The following are key points to remember from the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiovascular disease (CVD) in patients with diabetes, part 1 of 2:

1. The new ESC guidelines were developed by the ESC Task Force on the Management of CVD in patients with diabetes. There is no discussion of prediabetes because of lack of clear evidence. It provides a unique type 2 diabetes mellitus (T2DM) 10-year CVD risk score (SCORE₂-Diabetes) that is available for free at: Eur Heart J 2023;44:2544-56; https://doi.org/10.1093/eurheartj/ehad260.
2. Patients with diabetes are at increased risk of developing atherosclerotic cardiovascular disease (ASCVD) with its manifestations of coronary artery disease (CAD), chronic heart failure, atrial fibrillation (AF), and stroke, aortic and peripheral artery diseases, and is a major risk factor for chronic kidney disease, which enhances risk for CV and all-cause mortality.  SCORE₂-Diabetes integrates information on conventional CVD risk factors (i.e., age, smoking status, systolic blood pressure [SBP], and total and high-density lipoprotein cholesterol [HDL-C]) with diabetes-specific information (e.g., age at diabetes diagnosis, glycated hemoglobin [HbA1c], and estimated glomerular filtration rate [eGFR]). This model is calibrated to four clusters of countries (low, moderate, high, and very high CVD risk) using the similar methodology of the other ESC SCORE risk estimates.
3. When assessing CV risk in T2DM, consider medical and family history, symptoms, findings from examination, laboratory and other diagnostic test results, and the presence of ASCVD or severe target organ damage (TOD). There is not enough robust evidence to suggest that assessment of coronary artery calcium (CAC) or intima media thickness help reclassify CV risk in T2DM. Severe TOD is defined as:
   • eGFR <45 mL/min/1.73 m² irrespective of albuminuria, or
   • eGFR 45–59 mL/min/1.73 m² and microalbuminuria (urinary albumin-to-creatinine ratio [UACR] 30–300 mg/g; stage A2), or
   • Proteinuria (UACR >300 mg/g; stage A3), or
   • Presence of microvascular disease in at least three different sites, e.g., microalbuminuria (stage A2) plus retinopathy plus neuropathy.
4. Mediterranean diet is recommended in T2DM or obese patients who need to aim to reduce weight and increase physical exercise to improve metabolic control and overall CVD risk profile. Weight loss of >5% improves glycemic control, lipid levels, and BP in overweight and obese adults with T2DM.
   • Glucose-lowering medications with effects on weight loss (e.g., glucagon-like peptide-1 receptor agonists [GLP-1 RAs]) should be considered in patients with overweight or obesity to reduce weight.
   • Bariatric surgery should be considered for high- and very high-risk patients with body mass index (BMI) ≥35 kg/m² when repetitive and structured efforts of lifestyle changes combined with weight-reducing medications do not result in maintained weight loss.
   • Exercise interventions should be recommended in T2DM-associated comorbidities (e.g., frailty, neuropathy, or retinopathy). Introduce structured exercise training in patients with T2DM and established CVD; CAD, heart failure with preserved ejection fraction (HFpEF), HF with mildly reduced EF (HFmrEF), HF with reduced EF (HFrEF), or AF to improve metabolic control, exercise capacity, and quality of life, and to reduce CV events.
5. Reducing HbA1c decreases microvascular complications, particularly when achieving near-normal levels (HbA1c <7%), but the effects on macrovascular disease are more complex. Hypoglycemia is associated with an increased risk of vascular events; thus, recent consensus advocates hypoglycemic exposure at <1% (i.e., <15 min/day) in individuals at high CV risk.
   Tight glycemic control should be considered for reducing CAD in the long term. Prioritize the use of glucose-lowering agents with proven CV benefits followed by agents with proven CV safety over agents without proven CV benefit or proven CV safety. Observational studies have shown a U-shaped relationship between HbA1c and clinical outcome, suggesting that lower HbA1c is not always better.  Those with short life expectancy should be targeted to <8.5% with priority to agents with proven CV benefit, while those with longer life expectancy tighten target to <7%, avoiding hypoglycemia (sulfonylurea and insulin), and give priority to drugs with proven CV benefit and low hypoglycemic risk (GLP-1 RAs, sodium–glucose co-transporter-2 [SGLT2] inhibitors).
   • Hypoglycemic drug strategy begins with ASCVD risk strategy:
     • Low to moderate risk (no ASCVD or severe TOD and SCORE₂-diabetes <10%) metformin
     • High to very high risk (no ASCVD or severe TOD, SCORE₂-diabetes ≥10%) metformin and/or SGLT2 inhibitor and/or GLP-1 RA
     • Very high risk with ASCVD SGLT2 inhibitor and/or GLP-1 RA
   • Hypoglycemic agents for additional glucose control with some CV benefit:
     • Metformin
     • Pioglitazone
   • Hypoglycemic agents with proven CV safety:
     • Dipeptidyl peptidase-4 (DPP-4) inhibitors (the gliptins)
     • Sulfonylurea (limited to glimepiride in US)
     • Insulin glargine or insulin degludec
     • Oral GLP-1 RA semaglutide
     • Exenatide, extended release
6. BP and diabetes: History of hypertension was present in 80% of men and 87% of women with known diabetes and in 74% of men and 81% of women with newly diagnosed diabetes with a history of coronary heart disease.
   • Regular BP measurements by technique similar to American Heart Association (AHA) are recommended in diabetes to detect and treat hypertension to reduce CV risk. Measure BP 1 minute and 3 minutes after standing from a seated position in all patients on initial visit to exclude orthostatic hypotension; lying and standing BP measurements should also be considered in subsequent visits. Masked hypertension should be considered in patients with normal and high-normal office BP with hypertension mediated organ damage or at high CV risk.
   • Antihypertensive drug treatment is recommended in diabetes when office BP ≥140/90 mm Hg.
   • BP goal is to target SBP to 130 mm Hg and <130 mm Hg if tolerated, but not <120 mm Hg. In older people (aged >65 years), it is recommended to target SBP to 130–139 mm Hg. An on-treatment SBP target of <130 mm Hg may be considered in patients with diabetes at particularly high risk of a cerebrovascular event to further reduce risk of stroke.
   • In patients aged ≥70 years, SBP values <140 mm Hg, down to 130 mm Hg if tolerated are recommended. Diastolic BP treatment target <80 mm Hg is recommended for all treated patients.
7. Treatment of hypertension:
   • Lifestyle changes (weight loss if overweight, physical activity, alcohol restriction, sodium restriction, increased consumption of vegetables, using low-fat dairy products) are recommended.
   • Initiate treatment with a combination of a renin–angiotensin system inhibitor and a calcium channel blocker or thiazide/thiazide-like diuretic.
   • Home BP self-monitoring should be considered in patients with diabetes on antihypertensive treatments to check that BP is appropriately controlled.
   • 24-hour ambulatory BP monitoring should be considered to assess abnormal 24-hour BP patterns, including nocturnal hypertension and reduced or reversed nocturnal BP dipping, and to adjust antihypertensive treatment.
   • Consider beta-blockers at any treatment step when specifically indicated (e.g., HF, angina, post-myocardial infarction [MI], AF, or younger women with or planning pregnancy). A combination of two or more drugs at fixed doses in a single pill should be considered to improve adherence and to achieve earlier control.
8. Lipid targets are LDL-C based on CV risk categories:  ASCVD, severe target organ damage, or SCORE₂-Diabetes 10-year risk estimate.  A secondary goal of non-HDL-C should also be considered in patients with diabetes and combined dyslipidemias, although there are limited data from interventional trials.
   • ASCVD, target organ damage or very high risk (≥20%) LDL-C <55 mg/dL
   • SCORE₂-Diabetes high risk (10% to <20%) LDL-C <70 mg/dL
   • SCORE₂-Diabetes moderate risk (5% to <10%) LDL-C <100 mg/dL
   • SCORE₂-Diabetes low risk (<5%) no clear evidence of benefit
9. Lipid-lowering agents:  Statins remain the first-line therapy to reduce LDL-C in diabetes and dyslipidemia, due to their efficacy in preventing CV events and reducing CV mortality with no evidence for sex differences.
   • High-intensity statins (rosuvastatin and atorvastatin) are indicated in patients with diabetes at high or very high CV risk, as they lower LDL-C by 40–63% and significantly reduce the incidence of major cerebral and coronary complications.
   • Beneficial effect outweighs the potential diabetogenic effect of these drugs, estimated as a 9% increased risk of incident diabetes, especially in older patients and in patients already at risk of developing diabetes. Similar benefits were seen in both T1DM and T2DM.
   • Subjective adverse events (such as fatigue, myalgias, and nervous system symptoms) are more frequent than objective adverse events due to the nocebo effect, with women experiencing adverse events more frequently than men: 70–90% of patients who report statin intolerance are able to take a statin when re-challenged.
10. Nonstatin lipid-lowering drugs effective in diabetes:
    • Ezetimibe is effective when added to a statin, by reducing cholesterol absorption from the ileum. In patients post-acute coronary syndrome (ACS) receiving simvastatin plus ezetimibe, there was a 15% greater benefit in the subgroup of patients with diabetes. The combination of ezetimibe with a statin is recommended in patients with diabetes and a recent ACS, especially when an LDL-C target <55 mg/dL is required and not achieved with a statin alone.
    •  Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies given subcutaneously every 2 weeks alone or with ezetimibe or statins significantly reduce major adverse cardiovascular events in subgroups with diabetes, both with stable ASCVD and post-ACS. Inclisiran, an siRNA inhibitor of PCSK9 given subcutaneously every 6 months, provides a 50% reduction in LDL-C on top of statins in nondiabetics and diabetics but the event trial is in progress. Bempedoic acid is a nonstatin that lowers the LDL-C significantly in ASCVD and familial hypercholesterolemia regardless of diabetes and also does not induce or worsen diabetes. In a placebo-controlled trial, bempedoic acid was associated with a significantly lower four-component composite primary endpoint of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization.
    • Fibrates and triglyceride (TG)-lowering drug use for primary or secondary prevention is limited due to the risk of myopathy when used with statins. And there is little benefit in placebo-controlled trials aside from subgroup analysis including persons with very high TG levels. If TGs remain elevated even with a statin-based regimen, icosapent ethyl, a stable ester of eicosapentaenoic acid, might be preferred over other omega-3 fatty acids at the dose of 2 g twice a day with meals due to its favorable impact on CV outcomes reported in the REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl—Intervention Trial) trial, where benefit was consistent in patients with (58%) and without diabetes.
11. Antiplatelet drugs in diabetes without and with symptomatic ASCVD or revascularization:
    • In adults with T2DM without a history of symptomatic ASCVD or revascularization, aspirin (ASA) (75–100 QD) may be considered to prevent the first severe vascular event, in the absence of clear contraindications.
    • Patients with chronic coronary disease and diabetes or with prior revascularization are at very high CV risk, and low-dose ASA (75–100 mg QD) is recommended, although ad-hoc randomized controlled trials are lacking. Low dose is as effective as 3- to 4-fold higher doses.
    • Clopidogrel 75 mg provides an alternative in ASA-intolerant patients or can be combined with low-dose ASA as dual antiplatelet therapy (DAPT) in patients with chronic coronary syndrome (CCS) undergoing percutaneous coronary intervention (PCI).
    • COMPASS was a randomized controlled trial enrolling over 27,000 patients with stable ASCVD (previous MI, symptomatic CAD, and/or peripheral artery disease [PAD]) of whom 38% had diabetes. Adding very low-dose rivaroxaban (2.5 mg BID) to low-dose ASA for long-term prevention of serious vascular events should be considered in patients with diabetes and CCS or symptomatic PAD without high bleeding risk.
    • No evidence supports shortening or de-escalating DAPT post-ACS specifically in patients with diabetes.
12. Antithrombotic recommendations following revascularization for ACS and CCS in diabetes with no indication for anticoagulation:
    • ASA at a dose of 75–100 mg QD is recommended in patients with diabetes and previous MI or revascularization (coronary artery bypass grafting [CABG] or stenting).
    • In patients with ACS and diabetes who undergo PCI, a P2Y12 receptor inhibitor (ticagrelor or prasugrel) is recommended in addition to ASA (75–100 mg QD) maintained over 12 months.
    • Clopidogrel 75 mg QD following appropriate loading (e.g., 600 mg or ≥5 days already on maintenance therapy) is recommended in addition to ASA for 6 months following coronary stenting in patients with CCS, irrespective of stent type, unless a shorter duration is indicated due to the risk or occurrence of life-threatening bleeding.
    • Clopidogrel is recommended as an alternative in case of ASA intolerance.
    • In patients with diabetes and ACS treated with DAPT who are undergoing CABG and do not require long-term oral anticoagulant therapy, resuming a P2Y12 receptor inhibitor (ticagrelor 60 mg BID or prasugrel) as soon as deemed safe after surgery and continuing it up to 12 months is recommended.
    • Prolonging DAPT beyond 12 months after ACS should be considered for up to 3 years in patients with diabetes who have tolerated DAPT without major bleeding complications.
    • Adding 2.5 mg of rivaroxaban to low-dose ASA for long-term prevention of serious vascular events should be considered in patients with diabetes and CCS or symptomatic PAD without high bleeding risk.
13. Recommendations for antithrombotic therapy in patients with diabetes and ACS or CCS and/or post PCI requiring long-term oral anticoagulation:
    • In patients with AF and receiving antiplatelet therapy, eligible for anticoagulation, and without a contraindication, nonvitamin K antagonist oral anticoagulants (NOACs) are recommended in preference to warfarin or vitamin K antagonist.
    • In patients with ACS or CCS and diabetes undergoing coronary stent implantation and having an indication for anticoagulation, triple therapy with low-dose ASA, clopidogrel, and an OAC is recommended for ≥1 week, followed by dual therapy with an OAC and a single, oral, antiplatelet agent.
    • In patients with ACS or CCS and diabetes undergoing coronary stent implantation and having an indication for anticoagulation, prolonging triple therapy with low-dose ASA, clopidogrel, and an OAC should be considered for 1 and up to 3 months if the thrombotic risk outweighs the bleeding risk in the individual patient.
14. Gastric protection in patients with diabetes taking antithrombotic drugs:
    • When antithrombotic drugs are used in combination, proton pump inhibitors are recommended to prevent gastrointestinal (GI) bleeding.
    • When a single antiplatelet or anticoagulant drug is used, proton pump inhibitors should be considered to prevent GI bleeding, considering the bleeding risk of the individual patient.
    • When clopidogrel is used, omeprazole and esomeprazole are not recommended for gastric protection.
15. Screening for asymptomatic CAD in diabetes remains controversial. Various randomized controlled trials evaluating the impact of routine screening for CAD in asymptomatic patients with diabetes and no history of CAD showed no differences in CV outcomes at follow-up in those who underwent routine screening compared with standard recommendations.
16. The comprehensive management of patients with diabetes and established CAD should start with a healthy lifestyle and reducing or eliminating modifiable risk factors such as obesity, hypertension, or dyslipidemia. The goal of pharmacotherapy should be to substantially reduce serious CV events. Targets and pharmacotherapy for glycemia, BP, and LDL-C levels are addressed in the respective sections with antiangina medication similar to nondiabetics.
17. Recommendations for diabetes in ACS:
    • Glucose-lowering therapy should be considered in patients with ACS with persistent hyperglycemia, while episodes of hypoglycemia should be avoided.
    • Reperfusion strategies in ST-segment elevation MI (STEMI) and NSTEMI in diabetes should not differ from nondiabetics.
18. Recommendations for revascularization in diabetes:
    • Similar revascularization techniques are implemented (e.g., the use of drug-eluting stents and the radial approach for PCI, and the use of the left internal mammary artery as the graft for CABG) in patients with and without diabetes.
    • Myocardial revascularization in CCS is recommended when angina persists despite antianginal drugs or with documented large area of ischemia (>10% LV).
    • Complete revascularization is recommended in patients with STEMI and NSTEMI without cardiogenic shock and with multivessel CAD.

Note: Click the link under Related Content (top right) for Part 2 of this Journal Scan.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Interventions and ACS, Interventions and Vascular Medicine, Diet, Exercise, Hypertension

Keywords: Acute Coronary Syndrome, Antihypertensive Agents, Aspirin, Atherosclerosis, Atrial Fibrillation, Blood Pressure, Cholesterol, LDL, Diabetes Mellitus, Type 2, Diet, Dyslipidemias, ESC Congress, ESC23, Exercise, Heart Failure, Glycated Hemoglobin A, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Obesity, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Platelet Aggregation Inhibitors, Primary Prevention, Secondary Prevention, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Stroke, Vascular Diseases

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