Diabetes Care Volume 48, Supplement 1, January 2025 S207

10. Cardiovascular Disease and American Diabetes Association

Professional Practice Committee*
Risk Management: Standards of
Care in Diabetes—2025

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Diabetes Care 2025;48(Suppl. 1):S207–S238 | https://doi.org/10.2337/dc25-S010

10. CARDIOVASCULAR DISEASE AND RISK MANAGEMENT

The American Diabetes Association (ADA) “Standards of Care in Diabetes” includes
the ADA’s current clinical practice recommendations and is intended to provide the
components of diabetes care, general treatment goals and guidelines, and tools to
evaluate quality of care. Members of the ADA Professional Practice Committee, an
interprofessional expert committee, are responsible for updating the Standards of
Care annually, or more frequently as warranted. For a detailed description of ADA
standards, statements, and reports, as well as the evidence-grading system for ADA’s
clinical practice recommendations and a full list of Professional Practice Committee
members, please refer to Introduction and Methodology. Readers who wish to com-
ment 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.”

Atherosclerotic cardiovascular disease (ASCVD) broadly refers to a history of acute

coronary syndrome, myocardial infarction (MI), stable or unstable angina or coronary
or other arterial revascularization, stroke, transient ischemic attack, or peripheral ar-
tery disease (PAD) including aortic aneurysm and is the leading cause of morbidity
and mortality in people with diabetes (1). Diabetes itself confers independent ASCVD
risk, and among people with diabetes, all major cardiovascular risk factors, including
hypertension, hyperlipidemia, and obesity, are clustered and common (2). Numerous
studies have shown the efficacy of managing individual cardiovascular risk factors in
preventing or slowing ASCVD in people with diabetes. Furthermore, large benefits
are seen when multiple cardiovascular risk factors (glycemic, blood pressure, and
*A complete list of members of the American
lipid management) are addressed simultaneously, with evidence for long-lasting Diabetes Association Professional Practice Committee
benefits (3–5). Notably, most of the evidence supporting interventions to reduce car- can be found at https://doi.org/10.2337/dc25-SINT.
diovascular risk in diabetes comes from trials of people with type 2 diabetes. No ran- This section has received endorsement from the
domized trials have been specifically designed to assess the impact of cardiovascular American College of Cardiology.
risk reduction strategies in people with type 1 diabetes. Therefore, the recommenda- Duality of interest information for each author is
tions for cardiovascular risk factor modification for people with type 1 diabetes are available at https://doi.org/10.2337/dc25-SDIS.
extrapolated from data obtained in people with type 2 diabetes and are similar to Suggested citation: American Diabetes Association
those for people with type 2 diabetes. Professional Practice Committee. 10. Cardiovascular
Under the current paradigm of comprehensive risk factor modification, cardio- disease and risk management: Standards of Care
vascular morbidity and mortality have notably decreased in people with both type 1 in Diabetes—2025. Diabetes Care 2025;48(Suppl. 1):
S207–S238
and type 2 diabetes (1). In addition to the evidence from prospective intervention
studies to support comprehensive ASCVD risk factor reduction, a large cohort study © 2024 by the American Diabetes Association.
confirmed no or only marginally increased mortality, MI, and stroke risk compared Readers may use this article as long as the
work is properly cited, the use is educational
with the general population when all major cardiovascular risk factors are managed and not for profit, and the work is not altered.
to goal levels in people with type 2 diabetes (6). Despite these encouraging opportu- More information is available at https://www
nities to reduce morbidity and mortality, cardiovascular risk factors are predicted to .diabetesjournals.org/journals/pages/license.
S208 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

increase and only a minority of people prior MI are major risk factors and a cause of comorbidities has been termed cardiore-
with type 2 diabetes achieve recom- of myocardial injury in ischemic heart dis- nal metabolic disease or cardiovascular-
mended risk factor goals and are treated ease leading to HFrEF. In addition, people kidney-metabolic health (18,19). Reasons
with guideline-recommended therapy with diabetes are at risk for developing to concurrently consider cardiovascular
(7–9). Therefore, continued focus on deliv- structural heart disease and HFrEF in and kidney comorbidities in the manage-
ering high-quality comprehensive cardio- the absence of obstructive coronary ar- ment of people with diabetes include
vascular care and on addressing barriers to tery disease (14). The pathophysiology not only the common metabolic risk but
risk factor management are required to im- of heart failure in people with diabetes also the major benefit observed across
plement the treatment recommendations and further details of screening, diagno- the spectrum of cardiovascular disease,
(1,10) outlined in this section. sis, and treatment of people with heart heart failure, and renal outcomes in peo-

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Diabetes is also an important risk fac- failure and diabetes are also outlined ple with type 2 diabetes treated with
tor for incident heart failure, which is at in a previous consensus statement by sodium–glucose cotransporter 2 (SGLT2) in-
least twofold more prevalent in people the American Diabetes Association (ADA) hibitors or glucagon-like peptide 1 receptor
with diabetes compared with those with- (15). agonists (GLP-1 RAs). Therefore, in addi-
out diabetes and is a major cause of mor- There is an increasing appreciation of tion to the management of hyperglyce-
bidity and mortality (11). People with the common pathophysiology and interre- mia, hypertension, and hyperlipidemia,
diabetes may present with a wide spec- lationship of cardiometabolic risk factors treatment with SGLT2 inhibitors and/or
trum of heart failure, including heart fail- leading to both adverse cardiovascular GLP-1 RAs that have demonstrated benefit
ure with preserved ejection fraction and adverse kidney outcomes in people is considered a fundamental element of
(HFpEF), heart failure with mildly reduced with diabetes, including ASCVD, heart fail- risk reduction and the pharmacological
ejection fraction (HFmEF), or heart failure ure, and chronic kidney disease (CKD) strategy to improve cardiovascular and
with reduced ejection fraction (HFrEF) (16). These three comorbidities are fre- kidney outcomes in people with type 2 di-
(12). Comorbid conditions including excess quently caused by metabolic risk, which is abetes (Fig. 10.1). In addition to the
body weight and hypertension often pre- frequently driven by obesity and its associ- standards of care for the prevention and
cede the development of HFpEF and have ated risk factors, and the incidence of all treatment of cardiovascular disease out-
been implicated in the pathophysiology of three conditions rises with increasing A1C lined below, the reader is referred to
HFpEF (13). Coronary artery disease and levels (17). Collectively, this combination Section 9, “Pharmacologic Approaches to

REDUCTION IN DIABETES COMPLICATIONS

Agents With
Glycemic Blood Pressure Lipid Cardiovascular
Management Management Management and Kidney
Benefit

LIFESTYLE MODIFICATION
AND DIABETES EDUCATION

Figure 10.1—Multifactorial approach to reduction in risk of diabetes complications.

diabetesjournals.org/care Cardiovascular Disease and Risk Management S209

Glycemic Treatment,” and Section 11, blood pressure at home after appro- 10.5 In pregnant individuals with diabe-
“Chronic Kidney Disease and Risk Man- priate education. A tes and chronic hypertension, a blood
agement,” for a comprehensive review of pressure threshold of 140/90 mmHg
pharmacological management of hypergly- for initiation or titration of therapy is
cemia and kidney benefit from SGLT2 in- Blood pressure should be measured at ev-
associated with better pregnancy out-
hibitors and GLP-1 RAs. ery routine clinical visit by a trained indi-
comes than reserving treatment for
vidual who should follow the guidelines
established for the general population: severe hypertension, with no increase
HYPERTENSION AND BLOOD in risk of small-for-gestational-age birth
PRESSURE MANAGEMENT measurement in the seated position, with
feet on the floor and arm supported at weight. A There are limited data on
An elevated blood pressure is defined as the optimal lower limit, but therapy

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heart level, after 5 min of rest. Cuff size
a systolic blood pressure 120–129 mmHg should be deintensified for blood pres-
should be appropriate for the upper-arm
and a diastolic blood pressure <80 mmHg sure <90/60 mmHg. E A blood pres-
circumference (26). Individuals identified
(20). Hypertension is defined as a systolic sure goal of 110–135/85 mmHg is
to have elevated blood pressure or hyper-
blood pressure $130 mmHg or a diastolic suggested in the interest of reducing
tension should have blood pressure con-
blood pressure $80 mmHg (20). This is in the risk for accelerated maternal hy-
firmed using multiple readings, including
agreement with the definition of hyperten- pertension. A
measurements on a separate day, to diag-
sion by the American College of Cardiology
nose hypertension. However, in individu-
and American Heart Association (20). Hy-
als with cardiovascular disease and blood Randomized clinical trials have demon-
pertension is common among people with
pressure $180/110 mmHg, it is reason- strated unequivocally that treatment of
either type 1 or type 2 diabetes. Hyperten-
able to diagnose hypertension at a single hypertension reduces cardiovascular events
sion is a major risk factor for ASCVD, heart
visit (22). Postural changes in blood pres- as well as microvascular complications
failure, and microvascular complications. sure and pulse may be evidence of auto- (31–37). There has been controversy on
Moreover, numerous studies have shown nomic neuropathy and therefore require the recommendation of a specific blood
that antihypertensive therapy reduces adjustment of blood pressure goals. Or- pressure goal in people with diabetes.
ASCVD events, heart failure, and micro- thostatic blood pressure measurements The committee recognizes that there has
vascular complications. Please refer to should be checked on initial visit and as been no randomized controlled trial to
the ADA position statement “Diabetes indicated. specifically demonstrate a decreased inci-
and Hypertension” for a detailed review Home blood pressure self-monitoring dence of cardiovascular events in people
of the epidemiology, diagnosis, and and 24-h ambulatory blood pressure mon- with diabetes by achieving a blood pres-
treatment of hypertension (21) and itoring may provide evidence of white sure <130/80 mmHg. The recommenda-
hypertension guideline recommenda- coat hypertension, masked hypertension, tion to support a blood pressure goal of
tions (22–25). or other discrepancies between office and <130/80 mmHg in people with diabetes
true blood pressure (27,28). In addition to is consistent with guidelines from the
Screening and Diagnosis confirming or refuting a diagnosis of hyper- American College of Cardiology and
Recommendations tension, home blood pressure assessment American Heart Association (21), the
10.1 Blood pressure should be mea- may be useful to monitor antihypertensive International Society of Hypertension, and
sured at every routine clinical visit, treatment. A systematic review and meta- Europe European Society of Cardiology/
or at least every 6 months. Individ- analysis of prospective studies concluded European Society of Hypertension Blood
uals found to have elevated blood that blood pressure measurements from Pressure/Hypertension Guidelines (24).
pressure without a diagnosis of hy- either 24-h ambulatory or home blood The committee’s recommendation for the
pertension (systolic blood pressure pressure measurements can predict car- blood pressure goal of <130/80 mmHg
120–129 mmHg and diastolic blood diovascular risk (27–29). Moreover, home derives primarily from the collective evi-
pressure <80 mmHg) should have blood pressure monitoring may improve dence of the following randomized con-
blood pressure confirmed using multi- medication-taking behavior and thus help trolled trials. The Systolic Blood Pressure
ple readings, including measurements reduce cardiovascular risk (30). Intervention Trial (SPRINT) demonstrated
on a separate day, to diagnose hyper- that treatment to a goal systolic blood
tension. A Hypertension is defined as Treatment Goals pressure of <120 mmHg decreases cardio-
a systolic blood pressure $130 mmHg Recommendations vascular event rates by 25% in high-risk in-
or a diastolic blood pressure $80 mmHg 10.3 For people with diabetes and hy- dividuals, although people with diabetes
based on an average of two or more pertension, blood pressure goals should were excluded from this trial (38). The
measurements obtained on two or be individualized through a shared Strategy of Blood Pressure Intervention
more occasions. A Individuals with decision-making process that addresses in the Elderly Hypertensive Patients
blood pressure $180/110 mmHg and cardiovascular risk, potential adverse (STEP) trial included nearly 20% of peo-
cardiovascular disease could be diag- effects of antihypertensive medications, ple with diabetes and noted decreased
nosed with hypertension at a single and individual preferences. B cardiovascular events with treatment of
visit. E 10.4 The on-treatment blood pres- hypertension to a systolic blood pressure
goal of <130 mmHg (39). While the
10.2 Counsel all people with hyper- sure goal is <130/80 mmHg, if it can
tension and diabetes to monitor their ACCORD (Action to Control Cardiovascular
be safely attained. A
Risk in Diabetes) blood pressure trial
S210 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

(ACCORD BP) did not confirm that aiming of adverse outcomes needs to be weighed occurred more frequently in the intensive
for a systolic blood pressure <120 mmHg against the cardiovascular benefit of more treatment group (3.4%) compared with
in people with diabetes results in de- intensive blood pressure lowering. the standard treatment group (2.6%)
creased cardiovascular event rates, the ACCORD BP provides the strongest di- without significant differences in other
prespecified secondary outcome of stroke rect assessment of the benefits and risks adverse events, including dizziness, syn-
was reduced by 41% with intensive treat- of intensive blood pressure management cope, or fractures. For more information
ment (40). The Action in Diabetes and in people with type 2 diabetes (40). In on hypotensive events in older adults,
Vascular Disease: Preterax and Diamicron the study, a total of 4,733 individuals please see Section 13, “Older Adults.”
MR Controlled Evaluation (ADVANCE) trial with type 2 diabetes were assigned to In ADVANCE, 11,140 people with type 2
revealed that treatment with perindo- intensive therapy (aiming for a systolic diabetes were randomized to receive ei-

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pril and indapamide to an achieved blood pressure <120 mmHg) or standard ther treatment with a fixed combination
systolic blood pressure of 135 mmHg therapy (aiming for a systolic blood pres- of perindopril and indapamide or matching
significantly decreased cardiovascular sure <140 mmHg). The mean achieved placebo (41). The primary end point, a
event rates compared with a placebo systolic blood pressures were 119 mmHg composite of cardiovascular death, nonfatal
treatment with an achieved blood pres- and 133 mmHg in the intensive and stan- stroke or MI, or new or worsening renal or
sure of 140 mmHg (41). Therefore, it is dard groups, respectively. The primary eye disease, was reduced by 9% in the
recommended that people with diabetes composite outcome of nonfatal MI, non- combination treatment. The achieved
who have hypertension should be treated fatal stroke, or death from cardiovascu- systolic blood pressure was 135 mmHg
to blood pressure goals of <130/80 mmHg. lar causes was not significantly reduced in the treatment group and 140 mmHg in
Notably, there is an absence of high-quality in the intensive treatment group. The the placebo group.
data available to guide blood pressure prespecified secondary outcome of stroke The Hypertension Optimal Treatment
goals in people with type 1 diabetes, was significantly reduced by 41% in the (HOT) trial enrolled 18,790 individuals
but a similar blood pressure goal of intensive treatment group. Adverse events and aimed for a diastolic blood pressure
<130/80 mmHg is recommended in attributed to blood pressure treatment, <90 mmHg, <85 mmHg, or <80 mmHg
people with type 1 diabetes. As dis- including hypotension, syncope, bradycar- (42). The cardiovascular event rates, de-
cussed below, treatment should be in- dia, hyperkalemia, and elevations in se- fined as fatal or nonfatal MI, fatal and non-
dividualized, and treatment goals should rum creatinine, occurred more frequently fatal strokes, and all other cardiovascular
not be set to achieve <120/80 mmHg, in the intensive treatment arm than in events, were not significantly differ-
as a mean achieved blood pressure the standard therapy arm. ent between diastolic blood pressure
<120/80 mmHg is associated with ad- Of note, the ACCORD BP and SPRINT goals (#90 mmHg, #85 mmHg, and
verse events. For more information on trials aimed for a similar systolic blood #80 mmHg), although the lowest inci-
individualized blood pressure goals in pressure <120 mmHg, but in contrast to dence of cardiovascular events occurred
older individuals, please see Section SPRINT, the primary composite cardio- with an achieved diastolic blood pressure
13, “Older Adults.” vascular end point was nonsignificantly of 82 mmHg. However, in people with di-
reduced in ACCORD BP. The results have abetes, there was a significant 51% reduc-
Randomized Controlled Trials of Intensive been interpreted to be generally consis- tion in the treatment group with a goal
Versus Standard Blood Pressure Management tent between the two trials, but ACCORD diastolic blood pressure of <80 mmHg
SPRINT provides the strongest evidence BP was viewed as underpowered due to compared with a goal diastolic blood pres-
to support lower blood pressure goals the composite primary end point being sure of <90 mmHg.
in individuals at increased cardiovascu- less sensitive to blood pressure regula-
lar risk, although this trial excluded peo- tion (38,40). Meta-analyses of Trials
ple with diabetes (38). The trial enrolled The more recent STEP trial assigned To clarify optimal blood pressure goals in
9,361 individuals with a systolic blood 8,511 individuals aged 60–80 years with people with diabetes, multiple meta-anal-
pressure of $130 mmHg and increased hypertension to a systolic blood pres- yses have been performed. One of the
cardiovascular risk and treated to a sys- sure goal of 110 to <130 mmHg (in- largest meta-analyses included 73,913
tolic blood pressure goal of <120 mmHg tensive treatment) or a goal of 130 to people with diabetes. Compared with a
(intensive treatment) versus a goal of <150 mmHg (37). In this trial, the pri- less intensive blood pressure manage-
<140 mmHg (standard treatment). The mary composite outcome of stroke, acute ment, allocation to a tighter blood pres-
primary composite outcome of MI, coro- coronary syndrome, acute decompen- sure management significantly reduced
nary syndromes, stroke, heart failure, or sated heart failure, coronary revascu- the risk of stroke by 31% but did not re-
death from cardiovascular causes was re- larization, atrial fibrillation, or death duce the risk of MI (43). Another meta-
duced by 25% in the intensive treatment from cardiovascular causes occurred analysis of 19 trials that included 44,989
group. The achieved systolic blood pres- in 3.5% of individuals in the intensive individuals showed that a mean blood
sures in the trial were 121 mmHg and treatment group versus 4.6% in the pressure of 133/76 mmHg is associated
136 mmHg in the intensive versus stan- standard treatment group (hazard ratio with a 14% risk reduction for major
dard treatment group, respectively. Ad- [HR] 0.74 [95% CI 0.60–0.92]; P = 0.007). cardiovascular events compared with
verse outcomes, including hypotension, In this trial, 18.9% of individuals in the a mean blood pressure of 140/81 mmHg
syncope, electrolyte abnormality, and intensive treatment arm and 19.4% in (37). This benefit was greatest in people
acute kidney injury (AKI), were more com- the standard treatment arm had a di- with diabetes. An analysis of trials in-
mon in the intensive treatment arm; risk agnosis of type 2 diabetes. Hypotension cluding people with type 2 diabetes and
diabetesjournals.org/care Cardiovascular Disease and Risk Management S211

impaired glucose tolerance with achieved Extrapolation of these studies suggests achieved in the more intensively treated
systolic blood pressures of <135 mmHg that people with diabetes may also be group was 133.1 ± 0.5 mmHg, and the
in the intensive blood pressure treat- more likely to benefit from intensive mean diastolic blood pressure achieved in
ment group and <140 mmHg in the blood pressure management when they that group was 85.3 ± 0.3 mmHg. A similar
standard treatment group revealed a have high absolute cardiovascular risk. approach is supported by the Interna-
10% reduction in all-cause mortality and This approach is consistent with guide- tional Society for the Study of Hyper-
a 17% reduction in stroke (35). More lines from the American College of Cardi- tension in Pregnancy, which specifically
intensive reduction to <130 mmHg ology and American Heart Association, recommends use of antihypertensive
was associated with a further reduction which also advocate a blood pressure therapy to maintain systolic blood pressure
in stroke but not other cardiovascular goal of <130/80 mmHg for all people, between 110 and 140 mmHg and dia-

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events. with or without diabetes (21). stolic blood pressure between 80 and
Several meta-analyses stratified clini- Potential adverse effects of antihy- 85 mmHg (54).
cal trials by mean baseline blood pres- pertensive therapy (e.g., hypotension, The more recent Chronic Hypertension
sure or mean blood pressure attained in syncope, falls, AKI, and electrolyte ab- and Pregnancy (CHAP) trial assigned preg-
the intervention (or intensive treatment) normalities) should also be taken into nant individuals with mild chronic hyper-
arm. Based on these analyses, antihyper- account (38,40,49,50). Older individuals tension to antihypertensive medications
tensive treatment appears to be most ben- and those with CKD and frailty have to achieve a blood pressure goal of
eficial when mean baseline blood pressure been shown to be at higher risk of ad- <140/90 mmHg (active treatment group)
is $140/90 mmHg (20,31,32,34–36). Among verse effects of intensive blood pressure or to control treatment, in which antihy-
trials with lower baseline or attained blood management (49). In addition, individuals pertensive therapy was withheld unless
pressure, antihypertensive treatment with orthostatic hypotension, substantial severe hypertension (systolic pressure
reduced the risk of stroke, retinopathy, comorbidity, functional limitations, or pol- $160 mmHg or diastolic pressure
and albuminuria, but effects on other ypharmacy may be at high risk of adverse $105 mmHg) developed (control group)
ASCVD outcomes and heart failure were effects, and some individuals may prefer (55). The primary outcome, a composite
higher blood pressure goals to enhance of preeclampsia with severe features, med-
not evident. A recent systematic review
quality of life. However, ACCORD BP dem- ically indicated preterm birth at <35 weeks
and meta-analysis of nine trials enrolling
onstrated that intensive blood pressure of gestation, placental abruption, or fetal or
11,005 participants with type 2 diabetes
lowering decreased the risk of cardiovas- neonatal death, occurred in 30.2% of fe-
reported that intensive blood pressure
cular events irrespective of baseline dia- male participants in the active treatment
lowering resulted in a reduction in risk of
stolic blood pressure in individuals who group versus 37.0% in the control group
stroke (risk ratio 0.64 [95% CI 0.52–0.79])
also received standard glycemic manage- (P < 0.001). The mean systolic blood pres-
and macroalbuminuria (0.77 [0.63–0.93)
ment (51). Therefore, the presence of low sure between randomization and delivery
with a posttreatment blood pressure of
diastolic blood pressure is not necessarily was 129.5 mmHg in the active treatment
125/73 mmHg, suggesting that blood pres-
a contraindication to more intensive blood group and 132.6 mmHg in the control
sure goals could be lowered from the cur-
pressure management in the context of group. There are subtle difference in rec-
rent recommendations of 130/80 mmHg if otherwise standard care. ommendations by different guidelines;
tolerated (44). however, internationally, the majority of
Pregnancy and Antihypertensive Medications hypertension societies endorse a more ag-
Individualization of Treatment Goals There are few randomized controlled tri- gressive approach, recommending therapy
People with diabetes and clinicians should als of antihypertensive therapy in preg- when blood pressure is $140/90 mmHg
engage in a shared decision-making pro- nant individuals with diabetes. A 2018 and attaining a therapeutic goal of
cess to determine individual blood pressure Cochrane systematic review of antihy- 130/80 mmHg (56).
goals (20). This approach acknowledges pertensive therapy for mild to moderate Current evidence supports managing
that the benefits and risks of intensive chronic hypertension included 63 trials and blood pressure to 110–135/85 mmHg to
blood pressure goals are uncertain and over 5,909 women and suggested that an- reduce the risk of accelerated maternal
may vary across individuals and is con- tihypertensive therapy probably reduces hypertension and to minimize impair-
sistent with a person-focused approach the risk of developing severe hypertension ment of fetal growth. During pregnancy,
to care that values individual priorities but may not affect the risk of fetal or neo- treatment with ACE inhibitors, angioten-
and health care professional judgment natal death, small-for-gestational-age ba- sin receptor blockers (ARBs), direct renin
(45). Secondary analyses of ACCORD BP bies, or preterm birth (52). The Control of inhibitors, mineralocorticoid receptor an-
and SPRINT suggest that clinical factors Hypertension in Pregnancy Study (CHIPS) tagonists (MRAs), and neprilysin inhibitors
can help identify individuals more (53) enrolled mostly women with chronic are contraindicated, as they may cause fe-
likely to benefit from and less likely to hypertension. In CHIPS, aiming for a dia- tal damage. Special consideration should
be harmed by intensive blood pressure stolic blood pressure of 85 mmHg during be taken for individuals of childbearing po-
management (46,47). pregnancy was associated with reduced tential, and people intending to become
Absolute benefit from blood pressure likelihood of developing accelerated mater- pregnant should switch from an ACE in-
reduction correlated with absolute base- nal hypertension and no demonstrable ad- hibitor or ARB, renin inhibitor, MRA, or
line cardiovascular risk in SPRINT and in verse outcome for infants compared with neprilysin inhibitor to an alternative anti-
earlier clinical trials conducted at higher aiming for a higher diastolic blood pres- hypertensive medication approved during
baseline blood pressure levels (47,48). sure. The mean systolic blood pressure pregnancy. Antihypertensive drugs known
S212 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

to be effective and safe in pregnancy in- Behaviors and Well-being to Improve Health 10.11 An ACE inhibitor or ARB, at the
clude methyldopa, labetalol, and long- Outcomes”). A systematic review of 10 ran- maximum tolerated dose indicated for
acting nifedipine, while hydralazine may domized controlled trials reported that blood pressure treatment, is the rec-
be considered in the acute management compared with control diet, the modified ommended first-line treatment for
of hypertension in pregnancy or severe Dietary Approaches to Stop Hyperten- hypertension in people with diabetes
preeclampsia (56). Diuretics are not recom- sion (DASH) eating pattern could reduce and urinary albumin-to-creatinine
mended for blood pressure management mean systolic ( 3.26 mmHg [95% CI ratio $300 mg/g creatinine A or
in pregnancy but may be used during late- 5.58 to 0.94 mmHg]; P = 0.006) 30–299 mg/g creatinine. B If one
stage pregnancy if needed for volume and diastolic ( 2.07 mmHg [95% CI
class is not tolerated, the other should
management (56). The American College 3.68 to 0.46 mmHg]; P = 0.01)
be substituted. B

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of Obstetricians and Gynecologists also blood pressure (60).
10.12 Monitor for increased serum
recommends that, postpartum, individuals These lifestyle interventions are rea-
creatinine and for increased serum
with gestational hypertension, preeclamp- sonable for individuals with diabetes and
potassium levels when ACE inhibitors,
sia, and superimposed preeclampsia have mildly elevated blood pressure (systolic
ARBs, and mineralocorticoid receptor
their blood pressures observed for 72 h in >120 mmHg or diastolic >80 mmHg)
antagonists (MRAs) are used, for hy-
the hospital and 7–10 days postpartum. and should be initiated along with phar-
pokalemia when diuretics are used at
Long-term follow-up is recommended for macologic therapy when hypertension is
routine visits, and 7–14 days after ini-
these individuals, as they have increased diagnosed (Fig. 10.2) (59). A lifestyle ther-
tiation or after a dose change. B
lifetime cardiovascular risk (57). See Sec- apy plan should be developed in collabo-
10.13 ACE inhibitors, angiotensin re-
tion 15, “Management of Diabetes in ration with the person with diabetes and
ceptor blockers, MRAs, direct renin
Pregnancy,” for additional information. discussed as part of diabetes manage-
inhibitors, and neprilysin inhibitors
ment. Use of internet or mobile-based
should be avoided in sexually active
Treatment Strategies digital platforms to reinforce healthy be-
haviors may be considered as a compo- individuals of childbearing potential
Lifestyle Intervention
nent of care, as these interventions have who are not using reliable contra-
Recommendation
been found to enhance the efficacy of ception and are contraindicated in
10.6 For people with blood pressure pregnancy. A
medical therapy for hypertension (61,62).
>120/80 mmHg, lifestyle intervention
consists of weight loss when indi- Pharmacologic Interventions Initial Number of Antihypertensive Medi-
cated, a Dietary Approaches to Stop cations. Initial treatment for people with
Hypertension (DASH)–style eating pat- Recommendations
10.7 In individuals with confirmed office- diabetes depends on the severity of hy-
tern including reducing sodium and pertension (Fig. 10.2). Those with blood
increasing potassium intake, modera- based blood pressure $130/80 mmHg,
pharmacologic therapy should be pressure between 130/80 mmHg and
tion of alcohol intake, smoking cessa- 150/90 mmHg may begin with a single
tion, and increased physical activity. A initiated and titrated to achieve the
recommended blood pressure goal drug. For individuals with blood pres-
of <130/80 mmHg. A sure $150/90 mmHg, initial pharmaco-
Lifestyle management is an important 10.8 Individuals with confirmed office- logic treatment with two antihypertensive
component of hypertension treatment based blood pressure $150/90 mmHg medications is recommended to more
because it lowers blood pressure, enhances should, in addition to lifestyle therapy, effectively achieve blood pressure goals
the effectiveness of some antihypertensive have prompt initiation and timely titra- (63–65). Single-pill antihypertensive com-
medications, promotes other aspects of tion of two drugs or a single-pill combi- binations may improve medication tak-
metabolic and vascular health, and gener- nation of drugs demonstrated to reduce ing in some individuals (66).
ally leads to few adverse effects. Lifestyle cardiovascular events in people with di-
therapy consists of reducing excess body abetes. A Classes of Antihypertensive Medications.
weight through caloric restriction (see Sec- 10.9 Treatment for hypertension should Initial treatment for hypertension should
tion 8, “Obesity and Weight Management include drug classes demonstrated to include any of the drug classes demon-
for the Prevention and Treatment of Type 2 strated to reduce cardiovascular events
reduce cardiovascular events in people
Diabetes”), at least 150 min of modera- in people with diabetes (25): ACE inhibi-
with diabetes. A ACE inhibitors or an-
te-intensity aerobic activity per week (see tors (67,68), ARBs (67,68), thiazide-like di-
giotensin receptor blockers (ARBs) are
Section 3, “Prevention or Delay of Diabetes uretics (69), or dihydropyridine calcium
recommended first-line therapy for
and Associated Comorbidities”), restricting channel blockers (70). In people with di-
hypertension in people with diabetes
sodium intake (<2,300 mg/day), increasing abetes and established coronary artery
and coronary artery disease. A
consumption of fruits and vegetables disease, ACE inhibitors or ARBs are rec-
10.10 Multiple-drug therapy is gener-
(8–10 servings per day) and low-fat dairy ommended first-line therapy for hyper-
ally required to achieve blood pressure
products (2–3 servings per day), avoiding tension (71–73). For individuals with
goals. Avoid combinations of ACE in-
excessive alcohol consumption (no more albuminuria (urine albumin-to-creatinine
hibitors and ARBs and combinations of
than 2 servings per day in men and no ratio [UACR] $30 mg/g), initial treatment
ACE inhibitors or ARBs (including ARBs
more than 1 serving per day in women) should include an ACE inhibitor or ARB
and neprilysin inhibitors) with direct
(58), and increasing activity levels (59) to reduce the risk of progressive kidney
renin inhibitors. A
(see Section 5, “Facilitating Positive Health disease (21) (Fig. 10.2). In individuals
diabetesjournals.org/care Cardiovascular Disease and Risk Management S213

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Figure 10.2—Recommendations for the treatment of confirmed hypertension in nonpregnant people with diabetes. *An ACE inhibitor (ACEi) or an-
giotensin receptor blocker (ARB) is suggested for the treatment of hypertension in people with coronary artery disease (CAD) or urine albumin-
to-creatinine ratio 30–299 mg/g creatinine and is strongly recommended for individuals with urine albumin-to-creatinine ratio $300 mg/g cre-
atinine. †Dihydropyridine calcium channel blocker (CCB). ‡Thiazide-like diuretic; long-acting agents shown to reduce cardiovascular events,
such as chlorthalidone and indapamide, are preferred. BP, blood pressure. Adapted from de Boer et al. (21).

receiving ACE inhibitor or ARB therapy, kidney disease is low, and ACE inhibitors as blood pressure–lowering agents in the
continuation of those medications as and ARBs have not been found to afford absence of these conditions (33,76,77).
kidney function declines to estimated glo- superior cardioprotection compared
merular filtration rate (eGFR) <30 mL/min/ with thiazide-like diuretics or dihydro- Multiple-Drug Therapy. Multiple-drug ther-
1.73 m2 may provide cardiovascular bene- pyridine calcium channel blockers (75). apy is often required to achieve blood
fit without significantly increasing the risk b-Blockers are indicated in the setting pressure goals (Fig. 10.2), particularly in
of end-stage kidney disease (74). In the ab- of prior MI, active angina, or HFrEF but the setting of CKD in people with dia-
sence of albuminuria, risk of progressive have not been shown to reduce mortality betes. However, the use of both ACE
S214 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

inhibitors and ARBs in combination, or medications, white coat hypertension, 10.16 Intensify lifestyle therapy and
the combination of an ACE inhibitor or and primary and secondary hyperten- optimize glycemic management for
ARB and a direct renin inhibitor, is con- sion. Difficulty following the care plan people with diabetes with elevated
traindicated given the lack of added may also be a reason for resistant hyper-
triglyceride levels ($150 mg/dL
ASCVD benefit and increased rate of ad- tension. International Society of Hyperten-
[$1.7 mmol/L]) and/or low HDL cho-
verse events—namely, hyperkalemia, sion guidelines put a strong emphasis on
lesterol (<40 mg/dL [<1.0 mmol/L] for
syncope, and AKI (78–80). Titration of screening for care plan difficulties in man-
men and <50 mg/dL [<1.3 mmol/L]
and/or addition of further blood pressure agement of hypertension and recommend
using objective measures such as review for women). C
medications should be made in a timely
fashion to overcome therapeutic inertia in of pharmacy records, pill counting, and

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achieving blood pressure goals. the chemical analysis of blood or urine Lifestyle intervention, including weight
rather than subjective methods of de- loss in people with overweight or obe-
Bedtime Dosing. Although prior analyses tecting inconsistencies in care plan en- sity (when appropriate) (19,92), increased
of randomized clinical trials found a bene- gagement in routine clinical practice. physical activity, and medical nutrition
fit to evening versus morning dosing of an- However, this may not be feasible in all therapy, allows some individuals to re-
tihypertensive medications (81,82), these practice settings (22). duce ASCVD risk factors. Nutrition inter-
results have not been reproduced in sub- People with diabetes and confirmed re- vention should be tailored according to
sequent trials. Therefore, preferential use sistant hypertension should be evaluated each person’s age, pharmacologic treat-
of antihypertensives at bedtime is not rec- for secondary causes of hypertension, in- ment, lipid levels, and medical conditions.
ommended (83). cluding primary hyperaldosteronism, renal Recommendations should focus on ap-
artery stenosis, CKD, and obstructive sleep plication of a Mediterranean (93) or DASH
Hyperkalemia and Acute Kidney Injury. apnea. In general, barriers to medication eating pattern, reducing saturated and
Treatment with ACE inhibitors and ARBs or taking (such as cost and side effects) should trans fat intake, and increasing plant
MRAs can cause AKI and hyperkalemia, be identified and addressed (Fig. 10.2). stanol and sterol, n-3 fatty acid, and vis-
while diuretics can cause AKI and either hy- MRAs, including spironolactone and cous fiber (such as in oats, legumes, and
pokalemia or hyperkalemia (depending on eplerenone, are effective for manage- citrus) intake (19,92). Glycemic manage-
mechanism of action) (84,85). Detection ment of resistant hypertension in people ment may also beneficially modify plasma
and management of these abnormalities is with type 2 diabetes when added to ex- lipid levels, particularly in people with very
important because AKI and hyperkalemia isting treatment with an ACE inhibitor or high triglycerides and poor glycemic
each increase the risks of cardiovascular ARB, thiazide-like diuretic, or dihydropyr- management. See Section 5, “Facilitating
events and death (86). Therefore, serum idine calcium channel blocker (88). In addi- Positive Health Behaviors and Well-being
creatinine and potassium should be moni- tion, MRAs reduce albuminuria in people to Improve Health Outcomes,” for addi-
tored after initiation of treatment with an with diabetic nephropathy (89–91). How- tional nutrition information.
ACE inhibitor or ARB, MRA, or diuretic and ever, adding an MRA to a treatment plan
monitored during treatment and following that includes an ACE inhibitor or ARB may Ongoing Therapy and Monitoring
uptitration of these medications, particu- increase the risk for hyperkalemia, empha- With Lipid Panel
larly among individuals with reduced glo- sizing the importance of regular monitoring Recommendations
merular filtration who are at increased risk for serum creatinine and potassium in these 10.17 In adults with prediabetes or
of hyperkalemia and AKI (84,85,87). individuals, and long-term outcome studies diabetes not taking statins or other
are needed to better evaluate the role of lipid-lowering therapy, it is reasonable
Resistant Hypertension MRAs in blood pressure management. to obtain a lipid profile at the time of
Recommendation diagnosis, at an initial medical evalua-
10.14 Individuals with hypertension LIPID MANAGEMENT tion, annually thereafter, or more fre-
who are not meeting blood pres- Lifestyle Intervention quently if indicated. E
sure goals on three classes of anti- 10.18 Obtain a lipid profile at initia-
Recommendations
hypertensive medications (including tion of statins or other lipid-lowering
a diuretic) should be considered for 10.15 Lifestyle modification focusing
therapy, 4–12 weeks after initiation or
MRA therapy. A on weight loss (if indicated); appli-
a change in dose, and annually there-
cation of a Mediterranean or DASH
after, as it facilitates monitoring the
eating pattern; reduction of saturated
Resistant hypertension is defined as blood response to therapy and informs med-
fat and trans fat; increase of dietary n-3
pressure $140/90 mmHg despite a thera- ication-taking behavior. A
fatty acids, viscous fiber, and plant
peutic strategy that includes appropriate stanol and sterol intake; and in-
lifestyle management plus a diuretic and creased physical activity should be In adults with diabetes, it is reasonable
two other antihypertensive drugs with recommended to improve the lipid to obtain a lipid profile (total choles-
complementary mechanisms of action at profile and reduce the risk of devel- terol, LDL cholesterol, HDL cholesterol,
adequate doses. Prior to diagnosing resis- oping atherosclerotic cardiovascular and triglycerides) at the time of diagno-
tant hypertension, a number of other disease (ASCVD) in people with dia- sis, at the initial medical evaluation, and
conditions should be excluded, includ- at least every 5 years thereafter in indi-
betes. A
ing missed doses of antihypertensive viduals <40 years of age. In younger
diabetesjournals.org/care Cardiovascular Disease and Risk Management S215

people with longer duration of disease is reasonable to continue statin treat- the maximum tolerated statin dose
(such as those with youth-onset type 1 ment. B should be used. E
diabetes), more frequent lipid profiles 10.24 In adults with diabetes aged 10.29b For people with diabetes and
may be reasonable. A lipid panel should >75 years, it may be reasonable to ASCVD intolerant to statin therapy,
also be obtained immediately before initiate moderate-intensity statin ther- PCSK9 inhibitor therapy with mono-
initiating statin therapy. Once an indi- clonal antibody treatment, A bempe-
apy after discussion of potential bene-
vidual is taking a statin, LDL cholesterol
fits and risks. C doic acid therapy, A or PCSK9 inhibitor
levels should be assessed 4–12 weeks therapy with inclisiran siRNA E should
10.25 In people with diabetes intoler-
after initiation of statin therapy, after be considered as an alternative choles-
ant to statin therapy, treatment with
any change in dose, and annually (e.g., terol-lowering therapy.
bempedoic acid is recommended to re-

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to monitor for medication taking and effi-
duce cardiovascular event rates as an
cacy). Monitoring lipid profiles after initia-
alternative cholesterol-lowering plan. A
tion of statin therapy and during therapy
10.26 In most circumstances, lipid-
increases the likelihood of dose titration Initiating Statin Therapy
and following the statin treatment plan lowering agents should be stopped
People with type 2 diabetes have an in-
(94–96). If LDL cholesterol levels are not re- prior to conception and avoided in creased prevalence of lipid abnormali-
sponding despite medication taking, clinical sexually active individuals of child- ties, contributing to their high risk of
judgment is recommended to determine bearing potential who are not using ASCVD. Multiple clinical trials have dem-
the need for and timing of lipid panels. reliable contraception. B In some onstrated the beneficial effects of statin
In individuals, the highly variable LDL circumstances (e.g., for individuals therapy on ASCVD outcomes in subjects
cholesterol-lowering response seen with with familial hypercholesterolemia with and without coronary heart dis-
statins is poorly understood (97). Clinicians or prior ASCVD event), statin therapy ease (CHD) (99,100). Subgroup analyses
should attempt to find a dose or alternative may be continued when the benefits of people with diabetes in larger trials
statin that is tolerable if side effects occur. outweigh risks. E (101–105) and trials in people with diabe-
There is evidence for benefit from even ex- tes (106,107) showed significant primary
tremely low, less-than-daily statin doses (98). and secondary prevention of ASCVD
Secondary Prevention events and CHD death in people with dia-
STATIN TREATMENT Recommendations
betes. Meta-analyses including data from
10.27 For people of all ages with dia- >18,000 people with diabetes from 14
Primary Prevention
betes and ASCVD, high-intensity statin randomized trials of statin therapy (mean
Recommendations follow-up 4.3 years) demonstrated a 9%
therapy should be added to lifestyle
10.19 For people with diabetes aged proportional reduction in all-cause mortality
therapy. A
40–75 years without ASCVD, use and 13% reduction in vascular mortality for
10.28 For people with diabetes and
moderate-intensity statin therapy in each 1 mmol/L (39 mg/dL) reduction in LDL
ASCVD, treatment with high-inten-
addition to lifestyle therapy. A cholesterol (108). The cardiovascular benefit
sity statin therapy is recommended
10.20 For people with diabetes aged in this large meta-analysis did not depend
to obtain an LDL cholesterol reduc-
20–39 years with additional ASCVD on baseline LDL cholesterol levels and was
tion of $50% from baseline and an
risk factors, it may be reasonable to linearly related to the LDL cholesterol reduc-
LDL cholesterol goal of <55 mg/dL
initiate statin therapy in addition to tion without a low threshold beyond which
(<1.4 mmol/L). Addition of ezetimibe
lifestyle therapy. C there was no benefit observed (108). It is
10.21 For people with diabetes aged or a PCSK9 inhibitor with proven bene-
fit in this population is recommended important to note that the effects of statin
40–75 years at higher cardiovascular therapy do not differ based on sex (109).
risk, including those with one or more if this goal is not achieved on maxi-
mum tolerated statin therapy. B Accordingly, statins are the drugs of
additional ASCVD risk factors, high- choice for LDL cholesterol lowering and
intensity statin therapy is recom- 10.29a For individuals who do not
tolerate the intended statin intensity, cardioprotection. Table 10.1 shows the
mended to reduce LDL cholesterol two statin dosing intensities that are
by $50% of baseline and to obtain
an LDL cholesterol goal of <70 mg/dL
(<1.8 mmol/L). A Table 10.1—High-intensity and moderate-intensity statin therapy
10.22 For people with diabetes aged
High-intensity statin therapy Moderate-intensity statin therapy
40–75 years at higher cardiovascular (lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30–49%)
risk, especially those with multiple addi- Atorvastatin 40–80 mg Atorvastatin 10–20 mg
tional ASCVD risk factors and an LDL Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg
cholesterol $70 mg/dL ($1.8 mmol/L), Simvastatin 20–40 mg
it may be reasonable to add ezetimibe Pravastatin 40–80 mg
or a PCSK9 inhibitor to maximum toler- Lovastatin 40 mg
ated statin therapy. B Fluvastatin XL 80 mg
Pitavastatin 1–4 mg
10.23 In adults with diabetes aged
>75 years already on statin therapy, it Once-daily dosing. XL, extended release.
S216 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

recommended for use in clinical practice. risk factors (Fig. 10.3). The evidence is <70 mg/dL (<1.8 mmol/L) (117). While
High-intensity statin therapy will achieve strong for people with diabetes aged there are no randomized controlled trials
an approximately $50% reduction in LDL 40–75 years, an age-group well repre- specifically assessing cardiovascular out-
cholesterol, and moderate-intensity statin sented in statin trials showing benefit. comes of adding ezetimibe or PCSK9 in-
plans achieve 30–49% reductions in LDL Since cardiovascular risk is enhanced in hibitors to statin therapy in primary
cholesterol. Low-dose statin therapy is gen- people with diabetes, as noted above, in- prevention, a portion of the participants
erally not recommended in people with di- dividuals who also have multiple other without established cardiovascular dis-
abetes but is sometimes the only dose of coronary risk factors have increased risk, ease were included in some studies,
statin that an individual can tolerate. For equivalent to that of those with ASCVD. which also included participants with
individuals who do not tolerate the in- Therefore, current guidelines recommend established cardiovascular disease. A

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tended intensity of statin, the maximum that in people with diabetes who are at meta-analysis suggests that there is a
tolerated statin dose should be used. higher cardiovascular risk, especially those cardiovascular benefit of adding ezetimibe
As in those without diabetes, absolute with one or more ASCVD risk factors, or PCSK9 inhibitors to treatment for peo-
reductions in ASCVD outcomes (CHD death high-intensity statin therapy should be ple at high risk (118). There is less evidence
and nonfatal MI) are greatest in people prescribed to reduce LDL cholesterol by for individuals aged >75 years; relatively
with high baseline ASCVD risk (known $50% from baseline and to obtain an LDL few older people with diabetes have been
ASCVD and/or very high LDL cholesterol cholesterol of <70 mg/dL (<1.8 mmol/L) enrolled in primary prevention trials. How-
levels), but the overall benefits of statin (114–116). Since, in clinical practice, it is ever, heterogeneity by age has not been
therapy in people with diabetes at moder- frequently difficult to ascertain the seen in the relative benefit of lipid-lower-
ate or even low risk for ASCVD are convinc- baseline LDL cholesterol level prior to ing therapy in trials that included older
ing (110,111). The relative benefit of lipid- statin therapy initiation, in those indi- participants (100,107,108), and because
lowering therapy has been uniform across viduals, a focus on an LDL cholesterol older age confers higher risk, the absolute
most subgroups tested (100,108), including goal of <70 mg/dL (<1.8 mmol/L) rather benefits are actually greater (100,119).
subgroups that varied with respect to age than percent reduction in LDL choles- Moderate-intensity statin therapy is rec-
and other risk factors. terol is recommended. In those individu- ommended in people with diabetes who
als, it may also be reasonable to add are $75 years of age. However, the risk-
Primary Prevention (People Without ASCVD) ezetimibe or proprotein convertase benefit profile should be routinely evalu-
For primary prevention, moderate-dose subtilisin/kexin type 9 (PCSK9) inhibitor ated in this population, with downward ti-
statin therapy is recommended for those therapy to maximum tolerated statin tration of dose performed as needed.
aged $40 years (19,112,113), although therapy if needed to reduce LDL choles- See Section 13, “Older Adults,” for more
high-intensity therapy should be consid- terol levels by $50% and to achieve the details on clinical considerations for this
ered in the context of additional ASCVD recommended LDL cholesterol goal of population.

Lipid Management for Primary Prevention of Atherosclerotic Cardiovascular Disease

Events in People With Diabetes in Addition to Healthy Behavior Modification

In people 20-39 Consider statin therapy if there

are additional ASCVD risk factors.
years of age

Use moderate-intensity statin

Use bempedoic acid for those
therapy in those without
who are statin intolerant.
ASCVD risk factors.

In people 40-75
years of age
Use a high-intensity statin in It may be reasonable to add
those with ≥1 ASCVD risk factor, ezetimibe or PCSK9 inhibitor to
with an LDL cholesterol goal of maximum tolerated statin therapy
<70 mg/dL (<1.8 mmol/L). if LDL goal is not achieved.

Continue current statin

In people >75 therapy or consider initiating a
moderate-intensity statin after
years of age weighing benefits and risks.

Figure 10.3—Recommendations for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in people with diabetes using choles-
terol-lowering therapy. Adapted from “Standards of Care in Diabetes—2024 Abridged for Primary Care Professionals” (325).
diabetesjournals.org/care Cardiovascular Disease and Risk Management S217

Age <40 Years and/or Type 1 Diabetes. Very ezetimibe or a PCSK9 inhibitor is recom- The trial showed the addition of ezetimibe
little clinical trial evidence exists for peo- mended if this goal is not achieved on to a moderate-intensity statin led to a 6.4%
ple with type 2 diabetes under the age of maximum tolerated statin therapy. These relative benefit and a 2% absolute reduc-
40 years or for people with type 1 diabe- recommendations are based on the tion in major adverse cardiovascular events
tes of any age. For pediatric recommen- observation that high-intensity versus (atherosclerotic cardiovascular events), with
dations, see Section 14, “Children and moderate-intensity statin therapy reduces the degree of benefit being directly propor-
Adolescents.” In the Heart Protection cardiovascular event rates in high-risk in- tional to the change in LDL cholesterol
Study (lower age limit 40 years), the sub- dividuals with established cardiovascular (119). A subanalysis of participants with dia-
group of 600 people with type 1 diabe- disease in randomized trials (99). The Cho- betes (27% of the 18,144 participants)
tes had a reduction in risk proportionately lesterol Treatment Trialists’ Collaboration, showed a significant reduction of major ad-

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similar, although not statistically significant, involving 26 statin trials, of which 5 com- verse cardiovascular events with the combi-
to that in people with type 2 diabetes pared high-intensity versus moderate- nation treatment over moderate-intensity
(102). Even though the data are not defini- intensity statins, showed a 21% reduc- statin alone (122).
tive, similar statin treatment approaches tion in major cardiovascular events in
should be considered for people with people with diabetes for every 39 mg/dL Statins and PCSK9 Inhibitors
type 1 or type 2 diabetes, particularly in (1 mmol/L) of LDL cholesterol lowering, The addition of the PCSK9 inhibitors
the presence of other cardiovascular risk irrespective of baseline LDL cholesterol evolocumab and alirocumab to maxi-
factors. Individuals <40 years of age have or individual characteristics (108). The mum tolerated doses of statin therapy
lower risk of developing a cardiovascular evidence to support lower LDL choles- in participants who were at high risk for
event over a 10-year horizon; however, terol goals in people with diabetes and ASCVD demonstrated an average reduc-
their lifetime risk of developing cardiovascu- established cardiovascular disease de- tion in LDL cholesterol ranging from
lar disease and experiencing an MI, stroke, rives from multiple large, randomized tri- 36% to 59% (126,127). No cardiovascu-
or cardiovascular death is high. For people als investigating the benefits of adding lar outcome trials have been performed
who are <40 years of age and/or have nonstatin agents to statin therapy, includ- to assess whether PCSK9 inhibitor therapy
type 1 diabetes with other ASCVD risk fac- ing combination treatment with statins reduces ASCVD event rates in individuals
tors, it is recommended that the individual and ezetimibe (119,122) or PCSK9 inhibi- at low or moderate risk for ASCVD (pri-
and health care professional discuss the rel- tors (121,123–125). Each trial found a mary prevention). The evidence on the
ative benefits and risks and consider the large benefit in reducing ASCVD events effect of PSCK9 inhibition on ASCVD out-
use of moderate-intensity statin therapy. that was directly related to the degree of comes is from studies of treatment with
Please refer to “Type 1 Diabetes Mellitus further LDL cholesterol lowering. A large the monoclonal antibodies alirocumab
and Cardiovascular Disease: A Scientific number of participants with diabetes and evolocumab. When added to a maxi-
Statement From the American Heart Asso- were included in these trials, and prespe- mally tolerated statin, these agents re-
ciation and American Diabetes Association” cified analyses were completed to evalu- duced LDL cholesterol by 60% (121) and
(120) for additional discussion. ate cardiovascular outcomes in people significantly reduced the risk of major ad-
with and without diabetes (122,124,125). verse cardiovascular events by 15–20% in
Secondary Prevention (People With ASCVD) The decision to add a nonstatin agent the FOURIER (Further Cardiovascular Out-
Intensive therapy is indicated because should be made following a discussion be- comes Research With PCSK9 Inhibition in
cardiovascular event rates are increased tween a clinician and a person with diabe- Subjects With Elevated Risk) (evolocumab)
in people with diabetes and established tes about the net benefit, safety, and cost and ODYSSEY OUTCOMES (Evaluation of
ASCVD, and it has been shown to be of of combination therapy. Cardiovascular Outcomes After an Acute
benefit in multiple large meta-analyses and Coronary Syndrome During Treatment
randomized cardiovascular outcomes trials Combination Therapy for LDL With Alirocumab) trials (121,123,128).
(99,100,108,119,121). High-intensity statin Cholesterol Lowering In the subanalyses of the participants
therapy is recommended for all people with Statins and Ezetimibe with diabetes (40% in FOURIER and
diabetes and ASCVD to obtain an LDL cho- The best evidence for combination therapy 28.8% in ODYSSEY OUTCOMES), similar
lesterol reduction of $50% from baseline of statins and ezetimibe comes from the benefits were seen compared with those
and an LDL cholesterol goal of <55 mg/dL IMProved Reduction of Outcomes: Vytorin for individuals without diabetes in FOU-
(<1.4 mmol/L) (Fig. 10.4). The addition of Efficacy International Trial (IMPROVE-IT). RIER (125), whereas a greater absolute

Lipid Management for Secondary Prevention of Atherosclerotic Cardiovascular Disease Events in People With Diabetes

Add ezetimibe or a PCSK9- Use an alternative lipid-lowering treatment for those

Use lifestyle and high-intensity who are statin intolerant:
directed therapy with
statin therapy to reduce LDL
demonstrated benefit if LDL • PCSK9 inhibitor with monoclonal
cholesterol by ≥50% from
cholesterol goals are not antibody treatment
baseline to a goal of <55 mg/dL
met on maximum tolerated • Bempedoic acid
(<1.4 mmol/L).
statin therapy. • PCSK9 inhibitor with siRNA inclisiran

Figure 10.4—Recommendations for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in people with diabetes using choles-
terol-lowering therapy. Adapted from “Standards of Care in Diabetes—2024 Abridged for Primary Care Professionals” (325).
S218 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

reduction was seen for participants with shown to be effective for LDL choles- Inclisiran has also been proposed as an
diabetes (2.3% [95% CI 0.4–4.2]) than for terol reduction and fewer skeletal muscle– option for individuals with statin intoler-
those with prediabetes (1.2% [0.0–2.4]) related adverse effects when studied in ance. Although most of the individuals in
or normoglycemia (1.2% [ 0.3 to 2.7]) in populations considered statin intolerant. studies of inclisarin were on statin therapy,
the ODYSSEY OUTCOMES trial (124). The Study of Alirocumab in Patients With one short-term study (Trial to Evaluate the
In addition to the monoclonal antibod- Primary Hypercholesterolemia and Moder- Effect of ALN-PCSSC Treatment on Low-
ies, an siRNA, inclisiran, which also targets ate, High, or Very High Cardiovascular Risk, density Lipoprotein Cholesterol [ORION-1])
PSCK9, has demonstrated the ability to re- Who Are Intolerant to Statins (ODYSSEY included individuals with documented
duce LDL cholesterol by 49–52% in trials ALTERNATIVE) trial studied the reduction in statin intolerance (138) and could con-
evaluating individuals with established LDL cholesterol with alirocumab compared tinue into an open-label extension trial

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cardiovascular disease or ASCVD risk with ezetimibe or 20 mg atorvastatin in (Extension Trial of Inclisiran in Participants
equivalent (129). Inclisiran allows less individuals at moderate to very high car- With Cardiovascular Disease and High
frequent administration compared with diovascular risk for 24 weeks. The propor-
Cholesterol [ORION-3]), where an LDL
monoclonal antibodies and was admin- tion of the study population with type 2
cholesterol reduction of 45% was main-
istered on day 1, on day 90, and every diabetes was 24%. After the 24 weeks,
tained through the end of year 4 (139). It
6 months in these trials. In an exploratory alirocumab lowered LDL cholesterol levels
is important to note that of the ORION-3
analysis, the prespecified cardiovascular by 54.8% versus 20.1% with ezetimibe.
end point of nonadjudicated cardiovascu- There were similar rates of any adverse participants, only 23% had diabetes and
lar events, including cardiac death, signs event for all treatments; however, fewer 33% were not taking statin therapy. Al-
or symptoms of cardiac arrest, nonfatal events that led to treatment discontinua- though it may be expected that those with
MI, or stroke, occurred less frequently tion and few skeletal muscle–related ad- statin intolerance experienced a response
with inclisiran than placebo (7.4% vs. verse events occurred with alirocumab similar to the response of those on statin
10.2% in one trial and 7.8% vs. 10.3% (134). therapy, evaluation of response based on
in another trial). Cardiovascular outcome The Goal Achievement After Utilizing background lipid-lowering therapy was
trials using inclisiran in people with estab- an Anti-PCSK9 Antibody in Statin Intol- not described.
lished cardiovascular disease (130,131) erant Subjects 1, 2, and 3 (GAUSS 1, 2,
and for primary prevention in those at and 3) trials, as well as the Open-Label Bempedoic Acid
high risk for cardiovascular disease (132) Study of Long-term Evaluation Against Bempedoic acid, a novel LDL cholesterol–
are currently ongoing. LDL Cholesterol (OSLER) open-label ex- lowering agent acting in the same path-
tension of the GAUSS 1 and 2 trials, way as statin but without activity in skele-
Intolerance to Statin Therapy evaluated the safety and LDL cholesterol tal muscle, which limits the muscle-related
Statin therapy is a hallmark approach to reduction of evolocumab plus ezetimibe adverse effects, lowers LDL cholesterol lev-
cardiovascular prevention and treatment; compared with ezetimibe alone in indi- els by 15% for those on statins and 24%
however, a subset of individuals experi- viduals with statin intolerance. for those not taking statins (140). Use of
ence partial (inability to tolerate sufficient Reductions in LDL cholesterol ranged this agent with ezetimibe results in an ad-
dosage necessary to achieve therapeutic from 55% and 56% for evolocumab bi- ditional 19% reduction in LDL cholesterol
objectives due to adverse effects) or com- weekly and monthly plus daily oral pla- (140). The Evaluation of Major Cardiovas-
plete (inability to tolerate any dose) intol- cebo, respectively, to 19% and 16% for cular Events in Patients With, or at High
erance to statin therapy (133). Although ezetimibe daily plus biweekly or monthly Risk for, Cardiovascular Disease Who Are
the definition of statin intolerance differs subcutaneous placebo, respectively. Fewer Statin Intolerant Treated With Bempedoic
between organizations and across clinical musculoskeletal adverse effects occurred Acid or Placebo (CLEAR Outcomes) trial
study methods, these individuals will re- in those treated with evolocumab or eze- found a reduction in four-point major ad-
quire an alternative treatment approach. timibe than in those treated with ezeti- verse cardiovascular events by 13% com-
Initial steps in people intolerant to statins mibe plus placebo, although rates of
pared with placebo for individuals with
may include switching to a different high- discontinuation due to these effects were
established ASCVD (70% of population) or
intensity statin if a high-intensity statin is similar. Use of low-dose statins was al-
at high risk for ASCVD (30% of population)
indicated, switching to moderate-intensity lowed in these studies and was associated
and considered to be intolerant to statin
or low-intensity statin, lowering the statin with an increase in the incidence of
dose, or using nondaily dosing with sta- musculoskeletal adverse effects (135,136). therapy. It is important to note that 19%
tins. While considering these alternative Similar LDL cholesterol reductions were of individuals were on very-low-dose statin
treatment plans, the addition of nonstatin demonstrated in the GAUSS 3 trial after 24 therapy at baseline (141). Prespecified
treatment plans to maximum tolerated weeks (54.5% with evolocumab compared subanalyses evaluated the impact for indi-
statin therapy should be considered, as with 16.7% with ezetimibe), with slightly viduals with diabetes and showed a 17%
these are frequently associated with im- higher rates of musculoskeletal adverse reduction in four-point major adverse car-
proved medication-taking behavior and events (20.7% with evolocumab and diovascular events when treated with
achievement of LDL cholesterol goals (133). 28.8% with ezetimibe). The higher rates of bempedoic acid (142). For individuals re-
these adverse events may be due in part quiring primary prevention, the use of
PCSK9-Directed Therapies to the first phase of this trial, which ran- bempedoic acid resulted in a 30% reduc-
The PCSK9 monoclonal antibodies aliro- domized individuals to a statin rechallenge tion in primary composite outcome com-
cumab and evolocumab both have been with either atorvastatin or placebo (137). pared with placebo (143).
diabetesjournals.org/care Cardiovascular Disease and Risk Management S219

Lipid-Lowering Care Considerations for more information on preconception risk. The Reduction of Cardiovascular
for Individuals of Childbearing counseling and lipid-lowering treatment Events with Icosapent Ethyl-Intervention
Potential during pregnancy). Trial (REDUCE-IT) showed that the addition
Individuals of childbearing potential are of icosapent ethyl to statin therapy in this
less likely to be treated with statins or Treatment of Other Lipoprotein population resulted in a 25% relative risk re-
achieve their LDL cholesterol goals based Fractions or Goals duction (P < 0.001) for the primary end
on their cardiovascular risk (144–146). This point composite of cardiovascular death,
Recommendations
is likely related to concerns and lack of nonfatal MI, nonfatal stroke, coronary re-
knowledge related to use of lipid-lowering 10.30 For individuals with fasting triglyc-
eride levels $500 mg/dL ($5.7 mmol/L), vascularization, or unstable angina com-
agents during pregnancy. The trials evaluat- pared with placebo. This risk reduction was
ing the efficacy and safety of lipid-lowering evaluate for secondary causes of hyper-

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seen in individuals with or without diabetes
medications exclude individuals who are triglyceridemia and consider medical
at baseline. The composite of cardiovascu-
pregnant and require individuals of child- therapy to reduce the risk of pancreati-
lar death, nonfatal MI, or nonfatal stroke
tis. C
bearing potential to use contraception was reduced by 26% (P < 0.001). Addi-
(some requiring two forms). Therefore, for 10.31 In adults with hypertriglyceride-
tional ischemic end points were signifi-
many pregnant individuals, it is recom- mia (fasting triglycerides >150 mg/dL
cantly lower in the icosapent ethyl group
mended that they discontinue lipid-lowering [>1.7 mmol/L] or nonfasting triglycer-
than in the placebo group, including car-
therapies during gestation. However, some ides >175 mg/dL [>2.0 mmol/L]), clini-
diovascular death, which was reduced by
individuals are at higher risk for cardiovascu- cians should address and treat lifestyle
20% (P = 0.03). The proportions of individ-
lar events (e.g., those with familial hyper- factors (obesity and metabolic syn-
uals experiencing adverse events and seri-
cholesterolemia or preexisting ASCVD), and drome), secondary factors (diabetes, ous adverse events were similar between
the risk of discontinuing all lipid-lowering chronic liver or kidney disease and/or the active and placebo treatment groups.
therapy during preconception and preg- nephrotic syndrome, and hypothyroid- It should be noted that data are lacking for
nancy periods may be associated with an ism), and medications that raise trigly- other n-3 fatty acids, and results of the
increased risk for cardiovascular events. cerides. C REDUCE-IT trial should not be extrapolated
Consideration of initiating or continuing 10.32 In individuals with ASCVD or to other products (153). As an example,
statin therapy during pregnancy should other cardiovascular risk factors on a the addition of 4 g per day of a carboxylic
occur with these high-risk individuals. Al- statin with managed LDL cholesterol acid formulation of the n-3 fatty acids ei-
though the evidence is limited, statins did but elevated triglycerides (150–499 cosapentaenoic acid (EPA) and docosa-
not increase teratogenic effects for indi- mg/dL [1.7–5.6 mmol/L]), the addi- hexaenoic acid (DHA) (n-3 carboxylic acid)
viduals with familial hypercholesterolemia tion of icosapent ethyl can be consid- to statin therapy in individuals with ath-
(147,148), and a meta-analysis of prava- ered to reduce cardiovascular risk. B erogenic dyslipidemia and high cardiovas-
statin in pregnant individuals showed a re- cular risk, 70% of whom had diabetes, did
duction in preeclampsia, premature birth, Hypertriglyceridemia should be addressed not reduce the risk of major adverse car-
and neonatal intensive care unit admis- with nutritional and lifestyle changes, in- diovascular events compared with the in-
sions (149). There is limited information cluding weight loss and abstinence from ert comparator of corn oil (154).
regarding the use of lipid-lowering thera- alcohol (150). Severe hypertriglyceride- Low levels of HDL cholesterol, often as-
pies (other than bile acid sequestrants) mia (fasting triglycerides $500 mg/dL sociated with elevated triglyceride levels,
during pregnancy. Thus, it is recommended [$5.7 mmol/L] and especially >1,000 mg/dL are the most prevalent pattern of dyslipide-
that individuals of childbearing potential [>11.3 mmol/L]) may warrant pharma- mia in people with type 2 diabetes. How-
use a form of contraception when also us- cologic therapy (fibric acid derivatives ever, the evidence for the use of drugs that
ing lipid-lowering medications with un- and/or fish oil) and reduction in dietary target these lipid fractions is substantially
known risks, limited evidence on safety, or fat to reduce the risk of acute pancrea- less robust than that for statin therapy
known risks during pregnancy regardless titis (151). Moderate- or high-intensity (155). In a large trial in people with diabe-
of intention to become pregnant, as many statin therapy should also be used as tes, fenofibrate improved cardiovascular
pregnancies are unplanned, and precon- indicated to reduce risk of cardiovas- outcomes in subgroups with both elevated
ception counseling should be part of the cular events (see STATIN TREATMENT, above) triglycerides (>200 mg/dL [2.3 mmol/L])
routine care of individuals with diabetes (150,152). In people with hypertriglyceri- and low HDL cholesterol (<40 mg/dL
who have childbearing potential. Counsel- demia (fasting triglycerides >150 mg/dL [1.0 mmol/L]) (156); however, another fi-
ing should include the known benefits and [>1.7 mmol/L] or nonfasting triglycer- brate, pemafibrate, failed to reduce overall
risks of lipid-lowering medications versus ides >175 mg/dL [>2.0 mmol/L]), lifestyle cardiovascular outcomes in a similar popu-
the risks and benefits of not treating the interventions, treatment of secondary fac- lation (157).
conditions for which they are prescribed, tors, and avoidance of medications that
as well as other medications (e.g., non- might raise triglycerides are recommended. Other Combination Therapy
insulin glucose-lowering therapies and For individuals with established cardio- Recommendations
antihypertensive agents), during preg- vascular disease or with risk factors for 10.33 Statin plus fibrate combina-
nancy and recommendations for when cardiovascular disease with elevated triglycer- tion therapy has not been shown to
changes in medications should occur ides (150–499 mg/dL [1.7–5.6 mmol/L]) after improve ASCVD outcomes and is
prior to pregnancy (144) (see Section 15, maximizing statin therapy, icosapent ethyl generally not recommended. A
“Management of Diabetes in Pregnancy,” may be added to reduce cardiovascular
S220 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

10.34 Statin plus niacin combination may be limited to those with diabetes 10.36a For individuals with ASCVD
therapy has not been shown to pro- risk factors. An analysis of one of the and documented aspirin allergy, clopi-
vide additional cardiovascular bene- initial studies suggested that although dogrel (75 mg/day) should be used. B
statin use was associated with diabetes
fit above statin therapy alone, may 10.36b The length of treatment with
risk, the cardiovascular event rate reduc- dual antiplatelet therapy using low-
increase the risk of stroke with ad-
tion with statins far outweighed the risk dose aspirin and a P2Y12 inhibitor
ditional side effects, and is gener-
of incident diabetes, even for individuals in individuals with diabetes after an
ally not recommended. A
at highest risk for diabetes (164). The acute coronary syndrome, acute is-
absolute risk increase was small (over chemic stroke, or transient ischemic
Statin and Fibrate Combination Therapy 5 years of follow-up, 1.2% of participants on attack should be determined by an in-
Combination therapy (statin and fibrate)

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placebo developed diabetes and 1.5% on
terprofessional team approach that
is associated with an increased risk for rosuvastatin developed diabetes) (164). A
includes a cardiovascular or neurologi-
abnormal transaminase levels, myositis, meta-analysis of 13 randomized statin trials
cal specialist, respectively. E
and rhabdomyolysis. The risk of rhabdo- with 91,140 participants showed an odds
10.37 Combination therapy with aspi-
myolysis is more common with higher ratio of 1.09 for a new diagnosis of diabetes,
rin plus low-dose rivaroxaban should
doses of statins and renal insufficiency so that (on average) treatment of 255 indi-
be considered for individuals with sta-
and appears to be higher when statins viduals with statins for 4 years resulted in
ble coronary and/or peripheral artery
are combined with gemfibrozil (com- one additional case of diabetes while simul-
disease (PAD) and low bleeding risk
pared with fenofibrate) (158). taneously preventing 5.4 vascular events
to prevent major adverse limb and
In the ACCORD study, in people with among those 255 individuals (163).
cardiovascular events. A
type 2 diabetes who were at high risk for
10.38 Aspirin therapy (75–162 mg/day)
ASCVD, the combination of fenofibrate Lipid-Lowering Agents and Cognitive
may be considered as a primary preven-
and simvastatin did not reduce the rate of Function
tion strategy in those with diabetes who
fatal cardiovascular events, nonfatal MI, Although concerns regarding a potential
adverse impact of lipid-lowering agents are at increased cardiovascular risk af-
or nonfatal stroke compared with simva-
on cognitive function have been raised, ter a comprehensive discussion with
statin alone. Prespecified subgroup analy-
several lines of evidence argue against this the individual on the benefits versus
ses suggested heterogeneity in treatment
effects with possible benefit for men with association, as detailed in a 2018 European the comparable increased risk of
both a triglyceride level $204 mg/dL Atherosclerosis Society Consensus Panel bleeding. A
($2.3 mmol/L) and an HDL cholesterol statement (165). First, there are three
level #34 mg/dL (#0.9 mmol/L) (159). large, randomized trials of statin versus pla- Risk Reduction
cebo where specific cognitive tests were Aspirin has been shown to be effective in
Statin and Niacin Combination Therapy performed, and no differences were seen reducing cardiovascular morbidity and mor-
Large clinical trials, including the Athe- between statin and placebo (166–169). In tality in high-risk individuals with previous
rothrombosis Intervention in Metabolic addition, no change in cognitive function MI or stroke (secondary prevention) and is
Syndrome With Low HDL/High Triglycer- has been reported in studies with the ad- strongly recommended. In primary preven-
ides: Impact on Global Health Outcomes dition of ezetimibe (119) or PCSK9 inhibi- tion, however, among individuals with no
(AIM-HIGH) and Heart Protection Study 2– tors (121,170) to statin therapy, including previous cardiovascular events, its net ben-
Treatment of HDL to Reduce the Incidence among individuals treated to very low LDL efit is more controversial (162,174).
of Vascular Events (HPS2-THRIVE) trials, cholesterol levels. In addition, systematic Previous randomized controlled trials
failed to demonstrate a benefit of adding reviews of randomized controlled trials of aspirin, specifically in people with di-
niacin to individuals on appropriate statin and prospective cohort studies evaluating abetes, failed to consistently show a sig-
therapy. In fact, there was a possible in- cognition in individuals receiving statins nificant reduction in overall ASCVD end
creased risk of ischemic stroke in the AIM- found that published data do not reveal points, raising questions about the effi-
HIGH trial (160) and an increased inci- an adverse effect of statins on cognition cacy of aspirin for primary prevention in
dence of new-onset diabetes (absolute (171,172). Therefore, a concern that sta- people with diabetes, although some sex
excess, 1.3 percentage points; P < 0.001) tins or other lipid-lowering agents might differences were suggested (175–177).
and disturbances in diabetes manage- cause cognitive dysfunction or dementia is The Antithrombotic Trialists’ Collabora-
ment among those with diabetes in the not currently supported by evidence and tion published an individual participant–
HPS2-THRIVE trial in those on combina- should not deter their use in individuals level meta-analysis (178) of six large trials
tion therapy (161). Therefore, combina- with diabetes at high risk for ASCVD (173). of aspirin for primary prevention in the
tion therapy with a statin and niacin is not general population. These trials collectively
recommended, given the lack of efficacy enrolled over 95,000 participants, includ-
ANTIPLATELET AGENTS
on major ASCVD outcomes and increased ing almost 4,000 with diabetes. Overall,
side effects. Recommendations they found that aspirin reduced the risk of
10.35 Use aspirin therapy (75–162 serious vascular events by 12% (relative
Diabetes Risk With Statin Use mg/day) as a secondary prevention risk 0.88 [95% CI 0.82–0.94]). The largest
Several studies have reported a mod- strategy in those with diabetes and reduction was for nonfatal MI, with little
estly increased risk of incident type 2 di- a history of ASCVD. A effect on CHD death (relative risk 0.95
abetes with statin use (162,163), which [95% CI 0.78–1.15]) or total stroke.
diabetesjournals.org/care Cardiovascular Disease and Risk Management S221

Most recently, the ASCEND (A Study of may be as high as 5 per 1,000 per year in Aspirin Dosing
Cardiovascular Events iN Diabetes) trial real-world settings. However, for adults Average daily dosages used in most clin-
randomized 15,480 people with diabetes with ASCVD risk >1% per year, the num- ical trials involving people with diabetes
but no evident cardiovascular disease to ber of ASCVD events prevented will be ranged from 50 to 650 mg but were
aspirin 100 mg daily or placebo (179). The similar to the number of episodes of mostly in the range of 100–325 mg/day.
primary efficacy end point was vascular bleeding induced, although these compli- There is little evidence to support any
death, MI, stroke, or transient ischemic at- cations do not have equal effects on long- specific dose, but using the lowest pos-
tack. The primary safety outcome was ma- term health (182). sible dose may help to reduce side ef-
jor bleeding (i.e., intracranial hemorrhage, Recommendations for using aspirin fects (190). In the ADAPTABLE (Aspirin
sight-threatening bleeding in the eye, gas- as primary prevention include both men Dosing: A Patient-Centric Trial Assessing

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trointestinal bleeding, or other serious and women aged $50 years with diabetes Benefits and Long-term Effectiveness)
bleeding). During a mean follow-up of and at least one additional major risk fac- trial of individuals with established car-
7.4 years, there was a significant 12% re- tor (family history of premature ASCVD, diovascular disease, 38% of whom had
duction in the primary efficacy end point hypertension, dyslipidemia, smoking, or CKD diabetes, there were no significant differ-
(8.5% vs. 9.6%; P = 0.01). In contrast, major or albuminuria) who are not at increased ences in cardiovascular events or major
bleeding was significantly increased from risk of bleeding (e.g., older age, anemia, or bleeding between individuals assigned to
3.2% to 4.1% in the aspirin group (rate ra- renal disease) (183–186). Noninvasive im- 81 mg and those assigned to 325 mg of
tio 1.29; P = 0.003), with most of the ex- aging techniques such as coronary calcium aspirin daily (191). In the U.S., the most
cess being gastrointestinal bleeding and scoring may help further tailor aspirin common low-dose tablet is 81 mg. Al-
other extracranial bleeding. There were no though platelets from people with diabe-
therapy, particularly in those at low risk
significant differences by sex, weight, or tes have altered function, it is unclear
(187,188). For people >70 years of age
duration of diabetes or other baseline fac- what, if any, effect that finding has on the
(with or without diabetes), the balance ap-
tors, including ASCVD risk score. required dose of aspirin for cardioprotec-
pears to have greater risk than benefit
Two other large, randomized trials of tive effects in people with diabetes. Many
(179,181). Thus, for primary prevention,
aspirin for primary prevention, in people alternate pathways for platelet activation
the use of aspirin needs to be carefully
without diabetes (ARRIVE [Aspirin to Re- exist that are independent of thromboxane
considered and generally may not be rec-
duce Risk of Initial Vascular Events]) (180) A2 and thus are not sensitive to the effects
ommended. Aspirin may be considered in
and in the elderly (ASPREE [Aspirin in Re- of aspirin (192). “Aspirin resistance” has
the context of high cardiovascular risk with
ducing Events in the Elderly]) (181), in been described in people with diabetes
low bleeding risk but generally not in older
which 11% of participants had diabetes, when measured by a variety of ex vivo and
adults. Aspirin therapy for primary preven- in vitro methods (platelet aggregometry
found no benefit of aspirin on the primary
tion may be considered in the context of and measurement of thromboxane B2)
efficacy end point and an increased risk
of bleeding. In ARRIVE, with 12,546 indi- shared decision-making, which carefully (193), but other studies suggest no impair-
viduals over a period of 60 months of weighs the cardiovascular benefits with ment in aspirin response among people
follow-up, the primary end point occurred the fairly comparable increase in risk of with diabetes (194). A trial suggested that
in 4.29% vs. 4.48% of individuals in the bleeding. more frequent dosing of aspirin may re-
aspirin versus placebo groups (HR 0.96 For people with documented ASCVD, duce platelet reactivity in individuals with
[95% CI 0.81–1.13]; P = 0.60). Gastroin- use of aspirin for secondary prevention diabetes (195); however, these observa-
testinal bleeding events (characterized has far greater benefit than risk; for this tions alone are insufficient to empirically
as mild) occurred in 0.97% of individu- indication, aspirin is still recommended recommend that higher doses of aspirin be
als in the aspirin group vs. 0.46% in the (174). used in this group at this time. Another
placebo group (HR 2.11 [95% CI 1.36–3.28]; meta-analysis raised the hypothesis that
P = 0.0007). In ASPREE, which included Aspirin Use in People <50 Years of low-dose aspirin efficacy is reduced in
19,114 individuals, for cardiovascular dis- Age those weighing >70 kg (196); however, the
ease (fatal CHD, MI, stroke, or hospitaliza- Aspirin is not recommended for those at ASCEND trial found benefit of low-dose as-
tion for heart failure) after a median of low risk of ASCVD (such as men and pirin in those in this weight range, which
4.7 years of follow-up, the rates per women aged <50 years with diabetes would not validate this suggested hypothe-
1,000 person-years were 10.7 vs. 11.3 with no other major ASCVD risk factors), as sis (179). It appears that 75–162 mg/day is
events in aspirin vs. placebo groups (HR the low benefit is likely to be outweighed optimal.
0.95 [95% CI 0.83–1.08]). The rate of ma- by the risk of bleeding. Clinical judgment
jor hemorrhage per 1,000 person-years should be used for those at intermediate Indications for P2Y12 Receptor
was 8.6 events versus 6.2 events, respec- risk (younger individuals with one or more Antagonist Use
tively (HR 1.38 [95% CI 1.18–1.62]; P < risk factors or older individuals with no risk Combination dual antiplatelet therapy with
0.001). factors) until further research is available. aspirin and a P2Y12 receptor antagonist is
Thus, aspirin appears to have a modest Individuals’ willingness to undergo long- indicated after acute coronary syndromes
effect on ischemic vascular events, with term aspirin therapy should also be con- and coronary revascularization with stent-
the absolute decrease in events depend- sidered in shared decision-making (189). ing (197). In addition, current guidelines
ing on the underlying ASCVD risk. The Aspirin use in individuals aged <21 years recommend short-term dual antiplatelet
main adverse effect is an increased risk of is generally contraindicated due to the as- therapy after high-risk transient ischemic
gastrointestinal bleeding. The excess risk sociated risk of Reye syndrome. attack and minor stroke (198). The
S222 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

indications for dual antiplatelet therapy in people with diabetes, who comprised 10.40b In asymptomatic individuals
and length of treatment are rapidly evolv- 10,341 of the trial participants (205,206). with diabetes and abnormal natriuretic
ing and should be determined by an inter- A similar treatment strategy was evalu- peptide levels, echocardiography is rec-
professional team approach that includes ated in the Vascular Outcomes Study of ommended to identify stage B heart
a cardiovascular or neurological specialist, ASA (acetylsalicylic acid) Along with failure. A
as appropriate. Evidence supports use of Rivaroxaban in Endovascular or Surgical 10.41 In asymptomatic individuals
either ticagrelor or clopidogrel if no percuta- Limb Revascularization for Peripheral Ar-
with diabetes and age $65 years,
neous coronary intervention was performed tery Disease (VOYAGER PAD) trial (207),
microvascular disease in any location,
and clopidogrel, ticagrelor, or prasugrel if in which 6,564 individuals with PAD who
or foot complications or any end-organ
a percutaneous coronary intervention was had undergone revascularization were
damage from diabetes, screening for

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performed (199). In people with diabetes randomly assigned to receive rivaroxaban
PAD with ankle-brachial index testing
and prior MI (1–3 years before), adding tica- 2.5 mg twice daily plus aspirin or placebo
is recommended if a PAD diagnosis
grelor to aspirin significantly reduces the plus aspirin. Rivaroxaban treatment in this
would change management. B In indi-
risk of recurrent ischemic events, including group of individuals was also associated
with a significantly lower incidence of viduals with diabetes duration $10
cardiovascular and CHD death (200). Simi- years and high cardiovascular risk,
ischemic cardiovascular events, including
larly, the addition of ticagrelor to aspirin re- screening for PAD should be consid-
major adverse limb events. However, an
duced the risk of ischemic cardiovascular ered. E
increased risk of major bleeding was noted
events compared with aspirin alone in peo-
with rivaroxaban added to aspirin treatment
ple with diabetes and stable coronary artery
in both COMPASS and VOYAGER PAD.
disease (201,202). However, a higher inci-
The risks and benefits of dual antiplate- Treatment
dence of major bleeding, including intra-
let or antiplatelet plus anticoagulant treat-
cranial hemorrhage, was noted with dual Recommendations
ment strategies should be thoroughly
antiplatelet therapy. The net clinical bene- 10.42 Among people with type 2 dia-
discussed with eligible individuals, and
fit (ischemic benefit vs. bleeding risk) was shared decision-making should be used
betes who have established ASCVD or
improved with ticagrelor therapy in the established kidney disease, a sodium–
to determine an individually appropriate
large prespecified subgroup of individuals glucose cotransporter 2 (SGLT2) inhibi-
treatment approach. This field of cardio-
with history of percutaneous coronary in- tor or glucagon-like peptide 1 receptor
vascular risk reduction is evolving rapidly,
tervention, while no net benefit was seen agonist (GLP-1 RA) with demonstrated
as are the definitions of optimal care for
in individuals without prior percutaneous individuals with differing types and circum- cardiovascular disease benefit is recom-
coronary intervention (202). However, early stances of cardiovascular complications. mended as part of the comprehensive
aspirin discontinuation compared with cardiovascular risk reduction and/or
continued dual antiplatelet therapy after glucose-lowering treatment plans. A
CARDIOVASCULAR DISEASE
coronary stenting may reduce the risk 10.42a In people with type 2 diabe-
Screening tes and established ASCVD, multiple
of bleeding without a corresponding in-
crease in the risks of mortality and ische- Recommendations ASCVD risk factors, or chronic kidney
mic events, as shown in a prespecified 10.39a In asymptomatic individuals, disease (CKD), an SGLT2 inhibitor with
analysis of people with diabetes enrolled routine screening for coronary artery demonstrated cardiovascular benefit is
in the TWILIGHT (Ticagrelor With Aspirin disease is not recommended, as it does recommended to reduce the risk of
or Alone in High-Risk Patients After Coro- not improve outcomes as long as major adverse cardiovascular events
nary Intervention) trial and a meta-analysis ASCVD risk factors are treated. A and/or heart failure hospitalization. A
(203,204). 10.39b Consider investigations for 10.42b In people with type 2 diabe-
coronary artery disease in the pres- tes and established ASCVD or multi-
ence of any of the following: signs ple risk factors for ASCVD, a GLP-1
Combination Antiplatelet and
Anticoagulation Therapy or symptoms of cardiac or associated RA with demonstrated car-diovascular
Combination therapy with aspirin plus vascular disease, including carotid bruits, benefit is recommended to reduce the
low-dose rivaroxaban may be considered transient ischemic attack, stroke, claudi- risk of major adverse cardiovascular
for people with stable coronary and/or cation, or PAD; or electrocardiogram ab- events. A
PAD to prevent major adverse limb normalities (e.g., Q waves). E 10.42c In people with type 2 diabetes
and cardiovascular complications. In 10.40a Adults with diabetes are at and established ASCVD or multiple risk
the COMPASS (Cardiovascular Outcomes increased risk for the development factors for ASCVD, combined therapy
of asymptomatic cardiac structural or with an SGLT2 inhibitor with demon-
for People Using Anticoagulation Strate-
functional abnormalities (stage B heart strated cardiovascular benefit and a
gies) trial of 27,395 individuals with es-
failure) or symptomatic (stage C) heart GLP-1 RA with demonstrated cardio-
tablished coronary artery disease and/or
failure. Consider screening adults with vascular benefit may be considered
PAD, aspirin plus rivaroxaban 2.5 mg
diabetes by measuring a natriuretic pep- for additive reduction of the risk of
twice daily was superior to aspirin plus
tide (B-type natriuretic peptide [BNP] adverse cardiovascular and kidney
placebo in the reduction of cardiovascu-
or N-terminal pro-BNP [NT-proBNP]) to events. A
lar ischemic events, including major ad-
facilitate prevention of stage C heart 10.43a In people with type 2 diabetes
verse limb events. The absolute benefits
failure. B and established heart failure with
of combination therapy appeared larger
diabetesjournals.org/care Cardiovascular Disease and Risk Management S223

either preserved or reduced ejection with a nonsteroidal MRA with demon- people should already be receiving inten-
fraction, an SGLT2 inhibitor (including strated benefit to reduce the risk of sive medical therapy—an approach that
SGLT1/2 inhibitor) with proven benefit hospitalization for heart failure. A provides benefits similar to those of inva-
in this population is recommended to 10.46f In individuals with diabetes, sive revascularization (208,209). A random-
reduce the risk of worsening heart fail- guideline-directed medical therapy ized observational trial demonstrated no
ure and cardiovascular death. A for myocardial infarction and symp- clinical benefit of routine screening with
10.43b In people with type 2 diabetes tomatic stage C heart failure is recom- adenosine-stress radionuclide myocardial
and established heart failure with either mended with ACE inhibitors or ARBs, perfusion imaging in asymptomatic people
preserved or reduced ejection fraction, MRAs, angiotensin receptor or neprily- with type 2 diabetes and normal ECGs
an SGLT2 inhibitor with proven benefit sin inhibitor, b-blockers, and SGLT2 (210). Another randomized study showed

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in this population is recommended to inhibitors, similar to guideline-directed that routine screening with coronary com-
improve symptoms, physical limitations, puted tomography angiography did not
medical therapy for people without di-
and quality of life. A reduce the composite rate of all-cause
abetes. A
10.44 For individuals with type 2 diabe- mortality, nonfatal MI, or unstable angina
10.47 In people with type 2 diabetes
tes and CKD with albuminuria treated in asymptomatic people with type 1 or
with stable heart failure, metformin
with maximum tolerated doses of ACE type 2 diabetes (211). Studies have also
may be continued for glucose lower-
found that a risk factor–based approach to
inhibitor or ARB, recommend treatment ing if estimated glomerular filtration
the initial diagnostic evaluation and subse-
with a nonsteroidal MRA with demon- rate remains >30 mL/min/1.73 m2
strated benefit to improve cardiovascu- quent follow-up for coronary artery disease
but should be avoided in unstable or
lar outcomes and reduce the risk of fails to identify which people with type 2
hospitalized individuals with heart
CKD progression. A diabetes will have silent ischemia on
failure. B
10.45 In individuals with diabetes with screening tests (212,213).
10.48 Individuals with type 1 diabe-
established ASCVD or aged $55 years Any benefit of noninvasive coronary
tes and those with type 2 diabetes
with additional cardiovascular risk fac- artery disease screening methods, such
who are ketosis prone and/or follow
tors, ACE inhibitor or ARB therapy is as computed tomography calcium scor-
a ketogenic eating pattern who are
recommended to reduce the risk of ing, to identify subgroups for different
treated with SGLT inhibition should be
cardiovascular events and mortality. A treatment strategies remains unproven
educated on the risks and signs of ke-
10.46a In individuals with diabetes and in asymptomatic people with diabetes,
toacidosis and methods of risk manage- though research is ongoing. Coronary
asymptomatic stage B heart failure, an ment and provided with appropriate
interprofessional approach to optimize calcium scoring in asymptomatic people
tools for accurate ketone measurement with diabetes may help in risk stratifica-
guideline-directed medical therapy, (i.e., serum b-hydroxybutyrate). E
which should include a cardiovascular tion (214,215) and provide reasoning for
disease specialist, is recommended to treatment intensification and/or guiding
reduce the risk for progression to Cardiac Testing informed individual decision-making and
symptomatic (stage C) heart failure. A Candidates for advanced or invasive car- willingness for medication initiation and
10.46b In individuals with diabetes and diac testing include those with 1) symp- participation. However, their routine use
asymptomatic stage B heart failure, toms or signs of cardiac or vascular disease leads to radiation exposure and may re-
ACE inhibitors or ARBs and b-blockers and 2) an abnormal resting electrocardio- sult in unnecessary invasive testing, such
are recommended to reduce the risk gram (ECG). Exercise ECG testing without as coronary angiography and revasculari-
for progression to symptomatic (stage C) or with echocardiography may be used zation procedures. The ultimate balance
heart failure. A as the initial test. In adults with diabetes of benefit, cost, and risk of such an ap-
10.46c In individuals with type 2 diabe- $40 years of age, measurement of coro- proach in asymptomatic individuals re-
tes and asymptomatic stage B heart nary artery calcium is also reasonable for mains controversial, particularly in the
failure or with high risk of or established cardiovascular risk assessment. Pharmaco- modern setting of aggressive ASCVD risk
cardiovascular disease, treatment with logic stress echocardiography or nuclear factor management.
an SGLT inhibitor with proven heart imaging should be considered in individuals
failure prevention benefit is recom- with diabetes in whom resting ECG abnor- Screening for Asymptomatic Heart
malities preclude exercise stress testing Failure in People With Diabetes
mended to reduce the risk of hospitali-
(e.g., left bundle branch block or ST-T ab- People with diabetes are at an increased
zation for heart failure. A
normalities). In addition, individuals who risk for developing heart failure, as shown
10.46d In individuals with type 2 dia-
require stress testing and are unable to in multiple longitudinal, observational stud-
betes, obesity, and symptomatic heart
exercise should undergo pharmacologic ies (216,217). This association is not only
failure with preserved ejection fraction,
stress echocardiography or nuclear imaging. observed in people with type 2 diabetes
therapy with a GLP-1 RA with demon-
but also evident in people with type 1 dia-
strated benefit for reduction of heart
Screening Asymptomatic Individuals betes (216,217). In a large multinational
failure–related symptoms, physical limi-
for Atherosclerotic Cardiovascular cohort of 750,000 people with diabetes
tations, and exercise function is recom-
Disease without established cardiovascular disease,
mended. A
The screening of asymptomatic individuals heart failure and CKD were the most fre-
10.46e In individuals with type 2 dia-
with high ASCVD risk is not recommended quent first manifestations of cardiovascular
betes and CKD, recommend treatment
(Fig. 10.5), in part because these high-risk or kidney disease (218). For a detailed
S224 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

Screening for Undiagnosed Cardiovascular Disease

Coronary Artery Peripheral Artery
Disease Heart Failure Disease

Screen individuals with diabetes and age

Screen all adults with
65 years, any microvascular disease, foot
Routine screening is diabetes, which increases

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complications, or end-stage organ damage
not recommended for risks for asymptomatic
from diabetes, if a PAD diagnosis would
asymptomatic individuals. (stage B and symptomatic
Who to change management. Consider screening
(stage C HF.
Screen? anyone with a diabetes duration ≥10 years.

If signs or symptoms of
Measure BNP
cardiac or associated
or N-terminal pro-BNP.
vascular disease, or
Echocardiography is
electrocardiogram Screen with ankle-brachial index testing.
recommended for those
abnormalities are
with abnormal BNP levels.
present, screen using
routine methods.

Figure 10.5—Recommendations for screening of asymptomatic and undiagnosed cardiovascular disease. BNP, B-type natriuretic peptide; HF, heart
failure; PAD, peripheral artery disease. Adapted from “Standards of Care in Diabetes—2024 Abridged for Primary Care Professionals” (325).

review of screening, diagnosis, and treat- heart failure, heart failure hospitalization, evidence of diastolic dysfunction and in-
ment recommendations of heart failure in and newly diagnosed left ventricular dys- creased filling pressures (229). At this
people with diabetes, the reader is fur- function (222,227,228). stage, an interprofessional approach, which
ther referred to the ADA consensus re- Based on collective evidence, consider should include a cardiovascular disease
port “Heart Failure: An Underappreciated screening asymptomatic adults with dia- specialist, is recommended to implement a
Complication of Diabetes. A Consensus Re- betes for the development of cardiac guideline-directed medical treatment strat-
port of the American Diabetes Association” structural or functional abnormalities egy, which may reduce the risk of progres-
(15). (stage B heart failure) by measurement sion to symptomatic stages of heart failure
People with diabetes are at particularly of natriuretic peptides, including BNP or (221). The recommendations for screening
high risk for progression from asymptom- NT-proBNP levels. The biomarker thresh- and treatment of heart failure in people
atic stage A and B to symptomatic stage C old for abnormal values is BNP level with diabetes discussed in this section are
and D heart failure (219,220). Identifica- $50 pg/mL and NT-proBNP level $125 consistent with the ADA consensus report
tion, risk stratification, and early treatment pg/mL. Abnormal levels of natriuretic on heart failure (15) and with current
of risk factors in people with diabetes and peptide will need to be evaluated in the American Heart Association/American Col-
asymptomatic stages of heart failure re- context of each person, using clinical judg- lege of Cardiology/Heart Failure Society of
duce the risk for progression to symptom- ment, in the absence of any possible com- America guidelines for the management of
atic heart failure (221,222). In people with peting diagnoses, particularly recognizing heart failure (12).
type 2 diabetes, measurement of natri- conditions that may lead to increased lev-
uretic peptides, including B-type natriuretic els of natriuretic peptide, including renal Screening for Asymptomatic
peptide (BNP) or N-terminal pro-BNP (NT- insufficiency, pulmonary disease including Peripheral Artery Disease in People
proBNP), identifies people at risk for heart pulmonary hypertension and chronic ob- With Diabetes
failure development, progression of symp- structive lung disease, obstructive sleep The risk for PAD in people with diabetes is
toms, and heart failure–related mortality apnea, ischemic and hemorrhagic stroke, higher than that in people without diabe-
(223–225). A similar association and prog- and anemia. Conversely, natriuretic peptide tes (230–232). In the PAD Awareness, Risk,
nostic values of increased NT-proBNP with levels may be decreased in the population and Treatment: New Resources for Survival
increased cardiovascular and all-cause mor- with obesity, which impairs sensitivity of (PARTNERS) program, 30% of people aged
tality has been reported in people with testing. 50–69 years with a history of cigarette
type 1 diabetes (226). Results from several In people with diabetes and an abnor- smoking or diabetes, or aged $70 years
randomized controlled trials revealed that mal natriuretic peptide level, echocardiog- regardless of risk factors, had PAD (233).
more intensive treatment of risk factors in raphy is recommended as the next step to Similarly, in other screening studies, 26%
people with increased levels of natriuretic screen for structural heart disease and of people with diabetes have been shown
peptides reduces the risk for symptomatic echocardiographic Doppler indices for to have PAD (234), and diabetes increased
diabetesjournals.org/care Cardiovascular Disease and Risk Management S225

the odds of having PAD by 85% (235). No- if the individual has hypertension, and pos- outcome of MI, stroke, and cardiovascular
tably, classical symptoms of claudication sibly aspirin, unless there are contraindica- death by 14% (absolute rate 10.5% vs.
are uncommon, and almost half of people tions to a particular drug class. 12.1% in the placebo group, HR in the em-
with newly diagnosed PAD were asymp- Clear cardiovascular benefit exists for pagliflozin group 0.86 [95% CI 0.74–0.99];
tomatic (233). Conversely, up to two- ACE inhibitor or ARB therapy in people P = 0.04 for superiority) and cardiovascular
thirds of people with asymptomatic PAD with diabetes. The Heart Outcomes Pre- death by 38% (absolute rate 3.7% vs.
have been shown to have comorbid dia- vention Evaluation (HOPE) study random- 5.9%, HR 0.62 [95% CI 0.49–0.77]; P <
betes (236). Risk factors associated with ized 9,297 individuals aged $55 years 0.001) (255). Similarly, canagliflozin signifi-
an increased risk for PAD in people with with a history of vascular disease or dia- cantly reduced the composite outcome of
diabetes include age, smoking, hyperten- betes plus one other cardiovascular risk cardiovascular death, MI, or stroke versus

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sion, dyslipidemia, worse glycemic man- factor to either ramipril or placebo. Rami- placebo (occurring in 26.9 vs. 31.5 partici-
agement, longer duration of diabetes, pril significantly reduced cardiovascular pants per 1,000 person-years; HR 0.86
neuropathy, and retinopathy as well as a and all-cause mortality, MI, and stroke [95% CI 0.75–0.97]). Of note, there was
prior history of cardiovascular disease (245). ACE inhibitors or ARB therapy also an increased risk of lower-limb amputa-
(237,238). In addition, the presence of have well-established long-term benefit tion with canagliflozin (6.3 vs. 3.4 partici-
microvascular disease is associated with in people with diabetes and CKD or hy- pants per 1,000 person-years; HR 1.97
adverse outcomes in people with PAD, pertension, and these agents are recom- [95% CI 1.41–2.75]) (256). However, no
including an increased risk for future limb mended for hypertension management in significant increase in lower-limb amputa-
amputation (239,240). While a positive people with known ASCVD (particularly tions, fractures, AKI, or hyperkalemia was
screening test for PAD in an asymptom- coronary artery disease) (72,73,246). Peo- noted for canagliflozin relative to placebo
atic population has been associated ple with type 2 diabetes and CKD should in other trials of canagliflozin (257).
with increased cardiovascular event rates be considered for treatment with finere- The Dapagliflozin Effect on Cardiovas-
(241,242), prospective, randomized stud- none to reduce cardiovascular outcomes cular Events-Thrombosis in Myocardial
ies addressing whether screening for PAD and the risk of CKD progression (247–250). Infarction 58 (DECLARE-TIMI 58) trial
in people with diabetes improves long- b-Blockers should be used in individuals met the prespecified criteria for nonin-
term limb outcomes and cardiovascular with active angina or HFrEF and for 3 years feriority to placebo with respect to ma-
event rates are limited. In the randomized after MI in those with preserved left ven- jor adverse cardiovascular events but
controlled Viborg Vascular (VIVA) trial, tricular function (251,252). did not show a lower rate of major ad-
50,156 participants, some with and some verse cardiovascular events compared
without diabetes, were randomized to Glucose-Lowering Therapies and with placebo (8.8% in the dapagliflozin
combined vascular screening for abdomi- Cardiovascular Outcomes group and 9.4% in the placebo group;
nal aortic aneurysm, PAD, and hyperten- In 2008, the U.S. Food and Drug Adminis- HR 0.93 [95% CI 0.84–1.03]; P = 0.17)
sion or to no screening. Vascular screening tration (FDA) issued guidance for industry (258). A lower rate of cardiovascular death
was associated with increased pharmaco- to perform cardiovascular outcomes trials or hospitalization for heart failure was
logic therapy (antiplatelet, lipid-lowering, for all new medications for the treatment noted (4.9% vs. 5.8%; HR 0.83 [95% CI
and antihypertensive therapy), reduced in- of type 2 diabetes amid concerns of in- 0.73–0.95]; P = 0.005), which reflected a
hospital time for PAD and coronary artery creased cardiovascular risk (253). Previ- lower rate of hospitalization for heart fail-
disease, and reduced mortality (243). ously approved diabetes medications were ure (HR 0.73 [95% CI 0.61–0.88]). No dif-
Therefore, the committee recommends not subject to the guidance. Recently pub- ference was seen in cardiovascular death
screening for asymptomatic PAD using lished cardiovascular outcomes trials have between groups. Further studies have
ankle-brachial index in people with dia- provided additional data on cardiovascular shown renoprotective effects of dapa-
betes in whom a diagnosis of PAD may and renal outcomes in people with type 2 gliflozin (259).
help further intensify pharmacologic diabetes with cardiovascular disease or at The Evaluation of Ertugliflozin Efficacy
therapies. These people include those high risk for cardiovascular disease. and Safety Cardiovascular Outcomes Trial
with age $65 years, diabetes with dura- Cardiovascular outcomes trials of dipep- (VERTIS CV) (260) met the prespecified cri-
tion $10 years, microvascular disease, tidyl peptidase 4 (DPP-4) inhibitors have teria for noninferiority of ertugliflozin to pla-
clinical evidence of foot complications, all, so far, not shown cardiovascular bene- cebo with respect to the primary outcome
or any end-organ damage from diabetes. fits relative to placebo. In addition, the of major adverse cardiovascular events
CAROLINA (Cardiovascular Outcome Study (11.9% in the pooled ertugliflozin group
Lifestyle and Pharmacologic of Linagliptin Versus Glimepiride in Type 2 and 11.9% in the placebo group; HR 0.97
Interventions Diabetes) study demonstrated noninferior- [95% CI 0.85–1.11]; P < 0.001). However,
Intensive lifestyle intervention focusing ity between a DPP-4 inhibitor, linagliptin, ertugliflozin was not superior to placebo for
on weight loss through decreased calo- and a sulfonylurea, glimepiride, on cardio- the key secondary outcomes of death from
ric intake and increased physical activity, vascular outcomes despite lower rates of cardiovascular causes or hospitalization for
as performed in the Look AHEAD (Action hypoglycemia in the linagliptin treatment heart failure; death from cardiovascular
for Health in Diabetes) trial, may be consid- group (254). The BI 10773 (Empagliflozin) causes; or the composite of death from re-
ered for improving glucose management, Cardiovascular Outcome Event Trial in nal causes, renal replacement therapy, or
fitness, and some ASCVD risk factors (244). Type 2 Diabetes Mellitus Patients (EMPA- doubling of the serum creatinine level. The
Individuals at increased ASCVD risk should REG OUTCOME) showed that treatment HR for a secondary outcome of hospitali-
receive statin, ACE inhibitor, or ARB therapy with empagliflozin reduced the composite zation for heart failure (ertugliflozin vs.
S226 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

placebo) was 0.70 [95% CI 0.54–0.90], in people with established ASCVD, multi- incident heart failure is preceded by hyper-
consistent with findings from other SGLT2 ple risk factors for ASCVD, or albuminuric tension; up to 91% of all new heart failure
inhibitor cardiovascular outcomes trials. kidney disease (268,269). In people with development in the Framingham cohort
type 2 diabetes and established ASCVD, occurred in people with a previous diagno-
GLP-1 Receptor Agonist Trials multiple ASCVD risk factors, or CKD, an sis of hypertension (275). Therefore, man-
The Liraglutide Effect and Action in Diabe- SGLT2 inhibitor with demonstrated car- agement of hypertension constitutes a key
tes: Evaluation of Cardiovascular Outcome diovascular benefit is recommended to goal in people with diabetes and stage A
Results (LEADER) trial was a randomized, reduce the risk of major adverse cardiovas- or B heart failure. For example, in the UK
double-blind trial that assessed the effect cular events and/or heart failure hospitali- Prospective Diabetes Study (UKPDS) trial,
of liraglutide, a GLP-1 RA, versus placebo zation. In people with type 2 diabetes and intensive blood pressure management in

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on cardiovascular outcomes in 9,340 peo- established ASCVD or multiple risk factors people with type 2 diabetes reduced the
ple with type 2 diabetes at high risk for car- for ASCVD, a GLP-1 RA with demonstrated risk for heart failure by 56% (276). Simi-
diovascular disease or with cardiovascular cardiovascular benefit is recommended larly, in the SPRINT trial, intensive treat-
disease (261). Study participants had a to reduce the risk of major adverse car- ment of hypertension decreased the risk
mean age of 64 years and a mean duration diovascular events. For many individuals, for development of incident heart failure
of diabetes of nearly 13 years. Over 80% use of either an SGLT2 inhibitor or a GLP-1 by 36% (277). As discussed in the HYPERTEN-
of study participants had established car- RA to reduce cardiovascular risk is appro- SION AND BLOOD PRESSURE MANAGEMENT section
diovascular disease. After a median fol- priate. Emerging data suggest that use of above, use of ACE inhibitors or ARBs is the
low-up of 3.8 years, LEADER showed that both classes of drugs will provide an addi- preferred treatment strategy for man-
the primary composite outcome (MI, tive cardiovascular and kidney outcomes agement of hypertension in people with
stroke, or cardiovascular death) occurred benefit; thus, combination therapy with an diabetes, particularly in the presence of
in fewer participants in the treatment SGLT2 inhibitor and a GLP-1 RA may be con- albuminuria or coronary artery disease.
group (13.0%) than in the placebo group sidered to provide the complementary People with diabetes and stage B heart
(14.9%) (HR 0.87 [95% CI 0.78–0.97]; P < outcomes benefits associated with these failure who remain asymptomatic but
0.001 for noninferiority; P = 0.01 for superi- classes of medication (270). have evidence of structural heart disease,
ority). Deaths from cardiovascular causes including history of MI, acute coronary syn-
were significantly reduced in the liraglutide Prevention and Treatment of Heart drome, or left ventricular ejection fraction
group (4.7%) compared with the placebo Failure (LVEF) #40%, should be treated with ACE
group (6.0%) (HR 0.78 [95% CI 0.66–0.93]; Prevention of Symptomatic Heart Failure inhibitors or ARBs plus b-blockers accord-
P = 0.007) (261). ACE Inhibitors or ARBs and b-Blockers. ing to current treatment guidelines (12). In
Results of trials with semaglutide, albiglu- Early primary prevention strategies and the landmark Studies of Left Ventricular
tide, and dulaglutide, once-weekly GLP-1 treatment of associated risk factors re- Dysfunction (SOLVD) study, in which 15%
RAs, were consistent with the LEADER trial duce incident, symptomatic heart failure of people had diabetes, treatment with
(262–264). However, lixisenatide and ex- and should include lifestyle intervention enalapril reduced incident heart failure in
tended-release exenatide were not supe- with nutrition, physical activity, weight people with asymptomatic left ventricular
rior to placebo with respect to the primary management, and smoking cessation dysfunction by 20% (278). In the Survival
end point of cardiovascular outcomes (271–274) (Fig. 10.6). The vast majority of and Ventricular Enlargement (SAVE) study,
(265). In summary, there are now nu-
merous large randomized controlled
trials reporting statistically significant
Recommendations to reduce the risk of symptomatic heart failure in people with diabetes
reductions in cardiovascular events for
three of the FDA-approved SGLT2 inhibi-
tors (empagliflozin, canagliflozin, and da-
pagliflozin, with lesser benefits seen with
ACEi or ARB and β-blocker for hypertension, or recent history of myocardial
ertugliflozin) and four FDA-approved GLP- infarction/acute coronary syndrome, or reduced LVEF ≤40%
1 RAs (liraglutide, albiglutide [although
that agent was removed from the market
for business reasons], semaglutide [lower
risk of cardiovascular events in a moder- If high risk for or
If CKD
established CVD
ate-sized clinical trial but one not powered
as a cardiovascular outcomes trial], and
dulaglutide). Meta-analyses of the trials
reported to date suggest that GLP-1 RAs SGLT2 or SGLT1/2
SGLT2 inhibitor Finerenone
and SGLT2 inhibitors reduce risk of ath- inhibitor

erosclerotic major adverse cardiovascu-

lar events to a comparable degree in
Figure 10.6—Overview of recommendations for the prevention of the development of symp-
people with type 2 diabetes and estab- tomatic heart failure in people with diabetes. ACEi, ACE inhibitor; ARB, angiotensin receptor
lished ASCVD (266,267). SGLT2 inhibitors blocker; CKD, chronic kidney disease; CVD, cardiovascular disease; LVEF, left ventricle ejection
also reduce risk of heart failure hospitali- fraction; SGLT2, sodium–glucose cotransporter 2. Adapted from “Standards of Care in Diabe-
zation and progression of kidney disease tes—2024 Abridged for Primary Care Professionals” (325).
diabetesjournals.org/care Cardiovascular Disease and Risk Management S227

which enrolled asymptomatic people with randomization to the SGLT1/2 inhibitor so- failure in people with diabetes is simi-
reduced LVEF after MI, including 23% peo- tagliflozin reduced the primary outcome of lar to that for people without diabetes.
ple with diabetes, treatment with captopril death from cardiovascular causes, hospital- At these advanced stages of heart fail-
reduced the development of heart failure izations for heart failure, and urgent visits ure, a collaborative approach with a car-
by 37% (279). Subsequent retrospective for heart failure in people with type 2 dia- diovascular specialist is recommended.
analyses from both trials revealed that con- betes, CKD, and risk for cardiovascular The treatment recommendations are
comitant use of b-blockers was associated disease (284). Therefore, SGLT inhibitor detailed in current 2022 American Heart
with decreased risk of progression to treatment is recommended in asymptom- Association/American College of Cardi-
symptomatic heart failure (280,281). The atic people with type 2 diabetes at risk or ology/Heart Failure Society of America
Carvedilol Post-Infarct Survival Control in with established cardiovascular disease to guidelines for the management of heart

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Left Ventricular Dysfunction (CAPRICORN) prevent incident heart failure and hospi- failure (12).
study randomized people with a history talization from heart failure.
of MI and reduced LVEF to treatment Glucose-Lowering Medications and
with carvedilol (282). Approximately half Finerenone. Finerenone is a nonsteroidal Heart Failure: Discussion of Heart
of the study participants were asymptom- MRA and has recently been studied in Failure Outcomes
atic, and 23% of study participants had a people with diabetes and CKD, including Data on the effects of glucose-lowering
history of diabetes. Treatment with carve- the Finerenone in Reducing Kidney Fail- agents on heart failure outcomes have
dilol reduced mortality by 23%, and there ure and Disease Progression in Diabetic demonstrated that thiazolidinediones have
was a 14% risk reduction for heart failure Kidney Disease (FIDELIO-DKD) and the a strong and consistent relationship with
hospitalization. Finally, in the Reversal of Efficacy and Safety of Finerenone in increased risk of heart failure (286–288).
Ventricular Remodeling With Toprol-XL Therefore, thiazolidinedione use should be
Subjects With Type 2 Diabetes Mellitus
(REVERT) trial, in which 45% of the people avoided in people with symptomatic heart
and the Clinical Diagnosis of Diabetic
enrolled had diabetes, metoprolol improved failure. Restrictions to use of metformin in
Kidney Disease (FIGARO-DKD) studies.
adverse cardiac remodeling in asymptom- people with medically treated heart failure
In FIDELIO-DKD, finerenone was compared
atic individuals with an LVEF <40% and with placebo for the primary outcome of
were removed by the FDA in 2006 (289).
mild left ventricular dilatation (283). Observational studies of people with type 2
kidney failure, a sustained decrease of at
diabetes and heart failure suggest that
least 40% in the eGFR from baseline, or
SGLT Inhibitors. SGLT2 inhibitors consti- metformin users have better outcomes
death from renal causes in people with
tute a key treatment approach to reduce than individuals treated with other anti-
type 2 diabetes and CKD (285). A prespeci-
cardiovascular disease and heart failure hyperglycemic agents (290); however, no
fied secondary outcome was death from
outcomes in people with diabetes. Peo- randomized trial of metformin therapy
cardiovascular causes, nonfatal MI, non-
ple with type 2 diabetes and increased has been conducted in people with heart
fatal stroke, or hospitalization for heart fail- failure. Metformin may be used for the
cardiovascular risk or established cardio-
ure, which was reduced by 13% in the fi- management of hyperglycemia in people
vascular disease should be treated with
nerenone group. The incidence of heart with stable heart failure as long as kidney
an SGLT2 inhibitor to prevent the devel-
failure hospitalization occurred less in the function remains within the recommended
opment of incident heart failure. This in-
cludes people with type 2 diabetes and finerenone-treated group, and only 7.7% range for use (291).
asymptomatic stage B heart failure. In of study participants had a prior history of Studies examining the relationship be-
the EMPA-REG OUTCOME trial, only 10% heart failure. In the FIGARO-DKD trial, fi- tween DPP-4 inhibitors and heart failure
of study participants had a prior history nerenone reduced the primary outcome of have had mixed results. The Saxagliptin As-
of heart failure, and treatment with em- death from cardiovascular causes, nonfatal sessment of Vascular Outcomes Recorded
pagliflozin reduced the relative risk for MI, nonfatal stroke, or hospitalization for in Patients with Diabetes Mellitus–Throm-
hospitalization from heart failure by 35% heart failure (HR 0.87 [95% CI 0.76–0.98]; bolysis in Myocardial Infarction 53 (SAVOR-
(255). In the CANVAS Program, hospitali- P = 0.03) in people with type 2 diabetes TIMI 53) study showed that individuals
zation from heart failure was reduced by and CKD (248). Only 7.8% of all participants treated with the DPP-4 inhibitor saxaglip-
33% in people allocated to canagliflozin, had a prior history of heart failure, and the tin were more likely to be hospitalized
and only 14% of individuals enrolled had incidence of hospitalization for heart failure for heart failure than those given pla-
a prior history of heart failure (256). In was reduced in the finerenone-allocated cebo (3.5% vs. 2.8%, respectively) (292).
the DECLARE-TIMI 58 study, only 10% of treatment arm (HR 0.71 [95% CI 0.56– However, three other cardiovascular
study participants had a prior history of 0.90]). Owing to these observations, treat- outcomes trials—Examination of Cardio-
heart failure, and dapagliflozin reduced ment with finerenone is recommended in vascular Outcomes with Alogliptin versus
cardiovascular mortality and hospitaliza- people with type 2 diabetes and CKD to re- Standard of Care (EXAMINE) (293), Trial
tion for heart failure by 17%, which was duce the risk of progression from stage A Evaluating Cardiovascular Outcomes with
consistent across multiple study subgroups heart failure to symptomatic incident heart Sitagliptin (TECOS) (294), and the Cardio-
regardless of a prior history of heart failure failure. vascular and Renal Microvascular Out-
(258). Finally, in the Effect of Sotagliflozin come Study With Linagliptin (CARMELINA)
on Cardiovascular and Renal Events in Treatment of Symptomatic Heart Failure (295)—did not find a significant increase
Participants With Type 2 Diabetes and In general, current guideline-directed in risk of heart failure hospitalization with
Moderate Renal Impairment Who Are medical therapy for a history of MI DPP-4 inhibitor use compared with pla-
at Cardiovascular Risk (SCORED) trial, and symptomatic stage C and D heart cebo. No increased risk of heart failure
S228 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

hospitalization has been identified in the heart failure to those with preserved ejec- evaluated in the SCORED trial (284), which
cardiovascular outcomes trials of the GLP-1 tion fraction irrespective of the presence was ended early due to lack of funding,
RAs lixisenatide, liraglutide, semaglutide, of type 2 diabetes (250). A similar benefit and examined the safety and efficacy of
exenatide once weekly, albiglutide, or du- for heart failure outcomes was seen in sotagliflozin in people with type 2 diabe-
laglutide compared with placebo (261,264, the Dapagliflozin Evaluation to Improve tes and CKD and risks for cardiovascular
265,296,297). the Lives of Patients with Preserved Ejec- disease. Changes to the prespecified pri-
SGLT2 inhibitors reduce the incidence of tion Fraction Heart Failure (DELIVER) trial mary end points were made prior to un-
heart failure and improve heart failure– for dapagliflozin in people with mildly blinding to accommodate a lower-than-
related outcomes, including hospitalization reduced or preserved ejection fraction anticipated number of end point events.
for heart failure and heart failure–related (302). In addition, a large meta-analysis The primary end point of deaths from

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symptoms, in people with diabetes with (308) including the EMPEROR-Reduced, cardiovascular causes, hospitalizations for
preserved or reduced ejection fraction EMPEROR-Preserved, DAPA-HF, DELIVER, heart failure, and urgent visits for heart
(250,255–257,298–306). The results of and the Effect of Sotagliflozin on Cardio- failure was reduced with sotagliflozin. In
these clinical trials have been extensively vascular Events in Patients With Type 2 the SOLOIST trial, sotagliflozin initiated
outlined in the 2024 American Diabetes Diabetes Post Worsening Heart Failure during or shortly after hospitalization in
Association “Standards of Care in Dia- (SOLOIST-WHF) trials included 21,947 people with diabetes also reduced the risk
betes” (307). Briefly, in the EMPA-REG individuals and demonstrated reduced for the primary end point of deaths from
OUTCOME trial, the addition of empagliflo- risk for the composite of cardiovascular cardiovascular causes and hospitalizations
zin to standard care led to a significant 35% death or hospitalization for heart fail- and urgent visits for heart failure (309).
reduction in hospitalization for heart failure ure, cardiovascular death, first hospital- The trial was originally also intended to
compared with placebo (255). Similarly, in ization for heart failure, and all-cause evaluate the effects of SGLT inhibition in
CANVAS and DECLARE-TIMI 58, there were mortality. The findings on the studied people with HFpEF, and ultimately no evi-
33% and 27% reductions, respectively, in end points were consistent in both tri- dence of heterogeneity of treatment
hospitalization for heart failure with SGLT2 als of heart failure with mildly reduced effect by ejection fraction was noted.
inhibitor use versus placebo (256,258). Ad- or preserved ejection fraction and in all However, the relatively small percentage
ditional data from the CREDENCE trial with five trials combined. In addition to the of such individuals enrolled (only 21% of
canagliflozin showed a 39% reduction in hospitalization and mortality benefit in participants had ejection fraction >50%)
hospitalization for heart failure and a 31% people with heart failure, SGLT2 inhibi- and the early termination of the trial lim-
reduction in the composite of cardiovascu- tors improve clinical stability and func- ited the ability to determine the effects of
lar death or hospitalization for heart failure, tional status in individuals with heart sotagliflozin in HFpEF specifically (309).
in a population with CKD and albuminuria failure (301,304–306). Collectively, these One concern with expanded use of SGLT
(UACR >300–5,000 mg/g) (257). studies indicate that SGLT2 inhibitors re- inhibition is the infrequent but serious risk
The DAPA-HF trial specifically evalu- duce the risk for heart failure hospitaliza- of diabetic ketoacidosis, including the atypi-
ated the effects of dapagliflozin on the tion and cardiovascular death in a wide cal presentation of euglycemic ketoacidosis.
primary outcome of a composite of range of people with heart failure. There are multiple proposed pathways
worsening heart failure or cardiovascu- Therefore, in people with type 2 diabe- through which SGLT inhibition results in
lar death in individuals with New York tes and established HFpEF or HFrEF, an ketosis (increased b-hydroxybutyrate and
Heart Association (NYHA) class II, III, or SGLT2 inhibitor with proven benefit in acetoacetate), such as increased produc-
IV heart failure and an ejection fraction this population is recommended to tion due to reduction in insulin doses,
of 40% or less (299,307). Dapagliflozin reduce the risk of worsening heart increases in glucagon levels leading to in-
treatment had a lower risk of the primary failure and cardiovascular death. In creased lipolysis and ketone production,
outcome (HR 0.74 [95% CI 0.65–0.85]), addition, an SGLT2 inhibitor is rec- and decreased renal clearance of ketones
lower risk of first worsening heart failure ommended in this population to im- (310,311). Thus, the use of SGLT inhibitors
event (HR 0.70 [95% CI 0.59–0.83]), and prove symptoms, physical limitations, and (whether for glycemic management or an-
lower risk of cardiovascular death (HR quality of life. other indication) increases the susceptibil-
0.82 [95% CI 0.69–0.98]) compared with Sotagliflozin, a dual SGLT1 and SGLT2 ity to diabetic ketoacidosis, particularly
placebo. The effect of dapagliflozin on inhibitor, was recently approved by the when other risk factors or situations occur
the primary outcome was consistent re- FDA to reduce the risk of cardiovascular (including, but not limited to, insulin pump
gardless of the presence or absence of death, hospitalization for heart failure, malfunctions, significant reduction in insu-
type 2 diabetes (299). Similar results and urgent heart failure in people with lin doses, and nutritional intake plans with
were obtained in clinical trials with em- heart failure or type 2 diabetes, CKD, prolonged periods of fasting or carbohy-
pagliflozin (303). In Empagliflozin Out- and other cardiovascular risk factors. drate restriction). Although there were low
come Trial in Patients With Chronic Heart This drug is distinct from other SGLT in- rates of ketoacidosis in the cardiovascular
Failure With Preserved Ejection Fraction hibitors, as it lowers glucose via delayed and heart failure outcomes trials evaluating
(EMPEROR-Preserved), the primary out- glucose absorption in the gut via inhibition SGLT inhibition, these studies excluded
come of cardiovascular death or hospital- of the cotransporter SGLT1 in addition to individuals with type 1 diabetes and/or
ization for heart failure was reduced in increasing urinary glucose excretion; how- recent history of diabetic ketoacidosis
adults with NYHA functional class I–IV and ever, it is not currently approved by the (309,312). To decrease the risk of ketoaci-
chronic HFpEF (LVEF >40%), extending FDA for glycemic management of type 1 dosis when using SGLT inhibition in people
the previously seen benefit in people with or type 2 diabetes. Sotagliflozin was with type 1 diabetes, it is recommended
diabetesjournals.org/care Cardiovascular Disease and Risk Management S229

that clinicians assess the underlying sus- treatment, particularly as preventative the risk for new-onset heart failure and im-
ceptibility; provide education regarding strategies and monitoring can minimize, proves heart failure outcomes in people
the risks, symptoms, and prevention strat- but not eliminate, the risk of ketoacidosis with type 2 diabetes and CKD (247). Fur-
egies; and prescribe home monitoring sup- in those who are susceptible (318,319). thermore, the incidence of heart failure
plies for b-hydroxybutyrate (311,313). Use The selective nonsteroidal MRA finer- hospitalization was reduced in finerenone-
of these processes may have contributed enone has been shown in the FIGARO- treated people with type 2 diabetes. Finally,
to the lower rates of ketoacidosis seen in DKD trial, which included people with in a pooled analysis from both FIDELIO-
some of the studies of these agents for ad- type 2 diabetes and CKD, to reduce the pri- DKD and FIGARO-DKD, treatment with
junctive glycemic management in people mary composite outcome of death from finerenone reduced the composite of
with type 1 diabetes (314–316) compared cardiovascular causes, nonfatal myocardial cardiovascular death, nonfatal MI, nonfatal

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with those that did not include preventa- infarction, nonfatal stroke, or hospitaliza- stroke, or hospitalization for heart failure
tive strategies (310,317). Reassessment tion for heart failure (248). A prespecified was reduced (249). These collective studies
of susceptibility, education, and provision subgroup analysis from FIGARO-DKD fur- indicate that finerenone improves cardio-
of monitoring supplies should reoccur ther revealed that in individuals without vascular and renal outcomes in people
throughout the duration of SGLT inhibitor symptomatic HFrEF, finerenone reduces with type 2 diabetes. Therefore, in people

Individual is ≥18 years old with T2D and has ≥1 of the following:
ASCVD*, HF, CKD†, at high risk for ASCVD.‡§

Address concurrently.

Optimize guideline-directed medical Recommend starting SGLT2 inhibitor or

therapy for prevention (lifestyle, blood GLP-1 RA with proven CV benefit depending on
pressure, lipids, glucose, antiplatelet). patient-specific factors and comorbidities.ˡ

Discuss patient-clinician preferences and priorities.

No additional action SGLT2 inhibitor

GLP-1 RA selected.
taken at this time. selected.

Reassess and consider the addition of the

alternative class, if benefits outweigh risks.

* ASCVD is defined as a history of an acute coronary syndrome or myocardial infarction, stable or unstable angina, coronary heart disease with or without revascularization,
other arterial revascularization, stroke, or peripheral artery disease assumed to be atherosclerotic in origin.
† CKD is a clinical diagnosis marked by reduced eGFR, the presence of albuminuria, or both.
‡ Consider an SGLT2 inhibitor when the individual has established ASCVD, HF, or CKD or is at high risk for ASCVD. Consider a GLP-1 RA when the individual has established
ASCVD or is at high risk for ASCVD.
§ Individuals at high risk for ASCVD include those with end-organ damage such as left ventricular hypertrophy or retinopathy or with multiple CV risk factors (e.g., age,
hypertension, smoking, dyslipidemia, and obesity).
ˡ Most individuals enrolled in the relevant trials were on metformin at baseline as glucose-lowering therapy.

Figure 10.7—Approach to risk reduction with sodium–glucose cotransporter 2 (SGLT2) inhibitor or glucagon-like peptide 1 receptor agonist (GLP-1
RA) therapy in conjunction with other traditional, guideline-based preventive medical therapies for blood pressure, lipids, and glycemia and anti-
platelet therapy. ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtra-
tion rate; HF, heart failure; T2D, type 2 diabetes. Adapted with permission from Das et al. (324).
S230 Cardiovascular Disease and Risk Management Diabetes Care Volume 48, Supplement 1, January 2025

with type 2 diabetes and CKD with albu- metformin use. Such an approach has 8. Kazemian P, Shebl FM, McCann N, Walensky
minuria treated with maximum tolerated also been described in the ADA-endorsed RP, Wexler DJ. Evaluation of the cascade of
diabetes care in the United States, 2005–2016.
doses of ACE inhibitor or ARB, addition of American College of Cardiology “2020 JAMA Intern Med 2019;179:1376–1385
finerenone should be considered to im- Expert Consensus Decision Pathway on 9. Nelson AJ, O’Brien EC, Kaltenbach LA, et al.
prove cardiovascular outcomes, including Novel Therapies for Cardiovascular Risk Use of lipid-, blood pressure-, and glucose-
the risk for heart failure hospitalization, Reduction in Patients With Type 2 Dia- lowering pharmacotherapy in patients with type 2
and to reduce the risk of CKD progression. diabetes and atherosclerotic cardiovascular disease.
betes” (324). Figure 10.7, reproduced
JAMA Netw Open 2022;5:e2148030
Approximately 45% of people admitted from that decision pathway, outlines the 10. Gregg EW, Cheng YJ, Srinivasan M, et al.
for HFpEF have diabetes, and most people approach to risk reduction with SGLT2 in- Trends in cause-specific mortality among adults
with HFpEF have obesity (320,321). Con- hibitor or GLP-1 RA therapy in conjunction with and without diagnosed diabetes in the USA:

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versely, weight loss improves symptoms of with other traditional, guideline-based an epidemiological analysis of linked national
HFpEF (322). Therefore, the Semaglutide survey and vital statistics data. Lancet 2018;391:
preventive medical therapies for blood 2430–2440
Treatment Effect in People with Obesity pressure, lipids, and glycemia and antipla- 11. Kodama S, Fujihara K, Horikawa C, et al.
and HFpEF (STEP-HFpEF) trial evaluated telet therapy. Diabetes mellitus and risk of new-onset and
whether the GLP-1 RA semaglutide im- Adoption of these agents should be recurrent heart failure: a systematic review and
proves symptoms related to heart failure meta-analysis. ESC Heart Fail 2020;7:2146–2174
reasonably straightforward in people with
12. Heidenreich PA, Bozkurt B, Aguilar D, et al.
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HFpEF were assigned to receive once- SGLT2 inhibitor or GLP-1 RA therapy in the of Cardiology/American Heart Association Joint
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placebo. The primary end point was the culation 2022;145:e895–e1032
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