Diabetic Cardiomyopathy

Diabetic cardiomyopathy is myocardial dysfunction in people with diabetes that cannot be explained by coronary artery disease, hypertension, valve disease or other causes.

It progresses from early diastolic dysfunction and reduced strain with preserved ejection fraction, to a clinical heart failure with preserved ejection fraction phenotype with hypertrophy and fibrosis, and in some patients to dilatation and reduced ejection fraction.

Diabetes doubles the risk of heart failure in men and raises it about fivefold in women, and heart failure is found in about 10 to 20% of people with type 2 diabetes. The condition occurs with both type 1 and type 2 diabetes, and obesity and hypertension add to it.

Coexisting coronary disease, hypertension, chronic kidney disease and autonomic neuropathy usually contribute in practice.

Pathophysiology. Insulin resistance, hyperglycaemia, lipotoxicity, advanced glycation end products, oxidative stress, mitochondrial dysfunction and neurohumoral activation produce cardiomyocyte hypertrophy, interstitial and perivascular fibrosis, coronary microvascular rarefaction and impaired calcium handling.

These cause a stiff ventricle with impaired relaxation, raised filling pressure and, later, systolic dysfunction. Autonomic neuropathy adds resting tachycardia and orthostatic hypotension, and reduces exercise capacity.

• Many patients are asymptomatic early (stage B heart failure).
• Exertional dyspnoea, fatigue, reduced exercise tolerance, orthopnoea, oedema, palpitations. Silent ischaemia occurs.
• Resting tachycardia, orthostatic hypotension, and gastroparesis or erectile dysfunction from autonomic neuropathy.
• Signs of heart failure: raised venous pressure, third or fourth heart sound, crackles, oedema.
• Microvascular complications (retinopathy, nephropathy, neuropathy) are usually present and predict cardiomyopathy.

Red flags.

• Acute decompensated heart failure
• Chest pain or ischaemic ECG change (silent ischaemia is common)
• Syncope or orthostatic hypotension
• Albuminuria with falling eGFR
• Ejection fraction under 40%
• Rapid atrial fibrillation
• HbA1c over 75 mmol/mol (9%) with ketosis or volume depletion

• Screening in people with diabetes. Natriuretic peptide (NT-proBNP of 125 pg/mL or more suggests heart failure and prompts echocardiography), echocardiography at diagnosis of symptoms, ECG yearly.
• Echocardiography. E/e' ratio, left atrial volume index (over 34 mL/m2), left ventricular mass, relative wall thickness, global longitudinal strain (early reduction), ejection fraction.
• Cardiac MRI. Fibrosis (late gadolinium enhancement and extracellular volume) and exclusion of infiltrative disease and haemochromatosis.
• Exclude coronary disease by stress imaging, CT angiography or invasive angiography.
• Metabolic and renal assessment. HbA1c, fasting glucose, lipids, creatinine and eGFR, urinary albumin to creatinine ratio, TSH, ferritin and transferrin saturation.
• Autonomic testing. Heart rate variability, lying and standing blood pressure.
• Diagnosis is by exclusion of other causes of cardiomyopathy.

Differential diagnosis.

• Ischaemic cardiomyopathy and hypertensive heart disease
• Haemochromatosis (diabetes with cardiomyopathy and liver disease)
• Cardiac amyloidosis (AL and transthyretin)
• Hypertrophic cardiomyopathy and Fabry disease
• Obesity related and obstructive sleep apnoea cardiomyopathy
• Chronic kidney disease and valve disease
• Thiazolidinedione induced fluid retention
• Heart failure from saxagliptin or alogliptin
• Tachycardia induced and alcoholic cardiomyopathy
• Diabetic autonomic neuropathy without myocardial disease

Prevent and treat with glucose control, cardiovascular risk reduction and heart failure therapy.

• Glycaemic targets. HbA1c of 53 mmol/mol (7.0%) in most patients (48 to 58 mmol/mol, individualised). Avoid hypoglycaemia and large swings.
• SGLT2 inhibitors first line for heart failure with preserved or reduced ejection fraction in diabetes: dapagliflozin 10 mg orally once daily or empagliflozin 10 mg orally once daily, long term. Start at eGFR 25 mL/min/1.73 m2 or more for dapagliflozin and 20 mL/min/1.73 m2 or more for empagliflozin. Counsel on genital infection and hydration, and stop 3 days before major surgery and during acute illness with poor oral intake (euglycaemic ketoacidosis). Contraindicated in type 1 diabetes. Reduce diuretic and insulin or sulphonylurea doses at start to avoid volume depletion and hypoglycaemia.
• Metformin 500 mg orally once daily with food, increased every 1 to 2 weeks to 1 g twice daily (maximum 2 g daily). Reduce to a maximum of 1 g daily at eGFR 30 to 44 mL/min/1.73 m2, stop at eGFR under 30 mL/min/1.73 m2, and withhold with acute decompensation, contrast studies and sepsis. Check vitamin B12 yearly.
• GLP-1 receptor agonists (semaglutide 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg, increasing to 1 mg weekly, maximum 2 mg weekly for diabetes) lower cardiovascular events, and improve symptoms in obese patients with preserved ejection fraction. Evidence is weaker with reduced ejection fraction, so use with caution. Avoid in pancreatitis and personal or family history of medullary thyroid cancer.
• Finerenone 10 mg orally once daily at eGFR 25 to 59 mL/min/1.73 m2, or 20 mg once daily at eGFR 60 mL/min/1.73 m2 or more, in type 2 diabetes with chronic kidney disease and albuminuria, with potassium 5.0 mmol/L or less at start. Check potassium and creatinine at 4 weeks and then every 4 months. Withhold at potassium over 5.5 mmol/L. Contraindicated with strong CYP3A4 inhibitors (clarithromycin, ketoconazole, itraconazole, ritonavir) and in adrenal insufficiency. Do not combine with spironolactone.
• Medicines to avoid: pioglitazone (contraindicated in heart failure), saxagliptin and alogliptin (higher heart failure risk), and non-dihydropyridine calcium channel blockers with reduced ejection fraction. Use sulphonylureas, particularly glibenclamide, with caution, because of hypoglycaemia.
• Blood pressure under 130/80 mm Hg. Use an ACE inhibitor or angiotensin receptor blocker (ramipril 2.5 mg orally once daily, increased every 2 to 4 weeks to 10 mg once daily, maximum 10 mg daily and 5 mg daily at creatinine clearance under 30 mL/min; contraindicated in pregnancy and bilateral renal artery stenosis; check potassium and creatinine 1 to 2 weeks after each change), especially with albuminuria.
• Lipids. Atorvastatin 20 to 40 mg orally once daily (80 mg with established vascular disease), with liver enzymes at baseline and 3 months. Target LDL cholesterol under 1.8 mmol/L (70 mg/dL) in high risk diabetes and under 1.4 mmol/L (55 mg/dL) with established disease. Contraindicated in pregnancy.
• Heart failure with reduced ejection fraction. Full tolerated therapy:
  • Sacubitril/valsartan 49/51 mg orally twice daily, doubled at 2 to 4 weeks to the target 97/103 mg twice daily (maximum 194/206 mg daily). Start 24/26 mg twice daily if not on an ACE inhibitor or angiotensin receptor blocker, on low doses, with eGFR under 30 mL/min/1.73 m2, or with moderate liver impairment. Stop any ACE inhibitor 36 hours before. Contraindicated with previous angio oedema, severe liver impairment and pregnancy. Check potassium and creatinine 1 to 2 weeks after each change.
  • Bisoprolol 1.25 mg orally once daily, increased every 1 to 4 weeks to the target 10 mg once daily, maximum 10 mg daily in heart failure. Contraindicated in cardiogenic shock, high grade AV block without a pacemaker, sick sinus syndrome and severe asthma. Warn about masked hypoglycaemia in patients on insulin or sulphonylureas.
  • Spironolactone 25 mg orally once daily (12.5 mg at eGFR 30 to 49 mL/min/1.73 m2), up to 50 mg daily. Check potassium and creatinine at 1 week and 4 weeks, then every 3 months. Withhold at potassium over 5.5 mmol/L and avoid at eGFR under 30 mL/min/1.73 m2.
  • Dapagliflozin 10 mg orally once daily, long term (start at eGFR 25 mL/min/1.73 m2 or more; withhold during acute illness with poor oral intake; contraindicated in type 1 diabetes).
• Congestion. Furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed (higher doses in renal impairment under specialist care). Monitor sodium, potassium and creatinine.
• Coronary disease is common and often silent, so revascularise by usual indications. Aspirin 75 to 100 mg orally once daily for established vascular disease only.
• Atrial fibrillation: apixaban 5 mg orally twice daily, reduced to 2.5 mg twice daily when at least two of age 80 years or over, weight 60 kg or under and serum creatinine 133 micromol/L or over are present. Also 2.5 mg twice daily at creatinine clearance 15 to 29 mL/min, and avoided under 15 mL/min. Maximum 10 mg daily. Long term.
• Autonomic neuropathy. Slow postural changes, compression stockings, adequate fluids and salt where heart failure is absent, and review of antihypertensives.
• Lifestyle. Weight loss, supervised exercise training, smoking cessation, sodium restriction in heart failure.

Special groups.

• Type 1 diabetes: avoid SGLT2 inhibitors and use insulin for glycaemic control, with the ACE inhibitor or sacubitril/valsartan, bisoprolol and spironolactone doses used for heart failure.
• Pregnancy: stop ACE inhibitors, sacubitril/valsartan, spironolactone, finerenone, SGLT2 inhibitors, GLP-1 receptor agonists and statins before conception.
• Kidney impairment: limit metformin to 1 g daily at eGFR 30 to 44 mL/min/1.73 m2 and stop it under 30 mL/min/1.73 m2, start dapagliflozin at eGFR 25 mL/min/1.73 m2 or more and empagliflozin at 20 mL/min/1.73 m2 or more, start finerenone 10 mg at eGFR 25 to 59 mL/min/1.73 m2, and limit ramipril to 5 mg daily at creatinine clearance under 30 mL/min.
• Region: where diagnosis is late and insulin or newer drugs are unavailable, use metformin, an ACE inhibitor, a statin and generic heart failure drugs, and avoid pioglitazone.

Monitoring. HbA1c every 3 months until at target, then every 6 months. Potassium and creatinine 1 to 2 weeks after each change of ACE inhibitor, sacubitril/valsartan, spironolactone or finerenone (finerenone at 4 weeks and then every 4 months), and urinary albumin to creatinine ratio yearly. Natriuretic peptide yearly and echocardiography every 1 to 2 years, or with symptoms. Eye and foot screening yearly.

Referral and escalation. Refer to cardiology for heart failure, ischaemia or arrhythmia, and to endocrinology for poor control. Urgent for acute decompensation, ischaemia, ketoacidosis, or syncope.