It has been several years since the 2013 American College of Cardiology and the American Heart Association (ACC/AHA) published updated guidelines for the management of hypercholesterolemia.¹ While these guidelines were a major step in the right direction, a lot has changed in the lipid landscape since they were initially published. Futhermore, these guidelines were fairly limited in scope and did not address all clinical scenarios that clinicians might encounter in their practices, such as what do with high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B (apoB), and triglycerides. Given these limitations, it is useful to examine other more current recommendations from the 2016 European Society of Cardiology/European Atherosclerotic Society (ESC/EAS) guidelines and the 2017 American Association of Clinical Endocrinologists and American College of Endocrinology (AACE) guidelines in an attempt to update clinicians on state-of-the-art lipid management in 2017.^2,3

The 2017 AACE guidelines are extensive, providing 87 total recommendations on a broad range of clinical scenarios encountered in clinical practice. The document contains hundreds of citations and adheres to published proctocols for the production of clinical practice guidelines (CPGs). The 2016 ESC/EAS guidelines are similarly extensive with topics ranging from dietary effects on cholesterol to recommendations regarding the use of specific medications to treat a variety of dyslipidemias. They are equally well cited and researched and adhere to standard CPGs.

One of the most striking differences between the 2013 ACC/AHA guidelines and the AACE/ESC/EAS guidelines is the latter's focus on specific target LDL-C levels. While there is little doubt that higher statin intensity lowers ASCVD risk, it has now become apparent based upon the IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin vs Simvastatin) and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trials that lower is better when it comes to LDL-C and non-HDL-C.^4,5 Furthermore, extremely low LDL-C (<20 mg/dL) that were previously unheard of have been shown to be safe in short term follow-up and possibly beneficial.⁶ Based upon these more recent trials, both the AACE and the ESC/EAS have recommended specific LDL-C targets for specific risk categories (Table 1). This shift towards specific LDL-C goals is also supported by the recently published 2016 ACC expert consensus decision pathway on the role of non-statin therapies which also provides optional target LDL-C goals, making this recommendation even more compelling.⁷

Targeting specific LDL-C levels was given the strongest recommendation with a strong level of evidence by both organizations. Interestingly, target LDL-C levels were remarkably similar between the two guidelines, with the main difference being the AACE identifying an additional "extreme high-risk" category that the ESC/EAS does not recognize for which they recommend very aggressive LDL-C lowering (<55 mg/dL). The "extreme high-risk" group is primarily patients with progressive disease despite LDL-C <70 mg/dL while on statin therapy. It is very reassuring and compelling that both sets of guidelines have recommended similar target LDL-C levels and this should provide clinicians with the confidence to once again aim for specific and low LDL-C targets.

While LDL-C has justifiably received the lion's share of attention, it has become quite clear that despite aggressive LDL-C lowering, patients are often left with a significant amount of residual ASCVD risk.⁸ Both AACE and ESC/EAS guidelines have acknowledged this shortcoming and consider patients with triglycerides >200 mg/dL to be at substantially increased ASCVD risk. Furthermore, they recommend that fibrates may be considered in patients with triglycerides >200 mg/dL and HDL-C <40 mg/dL mg/dL as this may improve CV outcomes. While no randomized controlled trial has specifically proven this approach, there have been several post-hoc and pre-specified subgroup analyses of RCTs that support its utility in reducing the residual risk left behind after LDL-C lowering has been addressed.⁹ Because of this uncertainity, the ESC/EAS guidelines made this a somewhat weaker IIb recommendation with level of evidence C. The AACE guidelines, however, were more aggressive and gave this their strongest recommendation. Until we have further clinical trials to say otherwise, it is reasonable to at least consider fenofibrate therapy in patients who have elevated triglycerides, low HDL-C, and recurrent ASCVD events despite aggressive statin therapy.

There have been extensive debates about the best marker of atherogenic particles to target with lipid lowering therapies.¹⁰ While LDL-C has long remained the primary target, other markers such as non-HDL-C or apoB may offer improved ASCVD risk prediction. Clinical scenarios often arise in whichLDL-C has a "discordant" risk compared to non-HDL-C and apoB with LDL-C being relatively low but the atherogenic particle burden remaining high.¹¹ In this situation, non-HDL-C and apoB appear to be better predictors of ASCVD events and should be considered in addition to LDL-C levels. This scenario typically occurs when patients have triglycerides above 200 mg/dL. Based upon this, both the AACE and ESC guidelines have suggested that non-HDL-C and/or apoB be assessed and targeted in patients with TG >200 mg/dL. They offer specific target levels (Table 1) and have given this a class IIa recommendation.

As we await the newest ACC/AHA guidelines that are currently slated to be published in 2018, it is important to incorporate all of the latest clinical trial data into our practices as we manage our patients with dyslipidemia. Relying solely on the 2013 ACC/AHA guidelines, while certainly not wrong, is not taking advantage of important and potentially "guideline-changing" clinical trials that have been published since our guidelines were released four years ago. The AACE/ESC/EAS guidelines do a nice job of summarizing and synthesizing these data and are worth a closer look as we await our updated guidelines in the next several years.

Table 1: Atherosclerotic Cardiovascular Disease Risk Categories and LDL-C Treatment Goals

			Treatment goals
	Risk Category	Risk factorsa/10-Year riskb	LDL-C (mg/dL)	Non-HDL-C (mg/dL)	apoB (mg/dL)
Extreme Risk	AACE	Progressive ASCVD after achieving an LDL-C <70 mg/dL Established clinical cardiovascular disease in patients with DM, CKD ¾ , or HeFH History of premature ASCVD (<55 male, <65 female)	<55	<80	<70
	EAS	No recommendation made	-	-	-
Very High Risk	AACE	Established or recent hospitalization for ACS, Coronary, carotid or peripheral vascular disease, 10-year risk >20% Diabetes or CKD ¾ with 1 or more risk factor(s) HeFH	<70	<100	<80
	EAS	Established ASCVD Severe CKD (GFR <30) DM with target organ damage or major risk factor	<70	<100	<80
High Risk	AACE	>2 risk factors and 10-year risk 10-20% Diabetes or CKD ¾ with no other risk factors	<100	<130	<90
	EAS	Diabetes, moderate CKD (GFR 30-50), 10-year Risk 5-10%, Familial hypercholesterolemia	<100	<130	<100
Moderate Risk	AACE	<2 risk factors and 10-year risk <10%	<100	<130	<90
	EAS	10-year risk 1-5%	< 115	-	-
Low Risk	AACE	No risk factors	<130	<160	NR
	EAS	10-year risk <1%	< 115	-	-

References

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
2. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for the management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract 2017;23:1-87.
3. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidemias. Eur Heart J 2016;37:2999-3058.
4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
5. 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.
6. Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: Pooled data from randomized trials. J Am Coll Cardiol 2017;69:471-82.
7. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016;68:92-125.
8. Mora S, Wenger NK, Demicco DA, et al. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study. Circulation 2012;125:1979-87.
9. Watts GF, Ooi EM, Chan DC. Demystifying the management of hypertriglyceridaemia. Nat Rev Cardiol 2013;10:648-61.
10. Robinson JG, Wang S, Jacobson TA. Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol and nonhigh-density lipoprotein cholesterol for cardiovascular risk reduction in randomized trials. Am J Cardiol 2012;110:1468-76.
11. Wilkins JT, Li RC, Sniderman A, Chan C, Lloyd-Jones DM. Discordance between apolipoprotein B and LDL-cholesterol in young adults predicts coronary artery calcification: the CARDIA study. J Am Coll Cardiol 2016;67:193-201.

Keywords: Simvastatin, Cholesterol, HDL, Hypercholesterolemia, Fenofibrate, Fibric Acids, Apolipoproteins B, Triglycerides, Acute Coronary Syndrome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Dyslipidemias, Cholesterol, Outcome Assessment, Health Care

< Back to Listings