CARDIOVASCULAR DISEASE AND RISK MANAGEMENT: STANDARDSOF MEDICALCAREINDIABETESD2020
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Diabetes Care Volume 43, Supplement 1, January 2020 S111
10. Cardiovascular Disease and American Diabetes Association
Risk Management: Standards of
Medical Care in Diabetesd2020
Diabetes Care 2020;43(Suppl. 1):S111–S134 | https://doi.org/10.2337/dc20-s010
10. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT
The American Diabetes Association (ADA) “Standards of Medical Care in Diabe-
tes” 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/dc20-
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/dc20-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/
dc20-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 whenmultiple cardiovascular riskfactors are
addressed simultaneously. Under the current paradigm of aggressive risk factor mod-
ification 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).
This section has received endorsement from the
Heart failure is another major cause of morbidity and mortality from cardiovascu- American College of Cardiology.
lar disease. Recent studies have found that rates of incident heart failure hospitalization
Suggested citation: American Diabetes Asso-
(adjustedforageandsex)weretwofoldhigherinpatientswithdiabetescomparedwiththose ciation. 10. Cardiovascular disease and risk
without (5,6). People with diabetes may have heart failure with preserved ejection fraction management: Standards of Medical Care in
(HFpEF) or with reduced ejection fraction (HFrEF). Hypertension is often a precursor of heart Diabetesd2020. Diabetes Care 2020;43(Suppl.1):
failure of either type, and ASCVD can coexist with either type (7), whereas prior myocardial S111–S134
infarction (MI) is often a major factor in HFrEF. Rates of heart failure hospitalization have © 2019 by the American Diabetes Association.
been improved in recent trials including patients with type 2 diabetes, most of whom also Readers may use this article as long as the work
is properly cited, the use is educational and not
had ASCVD, with sodium–glucose cotransporter 2 (SGLT2) inhibitors (8–10). for profit, and the work is not altered. More infor-
For prevention and management of both ASCVD and heart failure, cardio- mation is available at http://www.diabetesjournals
vascular risk factors should be systematically assessed at least annually in all patients .org/content/license.S112 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
with diabetes. These risk factors in- epidemiology, diagnosis, and treatment
making process that addresses
clude obesity/overweight, hyperten- of hypertension (17).
cardiovascular risk, potential
sion, dyslipidemia, smoking, a family
Screening and Diagnosis adverse effects of antihyper-
history of premature coronary disease,
tensive medications, and pa-
chronic kidney disease, and the pres- Recommendations tient preferences. C
ence of albuminuria. Modifiable abnor- 10.1 Blood pressure should be mea- 10.4 For individuals with diabetes
mal risk factors should be treated as sured at every routine clinical and hypertension at higher car-
described in these guidelines. visit. Patients found to have el- diovascular risk (existing athero-
evated blood pressure ($140/90 sclerotic cardiovascular disease
THE RISK CALCULATOR mmHg) should have blood pres- [ASCVD] or 10-year ASCVD risk
The American College of Cardiology/ sure confirmed using multiple $15%), a blood pressure target
American Heart Association ASCVD risk readings, including measure- of ,130/80 mmHg may be ap-
calculator (Risk Estimator Plus) is generally ments on a separate day, to propriate, if it can be safely
a useful tool to estimate 10-year ASCVD diagnose hypertension. B attained. C
risk (available online at tools.acc.org/ 10.2 All hypertensive patients with 10.5 For individuals with diabetes
ASCVD-Risk-Estimator-Plus). The calcu- diabetes should monitor their and hypertension at lower risk
lator includes diabetes as a risk factor, blood pressure at home. B for cardiovascular disease (10-
since diabetes itself confers increased risk year atherosclerotic cardio-
for ASCVD, although it should be acknowl- Blood pressure should be measured at vascular disease risk ,15%),
edged that these risk calculators do not every routine clinical visit by a trained treat to a blood pressure target
account for the duration of diabetes or the individual and should follow the of ,140/90 mmHg. A
presence of diabetes complications, such guidelines established for the general pop- 10.6 In pregnant patients with dia-
as albuminuria. Although some variability ulation: measurement in the seated posi- betes and preexisting hyperten-
in calibration exists in various subgroups, tion, with feet on the floor and arm sion, a blood pressure target
including by sex, race, and diabetes, the supported at heart level, after 5 min of of #135/85 mmHg is suggested
overall risk prediction does not differ in rest. Cuff size should be appropriate for the in the interest of reducing the
those with or without diabetes (11–14), upper-arm circumference. Elevated values risk for accelerated maternal
validating the use of risk calculators in should be confirmed on a separate day. hypertension A and minimizing
people with diabetes. The 10-year risk of a Postural changes in blood pressure and impaired fetal growth. E
first ASCVD event should be assessed to pulse may be evidence of autonomic neu-
better stratify ASCVD risk and help guide ropathy and therefore require adjustment
therapy, as described below. of blood pressure targets. Orthostatic blood Randomized clinical trials have demon-
Recently, risk scores and other car- pressure measurements should be checked strated unequivocally that treatment of
diovascular biomarkers have been devel- on initial visit and as indicated. hypertension to blood pressure ,140/90
oped for risk stratification of secondary Home blood pressure self-monitoring mmHg reduces cardiovascular events
prevention patients (i.e., those who are and 24-h ambulatory blood pressure as well as microvascular complications
already high risk because they have monitoring may provide evidence of (21–27). Therefore, patients with type 1
ASCVD) but are not yet in widespread white coat hypertension, masked hyper- or type 2 diabetes who have hyperten-
use (15,16). With newer, more expensive tension, or other discrepancies between sion should, at a minimum, be treated
lipid-lowering therapies now available, office and “true” blood pressure (17). In to blood pressure targets of ,140/90
use of these risk assessments may help addition to confirming or refuting a di- mmHg. The benefits and risks of inten-
target these new therapies to “higher agnosis of hypertension, home blood sifying antihypertensive therapy to tar-
risk” ASCVD patients in the future. pressure assessment may be useful to get blood pressures lower than ,140/90
monitor antihypertensive treatment. mmHg (e.g., ,130/80 or ,120/80
Studies of individuals without diabetes mmHg) have been evaluated in large
HYPERTENSION/BLOOD PRESSURE found that home measurements may randomized clinical trials and meta-
CONTROL better correlate with ASCVD risk than analyses of clinical trials. Notably, there
Hypertension, defined as a sustained office measurements (18,19). Moreover, is an absence of high-quality data avail-
blood pressure $140/90 mmHg, is com- home blood pressure monitoring may able to guide blood pressure targets in
mon among patients with either type 1 improve patient medication adherence type 1 diabetes.
or type 2 diabetes. Hypertension is a and thus help reduce cardiovascular
major risk factor for both ASCVD and risk (20). Randomized Controlled Trials of Intensive
microvascular complications. Moreover, Versus Standard Blood Pressure Control
numerous studies have shown that anti- Treatment Goals The Action to Control Cardiovascular Risk
hypertensive therapy reduces ASCVD in Diabetes Blood Pressure (ACCORD BP)
Recommendations
events, heart failure, and microvascular trial provides the strongest direct assess-
10.3 For patients with diabetes and
complications. Please refer to the Amer- ment of the benefits and risks of intensive
hypertension, blood pressure
ican Diabetes Association (ADA) position blood pressure control among people
targets should be individual-
statement “Diabetes and Hyperten- with type 2 diabetes (28). In ACCORD
ized through a shared decision-
sion” for a detailed review of the BP, compared with standard bloodcare.diabetesjournals.org Cardiovascular Disease and Risk Management S113
pressure control (target systolic blood relevance of their results to people A number of post hoc analyses have
pressure ,140 mmHg), intensive blood with diabetes is less clear. The Action attempted to explain the apparently
pressure control (target systolic blood in Diabetes and Vascular Disease: Pre- divergent results of ACCORD BP and
pressure ,120 mmHg) did not reduce terax and Diamicron MR Controlled SPRINT. Some investigators have argued
total major atherosclerotic cardiovascu- Evaluation–Blood Pressure (ADVANCE that the divergent results are not due to
lar events but did reduce the risk of BP) trial did not explicitly test blood differences between people with and with-
stroke, at the expense of increased ad- pressure targets (29); the achieved out diabetes but rather are due to differ-
verse events (Table 10.1). The ACCORD blood pressure in the intervention ences in study design or to characteristics
BP results suggest that blood pressure group was higher than that achieved other than diabetes (31–33). Others have
targets more intensive than ,140/90 in the ACCORD BP intensive arm and opined that the divergent results are most
mmHg are not likely to improve car- would be consistent with a target readily explained by the lack of benefit of
diovascular outcomes among most blood pressure of ,140/ 90 mmHg. intensive blood pressure control on cardio-
people with type 2 diabetes but may Notably, ACCORD BP and SPRINT mea- vascular mortality in ACCORD BP, which
be reasonable for patients who may sured blood pressure using automated may be due to differential mechanisms
derive the most benefit and have office blood pressure measurement, underlying cardiovascular disease in type
been educated about added treatment which yields values that are generally 2 diabetes, to chance, or both (34).
burden, side effects, and costs, as dis- lower than typical office blood pres-
cussed below. sure readings by approximately 5–10 Meta-analyses of Trials
Additional studies, such as the Sys- mmHg (30), suggesting that im- To clarify optimal blood pressure targets
tolic Blood Pressure Intervention Trial plementing the ACCORD BP or SPRINT in patients with diabetes, meta-analyses
(SPRINT) and the Hypertension Optimal protocols in an outpatient clinic might have stratified clinical trials by mean
Treatment (HOT) trial, also examined require a systolic blood pressure tar- baseline blood pressure or mean blood
effects of intensive versus standard get higher than ,120 mmHg, such as pressure attained in the intervention (or
control (Table 10.1), though the ,130 mmHg. intensive treatment) arm. Based on these
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 SBP target: SBP target: c No benefit in primary end point: composite
T2D aged 40–79 years ,120 mmHg 130–140 mmHg of nonfatal MI, nonfatal stroke, and CVD
with prior evidence Achieved (mean) Achieved (mean) death
of CVD or multiple SBP/DBP: SBP/DBP: c Stroke risk reduced 41% with intensive
cardiovascular risk 119.3/64.4 mmHg 13.5/70.5 mmHg control, not sustained through follow-up
factors 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 Intervention: a single-pill, Control: placebo c Intervention reduced risk of primary
with T2D aged fixed-dose combination Achieved (mean) composite end point of major
55 years and older of perindopril and SBP/DBP: macrovascular and microvascular events
with prior evidence indapamide 141.6/75.2 mmHg (9%), death from any cause (14%), and
of CVD or multiple Achieved (mean) death from CVD (18%)
cardiovascular risk SBP/DBP: c 6-year observational follow-up found
factors 136/73 mmHg reduction in risk of death in intervention
group attenuated but still significant (174)
HOT (185) 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 more intensive
with diabetes targets
c In the subpopulation with diabetes, an
intensive DBP target was associated with
a significantly reduced risk (51%) of CVD
events
SPRINT (39) 9,361 participants SBP target: SBP target: c Intensive SBP target lowered risk of the
without diabetes ,120 mmHg ,140 mmHg primary composite outcome 25% (MI, ACS,
Achieved (mean): Achieved (mean): stroke, heart failure, and death due to CVD)
121.4 mmHg 136.2 mmHg 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).S114 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
analyses, antihypertensive treatment ap- syncope, falls, acute kidney injury, and recommends use of antihypertensive
pears to be beneficial when mean base- electrolyte abnormalities) should also be therapy to maintain systolic blood pres-
line blood pressure is $140/90 mmHg or taken into account (28,39–41). Patients sure between 110 and 140 mmHg and
mean attained intensive blood pressure with older age, chronic kidney disease, diastolic blood pressure between 80 and
is $130/80 mmHg (17,21,22,24–26). and frailty have been shown to be at 85 mmHg (44).
Among trials with lower baseline or higher risk of adverse effects of intensive During pregnancy, treatment with ACE
attained blood pressure, antihyperten- blood pressure control (41). In addition, inhibitors, angiotensin receptor blockers
sive treatment reduced the risk of stroke, patients with orthostatic hypotension, (ARBs), and spironolactone are contra-
retinopathy, and albuminuria, but effects substantial comorbidity, functional lim- indicated as they may cause fetal dam-
on other ASCVD outcomes and heart itations, or polypharmacy may be at high age. Antihypertensive drugs known to be
failure were not evident. Taken together, risk of adverse effects, and some patients effective and safe in pregnancy include
these meta-analyses consistently show may prefer higher blood pressure targets methyldopa, labetalol, and long-acting
that treating patients with baseline blood to enhance quality of life. Patients with nifedipine, while hydralzine may be con-
pressure $140 mmHg to targets ,140 low absolute cardiovascular risk (10-year sidered in the acute management of
mmHg is beneficial, while more-intensive ASCVD risk ,15%) or with a history of hypertension in pregnancy or severe
targets may offer additional (though adverse effects of intensive blood pres- preeclampsia (45). Diuretics are not rec-
probably less robust) benefits. sure control or at high risk of such ommended for blood pressure control in
adverse effects should have a higher pregnancy but may be used during late-
Individualization of Treatment Targets blood pressure target. In such patients, stage pregnancy if needed for volume
Patients and clinicians should engage in a blood pressure target of ,140/90 control (45,46). The American College of
a shared decision-making process to de- mmHg is recommended, if it can be safely Obstetricians and Gynecologists also rec-
termine individual blood pressure tar- attained. ommends that postpartum patients with
gets (17). This approach acknowledges gestational hypertension, preeclampsia,
that the benefits and risks of intensive Pregnancy and Antihypertensive and superimposed preeclampsia have
blood pressure targets are uncertain and Medications their blood pressures observed for
may vary across patients and is consis- There are few randomized controlled 72 h in the hospital and for 7–10 days
tent with a patient-focused approach to trials of antihypertensive therapy in preg- postpartum. Long-term follow-up is rec-
care that values patient priorities and nant women with diabetes. A 2014 ommended for these women as they
provider judgment (35). Secondary anal- Cochrane systematic review of antihy- have increased lifetime cardiovascular
yses of ACCORD BP and SPRINT suggest pertensive therapy for mild to moder- risk (47). See Section 14 “Management
that clinical factors can help determine ate chronic hypertension that included of Diabetes in Pregnancy” (https://doi
individuals more likely to benefit and 49 trials and over 4,700 women did not .org/10.2337/dc20-S014) for additional
less likely to be harmed by intensive find any conclusive evidence for or information.
blood pressure control (36). against blood pressure treatment to
Absolute benefit from blood pres- reduce the risk of preeclampsia for Treatment Strategies
sure reduction correlated with absolute the mother or effects on perinatal out- Lifestyle Intervention
baseline cardiovascular risk in SPRINT comes such as preterm birth, small-for-
Recommendation
and in earlier clinical trials conducted gestational-age infants, or fetal death
at higher baseline blood pressure levels (42). The more recent Control of Hyper- 10.7 For patients with blood pressure
(11,37). Extrapolation of these studies tension in Pregnancy Study (CHIPS) (43) .120/80 mmHg, lifestyle inter-
suggests that patients with diabetes enrolled mostly women with chronic vention consists of weight loss if
may also be more likely to benefit hypertension. In CHIPS, targeting a di- overweight or obese, a Dietary
from intensive blood pressure control astolic blood pressure of 85 mmHg dur- Approaches to Stop Hyperten-
when they have high absolute cardio- ing pregnancy was associated with sion (DASH)-style eating pattern
vascular risk. Therefore, it may be rea- reduced likelihood of developing accel- including reducing sodium and
sonable to target blood pressure erated maternal hypertension and no increasing potassium intake,
,130/80 mmHg among patients with demonstrable adverse outcome for in- moderation of alcohol intake,
diabetes and either clinically diag- fants compared with targeting a higher and increased physical activity. A
nosed cardiovascular disease (particu- diastolic blood pressure. The mean sys-
larly stroke, which was significantly tolic blood pressure achieved in the Lifestyle management is an important
reduced in ACCORD BP) or 10-year more intensively treated group was component of hypertension treatment
ASCVD risk $15%, if it can be attained 133.1 6 0.5 mmHg, and the mean di- because it lowers blood pressure, enhan-
safely. This approach is consistent with astolic blood pressure achieved in that ces the effectiveness of some antihyper-
guidelines from the American College of group was 85.3 6 0.3 mmHg. Therefore, tensive medications, promotes other
Cardiology/American Heart Association, current evidence supports controlling aspects of metabolic and vascular health,
which advocate a blood pressure target blood pressure to these levels, with a and generally leads to few adverse effects.
,130/80 mmHg for all patients, with or target of #135/85 mmHg. A similar Lifestyle therapy consists of reducing ex-
without diabetes (38). approach is supported by the Interna- cess body weight through caloric restric-
Potential adverse effects of antihyper- tional Society for the Study of Hyperten- tion, restricting sodium intake (,2,300
tensive therapy (e.g., hypotension, sion in Pregnancy, which specifically mg/day), increasing consumption of fruitscare.diabetesjournals.org Cardiovascular Disease and Risk Management S115
and vegetables (8–10 servings per day) the combination of an ACE inhibitor or
patients with diabetes and uri-
and low-fat dairy products (2–3 servings ARB and a direct renin inhibitor, is not
nary albumin-to-creatinine ra-
per day), avoiding excessive alcohol con- recommended given the lack of added
tio $300 mg/g creatinine A or
sumption (no more than 2 servings per ASCVD benefit and increased rate of
30–299 mg/g creatinine. B If
day in men and no more than 1 serving per adverse eventsdnamely, hyperkalemia,
one class is not tolerated, the
day in women) (48), and increasing ac- syncope, and acute kidney injury (AKI)
other should be substituted. B
tivity levels (49). (60–62). Titration of and/or addition of
10.13 For patients treated with an ACE
These lifestyle interventions are rea- further blood pressure medications
inhibitor, angiotensin receptor
sonable for individuals with diabetes and should be made in a timely fashion to
blocker, or diuretic, serum cre-
mildly elevated blood pressure (systolic overcome clinical inertia in achieving
atinine/estimated glomerular fil-
.120 mmHg or diastolic .80 mmHg) blood pressure targets.
tration rate and serum potassium
and should be initiated along with phar- Bedtime Dosing. Growing evidence sug-
levels should be monitored at
macologic therapy when hypertension is gests that there is an association be-
least annually. B
diagnosed (Fig. 10.1) (49). A lifestyle tween the absence of nocturnal blood
therapy plan should be developed in Initial Number of Antihypertensive pressure dipping and the incidence of
collaboration with the patient and dis- Medications. Initial treatment for people ASCVD. A meta-analysis of randomized
cussed as part of diabetes management. with diabetes depends on the severity clinical trials found a small benefit of
of hypertension (Fig. 10.1). Those with evening versus morning dosing of anti-
Pharmacologic Interventions blood pressure between 140/90 mmHg hypertensive medications with regard to
and 159/99 mmHg may begin with a blood pressure control but had no data
Recommendations
single drug. For patients with blood on clinical effects (63). In two subgroup
10.8 Patients with confirmed office-
based blood pressure $140/ pressure $160/100 mmHg, initial phar- analyses of a single subsequent random-
macologic treatment with two antihy- ized controlled trial, moving at least one
90 mmHg should, in addition
pertensive medications is recommended antihypertensive medication to bedtime
to lifestyle therapy, have prompt
in order to more effectively achieve significantly reduced cardiovascular events,
initiation and timely titration of
adequate blood pressure control (50–52). but results were based on a small num-
pharmacologic therapy to achieve
Single-pill antihypertensive combinations ber of events (64).
blood pressure goals. A Hyperkalemia and Acute Kidney Injury.
10.9 Patients with confirmed office- may improve medication adherence in
some patients (53). Treatment with ACE inhibitors or ARBs
based blood pressure $160/
Classes of Antihypertensive Medications. can cause AKI and hyperkalemia, while
100 mmHg should, in addition
Initial treatment for hypertension should diuretics can cause AKI and either hypo-
to lifestyle therapy, have prompt
include any of the drug classes demon- kalemia or hyperkalemia (depending on
initiation and timely titration of mechanism of action) (65,66). Detection
strated to reduce cardiovascular events
two drugs or a single-pill combi- and management of these abnormalities
in patients with diabetes: ACE inhibitors
nation of drugs demonstrated to is important because AKI and hyperkale-
(54,55), ARBs (54,55), thiazide-like di-
reduce cardiovascular events in mia each increase the risks of cardiovas-
uretics (56), or dihydropyridine calcium
patients with diabetes. A cular events and death (67). Therefore,
channel blockers (57). For patients
10.10 Treatment for hypertension serum creatinine and potassium should
with albuminuria (urine albumin-to-
should include drug classes
creatinine ratio [UACR] $30 mg/g), initial be monitored during treatment with an
demonstrated to reduce cardio-
treatment should include an ACE inhib- ACE inhibitor, ARB, or diuretic, particularly
vascular events in patients with
itor or ARB in order to reduce the risk among patients with reduced glomerular
diabetes (ACE inhibitors, angioten-
of progressive kidney disease (17) (Fig. filtration who are at increased risk of
sin receptor blockers, thiazide-like
10.1). In the absence of albuminuria, hyperkalemia and AKI (65,66,68).
diuretics, or dihydropyridine cal-
risk of progressive kidney disease is
cium channel blockers). A
low, and ACE inhibitors and ARBs have Resistant Hypertension
10.11 Multiple-drug therapy is gener-
not been found to afford superior Recommendation
ally required to achieve blood
cardioprotection when compared with 10.14 Patients with hypertension who
pressure targets. However, com-
thiazide-like diuretics or dihydropyridine are not meeting blood pres-
binations of ACE inhibitors and
calcium channel blockers (58). b-Blockers sure targets on three classes
angiotensin receptor blockers
may be used for the treatment of prior of antihypertensive medica-
and combinations of ACE inhib-
MI, active angina, or heart failure but tions (including a diuretic)
itors or angiotensin receptor
have not been shown to reduce mortality should be considered for min-
blockers with direct renin inhib-
as blood pressure–lowering agents in the eralocorticoid receptor antag-
itors should not be used. A
absence of these conditions (23,59). onist therapy. B
10.12 An ACE inhibitor or angiotensin
Multiple-Drug Therapy. Multiple-drug
receptor blocker, at the maxi-
therapy is often required to achieve Resistant hypertension is defined as
mum tolerated dose indicated
blood pressure targets (Fig. 10.1), par- blood pressure $140/90 mmHg despite
for blood pressure treatment,
ticularly in the setting of diabetic kidney a therapeutic strategy that includes ap-
is the recommended first-line
disease. However, the use of both ACE propriate lifestyle management plus a
treatment for hypertension in
inhibitors and ARBs in combination, or diuretic and two other antihypertensiveS116 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
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 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 from de Boer et al. (17).
drugs belonging to different classes at medication nonadherence, white coat should be identified and addressed (Fig.
adequate doses. Prior to diagnosing re- hypertension, and secondary hyperten- 10.1). Mineralocorticoid receptor antag-
sistant hypertension, a number of other sion. In general, barriers to medication onists are effective for management of
conditions should be excluded, including adherence (such as cost and side effects) resistant hypertension in patients withcare.diabetesjournals.org Cardiovascular Disease and Risk Management S117
type 2 diabetes when added to existing increasing plant stanols/sterols, n-3 fatty effects occur. There is evidence for ben-
treatment with an ACE inhibitor or ARB, acids, and viscous fiber (such as in oats, efit from even extremely low, less than
thiazide-like diuretic, and dihydropyri- legumes, and citrus) intake (76). Glyce- daily statin doses (78).
dine calcium channel blocker (69). mic control may also beneficially modify
Mineralocorticoid receptor antagonists plasma lipid levels, particularly in pa- STATIN TREATMENT
also reduce albuminuria and have addi- tients with very high triglycerides and Primary Prevention
tional cardiovascular benefits (70–73). poor glycemic control. See Section 5 Recommendations
However, adding a mineralocorticoid re- “Facilitating Behavior Change and Well- 10.19 For patients with diabetes aged
ceptor antagonist to a regimen including being to Improve Health Outcomes” 40–75 years without atheroscle-
an ACE inhibitor or ARB may increase the (https://doi.org/10.2337/dc20-S010) for ad- rotic cardiovascular disease, use
risk for hyperkalemia, emphasizing the ditional nutrition information. moderate-intensity statin ther-
importance of regular monitoring for apy in addition to lifestyle ther-
Ongoing Therapy and Monitoring
serum creatinine and potassium in these apy. A
With Lipid Panel
patients, and long-term outcome studies 10.20 For patients with diabetes
are needed to better evaluate the role of Recommendations aged 20–39 years with addi-
mineralocorticoid receptor antagonists 10.17 In adults not taking statins or tional atherosclerotic cardiovas-
in blood pressure management. other lipid-lowering therapy, it cular disease risk factors, it may be
is reasonable to obtain a lipid reasonable to initiate statin ther-
LIPID MANAGEMENT profile at the time of diabetes apy in addition to lifestyle
Lifestyle Intervention diagnosis, at an initial medical therapy. C
evaluation, and every 5 years 10.21 In patients with diabetes at
Recommendations
thereafter if under the age of higher risk, especially those
10.15 Lifestyle modification focusing
40 years, or more frequently if with multiple atherosclerotic
on weight loss (if indicated);
indicated. E cardiovascular disease risk fac-
application of a Mediterranean
10.18 Obtain a lipid profile at initia- tors or aged 50–70 years, it is
style or Dietary Approaches
tion of statins or other lipid- reasonable to use high-inten-
to Stop Hypertension (DASH)
lowering therapy, 4–12 weeks sity statin therapy. B
eating pattern; reduction of
after initiation or a change 10.22 In adults with diabetes and
saturated fat and trans fat;
in dose, and annually thereaf- 10-year atherosclerotic cardio-
increase of dietary n-3 fatty
ter as it may help to monitor vascular disease risk of 20% or
acids, viscous fiber, and plant
the response to therapy and in- higher, it may be reasonable to
stanols/sterols intake; and in-
form medication adherence. E add ezetimibe to maximally
creased physical activity should
tolerated statin therapy to re-
be recommended to improve In adults with diabetes, it is reasonable duce LDL cholesterol levels by
the lipid profile and reduce the to obtain a lipid profile (total cholesterol, 50% or more. C
risk of developing atheroscle- LDL cholesterol, HDL cholesterol, and tri-
rotic cardiovascular disease in glycerides) at the time of diagnosis, at the
patients with diabetes. A initial medical evaluation, and at least every Secondary Prevention
10.16 Intensify lifestyle therapy and 5 years thereafter in patients under the age
optimize glycemic control for Recommendations
of 40 years. In younger patients with longer
patients with elevated triglyc- 10.23 For patients of all ages with
duration of disease (such as those with
eride levels ($150 mg/dL [1.7 diabetes and atherosclerotic
youth-onset type 1 diabetes), more fre-
mmol/L]) and/or low HDL cho- cardiovascular disease, high-in-
quent lipid profiles may be reasonable. A
lesterol (,40 mg/dL [1.0 tensity statin therapy should be
lipid panel should also be obtained imme-
mmol/L] for men, ,50 mg/dL diately before initiating statin therapy.
added to lifestyle therapy. A
[1.3 mmol/L] for women). C 10.24 For patients with diabetes and
Once a patient is taking a statin, LDL
atherosclerotic cardiovascular
cholesterol levels should be assessed 4–
disease considered very high
Lifestyle intervention, including weight 12 weeks after initiation of statin therapy,
risk using specific criteria, if
loss (74), increased physical activity, and after any change in dose, and on an in-
LDL cholesterol is $70 mg/dL
medical nutrition therapy, allows some dividual basis (e.g., to monitor for medica-
on maximally tolerated statin
patients to reduce ASCVD risk factors. tion adherence and efficacy). If LDL
dose, consider adding additional
Nutrition intervention should be tailored cholesterol levels are not responding in
LDL-lowering therapy (such as
according to each patient’s age, diabetes spite of medication adherence, clinical
ezetimibe or PCSK9 inhibitor).
type, pharmacologic treatment, lipid judgment is recommended to determine
A Ezetimibe may be preferred
levels, and medical conditions. the need for and timing of lipid panels. In
due to lower cost.
Recommendations should focus on individual patients, the highly variable LDL
10.25 For patients who do not toler-
application of a Mediterranean style cholesterol–lowering response seen with
ate the intended intensity, the
diet (75) or Dietary Approaches to Stop statins is poorly understood (77). Clini-
maximally tolerated statin dose
Hypertension (DASH) eating pattern, re- cians should attempt to find a dose or
should be used. E
ducing saturated and trans fat intake and alternative statin that is tolerable if sideS118 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
the only dose of statin that a patient can it may also be reasonable to add ezeti-
10.26 In adults with diabetes aged
tolerate. For patients who do not tolerate mibe to maximally tolerated statin ther-
.75 years already on statin
the intended intensity of statin, the apy if needed to reduce LDL cholesterol
therapy, it is reasonable to
maximally tolerated statin dose should levels by 50% or more (12). The evidence
continue statin treatment. B
be used. is lower for patients aged .75 years;
10.27 In adults with diabetes aged .75
As in those without diabetes, absolute relatively few older patients with diabe-
years, it may be reasonable to
reductions in ASCVD outcomes (CHD tes have been enrolled in primary pre-
initiate statin therapy after dis-
death and nonfatal MI) are greatest in vention trials. However, heterogeneity
cussion of potential benefits and
people with high baseline ASCVD risk by age has not been seen in the relative
risks. C
(known ASCVD and/or very high LDL benefit of lipid-lowering therapy in tri-
10.28 Statin therapy is contraindi-
cholesterol levels), but the overall benefits als that included older participants
cated in pregnancy. B
of statin therapy in people with diabetes (80,87,88), and because older age con-
Initiating Statin Therapy Based on Risk at moderate or even low risk for ASCVD fers higher risk, the absolute benefits are
Patients with type 2 diabetes have an are convincing (89,90). The relative ben- actually greater (80,92). Moderate-in-
increased prevalence of lipid abnormalities, efit of lipid-lowering therapy has been tensity statin therapy is recommended
contributing to their high risk of ASCVD. uniform across most subgroups tested in patients with diabetes who are 75
Multiple clinical trials have demonstrated (80,88), including subgroups that varied years or older. However, the risk-benefit
the beneficial effects of statin therapy on with respect to age and other risk factors. profile should be routinely evaluated in
this population, with downward titra-
ASCVD outcomes in subjects with and Primary Prevention (Patients Without
ASCVD) tion of dose performed as needed. See
without CHD (79,80). Subgroup analyses
For primary prevention, moderate-dose sta- Section 12 “Older Adults” (https://doi
of patients with diabetes in larger trials
tin therapy is recommended for those .org/10.2337/dc20-S012) for more de-
(81–85) and trials in patients with diabetes
40 years and older (82,89,90), though tails on clinical considerations for this
(86,87) showed significant primary and
high-intensity therapy may be consid- population.
secondary prevention of ASCVD events
Agecare.diabetesjournals.org Cardiovascular Disease and Risk Management S119
American Diabetes Association” (93) Guidelines (12) for recommendations for feature who were receiving their maxi-
for additional discussion. primary and secondary prevention and for mally tolerated statin therapy (two-
statin and combination treatmentin adults thirds were on high-intensity statin)
Secondary Prevention (Patients With with diabetes (97). butwhostill had LDLcholesterol $70mg/dL
ASCVD) or non-HDL cholesterol $100 mg/dL (95).
Because risk is high in patients with Combination Therapy for LDL Patients were randomized to receive sub-
ASCVD, intensive therapy is indicated Cholesterol Lowering cutaneous injections of evolocumab (either
and has been shown to be of benefit Statins and Ezetimibe 140 mg every 2 weeks or 420 mg every
in multiple large randomized cardiovas- The IMProved Reduction of Outcomes: month based on patient preference)
cular outcomes trials (88,92,94,95). High- Vytorin Efficacy International Trial versus placebo. Evolocumab reduced
intensity statin therapy is recommended (IMPROVE-IT) was a randomized controlled LDL cholesterol by 59% from a me-
for all patients with diabetes and ASCVD. trial in 18,144 patients comparing the dian of 92 to 30 mg/dL in the treatment
This recommendation is based on the addition of ezetimibe to simvastatin arm.
Cholesterol Treatment Trialists’ Collab- therapy versus simvastatin alone. Indi- During the median follow-up of 2.2
oration involving 26 statin trials, of viduals were $50 years of age, had years, the composite outcome of cardio-
which 5 compared high-intensity versus experienced a recent acute coronary vascular death, MI, stroke, hospitaliza-
moderate-intensity statins. Together, syndrome (ACS), and were treated for tion for angina, or revascularization
they found reductions in nonfatal car- an average of 6 years. Overall, the ad- occurred in 11.3% vs. 9.8% of the placebo
diovascular events with more intensive dition of ezetimibe led to a 6.4% relative and evolocumab groups, respectively,
therapy, in patients with and without benefit and a 2% absolute reduction in representing a 15% relative risk reduc-
diabetes (80,84,94). major adverse cardiovascular events, tion (P , 0.001). The combined end
Over the past few years, there have with the degree of benefit being directly point of cardiovascular death, MI, or
been multiple large randomized trials proportional to the change in LDL cho- stroke was reduced by 20%, from
investigating the benefits of adding lesterol, which was 70 mg/dL in the statin 7.4% to 5.9% (P , 0.001). Importantly,
nonstatin agents to statin therapy, in- group on average and 54 mg/dL in the similar benefits were seen in a prespe-
cluding those that evaluated further combination group (92). In those with cified subgroup of patients with diabe-
lowering of LDL cholesterol with eze- diabetes (27% of participants), the com- tes, comprising 11,031 patients (40% of
timibe (92,96) and proprotein conver- bination of moderate-intensity simvas- the trial) (100).
tase subtilisin/kexin type 9 (PCSK9) tatin (40 mg) and ezetimibe (10 mg)
inhibitors (95). Each trial found a sig- showed a significant reduction of major Treatment of Other Lipoprotein
nificant benefit in the reduction of adverse cardiovascular events with an Fractions or Targets
ASCVD events that was directly related absolute risk reduction of 5% (40% vs. Recommendations
to the degree of further LDL cholesterol 45% cumulative incidence at 7 years) and 10.29 For patients with fasting tri-
lowering. These large trials included a a relative risk reduction of 14% (hazard glyceride levels $500 mg/dL,
significant number of participants with ratio [HR] 0.86 [95% CI 0.78–0.94]) over evaluate for secondary causes
diabetes. For very high-risk patients moderate-intensity simvastatin (40 mg) of hypertriglyceridemia and con-
with ASCVD who are on high-intensity alone (96). sider medical therapy to reduce
(and maximally tolerated) statin the risk of pancreatitis. C
therapy and have an LDL chole- Statins and PCSK9 Inhibitors 10.30 In adults with moderate hyper-
sterol $70 mg/dL, the addition of Placebo-controlled trials evaluating the triglyceridemia (fasting or non-
nonstatin LDL-lowering therapy can addition of the PCSK9 inhibitors evolo- fasting triglycerides 175–499
be considered following a clinician- cumab and alirocumab to maximally mg/dL), clinicians should ad-
patient discussion about the net ben- tolerated doses of statin therapy in dress and treat lifestyle factors
efit, safety, and cost. Definition of very participants who were at high risk for (obesity and metabolic syn-
high-risk patients with ASCVD includes ASCVD demonstrated an average reduc- drome), secondary factors
the use of specific criteria (major tion in LDL cholesterol ranging from (diabetes, chronic liver or kid-
ASCVD events and high-risk condi- 36% to 59%. These agents have been ney disease and/or nephrotic
tions); refer to the 2018 American Col- approved as adjunctive therapy for syndrome, hypothyroidism),
lege of Cardiology/American Heart patients with ASCVD or familial hyper- and medications that raise tri-
Association multisociety guideline on cholesterolemia who are receiving max- glycerides. C
the management of blood cholesterol imally tolerated statin therapy but
10.31 In patients with atherosclerotic
for further details regarding this def- require additional lowering of LDL cho-
cardiovascular disease or other
inition of risk (12). lesterol (98,99).
cardiovascular risk factors on a
Please see 2018 AHA/ACC/AACVPR/ The effects of PCSK9 inhibition on
statin with controlled LDL cho-
AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ ASCVD outcomes was investigated in
lesterol but elevated trigly-
NLA/PCNA Guideline on the Manage- the Further Cardiovascular Outcomes
cerides (135–499 mg/dL), the
ment of Blood Cholesterol: Executive Research With PCSK9 Inhibition in Sub-
addition of icosapent ethyl can
Summary: A Report of the American jects With Elevated Risk (FOURIER)
be considered to reduce cardio-
College of Cardiology/American Heart trial, which enrolled 27,564 patients with
vascular risk. A
Association Task Force on Clinical Practice prior ASCVD and an additional high-riskS120 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020
Hypertriglyceridemia should be ad- that for statin therapy (103). In a large [1.3 mmol/L]), and triglyceride levels of
dressed with dietary and lifestyle trial in patients with diabetes, fenofi- 150–400 mg/dL (1.7–4.5 mmol/L) to
changes including weight loss and ab- brate failed to reduce overall cardiovas- statin therapy plus extended-release ni-
stinence from alcohol (101). Severe cular outcomes (104). acin or placebo. The trial was halted early
hypertriglyceridemia (fasting triglycer- due to lack of efficacy on the primary
ides $500 mg/dL and especially .1,000 Other Combination Therapy ASCVD outcome (first event of the com-
mg/dL) may warrant pharmacologic ther- posite of death from CHD, nonfatal MI,
Recommendations
apy (fibric acid derivatives and/or fish ischemic stroke, hospitalization for an
10.32 Statin plus fibrate combination
oil) to reduce the risk of acute pancre- ACS, or symptom-driven coronary or
therapy has not been shown to
atitis. Moderate- or high-intensity statin cerebral revascularization) and a possible
improve atherosclerotic car-
therapy should also be used as indicated increase in ischemic stroke in those on
diovascular disease outcomes
to reduce risk of cardiovascular events combination therapy (108).
and is generally not recom-
(see STATIN TREATMENT ). In patients with The much larger Heart Protection
mended. A
moderate hypertriglyceridemia, lifestyle Study 2–Treatment of HDL to Reduce
10.33 Statin plus niacin combination
interventions, treatment of secondary the Incidence of Vascular Events (HPS2-
therapy has not been shown to
factors, and avoidance of medications THRIVE) trial also failed to show a benefit
provide additional cardiovas-
that might raise triglycerides are recom- of adding niacin to background statin
cular benefit above statin ther-
mended. therapy (109). A total of 25,673 patients
apy alone, may increase the
The Reduction of Cardiovascular with prior vascular disease were random-
risk of stroke with additional
Events with Icosapent Ethyl–Intervention ized to receive 2 g of extended-release
side effects, and is generally
Trial (REDUCE-IT) enrolled 8,179 adults niacin and 40 mg of laropiprant (an
not recommended. A
receiving statin therapy with mod- antagonist of the prostaglandin D2 re-
erately elevated triglycerides (135– ceptor DP1 that has been shown to
499 mg/dL, median baseline of 216 Statin and Fibrate Combination Therapy improve adherence to niacin therapy)
mg/dL) who had either established car- Combination therapy (statin and fibrate) versus a matching placebo daily and
diovascular disease (secondary preven- is associated with an increased risk for followed for a median follow-up period
tion cohort) or diabetes plus at least one abnormal transaminase levels, myositis, of 3.9 years. There was no significant
other cardiovascular risk factor (primary and rhabdomyolysis. The risk of rhabdo- difference in the rate of coronary death,
prevention cohort). Patients were ran- myolysis is more common with higher MI, stroke, or coronary revascularization
domized to icosapent ethyl 4 g/day (2 g doses of statins and renal insufficiency with the addition of niacin–laropiprant
twice daily with food) versus placebo. and appears to be higher when statins versus placebo (13.2% vs. 13.7%; rate
The trial met its primary end point, are combined with gemfibrozil (com- ratio 0.96; P 5 0.29). Niacin–laropiprant
demonstrating a 25% relative risk reduc- pared with fenofibrate) (105). was associated with an increased inci-
tion (P , 0.001) for the primary end point In the ACCORD study, in patients dence of new-onset diabetes (absolute
composite of cardiovascular death, non- with type 2 diabetes who were at high excess, 1.3 percentage points; P , 0.001)
fatal myocardial infarction, nonfatal risk for ASCVD, the combination of fe- and disturbances in diabetes control
stroke, coronary revascularization, or nofibrate and simvastatin did not reduce among those with diabetes. In addition,
unstable angina. The composite of car- the rate of fatal cardiovascular events, there was an increase in serious adverse
diovascular death, nonfatal myocardial nonfatal MI, or nonfatal stroke as com- events associated with the gastrointes-
infarction, or nonfatal stroke was re- pared with simvastatin alone. Prespeci- tinal system, musculoskeletal system,
duced by 26% (P , 0.001). Additional fied subgroup analyses suggested skin, and, unexpectedly, infection and
ischemic end points were significantly heterogeneity in treatment effects bleeding.
lower in the icosapent ethyl group than in with possible benefit for men with Therefore, combination therapy with
the placebo group, including cardiovas- both a triglyceride level $204 mg/dL a statin and niacin is not recommended
cular death, which was reduced by 20% (2.3 mmol/L) and an HDL cholesterol given the lack of efficacy on major
(P 5 0.03). The proportions of patients level #34 mg/dL (0.9 mmol/L) (106). ASCVD outcomes and increased side
experiencing adverse events and serious A prospective trial of a newer fibrate effects.
adverse events were similar between the in this specific population of patients is
active and placebo treatment groups. It ongoing (107). Diabetes Risk With Statin Use
should be noted that data are lacking Statin and Niacin Combination Therapy Several studies have reported a modestly
with other n-3 fatty acids, and results of The Atherothrombosis Intervention in increased risk of incident diabetes with
the REDUCE-IT trial should not be ex- Metabolic Syndrome With Low HDL/ statin use (110,111), which may be lim-
trapolated to other products (102). High Triglycerides: Impact on Global ited to those with diabetes risk factors.
Low levels of HDL cholesterol, often Health Outcomes (AIM-HIGH) trial ran- An analysis of one of the initial studies
associated with elevated triglyceride lev- domized over 3,000 patients (about suggested that although statin use was
els, are the most prevalent pattern of one-third with diabetes) with established associated with diabetes risk, the cardio-
dyslipidemia in individuals with type 2 ASCVD, low LDL cholesterol levels vascular event rate reduction with sta-
diabetes. However, the evidence for the (,180 mg/dL [4.7 mmol/L]), low HDL tins far outweighed the risk of incident
use of drugs that target these lipid frac- cholesterol levels (men ,40 mg/dL diabetes even for patients at highest
tions is substantially less robust than [1.0 mmol/L] and women ,50 mg/dL risk for diabetes (112). The absolutecare.diabetesjournals.org Cardiovascular Disease and Risk Management S121
risk increase was small (over 5 years of outcome was major bleeding (i.e., in-
clopidogrel (75 mg/day) should
follow-up, 1.2% of participants on placebo tracranial hemorrhage, sight-threatening
be used. B
developed diabetes and 1.5% on rosuvas- bleeding in the eye, gastrointestinal bleed-
10.36 Dual antiplatelet therapy (with
tatin developed diabetes) (112). A meta- ing, or other serious bleeding). During a
low-dose aspirin and a P2Y12
analysis of 13 randomized statin trials with mean follow-up of 7.4 years, there was a
inhibitor) is reasonable for a
91,140 participants showed an odds ratio of significant 12% reduction in the primary
year after an acute coronary
1.09 for a new diagnosis of diabetes, so that efficacy end point (8.5% vs. 9.6%; P 5
syndrome A and may have
(on average) treatment of 255 patients with 0.01). In contrast, major bleeding was
benefits beyond this period. B
statins for 4 years resulted in one additional significantly increased from 3.2% to
10.37 Aspirin therapy (75–162 mg/day)
case of diabetes while simultaneously pre- 4.1% in the aspirin group (rate ratio
may be considered as a pri-
venting 5.4 vascular events among those 1.29; P 5 0.003), with most of the excess
mary prevention strategy in
255 patients (111). being gastrointestinal bleeding and other
those with diabetes who are
extracranial bleeding. There were no sig-
at increased cardiovascular
Lipid-Lowering Agents and Cognitive nificant differences by sex, weight, or
risk, after a comprehensive dis-
Function duration of diabetes or other baseline
cussion with the patient on the
Although concerns regarding a potential factors including ASCVD risk score.
benefits versus the comparable
adverse impact of lipid-lowering agents on Two other large randomized trials of
increased risk of bleeding. A
cognitive function have been raised, sev- aspirin for primary prevention, in pa-
eral lines of evidence point against this tients without diabetes (ARRIVE [Aspirin
association, as detailed in a 2018 European Risk Reduction to Reduce Risk of Initial Vascular Events])
Atherosclerosis Society Consensus Panel Aspirin has been shown to be effective in (126) and in the elderly (ASPREE [Aspirin
statement (113). First, there are three large reducing cardiovascular morbidity and in Reducing Events in the Elderly]) (127),
randomized trials of statin versus placebo mortality in high-risk patients with pre- which included 11% with diabetes, found
where specific cognitive tests were per- vious MI or stroke (secondary preven- no benefit of aspirin on the primary efficacy
formed, and no differences were seen tion) and is strongly recommended. In end point and an increased risk of bleeding.
between statin and placebo (114–117). primary prevention, however, among In ARRIVE, with 12,546 patients over a pe-
In addition, no change in cognitive function patients with no previous cardiovascular riod of 60 months follow-up, the primary
has been reported in studies with the events, its net benefit is more contro- end point occurred in 4.29% vs. 4.48% of
addition of ezetimibe (92) or PCSK9 inhib- versial (120,121). patients in the aspirin versus placebo
itors (95,118) to statin therapy, including Previous randomized controlled trials groups (HR 0.96; 95% CI 0.81–1.13; P 5
among patients treated to very low LDL of aspirin specifically in patients with 0.60). Gastrointestinal bleeding events
cholesterol levels. In addition, the most diabetes failed to consistently show a (characterized as mild) occurred in 0.97%
recent systematic review of the U.S. Food significant reduction in overall ASCVD of patients in the aspirin group vs. 0.46% in
and Drug Administration’s (FDA’s) post- end points, raising questions about the the placebo group (HR 2.11; 95% CI 1.36–
marketing surveillance databases, ran- efficacy of aspirin for primary preven- 3.28; P 5 0.0007). In ASPREE, including
domized controlled trials, and cohort, tion in people with diabetes, although 19,114 persons, for the rate of cardiovas-
case-control, and cross-sectional studies some sex differences were suggested cular disease (fatal CHD, MI, stroke, or
evaluating cognition in patients receiving (122–124). hospitalization for heart failure) after a
statins found that published data do not The Antithrombotic Trialists’ Collabo- median of 4.7 years of follow-up, the rates
reveal an adverse effect of statins on ration published an individual patient– per 1,000 person-years were 10.7 vs. 11.3
cognition (119). Therefore, a concern level meta-analysis (120) of the six large events in aspirin vs. placebo groups (HR
that statins or other lipid-lowering agents trials of aspirin for primary prevention 0.95; 95% CI 0.83–1.08). The rate of major
might cause cognitive dysfunction or in the general population. These trials hemorrhage per 1,000 person-years was
dementia is not currently supported collectively enrolled over 95,000 partic- 8.6 events vs. 6.2 events, respectively (HR
by evidence and should not deter their ipants, including almost 4,000 with di- 1.38; 95% CI 1.18–1.62; P , 0.001).
use in individuals with diabetes at high abetes. Overall, they found that aspirin Thus, aspirin appears to have a modest
risk for ASCVD (119). reduced the risk of serious vascular effect on ischemic vascular events, with
events by 12% (relative risk 0.88 [95% the absolute decrease in events depend-
ANTIPLATELET AGENTS CI 0.82–0.94]). The largest reduction was ing on the underlying ASCVD risk. The
for nonfatal MI, with little effect on CHD main adverse effect is an increased risk
Recommendations
death (relative risk 0.95 [95% CI 0.78– of gastrointestinal bleeding. The excess
10.34 Use aspirin therapy (75–162
1.15]) or total stroke.
mg/day) as a secondary pre- risk may be as high as 5 per 1,000 per
Most recently, the ASCEND (A Study of
vention strategy in those with year in real-world settings. However, for
Cardiovascular Events iN Diabetes) trial
diabetes and a history of ath- adults with ASCVD risk .1% per year, the
randomized 15,480 patients with diabe-
erosclerotic cardiovascular number of ASCVD events prevented will
tes but no evident cardiovascular disease
disease. A be similar to the number of episodes
to aspirin 100 mg daily or placebo (125).
10.35 For patients with atheroscle- of bleeding induced, although these com-
The primary efficacy end point was vas-
rotic cardiovascular disease and
cular death, MI, or stroke or transient plications do not have equal effects on
documented aspirin allergy,
ischemic attack. The primary safety long-term health (128).You can also read
