Diabetes Mellitus and the Heart

Cardiovascular risk

Patients with diabetes mellitus have a significantly increased risk of developing cardiovascular diseases with their sequelae of acute myocardial infarction, stroke and cardiovascular death. For example, even today a 60-year-old male patient with diabetes has 6 years less life expectancy compared to a metabolically healthy male of the same age, and a 60-year-old patient with diabetes and a previous history of a heart attack has 12 years less [2]. These data highlight the need for targeted risk stratification of patients with diabetes and the consistent treatment of diabetes, associated risk factors and cardiovascular disease.

Patients with diabetes mellitus should be categorized according to their cardiovascular risk into those with very high cardiovascular risk, high cardiovascular risk and moderate cardiovascular risk [3].

Very high cardiovascular risk

Diabetes mellitus and existing cardiovascular disease, or end organ damage, or≥3 risk factors or diabetes duration>20 years.

High cardiovascular risk

Diabetes mellitus with a diabetes duration>10 years without end organ damage, but with an additional risk factor.

Moderate cardiovascular risk

Young patients (type 1 diabetes<35 years; type 2 diabetes<50 years) with a diabetes duration<10 years without other risk factors.

Further risk stratification

In addition to diagnostics for the above-mentioned risk stratification, patients with diabetes and hypertension or clinical suspicion of cardiovascular disease should receive a resting ECG. At present, no convincing data exist to use additional imaging techniques such as echocardiography, stress echocardiography, scintigraphy or MRI in asymptomatic patients with diabetes mellitus. As part of clinical routines, no determination of circulating biomarkers should be carried out as part of risk stratification.

Cardiovascular risk reduction

For the recommendations on the reduction of cardiovascular risk in diabetes treatment, refer to the DDG practice recommendations on the therapy of type 2 diabetes (see p. 65–92) and on the treatment of lipid metabolic disorders (see p. 160–165). Therefore, only the basic statements are listed here:

• Patients with diabetes should receive structured advice on how to stop smoking. For patients with diabetes, a Mediterranean diet enriched with polyunsaturated and monounsaturated fatty acids is recommended. Patients with diabetes should perform moderate to strenuous physical activity for at least 150 min/week.

• In patients with type 2 diabetes and very high cardiovascular risk, a target value for low-density lipoprotein (LDL) cholesterol of<55 mg/dL and a minimum of 50%reduction in cholesterol is recommended. For patients with a high cardiovascular risk, a target value of 70 mg/dL and a minimum of 50%reduction in cholesterol is recommended. For patients with a moderate risk, a reduction in LDL cholesterol to<100 mg/dL is recommended.

• The administration of aspirin (100 mg/day) is recommended for secondary prevention in patients with diabetes mellitus. In the context of primary prevention, patients with diabetes should not receive antiplatelet therapy. Platelet aggregation inhibition after acute coronary syndrome and/or coronary intervention (duration of dual antiplatelet therapy, etc.) should be coordinated with the treating cardiologist.

• In accordance with the new guideline of the European Society of Cardiology, patients with diabetes mellitus should have a target systolic blood pressure of 130 mmHg. If possible, systolic values<130 mmHg should be targeted. The diastolic blood pressure target is<80 mmHg. A blood pressure setting<120/70 mmHg should be avoided.

• When adjusting blood glucose levels, patients without a cardiovascular pre-existing condition should be treated according to the recommendations for type 2 diabetes; in patients with a pre-existing cardiovascular condition, hypoglycaemia should be avoided and proven therapy strategies in reducing cardiovascular risk should be used. Therefore, GLP-1 receptor agonists and/or SGLT-2 inhibitors with proven event reduction should be used for reducing cardiovascular events and mortality based on the results of large cardiovascular endpoint studies in cases of type 2 diabetes and cardiovascular diseases or a high/very high cardiovascular risk.

Diabetes and coronary heart disease

All patients with coronary heart disease should be examined for the presence of diabetes mellitus (see Diagnostics and Classification of Diabetes Mellitus, see P9–17). For prognostic factors, patients with diabetes mellitus and coronary heart disease should receive platelet aggregation inhibitors, ACE inhibitor therapy and lipid-lowering therapy with statins. The first year after myocardial infarction the administration of a beta-blocker leads to an improvement of the prognosis, whereby this effect decreases over the course of time. With respect to antidiabetic therapy, for patients with type 2 diabetes at high cardiovascular risk, a significant reduction in the 3-point Major Adverse Cardiac Event (MACE) was shown with empagliflozin [4] or canagliflozin [5] versus placebo. In addition, empagliflozin significantly reduced all-cause mortality [3]. In DECLARE, there was no significant effect for dapagliflozin vs. placebo [6]. However, it seems that the individual substance is less important for the different results in the studies than the patient population. Similarly, in LEADER with liraglutide [7], in SUSTAIN-6 semaglutide [8], in HARMONY with albiglutide [9], in REWIND with dulaglutide [10], and in PIONEER-6 [11] with oral semaglutide vs. placebo showed a significant reduction in the 3-point MACE endpoint. In addition, liraglutide and oral semaglutide vs. placebo reduced all-cause mortality in the LEADER trial and PIONEER 6 trial, respectively. Administration of semaglutide resulted in significant reduction of cardiovascular events [12]. Against the background of these data, therapy with one of these substances should be an integral part of blood glucose-lowering therapy in patients with diabetes and cardiovascular disease.

In the presence of coronary artery disease requiring intervention or surgery, the therapy of coronary revascularization in patients with diabetes does not differ from the therapy in patients without diabetes. In complex coronary findings with multi-vascular disease and low perioperative mortality, bypass surgery appears to be superior to coronary intervention. The decision on the revascularization procedure to be performed (coronary intervention or bypass surgery) should always be made by the interdisciplinary cardiac team in the case of complex coronary heart disease.

Diabetes and heart failure

Epidemiological and clinical data of recent years have shown that patients with diabetes mellitus have a significantly increased risk of developing heart failure and that the prognosis of patients with diabetes and heart failure is significantly worse than that of patients with heart failure without diabetes [13] [14]. According to the recommendation of the European Cardiology Guideline, a distinction is made between heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) ([Tab. 1]) [15]. In principle, it can be said that half of patients with heart failure and diabetes have impaired left ventricular function. In patients with HFrEF, the treatment of heart failure does not differ between patients with and without diabetes. This applies to both drug and device therapy (implantable cardioverter defibrillator [ICD], cardiac resynchronization therapy [CRT]). In terms of medication, HFrEF is treated as standard with a quadruple therapy consisting of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor neprilysin inhibitor (ARNI), β-blocker, mineralocorticoid receptor antagonist (MRA) and SGLT-2 (sodium-dependent glucose co-transporter 2) inhibitor. The addition of SGLT2 inhibitors to initial heart failure therapy is based on data from the DAPA-HF and EMPEROR-Reduced trials, both of which were conducted in patients with HFrEF with and without diabetes. Administration of dapagliflozin or empagliflozin significantly reduced worsening heart failure, cardiovascular death, or all-cause mortality regardless of the presence of diabetes mellitus in patients with HfrEF [16] [17] [18]. On the basis of these data, both substances are approved for the treatment of HFrEF.

Tab. 1 Definition of heart failure with preserved (HFpEF), mildly reduced (HFmrEF) and reduced ejection fraction (HFrEF).

HF type		HFrEF	HFmrEF	HFpEF
Criteria	1	Symptoms±signsa	Symptoms±signsa	Symptoms±signsa
	2	LVEF≤40%	LVEF 41–49%b	LVEF≥50%
	3	–	–	Objective evidence of structural and/or functional cardiac abnormalities suggestive of diastolic LV dysfunction/increased LV filling pressures, including elevated natriuretic peptidesc

^a In the early stages of HF (especially HFpEF) and in optimally treated patients, signs of heart failure may be absent. ^b The presence of other examination findings of structural heart disease (e. g., enlarged left atrium, LV hypertrophy, or echocardiographic evidence of impaired LV filling) makes the diagnosis of HFmrEF more likely. ^c The following applies to the diagnosis of HFpEF: The more abnormalities there are, the higher the likelihood of HFpEF. LVEF: Left ventricular ejection fraction.

For patients with HFpEF and HFmrEF (left ventricular ejection fraction [LVEF]>40%), there were no data for a long time that reliably demonstrated an improvement in the prognosis of patients. Recently, 2 large cardiovascular outcome trials, EMPEROR-preserved [1] and DELIVER [20] with the SGLT2 inhibitors empagliflozin and dapagliflozin, respectively, have shown that treatment with SGLT2 inhibitors significantly reduced the combined endpoint of hospitalization due to heart failure or cardiovascular death compared to placebo in patients with an ejection fraction greater than 40%. Predetermined subgroup analyses showed no significant difference between patients with and without diabetes mellitus [1]. On the basis of these data, empagliflozin and dapagliflozin are now approved for the treatment of heart failure regardless of the ejection fraction. In addition to the administration of the SGLT2 inhibitor, patients should continue to receive symptomatic therapy, e. g., diuretics, and therapy for comorbidities, e. g., cessation of arterial hypertension. In addition, in patients with diabetes and heart failure, it should be noted that glitazones and the dipeptidyl peptidase-4 (DPP4) inhibitor saxagliptin are contraindicated in patients with heart failure due to the increased risk of hospitalization for heart failure.

Two studies (FIGARO-DKD [21] and FIDELIO-DKD [22]) investigated the effect of the new non-steroidal mineralocorticoid receptor antagonist finerenone in patients with diabetes, chronic kidney disease (CKD) and albuminuria. In both studies, finerenone reduced the risk of kidney failure and cardiovascular events compared to placebo. A prespecified analysis of both studies together (FIDELITY) showed in 13171 patients that finerenone, in combination with optimized renin–angiotensin system (RAS) blockade, reduced the risk of the composite cardiovascular endpoint consisting of time to cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization due to heart failure by 14%. The effect was mainly due to a reduction in hospitalization due to heart failure, although patients with symptomatic heart failure with reduced pumping function were excluded from these studies [23]. Whether finerenone can reduce heart failure outcomes in patients with HFpEF is currently being investigated in a large cardiovascular endpoint study (FINARTS-HF; NCT04435626).

Diabetes and atrial fibrillation

The presence of diabetes mellitus is a separate risk factor for thromboembolic events in patients with atrial fibrillation. All patients with atrial fibrillation should be risk stratified for their risk of thromboembolism using the CHADS-VASC score ([Tab. 2]) and accordingly receive anticoagulation with vitamin K antagonists or new oral anticoagulants (NOACs) [19]. At this stage, no data exists that show a prognostic advantage of a rhythm restoration (cardioversion in the sinus rhythm) or frequency control in atrial fibrillation. In this respect, the procedure is comparable for patients with and without diabetes.

Tab. 2 Approach based on risk factors, expressed as point system with the acronym CHA₂DS₂ -VASc score.

Risk factor	Score
Chronic heart failure or left ventricular dysfunction	1
Hypertension	1
Age≥75 years old	2
Diabetes mellitus	1
Stroke/TIA/thromboembolism	2
Vascular disease history1	1
Age 65–74 years	1
Female	1
Maximum score	9

Note: As the age can be evaluated with 0, 1 or 2 points, the maximum score is 9. ¹ Condition after myocardial infarction, peripheral arterial occlusive disease, or plaque in the aorta.

Conflicts of Interest

KS has lectured for Amgen, AstraZeneca, Bayer, OmniaMed, Lilly, Boehringer Ingelheim, Novartis, NovoNordisc and MSD and has acted as a consultant for AstraZeneca, Amgen, Bayer, Böhringer Ingelheim and Lilly. DMW has lectured and consulted for Amgen, AstraZeneca, Boehringer Ingelheim, MSD, NovoNordisk and Sanofi-Aventis. NM has lectured for Amgen, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk; NM has conducted research projects supported by Boehringer Ingelheim and MSD, and has acted as a consultant to Amgen, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk, Lilly and Bayer. ALB has lectured for Amgen, AstraZeneca, Lilly, Boehringer Ingelheim, NovoNordisc and MSD and has acted as a consultant to Böhringer Ingelheim, AstraZeneca and NovoNordisk. AZ has worked as a consultant for: Bayer Health Care; Boehringer Ingelheim; Rigel; Cardiorentis; Medscape; Stealth Peptides; Sanofi Aventis; Medtronic; Novartis. He has received honoraria from: Bayer Health Care; Astra-Zeneca; Medtronic; ResMed; Boehringer Ingelheim; Rigel; Sanofi Aventis; Pfizer; Janssen-Cilag; Novartis; Bristol Myers Squib; Thoratec; Abiomed; Daiichi Sankyo; Abbott; Cardiac Dimensions. TF declares the following conflicts of interest: Speaker Panel: Abbott; Astra Zeneca; Böhringer Ingelheim, Berlin Chemie; Cipla, Eli Lilly; Fortbildungskolleg; MSD; Novartis, Novo Nordisk; Sanofi. Advisory Panel: Astra Zeneca; Bayer; Cipla, Eli Lilly; Fortbildungskolleg; Novo Nordisk; Pfizer; Sanofi; Bayer; Roche; Eyesense

• References

• 1 Anker SD, Butler J, Filippatos G. et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med 2021; 385: 1451-1461
• 2 Di Angelantonio E, Kaptoge S. Emerging Risk Factors C et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA 2015; 314: 52-60
• 3 Consentino FF, Grant PJ, Aboyans V. et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41: 255-323
• 4 Zinman B, Wanner C, Lachin JM. et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373
• 5 Neal B, Perkovic V, Mahaffey KW. et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377: 644-657
• 6 Wiviott SD, Raz I, Bonaca MP. et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2018; 380: 347-357
• 7 Marso SP, Daniels GH, Brown-Frandsen K. et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016; 375: 311-322
• 8 Marso SP, Bain SC, Consoli A. et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016; 375: 1834-1844
• 9 Hernandez AF, Green JB, Janmohamed S. et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebocontrolled trial. Lancet 2018; 392: 1519-1529
• 10 Gerstein HC, Colhoun HM, Dagenais GR. et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019; 394: 121-130
• 11 Husain M, Birkenfeld AL, Donsmark M. et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019; 381: 841-851
• 12 Marso SP, Bain SC, Consoli A. et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016; 375: 1834-1844
• 13 Nichols GA, Gullion CM, Koro CE. et al. The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care 2004; 27: 1879-1884
• 14 MacDonald MR, Petrie MC, Varyani F. et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008; 29: 1377-1385
• 15 McDonagh TA, Metra M, Adamo M. et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2021; 42: 3599-3726
• 16 McMurray JJV, Solomon SD, Inzucchi SE. et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019; 381: 1995-2008
• 17 Packer M, Anker SD, Butler J. et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med 2020; 383: 1413-1424
• 18 Zannad F, Ferreira JP, Pocock SJ. et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020; 396: 819-829
• 19 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC)Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESCEndorsed by the European Stroke Organisation (ESO). Eur Heart J 2016; 37: 2893-2962
• 20 Solomon SD, McMurray JJV, Claggett BE. et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med 2022; 387: 1089-1098
• 21 Pitt B, Filippatos GD, Agarwal R. et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med 2021; 385: 2252-2263
• 22 Bakris GL, Agarwal R, Anker SD. et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med 2020; 383: 2219-2229
• 23 Agarwal R, Filippatos G, Pitt B. et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022; 43: 474-484

Publication History

Article published online:
23 January 2024