inflammation not only drives the initiation, progression and complications of atherosclerosis, but there is also evidence that the systemic inflammatory reaction to acute myocardial infarction can accelerate atherosclerosis.(7) Neutrophil infiltration of the unstable plaque has been implicated as a key player in the transformation from stable to unstable plaque.(8) Thus, given that inflammatory pathways are important drivers of plaque disruption and thrombosis, would targeted anti-inflammatory therapy reduce cardiovascular event rates?

One approach to test this hypothesis was with low-dose colchicine in the LoDoCol study, featured in this month’s FOCUS ON article. Colchicine exhibits a range of anti-inflammatory effects, and is also effective in preventing neutrophil-mediated inflammation.(9-11) Evidence of a highly significant 67% reduction in cardiovascular outcomes, largely driven by reduction in acute coronary syndromes (ACS) in this study, highlights potential for reducing residual cardiovascular risk in secondary prevention patients.(12) Ongoing trials are testing other anti-inflammatory approaches. Notably, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS),(13) is evaluating canakinumab, a monoclonal antibody that inhibits the endogenous pro-inflammatory protein interleukin-1-beta (IL-1β) in patients with stable coronary artery disease. IL-1β promotes atherothrombosis and also plays a role in the autoimmune process that contributes to insulin resistance.

Thus, to optimise clinical benefit, it is likely that a multifaceted approach, targeting both lipid and non-lipid factors, will be needed. Targeting the inflammatory process to prevent progression to plaque instability and the ensuing clinical instability is likely to be crucial. The R3i believes that ongoing trials, such as those highlighted in this month’s posts, will help to define the optimal strategy to reducing residual cardiovascular risk that persists in high-risk patients.

References

1. Fruchart JC, Sacks FM, Hermans MP et al; Residual Risk Reduction Initiative (R3I). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.
2. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
3. Reyes-Soffer G, Ngai CI, Lovato L et al. Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD Lipid Trial. Diabetes Care 2012;
4. Fruchart JC. Selective peroxisome proliferator-activated receptorα modulators (SPPARMα): The next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovascular Diabetology 2013, 12:82 doi:10.1186/1475-2840-12-82.
5. Hermansen K, Baekdal TA, Düring M, Pietraszek A, Mortensen LS, Jørgensen H, Flint A. Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, cross-over trial. Diabetes Obes Metab 2013. doi: 10.1111/dom.12133. [Epub ahead of print].
6. LEADER trial. Available at http://clinicaltrials.gov/show/NCT01179048. Accessed 20 June 2013.
7. Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013; 368:2004-13.
8. Della Bona R, Cardillo MT, Leo M et al. Polymorphonuclear neutrophils and instability of the atherosclerotic plaque: a causative role? Inflammation Research 2013;62:537-50.
9. Roubille F, Kritikou E, Busseuil D, Barrere-Lemaire S, Tardif JC. Colchicine: an old wine in a new bottle? Antiinflamm Antiallergy Agents Med Chem 2013;12:14-23.
10. Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008;10:218-27.
11. Chia EW, Grainger R, Harper JL. Colchicine suppresses neutrophil superoxide production in a murine model of gouty arthritis: a rationale for use of low-dose colchicine. Br J Pharmacol 2008;153:1288-95.
12. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-10.
13. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Available at http://www.thecantos.org/cantos-summary.html. Accessed 20 June 2013.