Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

acute myocardial infarction or unstable angina

1st line – coronary intervention and medical management

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INITIAL
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acute myocardial infarction or unstable angina
1st line – 

coronary intervention and medical management

For people with ST-elevation myocardial infarction (STEMI) and ischemic symptoms for <12 hours, primary percutaneous coronary intervention (PCI) is recommended to improve survival.[337] Primary PCI is superior to fibrinolytic therapy and fibrinolytic therapy is therefore only recommended if PCI is not immediately available (i.e., within 120 minutes).[337] An analysis of data from 11 clinical trials compared PCI with fibrinolytic therapy in 2725 patients with STEMI, including 367 patients with diabetes.[340]​ Among patients with diabetes, 30-day mortality or nonfatal reinfarction rate was 19.3% for those treated with fibrinolytics and 9.2% for those who underwent primary PCI. If onset of ischemic symptoms is ≥12 hours and the patient is in cardiogenic shock or experiencing hemodynamic instability, primary PCI is indicated, or coronary artery bypass graft (CABG) if PCI is not feasible.[337] PCI may also be reasonable in patients who are stable and presenting 12-24 hours after symptom onset, as well as in those whose STEMI is complicated by ongoing ischemia, acute severe heart failure, or life-threatening arrhythmia.[337] 

Non-ST-elevation acute coronary syndrome (NSTE-ACS) most commonly manifests as non-ST-elevation MI (NSTEMI) but may also present as unstable angina.​[152]​ Immediate invasive strategy (coronary angiography with intent of revascularization) is required in patients with NSTEMI and cardiogenic shock, refractory angina, or hemodynamic/electrical instability.[337] Early invasive strategy (usually within 24 hours) is recommended for patients at high risk for CV events: for example, those with a high Global Registry of Acute Coronary Events (GRACE) score. Patients with low- or intermediate-risk NSTEMI should undergo coronary angiography before discharge with the intent of revascularization. Invasive strategy is important in NSTEMI as it will help determine the suitability for revascularization and the appropriate mode (PCI vs. CABG).[337]

All patients should receive aspirin and consider beta-blockers, nitrates, ACE inhibitors, and P2Y12 inhibitors as part of early management for STEMI and NSTEMI.[362]

For more comprehensive information on the acute management of these conditions, see ST-elevation myocardial infarction, Non-ST-elevation myocardial infarction, and Unstable angina.

Uncontrolled blood glucose levels in the perioperative or periprocedural period are associated with adverse outcomes for patients with diabetes. Benefits of good control include reductions in length of hospital stay and likelihood of readmission, as well as improved postoperative survival rates.[29]​ However, trials of tight glycemic control in critically ill patients have yielded mixed results.[369][370]​ In one study of acute coronary syndrome patients who presented with hyperglycemia, intensive glucose control was associated with harm and did not reduce infarct size.[306] One large randomized controlled trial raised questions about intensive blood glucose targets for inpatient glycemic control and found a lower mortality for intensive care unit (ICU) patients with a blood glucose target of 180 mg/dL (10 mmol/L) than for those with a blood glucose target of 81 to 108 mg/dL (4.5 to 6.0 mmol/L).[307] A concern has been whether there is any additional benefit to lowering blood glucose levels below about 140 to 180 mg/dL (7.8 to 10.0 mmol/L) in the ICU setting.[308] One randomized controlled trial examining the effects of periprocedural intensive glycemic control during early PCI on the rate of restenosis in hyperglycemic (glucose ≥140 mg/dL [≥7.8 mmol/L]) patients with a STEMI showed that intensive control led to a 50% reduction in restenosis at 6 months compared with conventional glycemic control.[341]

The American Diabetes Association (ADA) recommends that in critically ill patients, insulin therapy should be started for persistent hyperglycemia ≥180 mg/dL (≥10 mmol/L) (tested on two occasions).[29]​ Once insulin therapy is started, a target glucose range of 140 to 180 mg/dL (7.8 to 10.0 mmol/L) is recommended for most critically ill patients.[29]​ More stringent goals, such as 110 to 140 mg/dL (6.1 to 7.8 mmol/L), may be appropriate for selected patients (e.g., critically ill postsurgical patients or patients with cardiac surgery), as long as they can be achieved without significant hypoglycemia.[29]​ Critically ill patients require an intravenous insulin protocol that has demonstrated efficacy and safety for achieving targets without increasing risk for severe hypoglycemia.[29]​​

ACUTE

highly significant coronary artery disease: without acute myocardial infarction or unstable angina

1st line – coronary artery bypass graft and perioperative tight glycemic control

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ACUTE
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highly significant coronary artery disease: without acute myocardial infarction or unstable angina
|
left main stenosis
1st line – 

coronary artery bypass graft and perioperative tight glycemic control

The 2021 American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions coronary artery revascularization guidelines recommend coronary artery bypass graft (CABG) for left main disease.[337] However, they recognize that it is reasonable to consider PCI in patients with low- or intermediate-complexity disease in the rest of the coronary anatomy.[337]

Intravenous infusion of insulin allows for more rapid titration (and more reliable absorption) in critically ill patients than does subcutaneous injection. In the perioperative period for CABG, good glucose control may reduce infectious complications, such as sternal wound infections and mediastinitis, cardiac mortality caused by pump failure, and the risk of supraventricular tachycardia.[309][310][311]

1st line – revascularization and perioperative tight glycemic control

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ACUTE
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highly significant coronary artery disease: without acute myocardial infarction or unstable angina
|
multivessel coronary artery disease
1st line – 

revascularization and perioperative tight glycemic control

Patients with diabetes and complex multivessel coronary artery disease (CAD) should undergo a heart team approach to revascularization, inclusive of an interventional cardiologist and a cardiac surgeon.[337]

Either PCI with drug-eluting stents or coronary artery bypass graft (CABG) may be suitable depending on factors such as anatomic location of lesions, lesion length, presence of chronic total occlusions, left ventricular function, and comorbidity. CABG is generally recommended in preference to PCI to improve survival in patients with diabetes with multivessel CAD for which mechanical revascularization is likely to improve survival.[337][343][344]​ This is particularly recommended if a left internal mammary artery to left anterior descending artery (LIMA-LAD) graft is used and the patient is a good surgical candidate.[337]

Intravenous infusion of insulin allows for more rapid titration (and more reliable absorption) in critically ill patients than does subcutaneous injection. In the perioperative period for CABG, good glucose control may reduce infectious complications, such as sternal wound infections and mediastinitis, cardiac mortality caused by pump failure, and the risk of supraventricular tachycardia.[309][310][311]

1st line – medical management

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ACUTE
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highly significant coronary artery disease: without acute myocardial infarction or unstable angina
|
single-vessel coronary artery disease
1st line – 

medical management

In stable patients with single-vessel disease and no recent acute coronary syndrome or left ventricular dysfunction, the initial treatment is conservative and involves guideline-directed medical therapy for CAD. This may include antihypertensive agents, lipid-lowering agents, and antiplatelet therapy.[362] When optimized, medical therapy has demonstrated similar outcomes to revascularization.[363][364] This approach needs patient-physician discussion to tailor therapy based on symptoms, response to therapy, available expertise, and patient’s preferences.

Consider – revascularization and perioperative tight glycemic control

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ACUTE
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highly significant coronary artery disease: without acute myocardial infarction or unstable angina
|
single-vessel coronary artery disease
Consider – 

revascularization and perioperative tight glycemic control

Treatment recommended for SOME patients in selected patient group

The usefulness of coronary revascularization in improving survival is uncertain in patients with single-vessel disease involving the proximal left anterior descending artery with normal left ventricular function.[337]

Revascularization may be considered after patient-physician discussion as well as heart team discussion in regards to utility and timing.[337] 

Coronary revascularization also has an important role in patients who are symptomatic with angina refractory to maximal medical therapy.[337]

If revascularization is indicated, and the anatomy is amenable to PCI, PCI is preferred over coronary artery bypass graft (CABG) for single-vessel CAD.[337][343]

Intravenous infusion of insulin allows for more rapid titration (and more reliable absorption) in critically ill patients than does subcutaneous injection. In the perioperative period for CABG, good glucose control may reduce infectious complications, such as sternal wound infections and mediastinitis, cardiac mortality caused by pump failure, and the risk of supraventricular tachycardia.[310][311]

ONGOING

diabetic cardiovascular disease: stable and/or after intervention

1st line – ACE inhibitor or angiotensin-II receptor antagonist

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ONGOING
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diabetic cardiovascular disease: stable and/or after intervention
1st line – 

ACE inhibitor or angiotensin-II receptor antagonist

European and US guidelines recommend use of an ACE inhibitor (or an angiotensin-II receptor antagonist if an ACE inhibitor is not tolerated) in patients with diabetic CVD to reduce risk of cardiovascular events, regardless of hypertension, and particularly in patients with heart failure or chronic kidney disease (CKD).[6][320][321]

ACE inhibitors and angiotensin-II receptor antagonists should not be used in combination due to increased risk for acute kidney injury and hyperkalemia.[29]​​[314]​​ A dose reduction may be required in patients with renal impairment. ACE inhibitors have also shown increased risk for hypoglycemia in conjunction with insulin or insulin secretagogue (sulfonylurea or meglitinide).[315]

Serum creatinine/estimated glomerular filtration rate (eGFR) and potassium should be checked within 7-14 days of initiation of treatment with an ACE inhibitor or angiotensin-II receptor antagonist, as well as following uptitration of dose and then at least annually.[29]

Primary options

lisinopril: 5 mg orally once daily initially, increase gradually according to response, maximum 40 mg/day

OR

enalapril: 2.5 mg orally twice daily initially, increase gradually according to response, maximum 40 mg/day

OR

captopril: 6.25 mg orally three times daily initially, increase gradually according to response, maximum 150 mg/day

Secondary options

candesartan cilexetil: 4 mg orally once daily initially, increase gradually according to response, maximum 32 mg/day

OR

irbesartan: 75 mg orally once daily initially, increase gradually according to response, maximum 300 mg/day

OR

losartan: 25-50 mg orally once daily initially, increase gradually according to response, maximum 150 mg/day

OR

valsartan: 40 mg orally twice daily initially, increase gradually according to response, maximum 320 mg/day

Consider – additional antihypertensive therapy

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ONGOING
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diabetic cardiovascular disease: stable and/or after intervention
Consider – 

additional antihypertensive therapy

Treatment recommended for SOME patients in selected patient group

The American Diabetes Association (ADA) recommends an individualized approach to blood pressure (BP) management, with consideration of antihypertensive drug therapy for all nonpregnant patients with diabetes whose BP is persistently elevated above ≥130/80 mmHg. Guidelines recommend a target goal of <130/80 mmHg for nonpregnant people with diabetes, providing this can be safely attained.[6][29]​​[60][61]

The ADA recommends starting one antihypertensive agent for patients with initial BP ≥130/80 and <150/90 mmHg, and starting two antihypertensive agents for those with initial BP ≥150/90 mmHg.[29]

Patients with diabetic CVD, even if normotensive, should be treated with an ACE inhibitor, or an angiotensin-II receptor antagonist if an ACE inhibitor is not tolerated.[29][60]​ However, additional antihypertensive agents may be required.

For those whose BP is ≥150/90 mmHg, a calcium-channel blocker (e.g., amlodipine, felodipine, nifedipine) or a thiazide diuretic (e.g., hydrochlorothiazide) should be considered in addition at treatment initiation.[29]

Beta-blockers (e.g., metoprolol, bisoprolol, carvedilol) may be appropriate to improve outcomes as antihypertensive agents in patients with prior myocardial infarction (MI), active angina, atrial fibrillation with rapid ventricular response, or heart failure with reduced ejection fraction.[29]​ These patients are typically started on beta-blockers alone, with other antihypertensive therapies added as needed. If a beta-blocker is indicated, an agent should be selected that has concomitant vasodilatory effects to reduce potential for adverse metabolic impact.[114]​ Beta-blockers may mask symptoms of hypoglycemia and also have the potential to exacerbate hypoglycemic episodes, particularly when used concurrently with sulfonylureas.[29][318][319]

Multiple drug therapy is often required in order to achieve antihypertensive targets.[29]​​ If BP remains uncontrolled on monotherapy, add an agent from a different first-line class.[29]​​ If BP remains uncontrolled despite combination therapy with first-line agents (i.e., three classes of antihypertensive medication including a diuretic, plus lifestyle modifications), discontinue or minimize interfering substances such as nonsteroidal anti-inflammatory drugs (NSAIDs), evaluate for secondary causes of hypertension (including obstructive sleep apnea), and consider the addition of an aldosterone antagonist (e.g., spironolactone, eplerenone).[29]​​[114]​​ Referral to a hypertension specialist may also be necessary.[29]​​[114]​ The number of antihypertensive therapies required will vary between patients and is dependent on their clinical situation and tolerance.

People with diabetes and hypertension should monitor their BP at home in addition to having it checked regularly in the clinic setting.[29]

Serum creatinine/eGFR and potassium should be checked within 7-14 days of initiation of treatment with an aldosterone antagonist or diuretic, as well as following uptitration of dose and then at least annually.[29]

Primary options

hydrochlorothiazide: 12.5 to 25 mg orally once daily initially, increase gradually according to response, maximum 50 mg/day

-- AND / OR --

amlodipine: 2.5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day

or

felodipine: 2.5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day

or

nifedipine: 30-60 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 90 mg/day

-- AND / OR --

metoprolol tartrate: 50 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 450 mg/day

or

bisoprolol: 2.5 to 5 mg orally once daily initially, increase gradually according to response, maximum 20 mg/day

or

carvedilol: 6.25 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 50 mg/day

-- AND / OR --

spironolactone: 25-100 mg/day orally given in 1-2 divided doses

or

eplerenone: 50 mg orally once or twice daily

Plus – lipid control

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ONGOING
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diabetic cardiovascular disease: stable and/or after intervention
Plus – 

lipid control

Treatment recommended for ALL patients in selected patient group

For patients with diabetes and established CVD, guidelines recommend a low-density lipoprotein cholesterol (LDL-C) goal of <55 mg/dL (<1.42 mmol/L) and at least a 50% reduction from baseline.[6][29][113]​​

Statins are the first-line agent for pharmacologic treatment of dyslipidemia and may have additional therapeutic effects independent of lipid-lowering action.[29] Moderate-intensity statin therapy lowers LDL-C level by 30% to 50%, while high-intensity statin therapy lowers it by ≥50%.[113] Low-dose statin therapy is generally not recommended in people with diabetes, but it is sometimes the only dose of statin that an individual can tolerate.[29]

G​​​uidelines recommend high-intensity statin therapy in adults of all ages with diabetes and atherosclerotic CVD.[29][113] For people who do not tolerate the intended statin intensity, the maximum tolerated statin dose should be used.​​

Addition of ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (e.g., evolocumab, alirocumab) is recommended if the LDL-C reduction goal is not achieved on maximum tolerated statin therapy.[29]​

For people intolerant of statin therapy, a PCSK9 inhibitor, bempedoic acid, or inclisiran should be considered as alternative cholesterol-lowering therapies.[29]

A lipid profile should be checked: at initiation of statins or other lipid-lowering therapy; 4-12 weeks after initiation or a change in dose; and annually thereafter.[29]

Icosapent ethyl can be considered in patients with CVD who are on a statin and have controlled LDL-C but elevated triglycerides (135 to 499 mg/dL [1.53 to 5.64 mmol/L).[29] It has been shown to modestly reduce CV events.​​[114][115]​​​

If triglyceride levels exceed 500 mg/dL (5.65 mmol/L), fibrate therapy may be beneficial to reduce the risk of pancreatitis.[114] Fibrates are most often added to statin therapy, although the ADA notes that this approach is generally not recommended due to a lack of evidence of improvement in CVD outcomes.[29]​​ Furthermore, caution is recommended as combination statin and fibrate therapy can increase the risk of myositis and rhabdomyolysis. To lower the risk, fenofibrate is recommended over gemfibrozil.[47]

Primary options

atorvastatin: high intensity: 40-80 mg orally once daily

OR

rosuvastatin: high intensity: 20-40 mg orally once daily

OR

atorvastatin: high intensity: 40-80 mg orally once daily

or

rosuvastatin: high intensity: 20-40 mg orally once daily

-- AND --

ezetimibe: 10 mg orally once daily

OR

atorvastatin: high intensity: 40-80 mg orally once daily

or

rosuvastatin: high intensity: 20-40 mg orally once daily

-- AND --

evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly

or

alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously once monthly

OR

atorvastatin: high intensity: 40-80 mg orally once daily

or

rosuvastatin: high intensity: 20-40 mg orally once daily

-- AND --

ezetimibe: 10 mg orally once daily

-- AND --

evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly

or

alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously once monthly

Secondary options

bempedoic acid: 180 mg orally once daily

OR

inclisiran: 284 mg subcutaneously every 3 months for 2 doses, followed by 284 mg every 6 months

OR

evolocumab: 140 mg subcutaneously every 2 weeks; or 420 mg subcutaneously once monthly

OR

alirocumab: 75-150 mg subcutaneously every 2 weeks; or 300 mg subcutaneously once monthly

Tertiary options

atorvastatin: high intensity: 40-80 mg orally once daily

or

rosuvastatin: high intensity: 20-40 mg orally once daily

-- AND --

icosapent ethyl: 2 g orally twice daily

Plus – metformin

Back
ONGOING
|
diabetic cardiovascular disease: stable and/or after intervention
Plus – 

metformin

Treatment recommended for ALL patients in selected patient group

Hemoglobin A1c (HbA1c) goal for most nonpregnant adult patients is <7% (<53 mmol/mol) to optimize clinical outcomes, but should be individualized.[29]​ Less stringent goals may be appropriate for very young children; older adults; people with a history of severe hypoglycemia; and those with limited life expectancies, advanced microvascular or macrovascular complications, or comorbid conditions.[29]​​

US and European guidelines continue to recommend metformin, in combination with medical nutrition therapy and exercise, as the first-line treatment for glycemic control in patients with type 2 diabetes, regardless of the presence or absence of established atherosclerotic CVD.[29]​​[221][222]​​​ Evidence for the CV benefit of metformin is limited; however, it does not cause weight gain or hypoglycemia, and is widely available relative to other agents.[47]

Primary options

metformin: 500 mg orally (immediate-release) once daily initially, increase by 500 mg/day increments every week, maximum 1000 mg twice daily

Plus – glucagon-like peptide-1 receptor agonist or tirzepatide and/or sodium-glucose cotransporter inhibitor

Back
ONGOING
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diabetic cardiovascular disease: stable and/or after intervention
Plus – 

glucagon-like peptide-1 receptor agonist or tirzepatide and/or sodium-glucose cotransporter inhibitor

Treatment recommended for ALL patients in selected patient group

For patients with established atherosclerotic CVD, significant CVD risk factors, established heart failure (with either preserved or reduced ejection fraction), or established CKD, addition of a glucagon-like peptide-1 (GLP-1) receptor agonist or a sodium-glucose cotransporter 2 (SGLT2) inhibitor is strongly recommended to reduce the risk of adverse CV or kidney events.[29]​​[161][225]​​​​

The American Diabetes Association and European Association for the Study of Diabetes advise that for patients in whom atherosclerotic CVD predominates (e.g., previous MI, unstable angina, ischemic stroke, or indicators of high CV risk present), either a GLP-1 receptor agonist or an SGLT2 inhibitor can be used.[29][221]​​​ While definitions of what constitutes high CV risk vary, most comprise ≥55 years of age with two or more additional risk factors such as obesity, hypertension, smoking, dyslipidemia, or albuminuria.[221] Guidelines published by the American College of Physicians and American Heart Association/American Stroke Association specify that GLP-1 receptor agonists should be prioritized in patients with an increased risk for stroke.[118][222]​​​

For those patients in whom heart failure or CKD predominates, SGLT2 inhibitors should be favored.[29]​​[221][222]​​

If HbA1c remains above target and the patient is taking either an SGLT2 inhibitor or a GLP-1 receptor agonist, then combined therapy with an SGLT2 inhibitor plus a GLP-1 receptor agonist may be considered, since this may provide additive reduction in the risk of adverse CV and kidney events.[29]​​

Liraglutide, injectable semaglutide, and dulaglutide are the GLP-1 receptor agonists with the strongest evidence of CV risk reduction in patients with diabetes.[221]​​​​​[280][281][282][283]​​[284]​ In addition to their beneficial effects on CAD, GLP-1 receptor agonists are the only drug class that has been shown to convincingly reduce nonfatal stroke.[222][224][285]​​[286][287][288]​ Unlike for SGLT2 inhibitors, the evidence for GLP-1 receptor agonists in reducing heart failure or improving CV outcomes in patients with heart failure has been inconsistent across trials.[290]​ Data from retrospective studies and meta-analyses have shown superiority of GLP-1 receptor agonists in comparison with other antidiabetic medications such as SGLT2 inhibitors and DPP-4 inhibitors in terms of peripheral arterial disease (PAD).[292]​ However, data from CV outcome trials regarding the impact of GLP-1 receptor agonists on PAD are scarce and further prospective studies are needed.​​​​

Semaglutide is the only GLP-1 receptor agonist that is available in both oral and injectable formulations. However, conclusive evidence for the CV benefit of oral semaglutide has not yet been established in clinical studies.[281] For more information on oral semaglutide, see Emerging treatments.

The most common adverse effects of GLP-1 receptor agonists are gastrointestinal, particularly nausea, vomiting, and diarrhea; these are frequent but tend to reduce over time.[293] Patients should be counseled about potential for ileus.[29]​ An association with pancreatitis and pancreatic cancer has been reported in clinical trials, but causality has not been established; nonetheless, GLP-1 receptor agonists should be used with caution in patients with a history of pancreatitis.[29][293] After a review of available data, the FDA and European Medicines Agency (EMA) agreed that there was insufficient evidence to confirm an increased risk of pancreatic cancer with use of GLP-1-based therapies.[294] GLP-1 receptor agonists have also been associated with increased risk of gallbladder and biliary diseases including cholelithiasis and cholecystitis.[293]​​​​​

Hypoglycemia risk is increased when GLP-1 receptor agonists are used with sulfonylureas and insulin. Treatment deintensification of these agents or of diuretics, particularly in older and frail individuals, is recommended to avoid hypoglycemia and hypovolemia.[293] Diabetic ketoacidosis (DKA) has been reported in patients on a combination of a GLP-1 receptor agonists and insulin, when concomitant insulin was either rapidly reduced or discontinued; insulin reductions should therefore be undertaken in a cautious stepwise manner, with capillary blood glucose monitoring.[293]​​

In rodent studies, GLP-1 receptor agonists were associated with medullary thyroid cancer, resulting in a black box warning for these agents in patients with a personal or family history of multiple endocrine neoplasia type 2 or medullary thyroid cancer; however, there is conflicting evidence as to whether this risk applies in humans.[293][295][296][297][298]​​​​

The EMA is reviewing data on the risk of suicidal thoughts and thoughts of self-harm with GLP-1 receptor agonists, following reports of such occurrences in people using liraglutide and semaglutide.[299]

There is also some concern that GLP1-receptor agonists, through their rapid glucose-lowering effects, may increase the risk of transient worsening of preexisting diabetic retinopathy.[300][301][302]​ Further studies are required to elucidate this relationship.

Empagliflozin, dapagliflozin, and canagliflozin are the SGLT2 inhibitors with the strongest evidence of CV risk reduction in patients with diabetes.[120][221]​​[247][248][249][250][251][252][253]​ Ertugliflozin has shown benefit in reducing heart failure hospitalization, but not major adverse cardiac events, in patients with type 2 diabetes.[257][258]​​​ The European Society of Cardiology (ESC) recommends dapagliflozin or empagliflozin for all patients with type 2 diabetes and CKD to reduce risk of heart failure hospitalization or CV death, regardless of whether they have a pre-existing heart failure diagnosis.​[261]

SGLT2 inhibitors also reduce the risk of serious hyperkalemia in people with type 2 diabetes at high CV risk without increasing the risk of hypokalemia, allowing the titration of guideline-directed medical therapy in patients with heart failure.[268]

An initial decline in eGFR is commonly observed frequent after initiating an SGLT2 inhibitor but this decline is not associated with subsequent risk of CV or kidney events.[269]​ Thus, SGLT2 inhibitors should not be interrupted or discontinued in response to an initial eGFR decline.

SGLT2 inhibitors are generally well-tolerated; however, some serious adverse reactions have been documented. Adverse effects include a higher rate of diabetic ketoacidosis, acute kidney injury, fracture, and/or amputation. The EMA also warns of the potential increased risk of toe amputation.[270] The FDA states the risk of amputation, while increased with canagliflozin, is lower than previously described, particularly when appropriately monitored.[271] The FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA) warn of cases of necrotizing fasciitis of the perineum (also known as Fournier gangrene) observed in post-marketing surveillance of SGLT2 inhibitors.[272][273]​​​​ Thus, SGLT2 inhibitors should be avoided in patients with conditions that increase the risk for limb amputations, and in patients prone to urinary tract or genital infections.

Sotagliflozin is the first dual SGLT inhibitor.[274] It inhibits both renal SGLT2 (promoting significant excretion of glucose in the urine, in the same way as other already available SGLT2 selective inhibitors) and intestinal SGLT1 (delaying glucose absorption and therefore reducing postprandial glucose).[274]​ It has been approved in people with heart failure (both with and without diabetes) and in patients with type 2 diabetes who have CKD or high risk of/established CVD, to reduce the risk of hospitalization for heart failure.[29] It is not currently approved for glycemic management of type 1 or type 2 diabetes. One concern with expanded use of SGLT inhibition is the infrequent but serious risk of diabetic ketoacidosis (DKA), including the atypical presentation of euglycemic ketoacidosis.[29]​​​

Of note, the studies that led to the approved indication of sotagliflozin for heart failure excluded individuals with type 1 diabetes or a history of DKA.[275][276] In clinical trials of sotagliflozin in people with type 1 diabetes, results showed improvements in HbA1c and body weight; however, its use was associated with an eightfold increase in DKA compared with placebo.[29][277] The risks and benefits of SGLT inhibitors in people with type 1 diabetes continue to be evaluated, with consensus statements providing guidance on patient selection and precautions.[29][278]​​​

Primary options

empagliflozin: 10 mg orally once daily initially, increase according to response, maximum 25 mg/day

or

canagliflozin: 100 mg orally once daily initially, increase according to response, maximum 300 mg/day

or

dapagliflozin: 5 mg orally once daily initially, increase according to response, maximum 10 mg/day

or

sotagliflozin: 200 mg orally once daily initially, increase according to response, maximum 400 mg/day

-- AND / OR --

liraglutide: 0.6 mg subcutaneously once daily for 1 week, then increase to 1.2 mg once daily, adjust dose according to response, maximum 1.8 mg/day

or

semaglutide: 0.25 mg subcutaneously once weekly for 4 weeks, then increase to 0.5 mg once weekly for 4 weeks, adjust dose according to response, maximum 1 mg/week

or

dulaglutide: 0.75 mg subcutaneously once weekly, then increase to 1.5 mg once weekly, adjust dose according to response, maximum 4.5 mg/week

Plus – lifestyle and behavioral therapy

Back
ONGOING
|
diabetic cardiovascular disease: stable and/or after intervention
Plus – 

lifestyle and behavioral therapy

Treatment recommended for ALL patients in selected patient group

Therapeutic lifestyle interventions such as medical nutrition therapy and increased physical activity have been shown in large clinical trials to improve glycemic, lipid, and blood pressure control, and to improve insulin sensitivity and markers of inflammation. They are also effective in achieving sustained weight loss and improvements in fitness.[47][71][173][174][175]​​​[176]

There is no ideal amount of macronutrients that people with diabetes should consume, and studies suggest that such recommendations should be decided on an individual basis.[173][180]​​​ The Mediterranean Diet, Dietary Approaches to Stop Hypertension (DASH), vegetarian, and vegan diets have all been demonstrated to be effective for people with diabetes.[173][181][182][183][184]​​​​ European guidelines recommend a Mediterranean or plant-based diet with high unsaturated fat content for lowering CV risk in people with diabetes.[6] One meta-analysis found that red meat consumption was associated with higher risk of CVD and diabetes, while another reported moderate certainty evidence that a shift from animal-based to plant-based foods is beneficially associated with cardiometabolic health and all-cause mortality.[185][186]​​​

Reducing overall carbohydrate intake has demonstrated some evidence for improving glycemia and one study found that among people with type 2 diabetes, greater adherence to low-carbohydrate diet patterns was associated with significantly lower all-cause mortality.[187]​ However, the optimal degree of carbohydrate restriction, and long-term effects on CVD, are still unclear.[29]

Both World Health Organization (WHO) and European guidelines emphasize that carbohydrate quality, rather than quantity, is key.[132][188]​​​ The concept of carbohydrate quality refers to the nature and composition of carbohydrates in a food or in the diet, including the proportion of sugars, how quickly polysaccharides are metabolized and release glucose into the body (i.e., digestibility), and the amount of dietary fiber. It is recommended that carbohydrate intake should come primarily from high-fiber foods, such as whole grains, vegetables, whole fruits, and pulses.[188][132]​​​ Diets high in naturally occurring fiber have been shown to be protective against cardiometabolic disease and premature mortality. When choosing high-fiber foods, focus should be on minimally processed and largely intact whole grains, rather than products with finely milled whole grains that may also have added sugars, sodium, and saturated fats.[132][188]​​​​ Fiber-enriched foods and fiber supplements can be considered when sufficient intake cannot be obtained from diet alone.[132]​​

There is some evidence to suggest that reducing intake of high glycemic index foods, and generally reducing glycemic load, could be beneficial for preventing CVD; however, WHO guidelines do not make any recommendations on this, noting that there was a lack of consistent benefit from diets with lower glycemic index or glycemic load in observational studies, and little to no improvement in cardiometabolic risk factors in randomized controlled trials associated with lower glycemic index and glycemic load.[188][189]​​

Replacing saturated fats and trans-fats with unsaturated fats and carbohydrates from foods containing naturally occurring dietary fiber (such as whole grains, vegetables, fruits, and pulses) reduces low-density lipoprotein cholesterol and also benefits CVD risk.​[173][190][191]​​​ Saturated fat should comprise <10% of total energy intake and trans-fats <1%.[132][191]​​​ Dietary fats should mainly come from plant-based foods high in mono- and poly-unsaturated fats, such as nuts, seeds, and nonhydrogenated nontropical vegetable oils (e.g., olive oil, rapeseed/canola oil, soybean oil, sunflower oil, linseed oil).​​[132]

People with diabetes who have overweight or obesity should be supported with evidence-based nutritional support to achieve and maintain weight loss.[132] European guidelines recommend that a variety of weight-loss diets can be used equally effectively for weight management with type 2 diabetes, provided they can be followed and meet recommendations for protein, fat, micronutrient, and fiber intake. Neither extreme high-carbohydrate, nor very-low carbohydrate ketogenic diets are recommended, however.[132]​ One systematic umbrella review of published meta-analyses of studies comparing hypoenergetic diets for weight management in people with type 2 diabetes did not find evidence for any particular weight-loss diet over others (e.g., low-carbohydrate, high-protein, low-glycemic index, Mediterranean, high-monounsaturated fatty acid or vegetarian diets).​[192]

Intermittent fasting or time-restricted eating as strategies for weight and glucose management have gained popularity.[193]​ They have been shown to result in mild to moderate weight loss (3% to 8% loss from baseline) with no significant difference in weight loss when compared with continuous calorie restriction.[29] The ADA advises that due to its simplicity, intermittent fasting may lend itself as a useful strategy for people with diabetes who are looking for practical eating management tools.[29]​ People with diabetes who are on insulin and/or secretagogues should be medically monitored during the fasting period.[29]​​

Evidence indicates that low- and very-low-energy diets (<3500 kJ/day [<840 kcal/day]), using total diet replacement formula diet products (replacing all meals) or partial liquid meal replacement products (replacing 1-2 meals per day) for the weight-loss phase, are most effective for weight loss and reduction of other cardiometabolic risk factors when compared with the results from self-administered food-based weight-loss diets.[132][194]​​ Low-energy nutritionally complete formula diets with a total diet replacement induction phase also appear to be the most effective dietary approach for achieving type 2 diabetes remission.[132]​ One population-based cohort study found that those who achieved remission from diabetes, even for a short time, had a much lower risk of CVD events, including MI and stroke, as well macrovascular and microvascular complications.[195]​​​

Physical activity: at least 150 minutes divided over ≥3 days per week of moderate- to vigorous-intensity aerobic physical activity with no more than 2 consecutive days without exercise.[6][29]​​ Younger and more physically fit individuals should aim for ≥75 minutes per week of vigorous-intensity exercise or interval training.[29]​ In the absence of contraindications, resistance training 2-3 times per week on nonconsecutive days is also recommended.[6][29]​​​ The ADA recommends interrupting sedentary activity every 30 minutes with short bouts of physical activity.​[29]​ Older adults may benefit from flexibility and balance exercise 2-3 times per week.[29]

All patients with diabetes should be advised to quit smoking or not start.[29] Smoking counseling and other forms of smoking cessation therapy should be incorporated into routine diabetes care.[29] Varenicline combined with nicotine replacement therapy may be more effective than varenicline alone.[199] The ADA does not support e-cigarettes as an alternative to smoking or to facilitate smoking cessation.[29] Patients who quit smoking are prone to weight gain; therefore, it is important to have weight management strategies in place to maximize the CV benefits of smoking cessation.[47]​​​​​​

Consider – weight management

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ONGOING
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diabetic cardiovascular disease: stable and/or after intervention
Consider – 

weight management

Treatment recommended for SOME patients in selected patient group

Obesity pharmacotherapy should be considered as an adjunct to lifestyle interventions and behavioral counseling to improve cardiovascular (CV) risk factors in people with type 2 diabetes who have overweight or obesity.[6][29][178]​​​​​​​​ For those with a body mass index (BMI) of ≥27 kg/m² (≥25 kg/m² for Asian-Americans) who are motivated to lose weight, an initial 3-month trial of medication should be undertaken. When weight loss is <5% after 3 months of use, the benefits of ongoing treatment need to be balanced in the context of the glycemic response, the availability of other potential treatment options, treatment tolerance, and overall treatment burden.[29]​

The American Diabetes Association (ADA) advises that agents with both glucose-lowering and weight loss effects should be used first-line; this includes glucagon-like peptide 1 (GLP-1) receptor agonists (e.g., semaglutide, liraglutide) and tirzepatide (a dual glucose-dependent insulinotropic polypeptide [GIP] and GLP-1 receptor agonist). Two phase 3 trials have demonstrated the potential for use of tirzepatide for obesity, with adverse effects similar to those seen with GLP-1 receptor agonists.[200][201]​​​ If these medications are not tolerated or contraindicated, other obesity treatment options should be considered. Alternative pharmacologic options include phentermine, orlistat, phentermine/topiramate, or naltrexone/bupropion.[29]

​The European Society of Cardiology (ESC) recommends GLP-1 receptor agonists or sodium-glucose cotransporter-2 (SGLT2) inhibitors as the glucose-lowering agents of choice for weight loss in type 2 diabetes, in view of their proven CV benefits for these patients.[6][203]

For those not reaching goals, the ADA recommends evaluating weight management therapies and intensifying treatment with additional approaches (e.g., metabolic surgery, additional pharmacologic agents, and structured lifestyle management programs).[29]

As well as considering specific medications to treat obesity, healthcare professionals should carefully review the individual’s concomitant medications and, whenever possible, minimize or provide alternatives for medications that promote weight gain. Examples of medications associated with weight gain include antipsychotics (e.g., clozapine, olanzapine, risperidone), some antidepressants (e.g., tricyclic antidepressants, some selective serotonin-reuptake inhibitors, monoamine oxidase inhibitors), glucocorticoids, injectable progestins, some anticonvulsants (e.g., gabapentin, pregabalin), beta-blockers, and possibly sedating antihistamines and anticholinergics.[29]

A large number of studies have demonstrated that metabolic surgery achieves superior glycemic management and reduction of CV risk in people with type 2 diabetes and obesity compared with nonsurgical intervention.[9][204]​​​ It has also been shown to reduce microvascular complications, cancer risk, and all-cause mortality in people with obesity and type 2 diabetes.[29]​​[205][206][207]​​​​​​​​​​​ Of note, one meta-analysis reported a 50% reduction in macrovascular complications following bariatric surgery in patients with type 2 diabetes and extreme obesity (BMI ≥40 kg/m²).[205]​ Another meta-analysis found that metabolic surgery reduced the risk of any CV event by 44% and yielded a risk reduction of over 55% in overall mortality and 69% in CV mortality in patients with type 2 diabetes.[208]

Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most commonly performed procedures. Both result in an anatomically smaller stomach pouch; in VSG, approximately 80% of the stomach is removed, leaving behind a long, thin sleeve-shaped pouch, whereas RYGB creates a much smaller stomach pouch (roughly the size of a walnut), which is then attached to the distal small intestine, thereby bypassing the duodenum and jejunum.[29]

The ADA recommends metabolic surgery to treat type 2 diabetes in adults with BMI ≥30 kg/m² (≥27.5 kg/m² for Asian-Americans) who are otherwise good surgical candidates.[29]​​ The ESC recommends that bariatric surgery be considered for all patients with type 2 diabetes and BMI ≥35 kg/m² who have not achieved sufficient weight loss through lifestyle interventions and medication.[6]​ Metabolic surgery is best done in a high-volume, specialized center to reduce the risk of perioperative and longer-term complications.[29]​​

For more comprehensive information, see Obesity in adults.

Consider – antiplatelet therapy

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diabetic cardiovascular disease: stable and/or after intervention
Consider – 

antiplatelet therapy

Treatment recommended for SOME patients in selected patient group

Aspirin is recommended for secondary prevention in those with a history of atherosclerotic CVD. Clopidogrel (a P2Y12 inhibitor) is an alternative for patients with aspirin allergy or intolerance.[29]​

In people with stable coronary and/or peripheral artery disease and low bleeding risk, the ADA and ESC recommend combination treatment with aspirin and low-dose rivaroxaban (a direct oral anticoagulant) for secondary prevention.[29]​​[334]​​ Rivaroxaban has similar antiplatelet effects to aspirin, and may also improve endothelial function.[335]

Following acute coronary syndrome (ACS), dual antiplatelet therapy with a combination of aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) is indicated.[336]​ Evidence supports use of either ticagrelor or clopidogrel if no PCI was performed and clopidogrel, ticagrelor, or prasugrel if PCI was performed.[29][337]​​​ Generally, prasugrel and ticagrelor have better efficacy in patients with diabetes and are preferred to clopidogrel for patients who undergo PCI.[334][337]​​​

Short-term dual antiplatelet therapy is also recommended after high-risk transient ischemic attack (TIA) and minor stroke.[338]

Dual antiplatelet therapy may have benefit beyond 1 year in reducing long-term risk of recurrent atherosclerotic events.[334]​ However, recommendations regarding length of treatment are rapidly evolving and should be determined by an interprofessional team approach that includes a cardiologist following ACS or a neurologist following TIA/stroke.[29]​ The benefits versus risk of bleeding and thrombosis should be evaluated based on the coronary anatomy and extent of CAD, PCI complexity, bleeding risk, age, and patient’s medical comorbidities such as anemia or renal failure.[339]

To reduce risk of gastrointestinal bleeding, proton-pump inhibitors are recommended for all patients on a combination of antiplatelet or anticoagulant therapy, and should be considered for those on a single agent depending on their individual bleeding risk, according to the ESC.[6]

Primary options

aspirin: 75-162 mg orally once daily

Secondary options

clopidogrel: 75 mg orally once daily

OR

aspirin: 75-162 mg orally once daily

and

rivaroxaban: 2.5 mg orally twice daily

OR

aspirin: 325 mg orally as a loading dose, followed by 75-162 mg once daily

-- AND --

ticagrelor: 180 mg orally as a loading dose, followed by 90 mg twice daily for 12 months, then 60 mg twice daily if treatment is required beyond 12 months

or

prasugrel: 60 mg orally as a loading dose, followed by 10 mg once daily

or

clopidogrel: 300 mg orally as a loading dose, followed by 75 mg once daily

Consider – guideline-directed management and therapy

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ONGOING
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diabetic cardiovascular disease: stable and/or after intervention
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with heart failure
Consider – 

guideline-directed management and therapy

Treatment recommended for SOME patients in selected patient group

Patients with diabetes and heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) should receive heart failure (HF) therapy as per current HF guidelines.[29][161][260]

Presence of HF in patients with type 2 diabetes influences choice of antihyperglycemic agent. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are recommended in all patients with HF and type 2 diabetes mellitus, as they reduce risk of HF-related hospitalization and mortality. Thiazolidinediones (e.g., pioglitazone) and saxagliptin (a dipeptidyl peptidase-4 [DPP-4] inhibitor) have been associated with an increased risk of HF hospitalizations and are not recommended in patients with or at risk of HF. Metformin, insulin, and sitagliptin and linagliptin (DPP-4 inhibitors) are considered neutral in terms of their effect on HF outcomes.[6]​ In patients with obesity and HFpEF, semaglutide (a GLP-1 receptor agonist) has been shown to reduce HF-related symptoms, improve exercise function, and result in greater weight loss compared with placebo.[365]​ A GLP-1 receptor agonist may be preferred over other antihyperglycemic agents in those with HFpEF and obesity.

Screening for HF in patients with diabetes is important for starting therapy early and optimizing prognosis. The ADA recommends annual screening of asymptomatic adults with diabetes for HF.[29]

See Heart failure with reduced ejection fraction and Heart failure with preserved ejection fraction.

Consider – management of cardiovascular risk and kidney failure risk

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ONGOING
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diabetic cardiovascular disease: stable and/or after intervention
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with chronic kidney disease
Consider – 

management of cardiovascular risk and kidney failure risk

Treatment recommended for SOME patients in selected patient group

Reducing the risk of both cardiovascular (CV) and kidney adverse events is key in these patients. Standard lifestyle and risk factor modifications (e.g., BP control, lipid control, glycemic control, weight control) are important. Additionally, specific pharmacologic interventions are recommended.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, in addition to reducing hyperglycemia, have renal benefits through independent effects on renal tubular glucose reabsorption, weight, BP, intraglomerular pressures, albuminuria, and slowed glomerular filtration rate (GFR) loss, and are recommended in patients with type 2 diabetes, established atherosclerotic CVD, and chronic kidney disease (CKD) to reduce the risk of both CV and kidney adverse events.[6][29]

An ACE inhibitor or angiotensin-II receptor antagonist is recommended in patients with type 2 diabetes, established atherosclerotic CVD, and CKD, even if they are normotensive, to reduce the risk of cardiovascular events.[6][29]​​[320]

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has been shown in randomized trials to lower risks of CV events and CKD progression in patients with type 2 diabetes, CKD, and albuminuria.[367][368]​ In one trial, 45.3% of participants also had a history of CVD.[368]​ For people with type 2 diabetes and CKD with albuminuria treated with maximum tolerated doses of ACE inhibitors or angiotensin-II receptor antagonists, who are at an increased risk of cardiovascular events or CKD progression, the ADA and ESC recommend addition of finerenone.[6][29]

If additional glycemic control is needed, a glucagon-like peptide-1 (GLP-1) receptor agonist is recommended, as they improve renal outcomes independent of glucose lowering effect, and have benefits in CV risk reduction and weight control.[6][29]

Low-dose aspirin is recommended in patients with diabetes, CKD, and atherosclerotic CVD to protect against cardiovascular events.[6]

In patients with diabetes, CKD, and stable moderate or severe CAD, either an intensive medical strategy or an initial invasive strategy may be considered.[6]

Referral to a specialist should be considered.

See Diabetic kidney disease.

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