R3i Editorial

Statin therapy is undoubtedly the cornerstone of dyslipidaemia management, and effective in reducing the risk of cardiovascular events in both diabetic and non-diabetic patients by 20-30% per mmol/L reduction in low-density lipoprotein cholesterol (LDL-C), the primary lipid target.^1,2 It is also well known that statins lower elevated triglycerides. However, as reported in recent Landmark studies, it is clear that other treatment is still needed to attain guideline-recommended levels for triglycerides.³ Even in the primary prevention setting, as reported by Asghari and colleagues this month, the prevalence of elevated triglycerides (≥1.7 mmol/L) was nearly 2-fold higher in patients treated with statins compared with those who were not.⁴

Inadequate management of elevated triglycerides, a marker for apolipoprotein B-containing triglyceride-rich lipoproteins (TRL) and their remnants, is a key contributor to lipid-related residual cardiovascular risk. There is accumulating evidence from both observational and genetic studies that remnant cholesterol levels in TRL are causal in ischaemic heart disease, supported by mechanistic studies which show remnant cholesterol accumulation in the arterial wall.^5-7 Elevated remnant cholesterol not only contributes to lipid-related cardiovascular risk, but is also associated with low-grade inflammation, in contrast to elevated LDL-C, and is therefore implicated in the underlying pathogenesis of atherosclerosis.⁷ During the postprandial setting, TRL and remnants are increased and hypertriglyceridaemia protracted; plasma triglycerides usually return to baseline levels >6-8 hours after eating. Consequently, most individuals spend most of the waking period in a nonfasting or postprandial state. Evidence that nonfasting triglycerides are predictive of coronary heart disease,⁸ provides a strong rationale for targeting this parameter to reduce residual cardiovascular risk.

How to treat?
Despite this, effective management may be a conundrum for clinicians given current options, beyond lifestyle intervention and statins. Ezetimibe, fibrates (peroxisome proliferator-activated receptor-alpha [PPAR?] agonists), and omega-3 fatty acids have been shown to reduce elevated triglycerides with some evidence of cardiovascular benefit, and warrant consideration. However, the benefits of ezetimibe on top of statin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) and PRECISE-IVUS (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) are predominantly ascribed to its LDL-C lowering effect.^9.10 The benefit of combination treatment with fenofibrate plus simvastatin in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study was limited to the subgroup of patients with atherogenic dyslipidaemia (elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol); while a meta-analysis of the major fibrate trials confirmed this, but was exploratory and not definitive.^11,12 Novel approaches are definitely needed, and ongoing development from 2015 suggests promise for those targeting apolipoprotein C-III, as well as selective PPAR? modulators (SPPARM? agents).

This first perspective for 2016 emphasises that undertreatment of elevated triglycerides in statin-treated patients is still a key issue, warranting a further need to raise awareness among clinicians. This is an ongoing mission of the Residual Risk Reduction Initiative (R3i). There is a clear case for considering nonfasting triglycerides as a contributor to lipid-related residual cardiovascular risk and thus a preferable index for monitoring of treatment efficacy given that this is a truer physiological representation of the normal state. And finally, while there are available options for tackling residual hypertriglyceridaemia, 2015 has offered tantalising insights about possibilities for the future.

References

1. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
2. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
3. Reiner Ž, De Bacquer D, Kotseva K et al. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey. Atherosclerosis 2013;231300-7.
4. Asghari S, Aref-Eshghi E, Godwin M et al. Single and mixed dyslipidaemia in Canadian primary care settings: findings from the Canadian primary care sentinel surveillance network database. BMJ open 2015; 5:e007954
5. Varbo A, Nordestgaard BG. Remnant cholesterol and ischemic heart disease. Curr Opin Lipidol 2014;25:266-73.
6. 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.
7. Varbo A, Benn M, Tybjærg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298-309.
8. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299–308.
9. Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97.
10. Tsujita K, Sugiyama S, Sumida H et al. Impact of dual lipid-lowering strategy with Ezetimibe and Atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the Multicenter Randomized Controlled PRECISE-IVUS Trial. J Am Coll Cardiol 2015;66:495–507.
11. Ginsberg HN. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial: what we learn from subgroup analyses. Diabetes Care 2011;34 Suppl 2:S107-8.
12. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.