The American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines recently published its 2018 recommendations on management of LDL cholesterol (LDL-C) in people with diabetes. For primary prevention, moderate-intensity statin therapy is recommended for those aged 40–75 years, with a preference for high-intensity statin treatment for older subjects and for those with higher estimated risk or risk-enhancing factors following a patient-clinician discussion. Statin therapy may be reasonable in adults <40 years or >75 years of age where there is less evidence for benefit. For people with diabetes and established atherosclerotic cardiovascular disease, high-intensity statin therapy is recommended. The majority of these subjects have very high risk, and an LDL-C goal of <70 mg/dL is recommended. If this target is not achieved, ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor may be added.

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Clinical Practice Guidelines published its first guidelines on the management of blood cholesterol in people with diabetes in 2013 and has now updated and modified these recommendations in the 2018 guidelines (1). The guidelines were developed by a writing committee consisting of medical experts including cardiologists, internists, interventionists, a nurse practitioner, pharmacists, a physician assistant, a pediatrician, a nephrologist, a diabetologist (American Diabetes Association [ADA] representative), and a lay/patient representative, and all members were required to have no relationships with industry. The development of recommendations was based on all available evidence, based on a literature search of randomized controlled trials (RCTs), registries, nonrandomized comparative and descriptive studies, and systematic reviews from May 1980 through July 2017 using relevant keywords as well as considering the results of an independent evidence review committee that assessed the magnitude of benefits and harms from the addition of nonstatin medications to statin therapy in those with clinical atherosclerotic cardiovascular disease (ASCVD). Recommendations were based on ACC/AHA criteria that designate both a class of recommendation (COR) and a level of evidence (LOE). COR describes the estimated magnitude and certainty of benefit in proportion to risk, and LOE rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources.

ASCVD is the leading cause of morbidity and mortality in diabetes, and diabetes is a major contributor to the development of ASCVD in the population. The principal focus of the 2018 guidelines section on diabetes is on primary prevention of ASCVD in adults using pharmacotherapy to lower LDL cholesterol (LDL-C) in addition to a healthy lifestyle. Other sections of relevance to diabetes that are dealt with in the guidelines include secondary prevention of ASCVD, hypertriglyceridemia, and chronic kidney disease (CKD). As in the 2013 guidelines, the 2018 guidelines recommend moderate-intensity statin therapy for most adults for primary prevention, but the 2018 guidelines extend the recommendations for risk assessment in the 40–75-year age-group to upgrade statin therapy decision-making through consideration of an expanded list of risk-enhancing factors in addition to major risk factors in a clinician-patient discussion. Though evidence remains incomplete, greater attention is given in the 2018 guidelines to adults <40 years of age and those >75 years. For secondary prevention, the 2018 guidelines continue to recommend high-intensity statins but now recommend ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors added to maximally tolerated statin therapy for a subgroup of very high-risk patients who do not achieve an LDL-C below a threshold value of 70 mg/dL with statin therapy alone.

There is a wide spectrum of risk among individuals with diabetes (25) that varies with age, duration of diabetes, and the presence of traditional risk factors and risk enhancers common to the general population, as well as those specific to the population with diabetes (Fig. 1).

Figure 1

AHA/ACC MultiSociety 2018 guidelines for cholesterol management in people with diabetes. The COR indicates the strength of recommendation, encompassing the estimated magnitude and certainty of benefit in proportion to risk. The LOE rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources. COR I – strong (green); COR IIa – moderate (yellow); COR IIb – weak (orange). LOE A – high quality: multiple high-quality RCTs/meta-analyses; LOE B-R – moderate quality: at least one RCT/meta-analysis; LOE B-NR – moderate quality: one or more well-designed nonrandomized studies; LOE C-LD – limited data.

Figure 1

AHA/ACC MultiSociety 2018 guidelines for cholesterol management in people with diabetes. The COR indicates the strength of recommendation, encompassing the estimated magnitude and certainty of benefit in proportion to risk. The LOE rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources. COR I – strong (green); COR IIa – moderate (yellow); COR IIb – weak (orange). LOE A – high quality: multiple high-quality RCTs/meta-analyses; LOE B-R – moderate quality: at least one RCT/meta-analysis; LOE B-NR – moderate quality: one or more well-designed nonrandomized studies; LOE C-LD – limited data.

Close modal

Age 40–75 Years

RCTs of statin therapy included adults with diabetes aged 40–75 years. Therefore, evidence for benefit is principally derived from studies in this age-group. Most adults with diabetes in this age range are at intermediate or high risk for their first ASCVD event (25). A large meta-analysis of 14 RCTs of moderate-intensity statin therapy (30–50% LDL-C lowering) that included people with type 1 diabetes (n = 1,466) and type 2 diabetes (n = 17,220) demonstrated a 21% reduction in major vascular events per 1 mmol/L (∼39 mg/dL) reduction in LDL-C (6). The benefit was similar for type 1 and type 2 diabetes patients and whether or not they had a history of ASCVD. Of these studies, there were four primary prevention RCTs of statin therapy conducted exclusively in cohorts with diabetes, three of which showed significant reductions in ASCVD events (710). A meta-analysis of these four trials found that moderate-intensity statin therapy is associated with a risk reduction of 25% (11), similar to that found in people without diabetes or ASCVD. In addition, a large registry study (n = 24,230) in people with type 1 diabetes without a history of ASCVD found a 40% reduction in cardiovascular disease (CVD) death among those receiving lipid-lowering therapy compared with those who did not (12). Therefore, moderate-intensity statin treatment is indicated in such individuals on the basis of a high level of evidence and without the need for prior risk assessment.

Refinement of Risk Assessment

Strong general evidence indicates that the benefit from statin therapy is related to both global risk and intensity of treatment and is supported by meta-analyses comparing high-intensity versus moderate-intensity statin therapy (13), although no RCTs of high-intensity statin therapy have been carried out in cohorts of patients exclusively with diabetes. Because the level of ASCVD risk influences the decision to upgrade statin treatment from moderate to high intensity, evaluation of risk using the pooled cohorts equations (PCE) derived from studies of cohorts that included a large number of subjects who had diabetes will help refine risk estimates and therapeutic decision-making. However, this three-tiered ASCVD risk score, which categorizes individuals into borderline (5–7.4%), intermediate (7.5–19.9%), and high (≥20%) 10-year risk for ASCVD, does not determine whether statin intensity should be increased. Rather, it begins an evaluation that includes clinician judgment of the individual’s global risk, including an assessment of risk-enhancing factors as well as the potential for benefit from a high-intensity statin versus the potential for adverse effects or drug-drug interactions, and the evaluation should also take into account patient preferences and values.

Risk Enhancers

Although the PCE is the most robust tool for estimating 10-year risk in U.S. adults 40–75 years of age based on its inclusion of major independent risk factors, it has limitations when applied to individuals. One purpose of the clinician-patient risk discussion is to individualize risk status based on PCE as well as other risk enhancing factors prevalent in the general population that may be present in people with diabetes, as well as those specific to diabetes (1420) (Table 1).

Table 1

Risk enhancers in primary prevention

Specific to diabetesGeneral
Long duration (≥10 years for type 2 diabetes (3,14) or ≥20 years for type 1 diabetes (15Family history of premature ASCVD 
Albuminuria ≥30 μg of albumin/mg creatinine (16LDL-C levels ≥160 mg/dL 
eGFR <60 mL/min/1.73 m2 (16Metabolic syndrome 
Retinopathy (17CKD 
Neuropathy (18History of preeclampsia or premature menopause in women 
Ankle brachial index <0.9 (19,20Chronic inflammatory disorders 
High-risk ethnicity such as South Asian ancestry 
Triglyceride levels persistently >175 mg/dL 
If measured
Apolipoprotein B levels with elevations >130 mg/dL (may be useful if hypertriglyceridemia >200 mg/dL to rule out genetic disorders such as Type III or clarify ASCVD risk) 
hs-CRP ≥2 mg/L 
Lipoprotein(a) levels with elevations >50 mg/dL (>125 nmol/L). Elevated lipoprotein(a) levels especially useful in those with a family history of ASCVD 
Reduced ankle brachial index 
Specific to diabetesGeneral
Long duration (≥10 years for type 2 diabetes (3,14) or ≥20 years for type 1 diabetes (15Family history of premature ASCVD 
Albuminuria ≥30 μg of albumin/mg creatinine (16LDL-C levels ≥160 mg/dL 
eGFR <60 mL/min/1.73 m2 (16Metabolic syndrome 
Retinopathy (17CKD 
Neuropathy (18History of preeclampsia or premature menopause in women 
Ankle brachial index <0.9 (19,20Chronic inflammatory disorders 
High-risk ethnicity such as South Asian ancestry 
Triglyceride levels persistently >175 mg/dL 
If measured
Apolipoprotein B levels with elevations >130 mg/dL (may be useful if hypertriglyceridemia >200 mg/dL to rule out genetic disorders such as Type III or clarify ASCVD risk) 
hs-CRP ≥2 mg/L 
Lipoprotein(a) levels with elevations >50 mg/dL (>125 nmol/L). Elevated lipoprotein(a) levels especially useful in those with a family history of ASCVD 
Reduced ankle brachial index 

Coronary Calcium Scoring

The coronary artery calcium (CAC) score may be used in primary prevention among the general population in borderline or intermediate-risk individuals to identify lower-risk individuals with a CAC score of 0 for derisking purposes. Nonetheless, a study of adults with type 2 diabetes and without ASCVD who had a CAC score of 0 found a mean ASCVD 10-year risk of 8.0% (21), indicating that they were not at low risk or soon would not be at low risk. Recent data in adults with type 1 diabetes without ASCVD and with a CAC score of 0 showed that their mean ASCVD 10-year risk was 5.6% (22). Therefore, CAC scoring in people with diabetes aged 40–75 years is not recommended for derisking or revising risk assessment below the treatment threshold.

High-Intensity Statin Therapy (>50% LDL-C Lowering)

People with diabetes have a higher trajectory of lifetime risk than do those without diabetes. Furthermore, morbidity and mortality associated with a first event is increased in diabetes, and the residual risk among the statin-treated groups in the primary prevention trials of people with diabetes remained high (e.g., overall 8.5% had major cardiovascular events in 3.8 years [11]). In addition there is evidence of benefit from high-intensity statin treatment in primary prevention among men >50 years of age and women >60 years of age (23). On the basis of these considerations, high-intensity statin therapy to maximize risk reduction is preferred in patients with diabetes as they age or develop risk enhancers. In those who have a high ASCVD risk score of >20%, a risk discussion may be held on the benefits of achieving ≥50% LDL-C lowering, and in those in whom high-intensity statin cannot be tolerated or does not lower LDL-C as expected by ≥50%, addition of ezetimibe 10 mg/day to moderate-intensity statin therapy can achieve the same percent LDL-C lowering as that achieved with high-intensity statin therapy (24).

Age <40 Years

There is limited information on ASCVD rates among individuals 20–39 years of age and even less in children and adolescents with diabetes, and there is no information on whether statin therapy is beneficial in these age-groups. Available evidence indicates that although rates of ASCVD are low in people <30 years of age, they increase with time (3,14,25). They may reach intermediate risk levels by 30–39 years of age, especially in individuals with long-standing type 2 diabetes (3,25), who may have more advanced subclinical coronary atherosclerosis than do subjects without diabetes (26), and in those with type 1 diabetes of >20 years’ duration (15). ASCVD rates will also be influenced by hypertension and diabetic microvascular complications that may be prevalent in these age-groups (15,27). Thus, it may be reasonable to have a discussion about initiating moderate-intensity statin therapy with patients <40 years of age who have had type 2 diabetes for at least 10 years or type 1 diabetes for at least 20 years and in patients with one or more major CVD risk factor or diabetic complications (Table 1).

Age >75 Years

ASCVD risk increases incrementally with age in diabetes (24). In one long-term cohort study of people with type 2 diabetes without ASCVD, incident rates of myocardial infarction averaged 25.6 per 1,000 person-years in those >75 years of age (2), while another study in a type 1 diabetes cohort found the 10-year fatal CVD risk in those >75 years of age was 70% in men and 40% in women (4). Although no RCTs of statin therapy in people >75 years of age have been undertaken, a meta-analysis of two recent statin trials in older subjects demonstrated similar benefits in ASCVD reduction among those >70 versus ≤70 years of age (28). A recent large retrospective study found that statin therapy in new users without preexisting ASCVD was associated with reduced ASCVD events in people with type 2 diabetes aged 75–84 years but not in those ≥85 years of age, nor in those without diabetes (29). These studies do support the continuation of moderate- or high-intensity statin therapy for primary prevention in people >75 years of age with diabetes, who comprise about 20% 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. This becomes even more relevant in adults >75 years of age with diabetes who are not receiving statin therapy, in whom the diagnosis of diabetes may be recent or its duration unknown. It may therefore be reasonable to have a clinician-patient discussion in which the potential benefits and risks of initiating statin therapy in this age-group are reviewed.

CKD

The 2018 guidelines recommend that CKD be considered a risk-enhancing factor, and evidence indicates albuminuria (≥30 mg/g creatinine) or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 increases risk for ASCVD in diabetes independent of major risk factors (16). Trials show absolute benefit from statin use in subjects with CKD, and this benefit is consistent across eGFR stages (30). However, the relative risk reduction per unit of LDL-C lowering may be lower with more advanced CKD. Although people on dialysis have the highest absolute risk of events, the proportion of deaths thought to be due to atherosclerotic events is lower and the lack of benefit in RCTs with statin initiation among people on dialysis (31) raises the question of competing risks.

Hypertriglyceridemia

Patients with type 2 diabetes frequently have hypertriglyceridemia. The 2018 guidelines recommended that in adults 40–75 years of age with moderate (150–499 mg/dL) or severe (≥500 mg/dL) hypertriglyceridemia and ASCVD risk ≥7.5%, after considering lifestyle and secondary factors, it is reasonable to consider a persistently elevated triglyceride level (≥175 mg/dL) as a factor favoring initiation or intensification of statin therapy. In adults with persistently elevated or increasing severe hypertriglyceridemia and especially if ≥1,000 mg/dL, it is further reasonable to reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of n-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy. A recent RCT found that addition of high doses of a synthetic n-3 fatty acid preparation (icosapent ethyl) to statin therapy in patients with ASCVD and/or diabetes plus at least one other CVD risk factor, and with triglyceride levels 135–499 mg/dL and LDL-C levels 41–100 mg/dL, reduced ASCVD events by 25% (32). The U.S. Food and Drug Administration has approved icosapent ethyl for those with ASCVD or diabetes with at least two additional ASCVD risk factors and triglyceride levels >150 mg/dL. Based on this finding, the ADA has recommended that in patients with diabetes and ASCVD or other cardiac risk factors on a statin and with controlled LDL-C but elevated triglycerides (135–499 mg/dL), the addition of icosapent ethyl should be considered to reduce cardiovascular risk (33).

A meta-analysis of RCTs supports high-intensity statins for patients with ASCVD (13) (Fig. 1). The goal of therapy is to reduce LDL-C by >50%. If high-intensity statins are not tolerated, moderate-intensity statins are acceptable. For the latter, addition of ezetimibe may achieve >50% reduction in LDL-C and provide additional risk benefit (24). RCT data in patients >75 years of age are limited, but initiation or continuation of moderate-/high-intensity statin therapy is reasonable. Conservatively, up to one-fourth of patients with ASCVD have a very high-risk status (34). This condition is defined as a history of multiple major ASCVD events or one major ASCVD event plus multiple high-risk conditions: age ≥65 years, heterozygous familial hypercholesterolemia, prior percutaneous coronary intervention/coronary artery bypass grafting, diabetes, hypertension, CKD, current smoking, history of heart failure, and LDL-C ≥100 mg/dL on maximal statin plus ezetimibe. Most patients with diabetes and ASCVD fall into this category. Furthermore, in an RCT, addition of ezetimibe to moderate statin therapy in patients diagnosed with an acute coronary syndrome demonstrated significant additional benefit in the subgroup with diabetes and in those aged ≥75 years (35). In very high-risk patients, the goal for LDL-C on maximal statin therapy is a level <70 mg/dL. If this goal is not achieved with statins alone, adding ezetimibe is the next step. Then, if this combination does not reduce LDL-C to <70 mg/dL, adding a PCSK9 inhibitor can be considered. The latter is supported by two recent RCTs, which showed significant reductions of ASCVD events when PCSK9 inhibitors were added to maximal LDL-C–lowering therapy in patients with LDL-C ≥70 mg/dL (36,37). The relative risk reduction has been shown to be similar in people with or without diabetes (38,39). In these trials, although ezetimibe added to a statin was allowed, <10% of participants were taking ezetimibe at baseline. The rationale for ezetimibe before PCSK9 inhibitor is supported by simulation analyses indicating most patients treated with statin and ezetimibe achieve LDL-C <70 mg/dL (40,41). Recruitment criteria for PCSK9 inhibitor trials excluded patients with LDL-C <70 mg/dL; hence, no RCT evidence demonstrates that starting PCSK9 inhibitors in patients with LDL-C <70 mg/dL is either statistically or clinically efficacious. Moreover, in very high-risk patients recruited with LDL-C ≥70 mg/dL, adding ezetimibe to statin therapy incrementally reduces ASCVD events (24). The guidelines did not exclude using PCSK9 inhibitors without ezetimibe, but this approach was not favored. It should further be noted that RCTs with PCSK9 inhibitors lasted less than 3 years and thus did not exclude longer-term side effects, and unlike ezetimibe, PCSK9 inhibitors are not available in generic form.

It must be noted that cost-effectiveness analysis does not support widespread use of PCSK9 inhibitors when costs are at mid-2018 prices. Recently, prices have begun to decline, but cost-effectiveness at current prices is still relatively low by conventional analyses. As prices decline more, the use of these drugs may become acceptably cost-effective. If so, for patients at very high risk, PCSK9 inhibitors could enhance clinical utility when added to maximal therapy with statins and ezetimibe.

Although adults with diabetes vary in their risk for a first ASCVD event, diabetes is a major risk factor for ASCVD. Based on the results of multiple RCTs, those aged 40–75 years will benefit from statin therapy. Moderate-intensity statin therapy is recommended without the need for evaluation of ASCVD risk, but high-intensity statin therapy is preferred in older subjects and those with higher estimated risk or with risk-enhancing factors following a clinician-patient discussion. Although there have been no RCTs in subjects <40 years or >75 years, based on a consideration of risks versus benefits, statin therapy may be reasonable in these groups. The majority of patients with diabetes and ASCVD have a very high risk for a recurrent event and an LDL-C goal of <70 mg/dL is recommended for them. This may require the addition of ezetimibe to maximal-intensity statin therapy, which is likely to achieve this goal in the majority of those with LDL-C >70 mg/dL on statin therapy alone; if not, addition of a PCSK9 inhibitor may then be considered. The 2018 ACC/AHA guidelines are very similar to the ADA 2019 guidelines for lipid management (32), and the unanimity between the two sets of guidelines adds weight to these conclusions.

*

American Heart Association (AHA), American College of Cardiology (ACC), American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), American Academy of Physician Assistants (AAPA), Association of Black Cardiologists (ABC), American College of Preventive Medicine (ACPM), American Diabetes Association (ADA), American Geriatrics Society (AGS), American Pharmacists Association (APhA), American Society for Preventive Cardiology (ASPC), National Lipid Association (NLA), and Preventive Cardiovascular Nurses Association (PCNA)

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines
.
Circulation
2019
;
139
:
e1082
e1143
2.
Mulnier
HE
,
Seaman
HE
,
Raleigh
VS
, et al
.
Risk of myocardial infarction in men and women with type 2 diabetes in the UK: a cohort study using the General Practice Research Database
.
Diabetologia
2008
;
51
:
1639
1645
3.
Rana
JS
,
Liu
JY
,
Moffet
HH
,
Jaffe
M
,
Karter
AJ
.
Diabetes and prior coronary heart disease are not necessarily risk equivalent for future coronary heart disease events
.
J Gen Intern Med
2016
;
31
:
387
393
4.
Soedamah-Muthu
SS
,
Fuller
JH
,
Mulnier
HE
,
Raleigh
VS
,
Lawrenson
RA
,
Colhoun
HM
.
High risk of cardiovascular disease in patients with type 1 diabetes in the U.K.: a cohort study using the general practice research database
.
Diabetes Care
2006
;
29
:
798
804
5.
Wong
ND
,
Glovaci
D
,
Wong
K
, et al
.
Global cardiovascular disease risk assessment in United States adults with diabetes
.
Diab Vasc Dis Res
2012
;
9
:
146
152
6.
Cholesterol Treatment Trialists’ (CTT) Collaborators
;
Kearney
PM
,
Blackwell
L
,
Collins
R
, et al
.
Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis
.
Lancet
2008
;
371
:
117
125
7.
Colhoun
HM
,
Betteridge
DJ
,
Durrington
PN
, et al.;
CARDS investigators
.
Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial
.
Lancet
2004
;
364
:
685
696
8.
Collins
R
,
Armitage
J
,
Parish
S
,
Sleigh
P
,
Peto
R
;
Heart Protection Study Collaborative Group
.
MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial
.
Lancet
2003
;
361
:
2005
2016
9.
Sever
PS
,
Poulter
NR
,
Dahlöf
B
, et al
.
Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–lipid-lowering arm (ASCOT-LLA)
.
Diabetes Care
2005
;
28
:
1151
1157
10.
Knopp
RH
,
d’Emden
M
,
Smilde
JG
,
Pocock
SJ
.
Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN)
.
Diabetes Care
2006
;
29
:
1478
1485
11.
de Vries
FM
,
Denig
P
,
Pouwels
KB
,
Postma
MJ
,
Hak
E
.
Primary prevention of major cardiovascular and cerebrovascular events with statins in diabetic patients: a meta-analysis
.
Drugs
2012
;
72
:
2365
2373
12.
Hero
C
,
Rawshani
A
,
Svensson
AM
, et al
.
Association between use of lipid-lowering therapy and cardiovascular diseases and death in individuals with type 1 diabetes
.
Diabetes Care
2016
;
39
:
996
1003
13.
Cholesterol Treatment Trialists’ (CTT) Collaboration
;
Baigent
C
,
Blackwell
L
,
Emberson
J
, 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
1681
14.
Huo
X
,
Gao
L
,
Guo
L
, et al
.
Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study
.
Lancet Diabetes Endocrinol
2016
;
4
:
115
124
15.
Pambianco
G
,
Costacou
T
,
Ellis
D
,
Becker
DJ
,
Klein
R
,
Orchard
TJ
.
The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience
.
Diabetes
2006
;
55
:
1463
1469
16.
Svensson
MK
,
Cederholm
J
,
Eliasson
B
,
Zethelius
B
,
Gudbjörnsdottir
S
;
Swedish National Diabetes Register
.
Albuminuria and renal function as predictors of cardiovascular events and mortality in a general population of patients with type 2 diabetes: a nationwide observational study from the Swedish National Diabetes Register
.
Diab Vasc Dis Res
2013
;
10
:
520
529
17.
Guo
VY
,
Cao
B
,
Wu
X
,
Lee
JJW
,
Zee
BC
.
Prospective association between diabetic retinopathy and cardiovascular disease—a systematic review and meta-analysis of cohort studies
.
J Stroke Cerebrovasc Dis
2016
;
25
:
1688
1695
18.
Brownrigg
JR
,
de Lusignan
S
,
McGovern
A
, et al
.
Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus
.
Heart
2014
;
100
:
1837
1843
19.
Ogren
M
,
Hedblad
B
,
Engström
G
,
Janzon
L
.
Prevalence and prognostic significance of asymptomatic peripheral arterial disease in 68-year-old men with diabetes. Results from the population study ‘Men born in 1914’ from Malmö, Sweden
.
Eur J Vasc Endovasc Surg
2005
;
29
:
182
189
20.
Pang
XH
,
Han
J
,
Ye
WL
, et al
.
Lower extremity peripheral arterial disease is an independent predictor of coronary heart disease and stroke risks in patients with type 2 diabetes mellitus in China
.
Int J Endocrinol
2017
;
2017
:
9620513
21.
Malik
S
,
Budoff
MJ
,
Katz
R
, et al
.
Impact of subclinical atherosclerosis on cardiovascular disease events in individuals with metabolic syndrome and diabetes: the multi-ethnic study of atherosclerosis
.
Diabetes Care
2011
;
34
:
2285
2290
22.
Budoff
M
,
Backlund
JC
,
Bluemke
DA
, et al.;
DCCT/EDIC Research Group
.
The association of coronary artery calcification with subsequent incidence of cardiovascular disease in type 1 diabetes: the DCCT/EDIC trials
.
JACC Cardiovasc Imaging
2019
;
12
:
1341
1349
23.
Ridker
PM
,
Danielson
E
,
Fonseca
FA
, et al
.
Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein
.
N Engl J Med
2008
;
359
:
2195
2207
24.
Cannon
CP
,
Blazing
MA
,
Giugliano
RP
, et al.;
IMPROVE-IT Investigators
.
Ezetimibe added to statin therapy after acute coronary syndromes
.
N Engl J Med
2015
;
372
:
2387
2397
25.
Constantino
MI
,
Molyneaux
L
,
Limacher-Gisler
F
, et al
.
Long-term complications and mortality in young-onset diabetes: type 2 diabetes is more hazardous and lethal than type 1 diabetes
.
Diabetes Care
2013
;
36
:
3863
3869
26.
Nezarat
N
,
Budoff
MJ
,
Luo
Y
, et al
.
Presence, characteristics, and volumes of coronary plaque determined by computed tomography angiography in young type 2 diabetes mellitus
.
Am J Cardiol
2017
;
119
:
1566
1571
27.
Dabelea
D
,
Stafford
JM
,
Mayer-Davis
EJ
, et al.;
SEARCH for Diabetes in Youth Research Group
.
Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood
.
JAMA
2017
;
317
:
825
835
28.
Ridker
PM
,
Lonn
E
,
Paynter
NP
,
Glynn
R
,
Yusuf
S
.
Primary prevention with statin therapy in the elderly: new meta-analyses from the contemporary JUPITER and HOPE-3 randomized trials
.
Circulation
2017
;
135
:
1979
1981
29.
Ramos
R
,
Comas-Cufí
M
,
Martí-Lluch
R
, et al
.
Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study
.
BMJ
2018
;
362
:
k3359
30.
Cholesterol Treatment Trialists’ (CTT) Collaboration
;
Herrington
WG
,
Emberson
J
,
Mihaylova
B
, et al
.
Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials
.
Lancet Diabetes Endocrinol
2016
;
4
:
829
839
31.
Wanner
C
,
Krane
V
,
März
W
, et al.;
German Diabetes and Dialysis Study Investigators
.
Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis
.
N Engl J Med
2005
;
353
:
238
248
32.
Bhatt
DL
,
Steg
PG
,
Miller
M
, et al.;
REDUCE-IT Investigators
.
Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia
.
N Engl J Med
2019
;
380
:
11
22
33.
American Diabetes Association
.
10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2020
.
Diabetes Care
2020
;
43
(
Suppl. 1
):
S111
S134
34.
Bohula
EA
,
Morrow
DA
,
Giugliano
RP
, et al
.
Atherothrombotic risk stratification and ezetimibe for secondary prevention
.
J Am Coll Cardiol
2017
;
69
:
911
921
35.
Giugliano
RP
,
Cannon
CP
,
Blazing
MA
, et al.;
IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) Investigators
.
Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)
.
Circulation
2018
;
137
:
1571
1582
36.
Sabatine
MS
,
Giugliano
RP
,
Keech
AC
, et al.;
FOURIER Steering Committee and Investigators
.
Evolocumab and clinical outcomes in patients with cardiovascular disease
.
N Engl J Med
2017
;
376
:
1713
1722
37.
Schwartz
GG
,
Steg
PG
,
Szarek
M
, et al.;
ODYSSEY OUTCOMES Committees and Investigators
.
Alirocumab and cardiovascular outcomes after acute coronary syndrome
.
N Engl J Med
2018
;
379
:
2097
2107
38.
Leiter
LA
,
Zamorano
JL
,
Bujas-Bobanovic
M
, et al
.
Lipid-lowering efficacy and safety of alirocumab in patients with or without diabetes: A sub-analysis of ODYSSEY COMBO II
.
Diabetes Obes Metab
2017
;
19
:
989
996
39.
Sabatine
MS
,
Leiter
LA
,
Wiviott
SD
, et al
.
Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial
.
Lancet Diabetes Endocrinol
2017
;
5
:
941
950
40.
Cannon
CP
,
Khan
I
,
Klimchak
AC
,
Reynolds
MR
,
Sanchez
RJ
,
Sasiela
WJ
.
Simulation of lipid-lowering therapy intensification in a population with atherosclerotic cardiovascular disease
.
JAMA Cardiol
2017
;
2
:
959
966
41.
Virani
SS
,
Akeroyd
JM
,
Nambi
V
, et al
.
Estimation of eligibility for proprotein convertase subtilisin/kexin type 9 inhibitors and associated costs based on the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk): insights from the Department of Veterans Affairs
.
Circulation
2017
;
135
:
2572
2574
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license.