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June 18/25, 2019 Circulation. 2019;139:e1082–e1143. DOI: 10.1161/CIR.0000000000000625 e1098

CLINICAL STATEMENTS AND GUIDELINES

diabetes mellitus are at high-riskS4.3-5,S4.3-8 and clinical trial evidenceS4.3-26 suggests they are likely to benefit from continuing or initiating statin therapy, although this may be compromised by reduced longevity and increased adverse events.

Recommendation-Specific Supportive Text

1.	 Most adults 40 to 75 years of age with diabetes mellitus are at intermediate or high-risk (PCE ≥7.5% 10-year risk) of ASCVD events.S4.3-5,S4.3-6,S4.3-8,S4.3-9 Three of 4 double-blinded primary-prevention RCTs of moderate statin therapy in large cohorts with diabetes mellitus in this age range showed significant reductions in ASCVD events.S4.3-1,S4.3-2,S4.3-4,S4.3-7 A meta-analysis of these trials found that moderate-intensity statin therapy is associated with a risk reduction of 25%,S4.3-3 resulting in a risk level similar to that of people without diabetes mellitus and with no apparent difference in benefit between type 1 and type 2 diabetes mellitus. Therefore, on the basis of a high level of evidence, moderate-intensity statin therapy is indicated in patients 40 to 75 years of age with diabetes mellitus for primary prevention. 2.	 Although it is well recognized that the frequency of a first ASCVD event in adults with diabetes mellitus is significantly increased compared with those without diabetes mellitus, there is a wide spectrum of risk among individuals with diabetes mellitusS4.3-5,S4.3-6,S4.3-8,S4.3-9 that varies with age, duration of diabetes mellitus, and the presence of traditional risk factors and risk modifiers common to the general population, as well as those specific to the population with diabetes mellitus (Table 5). Because the decision to upgrade statin treatment from moderate to high intensity is influenced by the level of ASCVD risk, the PCE risk estimator in adults 40 to 75 years of age with diabetes mellitus has utility in refining treatment decisions in these patients.S4.3-10,S4.3-11 The ASCVD risk score, however, does not determine whether statin intensity should be increased. Rather, it begins an evaluation that includes clinician judgment of the individual’s global risk, the potential for benefit from a high-intensity statin versus the potential for adverse effects or drug-drug interactions and evaluation should also include patient preferences and values. 3.	 The occurrence of a first ASCVD event in patients 40 to 75 years of age with diabetes mellitus is associated with increased morbidity and mortality compared with those without diabetes mellitus, which places a particularly high premium on primary prevention in those with diabetes mellitus in that age range. Although trials using moderateintensity statin therapy demonstrate significant benefit in such individuals, the residual risk in the statin treatment groups in these trials remained high (eg, 8.5% had major cardiovascular events in 3.8 years).S4.3-3 Strong general evidence indicates that the benefit from statin therapy is related to both global risk and intensity of treatment,S4.3-12 and no RCTs of high-intensity statin therapy have been carried out in cohorts of patients exclusively with diabetes mellitus. On the basis of these considerations and the fact that patients with diabetes mellitus have a higher trajectory of lifetime risk than do those without diabetes mellitus, highintensity statin therapy is preferred in patients with diabetes mellitus as they age or develop risk modifiers (Table 5). 4.	 ASCVD risk increases incrementally with age in diabetes mellitus.S4.3-5,S4.3-6,S4.3-8 In one long-term cohort study of type 2 diabetes mellitus without ASCVD, incident rates of MI averaged 25.6 per 1000 person-yearsS4.3-5 in those >75 years of age, while another in a type 1 diabetes mellitus cohort found the 10-year fatal CVD risk in those >75 years of age was 70% in men and 40% in women.S4.3-8 Although no controlled statin trials in people >75 years of age are available, a meta-analysis of the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) and HOPE-3 (Heart Outcomes Prevention Evaluation) trials demonstrated similar benefits in ASCVD reduction among those >70 of age versus <70 years of age.S4.3-26 Although that study included few patients with diabetes mellitus, it does support the continuation of moderate- or high-intensity statin therapy for primary prevention in those >75 years of age with diabetes mellitus, who comprise 21% of the population in this age category. The clinician should note that the benefit may be offset by limited life span or increased susceptibility to adverse events in patients in this age group.

Table 5.  Diabetes-Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes Mellitus

Risk Enhancers Long duration (≥10 years for type 2 diabetes mellitusS4.3-20 or ≥20 years

for type 1 diabetes mellitusS4.3-6 Albuminuria ≥30 mcg of albumin/mg creatinineS4.3-25 eGFR <60 mL/min/1.73 m2S4.3-25 RetinopathyS4.3-19 NeuropathyS4.3-16 ABI <0.9S4.3-22,S4.3-24 ABI indicates ankle-brachial index; and eGFR, estimated glomerular filtration rate.

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