JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
7, 2017
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VOL. 70, NO.
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.07.001
THE PRESENT AND FUTURE
STATE-OF-THE-ART REVIEW
Primary Prevention of
Cardiovascular Disease in Diabetes Mellitus
Jonathan D. Newman, MD, MPH,a Arthur Z. Schwartzbard, MD,a Howard S. Weintraub, MD,a Ira J. Goldberg, MD,b
Jeffrey S. Berger, MD, MSa
ABSTRACT
Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in
T2D. Yet, <50% of U.S. adults with T2D meet recommended guidelines for CVD prevention. The burden of T2D is
increasing: by 2050, approximately 1 in 3 U.S. individuals may have T2D, and patients with T2D will comprise an increasingly
large proportion of the CVD population. The authors believe it is imperative that we expand the use of therapies proven to
reduce CVD risk in patients with T2D. The authors summarize evidence and guidelines for lifestyle (exercise, nutrition, and
weight management) and CVD risk factor (blood pressure, cholesterol and blood lipids, glycemic control, and the use
of aspirin) management for the prevention of CVD among patients with T2D. The authors believe appropriate lifestyle and
CVD risk factor management has the potential to significantly reduce the burden of CVD among patients with T2D.
(J Am Coll Cardiol 2017;70:883–93) © 2017 by the American College of Cardiology Foundation.
CLINICAL VIGNETTE hemoglobin (HbA 1c) of 7.5%, a total cholesterol of
200 mg/dl, high-density lipoprotein cholesterol
A 58-year-old Caucasian woman with a 7-year history (HDL-C) of 40 mg/dl, low-density lipoprotein
of type 2 diabetes mellitus (T2D) is seen by a cardi- cholesterol (LDL-C) of 100 mg/dl, and triglycerides of
ologist in clinic for cardiovascular (CV) risk factor 300 mg/dl. Routine chemistries including serum
management and counseling. There is no history of creatinine and complete blood count are normal. Spot
early-onset CV or cerebrovascular disease in her urinary albumin-to-creatinine ratio is 40 mg/g Cr
family. Her only regular medication is 1,000-mg daily (normal <30 mg/g Cr). The patient and her husband
extended-release metformin. She is a sedentary, are wondering what options are available to reduce
lifelong nonsmoker with minimal alcohol intake and her future risk of cardiovascular disease (CVD).
no illicit drug use. On examination, her blood pres-
sure (BP) is 135 mm Hg systolic (SBP) and 80 mm Hg THE CLINICAL PROBLEM
diastolic (DBP); she has a body mass index (BMI) of
30 kg/m 2. Distal pulses are brisk, and monofilament T2D is a major risk factor for CVD, which remains the
testing of lower extremity sensation is normal. most common cause of death for adults with T2D (1).
Laboratory testing is notable for a glycosylated Yet, less than one-half of adults with T2D in the
From the aDivision of Cardiology and the Center for the Prevention of Cardiovascular Disease, Department of Medicine, New York
University Medical Center; New York, New York; and the bDivision of Endocrinology, New York University Medical Center; New
York, New York. Dr. Newman was partially funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National
Institutes of Health (NIH) (K23HL125991) and the American Heart Association Mentored Clinical and Population Research Award
(15MCPRP24480132). Dr. Berger was partially funded by the NHLBI of the NIH (HL114978). Funders had no role in the design and
conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the
article. Dr. Weintraub has received honoraria from Amgen, Sanofi, and Gilead for consulting; has served on the speakers bureau
for Amgen; and has received research funding from Amarin and Sanofi. Dr. Berger has received research funding from AstraZeneca
and Janssen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received May 10, 2017; revised manuscript received June 30, 2017, accepted July 1, 2017.
884 Newman et al. JACC VOL. 70, NO. 7, 2017

Prevention of CVD in Diabetes AUGUST 15, 2017:883–93

ABBREVIATIONS United States meet recommended clinical
AND ACRONYMS guidelines for the prevention of CVD (2).
Despite improvements in CVD mortality, the
ACC = American College of
Cardiology
incidence of obesity, metabolic syndrome,
and T2D continues to rise, and it is estimated
ACE = angiotensin-converting
enzyme that by 2050, approximately 1 in 3 U.S. in-
ADA = American Diabetes dividuals will have T2D (3). Our goal was to
Association synthesize the current evidence and scienti-
AHA = American Heart fic statements from the American Diabetes
Association Association (ADA), American Heart Associa-
ARB = angiotensin II receptor tion (AHA) and American College of Cardiol-
blocker
ogy (ACC) applicable to CVD prevention for a
BMI = body mass index
patient with T2D and risk factors for CVD.
BP = blood pressure This summation may be broadly useful for
CI = confidence interval clinicians, including cardiologists, and other
CV = cardiovascular physician specialties caring for patients with
CVD = cardiovascular disease diabetes (1,4). The increasingly recognized
DBP = diastolic blood pressure important relationship between T2D and
DPP = Diabetes Prevention congestive heart failure is beyond the scope
Project of this review and is covered in depth else-
GI = gastrointestinal where (4). This clinical review focuses on 2
HbA1c = glycosylated major domains for the prevention of athero-
hemoglobin sclerotic risk in T2D: lifestyle management
HDL-C = high-density and management of CVD risk factors. Life-
lipoprotein cholesterol
style management reviews the roles of exer-
HR = hazard ratio cise, nutrition, weight management, and
LDL-C = low-density smoking cessation. CVD risk factor manage-
lipoprotein cholesterol
ment reviews the role of aspirin, glycemic
MI = myocardial infarction
control, management of blood pressure and
RCT = randomized clinical trial cholesterol, and new directions for risk
SBP = systolic blood pressure stratification and primary prevention of CVD
T1D = type 1 diabetes in patients with T2D.
T2D = type 2 diabetes
STRATEGIES AND EVIDENCE
LIFESTYLE MANAGEMENT. Lifestyle management,
including increased physical activity and diet control,
is the cornerstone of clinical care for patients with T2D.
Diet and physical activity are often evaluated together
as part of a comprehensive lifestyle intervention. We
first review evidence from lifestyle intervention
studies, and then consider evidence from studies of
exercise/physical activity and nutrition/diet alone for
CVD prevention among patients with T2D.
L i f e s t y l e . The largest and most extensive trial of
exercise and CV morbidity and mortality among pa-
tients with T2D was the Look AHEAD (Action for
Health in Diabetes) trial, which randomized 5,145
patients with T2D to an intensive lifestyle interven-
tion including caloric restriction, pre-specified caloric
intake of fats and protein, meal replacement,
and $175 min/week of moderate intensity physical
activity by week 26 or to usual care with diabetes
support and education (5). Mean weight loss from
baseline was greater at 1 year in the intervention
(8.6%) versus usual care (0.7%) groups, a difference
that was attenuated, but sustained, throughout the
trial (5). In addition to differences in mean weight
loss from baseline, patients in the intervention arm
had greater improvements in fitness and HDL-C
levels, and greater reduction in waist circumference
and requirements for medication to lower blood
glucose, pressure, and cholesterol (5). Despite these
benefits, after nearly 10 years of follow-up, the trial
was stopped early for futility to reduce CVD events
(403 CVD events in intervention vs. 418 for usual
care; hazard ratio [HR]: 0.95; 95% confidence interval
[CI]: 0.83 to 1.09; p ¼ 0.51) (5). Compared with usual
care, the intervention group had decreased use of
cardioprotective medications, especially statins,
which may have confounded the potential benefits of
the intensive intervention (1,6).
The Steno-2 study randomized a total of 160 par-
ticipants with T2D and albuminuria (30 to 300 mg
urinary albumin in 4 of 6 of the 24-h urine samples) to
either conventional multiple CV risk factor treat-
ments from their general practitioner or to a multi-
factorial intervention overseen by a project team at
the trial diabetes center that included smoking
cessation courses, restrictions in total and saturated
fat intake, light-to-moderate exercise 3 to 5 days/
week, and a stepwise intensive regimen that included
more stringent control of blood glucose (target
HbA 1c <6.5%) and BP (target <140/85 mm Hg for most
of the study), along with angiotensin-converting
enzyme (ACE) inhibitor regardless of BP and lipid-
lowering therapy (7,8). Participants randomized to
the intensive treatment arm had a 53% (HR: 0.47; 95%
CI: 0.24 to 0.73) reduction in the composite outcome
of CV death, nonfatal myocardial infarction (MI) or
stroke, revascularization, or amputation. Intensive
treatment was also associated with a significant
reduction in microvascular endpoints (nephropathy,
retinopathy, and autonomic neuropathy) (7).
Although both the Look AHEAD trial and the Steno-
2 study used multidimensional lifestyle interventions
for CVD prevention among T2D patients, the Diabetes
Prevention Project (DPP) provided important data on
diabetes prevention by comparing a lifestyle inter-
vention to metformin or placebo (9). Among >3,200
nondiabetic participants with impaired fasting and
post-load plasma glucose followed for nearly 3 years,
randomization to an intensive lifestyle intervention
with weight reduction of at least 7% initial body
weight through a low-calorie, low-fat diet and mod-
erate intensity physical activity ($150 min/week),
was associated with approximately 60% (HR: 0.42;
95% CI: 0.44 to 0.52) and 40% (HR: 0.61; 95% CI: 0.49

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JACC VOL. 70, NO. 7, 2017 Newman et al. 885
AUGUST 15, 2017:883–93 Prevention of CVD in Diabetes

T A B L E 1 Guideline-Based Care for CVD Prevention for Patients With Diabetes Mellitus

Risk Factor Specific Recommendation Level of Evidence (Ref. #)

Physical activity
Nutrition
Weight management
Cigarette Smoking
Glycemic control
Blood pressure
Cholesterol
Antiplatelet therapy
$150 min/week moderate intensity (50%–70% MPHR) over $3 days/week with ADA LOE: A (13)
#2 consecutive days without exercise
Mediterranean style diet may improve glycemic control and CVD risk factors ADA LOE: B (13)
Consumption of fruits, vegetables, legumes, whole grains, and dairy in place of other
carbohydrate sources
Carbohydrate monitoring as an important strategy for glycemic control
Counsel overweight and obese patients that lifestyle changes can lead to a sustained ACC/AHA Class I, LOE: A (20)
3%–5% rate of weight loss and clinically meaningful health benefits
Advise all patients not to use cigarettes, other tobacco products, or e-cigarettes ADA LOE: A (13)
Include smoking cessation counseling and other forms of treatment as a routine
component of care
Lower HbA1c #7% in most patients to reduce risk of microvascular disease ADA LOE: B (13)
Consider HbA1c <6.5% for patients with diabetes of short duration, long life ADA LOE: C (13)
expectancy, and no significant CVD if can be achieved safely
HbA1c <8% or higher for patients with severe hypoglycemia, limited life expectancy, ADA LOE: B (13)
and/or comorbid conditions
Achieve a goal of <140/90 mm Hg for most diabetic patients ADA LOE: A, JNC-8 LOE: E (13,43)
A goal of <130/80 mm Hg may be appropriate for younger diabetic patients with ADA LOE: B/C (13)
cerebrovascular disease or multiple CV risk factors,* assuming target can be safely
achieved
Pharmacotherapy should include either an ACE inhibitor or an ARB; if intolerant to one, ADA LOE: B/C (13,40)
substitute the other
Diabetic patients 40–75 yrs of age with LDL 70–189 mg/dl should receive at least ACC/AHA Class I, LOE: A; ADA LOE: A (13,54)
moderate-intensity statin†
If age 40–75 yrs with CV risk factors,* high-intensity statin‡ should be given ACC/AHA Class IIa, LOE: B (54)
Aspirin 75–162 mg is reasonable for diabetic patients $50 yrs of age with at least 1 CV ACC/AHA Class IIa, LOE: B; ADA LOE: C (1,13,30)
risk factor§ without increased GI bleeding riskk
Aspirin 75–162 mg might be reasonable for diabetic patients <50 yrs of age with 1 or ACC/AHA Class IIb, LOE: C; ADA LOE: E (1,13,30)
more CV risk factors¶

*One or more of the following major CV risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD or albuminuria. †Moderate-intensity statin therapy lowers LDL cholesterol on
average by 30% to 50%. ‡High-intensity statin lowers LDL cholesterol on average by >50%. §Corresponds to a 10-year ASCVD risk >10% (http://tools.acc.org/ASCVD-Risk-Estimator/). kPrior GI bleed,
peptic ulcer disease, or concurrent use of medications that increase bleeding risk (e.g., nonsteroidal anti-inflammatory drugs or warfarin). ¶Corresponds to a 5% to 10% 10-year ASCVD risk.
ACC/AHA ¼ American College of Cardiology/American Heart Association; ACE ¼ angiotensin-converting enzyme; ADA ¼ American diabetes Association; ARB ¼ angiotensin II receptor blocker;
ASCVD ¼ atherosclerotic cardiovascular disease; CV ¼ cardiovascular; CVD ¼ cardiovascular disease; GI ¼ gastrointestinal; HbA1c ¼ glycosylated hemoglobin; JNC-8 ¼ Eighth Joint National Committee;
LDL ¼ low density lipoprotein; LOE ¼ Level of Evidence; MPHR ¼ maximum predicted heart rate.

to 0.76) lower incidence of diabetes compared with
placebo and metformin, respectively (9). There have
not been sufficient events in the DPP Outcomes study
to permit examination by treatment group, but
similar improvements in multiple CVD risk factors
have been observed in all treatment groups after 10
years of follow-up (10).
E x e r c i s e . The Look-AHEAD trial, the Steno-2 study,
and the DPP all combined different lifestyle parame-
ters, including weight loss, physical activity and
exercise, and a dietary intervention (5,7,9). Studies
focused on exercise interventions have also demon-
strated improvements in CV risk factors (BP, dyslipi-
demia, and body composition) among T2D patients
(11). However, no clinical trial of exercise in T2D
patients has demonstrated a reduction in major CVD
endpoints or mortality. Current guidelines for exer-
cise and CVD risk reduction in diabetes are displayed
in Table 1. In addition to exercise quantity, limited
evidence suggests exercise type may be important for
cardiovascular prevention. A study of 262 sedentary
patients with type 2 diabetes and an HbA 1c $6.5%
were randomized to either aerobic exercise, resis-
tance exercise, a combination of both, or none for
9 months; the outcome was a reduction in HbA1c and
improved fitness as defined by increases in peak
and lean V O2 (oxygen consumption), treadmill time,
and other measures (12). There was a trend toward a
decreased HbA 1c for all groups, but the decrease in
HbA1c was significant only in the combined aerobic–
resistance exercise group (0.34%; 95% CI: 0.64%
to 0.03%). Participants in the aerobic–resistance
exercise group also experienced significant increases
in V O 2 max and decreases in waist circumference (12).
N u t r i t i o n . Each landmark lifestyle intervention trial
for CVD prevention in T2D has included a nutritional
component (5,7,9). Nutritional interventions have
also been examined independently for CVD preven-
tion in T2D. According to a recent position statement
from the ADA, a holistic approach to nutrition and
diet should be used for counseling patients with
diabetes to obtain individualized glycemic, BP, and
lipid goals; to achieve and maintain body weight; and
to delay or prevent complications of diabetes (13).

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886 Newman et al.
Prevention of CVD in Diabetes
These guidelines for patients with T2D emphasize
increased fruit, vegetable, and low-fat dairy con-
sumption, and decreased consumption of saturated
fat (13). Multiple options for dietary control in
patients with diabetes exist, including the DASH
(Dietary Approaches to Stop Hypertension) diet (14),
Mediterranean, low-fat, or controlled carbohydrate
diets are all effective in reducing CVD risk factors
(13). The PREDIMED (Prevención con Dieta Medi-
terránea) trial is the largest dietary (RCT) to date for
CVD risk reduction. The PREDIMED trial randomized
nearly 7,500 participants at high risk of CVD, almost
50% of whom had T2D, to a Mediterranean diet
supplemented with either extra-virgin olive oil or
mixed nuts, or to a control diet (15). The trial was
stopped early because of a 30% reduction in the
primary composite outcome of CV death, MI, or
stroke observed with the Mediterranean diet (15).
Patients with prevalent diabetes (a pre-specified
subgroup, n ¼ 3,614) had results similar to the main
trial population, suggesting that a Mediterranean diet
may prevent cardiovascular events in patients with
T2D (15). Data from the nondiabetic subgroup of the
PREDIMED study also indicates a Mediterranean diet
may reduce the risk of developing diabetes among
persons with high cardiovascular risk (16). There is
also additional evidence that diets with low carbo-
hydrate and low glycemic index foods may improve
glycemic control and CVD risk factors (17,18), and
may lower future diabetes risk (16). The importance
of low carbohydrate diets and use of the glycemic
index for CVD risk factor control in T2D warrants
further investigation.
W e i g h t m a n a g e m e n t . The primary approach to
weight management in patients with T2D includes
dietary change focused on caloric restriction;
increased energy expenditure through daily physical
activity and regular aerobic activity; and behavior
changes related to lifestyle (1). The Look AHEAD trial
employed these strategies for a trial of intensive
lifestyle management compared with usual care for
patients with T2D (5). In addition to the previously
described intervention for physical activity (5), the
intensive management arm of the Look AHEAD trial
also employed multiple dietary strategies (5). At
4 years, participants in the intensive intervention arm
lost nearly 5% of their initial weight, compared with
1% of initial weight among participants in the usual
care group (5). Despite the sustained weight loss and
improvement in CVD risk factors observed in the
intensive treatment group, the Look AHEAD trial did
not demonstrate a reduction in CVD events for T2D
patients assigned to the intensive lifestyle interven-
tion (5). Other clinical trials have also demonstrated
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JACC VOL. 70, NO. 7, 2017
AUGUST 15, 2017:883–93
salutary effects of intensive lifestyle interventions,
dietary counseling and caloric restriction on CV risk
factor control for patients with T2D, but without im-
provements in CVD outcomes (19). However, many
patients with T2D have difficulty achieving weight
loss goals with lifestyle interventions alone. In line
with current ACC/AHA/The Obesity Society guide-
lines (20), pharmacotherapy is indicated for weight
loss among individuals with a BMI of 25 to 30 kg/m 2
with additional risk factors for CVD, including T2D or
pre-diabetes, or a BMI >30 kg/m 2, regardless of
comorbidities. A more complete review of pharma-
cotherapy for weight loss among patients with T2D is
included elsewhere (1).
In contrast to the lifestyle intervention, bariatric
surgery for severe obesity (BMI $35 kg/m 2) improves
control of glycemia and CV risk factors (1,20). More-
over, compared with nonsurgical management in the
Swedish Obese Subjects study, bariatric surgery
reduces CVD mortality after nearly 15 years of follow-
up (adjusted HR: 0.47; 95% CI: 0.29 to 0.76; p ¼ 0.002).
S m o k i n g c e s s a t i o n . There is robust evidence to
support the causal links between cigarette smoking
and multiple poor health outcomes, including CVD
(13). A routine and thorough assessment of tobacco
use with cessation counseling and pharmacotherapy,
where appropriate, is strongly recommended for CVD
prevention among patients with and without T2D
(Table 1). Although some patients may gain weight in
the period after smoking cessation, recent research
indicates this weight gain does not significantly
attenuate the substantial CVD benefit from smoking
cessation (13,21).
T h e m u l t i f a c e t e d a p p r o a c h . As summarized in
Figure 1, programs combining lifestyle interventions
and medical therapy for CVD risk reduction are more
efficacious than either therapy alone. However, only a
few trials have evaluated the effect of multiple
simultaneous intensive interventions (5,7,22).
Some (7), but not all (5,22), have demonstrated an
improvement in CV outcomes with multifactorial
interventions. Taken together, these trials suggest
that multifactorial interventions targeting several
important risk factors simultaneously result in greater
CV risk factor control and likely greater reduction
in CVD risk compared with single risk factor
interventions. An individually tailored aggressive
management program to control multiple CVD risk
factors simultaneously represents the best potential to
prevent CVD morbidity and mortality among patients
with T2D (23).
CVD RISK FACTOR MANAGEMENT. The major do-
mains of CVD prevention and risk reduction for
JACC VOL. 70, NO. 7, 2017 Newman et al. 887
AUGUST 15, 2017:883–93 Prevention of CVD in Diabetes

F I G U R E 1 Primary Prevention of CVD Events in Patients With T2D

SBP Lifestyle +
Aspirin (28)* Statin (53)† <140 mm Hg (40)† Nutrition (15) Lifestyle Tx (5)‡ Medical Tx (7)†
0
–5%
(–17,9)
–10% –11%
(–19,0)
(–17,–5)
% Reduction in CVD Events (95% CI)

–21%
(–28,–14)
–20

–29%
(–47,–4)

–40

–53%
(–76,–27)

–60
Pharmacologic Physiologic Lifestyle

CVD events are defined as cardiovascular death, myocardial infarction, or stroke and: *all-cause mortality; †revascularization or amputation;
‡hospitalization for angina. CI ¼ confidence interval; CVD ¼ cardiovascular disease; SBP ¼ systolic blood pressure; T2D ¼ type 2 diabetes;
TX ¼ treatment.

patients with T2D include the use of aspirin, and the
control of blood pressure, cholesterol, and glycemia.
A s p i r i n . Despite a clear benefit of aspirin for the
secondary prevention of CVD among patients with
and without T2D (24), the use of aspirin for primary
prevention among patients
controversial.
Three trials to date specifically examined CVD
prevention with aspirin among patients with T2D
(25–27), only 1 of which (JPAD [Japanese Primary
Prevention of Atherosclerosis With Aspirin for Dia-
betes]) (25) was a primary prevention study. The
ETDRS (Early Treatment of Diabetic Retinopathy
Study) randomized over 3,700 participants 18 to
70 years of age with either type 1 diabetes (T1D) or
T2D and retinopathy, approximately one-third of
whom had prior CVD, to 650 mg of aspirin daily
versus placebo. With a 5-year combined event rate of
20% in the placebo group, aspirin use was associated
with a significant 17% reduction in fatal or nonfatal MI
(HR: 0.83; 95% CI: 0.65 to 1.03; p ¼ 0.04) and a
nonsignificant increase in stroke (27).
The POPADAD (Prevention of Arterial Disease and
Diabetes) trial used a factorial design to investigate
whether daily aspirin 100 mg with or without
antioxidant therapy was more effective than placebo
in reducing incident CVD in 1,276 U.K. participants
>40 years of age with diabetes and asymptomatic
peripheral artery disease, defined by an ankle
brachial index #0.99 (26). After a median follow-up of
with T2D remains 6.7 years, the primary cardiovascular composite
outcome was 18.2% in patients randomized to aspirin
or to placebo, respectively (26).
The JPAD study was an open label, primary pre-
vention study of 81 to 100 mg of aspirin among 2,539
Japanese participants with T2D (25), 26% of whom
were also taking statins (25). Despite a broad compos-
ite outcome that included angina, multiple forms of
peripheral vascular disease, and other outcomes not
included in the secondary prevention ETDRS and
POPADAD trials (26,27), the annual event rate was
nearly 50% lower in the JPAD trial compared with the
ERDRS and POPADAD trials (25). After 4.4 years of
follow-up, there was no difference in the primary CV
composite between participants in the aspirin group
(68 events, 5.4%) versus no aspirin group (86 events,
6.7%; HR: 0.80; 95% CI: 0.58 to 1.10). The incidence of
fatal coronary and cerebrovascular events, a pre-
specified secondary endpoint, was significantly
reduced in the low-dose aspirin group (p ¼ 0.0037).

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888 Newman et al.
Prevention of CVD in Diabetes
Through 2012, a number of meta-analyses have
synthesized data on the effects of aspirin for the
prevention of CVD patients in patients with diabetes
(28–30). Although these meta-analyses differ in the
included trials, the overall results suggest a modest
10% relative reduction in CVD events and $2-fold
relative increase in the risk of bleeding, predomi-
nantly gastrointestinal (GI) in origin, with low-dose
(75 to 162 mg) daily aspirin (1). In summary,
low-dose aspirin is reasonable for diabetic patients
with increased CVD risk (10-year risk >10%), without
an increased risk of GI bleeding (Table 1) (1,13,30).
This includes most diabetic men and women, $50
years of age, with at least 1 major CVD risk factor.
Low-dose aspirin might be reasonable for patients at
intermediate CVD risk (5% to 10% 10-year risk)
(Table 1) (1,13,30).
B P c o n t r o l . BP control, in particular control of sys-
tolic blood pressure (SBP) is a major objective of CV
risk reduction for patients with T2D. Seventy percent
to 80% of T2D patients have comorbid hypertension,
the presence of which increases the risk of many
adverse health outcomes, including MI, stroke, and
all-cause mortality, in addition to heart failure, ne-
phropathy, and other microvascular outcomes (1).
Epidemiological studies have demonstrated a pro-
gressive increase in micro- and macrovascular
disease risk among patients with T2D with increasing
SBP from approximately 115 mm Hg (31). Trials such
as the UKPDS (United Kingdom Prospective Diabetes
Study), HOT (Hypertension Optimal Treatment), and
the ADVANCE (Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified-Release
Controlled Evaluation) studies have unequivocally
demonstrated that antihypertensive drug therapy for
hypertensive diabetic patients reduces CVD risk
(32–34). Despite the abundance of clinical studies, the
appropriate threshold for initiating medical therapy
and treatment goals for BP reduction for T2D patients
remains much less clear.
RCTs have demonstrated the benefit (reduced
coronary heart disease, stroke, and diabetic
nephropathy) associated with lowering BP in diabetic
patients to <140 mm Hg systolic and <90 mm Hg
diastolic (35). Evidence supporting lower BP targets is
limited. The ACCORD trial examined whether a SBP
of <120 mm Hg provided greater CV risk reduction
compared with a SBP of 130 to 140 mm Hg (36), and
found no reduction in the primary composite
endpoint (nonfatal MI, nonfatal stroke, and CV death)
with intensive compared with standard BP control
(36). Intensive versus standard SBP reduction in the
ACCORD trial was associated with a 1% absolute
decrease in stroke, but this benefit was outweighed
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JACC VOL. 70, NO. 7, 2017
AUGUST 15, 2017:883–93
by a 2% absolute increase in significant adverse
events, including hypotension, bradycardia, and
hyperkalemia (36). In contrast to a strategy of tar-
geting a specific BP, the ADVANCE trial randomized
patients with diabetes to either a single-pill, fixed-
dose combination ACE inhibitor and diuretic or pla-
cebo, regardless of baseline blood pressure. Diabetic
participants in the ADVANCE trial randomized to
active treatment demonstrated significant reductions
in the primary composite of macro- and microvas-
cular events, along with significant reductions in all-
cause and CV mortality (34). Although both SBP and
DBP were lower with active treatment compared with
placebo, the ADVANCE trial was not intended to be a
comparison of CV risk reduction with more versus
less intensive BP targets (34). In addition to the SBP
targets of the ACCORD trial, there are earlier studies
evaluating “lower” versus “standard” DBP targets in
diabetic patients (33,37–39). There are limitations in
these earlier studies that, taken together, do not
clearly demonstrate a benefit with lower versus
standard DBP targets in patients with diabetes (35).
Although differing in analytic structure, recent
meta-analyses are largely in agreement and confirm
the protective effect of BP treatment for SBP
>140 mm Hg in diabetic patients, and show that this
benefit decreases with decreasing BP (40,41). There
may be a cerebrovascular benefit to commencement
of antihypertensive therapy below an initial
SBP <140 mm Hg and treatment to a SBP <130 mm Hg,
but uncertainty remains around these estimates
(40–42). Current recommendations are a goal BP
of <140/90 mm Hg for most diabetic patients (Table 1)
(13,43), but recognize that lower targets (e.g.,
SBP <130 mm Hg) may be appropriate for younger
patients with diabetes and a history of cerebrovascular
disease or multiple CV risk factors, assuming this lower
target can be reached safely (13,40,44).
Some trials have indicated ACE inhibitor or angio-
tensin II receptor blocker (ARB) use may have unique
CV benefits for the treatment of hypertension in pa-
tients with diabetes (45–47). However, evidence is
more consistent that the achieved BP, rather than the
specific drug or drug class used, is the principal
determinant of this benefit (43). Despite this, an ACE
inhibitor or ARB may still be preferred as initial
therapy in the hypertensive diabetic patient due to
the renal-protective effects and benefits for CVD risk
reduction and risk factor control (13). Angiotensin
inhibition with either an ACE inhibitor or ARB should
be considered for patients with T2D and an abnormal
urinary albumin excretion (urinary albumin-to creat-
inine ratio $30 mg/g Cr) (13), even if SBP
is <140 mm Hg (46).
JACC VOL. 70, NO. 7, 2017
AUGUST 15, 2017:883–93
C o n t r o l o f b l o o d c h o l e s t e r o l . Patients with dia-
betes have a number of lipoprotein abnormalities,
including increased triglycerides, low HDL-C, and
low, normal, or elevated LDL-C, with increased
numbers of dense LDL particles (48). Multiple clinical
trials and meta-analyses have demonstrated the
benefits of statins for primary and secondary pre-
vention of CVD (49). Subgroup analyses of patients
with diabetes in larger lipid-lowering statin trials
(50), and trials restricted to patients with diabetes
(51,52), demonstrate significant reductions in CV
events and death with statin use. A large meta-
analysis including >18,000 patients with diabetes
(>95% T2D) from 14 randomized trials of statin
therapy followed for a mean of 4.3 years demon-
strated about a 9% proportional reduction in all-
cause mortality and a 13% reduction in vascular
mortality per 1 mmol/l (39 mg/dl) reduction in LDL-C
(53). Outcomes were similar to those achieved in
patients without diabetes mellitus. Moreover, the
outcomes of proportionate LDL reduction were
similar for patients with T2D with and without a
history of vascular disease (53).
Consistent with the ACC/AHA guidelines on the
management of blood cholesterol (54), the ADA
has revised its treatment guidelines for the use of
statin therapy in patients with diabetes (13), a
summary of which is presented in Table 1. Current
guidelines indicate that all patients with diabetes
40 to 75 years of age with an LDL-C >70 mg/dl should
be treated with a statin (13,54). Patients with diabetes
and an LDL-C <70 mg/dl may still benefit from
primary prevention statin use if the 10-year risk
of atherosclerotic CVD is $7.5% (54). In general,
the statin dose should be at least of moderate
intensity (30% to 50% LDL-C reduction), unless
clinical CVD or CV risk factors are present, in which
case high-intensity statin (>50% LDL-C reduction)
therapy should be considered (13,54). Lowering
other lipoproteins such as triglycerides for CVD
risk reduction in patients with diabetes has not
proven beneficial (1), although subgroup analyses
of diabetic patients with hypertriglyceridemia and
low HDL-C may benefit from fibrate use on a back-
ground of statin therapy (55). Current ACC/AHA
guidelines continue to endorse the treatment of
patients with fasting triglycerides >500 mg/dl to
prevent more severe hypertriglyceridemia and
pancreatitis (54).
G l y c e m i c c o n t r o l . T2D is associated with a 2- to 4-
fold increased risk of CVD, with event rates corre-
lating with the degree of hyperglycemia (1). After
adjustment for other CVD risk factors, a 1% increase
in HbA 1c was associated with a 21% increased risk of
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Newman et al. 889
Prevention of CVD in Diabetes
CVD events, including MI (56). However, the corre-
lation between glycemia and microvascular disease is
stronger than for macrovascular disease, with a 37%
increase in retinopathy or nephropathy per 1%
increase in HbA 1c (57).
Earlier RCTs of patients with T1D and T2D
demonstrated a 25% to 70% reduction in microvas-
cular disease along with nonsignificant reductions in
macrovascular disease (58,59), that required 10þ
years of follow-up to reach statistical significance for
CVD risk reduction (60). Three major RCTs of diabetes
and macrovascular disease studied middle age or
older (mean age 60 to 68 years) participants with
established T2D for 8 to 11 years, with either CVD or
multiple CVD risk factors (61–63). These studies
compared intensive glucose control with an HbA 1c of
6.4% to 6.9% versus 7.0% to 8.4% in the standard
glucose control groups. None of the 3 studies could
demonstrate a benefit on macrovascular outcomes
with intensive therapy compared with standard gly-
cemic control (61–63). The ACCORD trial was stopped
early because of a 22% increase in all-cause mortality
(HR: 1.22; 95% CI: 1.01 to 1.46), driven by predomi-
nantly CV mortality (62). Reasons for the increased
mortality associated with intensive glucose control in
the ACCORD trial are unclear and are discussed in
detail elsewhere (64,65).
Current recommendations emphasize individuali-
zation of glycemic goals and suggest that for most
patients with T2D, an HbA 1c of <7% is a reasonable
target to reduce future risk of microvascular disease
events (AHA/ACC Class IIb, Level of Evidence: A;
ADA Level of Evidence: B) (13,64). More (e.g.,
HbA1c <6.5%) or less (HbA1c <8% or slightly higher)
may be appropriate depending on patient character-
istics and medical history (13).
Glucose-lowering agent selection for CV risk
r e d u c t i o n . Based on improved primary prevention
of macrovascular disease in a subset of patients
(n ¼ 342) from the UKPDS trial, metformin is generally
considered to be first-line therapy for glycemic
control (66). Recent trials have suggested other
pharmacological strategies may also reduce vascular
risk for patients with diabetes. In particular, a sodium
glucose cotransporter-2 (SGLT2) inhibitor (empagli-
flozin) and glucagon-like peptide (GLP)-1 analogues
(liraglutide and semaglutide), have recently demon-
strated a reduction in mortality (67,68) and CVD
events (67–69) among patients with diabetes and pre-
existing CVD or multiple CVD risk factors. Further
study in primary prevention populations are needed
to demonstrate whether these agents are superior or
additive to the CVD risk reduction reported with the
use of metformin.
890 Newman et al.
Prevention of CVD in Diabetes
C E NT R AL IL L U STR AT IO N Pathways of Cardiovascular Risk in Patients With T2D
Newman, J.D. et al. J Am Coll Cardiol. 2017;70(7):883–93.
CVD ¼ cardiovascular disease; T2D ¼ type 2 diabetes.
AREAS OF UNCERTAINTY. I n i t i a t i o n a n d g o a l s o f B P
r e d u c t i o n . Although the evidence is most robust to
initiate pharmacotherapy when BP is >140/90 mm Hg,
and to treat to a goal of <140/90 mm Hg for most
patients with diabetes (43), other evidence supports
initiating BP lowering below a SBP of 140 mm Hg and
treating to a SBP <130 mm Hg (40,44). More aggressive
BP goals could be considered in diabetic patients with
a history of cerebrovascular and/or microvascular
disease, such as retinopathy or nephropathy (40). A
recent meta-analysis suggests the reduction in major
CV events, MI, and stroke among patients at high CV
risk, including diabetes, with early treatment and
intensive BP reduction may outweigh the increased
risk of adverse events with intensive therapy (44).
Further study in high-risk stroke populations, with or
without microvascular disease, is necessary to validate
these findings and to determine whether a lower BP
target is beneficial in this subpopulation of patients
with diabetes mellitus (1,70).
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JACC VOL. 70, NO. 7, 2017
AUGUST 15, 2017:883–93
T 1 D v s . T 2 D . Management of CV risk for patients
with T1D relies largely on the evidence base for CV
risk in T2D, despite the longer duration of disease in
T1D vs. T2D and notable differences in the underlying
pathophysiology (71). Following the results of land-
mark trials in T1D including the DCCT (Diabetes
Control and Complications Trial) and its follow-up
observational study EDIC (Epidemiology of Diabetes
Interventions and Complications), intensive glycemic
control became the standard of care (72,73). However,
the basis of our understanding of CV risk factors and
disease in T1D predates widespread intensive glyce-
mic control in T1D. There is growing interest to better
understand the effects of intensive glycemic control
and weight gain on blood lipids in patients with T1D,
the types of lipid abnormalities in T1D, and the
prognostic role of albuminuria and renal function and
BP control in T1D (71). Future study will help deter-
mine whether CV risk reduction strategies differ be-
tween patients with T1D versus T2D.
JACC VOL. 70, NO. 7, 2017 Newman et al. 891
AUGUST 15, 2017:883–93 Prevention of CVD in Diabetes

T r i g l y c e r i d e l o w e r i n g . Lipid guidelines indicate if persistently elevated, to begin either an ACE in-

the efficacy of statin treatment to lower LDL-C con-
centrations and reduce CV events in patients with
T2D (54). However, the efficacy of treating other li-
poprotein abnormalities remains unproven. Low
levels of HDL, often in association with elevated tri-
glycerides, are the most prevalent pattern of dyslipi-
demia in patients with T2D (13). Triglyceride-rich
lipoproteins are often elevated in patients with T2D,
appear to be atherogenic, and may be a secondary
target for lipid-lowering therapy (1). The most selec-
tive of the triglyceride-lowering drugs are the
fibrates. Clinical trials of fibrates conducted to date do
not support triglyceride reduction in the presence or
absence of T2D as a means to reduce CV risk. Unfor-
tunately, these trials are few in number and have
methodological limitations rendering the overall
findings hypothesis generating (1). The definitive trial
of triglyceride lowering among patients with T2D and
elevated triglycerides, with or without low HDL-C, on
a background of statin therapy, has yet to be con-
ducted. Although combination therapy with a statin/
fibrate is generally not recommended, it may be
considered for men with elevated triglycerides and a
low HDL-C (1,13).
CONCLUSIONS AND RECOMMENDATIONS
hibitor or an ARB. Moderate-intensity statin therapy
was prescribed (atorvastatin 20 mg), and the patient
was counseled that if her BP increases or persistent
albuminuria is confirmed, a high-intensity statin
would be recommended. Because she has no history
of GI bleeding, peptic ulcer disease, or use of medi-
cations increasing bleeding risk, she was also started
on 81 mg of aspirin daily. The patient was counseled
to increase her metformin dose and/or initiate other
glucose-lowering therapies, but she preferred to
discuss these options with her endocrinologist.
Additional use of an SGLT-2 inhibitor or a GLP-1
analogue could be considered, even though the
benefit in recent trials favored participants with
established CVD at baseline (67–69).
CV risk reduction is critically important for the care
of patients with diabetes, with or without known CVD
and CV risk factors (Central Illustration). Use of sta-
tins, aspirin, glucose-lowering therapies, and BP
reduction should be considered on a background of
intensive lifestyle management including exercise,
nutrition, and weight management, in all patients
with T2D. The uniform use of proven medical thera-
pies could meaningfully impact the morbidity and
mortality for the diabetic patient over his or her
lifetime.

The patient discussed in the Clinical Vignette was

referred to a nutritionist for dietary counseling and ADDRESS FOR CORRESPONDENCE: Dr. Jonathan D.
weight loss planning, along with a combined resis- Newman, Division of Cardiology and the Center
tance and aerobic exercise training program. She was for the Prevention of Cardiovascular Disease,
amenable to treating her borderline BP with lifestyle Department of Medicine, New York University
modification, including the DASH diet. Because of the School of Medicine, TRB Room 853, 227 East 30th
variability in urinary albumin excretion (13), she was Street, New York, New York 10016. E-mail: Jonathan.
advised to repeat a urine collection in 3 months, and Newman@nyumc.org.

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KEY WORDS cardiovascular disease,
primary prevention, type 2 diabetes