R3i Editorial

Much has been made of the new guidelines for the management of cholesterol, from the American College of Cardiology (ACC) and American Heart Association (AHA).(1) Long-overdue since Adult Treatment Panel III, the guidelines sought to simplify lipid management for the clinician. Gone are recommendations for low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B as performance targets, integral to other international guidelines.(2,3)
Instead, the guidelines present a statin-centric approach, supported by evidence-from randomised controlled trials (which predominantly relate to statins) with the exclusion of lower levels of evidence. Four main groups who would benefit from statin therapy were identified (Table 1).

Table 1. Patient groups who would benefit from statin therapy


* Defined by the inclusion criteria for the secondary prevention statin randomised controlled trials (i.e. acute coronary syndromes, or a history of myocardial infarction [MI], stable or unstable angina, coronary or other arterial revascularisation, stroke, transient ischaemic attack, or peripheral arterial disease of atherosclerotic origin)

The guidelines recommend either “high-intensity” or “moderate-intensity” statins, categorised on the basis of the average expected reduction in LDL cholesterol levels (i.e. ≥50% and 30% to <50%, respectively). The former is recommended for the first two patient groups, and for diabetes patients with an estimated 10 year risk for ASCVD ≥7.5% based on the recently developed Pooled Cohort Equations.(4) Where high-intensity statin therapy is contraindicated or there are statin-associated adverse events, a moderate-intensity statin strategy is proposed. Moderate to high-intensity statin therapy is recommended for primary prevention patients without diabetes taking into account estimated 10 year ASCVD risk, contraindications and the potential for statin adverse effects and interactions.

No case for omitting non-LDL lipids and residual CV risk.

With this narrow focus, management of lipoproteins beyond LDL has been disregarded. Notably, the guidelines do not offer any recommendations for managing atherogenic dyslipidaemia, the combination of elevated triglycerides and low HDL cholesterol, which is justifiably considered an important driver of atherogenic risk, as well as a contributor to residual CV risk, even when LDL cholesterol is controlled on statin therapy.(2,5,6) The guidelines argue that outcomes evidence from randomised controlled trials do not support a strategy for secondary lowering of non-HDL cholesterol in patients with controlled LDL cholesterol levels. This expert group bases this conclusion on findings from two recent randomised controlled studies with niacin: AIM-HIGH and HPS2-THRIVE which showed that niacin failed to significantly impact CV outcomes.7,8) However, both trials had shortcomings. AIM-HIGH, which was specifically designed to evaluate the merits of targeting residual atherogenic dyslipidaemia (median HDL cholesterol 0.91 mmol/L [35 mg/dL] and median triglycerides 1.82 mmol/L [161 mg/dL]) in statin-treated patients with optimal LDL cholesterol levels, lacked statistical power for a number of reasons including funding constraints, and was further flawed by the inclusion of a low dose of niacin in the placebo comparator. The trial was prematurely terminated due to futility.(7) HPS2-THRIVE, although appropriately powered, was not a test for targeting atherogenic dyslipidaemia, as patients had baseline levels of HDL cholesterol (1.14 mmol/L or 44 mg/dL) and triglycerides (1.43 mmol/L or 125 mg/dL) which would not normally have merited initiation of niacin treatment in routine practice.(8)

The expert group disregarded post hoc analyses from the fibrate trials. While acknowledging the limitations inherent to such post hoc analyses, the R3i and other expert groups,6 do recognise that there is consistent evidence of a clinical benefit in targeting atherogenic dyslipidaemia to reduce residual CV risk. Indeed, a meta-analysis of subgroups with similar lipid criteria for atherogenic dyslipidaemia from the major fibrate trials, conducted by the R3i, showed that fibrate treatment was associated with a 35% relative reduction in CV risk in individuals with atherogenic dyslipidaemia versus 6% in individuals without this dyslipidaemia.(9) Furthermore, while there is ongoing controversy about the role of low HDL cholesterol as a direct contributor to residual CV risk,(10) there is accumulating evidence implicating a causal role for triglyceride-rich lipoproteins (TRLs) and their remnants (for which triglycerides are a marker), whose presence is often comorbid with low HDL cholesterol. Indeed, recent studies highlighted by the R3i strengthen this causal link. Data from the CARDIoGRAM collaborative group(11) showed that common genetic variants that influence plasma triglycerides levels are associated with increased coronary artery disease risk. A Mendelian randomisation study(12) showed a causal association between remnant cholesterol, contained in TRL, and ischaemic heart disease risk which was independent of HDL cholesterol plasma concentration. Most recently, this month’s Focus on article(13) highlights a meta-analysis of 61 studies in general populations from America, Asia, Australia and Europe, which provided robust evidence of an association between elevated triglycerides and increased risk for CVD and all-cause mortality. In this analysis, each 1 mmol/L increase in triglycerides was associated with 13% increase in CVD mortality and 12% increase in all-cause mortality. The US guidelines also run counter to a consistent body of expert opinion, including the European Atherosclerosis Society6 and International Atherosclerosis Society,(14) which support a strategy targeting atherogenic dyslipidaemia, especially for insulin-resistant individuals, to manage residual CV risk that remains despite appropriate LDL cholesterol management. It is also notable that both the US National Lipid Association and American Association of Clinical Endocrinologists have declined to endorse these new US guidelines due to concerns relating to the scientific basis for their recommendations and lack of consideration of strategies for patients at risk from cardiovascular disease with a statin-centric approach.(15,16)

Thus, the R3i believes that the paradigm shift in lipid management recommended by the new US guidelines is an oversimplification of the current evidence-base and risks confusion. The underlying aim of all guidelines should be to help clinicians in their routine practice select the best management strategies for an individual patient, taking into account not only outcomes data but also expert consensus on emerging evidence, as well as benefit versus risk considerations. As well as strength of the evidence, congruence of the evidence from mechanistic studies at large is as important to consider when drafting new guidelines. This is sadly lacking from the “new” approach taken.

In particular, the R3i believes that the failure to acknowledge the relevance of other atherogenic lipoproteins, notably TRLs, to lipid-related CV risk is one of several important omissions in this guideline. Clearly definitive outcomes data are needed, but the accumulating evidence from animal, genetic and clinical studies, as well as consistent expert consensus, implies a role for managing persistently elevated TRLs in patients who remain at high CV risk despite optimal statin therapy. Against the background of escalating rates of obesity, metabolic syndrome and type 2 diabetes, residual hypertriglyceridaemia is an increasingly relevant issue facing clinicians in their routine practice and should not be ignored.

References

1. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. J Am Coll Cardiol 2013; doi:10.1016/j.jacc.2013.11.002 [Epub ahead of print].
2. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2011;32:1769–818.
3. Anderson TJ, Grégoire J, Hegele RA et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013;29:151-67.
4. The Pooled Cohort Equations, downloadable spreadsheet and a web-based calculator are available from http://my.americanheart.org/cvriskcalculator and http://www.cardiosource.org/science-andquality/practice-guidelines-and-quality-standards/2013-prevention-guideline-tools.aspx.
5. 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 patients. Diab Vasc Dis Res 2008,5:319-35.
6. Chapman MJ, Ginsberg HN, Amarenco P et al; European Atherosclerosis Society Consensus Panel. 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.
7. The AIM-HIGH Investigators; Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New Engl J Med 2011;365:2255-67.
8. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279-91.
9. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010,363:682-4.
10. Genest J. High-Density Lipoprotein and Residual Cardiovascular Risk, De Minimis Non Curat Medicus or the COURAGE to be SMART?∗ J Am Coll Cardiol 2013;62:1842-4.
11. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013 Oct 6. doi: 10.1038/ng.2795.
12. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
13. Liu J, Zeng FF, Liu ZM, Zhang CX, Ling WH, Chen YM. . Effects of blood triglycerides on cardiovascular and all-cause mortality: a systematic review and meta-analysis of 61 prospective studies. Lipids Health Dis 2013 Oct 29;12(1):159. [Epub ahead of print].
14. The International Atherosclerosis Society. An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia. Full report [http://www.athero.org/download/IASPPGuidelines_FullReport_2.pdf].
15. National Lipid Association. NLA Statement on the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Available at https://www.lipid.org/nla/2013-accaha-guideline-treatment-blood-cholesterol-reduce-atherosclerotic-cardiovascular-risk.
16. American Association of Clinical Endocrinologists. Member alert re. guidelines. Available at https://www.aace.com/membership/member_alerts.