CARDIOVASCULAR DISEASE AND RISK MANAGEMENT: STANDARDSOF MEDICALCAREINDIABETESD2021 - SOMERSET PRESCRIBING ...
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Diabetes Care Volume 44, Supplement 1, January 2021 S125
10. Cardiovascular Disease and American Diabetes Association
Risk Management: Standards of
Medical Care in Diabetesd2021
Diabetes Care 2021;44(Suppl. 1):S125–S150 | https://doi.org/10.2337/dc21-S010
10. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT
The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”
includes the ADA’s current clinical practice recommendations and is intended to
provide the components of diabetes care, general treatment goals and guidelines,
and tools to evaluate quality of care. Members of the ADA Professional Practice
Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-
SPPC), are responsible for updating the Standards of Care annually, or more
frequently as warranted. For a detailed description of ADA standards, statements,
and reports, as well as the evidence-grading system for ADA’s clinical practice
recommendations, please refer to the Standards of Care Introduction (https://doi
.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care
are invited to do so at professional.diabetes.org/SOC.
For prevention and management of diabetes complications in children and adoles-
cents, please refer to Section 13 “Children and Adolescents” (https://doi.org/10.2337/
dc21-S013).
Atherosclerotic cardiovascular disease (ASCVD)ddefined as coronary heart disease
(CHD), cerebrovascular disease, or peripheral arterial disease presumed to be of
atherosclerotic origindis the leading cause of morbidity and mortality for individuals
with diabetes and results in an estimated $37.3 billion in cardiovascular-related
spending per year associated with diabetes (1). Common conditions coexisting with
type 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for ASCVD,
and diabetes itself confers independent risk. Numerous studies have shown the
efficacy of controlling individual cardiovascular risk factors in preventing or slowing
ASCVD in people with diabetes. Furthermore, large benefits are seen when multiple
cardiovascular risk factors are addressed simultaneously. Under the current paradigm
of aggressive risk factor modification in patients with diabetes, there is evidence that
measures of 10-year coronary heart disease (CHD) risk among U.S. adults with
diabetes have improved significantly over the past decade (2) and that ASCVD
morbidity and mortality have decreased (3,4).
Heart failure is another major cause of morbidity and mortality from cardiovascular This section has received endorsement from the
American College of Cardiology.
disease. Recent studies have found that rates of incident heart failure hospitalization
Suggested citation: American Diabetes Association.
(adjusted for age and sex) were twofold higher in patients with diabetes compared
10. Cardiovascular disease and risk management:
with those without (5,6). People with diabetes may have heart failure with preserved Standards of Medical Care in Diabetesd2021.
ejection fraction (HFpEF) or with reduced ejection fraction (HFrEF). Hypertension is Diabetes Care 2021;44(Suppl.1):S125–S150
often a precursor of heart failure of either type, and ASCVD can coexist with either type © 2020 by the American Diabetes Association.
(7), whereas prior myocardial infarction (MI) is often a major factor in HFrEF. Rates Readers may use this article as long as the work is
of heart failure hospitalization have been improved in recent trials including properly cited, the use is educational and not for
profit, and the work is not altered. More infor-
patients with type 2 diabetes, most of whom also had ASCVD, with sodium–glucose
mation is available at https://www.diabetesjournals
cotransporter 2 (SGLT2) inhibitors (8–10). .org/content/license.S126 Cardiovascular Disease and Risk Management Diabetes Care Volume 44, Supplement 1, January 2021
For prevention and management of among patients with either type 1 or blood pressure monitoring may improve
both ASCVD and heart failure, cardiovas- type 2 diabetes. Hypertension is a ma- patient medication adherence and thus
cular risk factors should be systematically jor risk factor for both ASCVD and mi- help reduce cardiovascular risk (20).
assessed at least annually in all patients crovascular complications. Moreover,
with diabetes. These risk factors include numerous studies have shown that
Treatment Goals
obesity/overweight, hypertension, dysli- antihypertensive therapy reduces ASCVD
pidemia, smoking, a family history of pre- events, heart failure, and microvascular Recommendations
mature coronary disease, chronic kidney complications. Please refer to the Amer- 10.3 For patients with diabetes and
disease, and the presence of albuminuria. ican Diabetes Association (ADA) position hypertension, blood pressure
Modifiable abnormal risk factors should statement “Diabetes and Hypertension” targets should be individual-
be treated as described in these guide- for a detailed review of the epidemiol- ized through a shared decision-
lines. Notably, the majority of evidence ogy, diagnosis, and treatment of hyper- making process that addresses
supporting interventions to reduce cardio- tension (17). cardiovascular risk, potential ad-
vascular risk in diabetes comes from trials of verse effects of antihypertensive
patients with type 2 diabetes. Few trials Screening and Diagnosis medications, and patient prefer-
have been specifically designed to assess Recommendations ences. C
the impact of cardiovascular risk reduction 10.1 Blood pressure should be mea- 10.4 For individuals with diabetes
strategies in patients with type 1 diabetes. sured at every routine clinical and hypertension at higher car-
visit. Patients found to have el- diovascular risk (existing athero-
THE RISK CALCULATOR evated blood pressure ($140/ sclerotic cardiovascular disease
90 mmHg) should have blood [ASCVD] or 10-year ASCVD risk
The American College of Cardiology/
pressure confirmed using multi- $15%), a blood pressure target
American Heart Association ASCVD risk
ple readings, including measure- of ,130/80 mmHg may be ap-
calculator (Risk Estimator Plus) is gener-
ments on a separate day, to propriate, if it can be safely
ally a useful tool to estimate 10-year risk
diagnose hypertension. B attained. C
of a first ASCVD event (available online
10.2 All hypertensive patients with 10.5 For individuals with diabetes and
at tools.acc.org/ASCVD-Risk-Estimator-
diabetes should monitor their hypertension at lower risk for
Plus). The calculator includes diabetes
blood pressure at home. B cardiovascular disease (10-year
as a risk factor, since diabetes itself
atherosclerotic cardiovascular
confers increased risk for ASCVD, al-
Blood pressure should be measured at disease risk ,15%), treat to a
though it should be acknowledged that
every routine clinical visit by a trained blood pressure target of ,140/
these risk calculators do not account for
individual and should follow the guide- 90 mmHg. A
the duration of diabetes or the pres-
lines established for the general pop- 10.6 In pregnant patients with diabetes
ence of diabetes complications, such as
ulation: measurement in the seated and preexisting hypertension, a
albuminuria. Although some variability
in calibration exists in various subgroups, position, with feet on the floor and arm blood pressure target of 110–
supported at heart level, after 5 min of 135/85 mmHg is suggested in the
including by sex, race, and diabetes, the
rest. Cuff size should be appropriate for interest of reducing the risk for
overall risk prediction does not differ in
the upper-arm circumference. Elevated accelerated maternal hyperten-
those with or without diabetes (11–14),
values should be confirmed on a separate sion A and minimizing impaired
validating the use of risk calculators in
day. Postural changes in blood pressure fetal growth. E
people with diabetes. The 10-year risk of a
first ASCVD event should be assessed to and pulse may be evidence of autonomic
better stratify ASCVD risk and help guide neuropathy and therefore require ad-
therapy, as described below. justment of blood pressure targets. Or- Randomized clinical trials have demon-
Recently, risk scores and other cardio- thostatic blood pressure measurements strated unequivocally that treatment of
vascular biomarkers have been developed should be checked on initial visit and as hypertension to blood pressure ,140/
for risk stratification of secondary pre- indicated. 90 mmHg reduces cardiovascular events
vention patients (i.e., those who are al- Home blood pressure self-monitoring as well as microvascular complications
ready high risk because they have ASCVD) and 24-h ambulatory blood pressure (21–27). Therefore, patients with type 1
but are not yet in widespread use (15,16). monitoring may provide evidence of or type 2 diabetes who have hypertension
With newer, more expensive lipid-lowering white coat hypertension, masked hyper- should, at a minimum, be treated to blood
therapies now available, use of these risk tension, or other discrepancies between pressure targets of ,140/90 mmHg. The
assessments may help target these new office and “true” blood pressure (17). In benefits and risks of intensifying anti-
therapies to “higher risk” ASCVD pa- addition to confirming or refuting a di- hypertensive therapy to target blood
tients in the future. agnosis of hypertension, home blood pressures lower than ,140/90 mmHg
pressure assessment may be useful to (e.g., ,130/80 or ,120/80 mmHg) have
monitor antihypertensive treatment. Stud- been evaluated in large randomized clin-
HYPERTENSION/BLOOD PRESSURE ies of individuals without diabetes found ical trials and meta-analyses of clinical
CONTROL that home measurements may better trials. Notably, there is an absence of
Hypertension, defined as a sustained blood correlate with ASCVD risk than office high-quality data available to guide blood
pressure $140/90 mmHg, is common measurements (18,19). Moreover, home pressure targets in type 1 diabetes.care.diabetesjournals.org Cardiovascular Disease and Risk Management S127
Randomized Controlled Trials of Intensive suggest that blood pressure targets Vascular Disease: Preterax and Diami-
Versus Standard Blood Pressure Control more intensive than ,140/90 mmHg cron MR Controlled Evaluation–Blood
The Action to Control Cardiovascular Risk are not likely to improve cardiovascular Pressure (ADVANCE BP) trial did not
in Diabetes Blood Pressure (ACCORD BP) outcomes among most people with type 2 explicitly test blood pressure targets
trial provides the strongest direct assess- diabetes but may be reasonable for pa- (29); the achieved blood pressure in
ment of the benefits and risks of intensive tients who may derive the most benefit the intervention group was higher
blood pressure control among people and have been educated about added than that achieved in the ACCORD BP
with type 2 diabetes (28). In ACCORD treatment burden, side effects, and costs, intensive arm and would be consistent
BP, compared with standard blood pres- as discussed below. with a target blood pressure of ,140/
sure control (target systolic blood pres- Additional studies, such as the Systolic 90 mmHg. Notably, ACCORD BP and
sure ,140 mmHg), intensive blood Blood Pressure Intervention Trial SPRINT measured blood pressure using
pressure control (target systolic blood (SPRINT) and the Hypertension Optimal automated office blood pressure mea-
pressure ,120 mmHg) did not reduce Treatment (HOT) trial, also examined surement, which yields values that are
total major atherosclerotic cardiovascular effects of intensive versus standard con- generally lower than typical office blood
events but did reduce the risk of stroke, at trol (Table 10.1), though the relevance of pressure readings by approximately 5–
the expense of increased adverse events their results to people with diabetes is 10 mmHg (30), suggesting that imple-
(Table 10.1). The ACCORD BP results less clear. The Action in Diabetes and menting the ACCORD BP or SPRINT
Table 10.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies
Clinical trial Population Intensive Standard Outcomes
ACCORD BP (28) 4,733 participants with T2D SBP target: SBP target: c No benefit in primary end point:
aged 40–79 years with ,120 mmHg 130–140 mmHg composite of nonfatal MI,
prior evidence of CVD or Achieved (mean) Achieved (mean) nonfatal stroke, and CVD death
multiple cardiovascular SBP/DBP: SBP/DBP: c Stroke risk reduced 41% with
risk factors 119.3/64.4 mmHg 13.5/70.5 mmHg intensive control, not sustained
through follow-up beyond the
period of active treatment
c Adverse events more common
in intensive group, particularly
elevated serum creatinine and
electrolyte abnormalities
ADVANCE BP (29) 11,140 participants with Intervention: a single-pill, Control: placebo c Intervention reduced risk of
T2D aged 55 years and fixed-dose combination Achieved (mean) primary composite end point of
older with prior evidence of of perindopril and SBP/DBP: major macrovascular and
CVD or multiple cardiovascular indapamide 141.6/75.2 mmHg microvascular events (9%),
risk factors Achieved (mean) death from any cause (14%), and
SBP/DBP: death from CVD (18%)
136/73 mmHg c 6-year observational follow-up
found reduction in risk of death in
intervention group attenuated
but still significant (198)
HOT (199) 18,790 participants, DBP target: DBP target: c In the overall trial, there was no
including 1,501 #80 mmHg #90 mmHg cardiovascular benefit with
with diabetes more intensive targets
c In the subpopulation with
diabetes, an intensive DBP
target was associated with
a significantly reduced risk (51%)
of CVD events
SPRINT (40) 9,361 participants SBP target: SBP target: c Intensive SBP target lowered risk
without diabetes ,120 mmHg ,140 mmHg of the primary composite
Achieved (mean): Achieved (mean): outcome 25% (MI, ACS, stroke,
121.4 mmHg 136.2 mmHg heart failure, and death due to
CVD)
c Intensive target reduced risk of
death 27%
c Intensive therapy increased risks
of electrolyte abnormalities and
AKI
ACCORD BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial; ACS, acute coronary syndrome; ADVANCE BP, Action in Diabetes and
Vascular Disease: Preterax and Diamicron MR Controlled Evaluation–Blood Pressure trial; AKI, acute kidney injury; CVD, cardiovascular disease; DBP,
diastolic blood pressure; HOT, Hypertension Optimal Treatment trial; MI, myocardial infarction; SBP, systolic blood pressure; SPRINT, Systolic Blood
Pressure Intervention Trial; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes and Hypertension” (17).S128 Cardiovascular Disease and Risk Management Diabetes Care Volume 44, Supplement 1, January 2021
protocols in an outpatient clinic might may vary across patients and is consis- women with diabetes. A 2014 Cochrane
require a systolic blood pressure tar- tent with a patient-focused approach to systematic review of antihypertensive
get higher than ,120 mmHg, such as care that values patient priorities and therapy for mild to moderate chronic
,130 mmHg. provider judgment (36). Secondary anal- hypertension that included 49 trials and
A number of post hoc analyses have yses of ACCORD BP and SPRINT suggest over 4,700 women did not find any con-
attempted to explain the apparently di- that clinical factors can help determine clusive evidence for or against blood pres-
vergent results of ACCORD BP and individuals more likely to benefit and less sure treatment to reduce the risk of
SPRINT. Some investigators have argued likely to be harmed by intensive blood preeclampsia for the mother or effects
that the divergent results are not due to pressure control (37,38). on perinatal outcomes such as preterm
differences between people with and Absolute benefit from blood pressure birth, small-for-gestational-age infants, or
without diabetes but rather are due to reduction correlated with absolute base- fetal death (42). The more recent Control of
differences in study design or to charac- line cardiovascular risk in SPRINT and in Hypertension in Pregnancy Study (CHIPS)
teristics other than diabetes (31–33). earlier clinical trials conducted at higher (43) enrolled mostly women with chronic
Others have opined that the divergent baseline blood pressure levels (11,38). hypertension. In CHIPS, targeting a diastolic
results are most readily explained by the Extrapolation of these studies suggests blood pressure of 85 mmHg during preg-
lack of benefit of intensive blood pres- that patients with diabetes may also be nancy was associated with reduced likeli-
sure control on cardiovascular mortality more likely to benefit from intensive hood of developing accelerated maternal
in ACCORD BP, which may be due to blood pressure control when they hypertension and no demonstrable ad-
differential mechanisms underlying car- have high absolute cardiovascular risk. verse outcome for infants compared
diovascular disease in type 2 diabetes, to Therefore, it may be reasonable to target with targeting a higher diastolic blood
chance, or both (34). Interestingly, a post blood pressure ,130/80 mmHg among pressure. The mean systolic blood pressure
hoc analysis has found that intensive patients with diabetes and either clini- achieved in the more intensively treated
blood pressure lowering increased the cally diagnosed cardiovascular disease group was 133.1 6 0.5 mmHg, and the
risk of incident chronic kidney disease in (particularly stroke, which was signifi- mean diastolic blood pressure achieved in
both ACCORD BP and SPRINT, with the cantly reduced in ACCORD BP) or that group was 85.3 6 0.3 mmHg. A similar
absolute risk of incident chronic kidney 10-year ASCVD risk $15%, if it can be approach is supported by the International
disease being higher in individuals with attained safely. This approach is consis- Society for the Study of Hypertension in
type 2 diabetes (35). tent with guidelines from the American Pregnancy, which specifically recommends
College of Cardiology/American Heart use of antihypertensive therapy to main-
Meta-analyses of Trials Association, which advocate a blood tain systolic blood pressure between
To clarify optimal blood pressure targets pressure target ,130/80 mmHg for all 110 and 140 mmHg and diastolic blood
in patients with diabetes, meta-analyses patients, with or without diabetes (39). pressure between 80 and 85 mmHg (44).
have stratified clinical trials by mean Potential adverse effects of antihyper- Current evidence supports controlling
baseline blood pressure or mean blood tensive therapy (e.g., hypotension, syn- blood pressure to 110–135/85 mmHg to
pressure attained in the intervention (or cope, falls, acute kidney injury, and reduce the risk of accelerated maternal
intensive treatment) arm. Based on these electrolyte abnormalities) should also hypertension but also to minimize impair-
analyses, antihypertensive treatment ap- be taken into account (28,35,40,41). Pa- ment of fetal growth. During pregnancy,
pears to be beneficial when mean base- tients with older age, chronic kidney treatment with ACE inhibitors, angiotensin
line blood pressure is $140/90 mmHg or disease, and frailty have been shown to receptor blockers, and spironolactone are
mean attained intensive blood pressure be at higher risk of adverse effects of contraindicated as they may cause fetal
is $130/80 mmHg (17,21,22,24–26). intensive blood pressure control (41). In damage. Antihypertensive drugs known to
Among trials with lower baseline or addition, patients with orthostatic hypo- be effective and safe in pregnancy include
attained blood pressure, antihyperten- tension, substantial comorbidity, func- methyldopa, labetalol, and long-acting ni-
sive treatment reduced the risk of stroke, tional limitations, or polypharmacy may fedipine, while hydralzine may be con-
retinopathy, and albuminuria, but effects be at high risk of adverse effects, and some sidered in the acute management of
on other ASCVD outcomes and heart patients may prefer higher blood pressure hypertension in pregnancy or severe pre-
failure were not evident. Taken together, targets to enhance quality of life. Patients eclampsia (45). Diuretics are not recom-
these meta-analyses consistently show with low absolute cardiovascular risk (10- mended for blood pressure control in
that treating patients with baseline year ASCVD risk ,15%) or with a history of pregnancy but may be used during late-
blood pressure $140 mmHg to targets adverse effects of intensive blood pres- stage pregnancy if needed for volume
,140 mmHg is beneficial, while more- sure control or at high risk of such adverse control (45,46). The American College of
intensive targets may offer additional effects should have a higher blood pres- Obstetricians and Gynecologists also rec-
(though probably less robust) benefits. sure target. In such patients, a blood ommends that postpartum patients with
Individualization of Treatment Targets pressure target of ,140/90 mmHg is gestational hypertension, preeclampsia,
Patients and clinicians should engage in a recommended, if it can be safely attained. and superimposed preeclampsia have their
shared decision-making process to de- blood pressures observed for 72 h in the
termine individual blood pressure tar- Pregnancy and Antihypertensive hospital and for 7–10 days postpartum.
gets (17). This approach acknowledges Medications Long-term follow-up is recommended for
that the benefits and risks of intensive There are few randomized controlled trials these women as they have increased life-
blood pressure targets are uncertain and of antihypertensive therapy in pregnant time cardiovascular risk (47). See Sectioncare.diabetesjournals.org Cardiovascular Disease and Risk Management S129
14 “Management of Diabetes in Preg- antihypertensive combinations may im-
10.9 Patients with confirmed office-
nancy” (https://doi.org/10.2337/dc21-S014) prove medication adherence in some
based blood pressure $160/
for additional information. patients (53).
100 mmHg should, in addition
to lifestyle therapy, have prompt Classes of Antihypertensive Medications.
Treatment Strategies
initiation and timely titration of Initial treatment for hypertension should
Lifestyle Intervention
two drugs or a single-pill com- include any of the drug classes demon-
Recommendation bination of drugs demonstrated strated to reduce cardiovascular events
10.7 For patients with blood pres- to reduce cardiovascular events in patients with diabetes: ACE inhibitors
sure .120/80 mmHg, lifestyle in patients with diabetes. A (54,55), angiotensin receptor blockers
intervention consists of weight 10.10 Treatment for hypertension (ARBs) (54,55), thiazide-like diuretics (56),
loss when indicated, a Dietary should include drug classes dem- or dihydropyridine calcium channel block-
Approaches to Stop Hyperten- onstrated to reduce cardiovas- ers (57). In patients with diabetes and
sion (DASH)-style eating pattern cular events in patients with established coronary artery disease, ACE
including reducing sodium and diabetes. A ACE inhibitors or inhibitors or ARBs are recommended first-
increasing potassium intake, angiotensin receptor blockers line therapy for hypertension (58–60). For
moderation of alcohol intake, are recommended first-line ther- patients with albuminuria (urine albumin-
and increased physical activity. A apy for hypertension in people to-creatinine ratio [UACR] $30 mg/g),
with diabetes and coronary ar- initial treatment should include an ACE
Lifestyle management is an important tery disease. A inhibitor or ARB in order to reduce the
component of hypertension treatment 10.11 Multiple-drug therapy is gener- risk of progressive kidney disease (17)
because it lowers blood pressure, enhan- ally required to achieve blood (Fig. 10.1). In the absence of albumin-
ces the effectiveness of some antihyper- pressure targets. However, uria, risk of progressive kidney disease is
tensive medications, promotes other combinations of ACE inhibitors low, and ACE inhibitors and ARBs have not
aspects of metabolic and vascular health, and angiotensin receptor block- been found to afford superior cardiopro-
and generally leads to few adverse ef- ers and combinations of ACE tection when compared with thiazide-like
fects. Lifestyle therapy consists of re- inhibitors or angiotensin recep- diuretics or dihydropyridine calcium channel
ducing excess body weight through tor blockers with direct renin blockers (61). b-Blockers are indicated in the
caloric restriction (see Section 8 “Obe- inhibitors should not be used. A setting of prior MI, active angina, or HfrEF
sity Management for the Treatment of 10.12 An ACE inhibitor or angiotensin but have not been shown to reduce mor-
Type 2 Diabetes,” https://doi.org/10.2337/ receptor blocker, at the max- tality as blood pressure–lowering agents in
dc21-S008), restricting sodium intake imum tolerated dose indicated the absence of these conditions (23,62,63).
(,2,300 mg/day), increasing consump- for blood pressure treatment, Multiple-Drug Therapy. Multiple-drug
tion of fruits and vegetables (8–10 serv- is the recommended first-line therapy is often required to achieve
ings per day) and low-fat dairy products treatment for hypertension in blood pressure targets (Fig. 10.1), par-
(2–3 servings per day), avoiding exces- patients with diabetes and uri- ticularly in the setting of diabetic kid-
sive alcohol consumption (no more than nary albumin-to-creatinine ra- ney disease. However, the use of both
2 servings per day in men and no more than tio $300 mg/g creatinine A or ACE inhibitors and ARBs in combination,
1 serving per day in women) (48), and 30–299 mg/g creatinine. B If or the combination of an ACE inhibitor or
increasing activity levels (49). one class is not tolerated, the ARB and a direct renin inhibitor, is not
These lifestyle interventions are rea- other should be substituted. B recommended given the lack of added
sonable for individuals with diabetes and 10.13 For patients treated with an ACE ASCVD benefit and increased rate of ad-
mildly elevated blood pressure (systolic inhibitor, angiotensin receptor verse eventsdnamely, hyperkalemia, syn-
.120 mmHg or diastolic .80 mmHg) blocker, or diuretic, serum cre- cope, and acute kidney injury (AKI) (64–66).
and should be initiated along with phar- atinine/estimated glomerular Titration of and/or addition of further blood
macologic therapy when hypertension is filtration rate and serum potas- pressure medications should be made in a
diagnosed (Fig. 10.1) (49). A lifestyle therapy sium levels should be moni- timely fashion to overcome therapeutic
plan should be developed in collaboration tored at least annually. B inertia in achieving blood pressure targets.
with the patient and discussed as part of
Bedtime Dosing. Growing evidence sug-
diabetes management.
Initial Number of Antihypertensive Medications. gests that there is an association be-
Pharmacologic Interventions Initial treatment for people with diabetes tween the absence of nocturnal blood
depends on the severity of hypertension (Fig. pressure dipping and the incidence of
Recommendations
10.1). Those with blood pressure between ASCVD. A meta-analysis of randomized
10.8 Patients with confirmed office-
140/90 mmHg and 159/99 mmHg may clinicaltrials foundasmall benefitofevening
based blood pressure $140/
begin with a single drug. For patients with versus morning dosing of antihypertensive
90 mmHg should, in addition to
blood pressure $160/100 mmHg, initial medications with regard to blood pressure
lifestyle therapy, have prompt
pharmacologic treatment with two anti- control but had no data on clinical effects
initiation and timely titration
hypertensive medications is recommended (67). In two subgroup analyses of a sin-
of pharmacologic therapy to
in order to more effectively achieve adequate gle subsequent randomized controlled
achieve blood pressure goals. A
blood pressure control (50–52). Single-pill trial, moving at least one antihypertensiveS130 Cardiovascular Disease and Risk Management Diabetes Care Volume 44, Supplement 1, January 2021
Figure 10.1—Recommendations for the treatment of confirmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB)
is suggested to treat hypertension for patients with coronary artery disease (CAD) or urine albumin-to-creatinine ratio 30–299 mg/g creatinine and strongly
recommended for patients with urine albumin-to-creatinine ratio $300 mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown to reduce cardiovascular
events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine calcium channel blocker (CCB). BP, blood pressure. Adapted fromde Boer et al. (17).
medication to bedtime significantly reduced can cause AKI and hyperkalemia, while is important because AKI and hyperkalemia
cardiovascular events, but results were diuretics can cause AKI and either hypo- each increase the risks of cardiovascular
based on a small number of events (68). kalemia or hyperkalemia (depending on events and death (71). Therefore, serum
Hyperkalemia and Acute Kidney Injury. mechanism of action) (69,70). Detection creatinine and potassium should be mon-
Treatment with ACE inhibitors or ARBs and management of these abnormalities itored during treatment with an ACEcare.diabetesjournals.org Cardiovascular Disease and Risk Management S131
inhibitor, ARB, or diuretic, particularly
Stop Hypertension (DASH) eat- 10.18 Obtain a lipid profile at initi-
among patients with reduced glomerular
ing pattern; reduction of satu- ation of statins or other lipid-
filtration who are at increased risk of
rated fat and trans fat; increase lowering therapy, 4–12 weeks
hyperkalemia and AKI (69,70,72).
of dietary n-3 fatty acids, vis- after initiation or a change in
Resistant Hypertension
cous fiber, and plant stanols/ dose, and annually thereafter
sterols intake; and increased as it may help to monitor the
Recommendation physical activity should be rec- response to therapy and in-
10.14 Patients with hypertension who ommended to improve the lipid form medication adherence. E
are not meeting blood pressure profile and reduce the risk of
targets on three classes of an- developing atherosclerotic car- In adults with diabetes, it is reasonable to
tihypertensive medications (in- diovascular disease in patients obtain a lipid profile (total cholesterol,
cluding a diuretic) should be with diabetes. A LDL cholesterol, HDL cholesterol, and
considered for mineralocorti- 10.16 Intensify lifestyle therapy and triglycerides) at the time of diagnosis,
coid receptor antagonist ther- optimize glycemic control for at the initial medical evaluation, and at
apy. B patients with elevated triglyc- least every 5 years thereafter in patients
eride levels ($150 mg/dL [1.7 under the age of 40 years. In younger
Resistant hypertension is defined as mmol/L]) and/or low HDL cho- patients with longer duration of disease
blood pressure $140/90 mmHg despite lesterol (,40 mg/dL [1.0 (such as those with youth-onset type 1
a therapeutic strategy that includes ap- mmol/L] for men, ,50 mg/dL diabetes), more frequent lipid profiles
propriate lifestyle management plus a [1.3 mmol/L] for women). C may be reasonable. A lipid panel should
diuretic and two other antihypertensive also be obtained immediately before
drugs belonging to different classes at Lifestyle intervention, including weight initiating statin therapy. Once a patient
adequate doses. Prior to diagnosing re- loss (78), increased physical activity, and is taking a statin, LDL cholesterol levels
sistant hypertension, a number of other medical nutrition therapy, allows some should be assessed 4–12 weeks after
conditions should be excluded, including patients to reduce ASCVD risk factors. initiation of statin therapy, after any
medication nonadherence, white coat Nutrition intervention should be tailored change in dose, and on an individual
hypertension, and secondary hyperten- according to each patient’s age, diabetes basis (e.g., to monitor for medica-
sion. In general, barriers to medication type, pharmacologic treatment, lipid lev- tion adherence and efficacy). If LDL
adherence (such as cost and side effects) els, and medical conditions. cholesterol levels are not responding
should be identified and addressed (Fig. Recommendations should focus on in spite of medication adherence, clin-
10.1). Mineralocorticoid receptor antag- application of a Mediterranean style ical judgment is recommended to de-
onists are effective for management of diet (79) or Dietary Approaches to termine the need for and timing of lipid
resistant hypertension in patients with Stop Hypertension (DASH) eating pat- panels. In individual patients, the highly
type 2 diabetes when added to existing tern, reducing saturated and trans fat variable LDL cholesterol–lowering re-
treatment with an ACE inhibitor or ARB, intake and increasing plant stanols/ sponse seen with statins is poorly un-
thiazide-like diuretic, and dihydropyri- sterols, n-3 fatty acids, and viscous fiber derstood (81). Clinicians should attempt
dine calcium channel blocker (73). Min- (such as in oats, legumes, and citrus) to find a dose or alternative statin that
eralocorticoid receptor antagonists also intake (80). Glycemic control may also is tolerable if side effects occur. There
reduce albuminuria and have additional beneficially modify plasma lipid levels, is evidence for benefit from even ex-
cardiovascular benefits (74–77). How- particularly in patients with very high tremely low, less than daily statin doses
ever, adding a mineralocorticoid recep- triglycerides and poor glycemic control. (82).
tor antagonist to a regimen including an See Section 5 “Facilitating Behavior
ACE inhibitor or ARB may increase the risk Change and Well-being to Improve
for hyperkalemia, emphasizing the im- Health Outcomes” (https://doi.org/10 STATIN TREATMENT
portance of regular monitoring for serum .2337/dc21-S005) for additional nutri- Primary Prevention
creatinine and potassium in these pa- tion information.
Recommendations
tients, and long-term outcome studies
are needed to better evaluate the role of 10.19 For patients with diabetes
Ongoing Therapy and Monitoring With
mineralocorticoid receptor antagonists aged 40–75 years without ath-
Lipid Panel
in blood pressure management. erosclerotic cardiovascular dis-
Recommendations ease, use moderate-intensity
10.17 In adults not taking statins or statin therapy in addition to
LIPID MANAGEMENT other lipid-lowering therapy, lifestyle therapy. A
it is reasonable to obtain a 10.20 For patients with diabetes
Lifestyle Intervention
lipid profile at the time of aged 20–39 years with addi-
Recommendations diabetes diagnosis, at an ini- tional atherosclerotic cardio-
10.15 Lifestyle modification focusing tial medical evaluation, and vascular disease risk factors,
on weight loss (if indicated); every 5 years thereafter if un- it may be reasonable to initiate
application of a Mediterranean der the age of 40 years, or statin therapy in addition to
style or Dietary Approaches to more frequently if indicated. E lifestyle therapy. CS132 Cardiovascular Disease and Risk Management Diabetes Care Volume 44, Supplement 1, January 2021
with and without CHD (83,84). Subgroup Primary Prevention (Patients Without
10.21 In patients with diabetes at ASCVD)
analyses of patients with diabetes in
higher risk, especially those
larger trials (85–89) and trials in patients For primary prevention, moderate-dose
with multiple atherosclerotic
with diabetes (90,91) showed significant statin therapy is recommended for those
cardiovascular disease risk fac-
primary and secondary prevention of 40 years and older (86,93,94), though
tors or aged 50–70 years, it is
ASCVD events and CHD death in patients high-intensity therapy may be consid-
reasonable to use high-inten-
with diabetes. Meta-analyses, including ered on an individual basis in the context
sity statin therapy. B
data from over 18,000 patients with of additional ASCVD risk factors. The
10.22 In adults with diabetes and
diabetes from 14 randomized trials of evidence is strong for patients with di-
10-year atherosclerotic car-
statin therapy (mean follow-up 4.3 abetes aged 40–75 years, an age-group
diovascular disease risk of
years), demonstrate a 9% proportional well represented in statin trials showing
20% or higher, it may be
reduction in all-cause mortality and 13% benefit. Since risk is enhanced in patients
reasonable to add ezetimibe
reduction in vascular mortality for each with diabetes, as noted above, patients
to maximally tolerated statin
1 mmol/L (39 mg/dL) reduction in LDL who also have multiple other coronary
therapy to reduce LDL cho-
cholesterol (92). risk factors have increased risk, equiva-
lesterol levels by 50% or
Accordingly, statins are the drugs of lent to that of those with ASCVD. As such,
more. C
choice for LDL cholesterol lowering and recent guidelines recommend that in
cardioprotection. Table 10.2 shows the patients with diabetes who are at higher
Secondary Prevention two statin dosing intensities that are risk, especially those with multiple
recommended for use in clinical practice: ASCVD risk factors or aged 50–70 years,
Recommendations
high-intensity statin therapy will achieve it is reasonable to prescribe high-intensity
10.23 For patients of all ages with
diabetes and atherosclerotic approximately a $50% reduction in LDL statin therapy (12,95). Furthermore,
cholesterol, and moderate-intensity sta- for patients with diabetes whose ASCVD
cardiovascular disease, high-
tin regimens achieve 30–49% reductions risk is $20%, i.e., an ASCVD risk equiv-
intensity statin therapy should
in LDL cholesterol. Low-dose statin ther- alent, the same high-intensity statin ther-
be added to lifestyle therapy. A
apy is generally not recommended in apy is recommended as for those with
10.24 For patients with diabetes
patients with diabetes but is sometimes documented ASCVD (12). In those indi-
and atherosclerotic cardio-
the only dose of statin that a patient can viduals, it may also be reasonable to add
vascular disease considered
tolerate. For patients who do not tolerate ezetimibe to maximally tolerated statin
very high risk using specific
the intended intensity of statin, the therapy if needed to reduce LDL choles-
criteria, if LDL cholesterol is
maximally tolerated statin dose should terol levels by 50% or more (12). The
$70 mg/dL on maximally tol-
be used. evidence is lower for patients aged .75
erated statin dose, consider
As in those without diabetes, absolute years; relatively few older patients with
adding additional LDL-lowering
reductions in ASCVD outcomes (CHD diabetes have been enrolled in primary
therapy (such as ezetimibe or
death and nonfatal MI) are greatest in prevention trials. However, heterogene-
PCSK9 inhibitor). A Ezetimibe
people with high baseline ASCVD risk ity by age has not been seen in the
may be preferred due to lower
(known ASCVD and/or very high LDL relative benefit of lipid-lowering therapy
cost.
cholesterol levels), but the overall bene- in trials that included older participants
10.25 For patients who do not tol-
erate the intended intensity, fits of statin therapy in people with di- (84,91,92), and because older age con-
abetes at moderate or even low risk for fers higher risk, the absolute benefits
the maximally tolerated statin
ASCVD are convincing (93,94). The rela- are actually greater (84,96). Moderate-
dose should be used. E
tive benefit of lipid-lowering therapy has intensity statin therapy is recommended
10.26 In adults with diabetes aged
been uniform across most subgroups in patients with diabetes who are 75 years
.75 years already on statin
tested (84,92), including subgroups or older. However, the risk-benefit pro-
therapy, it is reasonable to
that varied with respect to age and other file should be routinely evaluated in this
continue statin treatment. B
risk factors. population, with downward titration of
10.27 In adults with diabetes aged
.75 years, it may be reason-
able to initiate statin therapy
after discussion of potential Table 10.2—High-intensity and moderate-intensity statin therapy*
benefits and risks. C High-intensity statin therapy Moderate-intensity statin therapy
10.28 Statin therapy is contraindi- (lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30–49%)
cated in pregnancy. B Atorvastatin 40–80 mg Atorvastatin 10–20 mg
Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg
Initiating Statin Therapy Based on Risk Simvastatin 20–40 mg
Patients with type 2 diabetes have an Pravastatin 40–80 mg
increased prevalence of lipid abnormal- Lovastatin 40 mg
ities, contributing to their high risk of Fluvastatin XL 80 mg
ASCVD. Multiple clinical trials have dem- Pitavastatin 1–4 mg
onstrated the beneficial effects of statin *Once-daily dosing. XL, extended release.
therapy on ASCVD outcomes in subjectscare.diabetesjournals.org Cardiovascular Disease and Risk Management S133
dose performed as needed. See Section investigating the benefits of adding non- the statin group on average and 54 mg/
12 “Older Adults” (https://doi.org/10 statin agents to statin therapy, including dL in the combination group (96). In
.2337/dc21-S012) for more details on those that evaluated further lowering of those with diabetes (27% of partici-
clinical considerations for this population. LDL cholesterol with ezetimibe (96,100) pants), the combination of moderate-
and proprotein convertase subtilisin/ intensity simvastatin (40 mg) and eze-
AgeS134 Cardiovascular Disease and Risk Management Diabetes Care Volume 44, Supplement 1, January 2021
patients with diabetes, comprising dyslipidemia in individuals with type 2 di-
can be considered to reduce
11,031 patients (40% of the trial) (104). abetes. However, the evidence for the use
cardiovascular risk. A
In the ODYSSEY OUTCOMES trial (Eval- of drugs that target these lipid fractions is
uation of Cardiovascular Outcomes After substantially less robust than that for statin
an Acute Coronary Syndrome During Hypertriglyceridemia should be addressed therapy (109). In a large trial in patients
Treatment With Alirocumab), 18,924 pa- with dietary and lifestyle changes includ- with diabetes, fenofibrate failed to reduce
tients (28.8% of whom had diabetes) with ing weight loss and abstinence from overall cardiovascular outcomes (110).
recent acute coronary syndrome were alcohol (107). Severe hypertriglyceride-
randomized to the PCSK9 inhibitor alir- mia (fasting triglycerides $500 mg/dL
Other Combination Therapy
ocumab or placebo every 2 weeks in ad- and especially .1,000 mg/dL) may war-
dition to maximally tolerated statin therapy, rant pharmacologic therapy (fibric acid Recommendations
with alirocumab dosing titrated between derivatives and/or fish oil) and reduction 10.32 Statin plus fibrate combination
75 and 150 mg to achieve LDL cholesterol in dietary fat to reduce the risk of acute therapy has not been shown to
levels between 25 and 50 mg/dL (105). pancreatitis. Moderate- or high-intensity improve atherosclerotic car-
Over a median follow-up of 2.8 years, a statin therapy should also be used as in- diovascular disease outcomes
composite primary end point (compris- dicated to reduce risk of cardiovascular and is generally not recom-
ing death from coronary heart disease, events (see STATIN TREATMENT). In patients mended. A
nonfatal MI, fatal or nonfatal ischemic with moderate hypertriglyceridemia, life- 10.33 Statin plus niacin combination
stroke, or unstable angina requiring hos- style interventions, treatment of secondary therapy has not been shown to
pital admission) occurred in 903 patients factors, and avoidance of medications that provide additional cardiovas-
(9.5%) in the alirocumab group and in might raise triglycerides are recommended. cular benefit above statin ther-
1,052 patients (11.1%) in the placebo The Reduction of Cardiovascular Events apy alone, may increase the
group (HR 0.85 [95% CI 0.78–0.93]; P , with Icosapent Ethyl–Intervention Trial risk of stroke with additional
0.001). Combination therapy with aliro- (REDUCE-IT) enrolled 8,179 adults receiv- side effects, and is generally
cumab plus statin therapy resulted in a ing statin therapy with moderately el- not recommended. A
greater absolute reduction in the inci- evated triglycerides (135–499 mg/dL,
dence of the primary end point in patients median baseline of 216 mg/dL) who had
with diabetes (2.3% [95% CI 0.4–4.2]) than either established cardiovascular disease Statin and Fibrate Combination Therapy
in those with prediabetes (1.2% [0.0–2.4]) (secondary prevention cohort) or diabetes Combination therapy (statin and fibrate)
or normoglycemia (1.2% [–0.3 to 2.7]) plus at least one other cardiovascular risk is associated with an increased risk for
(106). factor (primary prevention cohort). Pa- abnormal transaminase levels, myositis,
tients were randomized to icosapent ethyl and rhabdomyolysis. The risk of rhabdo-
Treatment of Other Lipoprotein 4 g/day (2 g twice daily with food) versus myolysis is more common with higher
Fractions or Targets placebo. The trial met its primary end doses of statins and renal insufficiency
point, demonstrating a 25% relative risk and appears to be higher when statins are
Recommendations combined with gemfibrozil (compared
reduction (P , 0.001) for the primary end
10.29 For patients with fasting triglyc- with fenofibrate) (111).
point composite of cardiovascular death,
eride levels $500 mg/dL, eval- In the ACCORD study, in patients with
nonfatal myocardial infarction, nonfatal
uate for secondary causes of type 2 diabetes who were at high risk for
stroke, coronary revascularization, or un-
hypertriglyceridemia and con- ASCVD, the combination of fenofibrate
stable angina. This reduction in risk was
sider medical therapy to reduce and simvastatin did not reduce the rate of
seen in patients with or without diabetes at
the risk of pancreatitis. C fatal cardiovascular events, nonfatal MI,
baseline. The composite of cardiovascular
10.30 In adults with moderate hyper- or nonfatal stroke as compared with
death, nonfatal myocardial infarction, or
triglyceridemia (fasting or non- simvastatin alone. Prespecified subgroup
nonfatal stroke was reduced by 26%
fasting triglycerides 175–499 analyses suggested heterogeneity in
(P , 0.001). Additional ischemic end
mg/dL),cliniciansshouldaddress treatment effects with possible benefit
points were significantly lower in the
and treat lifestyle factors (obe- for men with both a triglyceride level
icosapent ethyl group than in the placebo
sity and metabolic syndrome),
group, including cardiovascular death, $204 mg/dL (2.3 mmol/L) and an HDL
secondary factors (diabetes,
which was reduced by 20% (P 5 cholesterol level #34 mg/dL (0.9 mmol/L)
chronic liver or kidney disease
0.03). The proportions of patients expe- (112). A prospective trial of a newer fibrate
and/or nephrotic syndrome, hy- in this specific population of patients is
riencing adverse events and serious ad-
pothyroidism), and medications ongoing (113).
verse events were similar between the
that raise triglycerides. C
active and placebo treatment groups. It Statin and Niacin Combination Therapy
10.31 In patients with atheroscle-
should be noted that data are lacking with The Atherothrombosis Intervention in
rotic cardiovascular disease or
other n-3 fatty acids, and results of the Metabolic Syndrome With Low HDL/
other cardiovascular risk factors
REDUCE-IT trial should not be extrapo- High Triglycerides: Impact on Global
on a statin with controlled
lated to other products (108). Health Outcomes (AIM-HIGH) trial ran-
LDL cholesterol but elevated
Low levels of HDL cholesterol, often domized over 3,000 patients (about
triglycerides (135–499 mg/dL),
associated with elevated triglyceride lev- one-third with diabetes) with estab-
the addition of icosapent ethyl
els, are the most prevalent pattern of lished ASCVD, low LDL cholesterol levelscare.diabetesjournals.org Cardiovascular Disease and Risk Management S135
(,180 mg/dL [4.7 mmol/L]), low HDL diabetes even for patients at highest
atherosclerotic cardiovascular
cholesterol levels (men ,40 mg/dL risk for diabetes (118). The absolute
disease. A
[1.0 mmol/L] and women ,50 mg/dL risk increase was small (over 5 years
10.35 For patients with atheroscle-
[1.3 mmol/L]), and triglyceride levels of of follow-up, 1.2% of participants on
rotic cardiovascular disease and
150–400 mg/dL (1.7–4.5 mmol/L) to placebo developed diabetes and 1.5%
documented aspirin allergy,
statin therapy plus extended-release ni- on rosuvastatin developed diabetes)
clopidogrel (75 mg/day) should
acin or placebo. The trial was halted early (118). A meta-analysis of 13 randomized
be used. B
due to lack of efficacy on the primary statin trials with 91,140 participants
10.36 Dual antiplatelet therapy (with
ASCVD outcome (first event of the com- showed an odds ratio of 1.09 for a
low-dose aspirin and a P2Y12
posite of death from CHD, nonfatal MI, new diagnosis of diabetes, so that (on
inhibitor) is reasonable for a
ischemic stroke, hospitalization for an average) treatment of 255 patients with
year after an acute coronary
ACS, or symptom-driven coronary or statins for 4 years resulted in one addi-
syndrome and may have ben-
cerebral revascularization) and a possible tional case of diabetes while simulta-
efits beyond this period. A
increase in ischemic stroke in those on neously preventing 5.4 vascular events
10.37 Long-term treatment with dual
combination therapy (114). among those 255 patients (117).
antiplatelet therapy should be
The much larger Heart Protection
considered for patients with
Study 2–Treatment of HDL to Reduce Lipid-Lowering Agents and Cognitive
prior coronary intervention,
the Incidence of Vascular Events (HPS2- Function
high ischemic risk, and low
THRIVE) trial also failed to show a benefit Although concerns regarding a potential
bleeding risk to prevent major
of adding niacin to background statin adverse impact of lipid-lowering agents
adverse cardiovascular events. A
therapy (115). A total of 25,673 patients on cognitive function have been raised,
10.38 Combination therapy with as-
with prior vascular disease were random- several lines of evidence point against
pirin plus low-dose rivaroxa-
ized to receive 2 g of extended-release this association, as detailed in a 2018 Eu-
ban should be considered for
niacin and 40 mg of laropiprant (an ropean Atherosclerosis Society Consen-
patients with stable coronary
antagonist of the prostaglandin D2 re- sus Panel statement (119). First, there
and/or peripheral artery disease
ceptor DP1 that has been shown to are three large randomized trials of statin
and low bleeding risk to pre-
improve adherence to niacin therapy) versus placebo where specific cognitive
vent major adverse limb and
versus a matching placebo daily and tests were performed, and no differ-
cardiovascular events. A
followed for a median follow-up period ences were seen between statin and
10.39 Aspirin therapy (75–162 mg/
of 3.9 years. There was no significant placebo (120–123). In addition, no
day) may be considered as a
difference in the rate of coronary death, change in cognitive function has been
primary prevention strategy in
MI, stroke, or coronary revascularization reported in studies with the addition
those with diabetes who are at
with the addition of niacin–laropiprant of ezetimibe (96) or PCSK9 inhibitors
increased cardiovascular risk,
versus placebo (13.2% vs. 13.7%; rate (99,124) to statin therapy, including
after a comprehensive discus-
ratio 0.96; P 5 0.29). Niacin–laropiprant among patients treated to very low
sion with the patient on the
was associated with an increased inci- LDL cholesterol levels. In addition, the
benefits versus the comparable
dence of new-onset diabetes (absolute most recent systematic review of the
increased risk of bleeding. A
excess, 1.3 percentage points; P , 0.001) U.S. Food and Drug Administration’s
and disturbances in diabetes control (FDA’s) postmarketing surveillance da-
among those with diabetes. In addition, tabases, randomized controlled trials, Risk Reduction
there was an increase in serious adverse and cohort, case-control, and cross- Aspirin has been shown to be effective in
events associated with the gastrointes- sectional studies evaluating cognition in reducing cardiovascular morbidity and
tinal system, musculoskeletal system, patients receiving statins found that mortality in high-risk patients with pre-
skin, and, unexpectedly, infection and published data do not reveal an adverse vious MI or stroke (secondary prevention)
bleeding. effect of statins on cognition (125). and is strongly recommended. In primary
Therefore, combination therapy with a Therefore, a concern that statins or prevention, however, among patients with
statin and niacin is not recommended other lipid-lowering agents might cause no previous cardiovascular events, its net
given the lack of efficacy on major ASCVD cognitive dysfunction or dementia is not benefit is more controversial (126,127).
outcomes and increased side effects. currently supported by evidence and Previous randomized controlled trials
should not deter their use in individuals of aspirin specifically in patients with
Diabetes Risk With Statin Use with diabetes at high risk for ASCVD diabetes failed to consistently show a
Several studies have reported a modestly (125). significant reduction in overall ASCVD
increased risk of incident diabetes with end points, raising questions about the
statin use (116,117), which may be lim- ANTIPLATELET AGENTS efficacy of aspirin for primary prevention
ited to those with diabetes risk factors. in people with diabetes, although some sex
Recommendations
An analysis of one of the initial studies differences were suggested (128–130).
10.34 Use aspirin therapy (75–162
suggested that although statin use was The Antithrombotic Trialists’ Collabo-
mg/day) as a secondary pre-
associated with diabetes risk, the cardio- ration published an individual patient–
vention strategy in those
vascular event rate reduction with statins level meta-analysis (126) of the six large
with diabetes and a history of
far outweighed the risk of incident trials of aspirin for primary prevention inS136 Cardiovascular Disease and Risk Management Diabetes Care Volume 44, Supplement 1, January 2021
the general population. These trials col- groups (HR 0.95 [95% CI 0.83–1.08]). The judgment should be used for those at
lectively enrolled over 95,000 participants, rate of major hemorrhage per 1,000 per- intermediate risk (younger patients with
including almost 4,000 with diabetes. son-years was 8.6 events vs. 6.2 events, one or more risk factors or older patients
Overall, they found that aspirin reduced respectively (HR 1.38 [95% CI 1.18–1.62]; with no risk factors) until further research
the risk of serious vascular events by 12% P , 0.001). is available. Patients’ willingness to un-
(relative risk 0.88 [95% CI 0.82–0.94]). Thus, aspirin appears to have a modest dergo long-term aspirin therapy should
The largest reduction was for nonfatal effect on ischemic vascular events, with also be considered (141). Aspirin use in
MI, with little effect on CHD death (rel- the absolute decrease in events depend- patients aged ,21 years is generally
ative risk 0.95 [95% CI 0.78–1.15]) or total ing on the underlying ASCVD risk. The contraindicated due to the associated
stroke. main adverse effect is an increased risk of risk of Reye syndrome.
Most recently, the ASCEND (A Study of gastrointestinal bleeding. The excess risk
Cardiovascular Events iN Diabetes) trial may be as high as 5 per 1,000 per year in Aspirin Dosing
randomized 15,480 patients with diabe- real-world settings. However, for adults Average daily dosages used in most
tes but no evident cardiovascular disease with ASCVD risk .1% per year, the clinical trials involving patients with di-
to aspirin 100 mg daily or placebo (131). number of ASCVD events prevented abetes ranged from 50 mg to 650 mg but
The primary efficacy end point was vas- will be similar to the number of episodes were mostly in the range of 100–325 mg/
cular death, MI, or stroke or transient of bleeding induced, although these com- day. There is little evidence to support
ischemic attack. The primary safety plications do not have equal effects on any specific dose, but using the lowest
outcome was major bleeding (i.e., in- long-term health (134). possible dose may help to reduce side
tracranial hemorrhage, sight-threatening Recommendations for using aspirin as effects (142). In the U.S., the most com-
bleeding in the eye, gastrointestinal primary prevention include both men mon low-dose tablet is 81 mg. Although
bleeding, or other serious bleeding). and women aged $50 years with di- platelets from patients with diabetes
During a mean follow-up of 7.4 years, abetes and at least one additional major have altered function, it is unclear
there was a significant 12% reduction in risk factor (family history of premature what, if any, effect that finding has on
the primary efficacy end point (8.5% vs. ASCVD, hypertension, dyslipidemia, the required dose of aspirin for cardio-
9.6%; P 5 0.01). In contrast, major smoking, or chronic kidney disease/ protective effects in the patient with
bleeding was significantly increased albuminuria) who are not at increased diabetes. Many alternate pathways for
from 3.2% to 4.1% in the aspirin group risk of bleeding (e.g., older age, anemia, platelet activation exist that are inde-
(rate ratio 1.29; P 5 0.003), with most renal disease) (135–138). Noninvasive pendent of thromboxane A2 and thus are
of the excess being gastrointestinal imaging techniques such as coronary not sensitive to the effects of aspirin
bleeding and other extracranial bleed- calcium scoring may potentially help (143). “Aspirin resistance” has been de-
ing. There were no significant differ- further tailor aspirin therapy, particularly scribed in patients with diabetes when
ences by sex, weight, or duration of in those at low risk (139,140). For pa- measured by a variety of ex vivo and
diabetes or other baseline factors in- tients over the age of 70 years (with or in vitro methods (platelet aggregometry,
cluding ASCVD risk score. without diabetes), the balance appears measurement of thromboxane B2) (144),
Two other large randomized trials of to have greater risk than benefit but other studies suggest no impairment
aspirin for primary prevention, in pa- (131,133). Thus, for primary prevention, in aspirin response among patients with
tients without diabetes (ARRIVE [Aspirin the use of aspirin needs to be carefully diabetes (145). A recent trial suggested
to Reduce Risk of Initial Vascular Events]) considered and may generally not be that more frequent dosing regimens of
(132) and in the elderly (ASPREE [Aspirin recommended. Aspirin may be consid- aspirin may reduce platelet reactivity in
in Reducing Events in the Elderly]) (133), ered in the context of high cardiovascular individuals with diabetes (146); however,
which included 11% with diabetes, found risk with low bleeding risk, but generally these observations alone are insufficient
no benefit of aspirin on the primary not in older adults. Aspirin therapy for to empirically recommend that higher
efficacy end point and an increased risk primary prevention may be considered in doses of aspirin be used in this group at
of bleeding. In ARRIVE, with 12,546 pa- the context of shared decision-making, this time. Another recent meta-analysis
tients over a period of 60 months follow- which carefully weighs the cardiovascu- raised the hypothesis that low-dose as-
up, the primary end point occurred in lar benefits with the fairly comparable pirin efficacy is reduced in those weighing
4.29% vs. 4.48% of patients in the aspirin increase in risk of bleeding. For patients more than 70 kg (147); however, the
versus placebo groups (HR 0.96 [95% CI with documented ASCVD, use of aspirin ASCEND trial found benefit of low-dose
0.81–1.13]; P 5 0.60). Gastrointestinal for secondary prevention has far greater aspirin in those in this weight range,
bleeding events (characterized as mild) benefit than risk; for this indication, which would thus not validate this sug-
occurred in 0.97% of patients in the aspirin aspirin is still recommended (126). gested hypothesis (131). It appears that
group vs. 0.46% in the placebo group (HR 75–162 mg/day is optimal.
2.11 [95% CI 1.36–3.28]; P 5 0.0007). In Aspirin Use in PeopleYou can also read
