Standards of Medical Care in Diabetes - 2022: 10. Cardiovascular Disease and Risk Management

S144 Diabetes Care Volume 45, Supplement 1, January 2022
10. Cardiovascular Disease and American Diabetes Association

Professional Practice Committee*
Risk Management: Standards of
Medical Care in Diabetes—2022
Diabetes Care 2022;45(Suppl. 1):S144–S174 | https://doi.org/10.2337/dc22-S010
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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 pro-
vide the components of diabetes care, general treatment goals and guidelines, and
tools to evaluate quality of care. Members of the ADA Professional Practice Commit-
tee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are
responsible for updating the Standards of Care annually, or more frequently as war-
ranted. 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/dc22-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 14, “Children and Adolescents” (https://doi.org/
10.2337/dc22-S014).
Atherosclerotic cardiovascular disease (ASCVD)—defined as coronary heart disease

(CHD), cerebrovascular disease, or peripheral arterial disease presumed to be of
atherosclerotic origin—is the leading cause of morbidity and mortality for individu-
als 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 *A complete list of members of the American
multiple cardiovascular risk factors are addressed simultaneously. Under the cur- Diabetes Association Professional Practice Com-
mittee can be found at https://doi.org/10.2337/
rent paradigm of aggressive risk factor modification in patients with diabetes, there
dc22-SPPC.
is evidence that measures of 10-year coronary heart disease (CHD) risk among U.S.
This section has received endorsement from the
adults with diabetes have improved significantly over the past decade (2) and that American College of Cardiology.
ASCVD morbidity and mortality have decreased (3,4).
Suggested citation: American Diabetes Asso-
Heart failure is another major cause of morbidity and mortality from cardio- ciation Professional Practice Committee. 10.
vascular disease. Recent studies have found that rates of incident heart failure Cardiovascular disease and risk management:
hospitalization (adjusted for age and sex) were twofold higher in patients with Standards of Medical Care in Diabetes—2022.
diabetes compared with those without (5,6). People with diabetes may have Diabetes Care 2022;45(Suppl. 1):S144–S174
heart failure with preserved ejection fraction (HFpEF) or with reduced ejection © 2021 by the American Diabetes Association.
fraction (HFrEF). Hypertension is often a precursor of heart failure of either Readers may use this article as long as the
work is properly cited, the use is educational
type, and ASCVD can coexist with either type (7), whereas prior myocardial
and not for profit, and the work is not altered.
infarction (MI) is often a major factor in HFrEF. Rates of heart failure hospitali- More information is available at https://
zation have been improved in recent trials including patients with type 2 diabetesjournals.org/journals/pages/license.
care.diabetesjournals.org Cardiovascular Disease and Risk Management S145
diabetes, most of whom also had blood pressure, and lipids and the incor- ASCVD risk and help guide therapy, as
ASCVD, with sodium–glucose cotrans- poration of specific therapies with car- described below.
porter 2 (SGLT2) inhibitors (8–10). diovascular and kidney outcomes benefit Recently, risk scores and other cardio-
For prevention and management of (as individually appropriate) are consid- vascular biomarkers have been dev-
both ASCVD and heart failure, cardiovas- ered fundamental elements of global risk eloped for risk stratification of secondary
cular risk factors should be systematically reduction in diabetes. prevention patients (i.e., those who are
assessed at least annually in all patients already high risk because they have
with diabetes. These risk factors include ASCVD) but are not yet in widespread
THE RISK CALCULATOR use (15,16). With newer, more expensive
duration of diabetes, obesity/overweight,
hypertension, dyslipidemia, smoking, a The American College of Cardiology/ lipid-lowering therapies now available,
family history of premature coronary dis- American Heart Association ASCVD risk use of these risk assessments may help
ease, chronic kidney disease, and the calculator (Risk Estimator Plus) is gener- target these new therapies to “higher
risk” ASCVD patients in the future.

presence of albuminuria. Modifiable ally a useful tool to estimate 10-year risk
abnormal risk factors should be treated of a first ASCVD event (available online
as described in these guidelines. Notably, at tools.acc.org/ASCVD-Risk-Estimator- HYPERTENSION/BLOOD PRESSURE
the majority of evidence supporting inter- Plus). The calculator includes diabetes CONTROL
ventions to reduce cardiovascular risk in as a risk factor, since diabetes itself Hypertension, defined as a sustained
diabetes comes from trials of patients confers increased risk for ASCVD, blood pressure $140/90 mmHg, is com-
with type 2 diabetes. Few trials have although it should be acknowledged mon among patients with either type 1 or
been specifically designed to assess the that these risk calculators do not type 2 diabetes. Hypertension is a major
impact of cardiovascular risk reduction account for the duration of diabetes or risk factor for both ASCVD and microvas-
strategies in patients with type 1 diabetes. the presence of diabetes complications, cular complications. Moreover, numerous
As depicted in Fig. 10.1, a comprehen- such as albuminuria. Although some studies have shown that antihypertensive
sive approach to the reduction in risk of variability in calibration exists in various therapy reduces ASCVD events, heart fail-
diabetes-related complications is recom- subgroups, including by sex, race, and ure, and microvascular complications.
mended. Therapy that includes multiple, diabetes, the overall risk prediction Please refer to the American Diabetes
concurrent evidence-based approaches does not differ in those with or without Association (ADA) position statement
to care will provide complementary diabetes (11–14), validating the use of “Diabetes and Hypertension” for a
risk calculators in people with diabetes. detailed review of the epidemiology, diag-
reduction in the risks of microvascular,
nosis, and treatment of hypertension (17).
kidney, neurologic, and cardiovascular The 10-year risk of a first ASCVD event
complications. Management of glycemia, should be assessed to better stratify
Screening and Diagnosis
Recommendations
10.1 Blood pressure should be mea-
sured at every routine clinical
visit. When possible, patients
found to have elevated blood
pressure ($140/90 mmHg)
should have blood pressure
confirmed using multiple read-
ings, including measurements
on a separate day, to diagnose
hypertension. A Patients with
blood pressure $180/110 mmHg
and cardiovascular disease could
be diagnosed with hypertension
at a single visit. E
10.2 All hypertensive patients with
diabetes should monitor their
blood pressure at home. A
Blood pressure should be measured at

every routine clinical visit by a trained
individual and should follow the guide-
lines established for the general popu-
lation: measurement in the seated
Figure 10.1—Multifactorial approach to reduction in risk of diabetes complications. *Risk reduc- position, with feet on the floor and
tion interventions to be applied as individually appropriate. arm supported at heart level, after 5
S146 Cardiovascular Disease and Risk Management Diabetes Care Volume 45, Supplement 1, January 2022
min of rest. Cuff size should be appro- to a blood pressure target of Additional studies, such as the Sys-
priate for the upper-arm circumfer- <140/90 mmHg. A tolic Blood Pressure Intervention Trial
ence. Elevated values should preferably 10.6 In pregnant patients with dia- (SPRINT) and the Hypertension Optimal
be confirmed on a separate day; how- betes and preexisting hyper- Treatment (HOT) trial, also examined
ever, in patients with cardiovascular effects of intensive versus standard
tension, a blood pressure
disease and blood pressure $180/110 control (Table 10.1), though the rele-
target of 110–135/85 mmHg is
mmHg, it is reasonable to diagnose vance of their results to people with
suggested in the interest of
hypertension at a single visit (18). Pos- diabetes is less clear. The Action in
tural changes in blood pressure and reducing the risk for acceler-
Diabetes and Vascular Disease: Pre-
pulse may be evidence of autonomic ated maternal hypertension A
terax and Diamicron MR Controlled
neuropathy and therefore require and minimizing impaired fetal
Evaluation–Blood Pressure (ADVANCE
adjustment of blood pressure targets. growth. E
BP) trial did not explicitly test blood
Orthostatic blood pressure measure- pressure targets (30); the achieved

ments should be checked on initial visit Randomized clinical trials have demon- blood pressure in the intervention
and as indicated. strated unequivocally that treatment of group was higher than that achieved
Home blood pressure self-monitoring hypertension to blood pressure <140/ in the ACCORD BP intensive arm and
and 24-h ambulatory blood pressure 90 mmHg reduces cardiovascular events would be consistent with a target
monitoring may provide evidence of as well as microvascular complications blood pressure of <140/90 mmHg.
white coat hypertension, masked hyper- (22–28). Therefore, patients with type 1 Notably, ACCORD BP and SPRINT mea-
tension, or other discrepancies between or type 2 diabetes who have hyperten- sured blood pressure using automated
office and “true” blood pressure sion should, at a minimum, be treated office blood pressure measurement,
(17,18a,18b). In addition to confirming to blood pressure targets of <140/90 which yields values that are generally
or refuting a diagnosis of hypertension, mmHg. The benefits and risks of intensi- lower than typical office blood pres-
home blood pressure assessment may fying antihypertensive therapy to target sure readings by approximately 5–10
be useful to monitor antihypertensive blood pressures lower than <140/90 mmHg (31), suggesting that imple-
treatment. Studies of individuals without mmHg (e.g., <130/80 or <120/80 menting the ACCORD BP or SPRINT
diabetes found that home measure- mmHg) have been evaluated in large protocols in an outpatient clinic might
ments may better correlate with ASCVD randomized clinical trials and meta-anal- require a systolic blood pressure tar-
risk than office measurements (19,20). yses of clinical trials. Notably, there is get higher than <120 mmHg, such as
Moreover, home blood pressure moni- an absence of high-quality data avail- <130 mmHg.
toring may improve patient medication able to guide blood pressure targets in A number of post hoc analyses have
adherence and thus help reduce cardio- type 1 diabetes. attempted to explain the apparently
vascular risk (21).
divergent results of ACCORD BP and
Randomized Controlled Trials of Intensive SPRINT. Some investigators have argued
Treatment Goals Versus Standard Blood Pressure Control that the divergent results are not due
The Action to Control Cardiovascular to differences between people with and
Recommendations
Risk in Diabetes Blood Pressure (ACCORD without diabetes but rather are due to
10.3 For patients with diabetes and BP) trial provides the strongest direct differences in study design or to charac-
hypertension, blood pressure tar- assessment of the benefits and risks of teristics other than diabetes (32–34).
gets should be individualized intensive blood pressure control among Others have opined that the divergent
through a shared decision-making people with type 2 diabetes (29). In results are most readily explained by
process that addresses cardiovas-
ACCORD BP, compared with standard the lack of benefit of intensive blood
cular risk, potential adverse
blood pressure control (target systolic pressure control on cardiovascular mor-
effects of antihypertensive
blood pressure <140 mmHg), intensive tality in ACCORD BP, which may be due
medications, and patient pref-
blood pressure control (target systolic to differential mechanisms underlying
erences. B
blood pressure <120 mmHg) did not cardiovascular disease in type 2 diabe-
10.4 For individuals with diabetes
reduce total major atherosclerotic tes, to chance, or both (35). Interest-
and hypertension at higher
cardiovascular events but did reduce ingly, a post hoc analysis has found that
cardiovascular risk (existing
the risk of stroke, at the expense of inc- intensive blood pressure lowering
atherosclerotic cardiovascular
reased adverse events (Table 10.1). The increased the risk of incident chronic
disease [ASCVD] or 10-year
ACCORD BP results suggest that blood kidney disease in both ACCORD BP and
ASCVD risk $15%), a blood
pressure targets more intensive than SPRINT, with the absolute risk of inci-
pressure target of <130/80
<140/90 mmHg are not likely to imp- dent chronic kidney disease being
mmHg may be appropriate, if
rove cardiovascular outcomes among higher in individuals with type 2 diabe-
it can be safely attained. B
most people with type 2 diabetes but tes (36).
10.5 For individuals with diabetes
may be reasonable for patients who may
and hypertension at lower risk
derive the most benefit and have been Meta-analyses of Trials
for cardiovascular disease (10-
educated about added treatment bur- To clarify optimal blood pressure targets
year atherosclerotic cardiovas-
den, side effects, and costs, as discussed in patients with diabetes, meta-analyses
cular disease risk <15%), treat
below. have stratified clinical trials by mean
Table 10.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies
Clinical trial Population Intensive Standard Outcomes
ACCORD BP (29) 4,733 participants with T2D SBP target: SBP target: 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: Stroke risk reduced 41% with
risk factors 119.3/64.4 mmHg 135/70.5 mmHg intensive control, not sustained
through follow-up beyond the
period of active treatment
Adverse events more common
in intensive group, particularly
elevated serum creatinine and
electrolyte abnormalities

ADVANCE BP (30) 11,140 participants with Intervention: a single-pill, Control: placebo Intervention reduced risk of
T2D aged 55 years and fixed-dose combination Achieved (mean) primary composite end point of
older with prior of perindopril and SBP/DBP: major macrovascular and
evidence of CVD or indapamide 141.6/75.2 mmHg microvascular events (9%),
multiple cardiovascular Achieved (mean) death from any cause (14%),
risk factors SBP/DBP: and death from CVD (18%)
136/73 mmHg 6-year observational follow-up
found reduction in risk of death
in intervention group attenuated
but still significant (198)
HOT (221) 18,790 participants, DBP target: DBP target: In the overall trial, there was no
including 1,501 #80 mmHg #90 mmHg cardiovascular benefit with
with diabetes Achieved (mean): more intensive targets
81.1 mmHg, #80 In the subpopulation with
group; 85.2 mmHg, diabetes, an intensive DBP
#90 group target was associated with a
significantly reduced risk (51%)
of CVD events
SPRINT (41) 9,361 participants SBP target: SBP target: Intensive SBP target lowered
without diabetes <120 mmHg <140 mmHg risk 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)
Intensive target reduced risk of
death 27%
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, dia-
stolic 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).
baseline blood pressure or mean blood blood pressure $140 mmHg to judgment (37). Secondary analyses of
pressure attained in the intervention (or targets <140 mmHg is beneficial, while ACCORD BP and SPRINT suggest that clin-
intensive treatment) arm. Based on these more intensive targets may offer additional ical factors can help determine individu-
analyses, antihypertensive treatment appears (though probably less robust) benefits. als more likely to benefit and less likely
to be beneficial when mean baseline blood to be harmed by intensive blood pres-
pressure is $140/90 mmHg or mean Individualization of Treatment Targets sure control (38,39).
attained intensive blood pressure is $130/ Patients and clinicians should engage in a Absolute benefit from blood pressure
80 mmHg (17,22,23,25–27). Among trials shared decision-making process to deter- reduction correlated with absolute
with lower baseline or attained blood pres- mine individual blood pressure targets baseline cardiovascular risk in SPRINT
sure, antihypertensive treatment reduced (17). This approach acknowledges that and in earlier clinical trials conducted at
the risk of stroke, retinopathy, and albumin- the benefits and risks of intensive blood higher baseline blood pressure levels
uria, but effects on other ASCVD outcomes pressure targets are uncertain and may (11,39). Extrapolation of these studies
and heart failure were not evident. Taken vary across patients and is consistent suggests that patients with diabetes
together, these meta-analyses consistently with a patient-focused approach to care may also be more likely to benefit from
show that treating patients with baseline that values patient priorities and provider intensive blood pressure control when
they have high absolute cardiovascular any conclusive evidence for or against doi.org/10.2337/dc22-S015), for add-
risk. Therefore, it may be reasonable to blood pressure treatment to reduce the itional information.
target blood pressure <130/80 mmHg risk of preeclampsia for the mother or
among patients with diabetes and effects on perinatal outcomes such as
either clinically diagnosed cardiovascu- preterm birth, small-for-gestational-age Treatment Strategies
lar disease (particularly stroke, which infants, or fetal death (44). The more Lifestyle Intervention
was significantly reduced in ACCORD recent Control of Hypertension in Preg- Recommendation
BP) or 10-year ASCVD risk $15%, if it nancy Study (CHIPS) (45) enrolled mostly 10.7 For patients with blood pres-
can be attained safely. This approach is women with chronic hypertension. In sure >120/80 mmHg, life-
consistent with guidelines from the CHIPS, targeting a diastolic blood pres- style intervention consists of
American College of Cardiology/Ameri- sure of 85 mmHg during pregnancy was weight loss when indicated, a
can Heart Association, which advocate a associated with reduced likelihood of Dietary Approaches to Stop
blood pressure target <130/80 mmHg

developing accelerated maternal hyper- Hypertension (DASH)-style eating
for all patients, with or without diabetes tension and no demonstrable adverse pattern including reducing sodium
(40). outcome for infants compared with tar- and increasing potassium intake,
Potential adverse effects of antihy- geting a higher diastolic blood pressure. moderation of alcohol intake,
pertensive therapy (e.g., hypotension, The mean systolic blood pressure and increased physical activity. A
syncope, falls, acute kidney injury, and achieved in the more intensively treated
electrolyte abnormalities) should also group was 133.1 ± 0.5 mmHg, and the
be taken into account (29,36,41,42). mean diastolic blood pressure achieved Lifestyle management is an important
Patients with older age, chronic kidney in that group was 85.3 ± 0.3 mmHg. A component of hypertension treatment
disease, and frailty have been shown to similar approach is supported by the because it lowers blood pressure, enhan-
be at higher risk of adverse effects of International Society for the Study of ces the effectiveness of some antihyper-
intensive blood pressure control (42). In Hypertension in Pregnancy, which specifi-
addition, patients with orthostatic hypo- tensive medications, promotes other
cally recommends use of antihyperten- aspects of metabolic and vascular health,
tension, substantial comorbidity, func-
sive therapy to maintain systolic blood and generally leads to few adverse
tional limitations, or polypharmacy may
pressure between 110 and 140 mmHg effects. Lifestyle therapy consists of
be at high risk of adverse effects, and
and diastolic blood pressure between 80 reducing excess body weight through
some patients may prefer higher blood
and 85 mmHg (46). Current evidence caloric restriction (see Section 8, “Obesity
pressure targets to enhance quality of
supports controlling blood pressure to and Weight Management for the Preven-
life. However, in ACCORD BP, it was
110–135/85 mmHg to reduce the risk of tion and Treatment of Type 2 Diabetes,”
found that intensive blood pressure
accelerated maternal hypertension but https://doi.org/10.2337/dc22-S008),
lowering decreased the risk of
also to minimize impairment of fetal
cardiovascular events irrespective of restricting sodium intake (<2,300 mg/
growth. During pregnancy, treatment
baseline diastolic blood pressure in day), increasing consumption of fruits
with ACE inhibitors, angiotensin receptor
patients who also received standard gly- and vegetables (8–10 servings per
cemic control (43). Therefore, the pres- blockers, and spironolactone are contra-
day) and low-fat dairy products (2–3
ence of low diastolic blood pressure is indicated as they may cause fetal dam-
servings per day), avoiding excessive
not necessarily a contraindication age. Antihypertensive drugs known to be
alcohol consumption (no more than 2
to more intensive blood pressure man- effective and safe in pregnancy include
servings per day in men and no more
agement in the context of otherwise methyldopa, labetalol, and long-acting
than 1 serving per day in women)
standard care. nifedipine, while hydralzine may be con-
sidered in the acute management of (50), and increasing activity levels
Patients with low absolute cardiovas- (51).
cular risk (10-year ASCVD risk <15%) or hypertension in pregnancy or severe
preeclampsia (47). Diuretics are not rec- These lifestyle interventions are rea-
with a history of adverse effects of sonable for individuals with diabetes and
intensive blood pressure control or at ommended for blood pressure control in
pregnancy but may be used during late- mildly elevated blood pressure (systolic
high risk of adverse effects should have
stage pregnancy if needed for volume >120 mmHg or diastolic >80 mmHg)
a higher blood pressure target. In such
control (47,48). The American College of and should be initiated along with phar-
patients, a blood pressure target of
macologic therapy when hypertension is
<140/90 mmHg is recommended, if it Obstetricians and Gynecologists also rec-
can be safely attained. ommends that postpartum patients with diagnosed (Fig. 10.2) (51). A lifestyle ther-
gestational hypertension, preeclampsia, apy plan should be developed in collabo-
Pregnancy and Antihypertensive Medications and superimposed preeclampsia have ration with the patient and discussed as
There are few randomized controlled tri- their blood pressures observed for 72 h part of diabetes management. Use of
als of antihypertensive therapy in preg- in the hospital and for 7–10 days post- internet or mobile-based digital platforms
nant women with diabetes. A 2014 partum. Long-term follow-up is recom- to reinforce healthy behaviors may be
Cochrane systematic review of antihyper- mended for these women as they have considered as a component of care, as
tensive therapy for mild to moderate increased lifetime cardiovascular risk these interventions have been found to
chronic hypertension that included 49 tri- (49). See Section 15, “Management enhance the efficacy of medical therapy
als and over 4,700 women did not find of Diabetes in Pregnancy” (https:// for hypertension (52,53).
Pharmacologic Interventions
to achieve blood pressure demonstrated to reduce car-
Recommendations goals. A diovascular events in patients
10.9 Patients with confirmed office- with diabetes. A
10.8 Patients with confirmed office-
based blood pressure $160/ 10.10 Treatment for hypertension
based blood pressure $140/
100 mmHg should, in addition should include drug classes
90 mmHg should, in addition to lifestyle therapy, have demonstrated to reduce car-
to lifestyle therapy, have prompt prompt initiation and timely diovascular events in patients
initiation and timely titration titration of two drugs or a sin- with diabetes. A ACE inhibitors
of pharmacologic therapy gle-pill combination of drugs or angiotensin receptor
Figure 10.2—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 cal-
cium channel blocker (CCB). BP, blood pressure. Adapted from de Boer et al. (17).
blockers are recommended artery disease, ACE inhibitors or ARBs mechanism of action) (74,75). Detection
first-line therapy for hyperten- are recommended first-line therapy for and management of these abnormali-
sion in people with diabetes hypertension (62–64). For patients with ties is important because AKI and hyper-
and coronary artery disease. A albuminuria (urine albumin-to-creati- kalemia each increase the risks of
10.11 Multiple-drug therapy is gener- nine ratio [UACR] $30 mg/g), initial cardiovascular events and death (76).
ally required to achieve blood treatment should include an ACE inhibi- Therefore, serum creatinine and potas-
pressure targets. However, com- tor or ARB in order to reduce the risk of sium should be monitored during treat-
binations of ACE inhibitors and progressive kidney disease (17) (Fig. ment with an ACE inhibitor, ARB, or
10.2). In patients receiving ACE inhibitor diuretic, particularly among patients
angiotensin receptor blockers
or ARB therapy, continuation of those with reduced glomerular filtration who
and combinations of ACE inhibi-
medications as kidney function declines are at increased risk of hyperkalemia
tors or angiotensin receptor
to estimated glomerular filtration rate and AKI (74,75,77).
blockers with direct renin inhibi-
(eGFR) <30 mL/min/1.73 m2 may provide

tors should not be used. A
cardiovascular benefit without signifi-
10.12 An ACE inhibitor or angiotensin Resistant Hypertension
cantly increasing the risk of end-stage kid-
receptor blocker, at the maxi-
ney disease (65). In the absence of Recommendation
mum tolerated dose indicated
albuminuria, risk of progressive kidney 10.14 Patients with hypertension
for blood pressure treatment,
disease is low, and ACE inhibitors and who are not meeting blood
is the recommended first-line
ARBs have not been found to afford pressure targets on three clas-
treatment for hypertension in
superior cardioprotection when compared ses of antihypertensive medi-
patients with diabetes and uri-
with thiazide-like diuretics or dihydropyri- cations (including a diuretic)
nary albumin-to-creatinine ratio
dine calcium channel blockers (66). should be considered for min-
$300 mg/g creatinine A or
b-Blockers are indicated in the setting of eralocorticoid receptor antago-
30–299 mg/g creatinine. B If
prior MI, active angina, or HfrEF but have nist therapy. B
one class is not tolerated, the not been shown to reduce mortality as
other should be substituted. B blood pressure–lowering agents in the
10.13 For patients treated with an absence of these conditions (24,67,68). Resistant hypertension is defined as
ACE inhibitor, angiotensin recep- blood pressure $140/90 mmHg despite
tor blocker, or diuretic, serum Multiple-Drug Therapy. Multiple-drug a therapeutic strategy that includes
creatinine/estimated glomerular therapy is often required to achieve appropriate lifestyle management plus a
filtration rate and serum potas- blood pressure targets (Fig. 10.2), par- diuretic and two other antihypertensive
sium levels should be moni- ticularly in the setting of diabetic kidney drugs with complimentary mechanisms
tored at least annually. B disease. However, the use of both ACE of action at adequate doses. Prior to
inhibitors and ARBs in combination, or diagnosing resistant hypertension, a
Initial Number of Antihypertensive Medi- the combination of an ACE inhibitor or number of other conditions should be
cations. Initial treatment for people with ARB and a direct renin inhibitor, is con- excluded, including medication nonad-
diabetes depends on the severity of traindicated given the lack of added herence, white coat hypertension, and
hypertension (Fig. 10.2). Those with ASCVD benefit and increased rate of secondary hypertension. In general, bar-
blood pressure between 140/90 mmHg adverse events—namely, hyperkalemia, riers to medication adherence (such as
and 159/99 mmHg may begin with a sin- syncope, and acute kidney injury (AKI) cost and side effects) should be identi-
gle drug. For patients with blood pressure (69–71). Titration of and/or addition of
fied and addressed (Fig. 10.2). Mineralo-
$160/100 mmHg, initial pharmacologic further blood pressure medications
corticoid receptor antagonists are
treatment with two antihypertensive should be made in a timely fashion to
effective for management of resistant
medications is recommended in order to overcome therapeutic inertia in achiev-
hypertension in patients with type 2 dia-
more effectively achieve adequate blood ing blood pressure targets.
pressure control (54–56). Single-pill anti- betes when added to existing treatment
hypertensive combinations may improve with an ACE inhibitor or ARB, thiazide-
Bedtime Dosing. Although prior analyses
medication adherence in some patients of randomized clinical trials found a ben- like diuretic, and dihydropyridine cal-
(57). efit to evening versus morning dosing cium channel blocker (78). Mineralocor-
of antihypertensive medications (72,73), ticoid receptor antagonists also reduce
Classes of Antihypertensive Medications. these results have not been reproduced albuminuria and have additional cardio-
Initial treatment for hypertension in subsequent trials. Therefore, preferen- vascular benefits (79–82). However,
should include any of the drug classes tial use of antihypertensives at bedtime adding a mineralocorticoid receptor
demonstrated to reduce cardiovascular is not recommended (73a). antagonist to a regimen including an
events in patients with diabetes: ACE ACE inhibitor or ARB may increase the
inhibitors (58,59), angiotensin receptor Hyperkalemia and Acute Kidney Injury. risk for hyperkalemia, emphasizing the
blockers (ARBs) (58,59), thiazide-like Treatment with ACE inhibitors or ARBs importance of regular monitoring for
diuretics (60), or dihydropyridine cal- can cause AKI and hyperkalemia, while serum creatinine and potassium in these
cium channel blockers (61). In patients diuretics can cause AKI and either hypo- patients, and long-term outcome studies
with diabetes and established coronary kalemia or hyperkalemia (depending on are needed to better evaluate the role
of mineralocorticoid receptor antago- Ongoing Therapy and Monitoring

atherosclerotic cardiovascular
nists in blood pressure management. With Lipid Panel
disease, use moderate-inten-
Recommendations sity statin therapy in addition
LIPID MANAGEMENT to lifestyle therapy. A
10.17 In adults not taking statins or
Lifestyle Intervention other lipid-lowering therapy, it 10.20 For patients with diabetes
is reasonable to obtain a lipid aged 20–39 years with addi-
Recommendations tional atherosclerotic cardio-
profile at the time of diabetes
10.15 Lifestyle modification focusing vascular disease risk factors,
diagnosis, at an initial medical
on weight loss (if indicated); it may be reasonable to initi-
evaluation, and every 5 years
application of a Mediterranean ate statin therapy in addition
thereafter if under the age of
style or Dietary Approaches to 40 years, or more frequently if to lifestyle therapy. C
Stop Hypertension (DASH) eat- indicated. E 10.21 In patients with diabetes at

ing pattern; reduction of satu- 10.18 Obtain a lipid profile at initia- higher risk, especially those
rated fat and trans fat; increase tion of statins or other lipid- with multiple atherosclerotic
of dietary n-3 fatty acids, vis- lowering therapy, 4–12 weeks cardiovascular disease risk
cous fiber, and plant stanols/ after initiation or a change in factors or aged 50–70 years,
sterols intake; and increased dose, and annually thereafter it is reasonable to use high-
physical activity should be rec- as it may help to monitor the intensity statin therapy. B
ommended to improve the lipid response to therapy and inform 10.22 In adults with diabetes and 10-
profile and reduce the risk of medication adherence. E year atherosclerotic cardiovas-
developing atherosclerotic car- cular disease risk of 20% or
diovascular disease in patients higher, it may be reasonable to
In adults with diabetes, it is reasonable
with diabetes. A add ezetimibe to maximally
to obtain a lipid profile (total cholesterol,
10.16 Intensify lifestyle therapy and tolerated statin therapy to
LDL cholesterol, HDL cholesterol, and tri-
optimize glycemic control for reduce LDL cholesterol levels
glycerides) at the time of diagnosis, at
patients with elevated triglyc- by 50% or more. C
the initial medical evaluation, and at
eride levels ($150 mg/dL [1.7 least every 5 years thereafter in patients
mmol/L]) and/or low HDL under the age of 40 years. In younger Secondary Prevention
cholesterol (<40 mg/dL [1.0 patients with longer duration of disease
Recommendations
mmol/L] for men, <50 mg/dL (such as those with youth-onset type 1
10.23 For patients of all ages with dia-
[1.3 mmol/L] for women). C diabetes), more frequent lipid profiles
betes and atherosclerotic cardio-
may be reasonable. A lipid panel should
vascular disease, high-intensity
Lifestyle intervention, including weight also be obtained immediately before ini-
tiating statin therapy. Once a patient is statin therapy should be added
loss (83), increased physical activity, and to lifestyle therapy. A
taking a statin, LDL cholesterol levels
medical nutrition therapy, allows some 10.24 For patients with diabetes and
should be assessed 4–12 weeks after ini-
patients to reduce ASCVD risk factors. atherosclerotic cardiovascular
tiation of statin therapy, after any change
Nutrition intervention should be tailored disease considered very high
in dose, and on an individual basis (e.g.,
according to each patient’s age, diabetes to monitor for medication adherence risk using specific criteria, if LDL
type, pharmacologic treatment, lipid lev- and efficacy). If LDL cholesterol levels are cholesterol is $70 mg/dL on
els, and medical conditions. not responding in spite of medication maximally tolerated statin dose,
Recommendations should focus on adherence, clinical judgment is recom- consider adding additional LDL-
application of a Mediterranean style mended to determine the need for and lowering therapy (such as ezeti-
diet (84) or Dietary Approaches to timing of lipid panels. In individual mibe or PCSK9 inhibitor). A
Stop Hypertension (DASH) eating pat- patients, the highly variable LDL choles- 10.25 For patients who do not toler-
tern, reducing saturated and trans fat terol–lowering response seen with statins ate the intended intensity, the
intake and increasing plant stanols/ is poorly understood (87). Clinicians should maximally tolerated statin
sterols, n-3 fatty acids, and viscous attempt to find a dose or alternative statin dose should be used. E
fiber (such as in oats, legumes, and that is tolerable if side effects occur. There 10.26 In adults with diabetes aged
citrus) intake (85,86). Glycemic con- is evidence for benefit from even extremely >75 years already on statin
trol may also beneficially modify low, less than daily statin doses (88). therapy, it is reasonable to
plasma lipid levels, particularly in continue statin treatment. B
patients with very high triglycerides 10.27 In adults with diabetes aged
and poor glycemic control. See Sec-
STATIN TREATMENT >75 years, it may be reason-
tion 5, “Facilitating Behavior Change Primary Prevention able to initiate statin therapy
after discussion of potential
and Well-being to Improve Health Recommendations benefits and risks. C
Outcomes” (https://doi.org/10.2337/ 10.19 For patients with diabetes 10.28 Statin therapy is contraindi-
dc22-S005), for additional nutrition aged 40–75 years without cated in pregnancy. B
information.
Initiating Statin Therapy Based on Risk aged 40–75 years, an age-group well rep- 1 diabetes of any age. For pediatric rec-
Patients with type 2 diabetes have an resented in statin trials showing benefit. ommendations, see Section 14, “Children
increased prevalence of lipid abnormali- Since risk is enhanced in patients with and Adolescents” (https://doi.org/10.2337/
ties, contributing to their high risk of diabetes, as noted above, patients who dc22-S014). In the Heart Protection Study
ASCVD. Multiple clinical trials have dem- also have multiple other coronary risk (lower age limit 40 years), the subgroup of
onstrated the beneficial effects of statin factors have increased risk, equivalent to 600 patients with type 1 diabetes had
therapy on ASCVD outcomes in subjects that of those with ASCVD. As such, a proportionately similar, although not
with and without CHD (89,90). Subgroup recent guidelines recommend that in statistically significant, reduction in risk
analyses of patients with diabetes in patients with diabetes who are at higher to that in patients with type 2 diabetes
larger trials (91–95) and trials in patients risk, especially those with multiple ASCVD (92). Even though the data are not defin-
with diabetes (96,97) showed significant risk factors or aged 50–70 years, it is itive, similar statin treatment approaches
primary and secondary prevention of reasonable to prescribe high-intensity should be considered for patients with
ASCVD events and CHD death in patients

statin therapy (12,101). Furthermore, for type 1 or type 2 diabetes, particularly in
with diabetes. Meta-analyses, including patients with diabetes whose ASCVD the presence of other cardiovascular risk
data from over 18,000 patients with dia- risk is $20%, i.e., an ASCVD risk equiva- factors. Patients below the age of 40
betes from 14 randomized trials of statin lent, the same high-intensity statin ther- have lower risk of developing a cardio-
therapy (mean follow-up 4.3 years), apy is recommended as for those with vascular event over a 10-year horizon;
demonstrate a 9% proportional reduc- documented ASCVD (12). In those indi- however, their lifetime risk of developing
tion in all-cause mortality and 13% viduals, it may also be reasonable to add cardiovascular disease and suffering an
reduction in vascular mortality for each 1 ezetimibe to maximally tolerated statin MI, stroke, or cardiovascular death is
mmol/L (39 mg/dL) reduction in LDL cho- therapy if needed to reduce LDL choles- high. For patients who are younger than
lesterol (98).
terol levels by 50% or more (12). The evi- 40 years of age and/or have type 1 dia-
Accordingly, statins are the drugs of
dence is lower for patients aged >75 betes with other ASCVD risk factors, it is
choice for LDL cholesterol lowering and
years; relatively few older patients with recommended that the patient and
cardioprotection. Table 10.2 shows the
diabetes have been enrolled in primary health care provider discuss the relative
two statin dosing intensities that are rec-
prevention trials. However, heterogeneity benefits and risks and consider the use
ommended for use in clinical practice:
by age has not been seen in the relative of moderate-intensity statin therapy. Please
high-intensity statin therapy will achieve
benefit of lipid-lowering therapy in refer to “Type 1 Diabetes Mellitus and Car-
approximately a $50% reduction in LDL
trials that included older participants diovascular Disease: A Scientific Statement
cholesterol, and moderate-intensity statin
(90,97,98), and because older age confers From the American Heart Association and
regimens achieve 30–49% reductions in
higher risk, the absolute benefits are American Diabetes Association” (103) for
LDL cholesterol. Low-dose statin therapy
actually greater (90,102). Moderate-inten- additional discussion.
is generally not recommended in patients
sity statin therapy is recommended in
with diabetes but is sometimes the only
dose of statin that a patient can tolerate. patients with diabetes who are 75 years Secondary Prevention (Patients With ASCVD)
or older. However, the risk-benefit profile Because risk is high in patients with
For patients who do not tolerate the
intended intensity of statin, the maximally should be routinely evaluated in this popu- ASCVD, intensive therapy is indicated and
tolerated statin dose should be used. lation, with downward titration of dose has been shown to be of benefit in multi-
As in those without diabetes, absolute performed as needed. See Section 13, ple large randomized cardiovascular out-
reductions in ASCVD outcomes (CHD “Older Adults” (https://doi.org/10.2337/ comes trials (98,102,104,105). High-
death and nonfatal MI) are greatest in dc22-S013), for more details on clinical intensity statin therapy is recommended
people with high baseline ASCVD risk considerations for this population. for all patients with diabetes and ASCVD.
(known ASCVD and/or very high LDL cho- This recommendation is based on the
lesterol levels), but the overall benefits of Age <40 Years and/or Type 1 Diabetes. Cholesterol Treatment Trialists’ Collabora-
statin therapy in people with diabetes at Very little clinical trial evidence exists for tion involving 26 statin trials, of which 5
moderate or even low risk for ASCVD are patients with type 2 diabetes under the compared high-intensity versus moder-
convincing (99,100). The relative benefit age of 40 years or for patients with type ate-intensity statins. Together, they found
of lipid-lowering therapy has been uni-
form across most subgroups tested Table 10.2—High-intensity and moderate-intensity statin therapy*
(90,98), including subgroups that varied
High-intensity statin therapy Moderate-intensity statin therapy
with respect to age and other risk factors. (lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30–49%)
Atorvastatin 40–80 mg Atorvastatin 10–20 mg
Primary Prevention (Patients Without ASCVD)
Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg
For primary prevention, moderate-dose Simvastatin 20–40 mg
statin therapy is recommended for those Pravastatin 40–80 mg
40 years and older (92,99,100), though Lovastatin 40 mg
high-intensity therapy may be considered Fluvastatin XL 80 mg
on an individual basis in the context of Pitavastatin 1–4 mg
additional ASCVD risk factors. The evi- *Once-daily dosing. XL, extended release.
dence is strong for patients with diabetes
reductions in nonfatal cardiovascular simvastatin therapy versus simvastatin 59% from a median of 92 to 30 mg/dL
events with more intensive therapy, in alone. Individuals were $50 years of in the treatment arm.
patients with and without diabetes age, had experienced a recent acute During the median follow-up of 2.2
(90,94,104). coronary syndrome (ACS) and were years, the composite outcome of cardio-
Over the past few years, there have treated for an average of 6 years. Over- vascular death, MI, stroke, hospitalization
been multiple large randomized trials all, the addition of ezetimibe led for angina, or revascularization occurred
investigating the benefits of adding non- to a 6.4% relative benefit and a 2% in 11.3% vs. 9.8% of the placebo and
statin agents to statin therapy, including absolute reduction in major adverse car- evolocumab groups, respectively, repre-
those that evaluated further lowering of diovascular events (atherosclerotic car- senting a 15% relative risk reduction (P <
LDL cholesterol with ezetimibe (102,106) diovascular events), with the degree of 0.001). The combined end point of cardio-
and proprotein convertase subtilisin/kexin benefit being directly proportional to vascular death, MI, or stroke was reduced
type 9 (PCSK9) inhibitors (105). Each trial the change in LDL cholesterol, which by 20%, from 7.4% to 5.9% (P < 0.001).
found a significant benefit in the reduc- was 70 mg/dL in the statin group on Evolocumab therapy also significantly

tion of ASCVD events that was directly average and 54 mg/dL in the combina- reduced all strokes (1.5% vs. 1.9%; HR
related to the degree of further LDL cho- tion group (102). In those with diabetes 0.79 [95% CI 0.66–0.95]; P 5 0.01) and
lesterol lowering. These large trials (27% of participants), the combination ischemic stroke (1.2% vs. 1.6%; HR 0.75
included a significant number of partici- of moderate-intensity simvastatin (40 [95% CI 0.62–0.92]; P 5 0.005) in the
pants with diabetes. For very high-risk mg) and ezetimibe (10 mg) showed a total population, with findings being con-
patients with ASCVD who are on high- significant reduction of major adverse sistent in patients with or without a his-
intensity (and maximally tolerated) statin cardiovascular events with an absolute tory of ischemic stroke at baseline (110).
therapy and have an LDL cholesterol $70 risk reduction of 5% (40% vs. 45% Importantly, similar benefits were seen in
mg/dL, the addition of nonstatin LDL- cumulative incidence at 7 years) and a a prespecified subgroup of patients with
lowering therapy can be considered. The relative risk reduction of 14% (hazard diabetes, comprising 11,031 patients
decision to add a nonstatin agent should ratio [HR] 0.86 [95% CI 0.78–0.94]) over (40% of the trial) (111).
be made following a clinician-patient dis- moderate-intensity simvastatin (40 mg) In the ODYSSEY OUTCOMES trial
cussion about the net benefit, safety, and alone (106). (Evaluation of Cardiovascular Outcomes
cost of combination therapy. Although After an Acute Coronary Syndrome Dur-
the costs of PCSK9 inhibitor therapy have Statins and PCSK9 Inhibitors ing Treatment With Alirocumab), 18,924
decreased over time, the lower cost of Placebo-controlled trials evaluating the patients (28.8% of whom had diabetes)
ezetimibe may be preferred by many addition of the PCSK9 inhibitors evolo- with recent acute coronary syndrome
patients. Definition of very high-risk cumab and alirocumab to maximally tol- were randomized to the PCSK9 inhibitor
patients with ASCVD includes the use of erated doses of statin therapy in alirocumab or placebo every 2 weeks in
specific criteria (major ASCVD events and participants who were at high risk for addition to maximally tolerated statin
high-risk conditions); refer to the “2018 ASCVD demonstrated an average reduc- therapy, with alirocumab dosing titrated
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ tion in LDL cholesterol ranging from between 75 and 150 mg to achieve LDL
ADA/AGS/APhA/ASPC/NLA/PCNA Gui- 36% to 59%. These agents have been cholesterol levels between 25 and 50
deline on the Management of Blood Cho- approved as adjunctive therapy for mg/dL (112). Over a median follow-up
lesterol: Executive Summary: A Report of patients with ASCVD or familial hyper- of 2.8 years, a composite primary end
the American College of Cardiology/Amer- cholesterolemia who are receiving maxi- point (comprising death from coronary
ican Heart Association Task Force on Clini- mally tolerated statin therapy but heart disease, nonfatal MI, fatal or non-
cal Practice Guidelines” (12) for further require additional lowering of LDL cho- fatal ischemic stroke, or unstable angina
details regarding this definition of risk, lesterol (108,109). requiring hospital admission) occurred
and to the additional “2018 ACC Expert The effects of PCSK9 inhibition on in 903 patients (9.5%) in the alirocumab
Consensus Decision Pathway on Novel ASCVD outcomes was investigated in group and in 1,052 patients (11.1%) in
Therapies for Cardiovascular Risk Reduc- the Further Cardiovascular Outcomes the placebo group (HR 0.85 [95% CI
tion in Patients With Type 2 Diabetes and Research With PCSK9 Inhibition in Sub- 0.78–0.93]; P < 0.001). Combination
Atherosclerotic Cardiovascular Disease” jects With Elevated Risk (FOURIER) trial, therapy with alirocumab plus statin
(107) for recommendations for primary which enrolled 27,564 patients with therapy resulted in a greater absolute
and secondary prevention and for statin prior ASCVD and an additional high-risk reduction in the incidence of the pri-
and combination treatment in adults with feature who were receiving their maxi- mary end point in patients with diabe-
diabetes. mally tolerated statin therapy (two- tes (2.3% [95% CI 0.4–4.2]) than in
thirds were on high-intensity statin) but those with prediabetes (1.2% [0.0–2.4])
Combination Therapy for LDL who still had LDL cholesterol $70 mg/ or normoglycemia (1.2% [–0.3 to 2.7])
Cholesterol Lowering dL or non-HDL cholesterol $100 mg/dL (113).
Statins and Ezetimibe (105). Patients were randomized to
The IMProved Reduction of Outcomes: receive subcutaneous injections of evo- Statins and Bempedoic Acid
Vytorin Efficacy International Trial locumab (either 140 mg every 2 weeks Bempedoic acid is a novel LDL
(IMPROVE-IT) was a randomized con- or 420 mg every month based on cholesterol–lowering agent that is indi-
trolled trial in 18,144 patients compar- patient preference) versus placebo. Evo- cated as an adjunct to diet and maxi-
ing the addition of ezetimibe to locumab reduced LDL cholesterol by mally tolerated statin therapy for the
treatment of adults with heterozygous pancreatitis. Moderate- or high-intensity the use of drugs that target these lipid
familial hypercholesterolemia or estab- statin therapy should also be used as fractions is substantially less robust
lished atherosclerotic cardiovascular indicated to reduce risk of cardiovascular than that for statin therapy (119). In a
disease who require additional lower- events (see STATIN TREATMENT). In pati- large trial in patients with diabetes,
ing of LDL cholesterol. A pooled analy- ents with moderate hypertriglyceridemia, fenofibrate failed to reduce overall car-
sis suggests that bempedoic acid lifestyle interventions, treatment of sec- diovascular outcomes (120).
therapy lowers LDL cholesterol levels ondary factors, and avoidance of medica-
by about 23% compared with placebo tions that might raise triglycerides are Other Combination Therapy
(114). At this time, there are no com- recommended.
pleted trials demonstrating a cardiovas- The Reduction of Cardiovascular Events Recommendations
cular outcomes benefit to use of this with Icosapent Ethyl–Intervention Trial 10.32 Statin plus fibrate combination
medication; however, this agent may (REDUCE-IT) enrolled 8,179 adults receiving therapy has not been shown
statin therapy with moderately elevated to improve atherosclerotic car-

be considered for patients who cannot
use or tolerate other evidence-based triglycerides (135–499 mg/dL, median diovascular disease outcomes
LDL cholesterol–lowering approaches, baseline of 216 mg/dL) who had either and is generally not recom-
or for whom those other therapies are established cardiovascular disease (second- mended. A
inadequately effective (115). ary prevention cohort) or diabetes plus at 10.33 Statin plus niacin combination
least one other cardiovascular risk factor therapy has not been shown
Treatment of Other Lipoprotein (primary prevention cohort). Patients were to provide additional cardiovas-
Fractions or Targets randomized to icosapent ethyl 4 g/day (2 cular benefit above statin ther-
g twice daily with food) versus placebo. apy alone, may increase the
Recommendations The trial met its primary end point, dem- risk of stroke with additional
10.29 For patients with fasting triglyc- onstrating a 25% relative risk reduction side effects, and is generally
eride levels $500 mg/dL, eval- (P < 0.001) for the primary end point not recommended. A
uate for secondary causes of composite of cardiovascular death, nonfa-
hypertriglyceridemia and con- tal MI, nonfatal stroke, coronary revascu-
Statin and Fibrate Combination Therapy
sider medical therapy to reduce larization, or unstable angina. This
Combination therapy (statin and fibrate)
the risk of pancreatitis. C reduction in risk was seen in patients with
is associated with an increased risk for
10.30 In adults with moderate hypertri- or without diabetes at baseline. The com-
posite of cardiovascular death, nonfatal abnormal transaminase levels, myositis,
glyceridemia (fasting or non–fast-
MI, or nonfatal stroke was reduced by and rhabdomyolysis. The risk of rhabdo-
ing triglycerides 175–499 mg/dL),
26% (P < 0.001). Additional ischemic end myolysis is more common with higher
clinicians should address and
points were significantly lower in the ico- doses of statins and renal insufficiency
treat lifestyle factors (obesity and
sapent ethyl group than in the placebo and appears to be higher when statins
metabolic syndrome), secondary
group, including cardiovascular death, are combined with gemfibrozil (com-
factors (diabetes, chronic liver or
which was reduced by 20% (P 5 0.03). pared with fenofibrate) (121).
kidney disease and/or nephrotic In the ACCORD study, in patients with
syndrome, hypothyroidism), and The proportions of patients experiencing
adverse events and serious adverse type 2 diabetes who were at high risk for
medications that raise triglycer- ASCVD, the combination of fenofibrate
ides. C events were similar between the active
and placebo treatment groups. It should and simvastatin did not reduce the rate
10.31 In patients with atherosclerotic of fatal cardiovascular events, nonfatal
cardiovascular disease or other be noted that data are lacking with other
n-3 fatty acids, and results of the MI, or nonfatal stroke as compared with
cardiovascular risk factors on a simvastatin alone. Prespecified subgroup
REDUCE-IT trial should not be extrapo-
statin with controlled LDL cho- analyses suggested heterogeneity in treat-
lated to other products (117). As an
lesterol but elevated triglycer- ment effects with possible benefit for
example, the addition of 4 g per day of a
ides (135–499 mg/dL), the men with both a triglyceride level $204
carboxylic acid formulation of the n-3
addition of icosapent ethyl can mg/dL (2.3 mmol/L) and an HDL choles-
fatty acids eicosapentaenoic acid (EPA)
be considered to reduce car- terol level #34 mg/dL (0.9 mmol/L)
and docosahexaenoic acid (DHA) (n-3 car-
diovascular risk. A (122). A prospective trial of a newer
boxylic acid) to statin therapy in patients
with atherogenic dyslipidemia and high fibrate in this specific population of
cardiovascular risk, 70% of whom had patients is ongoing (123).
Hypertriglyceridemia should be addressed diabetes, did not reduce the risk of major
with dietary and lifestyle changes includ- adverse cardiovascular events compared Statin and Niacin Combination Therapy
ing weight loss and abstinence from alco- with the inert comparator of corn oil The Atherothrombosis Intervention in
hol (116). Severe hypertriglyceridemia (118). Metabolic Syndrome With Low HDL/High
(fasting triglycerides $500 mg/dL and Low levels of HDL cholesterol, often Triglycerides: Impact on Global Health
especially >1,000 mg/dL) may warrant associated with elevated triglyceride Outcomes (AIM-HIGH) trial randomized
pharmacologic therapy (fibric acid deriva- levels, are the most prevalent pattern over 3,000 patients (about one-third with
tives and/or fish oil) and reduction in die- of dyslipidemia in individuals with type diabetes) with established ASCVD, LDL
tary fat to reduce the risk of acute 2 diabetes. However, the evidence for cholesterol levels <180 mg/dL [4.7
mmol/L], low HDL cholesterol levels the cardiovascular event rate reduction vention strategy in those
(men <40 mg/dL [1.0 mmol/L] and with statins far outweighed the risk of with diabetes and a history
women <50 mg/dL [1.3 mmol/L]), and incident diabetes even for patients at of atherosclerotic cardiovas-
triglyceride levels of 150–400 mg/dL highest risk for diabetes (128). The cular disease. A
(1.7–4.5 mmol/L) to statin therapy plus absolute risk increase was small (over 5 10.35 For patients with atheroscle-
extended-release niacin or placebo. The years of follow-up, 1.2% of participants
rotic cardiovascular disease and
trial was halted early due to lack of effi- on placebo developed diabetes and
documented aspirin allergy, clo-
cacy on the primary ASCVD outcome 1.5% on rosuvastatin developed diabe-
pidogrel (75 mg/day) should be
(first event of the composite of death tes) (128). A meta-analysis of 13 ran-
used. B
from CHD, nonfatal MI, ischemic stroke, domized statin trials with 91,140
10.36 Dual antiplatelet therapy (with
hospitalization for an ACS, or symptom- participants showed an odds ratio of
low-dose aspirin and a P2Y12
driven coronary or cerebral revasculariza- 1.09 for a new diagnosis of diabetes, so
that (on average) treatment of 255 inhibitor) is reasonable for a

tion) and a possible increase in ischemic year after an acute coronary
stroke in those on combination therapy patients with statins for 4 years resulted
in one additional case of diabetes while syndrome and may have bene-
(124).
simultaneously preventing 5.4 vascular fits beyond this period. A
The much larger Heart Protection
events among those 255 patients (127). 10.37 Long-term treatment with dual
Study 2–Treatment of HDL to Reduce
antiplatelet therapy should be
the Incidence of Vascular Events (HPS2-
Lipid-Lowering Agents and Cognitive considered for patients with
THRIVE) trial also failed to show a bene-
Function prior coronary intervention,
fit of adding niacin to background statin
Although concerns regarding a potential high ischemic risk, and low
therapy (125). A total of 25,673 patients
adverse impact of lipid-lowering agents bleeding risk to prevent
with prior vascular disease were ran-
on cognitive function have been raised, major adverse cardiovascular
domized to receive 2 g of extended-
several lines of evidence point against events. A
release niacin and 40 mg of laropiprant
this association, as detailed in a 2018 10.38 Combination therapy with aspi-
(an antagonist of the prostaglandin D2
European Atherosclerosis Society Con- rin plus low-dose rivaroxaban
receptor DP1 that has been shown to
sensus Panel statement (129). First, should be considered for
improve adherence to niacin therapy)
there are three large randomized trials patients with stable coronary
versus a matching placebo daily and fol- of statin versus placebo where specific and/or peripheral artery dis-
lowed for a median follow-up period of cognitive tests were performed, and no ease and low bleeding risk to
3.9 years. There was no significant dif- differences were seen between statin prevent major adverse limb
ference in the rate of coronary death, and placebo (130–133). In addition, no and cardiovascular events. A
MI, stroke, or coronary revascularization change in cognitive function has been 10.39 Aspirin therapy (75–162 mg/
with the addition of niacin–laropiprant reported in studies with the addition of day) may be considered as a
versus placebo (13.2% vs. 13.7%; rate ezetimibe (102) or PCSK9 inhibitors primary prevention strategy in
ratio 0.96; P 5 0.29). Niacin–laropiprant (105,134) to statin therapy, including those with diabetes who are at
was associated with an increased inci- among patients treated to very low LDL
dence of new-onset diabetes (absolute increased cardiovascular risk,
cholesterol levels. In addition, the most after a comprehensive discus-
excess, 1.3 percentage points; P < recent systematic review of the U.S.
0.001) and disturbances in diabetes sion with the patient on the
Food and Drug Administration’s (FDA’s)
control among those with diabetes. In benefits versus the comparable
postmarketing surveillance databases,
addition, there was an increase in seri- increased risk of bleeding. A
randomized controlled trials, and cohort,
ous adverse events associated with the case-control, and cross-sectional studies
gastrointestinal system, musculoskeletal evaluating cognition in patients receiving Risk Reduction
system, skin, and, unexpectedly, infec- statins found that published data do not Aspirin has been shown to be effective
tion and bleeding. reveal an adverse effect of statins on cog- in reducing cardiovascular morbidity
Therefore, combination therapy with nition (135). Therefore, a concern that and mortality in high-risk patients with
a statin and niacin is not recommended statins or other lipid-lowering agents previous MI or stroke (secondary pre-
given the lack of efficacy on major might cause cognitive dysfunction or vention) and is strongly recommended.
ASCVD outcomes and increased side dementia is not currently supported by In primary prevention, however, among
effects. evidence and should not deter their use patients with no previous cardiovascular
in individuals with diabetes at high risk events, its net benefit is more contro-
Diabetes Risk With Statin Use for ASCVD (135). versial (136,137).
Several studies have reported a mod- Previous randomized controlled trials
estly increased risk of incident diabetes ANTIPLATELET AGENTS of aspirin specifically in patients with
with statin use (126,127), which may be diabetes failed to consistently show a
limited to those with diabetes risk fac- Recommendations significant reduction in overall ASCVD
tors. An analysis of one of the initial 10.34 Use aspirin therapy (75–162 end points, raising questions about the
studies suggested that although statin mg/day) as a secondary pre- efficacy of aspirin for primary preven-
use was associated with diabetes risk, tion in people with diabetes, although
some sex differences were suggested 1.36–3.28]; P 5 0.0007). In ASPREE, Aspirin Use in People <50 Years of
(138–140). including 19,114 individuals, for cardio- Age
The Antithrombotic Trialists’ Col- vascular disease (fatal CHD, MI, stroke, Aspirin is not recommended for those at
laboration published an individual or hospitalization for heart failure) after low risk of ASCVD (such as men and
patient–level meta-analysis (136) of the a median of 4.7 years of follow-up, the women aged <50 years with diabetes
six large trials of aspirin for primary pre- rates per 1,000 person-years were 10.7 with no other major ASCVD risk factors)
vention in the general population. These as the low benefit is likely to be out-
vs. 11.3 events in aspirin vs. placebo
trials collectively enrolled over 95,000 weighed by the risks of bleeding. Clinical
groups (HR 0.95 [95% CI 0.83–1.08]). The
participants, including almost 4,000 with judgment should be used for those at
rate of major hemorrhage per 1,000 per-
diabetes. Overall, they found that aspirin intermediate risk (younger patients with
son-years was 8.6 events vs. 6.2 events,
reduced the risk of serious vascular one or more risk factors or older patients
respectively (HR 1.38 [95% CI 1.18–1.62];
events by 12% (relative risk 0.88 [95% CI with no risk factors) until further
P < 0.001).
0.82–0.94]). The largest reduction was research is available. Patients’ willingness

Thus, aspirin appears to have a mod-
for nonfatal MI, with little effect on to undergo long-term aspirin therapy
est effect on ischemic vascular events, should also be considered (151). Aspirin
CHD death (relative risk 0.95 [95% CI
with the absolute decrease in events use in patients aged <21 years is gener-
0.78–1.15]) or total stroke.
depending on the underlying ASCVD risk. ally contraindicated due to the associ-
Most recently, the ASCEND (A Study
The main adverse effect is an increased ated risk of Reye syndrome.
of Cardiovascular Events iN Diabetes)
trial randomized 15,480 patients with risk of gastrointestinal bleeding. The
diabetes but no evident cardiovascular excess risk may be as high as 5 per 1,000 Aspirin Dosing
disease to aspirin 100 mg daily or pla- per year in real-world settings. However, Average daily dosages used in most clini-
cebo (141). The primary efficacy end for adults with ASCVD risk >1% per year, cal trials involving patients with diabetes
point was vascular death, MI, or stroke the number of ASCVD events prevented ranged from 50 mg to 650 mg but were
or transient ischemic attack. The pri- will be similar to the number of episodes mostly in the range of 100–325 mg/day.
mary safety outcome was major bleed- of bleeding induced, although these com- There is little evidence to support any
ing (i.e., intracranial hemorrhage, sight- plications do not have equal effects on specific dose, but using the lowest possi-
threatening bleeding in the eye, gastro- long-term health (144). ble dose may help to reduce side effects
intestinal bleeding, or other serious Recommendations for using aspirin as (152). In the ADAPTABLE (Aspirin Dosing:
bleeding). During a mean follow-up of primary prevention include both men and A Patient-Centric Trial Assessing Benefits
7.4 years, there was a significant 12% women aged $50 years with diabetes and and Long-term Effectiveness) trial of
reduction in the primary efficacy end at least one additional major risk factor patients with established cardiovascular
point (8.5% vs. 9.6%; P 5 0.01). In con- (family history of premature ASCVD, hyper- disease, 38% of whom had diabetes,
trast, major bleeding was significantly tension, dyslipidemia, smoking, or chronic there were no significant differences in
increased from 3.2% to 4.1% in the kidney disease/albuminuria) who are not at cardiovascular events or major bleeding
aspirin group (rate ratio 1.29; P 5 increased risk of bleeding (e.g., older age, between patients assigned to 81 mg and
0.003), with most of the excess being anemia, renal disease) (145–148). Noninva- those assigned to 325 mg of aspirin daily
gastrointestinal bleeding and other sive imaging techniques such as coronary (153). In the U.S., the most common
extracranial bleeding. There were no sig- calcium scoring may potentially help further low-dose tablet is 81 mg. Although plate-
nificant differences by sex, weight, or tailor aspirin therapy, particularly in those at lets from patients with diabetes have
duration of diabetes or other baseline low risk (149,150). For patients over the altered function, it is unclear what, if
factors including ASCVD risk score. any, effect that finding has on the
age of 70 years (with or without diabetes),
Two other large randomized trials of required dose of aspirin for cardioprotec-
the balance appears to have greater risk
aspirin for primary prevention, in tive effects in the patient with diabetes.
than benefit (141,143). Thus, for primary
patients without diabetes (ARRIVE [Aspi- Many alternate pathways for platelet
prevention, the use of aspirin needs to be
rin to Reduce Risk of Initial Vascular activation exist that are independent of
carefully considered and may generally not
Events]) (142) and in the elderly (ASPREE thromboxane A2 and thus are not sensi-
be recommended. Aspirin may be consid- tive to the effects of aspirin (154).
[Aspirin in Reducing Events in the
Elderly]) (143), which included 11% with ered in the context of high cardiovascular “Aspirin resistance” has been described
diabetes, found no benefit of aspirin on risk with low bleeding risk, but generally in patients with diabetes when mea-
the primary efficacy end point and an not in older adults. Aspirin therapy for pri- sured by a variety of ex vivo and in vitro
increased risk of bleeding. In ARRIVE, mary prevention may be considered in the methods (platelet aggregometry, mea-
with 12,546 patients over a period of 60 context of shared decision-making, which surement of thromboxane B2) (155), but
months follow-up, the primary end point carefully weighs the cardiovascular benefits other studies suggest no impairment in
occurred in 4.29% vs. 4.48% of patients with the fairly comparable increase in risk aspirin response among patients with
in the aspirin versus placebo groups (HR of bleeding. diabetes (156). A recent trial suggested
0.96 [95% CI 0.81–1.13]; P 5 0.60). Gas- For patients with documented ASCVD, that more frequent dosing regimens of
trointestinal bleeding events (character- use of aspirin for secondary prevention aspirin may reduce platelet reactivity in
ized as mild) occurred in 0.97% of has far greater benefit than risk; for this individuals with diabetes (157); however,
patients in the aspirin group vs. 0.46% in indication, aspirin is still recommended these observations alone are insufficient
the placebo group (HR 2.11 [95% CI (136). to empirically recommend that higher
doses of aspirin be used in this group at peripheral artery disease to prevent presence of any of the follow-
this time. Another recent meta-analysis major adverse limb and cardiovascular ing: atypical cardiac symptoms
raised the hypothesis that low-dose aspi- complications. In the COMPASS (Cardio- (e.g., unexplained dyspnea,
rin efficacy is reduced in those weighing vascular Outcomes for People Using chest discomfort); signs or
more than 70 kg (158); however, the Anticoagulation Strategies) trial of
symptoms of associated vas-
ASCEND trial found benefit of low-dose 27,395 patients with established coro-
cular disease including carotid
aspirin in those in this weight range, nary artery disease and/or peripheral
bruits, transient ischemic
which would thus not validate this sug- artery disease, aspirin plus rivaroxaban
attack, stroke, claudication, or
gested hypothesis (141). It appears that 2.5 mg twice daily was superior to aspi-
peripheral arterial disease; or
75–162 mg/day is optimal. rin plus placebo in the reduction of car-
diovascular ischemic events including electrocardiogram abnormali-
major adverse limb events. The absolute ties (e.g., Q waves). E
Indications for P2Y12 Receptor
Antagonist Use benefits of combination therapy app-

A P2Y12 receptor antagonist in combina- eared larger in patients with diabetes, Treatment
tion with aspirin is reasonable for at least who comprised 10,341 of the trial partici-
pants (165,166). A similar treatment Recommendations
1 year in patients following an ACS and
strategy was evaluated in the Vascular 10.42 Among patients with type 2
may have benefits beyond this period.
Outcomes Study of ASA (acetylsalicylic diabetes who have estab-
Evidence supports use of either ticagre-
acid) Along with Rivaroxaban in Endovas- lished atherosclerotic car-
lor or clopidogrel if no percutaneous cor-
cular or Surgical Limb Revascularization diovascular disease or esta-
onary intervention was performed and
for Peripheral Artery Disease (VOYAGER blished kidney disease, a
clopidogrel, ticagrelor, or prasugrel if a
PAD) trial (167), in which 6,564 patients sodium–glucose cotrans-
percutaneous coronary intervention was
with peripheral artery disease who had porter 2 inhibitor or gluca-
performed (159). In patients with diabe-
undergone revascularization were ran- gon-like peptide 1 receptor
tes and prior MI (1–3 years before), add-
domly assigned to receive rivaroxaban agonist with demonstrated
ing ticagrelor to aspirin significantly
2.5 mg twice daily plus aspirin or placebo cardiovascular disease ben-
reduces the risk of recurrent ischemic
plus aspirin. Rivaroxaban treatment in efit (Table 10.3B and Table
events including cardiovascular and CHD
this group of patients was also associated 10.3C) is recommended as
death (160). Similarly, the addition of
with a significantly lower incidence of part of the comprehensive
ticagrelor to aspirin reduced the risk of
ischemic cardiovascular events, includ- cardiovascular risk reduc-
ischemic cardiovascular events compared
ing major adverse limb events. How- tion and/or glucose-lower-
with aspirin alone in patients with diabe-
ever, an increased risk of major ing regimens. A
tes and stable coronary artery disease
bleeding was noted with rivaroxaban 10.42a In patients with type 2 dia-
(161,162). However, a higher incidence
added to aspirin treatment in both betes and established ath-
of major bleeding, including intracranial
COMPASS and VOYAGER PAD. erosclerotic cardiovascular
hemorrhage, was noted with dual anti-
The risks and benefits of dual antiplate- disease, multiple atheroscle-
platelet therapy. The net clinical benefit
let or antiplatelet plus anticoagulant treat- rotic cardiovascular disease
(ischemic benefit vs. bleeding risk) was
ment strategies should be thoroughly risk factors, or diabetic kid-
improved with ticagrelor therapy in the
discussed with eligible patients, and ney disease, a sodium–
large prespecified subgroup of patients shared decision-making should be used glucose cotransporter 2
with history of percutaneous coronary to determine an individually appropriate inhibitor with demonstrated
intervention, while no net benefit was treatment approach. This field of cardio- cardiovascular benefit is rec-
seen in patients without prior percutane- vascular risk reduction is evolving rapidly, ommended to reduce the
ous coronary intervention (162). However, as are the definitions of optimal care for risk of major adverse cardio-
early aspirin discontinuation compared patients with differing types and circum- vascular events and/or heart
with continued dual antiplatelet therapy stances of cardiovascular complications. failure hospitalization. A
after coronary stenting may reduce the
10.42b In patients with type 2 dia-
risk of bleeding without a corresponding CARDIOVASCULAR DISEASE betes and established ath-
increase in the risks of mortality and
Screening erosclerotic cardiovascular
ischemic events, as shown in a prespeci-
disease or multiple risk
fied analysis of patients with diabetes Recommendations factors for atherosclerotic
enrolled in the TWILIGHT (Ticagrelor With 10.40 In asymptomatic patients, rou- cardiovascular disease, a
Aspirin or Alone in High-Risk Patients tine screening for coronary glucagon-like peptide 1 re-
After Coronary Intervention) trial and a artery disease is not recom- ceptor agonist with demon-
recent meta-analysis (163,164). mended as it does not improve strated cardiovascular benefit
outcomes as long as athero- is recommended to reduce
Combination Antiplatelet and sclerotic cardiovascular disease the risk of major adverse car-
Anticoagulation Therapy
risk factors are treated. A diovascular events. A
Combination therapy with aspirin plus
10.41 Consider investigations for 10.42c In patients with type 2 diabe-
low dose rivaroxaban may be considered
coronary artery disease in the tes and established athero-
for patients with stable coronary and/or
sclerotic cardiovascular disease and 2) an abnormal resting electrocar- scoring and computed tomography angi-
or multiple risk factors for diogram (ECG). Exercise ECG testing ography, to identify patient subgroups for
atherosclerotic cardiovascular without or with echocardiography different treatment strategies remains
disease, combined therapy may be used as the initial test. In unproven in asymptomatic patients with
with a sodium–glucose co- adults with diabetes $40 years of age, diabetes, though research is ongoing.
transporter 2 inhibitor with measurement of coronary artery cal- Although asymptomatic patients with dia-
demonstrated cardiovascular cium is also reasonable for cardiovas- betes with higher coronary disease bur-
benefit and a glucagon-like cular risk assessment. Pharmacologic den have more future cardiac events
peptide 1 receptor agonist stress echocardiography or nuclear (172,178,179), the role of these tests
with demonstrated cardiovas- imaging should be considered in indi- beyond risk stratification is not clear.
cular benefit may be consid- viduals with diabetes in whom resting While coronary artery screening
ered for additive reduction in ECG abnormalities preclude exercise methods, such as calcium scoring, may
improve cardiovascular risk assessment

the risk of adverse cardiovas- stress testing (e.g., left bundle branch
cular and kidney events. A block or ST-T abnormalities). In addi- in people with type 2 diabetes (180),
10.43 In patients with type 2 diabe- tion, individuals who require stress their routine use leads to radiation
tes and established heart fail- testing and are unable to exercise exposure and may result in unnecessary
ure with reduced ejection should undergo pharmacologic stress invasive testing such as coronary angi-
fraction, a sodium–glucose echocardiography or nuclear imaging. ography and revascularization proce-
cotransporter 2 inhibitor with dures. The ultimate balance of benefit,
proven benefit in this patient Screening Asymptomatic Patients cost, and risks of such an approach in
The screening of asymptomatic patients asymptomatic patients remains contro-
population is recommended
with high ASCVD risk is not recom- versial, particularly in the modern set-
to reduce risk of worsening
mended (168), in part because these ting of aggressive ASCVD risk factor
heart failure and cardiovascu-
high-risk patients should already be control.
lar death. A
10.44 In patients with known ath- receiving intensive medical therapy—an
approach that provides benefit similar Lifestyle and Pharmacologic
erosclerotic cardiovascular
Interventions
disease, particularly coro- to invasive revascularization (169,170).
Intensive lifestyle intervention focusing
nary artery disease, ACE There is also some evidence that silent
on weight loss through decreased caloric
inhibitor or angiotensin ischemia may reverse over time, adding
intake and increased physical activity as
receptor blocker therapy is to the controversy concerning aggres-
performed in the Action for Health in
recommended to reduce sive screening strategies (171). In pro-
Diabetes (Look AHEAD) trial may be con-
the risk of cardiovascular spective studies, coronary artery calcium
sidered for improving glucose control, fit-
events. A has been established as an independent
ness, and some ASCVD risk factors (181).
10.45 In patients with prior myo- predictor of future ASCVD events in
Patients at increased ASCVD risk should
cardial infarction, b-block- patients with diabetes and is consistently
receive statin, ACE inhibitor, or ARB ther-
ers should be continued for superior to both the UK Prospective Dia- apy if the patient has hypertension, and
3 years after the event. B betes Study (UKPDS) risk engine and the possibly aspirin, unless there are contra-
10.46 Treatment of patients with Framingham Risk Score in predicting risk indications to a particular drug class.
heart failure with reduced in this population (172–174). However, a Clear benefit exists for ACE inhibitor or
ejection fraction should randomized observational trial demon- ARB therapy in patients with diabetic kid-
include a b-blocker with strated no clinical benefit to routine ney disease or hypertension, and these
proven cardiovascular out- screening of asymptomatic patients with agents are recommended for hyperten-
comes benefit, unless other- type 2 diabetes and normal ECGs (175). sion management in patients with known
wise contraindicated. A Despite abnormal myocardial perfusion ASCVD (particularly coronary artery dis-
10.47 In patients with type 2 dia- imaging in more than one in five patients, ease) (63,64,182). b-Blockers should be
betes with stable heart fail- cardiac outcomes were essentially equal used in patients with active angina or
ure, metformin may be (and very low) in screened versus HFrEF and for 3 years after MI in patients
continued for glucose low- unscreened patients. Accordingly, indis- with preserved left ventricular function
ering if estimated glomeru- criminate screening is not considered (183,184).
lar filtration rate remains cost-effective. Studies have found that a
>30 mL/min/1.73 m2 but risk factor–based approach to the initial Glucose-Lowering Therapies and
should be avoided in unsta- diagnostic evaluation and subsequent fol- Cardiovascular Outcomes
ble or hospitalized patients low-up for coronary artery disease fails to In 2008, the FDA issued a guidance for
with heart failure. B identify which patients with type 2 diabe- industry to perform cardiovascular out-
tes will have silent ischemia on screening comes trials for all new medications for
Cardiac Testing tests (176,177). the treatment for type 2 diabetes amid
Candidates for advanced or invasive Any benefit of newer noninvasive coro- concerns of increased cardiovascular
cardiac testing include those with 1) nary artery disease screening methods, risk (185). Previously approved diabetes
typical or atypical cardiac symptoms such as computed tomography calcium medications were not subject to the
Table 10.3A—Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed after the
issuance of the FDA 2008 guidelines: DPP-4 inhibitors
CARMELINA CAROLINA
SAVOR-TIMI 53 (214) EXAMINE (222) TECOS (216) (186,223) (186,224)
(n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,979) (n 5 6,042)
Intervention Saxagliptin/placebo Alogliptin/placebo Sitagliptin/placebo Linagliptin/placebo Linagliptin/
glimepiride
Main inclusion criteria Type 2 diabetes and Type 2 diabetes and Type 2 diabetes and Type 2 diabetes and Type 2 diabetes and
history of or ACS within 15–90 preexisting CVD high CV and high CV risk
multiple risk days before renal risk
factors for CVD randomization
A1C inclusion criteria $6.5 6.5–11.0 6.5–8.0 6.5–10.0 6.5–8.5

(%)
Age (years)† 65.1 61.0 65.4 65.8 64.0
Race (% White) 75.2 72.7 67.9 80.2 73.0
Sex (% male) 66.9 67.9 70.7 62.9 60.0
Diabetes duration 10.3 7.1 11.6 14.7 6.2
(years)†
Median follow-up 2.1 1.5 3.0 2.2 6.3
(years)
Statin use (%) 78 91 80 71.8 64.1
Metformin use (%) 70 66 82 54.8 82.5
Prior CVD/CHF (%) 78/13 100/28 74/18 57/26.8 34.5/4.5
Mean baseline A1C 8.0 8.0 7.2 7.9 7.2
(%)
Mean difference in 0.3‡ 0.3‡ 0.3‡ 0.36‡ 0
A1C between
groups at end of
treatment (%)
Year started/reported 2010/2013 2009/2013 2008/2015 2013/2018 2010/2019
Primary outcome§ 3-point MACE 1.00 3-point MACE 0.96 4-point MACE 0.98 3-point MACE 1.02 3-point MACE 0.98
(0.89–1.12) (95% UL #1.16) (0.89–1.08) (0.89–1.17) (0.84–1.14)
Key secondary Expanded MACE 1.02 4-point MACE 0.95 3-point MACE 0.99 Kidney composite 4-point MACE 0.99
outcome§ (0.94–1.11) (95% UL #1.14) (0.89–1.10) (ESRD, sustained (0.86–1.14)
$40% decrease
in eGFR, or renal
death) 1.04
(0.89–1.22)
Cardiovascular death§ 1.03 (0.87–1.22) 0.85 (0.66–1.10) 1.03 (0.89–1.19) 0.96 (0.81–1.14) 1.00 (0.81–1.24)
MI§ 0.95 (0.80–1.12) 1.08 (0.88–1.33) 0.95 (0.81–1.11) 1.12 (0.90–1.40) 1.03 (0.82–1.29)
Stroke§ 1.11 (0.88–1.39) 0.91 (0.55–1.50) 0.97 (0.79–1.19) 0.91 (0.67–1.23) 0.86 (0.66–1.12)
HF hospitalization§ 1.27 (1.07–1.51) 1.19 (0.90–1.58) 1.00 (0.83–1.20) 0.90 (0.74–1.08) 1.21 (0.92–1.59)
Unstable angina 1.19 (0.89–1.60) 0.90 (0.60–1.37) 0.90 (0.70–1.16) 0.87 (0.57–1.31) 1.07 (0.74–1.54)
hospitalization§
All-cause mortality§ 1.11 (0.96–1.27) 0.88 (0.71–1.09) 1.01 (0.90–1.14) 0.98 (0.84–1.13) 0.91 (0.78–1.06)
Worsening 1.08 (0.88–1.32) — — Kidney composite —
nephropathy§jj (see above)
—, not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; DPP-
4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GLP-1, glucagon-like peptide 1; HF, heart
failure; MACE, major adverse cardiovascular event; MI, myocardial infarction; UL, upper limit. Data from this table was adapted from Cefalu
et al. (225) in the January 2018 issue of Diabetes Care. †Age was reported as means in all trials except EXAMINE, which reported medians;
diabetes duration was reported as means in all trials except SAVOR-TIMI 53 and EXAMINE, which reported medians. ‡Significant difference in
A1C between groups (P < 0.05). §Outcomes reported as hazard ratio (95% CI). jjWorsening nephropathy is defined as a doubling of creatinine
level, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL (530 mmol/L) in SAVOR-TIMI 53. Worsening nephropathy was a
prespecified exploratory adjudicated outcome in SAVOR-TIMI 53.
S160
Table 10.3B—Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: GLP-1
receptor agonists
ELIXA (199) LEADER (194) SUSTAIN-6 (195)* EXSCEL (200) REWIND (198) PIONEER-6 (196)
(n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,901) (n 5 3,183)
Intervention Lixisenatide/placebo Liraglutide/placebo Semaglutide s.c. Exenatide QW/ Dulaglutide/ Semaglutide oral/
injection/placebo placebo placebo placebo
Main inclusion criteria Type 2 diabetes and Type 2 diabetes and Type 2 diabetes Type 2 diabetes Type 2 diabetes Type 2 diabetes
history of ACS preexisting CVD, and preexisting with or without and prior ASCVD and high CV risk
(<180 days) CKD, or HF at $50 CVD, HF, or CKD preexisting CVD event or risk (age of $50
years of age or CV at $50 years of factors for years with
Cardiovascular Disease and Risk Management
risk at $60 years age or CV risk at ASCVD established CVD

of age $60 years of age or CKD, or age
of $60 years
with CV risk
factors only)
A1C inclusion criteria (%) 5.5–11.0 $7.0 $7.0 6.5–10.0 #9.5 None
Age (years)† 60.3 64.3 64.6 62 66.2 66
Race (% White) 75.2 77.5 83.0 75.8 75.7 72.3
Sex (% male) 69.3 64.3 60.7 62 53.7 68.4
Diabetes duration 9.3 12.8 13.9 12 10.5 14.9
(years)†
Median follow-up (years) 2.1 3.8 2.1 3.2 5.4 1.3
Statin use (%) 93 72 73 74 66 85.2 (all lipid-
lowering)
Metformin use (%) 66 76 73 77 81 77.4
Prior CVD/CHF (%) 100/22 81/18 60/24 73.1/16.2 32/9 84.7/12.2
Mean baseline A1C (%) 7.7 8.7 8.7 8.0 7.4 8.2
Mean difference in A1C 0.3‡^ 0.4‡ 0.7 or 1.0Ù 0.53‡^ 0.61‡ 0.7
between groups at
end of treatment (%)
Year started/reported 2010/2015 2010/2016 2013/2016 2010/2017 2011/2019 2017/2019
Primary outcome§ 4-point MACE 1.02 3-point MACE 0.87 3-point MACE 0.74 3-point MACE 0.91 3-point MACE 0.88 3-point MACE 0.79
(0.89–1.17) (0.78–0.97) (0.58–0.95) (0.83–1.00) (0.79–0.99) (0.57–1.11)
Continued on p. S161
Diabetes Care Volume 45, Supplement 1, January 2022

Table 10.3B—Continued
ELIXA (199) LEADER (194) SUSTAIN-6 (195)* EXSCEL (200) REWIND (198) PIONEER-6 (196)
(n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,901) (n 5 3,183)
Key secondary Expanded MACE 1.02 Expanded MACE 0.88 Expanded MACE 0.74 Individual Composite Expanded MACE or
outcome§ (0.90–1.11) (0.81–0.96) (0.62–0.89) components of microvascular HF
MACE (see below) outcome (eye or hospitalization
renal outcome) 0.82 (0.61–1.10)
care.diabetesjournals.org
0.87 (0.79–0.95)
Cardiovascular 0.98 (0.78–1.22) 0.78 (0.66–0.93) 0.98 (0.65–1.48) 0.88 (0.76–1.02) 0.91 (0.78–1.06) 0.49 (0.27–0.92)
death§
MI§ 1.03 (0.87–1.22) 0.86 (0.73–1.00) 0.74 (0.51–1.08) 0.97 (0.85–1.10) 0.96 (0.79–1.15) 1.18 (0.73–1.90)
Stroke§ 1.12 (0.79–1.58) 0.86 (0.71–1.06) 0.61 (0.38–0.99) 0.85 (0.70–1.03) 0.76 (0.61–0.95) 0.74 (0.35–1.57)
HF hospitalization§ 0.96 (0.75–1.23) 0.87 (0.73–1.05) 1.11 (0.77–1.61) 0.94 (0.78–1.13) 0.93 (0.77–1.12) 0.86 (0.48–1.55)
Unstable angina 1.11 (0.47–2.62) 0.98 (0.76–1.26) 0.82 (0.47–1.44) 1.05 (0.94–1.18) 1.14 (0.84–1.54) 1.56 (0.60–4.01)
hospitalization§
All-cause mortality§ 0.94 (0.78–1.13) 0.85 (0.74–0.97) 1.05 (0.74–1.50) 0.86 (0.77–0.97) 0.90 (0.80–1.01) 0.51 (0.31–0.84)
Worsening — 0.78 (0.67–0.92) 0.64 (0.46–0.88) — 0.85 (0.77–0.93) —
nephropathy§jj
—, not assessed/reported; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease;
GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiovascular event; MI, myocardial infarction. Data from this table was adapted from Cefalu et al. (225) in the January 2018 issue of Dia-
betes Care. *Powered to rule out a hazard ratio of 1.8; superiority hypothesis not prespecified. †Age was reported as means in all trials; diabetes duration was reported as means in all trials except EXSCEL, which
reported medians. ‡Significant difference in A1C between groups (P < 0.05). ÙA1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide. §Outcomes reported as hazard ratio (95% CI).
jjWorsening nephropathy is defined as the new onset of urine albumin-to-creatinine ratio >300 mg/g creatinine or a doubling of the serum creatinine level and an estimated glomerular filtration rate of <45
mL/min/1.73 m2, the need for continuous renal replacement therapy, or death from renal disease in LEADER and SUSTAIN-6 and as new macroalbuminuria, a sustained decline in estimated glomerular filtration
rate of 30% or more from baseline, or chronic renal replacement therapy in REWIND. Worsening nephropathy was a prespecified exploratory adjudicated outcome in LEADER, SUSTAIN-6, and REWIND.
of results.
SGLT2 Inhibitor Trials
cardiovascular disease.
(https://doi.org/10.2337/dc22-S011).
conducted that separately assessed 1)

SGLT2 inhibitor canagliflozin have been
death in adults with type 2 diabetes and
0.49–0.77]; P < 0.001) (8). The FDA added
participants had a mean age of 63
0.74–0.99]; P 5 0.04 for superiority) and

7,020 patients with type 2 diabetes and
placebo on cardiovascular outcomes in
disease is included in Section 11, “Chronic
renal outcomes in patients with type 2
(see Table 10.3A, Table 10.3B, and

additional data on cardiovascular and
cular outcomes trials have provided
Two large outcomes trials of the

rate 3.7% vs. 5.9%, HR 0.62 [95% CI
cardiovascular death by 38% (absolute
empagliflozin group 0.86 [95% CI
vs. 12.1% in the placebo group, HR in the
showed that over a median follow-up of
blind trial that assessed the effect of
Cardiovascular outcomes trials of
Kidney Disease and Risk Management”
the risk of major adverse cardiovascular

an indication for empagliflozin to reduce
Table 10.3C). An expanded review of
cular death by 14% (absolute rate 10.5%

ite outcome of MI, stroke, and cardiovas-
3.1 years, treatment reduced the compos-
10 years, and 99% had established car-
OUTCOME) was a randomized, double-
empagliflozin, an SGLT2 inhibitor, versus

betes Mellitus Patients (EMPA-REG
The BI 10773 (Empagliflozin) Cardiovas-
outcomes despite lower rates of hypo-
nylurea, glimepiride, on cardiovascular
DPP-4 inhibitor, linagliptin, and a sulfo-
demonstrated noninferiority between a
tion, the CAROLINA (Cardiovascular
lar benefits relative to placebo. In addi-
have all, so far, not shown cardiovascu-
at high risk for cardiovascular disease
dipeptidyl peptidase 4 (DPP-4) inhibitors

the effects of glucose-lowering and other
diabetes with cardiovascular disease or
diovascular disease. EMPA-REG OUTCOME

therapies in patients with chronic kidney
group (186). However, results from

Outcome Study of Linagliptin Versus Gli-
guidance. Recently published cardiovas-
years, 57% had diabetes for more than

other new agents have provided a mix
glycemia in the linagliptin treatment
existing cardiovascular disease. Study

cular Outcome Event Trial in Type 2 Dia-
mepiride in Type 2 Diabetes) study
S161

S162
Table 10.3C—Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: SGLT2
inhibitors
EMPEROR-Reduced
EMPA-REG CANVAS Program DECLARE-TIMI DAPA-CKD (190,226) DAPA-HF (191) (217,219)
OUTCOME (8) (9) 58 (189) CREDENCE (187) (n 5 4,304; 2,906 VERTIS CV (192,227) (n 5 4,744; 1,983 (n 5 3,730; 1,856
(n 5 7,020) (n 5 10,142) (n 5 17,160) (n 5 4,401) with diabetes) (n 5 8,246) with diabetes) with diabetes)
Intervention Empagliflozin/ Canagliflozin/ Dapagliflozin/placebo Canagliflozin/placebo Dapagliflozin/ Ertugliflozin/placebo Dapagliflozin/placebo Empagliflozin/placebo*
placebo placebo placebo
Main inclusion Type 2 diabetes Type 2 diabetes Type 2 diabetes and Type 2 diabetes and Albuminuric kidney Type 2 diabetes and NYHA class II, III, or IV NYHA class II, III, or IV
criteria and preexisting and preexisting established ASCVD albuminuric kidney disease, with or ASCVD heart failure and an heart failure and an
CVD CVD at $30 or multiple risk disease without diabetes ejection fraction ejection fraction
years of age or factors for ASCVD #40%, with or #40%, with or
>2 CV risk without diabetes without diabetes

factors at $50
years of age
A1C inclusion 7.0–10.0 7.0–10.5 $6.5 6.5–12 __ 7.0–10.5 __ __
criteria (%)
Age (years)† 63.1 63.3 64.0 63 61.8 64.4 66 67.2, 66.5
Race (% White) 72.4 78.3 79.6 66.6 53.2 87.8 70.3 71.1, 69.8
Sex (% male) 71.5 64.2 62.6 66.1 66.9 70 76.6 76.5, 75.6
Diabetes duration 57% >10 13.5 11.0 15.8 12.9
(years)†
Median follow-up 3.1 3.6 4.2 2.6 2.4 3.5 1.5 1.3
(years)
Statin use (%) 77 75 75 (statin or 69 64.9 __ __ __
ezetimibe use)
Metformin 74 77 82 57.8 29 51.2% (of patients
use (%) with diabetes)
Prior 99/10 65.6/14.4 40/10 50.4/14.8 37.4/10.9 99.9/23.1 100% with CHF 100% with CHF
CVD/CHF (%)
Mean baseline A1C 8.1 8.2 8.3 8.3 7.1% 8.2 __ __
(%) (7.8% in those
with diabetes)
Mean difference in 0.3Ù 0.58‡ 0.43‡ 0.31 N/A 0.48 to 0.5 N/A N/A
A1C between
groups at end of
treatment (%)
Year started/ 2010/2015 2009/2017 2013/2018 2017/2019 2017/2020 2013/2020 2017/2019 2017/2020
reported
Diabetes Care Volume 45, Supplement 1, January 2022
Continued on p. S163

Table 10.3C—Continued
EMPEROR-Reduced
EMPA-REG CANVAS Program DECLARE-TIMI DAPA-CKD (190,226) DAPA-HF (191) (217,219)
OUTCOME (8) (9) 58 (189) CREDENCE (187) (n 5 4,304; 2,906 VERTIS CV (192,227) (n 5 4,744; 1,983 (n 5 3,730; 1,856
(n 5 7,020) (n 5 10,142) (n 5 17,160) (n 5 4,401) with diabetes) (n 5 8,246) with diabetes) with diabetes)
Primary outcome§ 3-point MACE 0.86 3-point MACE 0.86 3-point MACE 0.93 ESRD, doubling of $50% decline in 3-point MACE 0.97 Worsening heart CV death or HF
(0.74–0.99) (0.75–0.97) (0.84–1.03) creatinine, or death eGFR, ESKD, or (0.85–1.11) failure or death hospitalization 0.75
care.diabetesjournals.org
CV death or HF from renal or CV death from renal from CV causes (0.65–0.86)

hospitalization 0.83 cause 0.70 or CV cause 0.61 0.74 (0.65–0.85)
(0.73–0.95) (0.59–0.82) (0.51–0.72) Results did not differ
by diabetes status
Key secondary 4-point MACE 0.89 All-cause and CV Death from any cause CV death or HF $50% decline in CV death or HF CV death or HF Total HF
outcome§ (0.78–1.01) mortality (see 0.93 (0.82–1.04) hospitalization 0.69 eGFR, ESKD, or hospitalization 0.88 hospitalization 0.75 hospitalizations
below) (0.57–0.83) death from renal (0.75–1.03) (0.65–0.85) 0.70 (0.58–0.85)
3-point MACE 0.80 cause 0.56
(0.67–0.95) (0.45–0.68)
Renal composite CV death or HF CV death 0.92 Mean slope of change in
($40% decrease hospitalization 0.71 (0.77–1.11) eGFR 1.73 (1.10–2.37)
in eGFR rate to (0.55–0.92) Renal death, renal
<60 mL/min/1.73 Death from any replacement
m2, new ESRD, or cause 0.69 therapy, or doubling
death from renal (0.53–0.88) of creatinine 0.81
or CV causes 0.76 (0.63–1.04)
(0.67–0.87)
Cardiovascular 0.62 (0.49–0.77) 0.87 (0.72–1.06) 0.98 (0.82–1.17) 0.78 (0.61–1.00) 0.81 (0.58–1.12) 0.92 (0.77–1.11) 0.82 (0.69–0.98) 0.92 (0.75–1.12)
death§
MI§ 0.87 (0.70–1.09) 0.89 (0.73–1.09) 0.89 (0.77–1.01) — 1.04 (0.86–1.26) —
Stroke§ 1.18 (0.89–1.56) 0.87 (0.69–1.09) 1.01 (0.84–1.21) — 1.06 (0.82–1.37) —
HF hospitalization§ 0.65 (0.50–0.85) 0.67 (0.52–0.87) 0.73 (0.61–0.88) 0.61 (0.47–0.80) 0.70 (0.54–0.90) 0.70 (0.59–0.83) 0.69 (0.59–0.81)
Unstable angina 0.99 (0.74–1.34) — — — __
hospitalization§
All-cause mortality§ 0.68 (0.57–0.82) 0.87 (0.74–1.01) 0.93 (0.82–1.04) 0.83 (0.68–1.02) 0.69 (0.53–0.88) 0.93 (0.80–1.08) 0.83 (0.71–0.97) 0.92 (0.77–1.10)
Worsening 0.61 (0.53–0.70) 0.60 (0.47–0.77) 0.53 (0.43–0.66) (See primary (See primary (See secondary 0.71 (0.44–1.16) Composite renal
nephropathy§jj outcome) outcome) outcomes) outcome 0.50
(0.32–0.77)
—, not assessed/reported; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure;
MACE, major adverse cardiovascular event; MI, myocardial infarction; SGLT2, sodium–glucose cotransporter 2; NYHA, New York Heart Association. Data from this table was adapted from Cefalu et al.
(225) in the January 2018 issue of Diabetes Care. *Baseline characteristics for EMPEROR-Reduced displayed as empagliflozin, placebo. †Age was reported as means in all trials; diabetes duration was
reported as means in all trials except EMPA-REG OUTCOME, which reported as percentage of population with diabetes duration >10 years, and DECLARE-TIMI 58, which reported median. ‡Significant
difference in A1C between groups (P < 0.05). ÙA1C change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for 10 mg and 0.36% for 25 mg of empagliflozin).
§Outcomes reported as hazard ratio (95% CI). jjDefinitions of worsening nephropathy differed between trials.
S163

the cardiovascular effects of treatment end point of end-stage kidney disease mg daily or placebo. The primary out-
in patients at high risk for major alone by 32% (HR 0.68 [95% CI come was a composite of sustained
adverse cardiovascular events and 2) 0.54–0.86]). Canagliflozin was additionally decline in eGFR of at least 50%, end-
the impact of canagliflozin therapy on found to have a lower risk of the compos- stage kidney disease, or death from renal
cardiorenal outcomes in patients with ite of cardiovascular death, MI, or stroke or cardiovascular causes. Over a median
diabetes-related chronic kidney disease (HR 0.80 [95% CI 0.67–0.95]), as well as follow-up period of 2.4 years, a primary
(187). First, the Canagliflozin Cardiovas- lower risk of hospitalizations for heart fail- outcome event occurred in 9.2% of
cular Assessment Study (CANVAS) Pro- ure (HR 0.61 [95% CI 0.47–0.80]) and of participants in the dapagliflozin group
gram integrated data from two trials. the composite of cardiovascular death or and 14.5% of those in the placebo
The CANVAS trial that started in 2009 hospitalization for heart failure (HR 0.69 group. The risk of the primary compos-
was partially unblinded prior to comple- [95% CI 0.57–0.83]). In terms of safety, ite outcome was significantly lower
tion because of the need to file interim no significant increase in lower-limb with dapagliflozin therapy compared
cardiovascular outcomes data for regu- amputations, fractures, acute kidney with placebo (HR 0.61 [95% CI 0.51–

latory approval of the drug (188). There- injury, or hyperkalemia was noted for 0.72]), as were the risks for a renal
after, the postapproval CANVAS-Renal canagliflozin relative to placebo in CRE- composite outcome of sustained
(CANVAS-R) trial was started in 2014. DENCE. An increased risk for diabetic decline in eGFR of at least 50%, end-
Combining both of these trials, 10,142 ketoacidosis was noted, however, with stage kidney disease, or death from
participants with type 2 diabetes were 2.2 and 0.2 events per 1,000 patient- renal causes (HR 0.56 [95% CI
randomized to canagliflozin or placebo years noted in the canagliflozin and pla- 0.45–0.68]), and a composite of cardio-
and were followed for an average 3.6 cebo groups, respectively (HR 10.80 [95% vascular death or hospitalization for
years. The mean age of patients was 63 CI 1.39–83.65]) (187). heart failure (HR 0.71 [95% CI
years, and 66% had a history of cardio- The Dapagliflozin Effect on Cardiovas- 0.55–0.92]). The effects of dapagliflozin
vascular disease. The combined analysis cular Events–Thrombosis in Myocardial therapy were similar in patients with
of the two trials found that canagliflozin Infarction 58 (DECLARE-TIMI 58) trial and without type 2 diabetes.
significantly reduced the composite out- was another randomized, double-blind Results of the Dapagliflozin and Pre-
come of cardiovascular death, MI, or trial that assessed the effects of dapagli- vention of Adverse Outcomes in Heart
stroke versus placebo (occurring in 26.9 flozin versus placebo on cardiovascular Failure (DAPA-HF) trial and the Empagli-
vs. 31.5 participants per 1,000 patient- and renal outcomes in 17,160 patients flozin Outcome Trial in Patients With
years; HR 0.86 [95% CI 0.75–0.97]). The with type 2 diabetes and established Chronic Heart Failure and a Reduced Ejec-
specific estimates for canagliflozin ver- ASCVD or multiple risk factors for athero- tion Fraction (EMPEROR-Reduced), which
sus placebo on the primary composite sclerotic cardiovascular disease (189). assessed the effects of dapagliflozin and
cardiovascular outcome were HR 0.88 Study participants had a mean age of 64 empagliflozin, respectively, in patients
(95% CI 0.75–1.03) for the CANVAS trial years, with 40% of study participants with established heart failure (191), are
and 0.82 (0.66–1.01) for CANVAS-R, having established ASCVD at baseline—a described below in GLUCOSE-LOWERING THERA-
with no heterogeneity found between characteristic of this trial that differs from PIES AND HEART FAILURE.
trials. Of note, there was an increased other large cardiovascular trials where a The Evaluation of Ertugliflozin Efficacy
risk of lower-limb amputation with can- majority of participants had established and Safety Cardiovascular Outcomes
agliflozin (6.3 vs. 3.4 participants per cardiovascular disease. DECLARE-TIMI 58 Trial (VERTIS CV) (192) was a random-
1,000 patient-years; HR 1.97 [95% CI met the prespecified criteria for noninfer- ized, double-blind trial that established
1.41–2.75]) (9). Second, the Canagliflozin iority to placebo with respect to major the effects of ertugliflozin versus pla-
and Renal Events in Diabetes with Estab- adverse cardiovascular events but did not cebo on cardiovascular outcomes in
lished Nephropathy Clinical Evaluation show a lower rate of major adverse car- 8,246 patients with type 2 diabetes and
(CREDENCE) trial randomized 4,401 diovascular events when compared with established ASCVD. Participants were
patients with type 2 diabetes and chronic placebo (8.8% in the dapagliflozin group assigned to the addition of 5 mg or 15
diabetes-related kidney disease (UACR and 9.4% in the placebo group; HR 0.93 mg of ertugliflozin or to placebo once
>300 mg/g and eGFR 30 to <90 mL/ [95% CI 0.84–1.03]; P 5 0.17). A lower rate daily to background standard care.
min/1.73 m2) to canagliflozin 100 mg of cardiovascular death or hospitalization for Study participants had a mean age of
daily or placebo (187). The primary heart failure was noted (4.9% vs. 5.8%; HR 64.4 years and a mean duration of dia-
outcome was a composite of end-stage 0.83 [95% CI 0.73–0.95]; P 5 0.005), which betes of 13 years at baseline and were
kidney disease, doubling of serum creati- reflected a lower rate of hospitalization for followed for a median of 3.0 years.
nine, or death from renal or cardiovascu- heart failure (HR 0.73 [95% CI 0.61–0.88]). VERTIS CV met the prespecified criteria
lar causes. The trial was stopped early No difference was seen in cardiovascular for noninferiority of ertugliflozin to pla-
due to conclusive evidence of efficacy death between groups. cebo with respect to the primary out-
identified during a prespecified interim In the Dapagliflozin and Prevention of come of major adverse cardiovascular
analysis with no unexpected safety sig- Adverse Outcomes in Chronic Kidney Dis- events (11.9% in the pooled ertugliflozin
nals. The risk of the primary composite ease (DAPA-CKD) trial (190), 4,304 group and 11.9% in the placebo group;
outcome was 30% lower with canagliflo- patients with chronic kidney disease HR 0.97 [95% CI 0.85–1.11]; P < 0.001).
zin treatment when compared with pla- (UACR 200–5,000 mg/g and eGFR 25–75 Ertugliflozin was not superior to placebo
cebo (HR 0.70 [95% CI 0.59–0.82]). mL/min/1.73 m2), with or without diabe- for the key secondary outcomes of
Moreover, it reduced the prespecified tes, were randomized to dapagliflozin 10 death from cardiovascular causes or
hospitalization for heart failure; death diarrhea potentially related to the inhibi- (HR 0.74 [95% CI 0.58–0.95]; P <
from cardiovascular causes; or the com- tion of SGLT1. 0.001). More patients discontinued
posite of death from renal causes, renal treatment in the semaglutide group
replacement therapy, or doubling of the GLP-1 Receptor Agonist Trials because of adverse events, mainly gas-
serum creatinine level. The hazard ratio The Liraglutide Effect and Action in Dia- trointestinal. The cardiovascular effects
for a secondary outcome of hospitaliza- betes: Evaluation of Cardiovascular Out- of the oral formulation of semaglutide
tion for heart failure (ertugliflozin vs. pla- come Results (LEADER) trial was a compared with placebo have been
cebo) was 0.70 [95% CI 0.54–0.90], randomized, double-blind trial that assessed in Peptide Innovation for Early
consistent with findings from other SGLT2 assessed the effect of liraglutide, a glu- Diabetes Treatment (PIONEER) 6, a pre-
inhibitor cardiovascular outcomes trials. cagon-like peptide 1 (GLP-1) receptor approval trial designed to rule out an
Sotagliflozin, an investigational SGLT1 agonist, versus placebo on cardiovascu- unacceptable increase in cardiovascular
and SGLT2 inhibitor that lowers glucose lar outcomes in 9,340 patients with risk. In this trial of 3,183 patients with
via delayed glucose absorption in the gut type 2 diabetes at high risk for cardio- type 2 diabetes and high cardiovascular

in addition to increasing urinary glucose vascular disease or with cardiovascular risk followed for a median of 15.9
excretion, has been evaluated in the disease. Study participants had a mean months, oral semaglutide was noninfe-
Effect of Sotagliflozin on Cardiovascular age of 64 years and a mean duration of rior to placebo for the primary compos-
and Renal Events in Patients With Type 2 diabetes of nearly 13 years. Over 80% ite outcome of cardiovascular death,
Diabetes and Moderate Renal Impair- of study participants had established nonfatal MI, or nonfatal stroke (HR 0.79
ment Who Are at Cardiovascular Risk cardiovascular disease. After a median [95% CI 0.57–1.11]; P < 0.001 for non-
(SCORED) trial (193). A total of 10,584 follow-up of 3.8 years, LEADER showed inferiority) (196). The cardiovascular
patients with type 2 diabetes, chronic that the primary composite outcome effects of this formulation of semaglu-
kidney disease, and additional cardiovas- (MI, stroke, or cardiovascular death) tide will be further tested in a large,
cular risk were enrolled in SCORED and occurred in fewer participants in the longer-term outcomes trial.
randomized to sotagliflozin 200 mg once treatment group (13.0%) when com- The Harmony Outcomes trial ran-
daily (uptitrated to 400 mg once daily if pared with the placebo group (14.9%) domized 9,463 patients with type 2 dia-
tolerated) or placebo. SCORED ended (HR 0.87 [95% CI 0.78–0.97]; P < 0.001 betes and cardiovascular disease to
early due to a lack of funding; thus, for noninferiority; P 5 0.01 for superior- once-weekly subcutaneous albiglutide
changes to the prespecified primary end ity). Deaths from cardiovascular causes or matching placebo, in addition to their
points were made prior to unblinding to were significantly reduced in the liraglu- standard care. Over a median duration
accommodate a lower than anticipated tide group (4.7%) compared with the of 1.6 years, the GLP-1 receptor agonist
number of end point events. The primary placebo group (6.0%) (HR 0.78 [95% CI reduced the risk of cardiovascular
end point of the trial was the total num- 0.66–0.93]; P 5 0.007) (194). The FDA death, MI, or stroke to an incidence
ber of deaths from cardiovascular causes, approved the use of liraglutide to rate of 4.6 events per 100 person-years
hospitalizations for heart failure, and reduce the risk of major adverse cardio- in the albiglutide group vs. 5.9 events in
urgent visits for heart failure. After a vascular events, including heart attack, the placebo group (HR ratio 0.78, P 5
median of 16 months of follow-up, the stroke, and cardiovascular death, in 0.0006 for superiority) (197). This agent
rate of primary end point events was adults with type 2 diabetes and estab- is not currently available for clinical use.
reduced with sotagliflozin (5.6 events per lished cardiovascular disease. The Researching Cardiovascular Events
100 patient-years in the sotagliflozin Results from a moderate-sized trial of With a Weekly Incretin in Diabetes
group and 7.5 events per 100 patient- another GLP-1 receptor agonist, sema- (REWIND) trial was a randomized, dou-
years in the placebo group [HR 0.74 glutide, were consistent with the ble-blind, placebo-controlled trial that
(95% CI 0.63–0.88); P < 0.001]). Sotagli- LEADER trial (195). Semaglutide is a assessed the effect of the once-weekly
flozin also reduced the risk of the sec- once-weekly GLP-1 receptor agonist GLP-1 receptor agonist dulaglutide ver-
ondary end point of total number of approved by the FDA for the treatment sus placebo on major adverse cardiovas-
hospitalizations for heart failure and of type 2 diabetes. The Trial to Evaluate cular events in 9,990 patients with
urgent visits for heart failure (3.5% in the Cardiovascular and Other Long-term type 2 diabetes at risk for cardiovascular
sotagliflozin group and 5.1% in the pla- Outcomes With Semaglutide in Subjects events or with a history of cardiovascular
cebo group; HR 0.67 [95% CI 0.55–0.82]; With Type 2 Diabetes (SUSTAIN-6) was disease (198). Study participants had a
P < 0.001) but not the secondary end the initial randomized trial powered to mean age of 66 years and a mean dura-
point of deaths from cardiovascular test noninferiority of semaglutide for tion of diabetes of 10 years. Approxi-
causes. No significant between-group dif- the purpose of regulatory approval. In mately 32% of participants had history
ferences were found for the outcome of this study, 3,297 patients with type 2 of atherosclerotic cardiovascular events
all-cause mortality or for a composite diabetes were randomized to receive at baseline. After a median follow-up of
renal outcome comprising the first occur- once-weekly semaglutide (0.5 mg or 1.0 5.4 years, the primary composite out-
rence of long-term dialysis, renal trans- mg) or placebo for 2 years. The primary come of nonfatal MI, nonfatal stroke,
plantation, or a sustained reduction in outcome (the first occurrence of cardio- or death from cardiovascular causes
eGFR. In general, the adverse effects of vascular death, nonfatal MI, or nonfatal occurred in 12.0% and 13.4% of partici-
sotagliflozin were similar to those seen stroke) occurred in 108 patients (6.6%) pants in the dulaglutide and placebo
with use of SGLT2 inhibitors, but they in the semaglutide group vs. 146 treatment groups, respectively (HR 0.88
also included an increased rate of patients (8.9%) in the placebo group [95% CI 0.79–0.99]; P 5 0.026). These
findings equated to incidence rates of not differ significantly between the two the investigational GLP-1 receptor agonist
2.4 and 2.7 events per 100 person-years, groups. efpeglenatide or placebo (205). Randomiza-
respectively. The results were consistent In summary, there are now numerous tion was stratified by current or potential
across the subgroups of patients with large randomized controlled trials report- use of SGLT2 inhibitor therapy, a class ulti-
and without history of CV events. All- ing statistically significant reductions in mately used by >15% of the trial partici-
cause mortality did not differ between cardiovascular events for three of the pants. Over a median follow-up of 1.8
groups (P 5 0.067). FDA-approved SGLT2 inhibitors (empagli- years, efpeglenatide therapy reduced the
The Evaluation of Lixisenatide in flozin, canagliflozin, dapagliflozin, with risk of incident major adverse cardiovascular
Acute Coronary Syndrome (ELIXA) trial lesser benefits seen with ertugliflozin) events by 27% and of a composite renal
studied the once-daily GLP-1 receptor and four FDA-approved GLP-1 receptor outcome event by 32%. Importantly, the
agonist lixisenatide on cardiovascular agonists (liraglutide, albiglutide [although effects of efpeglenatide did not vary by use
outcomes in patients with type 2 diabe- that agent was removed from the mar- of SGLT2 inhibitors, suggesting that the ben-
tes who had had a recent acute coro- ket for business reasons], semaglutide eficial effects of the GLP-1 receptor agonist

nary event (199). A total of 6,068 [lower risk of cardiovascular events in a were independent of those provided by
patients with type 2 diabetes with a moderate-sized clinical trial but one not SGLT2 inhibitor therapy.
recent hospitalization for MI or unstable powered as a cardiovascular outcomes
angina within the previous 180 days trial], and dulaglutide). Meta-analyses of Glucose-Lowering Therapies and Heart
were randomized to receive lixisenatide the trials reported to date suggest that Failure
or placebo in addition to standard care GLP-1 receptor agonists and SGLT2 inhib- As many as 50% of patients with type 2
and were followed for a median of itors reduce risk of atherosclerotic major diabetes may develop heart failure
2.1 years. The primary outcome of adverse cardiovascular events to a com- (206). These conditions, which are each
cardiovascular death, MI, stroke, or hos- parable degree in patients with type 2 associated with increased morbidity and
pitalization for unstable angina occurred diabetes and established ASCVD mortality, commonly coincide and inde-
in 406 patients (13.4%) in the lixisena- (201,202). SGLT2 inhibitors also reduce pendently contribute to adverse out-
tide group vs. 399 (13.2%) in the pla- risk of heart failure hospitalization and comes (207). Strategies to mitigate
cebo group (HR 1.2 [95% CI 0.89–1.17]), progression of kidney disease in patients these risks are needed, and the heart
which demonstrated the noninferiority with established ASCVD, multiple risk failure–related risks and benefits of glu-
of lixisenatide to placebo (P < 0.001) factors for ASCVD, or albuminuric kidney cose-lowering medications should be
but did not show superiority (P 5 0.81). disease (203,204). In patients with type 2 considered carefully when determining
The Exenatide Study of Cardiovascular diabetes and established ASCVD, multiple a regimen of care for patients with dia-
Event Lowering (EXSCEL) trial also ASCVD risk factors, or diabetic kidney betes and either established heart fail-
reported results with the once-weekly disease, an SGLT2 inhibitor with demon- ure or high risk for the development of
GLP-1 receptor agonist extended-release strated cardiovascular benefit is recom- heart failure.
exenatide and found that major adverse mended to reduce the risk of major Data on the effects of glucose-lower-
cardiovascular events were numerically adverse cardiovascular events and/or ing agents on heart failure outcomes
lower with use of extended-release exe- heart failure hospitalization. In patients have demonstrated that thiazolidine-
natide compared with placebo, although with type 2 diabetes and established diones have a strong and consistent
this difference was not statistically signif- ASCVD or multiple risk factors for ASCVD, relationship with increased risk of heart
icant (200). A total of 14,752 patients a glucagon-like peptide 1 receptor agonist failure (208–210). Therefore, thiazolidi-
with type 2 diabetes (of whom 10,782 with demonstrated cardiovascular benefit nedione use should be avoided in
[73.1%] had previous cardiovascular dis- is recommended to reduce the risk of patients with symptomatic heart failure.
ease) were randomized to receive major adverse cardiovascular events. For Restrictions to use of metformin in
extended-release exenatide 2 mg or pla- many patients, use of either an SGLT2 patients with medically treated heart
cebo and followed for a median of 3.2 inhibitor or a GLP-1 receptor agonist to failure were removed by the FDA in
years. The primary end point of cardio- reduce cardiovascular risk is appropriate. 2006 (211). Observational studies of
vascular death, MI, or stroke occurred in Emerging data suggest that use of both patients with type 2 diabetes and heart
839 patients (11.4%; 3.7 events per 100 classes of drugs will provide an additive failure suggest that metformin users
person-years) in the exenatide group cardiovascular and kidney outcomes ben- have better outcomes than patients
and in 905 patients (12.2%; 4.0 events efit; thus, combination therapy with an treated with other antihyperglycemic
per 100 person-years) in the placebo SGLT2 inhibitor and a GLP-1 receptor ago- agents (212); however, no randomized
group (HR 0.91 [95% CI 0.83–1.00]; P < nist may be considered to provide the trial of metformin therapy has been
0.001 for noninferiority), but exenatide complementary outcomes benefits associ- conducted in patients with heart failure.
was not superior to placebo with ated with these classes of medication. Metformin may be used for the man-
respect to the primary end point (P 5 Evidence to support such an approach agement of hyperglycemia in patients
0.06 for superiority). However, all-cause includes findings from AMPLITUDE-O (Effect with stable heart failure as long as kid-
mortality was lower in the exenatide of Efpeglenatide on Cardiovascular Out- ney function remains within the recom-
group (HR 0.86 [95% CI 0.77–0.97]). The comes), the recently completed outcomes mended range for use (213).
incidence of acute pancreatitis, pancre- trial of patients with type 2 diabetes and Recent studies examining the relation-
atic cancer, medullary thyroid carci- either cardiovascular or kidney disease plus ship between DPP-4 inhibitors and
noma, and serious adverse events did at least one other risk factor randomized to heart failure have had mixed results.
The Saxagliptin Assessment of Vascular suggested, but did not prove, that SGLT2 represent a class effect, and they
Outcomes Recorded in Patients with Dia- inhibitors would be beneficial in the treat- appear unrelated to glucose lowering
betes Mellitus – Thrombolysis in Myocar- ment of patients with established heart given comparable outcomes in HFrEF
dial Infarction 53 (SAVOR-TIMI 53) study failure. More recently, the placebo-con- patients with and without diabetes.
showed that patients treated with the trolled DAPA-HF trial evaluated the effects Additional data are accumulating
DPP-4 inhibitor saxagliptin were more of dapagliflozin on the primary outcome regarding the effects of SGLT inhibition
likely to be hospitalized for heart failure of a composite of worsening heart failure in patients hospitalized for acute
than those given placebo (3.5% vs. 2.8%, or cardiovascular death in patients with decompensated heart failure and in
respectively) (214). However, three other New York Heart Association (NYHA) class heart failure patients with HFpEF. As an
cardiovascular outcomes trials—Examina- II, III, or IV heart failure and an ejection example, the investigational SGLT1 and
tion of Cardiovascular Outcomes with fraction of 40% or less. Of the 4,744 trial SGLT2 inhibitor sotagliflozin has also
Alogliptin versus Standard of Care participants, 45% had a history of type 2 been studied in the Effect of Sotagliflo-
(EXAMINE) (215), Trial Evaluating Cardio- diabetes. Over a median of 18.2 months, zin on Cardiovascular Events in Patients

vascular Outcomes with Sitagliptin the group assigned to dapagliflozin treat- With Type 2 Diabetes Post Worsening
(TECOS) (216), and the Cardiovascular ment had a lower risk of the primary out- Heart Failure (SOLOIST-WHF) trial (218).
and Renal Microvascular Outcome Study come (HR 0.74 [95% CI 0.65–0.85]), lower In SOLOIST-WHF, 1,222 patients with
With Linagliptin (CARMELINA) (186)—did risk of first worsening heart failure event type 2 diabetes who were recently hos-
not find a significant increase in risk of (HR 0.70 [95% CI 0.59–0.83]), and lower pitalized for worsening heart failure
heart failure hospitalization with DPP-4 risk of cardiovascular death (HR 0.82 [95% were randomized to sotagliflozin 200
inhibitor use compared with placebo. No CI 0.69–0.98]) compared with placebo. The mg once daily (with uptitration to 400
increased risk of heart failure hospitaliza- effect of dapagliflozin on the primary out- mg once daily if tolerated) or placebo
tion has been identified in the cardiovas- come was consistent regardless of the either before or within 3 days after hos-
cular outcomes trials of the GLP-1 presence or absence of type 2 diabetes pital discharge. Patients were eligible if
receptor agonists lixisenatide, liraglutide, (191). Ongoing trials are assessing the hospitalized for signs and symptoms of
semaglutide, exenatide once-weekly, effects of several SGLT2 inhibitors in heart heart failure (including elevated natri-
albiglutide, or dulaglutide compared with failure patients with both reduced and uretic peptide levels) requiring treat-
placebo (Table 10.3B) (194,195,198– preserved ejection fraction. ment with intravenous diuretic therapy.
200). EMPEROR-Reduced assessed the Exclusion criteria included end-stage
Reduced incidence of heart failure effects of empagliflozin 10 mg once daily heart failure or recent acute coronary
has been observed with the use of versus placebo on a primary composite syndrome or intervention, or an eGFR
SGLT2 inhibitors (187,189). In EMPA- outcome of cardiovascular death or hos- <30 mL/min/1.73 m2). Patients were
REG OUTCOME, the addition of empa- pitalization for worsening heart failure in required to be clinically stable prior to
gliflozin to standard care led to a a population of 3,730 patients with randomization, defined as no use of
significant 35% reduction in hospitali- NYHA class II, III, or IV heart failure and supplemental oxygen, a systolic blood
zation for heart failure compared with an ejection fraction of 40% or less (217). pressure $100 mmHg, and no need for
placebo (8). Although the majority of At baseline, 49.8% of participants had a intravenous inotropic or vasodilator
patients in the study did not have history of diabetes. Over a median fol- therapy other than nitrates. Similar to
heart failure at baseline, this benefit low-up of 16 months, those in the empa- SCORED, SOLOIST-WHF ended early due
was consistent in patients with and with- gliflozin-treated group had a reduced risk to a lack of funding, resulting in a
out a history of heart failure (10). Simi- of the primary outcome (HR 0.75 [95% change to the prespecified primary end
larly, in CANVAS and DECLARE-TIMI 58, CI 0.65–0.86]; P < 0.001) and fewer total point prior to unblinding to accommo-
there were 33% and 27% reductions in hospitalizations for heart failure (HR 0.70 date a lower than anticipated number
hospitalization for heart failure, respec- [95% CI 0.58–0.85]; P < 0.001). The of end point events. At a median fol-
tively, with SGLT2 inhibitor use versus effect of empagliflozin on the primary low-up of 9 months, the rate of primary
placebo (9,189). Additional data from outcome was consistent irrespective of end point events (the total number of
the CREDENCE trial with canagliflozin diabetes diagnosis at baseline. The risk of cardiovascular deaths and hospitaliza-
showed a 39% reduction in hospitaliza- a prespecified renal composite outcome tions and urgent visits for heart failure)
tion for heart failure, and 31% reduc- (chronic dialysis, renal transplantation, or was lower in the sotagliflozin group
tion in the composite of cardiovascular a sustained reduction in eGFR) was than in the placebo group (51.0 vs.
death or hospitalization for heart fail- lower in the empagliflozin group than in 76.3; HR 0.67 [95% CI 0.52–0.85]; P <
ure, in a diabetic kidney disease popu- the placebo group (1.6% in the empagli- 0.001). No significant between-group dif-
lation with albuminuria (UACR of >300 flozin group vs. 3.1% in the placebo ferences were found in the rates of car-
to 5,000 mg/g) (187). These combined group; HR 0.50 [95% CI 0.32–0.77]). diovascular death or all-cause mortality.
findings from four large outcomes tri- Therefore, in patients with type 2 dia- Both diarrhea (6.1% vs. 3.4%) and severe
als of three different SGLT2 inhibitors betes and established HFrEF, an SGLT2 hypoglycemia (1.5% vs. 0.3%) were more
are highly consistent and clearly indicate inhibitor with proven benefit in this common with sotagliflozin than with
robust benefits of SGLT2 inhibitors in the patient population is recommended to placebo. The trial was originally also
prevention of heart failure hospitalizations. reduce the risk of worsening heart fail- intended to evaluate the effects of SGLT
The EMPA-REG OUTCOME, CANVAS, ure and cardiovascular death. The bene- inhibition in patients with HFpEF, and ulti-
DECLARE-TIMI 58, and CREDENCE trials fits seen in this patient population likely mately no evidence of heterogeneity of
treatment effect by ejection fraction was dc22-S009), patients with type 2 dia- traditional, guideline-based preventive
noted. However, the relatively small per- betes with or at high risk for ASCVD, medical therapies for blood pressure,
centage of such patients enrolled (only heart failure, or CKD should be treated lipids, and glycemia and antiplatelet
21% of participants had ejection fraction with a cardioprotective SGLT2 inhibitor therapy.
>50%) and the early termination of the and/or GLP-1 receptor agonist as part of Adoption of these agents should be
trial limited the ability to determine the the comprehensive approach to cardio- reasonably straightforward in patients
effects of sotagliflozin in HFpEF specifi- vascular and kidney risk reduction. with established cardiovascular or kid-
cally. Additional data regarding the impact Importantly, these agents should be ney disease who are later diagnosed
of SGLT2 inhibitor therapy in patients included in the regimen of care irrespec- with diabetes, as the cardioprotective
with HFpEF will soon be available from tive of the need for additional glucose agents can be used from the outset of
EMPEROR-Preserved, the empagliflozin lowering, and irrespective of metfor- diabetes management. On the other hand,
outcome trial of nearly 6,000 patients min use. Such an approach has also incorporation of SGLT2 inhibitor or GLP-1

with symptomatic heart failure with pre- been described in the ADA-endorsed receptor agonist therapy in the care of
served ejection fraction (left ventricular American College of Cardiology “2020 patients with more long-standing diabetes
ejection fraction >40%) (219), with or Expert Consensus Decision Pathway on may be more challenging, particularly if
without type 2 diabetes. Novel Therapies for Cardiovascular Risk patients are using an already complex glu-
Reduction in Patients With Type 2 Dia- cose-lowering regimen. In such patients,
Clinical Approach betes” (220). Figure 10.3, reproduced SGLT2 inhibitor or GLP-1 receptor agonist
As has been carefully outlined in Fig. from that decision pathway, outlines therapy may need to replace some or all of
9.3 in the preceding Section 9, the approach to risk reduction with their existing medications to minimize risks
“Pharmacologic Approaches to Glycemic SGLT2 inhibitor or GLP-1 receptor ago- of hypoglycemia and adverse side effects,
Treatment” (https://doi.org/10.2337/ nist therapy in conjunction with other and potentially to minimize medication
Figure 10.3—Approach to risk reduction with SGLT2 inhibitor or GLP-1 receptor agonist therapy in conjunction with other traditional, guideline-based pre-
ventive medical therapies for blood pressure, lipids, and glycemia and antiplatelet therapy. Reprinted with permission from Das et al. (220).
costs. Close collaboration between primary 14. DeFilippis AP, Young R, McEvoy JW, et al. Risk systematic review and meta-analyses. BMJ
and specialty care providers can help to score overestimation: the impact of individual 2016;352:i717
cardiovascular risk factors and preventive 26. Bangalore S, Kumar S, Lobach I, Messerli FH.
facilitate these transitions in clinical care therapies on the performance of the American Blood pressure targets in subjects with type 2
and, in turn, improve outcomes for high- Heart Association-American College of Cardiology- diabetes mellitus/impaired fasting glucose:
risk patients with type 2 diabetes. Atherosclerotic Cardiovascular Disease risk score observations from traditional and bayesian
in a modern multi-ethnic cohort. Eur Heart J random-effects meta-analyses of randomized
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Standards of Medical Care in Diabetes - 2022: 10. Cardiovascular Disease and Risk Management

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Standards of Medical Care in Diabetes - 2022: 10. Cardiovascular Disease and Risk Management

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S144 Diabetes Care Volume 45, Supplement 1, January 2022

10. Cardiovascular Disease and American Diabetes Association

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The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”

For prevention and management of diabetes complications in children and adoles-

Atherosclerotic cardiovascular disease (ASCVD)—deﬁned as coronary heart disease

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Blood pressure should be measured at

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of mineralocorticoid receptor antago- Ongoing Therapy and Monitoring

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risk at $60 years age or CV risk at ASCVD established CVD

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SGLT2 Inhibitor Trials

conducted that separately assessed 1)

0.74–0.99]; P 5 0.04 for superiority) and

(see Table 10.3A, Table 10.3B, and

Two large outcomes trials of the

the risk of major adverse cardiovascular

cular death by 14% (absolute rate 10.5%

empagliﬂozin, an SGLT2 inhibitor, versus

dipeptidyl peptidase 4 (DPP-4) inhibitors

diovascular disease. EMPA-REG OUTCOME

group (186). However, results from

years, 57% had diabetes for more than

existing cardiovascular disease. Study

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>2 CV risk without diabetes without diabetes

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CV death or HF from renal or CV death from renal from CV causes (0.65–0.86)

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inhibitors for primary and secondary prevention availability/fda-drug-safety-communication-fda-

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