R3i Editorial

Current therapeutic options are insufficient to address the high level of residual cardiovascular risk in high-risk patients that persists despite best-evidence-based treatments. As reinforced in the recent Call to Action position statement,1 the R3i believe that atherogenic dyslipidaemia, elevated triglycerides and low plasma high-density lipoprotein (HDL) cholesterol, is an important contributor to lipid-related residual cardiovascular risk. However, it is also clear that we need novel strategies to target this.

So far, the range of possibilities include the next generation peroxisome proliferator-activated receptors (PPAR) agonists – including the PPARα modulator (SPPARM) K 877,2 cholesteryl ester transfer protein (CETP) inhibitors, immunotherapy targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as apolipoprotein (apo) A-I based therapies. However, the success of each of these may depend on their primary target. With the pendulum of evidence shifting in favour of triglycerides – rather than HDL-C – we may need to re-evaluate the rationale for each approach.

Certainly, the cloud over targeting HDL and/or HDL-C has not been lifted by recent news. AIM-HIGH and HPS2-THRIVE failed to show benefit with niacin; indeed, as discussed in new reports from the HPS2-THRIVE Collaborative Group and AIM-HIGH there were significant harms associated with this therapy.3,4 The R3i believes that the debate surrounding the role for niacin has been effectively silenced with these latest reports (see News from the Literature).

Other alternatives targeting HDL also have limitations. In this month’s Landmark trial, the failed CHI-SQUARE trial is discussed.5 The trial investigated the effect of CER-001, a lipoprotein particle mimicking pre-beta HDL and consisting of a combination of recombinant human apo A-I and two phospholipids, in patients with acute coronary syndrome (ACS) in the last 14 days. This was not a cardiovascular outcomes trial; the primary aim was to assess the effect of CER-001 (3, 6 or 12 mg/kg given as 6 weekly infusions) on coronary atherosclerosis progression using state-of-the-art intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Despite a well-defined study methodology in a large number of ACS patients there was no favourable benefit on the primary endpoint (nominal change in the total atheroma volume), as well as the other study endpoints. The authors suggested that the composition of CER-001 or the dosing regimen may have been possible contributors to the lack of benefit. Moreover, the selection of patient population was also questioned, especially in the light of experimental evidence showing that HDL functionality is impaired in the inflammatory milieu associated with ACS.6,7 Whatever the reason, it is clear that there is still no convincing evidence that raising HDL number or HDL-C level will translate to reduced atherosclerotic burden and improved clinical outcomes, compared with placebo. Controversy continues……

In contrast, there is growing support for the role of triglycerides, a marker for triglyceride-rich lipoproteins and their remnants, in lipid-related residual cardiovascular risk. In contrast to HDL-C, accumulating evidence from genetic studies shows that triglyceride-rich lipoproteins and their remnants are causal in ischaemic heart disease.8-10 Consequently, a key question implicit from such findings is whether there are specific mutations associated with low triglycerides, and if so, whether carriage of such mutations would confer reduced cardiovascular risk. Both questions have been conclusively answered in two studies discussed in this month’s Focus,11,12 and set the scene for a new possibility for targeting lipid-related residual cardiovascular risk.

Both studies identified key loss-of-function or missense mutations in the APOC3 gene coding for triglyceride-rich associated apolipoprotein C-III resulting in resulting in lifelong exposure to low fasting and postprandial triglycerides and reduced risk for cardiovascular disease. Importantly, the magnitude of benefit in each study was similar, at ∼40%. These findings can be considered ‘proof of principle’ that it might be possible to develop a new class of pharmaceutical agents to protect against ischaemic heart disease.

The next question is whether targeting APOC3 will offer opportunities for reducing lipid-related residual cardiovascular risk? Certainly, there are novel approaches targeting APOC3 in early development, including antisense APOC3 oligonucleotides. We need to wait and watch this space…...

The R3i believes that triglyceride-lowering drugs reflect an important clinical need to address the high lipid-related residual risk that persists despite best evidence-based treatment. Current approaches have relatively modest impact on triglyceride levels; novel approaches such as those specifically targeting APOC3 may offer new promise to reduce the clinical burden of lipid-related residual cardiovascular risk.

References

1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014 Jan 24;13:26.
2. Fruchart JC: Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009;205:1–8.
3. The HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
4. Anderson TJ, Boden WE, Desvigne-Nickens P, Fleg JL, Kashyap ML, McBride R, Probstfield JL. Safety profile of extended-release niacin in the AIM-HIGH Trial. N Engl J Med 2014;371:288-90.
5. Tardif JC, Ballantyne CM, Barter P et al; for the Can Hdl Infusions Significantly QUicken Atherosclerosis Regression (CHI-SQUARE) Investigators. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J. 2014 Apr 29. [Epub ahead of print].
6. Kratzer A, Giral H, Landmesser U. High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease. Cardiovasc Res 2014. pii: cvu139. [Epub ahead of print].
7. Riwanto M, Landmesser U. High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease. J Lipid Res 2013;54:3227-43.
8. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345-52.
9. Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013;45:1274-83.
10. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
11. The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, Peloso GM, Auer PL et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.
12. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.