Introduction

The 2013 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines on the treatment of blood cholesterol represented a major paradigm shift in that they focused primarily on statin benefit groups and incorporated atherosclerotic cardiovascular disease (ASCVD) risk estimation via the pooled cohort equations (PCEs) into treatment algorithms.¹ They differed from prior guidelines by pushing away from the old dogma of "treat to target" by any means, and rather focused on statin intensity and relative reduction in low-density lipoprotein cholesterol (LDL-C) compared to baseline. Since 2013, additional randomized clinical trial (RCT) evidence has emerged to support selective use of non-statin therapies as treatment adjuncts and the use of LDL-C thresholds. Further evidence suggests that the relationship between LDL-C and ASCVD risk tracks down to very low values of LDL-C. Herein, we discuss the major changes in the ACC/AHA cholesterol guidelines from 2013 to 2018 and provide a brief review of the evidence that supports these guidelines.

The updated guidelines share many fundamental components of the 2013 guidelines and make modifications to prior recommendations with similar overarching themes. Of continued emphasis is the strategy to highlight a heart-healthy lifestyle from adolescence onward. For young adults age 20-40, the new guidelines promote assessment of lifetime risk and emphasize comprehensive and intensive lifestyle improvements to prevent development of the metabolic syndrome. For all patients at all visits it is important to encourage dietary and exercise improvements in order to prevent and mitigate obesity, hypertension and hypercholesterolemia.

From the perspective of statin therapy, the new guidelines are similar to the old ones in that they continue to break down statin benefit into four major categories: 1) those with clinical ASCVD; 2) those with LDL-C ≥190 mg/dL; 3) those with diabetes mellitus aged 40-75 years old with LDL-C ≥70 mg/dL; and 4) those with no diabetes but with LDL-C ≥70 mg/dL and ≥7.5% 10-year ASCVD risk. In addition to lifestyle intervention, statins remain first line therapy for patients in any of these categories. Similar to prior guidelines, clinician-patient risk discussions are endorsed upfront so that initiation of statin therapy becomes a shared decision that takes into account the patient's personal goals, values and unique clinical circumstances.

Utilization of Treatment Thresholds and Adjunctive Non-Statin Therapies

One of the most significant changes in the updated guidelines is the stronger support for selective use of adjunct non-statin medications for LDL-C reduction in high-risk patients. The 2018 guidelines bring numbers back, advocating for use of LDL-C treatment thresholds to inform the need to add RCT-proven, non-statin therapies (ezetimibe and PCSK9 inhibitors).² Indeed, this approach is consistent with the way patients were selected for participation in the RCTs. In adults with clinical ASCVD, the new guidelines recommend considering the addition of ezetimibe if LDL-C remains ≥70 mg/dL after a patient is on maximally tolerated statin therapy. For patients with very high ASCVD risk (recent ACS, h/o MI/stroke, PAD) already on maximally tolerated statin and ezetimibe, the clinician and patient can consider adding a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (alirocumab or evolocumab) if the LDL-C remains ≥70 mg/dL.^3-4

Important to the decision of choosing an adjunct agent is understanding the degree of LDL-C reduction that is expected with various therapies. Absolute mg/dL reduction in LDL-C is dependent on baseline LDL-C values and the potency of lipid lowering therapy; each reduction in LDL-C by 40 mg/dL is associated with approximately 20-25% relative reduction in ASCVD risk regardless of therapy chosen.⁵ Furthermore, patients with highest absolute baseline risk are known to derive the most benefit. As compared to high intensity statins which are known to reduce LDL-C by roughly 50%, ezetimibe reduces LDL-C levels by an additional 20-25% and FDA approved doses of PCSK9 inhibitors evolocumab and alirocumab reduce LDL-C levels by approximately 60%.^6-7,3

The updated guidelines similarly recommend use of a high intensity statin to reduce high lifetime risk in patients with severe primary hypercholesterolemia (LDL-C ≥190) without need to calculate ASCVD for risk stratification but add to prior guidelines by more specifically delineating the indication for adjunct therapy in this population. If LDL-C remains 100 mg/dL or more in this group, the new guidelines encourage consideration of ezetimibe, especially if there is a family history of premature ASCVD. PCSK9 inhibitors may also be considered in select patients with persistently elevated lipids after evaluating price and cost-effectiveness. The new guidelines also recommend cascade screening of first-degree relatives.

Risk Stratification for Primary Prevention in Patients With Indeterminate Risk

Whereas the 2013 guidelines indicated that individuals without diabetes or ASCVD aged 40-75, with LDL-C 70-189 mg/dL and ≥7.5% 10-year ASCVD risk merited clinician-patient risk discussion to consider statin treatment, the updated guidelines offer additional risk-assessment strategies to prevent unnecessary prescribing. First, the clinician should assess for major risk factors such as hypertension, active or significant prior smoking and HbA1c, as these may change the risk-benefit conversation for patients. Next, it is important to assess for risk enhancing factors that would favor statin prescription in this population, such as: 1) persistently elevated LDL-C ≥160 mg/dL; 2) metabolic syndrome; 3) chronic kidney disease; 4) early menopause or pre-eclampsia in women; 5) family history of premature ASCVD; 6) chronic inflammatory disorders (human immunodeficiency virus, rheumatoid arthritis, psoriasis); 7) South Asian descent; 8) low ankle-brachial index; or 9) persistently elevated TG (≥175), Lp(a) ≥50 mg/dL or ≥125 nmol/L, apoB ≥130 mg/dL, or hsCRP ≥2 mg/L.

For patients with indeterminate or uncertain risk with a 10-year ASCVD risk of 7.5-20%, it is reasonable to consider coronary artery calcium (CAC) scoring to non-invasively risk-stratify projected benefit for statin therapy. If the CAC score is 0, this indicates a low 10-15 year risk, with much less potential short-term benefit from a statin. In this situation, clinicians and patients may reasonably choose to hold off on statin treatment, focus solely on lifestyle modification, and then reassess in 5-10 years. Exceptions may be cases with a strong family history of premature ASCVD, current smoking or diabetes mellitus.

If the CAC score is ≥100, this indicates that the patient is at a secondary prevention risk level, and statin therapy would likely be of benefit. For a CAC score of 1-100, it is reasonable to consider adding a statin after clinician-patient risk benefit conversation. Similar to the 2013 guidelines, the 2018 guidelines place considerable importance on the clinician-patient risk discussion regarding starting statin therapy in addition to lifestyle changes for primary prevention. The 2018 guidelines also recommend consideration of potential for adverse effects, medication costs and patient preferences in these discussions.

Lipid Reducing Therapies in Patients with Diabetes Mellitus

Lipid management guidelines have only changed slightly for patients with diabetes mellitus from 2013 to 2018, specifically with respect to the tools utilized to guide statin intensity management in these patients. For all patients with diabetes aged 40-75 with LDL-C ≥70 mg/dL, the new guidelines suggest starting moderate intensity statin without formal estimation of 10-year ASCVD risk by the PCEs. Whereas prior guidelines suggested high intensity statins for this population if their 10-year ASCVD risk is ≥7.5%, new guidelines replace this qualifier with those "with multiple risk factors" or in those >50 years of age.

Monitoring Lipid Levels in the New Era

Given increasing reliance on LDL-C thresholds in the new guidelines, following up the response to lipid-lowering therapy is important to determine if treatment is optimized. Similar to prior guidelines, 2018 guidelines recommend follow-up 4-12 weeks after prescribing lipid-lowering therapy to assess LDL-C percent-reduction and to monitor adherence to medication and lifestyle changes. The expected percent decrease provides an assessment of adherence to therapy. One can then consider LDL-C thresholds for adjunct therapeutics, as discussed above.

With increased focus on lower LDL-C cutoffs, the 2018 cholesterol guidelines promote the use of the Martin/Hopkins LDL-C method, which replaces the fixed factor of five used for the triglyceride to VLDL-C ratio with the traditional Friedewald equation with modified patient-specific variables.⁸ Recent analyses have shown that the Friedewald equation is prone to inaccuracy in the modern treatment era at low-LDL-C levels and high trigylcerdies.⁹ The Martin/Hopkins equation demonstrates superior accuracy in these settings and furthermore boasts an accuracy advantage in the non-fasting setting,¹⁰ which confers additional benefits of convenience for patients and laboratories. The equation has been validated abroad in countries such as Japan, Korea and Mexico,^11,12,13 and has been incorporated by laboratories on a global scale (including by Quest Diagnostics and by our own laboratory at Johns Hopkins).

Areas Where More Information is Needed for Future Guidelines

While the new guidelines provide important updates based on recent RCT data, there continue to exist clinical "gray zones" where the indication for statin and non-statin therapy for primary prevention is less clear, such as in the very elderly. Furthermore, although there is evidence to suggest that the DASH and Mediterranean diets in addition to regular exercise is important for all patients for primary and secondary prevention,¹⁴ data are lacking with regard to added health benefits of specific dietary variants such as low carb and vegetarian/vegan diet and various commonly practiced exercise routines. Despite the importance of these non-pharmaceutical interventions, sufficient research in these areas is generally lacking. Finally, with regard to adjunct therapy, continued work is warranted to update cost-benefit analyses of ezetimibe and PCSK9 inhibitors as prices and the clinical landscape evolve.

Conclusions

The 2018 AHA/ACC Cholesterol Guidelines build upon fundamental principles proposed in the 2013 guidelines, with key modifications based on recent RCT data to incorporate LDL-C thresholds, using more accurate LDL-C estimation, to optimize use of ezetimibe and PCSK9 inhibitors in addition to maximal statin therapy and lifestyle for ASCVD risk reduction. The new guidelines also feature additional risk-enhancing factors and CAC scoring in primary prevention patients with intermediate risk. While addition of thresholds and risk stratification tools may add an additional degree of complexity to our current diagnostic and therapeutic lipid algorithms, their implementation has the potential to lead to more personalized preventive care. In the case of the updated cholesterol guidelines, we do believe the juice was worth the squeeze.

Table 1: Differences Among 2013 and 2018 ACC/AHA Cholesterol Guidelines

	2013 Cholesterol Guidelines	2018 Cholesterol Guidelines
Use of LDL-C thresholds	Not supported	Supported
Recommended therapies for LDL-C reduction	Start with guideline-directed statin intensity and increase up to maximally tolerated statin dosing if not achieving expected LDL-C reduction goal (≥50% for high-intensity, 30-50% moderate intensity). Consider adjunctive therapies if not able to achieve percent reduction with maximally tolerated statin alone.	In secondary prevention, maximize lifestyle and statin therapy, and if LDL-C 70 mg/dL or more consider adding ezetimibe and subsequently PCSK9 inhibitors.
Coronary artery calcium scoring	In primary prevention, additional factors may help risk-stratify in those whose risk is uncertain.  May consider CAC score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity as evidence of likely to benefit from treatment.	In patients without diabetes and LDL-C 70 mg/dL or above with intermediate risk (ASCVD 7.5-20%); CAC score ≥100 Agatston units favors treatment with a statin. The absence of CAC indicates that the decision about statin therapy can likely be deferred for at least 5 years.
Other risk enhancing factors for primary prevention treatment candidacy	LDL-C ≥160 mg/dL, hs-CRP ≥2.0 mg/L, ABI <0.9, elevated lifetime ASCVD risk, family history of premature ASCVD.	LDL-C ≥160 mg/dL, apoB ≥130 mg/dL, increased Lp(a), hsCRP ≥ 2.0 mg/L, low ABI (<0.9), metabolic syndrome, chronic kidney disease, chronic inflammatory disorders (e.g. HIV, RA, psoriasis) premature menopause, South Asian ancestry, family history of premature ASCVD.
Statin management in persons with diabetes age 40-75 with LDL-C 70-189 mg/dL	Use 10-year ASCVD risk calculator to determine if eligible for a clinician patient risk discussion regarding moderate or high intensity statin.	Start moderate intensity statin without need to calculate 10-year ASCVD risk. If multiple risk factors or 50-75 years of age, reasonable to start a high intensity statin.
Heart-healthy lifestyle	Better dietary and exercise habits for all.	Better dietary and exercise habits for all. Assess lifetime risk of ASCVD in young adults and intervene to prevent the metabolic syndrome.
Familial hypercholesterolemia	Patients who have fallen short of treatment goals of 100 mg/dL are not considered "treatment failures," and observational data has shown significant reductions in ASCVD events without achieving specific LDL-C goals.	If LDL-C ≥100 mg/dL in patients with FH, can add ezetimibe and/or PCSK9 inhibitor. Recommend cascade screening of first-degree relatives.
Method of cholesterol calculation	The Friedewald Equation.	Consider Martin-Hopkins LDL-C estimation at low LDL-C

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. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018. Epub ahead of print.
3. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
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. Cholesterol Treatment Tiralists' (CTT) Collaboration, Baigent C, Blackwell L, 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.
6. Canon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
7. Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 2012;223:251-61.
8. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013;330:2061-8.
9. Whelton SP, Meeusen JW, Donato LJ, et al. Evaluating the atherogenic burden of individuals with a Friedwald-estimated low-density lipoprotein cholesterol <70 mg/dL compared with a novel low-density lipoprotein estimation method. J Clin Lipidol 2017;11:1065-72.
10. Sathiyakumar V, Park J, Golozar A, et al. Fasting versus nonfasting and low-density lipoprotein cholesterol accuracy. Circulation 2018;137:10-9.
11. Chaen H, Kinchiku S, Miyata M, et al. Validity of a novel method for estimation of low-density lipoprotein cholesterol levels in diabetic patients. J Atheroscler Thromb 2016;23:1355-64.
12. Lee J, Jang S, Son H. Validation of the Martin Method for estimating low-density lipoprotein cholesterol levels in Korean adults: findings from the Korea National Health and Nutrition Examination Survey, 2009-2011. PLoS One 2016;11:e0148147.
13. Mehta R, Reyes-Rodruguez E, Yaxmehen Bello-Chavolla O, et al. Performance of LDL-C calculated with Martin's formula compared to the Friedwald equation in familial combined hyperlipidemia. Atherosclerosis 2018;277:204-10.
14. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC Health Promotion Series. J Am Coll Cardiol 2018;72:1141-56.

Keywords: Dyslipidemias, Algorithms, American Heart Association, Antibodies, Monoclonal, Atherosclerosis, Cholesterol, Cholesterol, LDL, Cohort Studies, Cost-Benefit Analysis, Diabetes Mellitus, Diet, Mediterranean, Diet, Vegetarian, Antibodies, Monoclonal, Follow-Up Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hypertension, Life Style, Medication Adherence, Metabolic Syndrome, Obesity, Primary Prevention, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Stroke, Subtilisins, Triglycerides

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