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Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 June 18/25, 2019 e1097 CLINICAL STATEMENTS AND GUIDELINES

2 404 patients with heterozygous FH (molecularly defined) taking contemporary statin with or without ezetimibe treatment regimens identified age >30 years, male sex, history of ASCVD, high blood pressure, increased waist circumference, active smoking, Lp(a) ≥50 mg/dL, and LDL-C levels ≥100 mg/dL (≥2.6 mmol/L) as independent predictors of incident ASCVD over a 5.5-year follow-up period.S4.2-14 Because other medical interventions that lower LDL-C levels via increased expression of LDL receptors reduce ASCVD risk,S4.2-9 the use of PCSK9 inhibitors in selected maximally treated patients with heterozygous FH with persistently elevated LDL-C levels may be considered after a clinician–patient discussion of the net benefits versus the cost of such therapy. 5.	 Regardless of whether a patient with LDL-C levels ≥190 mg/dL (≥4.9 mmol/L) is found to have a genetic mutation associated with FH, those with very high LDL-C values are most likely to achieve the greatest benefit from evidence-based LDL-C– lowering therapy. Consequently, patients who have a baseline LDL-C level ≥220 mg/dL (≥5.7 mmol/L) and an on-treatment LDL-C level ≥130 mg/dL (≥3.4 mmol/L) despite maximally tolerated statin and ezetimibe therapy may be considered for treatment with a PCSK9 inhibitor after a clinician–patient discussion of the net benefits versus the costs of such therapy. 6.	 The cost-effectiveness of PCSK9 inhibitors for primary prevention among patients with LDL-C levels >190 mg/dL (≥4.9 mmol/L), or with FH, has not been evaluated extensively, and their clinical effectiveness in reducing ASCVD events in these patients has also not been established. The 2 published cost-effectiveness models for primary prevention (see Online Data Supplements 44 and 45 and Section 7.) report very different results, with one suggesting an incremental costeffectiveness ratio of $503 000 per QALY added, and the other reporting $75 000 per QALY added. Because of the lack of consistent evidence, the use of PCSK9 inhibitors has uncertain value for the primary prevention of ASCVD in patients with severe hypercholesterolemia.

4.3 Diabetes Mellitus in Adults

Recommendations for Patients With Diabetes Mellitus Referenced studies that support recommendations are summarized in Online Data Supplements 11 and 12.

COR LOE Recommendations

I A 1.  In adults 40 to 75 years of age with diabetes mellitus, regardless of estimated 10-year ASCVD risk, moderate-intensity statin therapy is indicated.S4.3-1–S4.3-9 IIa B-NR 2.  In adults 40 to 75 years of age with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it is reasonable to assess the 10-year risk of a first ASCVD event by using the race and sex-specific PCE to help stratify ASCVD risk.S4.3-10,S4.3-11

IIa B-R 3.  In adults with diabetes mellitus who have multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more.S4.3-12,S4.3-13

IIa B-NR 4.  In adults older than 75 years of age with diabetes mellitus and who are already on statin therapy, it is reasonable to continue statin therapy.S4.3-5,S4.3-8,S4.3-13

IIb C-LD 5.  In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.S4.3-14,S4.3-15

IIb C-LD 6.  In adults older than 75 years with diabetes mellitus, it may be reasonable to initiate statin therapy after a clinician–patient discussion of potential benefits and risks.S4.3-5,S4.3-8,S4.3-13

IIb C-LD 7.  In adults 20 to 39 years of age with diabetes mellitus that is either of long duration (≥10 years of type 2 diabetes mellitus, ≥20 years of type 1 diabetes mellitus), albuminuria (≥30 mcg of albumin/mg creatinine), estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2, retinopathy, neuropathy, or ankle-brachial index (ABI; <0.9), it may be reasonable to initiate statin therapy.S4.3-5,S4.3-6,S4.3-8,S4.3-16–S4.3-25

Synopsis

Although most adults 40 to 75 years of age with diabetes mellitus are at intermediate or high-risk of their first ASCVD event,S4.3-5,S4.3-6,S4.3-8,S4.3-9 evaluation of AS- CVD risk will help refine risk estimates and therapeutic decision-making. Because primary-prevention trials demonstrate that moderate-intensity statin therapy in large cohorts with diabetes mellitus provides significant benefit,S4.3-1–S4.3-4,S4.3-7 this treatment is indicated in such individuals. However, given the increased morbidity and mortality associated with a first event in diabetes mellitus and the residual risk among the statin-treated groups in these trials, together with the evidence of benefit from high-intensity statin treatment in primary prevention among men >50 years of age and women >60 years of age,S4.3-13 high-intensity statin therapy to maximize risk reduction is preferred for patients with diabetes mellitus as they age or if they have risk modifiers. Adults 20 to 39 years of age are mostly at low 10-year risk, although moderate-intensity statin therapy in those with long-standing diabetes mellitus or a concomitant higher-risk condition may be reasonable (Table 5).S4.3-17,S4.3-20,S4.3-21 Adults >75 years of age with

Recommendations for Patients With Diabetes Mellitus (Continued)

COR LOE Recommendations

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