PRIMARY PREVENTION OF CARDIOVASCULAR€DISEASE IN DIABETES

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 70, NO. 7, 2017

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

low-density

lipoprotein

A 58-year-old Caucasian woman with a 7-year history

(HDL-C)

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).

of

40

mg/dl,

no illicit drug use. On examination, her blood pressure (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 Listen to this manuscript’s

University Medical Center; New York, New York; and the bDivision of Endocrinology, New York University Medical Center; New

audio summary by

York, New York. Dr. Newman was partially funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National

JACC Editor-in-Chief

Institutes of Health (NIH) (K23HL125991) and the American Heart Association Mentored Clinical and Population Research Award

Dr. Valentin Fuster.

(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.

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Newman et al.

JACC VOL. 70, NO. 7, 2017 AUGUST 15, 2017:883–93

Prevention of CVD in Diabetes

ABBREVIATIONS

United States meet recommended clinical

baseline was greater at 1 year in the intervention

AND ACRONYMS

guidelines for the prevention of CVD (2).

(8.6%) versus usual care (0.7%) groups, a difference

Despite improvements in CVD mortality, the

that was attenuated, but sustained, throughout the

incidence of obesity, metabolic syndrome,

trial (5). In addition to differences in mean weight

and T2D continues to rise, and it is estimated

loss from baseline, patients in the intervention arm

enzyme

that by 2050, approximately 1 in 3 U.S. in-

had greater improvements in fitness and HDL-C

ADA = American Diabetes

dividuals will have T2D (3). Our goal was to

levels, and greater reduction in waist circumference

Association

synthesize the current evidence and scienti-

and requirements for medication to lower blood

AHA = American Heart

fic statements from the American Diabetes

glucose, pressure, and cholesterol (5). Despite these

Association

Association (ADA), American Heart Associa-

benefits, after nearly 10 years of follow-up, the trial

ARB = angiotensin II receptor

tion (AHA) and American College of Cardiol-

was stopped early for futility to reduce CVD events

ogy (ACC) applicable to CVD prevention for a

(403 CVD events in intervention vs. 418 for usual

ACC = American College of Cardiology

ACE = angiotensin-converting

blocker

BMI = body mass index

patient with T2D and risk factors for CVD.

care; hazard ratio [HR]: 0.95; 95% confidence interval

BP = blood pressure

This summation may be broadly useful for

[CI]: 0.83 to 1.09; p ¼ 0.51) (5). Compared with usual

CI = confidence interval

clinicians, including cardiologists, and other

care, the intervention group had decreased use of

CV = cardiovascular

physician specialties caring for patients with

cardioprotective

CVD = cardiovascular disease

diabetes (1,4). The increasingly recognized

which may have confounded the potential benefits of

DBP = diastolic blood pressure

important relationship between T2D and

the intensive intervention (1,6).

DPP = Diabetes Prevention

congestive heart failure is beyond the scope

The Steno-2 study randomized a total of 160 par-

Project

of this review and is covered in depth else-

ticipants with T2D and albuminuria (30 to 300 mg

GI = gastrointestinal

where (4). This clinical review focuses on 2

urinary albumin in 4 of 6 of the 24-h urine samples) to

HbA1c = glycosylated

major domains for the prevention of athero-

either conventional multiple CV risk factor treat-

hemoglobin

sclerotic risk in T2D: lifestyle management

ments from their general practitioner or to a multi-

HDL-C = high-density

and management of CVD risk factors. Life-

factorial intervention overseen by a project team at

lipoprotein cholesterol

style management reviews the roles of exer-

the trial diabetes center that included smoking

HR = hazard ratio

cise, nutrition, weight management, and

cessation courses, restrictions in total and saturated

LDL-C = low-density

smoking cessation. CVD risk factor manage-

fat intake, light-to-moderate exercise 3 to 5 days/

ment reviews the role of aspirin, glycemic

week, and a stepwise intensive regimen that included

control, management of blood pressure and

more stringent control of blood glucose (target

lipoprotein cholesterol

MI = myocardial infarction

medications,

especially

statins,

RCT = randomized clinical trial

cholesterol, and new directions for risk

HbA 1c <6.5%) and BP (target <140/85 mm Hg for most

SBP = systolic blood pressure

stratification and primary prevention of CVD

of the study), along with angiotensin-converting

T1D = type 1 diabetes

in patients with T2D.

enzyme (ACE) inhibitor regardless of BP and lipidlowering therapy (7,8). Participants randomized to

T2D = type 2 diabetes

STRATEGIES AND EVIDENCE

the intensive treatment arm had a 53% (HR: 0.47; 95% CI: 0.24 to 0.73) reduction in the composite outcome

LIFESTYLE

MANAGEMENT. Lifestyle

management,

of CV death, nonfatal myocardial infarction (MI) or

including increased physical activity and diet control,

stroke, revascularization, or amputation. Intensive

is the cornerstone of clinical care for patients with T2D.

treatment was also associated with a significant

Diet and physical activity are often evaluated together

reduction in microvascular endpoints (nephropathy,

as part of a comprehensive lifestyle intervention. We

retinopathy, and autonomic neuropathy) (7).

first review evidence from lifestyle intervention

Although both the Look AHEAD trial and the Steno-

studies, and then consider evidence from studies of

2 study used multidimensional lifestyle interventions

exercise/physical activity and nutrition/diet alone for

for CVD prevention among T2D patients, the Diabetes

CVD prevention among patients with T2D.

Prevention Project (DPP) provided important data on

L i f e s t y l e . The largest and most extensive trial of

diabetes prevention by comparing a lifestyle inter-

exercise and CV morbidity and mortality among pa-

vention to metformin or placebo (9). Among >3,200

tients with T2D was the Look AHEAD (Action for

nondiabetic participants with impaired fasting and

Health in Diabetes) trial, which randomized 5,145

post-load plasma glucose followed for nearly 3 years,

patients with T2D to an intensive lifestyle interven-

randomization to an intensive lifestyle intervention

tion including caloric restriction, pre-specified caloric

with weight reduction of at least 7% initial body

intake

weight through a low-calorie, low-fat diet and mod-

of

fats

and

protein,

meal

replacement,

and $175 min/week of moderate intensity physical

erate intensity physical activity ($150 min/week),

activity by week 26 or to usual care with diabetes

was associated with approximately 60% (HR: 0.42;

support and education (5). Mean weight loss from

95% CI: 0.44 to 0.52) and 40% (HR: 0.61; 95% CI: 0.49

Newman et al.


885


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

$150 min/week moderate intensity (50%–70% MPHR) over $3 days/week with #2 consecutive days without exercise

ADA LOE: A (13)

Nutrition

Mediterranean style diet may improve glycemic control and CVD risk factors Consumption of fruits, vegetables, legumes, whole grains, and dairy in place of other carbohydrate sources Carbohydrate monitoring as an important strategy for glycemic control

ADA LOE: B (13)

Weight management

Counsel overweight and obese patients that lifestyle changes can lead to a sustained 3%–5% rate of weight loss and clinically meaningful health benefits

ACC/AHA Class I, LOE: A (20)

Cigarette Smoking

Advise all patients not to use cigarettes, other tobacco products, or e-cigarettes Include smoking cessation counseling and other forms of treatment as a routine component of care

ADA LOE: A (13)

Glycemic control

Blood pressure

Cholesterol

Antiplatelet therapy

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 expectancy, and no significant CVD if can be achieved safely

ADA LOE: C (13)

HbA1c <8% or higher for patients with severe hypoglycemia, limited life expectancy, and/or comorbid conditions

ADA LOE: B (13)

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 cerebrovascular disease or multiple CV risk factors,* assuming target can be safely achieved

ADA LOE: B/C (13)

Pharmacotherapy should include either an ACE inhibitor or an ARB; if intolerant to one, substitute the other

ADA LOE: B/C (13,40)

Diabetic patients 40–75 yrs of age with LDL 70–189 mg/dl should receive at least moderate-intensity statin†

ACC/AHA Class I, LOE: A; ADA LOE: A (13,54)

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 risk factor§ without increased GI bleeding riskk

ACC/AHA Class IIa, LOE: B; ADA LOE: C (1,13,30)

Aspirin 75–162 mg might be reasonable for diabetic patients <50 yrs of age with 1 or more CV risk factors¶

ACC/AHA Class IIb, LOE: C; ADA LOE: E (1,13,30)

*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

were randomized to either aerobic exercise, resis-

placebo and metformin, respectively (9). There have

tance exercise, a combination of both, or none for

not been sufficient events in the DPP Outcomes study

9 months; the outcome was a reduction in HbA1c and

to permit examination by treatment group, but

improved fitness as defined by increases in peak

similar improvements in multiple CVD risk factors

and lean V O2 (oxygen consumption), treadmill time,

have been observed in all treatment groups after 10

and other measures (12). There was a trend toward a

years of follow-up (10).

decreased HbA 1c for all groups, but the decrease in

E x e r c i s e . The Look-AHEAD trial, the Steno-2 study,

HbA1c was significant only in the combined aerobic–

and the DPP all combined different lifestyle parame-

resistance exercise group (0.34%; 95% CI: 0.64%

ters, including weight loss, physical activity and

to 0.03%). Participants in the aerobic–resistance

exercise, and a dietary intervention (5,7,9). Studies

exercise group also experienced significant increases

focused on exercise interventions have also demon-

in V O 2 max and decreases in waist circumference (12).

strated improvements in CV risk factors (BP, dyslipi-

N u t r i t i o n . Each landmark lifestyle intervention trial

demia, and body composition) among T2D patients

for CVD prevention in T2D has included a nutritional

(11). However, no clinical trial of exercise in T2D

component (5,7,9). Nutritional interventions have

patients has demonstrated a reduction in major CVD

also been examined independently for CVD preven-

endpoints or mortality. Current guidelines for exer-

tion in T2D. According to a recent position statement

cise and CVD risk reduction in diabetes are displayed

from the ADA, a holistic approach to nutrition and

in Table 1. In addition to exercise quantity, limited

diet should be used for counseling patients with

evidence suggests exercise type may be important for

diabetes to obtain individualized glycemic, BP, and

cardiovascular prevention. A study of 262 sedentary

lipid goals; to achieve and maintain body weight; and

patients with type 2 diabetes and an HbA 1c $6.5%

to delay or prevent complications of diabetes (13).

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Newman et al.



These guidelines for patients with T2D emphasize

salutary effects of intensive lifestyle interventions,

increased fruit, vegetable, and low-fat dairy con-

dietary counseling and caloric restriction on CV risk

sumption, and decreased consumption of saturated

factor control for patients with T2D, but without im-

fat (13). Multiple options for dietary control in

provements in CVD outcomes (19). However, many

patients with diabetes exist, including the DASH

patients with T2D have difficulty achieving weight

(Dietary Approaches to Stop Hypertension) diet (14),

loss goals with lifestyle interventions alone. In line

Mediterranean, low-fat, or controlled carbohydrate

with current ACC/AHA/The Obesity Society guide-

diets are all effective in reducing CVD risk factors

lines (20), pharmacotherapy is indicated for weight

(13). The PREDIMED (Prevención con Dieta Medi-

loss among individuals with a BMI of 25 to 30 kg/m 2

terránea) trial is the largest dietary (RCT) to date for

with additional risk factors for CVD, including T2D or

CVD risk reduction. The PREDIMED trial randomized

pre-diabetes, or a BMI >30 kg/m 2, regardless of

nearly 7,500 participants at high risk of CVD, almost

comorbidities. A more complete review of pharma-

50% of whom had T2D, to a Mediterranean diet

cotherapy for weight loss among patients with T2D is

supplemented with either extra-virgin olive oil or

included elsewhere (1).

mixed nuts, or to a control diet (15). The trial was

In contrast to the lifestyle intervention, bariatric

stopped early because of a 30% reduction in the

surgery for severe obesity (BMI $35 kg/m 2) improves

primary composite outcome of CV death, MI, or

control of glycemia and CV risk factors (1,20). More-

stroke observed with the Mediterranean diet (15).

over, compared with nonsurgical management in the

Patients with prevalent diabetes (a pre-specified

Swedish Obese Subjects study, bariatric surgery

subgroup, n ¼ 3,614) had results similar to the main

reduces CVD mortality after nearly 15 years of follow-

trial population, suggesting that a Mediterranean diet

up (adjusted HR: 0.47; 95% CI: 0.29 to 0.76; p ¼ 0.002).

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 carbohydrate 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

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).

weight management in patients with T2D includes

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

dietary

restriction;

Figure 1, programs combining lifestyle interventions

increased energy expenditure through daily physical

and medical therapy for CVD risk reduction are more

change

focused

on

caloric

activity and regular aerobic activity; and behavior

efficacious than either therapy alone. However, only a

changes related to lifestyle (1). The Look AHEAD trial

few trials have evaluated the effect of multiple

employed these strategies for a trial of intensive

simultaneous

lifestyle management compared with usual care for

Some (7), but not all (5,22), have demonstrated an

patients with T2D (5). In addition to the previously

improvement in CV outcomes with multifactorial

described intervention for physical activity (5), the

interventions. Taken together, these trials suggest

intensive management arm of the Look AHEAD trial

that multifactorial interventions targeting several

also employed multiple dietary strategies (5). At

important risk factors simultaneously result in greater

4 years, participants in the intensive intervention arm

CV risk factor control and likely greater reduction

lost nearly 5% of their initial weight, compared with

in CVD

1% of initial weight among participants in the usual

interventions. An individually tailored aggressive

care group (5). Despite the sustained weight loss and

management program to control multiple CVD risk

improvement in CVD risk factors observed in the

factors simultaneously represents the best potential to

intensive treatment group, the Look AHEAD trial did

prevent CVD morbidity and mortality among patients

not demonstrate a reduction in CVD events for T2D

with T2D (23).

patients assigned to the intensive lifestyle interven-

CVD RISK FACTOR MANAGEMENT. The major do-

tion (5). Other clinical trials have also demonstrated

mains of CVD prevention and risk reduction for

intensive

interventions

risk compared with single

(5,7,22).

risk factor

Newman et al.



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

0

Aspirin (28)*

SBP Lifestyle + Statin (53)† <140 mm Hg (40)† Nutrition (15) Lifestyle Tx (5)‡ Medical Tx (7)† –5% (–17,9)

–10%

–11%

% Reduction in CVD Events (95% CI)

(–19,0)

(–17,–5)

–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

antioxidant therapy was more effective than placebo

control of blood pressure, cholesterol, and glycemia.

in reducing incident CVD in 1,276 U.K. participants

A s p i r i n . Despite a clear benefit of aspirin for the

>40 years of age with diabetes and asymptomatic

secondary prevention of CVD among patients with

peripheral artery disease, defined by an ankle

and without T2D (24), the use of aspirin for primary

brachial index #0.99 (26). After a median follow-up of

prevention

6.7 years, the primary cardiovascular composite

among

patients

with

T2D

remains

controversial. Three trials to date specifically examined CVD

outcome was 18.2% in patients randomized to aspirin or to placebo, respectively (26).

prevention with aspirin among patients with T2D

The JPAD study was an open label, primary pre-

(25–27), only 1 of which (JPAD [Japanese Primary

vention study of 81 to 100 mg of aspirin among 2,539

Prevention of Atherosclerosis With Aspirin for Dia-

Japanese participants with T2D (25), 26% of whom

betes]) (25) was a primary prevention study. The

were also taking statins (25). Despite a broad compos-

ETDRS (Early Treatment of Diabetic Retinopathy

ite outcome that included angina, multiple forms of

Study) randomized over 3,700 participants 18 to

peripheral vascular disease, and other outcomes not

70 years of age with either type 1 diabetes (T1D) or

included in the secondary prevention ETDRS and

T2D and retinopathy, approximately one-third of

POPADAD trials (26,27), the annual event rate was

whom had prior CVD, to 650 mg of aspirin daily

nearly 50% lower in the JPAD trial compared with the

versus placebo. With a 5-year combined event rate of

ERDRS and POPADAD trials (25). After 4.4 years of

20% in the placebo group, aspirin use was associated

follow-up, there was no difference in the primary CV

with a significant 17% reduction in fatal or nonfatal MI

composite between participants in the aspirin group

(HR: 0.83; 95% CI: 0.65 to 1.03; p ¼ 0.04) and a

(68 events, 5.4%) versus no aspirin group (86 events,

nonsignificant increase in stroke (27).

6.7%; HR: 0.80; 95% CI: 0.58 to 1.10). The incidence of

The POPADAD (Prevention of Arterial Disease and

fatal coronary and cerebrovascular events, a pre-

Diabetes) trial used a factorial design to investigate

specified

whether daily aspirin 100 mg with or without

reduced in the low-dose aspirin group (p ¼ 0.0037).

secondary

endpoint,

was

significantly

887

888

Newman et al.



Through 2012, a number of meta-analyses have

by a 2% absolute increase in significant adverse

synthesized data on the effects of aspirin for the

events, including hypotension, bradycardia, and

prevention of CVD patients in patients with diabetes

hyperkalemia (36). In contrast to a strategy of tar-

(28–30). Although these meta-analyses differ in the

geting a specific BP, the ADVANCE trial randomized

included trials, the overall results suggest a modest

patients with diabetes to either a single-pill, fixed-

10% relative reduction in CVD events and $2-fold

dose combination ACE inhibitor and diuretic or pla-

relative increase in the risk of bleeding, predomi-

cebo, regardless of baseline blood pressure. Diabetic

nantly gastrointestinal (GI) in origin, with low-dose

participants in the ADVANCE trial randomized to

(75 to 162 mg) daily aspirin (1). In summary,

active treatment demonstrated significant reductions

low-dose aspirin is reasonable for diabetic patients

in the primary composite of macro- and microvas-

with increased CVD risk (10-year risk >10%), without

cular events, along with significant reductions in all-

an increased risk of GI bleeding (Table 1) (1,13,30).

cause and CV mortality (34). Although both SBP and

This includes most diabetic men and women, $50

DBP were lower with active treatment compared with

years of age, with at least 1 major CVD risk factor.

placebo, the ADVANCE trial was not intended to be a

Low-dose aspirin might be reasonable for patients at

comparison of CV risk reduction with more versus

intermediate CVD risk (5% to 10% 10-year risk)

less intensive BP targets (34). In addition to the SBP

(Table 1) (1,13,30).

targets of the ACCORD trial, there are earlier studies

B P c o n t r o l . BP control, in particular control of sys-

evaluating “lower” versus “standard” DBP targets in

tolic blood pressure (SBP) is a major objective of CV

diabetic patients (33,37–39). There are limitations in

risk reduction for patients with T2D. Seventy percent

these earlier studies that, taken together, do not

to 80% of T2D patients have comorbid hypertension,

clearly demonstrate a benefit with lower versus

the presence of which increases the risk of many

standard DBP targets in patients with diabetes (35).

adverse health outcomes, including MI, stroke, and

Although differing in analytic structure, recent

all-cause mortality, in addition to heart failure, ne-

meta-analyses are largely in agreement and confirm

phropathy, and other microvascular outcomes (1).

the protective effect of BP treatment for SBP

Epidemiological studies have demonstrated a pro-

>140 mm Hg in diabetic patients, and show that this

gressive

macrovascular

benefit decreases with decreasing BP (40,41). There

disease risk among patients with T2D with increasing

may be a cerebrovascular benefit to commencement

SBP from approximately 115 mm Hg (31). Trials such

of

as the UKPDS (United Kingdom Prospective Diabetes

SBP <140 mm Hg and treatment to a SBP <130 mm Hg,

Study), HOT (Hypertension Optimal Treatment), and

but uncertainty remains around these estimates

increase

in

micro-

and

antihypertensive

therapy

below

an

initial

the ADVANCE (Action in Diabetes and Vascular

(40–42). Current recommendations are a goal BP

Disease: Preterax and Diamicron Modified-Release

of <140/90 mm Hg for most diabetic patients (Table 1)

Controlled Evaluation) studies have unequivocally

(13,43), but recognize that lower

demonstrated that antihypertensive drug therapy for

SBP <130 mm Hg) may be appropriate for younger

hypertensive diabetic patients reduces CVD risk

patients with diabetes and a history of cerebrovascular

(32–34). Despite the abundance of clinical studies, the

disease or multiple CV risk factors, assuming this lower

appropriate threshold for initiating medical therapy

target can be reached safely (13,40,44).

and treatment goals for BP reduction for T2D patients remains much less clear. disease,

tients with diabetes (45–47). However, evidence is

nephropathy) associated with lowering BP in diabetic

more consistent that the achieved BP, rather than the

patients to <140 mm Hg systolic and <90 mm Hg

specific drug or drug class used, is the principal

diastolic (35). Evidence supporting lower BP targets is

determinant of this benefit (43). Despite this, an ACE

limited. The ACCORD trial examined whether a SBP

inhibitor or ARB may still be preferred as initial

of <120 mm Hg provided greater CV risk reduction

therapy in the hypertensive diabetic patient due to

compared with a SBP of 130 to 140 mm Hg (36), and

the renal-protective effects and benefits for CVD risk

found

composite

reduction and risk factor control (13). Angiotensin

endpoint (nonfatal MI, nonfatal stroke, and CV death)

inhibition with either an ACE inhibitor or ARB should

with intensive compared with standard BP control

be considered for patients with T2D and an abnormal

(36). Intensive versus standard SBP reduction in the

urinary albumin excretion (urinary albumin-to creat-

reduction

in

stroke,

the

and

CV benefits for the treatment of hypertension in pa-

diabetic

no

heart

Some trials have indicated ACE inhibitor or angiotensin II receptor blocker (ARB) use may have unique

RCTs have demonstrated the benefit (reduced coronary

targets (e.g.,

primary

$30

ACCORD trial was associated with a 1% absolute

inine

decrease in stroke, but this benefit was outweighed

is <140 mm Hg (46).

ratio

mg/g

Cr)

(13),

even

if

SBP

Newman et al.



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-

CVD events, including MI (56). However, the corre-

betes have a number of lipoprotein abnormalities,

lation between glycemia and microvascular disease is

including increased triglycerides, low HDL-C, and

stronger than for macrovascular disease, with a 37%

low, normal, or elevated LDL-C, with increased

increase in retinopathy or nephropathy per 1%

numbers of dense LDL particles (48). Multiple clinical

increase in HbA 1c (57).

trials and meta-analyses have demonstrated the

Earlier RCTs of patients with T1D and T2D

benefits of statins for primary and secondary pre-

demonstrated a 25% to 70% reduction in microvas-

vention of CVD (49). Subgroup analyses of patients

cular disease along with nonsignificant reductions in

with diabetes in larger lipid-lowering statin trials

macrovascular disease (58,59), that required 10þ

(50), and trials restricted to patients with diabetes

years of follow-up to reach statistical significance for

(51,52), demonstrate significant reductions in CV

CVD risk reduction (60). Three major RCTs of diabetes

events and death with statin use. A large meta-

and macrovascular disease studied middle age or

analysis including >18,000 patients with diabetes

older (mean age 60 to 68 years) participants with

(>95% T2D) from 14 randomized trials of statin

established T2D for 8 to 11 years, with either CVD or

therapy followed for a mean of 4.3 years demon-

multiple CVD risk factors (61–63). These studies

strated about a 9% proportional reduction in all-

compared intensive glucose control with an HbA 1c of

cause mortality and a 13% reduction in vascular

6.4% to 6.9% versus 7.0% to 8.4% in the standard

mortality per 1 mmol/l (39 mg/dl) reduction in LDL-C

glucose control groups. None of the 3 studies could

(53). Outcomes were similar to those achieved in

demonstrate a benefit on macrovascular outcomes

patients without diabetes mellitus. Moreover, the

with intensive therapy compared with standard gly-

outcomes of proportionate LDL reduction were

cemic control (61–63). The ACCORD trial was stopped

similar for patients with T2D with and without a

early because of a 22% increase in all-cause mortality

history of vascular disease (53).

(HR: 1.22; 95% CI: 1.01 to 1.46), driven by predomi-

Consistent with the ACC/AHA guidelines on the

nantly CV mortality (62). Reasons for the increased

management of blood cholesterol (54), the ADA

mortality associated with intensive glucose control in

has revised its treatment guidelines for the use of

the ACCORD trial are unclear and are discussed in

statin therapy in patients with diabetes (13), a

detail elsewhere (64,65).

summary of which is presented in Table 1. Current

Current recommendations emphasize individuali-

guidelines indicate that all patients with diabetes

zation of glycemic goals and suggest that for most

40 to 75 years of age with an LDL-C >70 mg/dl should

patients with T2D, an HbA 1c of <7% is a reasonable

be treated with a statin (13,54). Patients with diabetes

target to reduce future risk of microvascular disease

and an LDL-C <70 mg/dl may still benefit from

events (AHA/ACC Class IIb, Level of Evidence: A;

primary prevention statin use if the 10-year risk

ADA Level of Evidence: B) (13,64). More (e.g.,

of atherosclerotic CVD is $7.5% (54). In general,

HbA1c <6.5%) or less (HbA1c <8% or slightly higher)

the statin dose should be at least of moderate

may be appropriate depending on patient character-

intensity (30% to 50% LDL-C reduction), unless

istics and medical history (13).

clinical CVD or CV risk factors are present, in which

Glucose-lowering agent selection for CV risk

case high-intensity statin (>50% LDL-C reduction)

r e d u c t i o n . Based on improved primary prevention

therapy should be considered (13,54). Lowering

of macrovascular disease in a subset of patients

other lipoproteins such as triglycerides for CVD

(n ¼ 342) from the UKPDS trial, metformin is generally

risk reduction in patients with diabetes has not

considered to be first-line therapy for glycemic

proven beneficial (1), although subgroup analyses

control (66). Recent trials have suggested other

of diabetic patients with hypertriglyceridemia and

pharmacological strategies may also reduce vascular

low HDL-C may benefit from fibrate use on a back-

risk for patients with diabetes. In particular, a sodium

ground of statin therapy (55). Current ACC/AHA

glucose cotransporter-2 (SGLT2) inhibitor (empagli-

guidelines continue to endorse the treatment of

flozin) and glucagon-like peptide (GLP)-1 analogues

patients with fasting triglycerides >500 mg/dl to

(liraglutide and semaglutide), have recently demon-

prevent

strated a reduction in mortality (67,68) and CVD

more

severe

hypertriglyceridemia

and

pancreatitis (54).

events (67–69) among patients with diabetes and pre-

G l y c e m i c c o n t r o l . T2D is associated with a 2- to 4-

existing CVD or multiple CVD risk factors. Further

fold increased risk of CVD, with event rates corre-

study in primary prevention populations are needed

lating with the degree of hyperglycemia (1). After

to demonstrate whether these agents are superior or

adjustment for other CVD risk factors, a 1% increase

additive to the CVD risk reduction reported with the

in HbA 1c was associated with a 21% increased risk of

use of metformin.

889

890

Newman et al.



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

T 1 D v s . T 2 D . Management of CV risk for patients

r e d u c t i o n . Although the evidence is most robust to

with T1D relies largely on the evidence base for CV

initiate pharmacotherapy when BP is >140/90 mm Hg,

risk in T2D, despite the longer duration of disease in

and to treat to a goal of <140/90 mm Hg for most

T1D vs. T2D and notable differences in the underlying

patients with diabetes (43), other evidence supports

pathophysiology (71). Following the results of land-

initiating BP lowering below a SBP of 140 mm Hg and

mark trials in T1D including the DCCT (Diabetes

treating to a SBP <130 mm Hg (40,44). More aggressive

Control and Complications Trial) and its follow-up

BP goals could be considered in diabetic patients with

observational study EDIC (Epidemiology of Diabetes

a history of cerebrovascular and/or microvascular

Interventions and Complications), intensive glycemic

disease, such as retinopathy or nephropathy (40). A

control became the standard of care (72,73). However,

recent meta-analysis suggests the reduction in major

the basis of our understanding of CV risk factors and

CV events, MI, and stroke among patients at high CV

disease in T1D predates widespread intensive glyce-

risk, including diabetes, with early treatment and

mic control in T1D. There is growing interest to better

intensive BP reduction may outweigh the increased

understand the effects of intensive glycemic control

risk of adverse events with intensive therapy (44).

and weight gain on blood lipids in patients with T1D,

Further study in high-risk stroke populations, with or

the types of lipid abnormalities in T1D, and the

without microvascular disease, is necessary to validate

prognostic role of albuminuria and renal function and

these findings and to determine whether a lower BP

BP control in T1D (71). Future study will help deter-

target is beneficial in this subpopulation of patients

mine whether CV risk reduction strategies differ be-

with diabetes mellitus (1,70).

tween patients with T1D versus T2D.

Newman et al.



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-

hibitor or an ARB. Moderate-intensity statin therapy

centrations and reduce CV events in patients with

was prescribed (atorvastatin 20 mg), and the patient

T2D (54). However, the efficacy of treating other li-

was counseled that if her BP increases or persistent

poprotein abnormalities remains unproven. Low

albuminuria is confirmed, a high-intensity statin

levels of HDL, often in association with elevated tri-

would be recommended. Because she has no history

glycerides, are the most prevalent pattern of dyslipi-

of GI bleeding, peptic ulcer disease, or use of medi-

demia in patients with T2D (13). Triglyceride-rich

cations increasing bleeding risk, she was also started

lipoproteins are often elevated in patients with T2D,

on 81 mg of aspirin daily. The patient was counseled

appear to be atherogenic, and may be a secondary

to increase her metformin dose and/or initiate other

target for lipid-lowering therapy (1). The most selec-

glucose-lowering therapies, but she preferred to

tive of the triglyceride-lowering drugs are the

discuss these options with her endocrinologist.

fibrates. Clinical trials of fibrates conducted to date do

Additional use of an SGLT-2 inhibitor or a GLP-1

not support triglyceride reduction in the presence or

analogue could be considered, even though the

absence of T2D as a means to reduce CV risk. Unfor-

benefit in recent trials favored participants with

tunately, these trials are few in number and have

established CVD at baseline (67–69).

methodological limitations rendering the overall

CV risk reduction is critically important for the care

findings hypothesis generating (1). The definitive trial

of patients with diabetes, with or without known CVD

of triglyceride lowering among patients with T2D and

and CV risk factors (Central Illustration). Use of sta-

elevated triglycerides, with or without low HDL-C, on

tins, aspirin, glucose-lowering therapies, and BP

a background of statin therapy, has yet to be con-

reduction should be considered on a background of

ducted. Although combination therapy with a statin/

intensive lifestyle management including exercise,

fibrate is generally not recommended, it may be

nutrition, and weight management, in all patients

considered for men with elevated triglycerides and a

with T2D. The uniform use of proven medical thera-

low HDL-C (1,13).

pies could meaningfully impact the morbidity and

CONCLUSIONS AND RECOMMENDATIONS

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

amenable to treating her borderline BP with lifestyle

Department

the

Prevention of

of

Medicine,

Cardiovascular New

York

Disease, 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

[email protected].

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KEY WORDS cardiovascular disease, primary prevention, type 2 diabetes

893

PRIMARY PREVENTION OF CARDIOVASCULAR€DISEASE IN DIABETES

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