Diabetes mellitus and heart failure − interconnected units with complex pathogenesis

Development of heart failure in diabetics

One of the basic mechanisms of myocardial damage is immune dysregulation occurring in the bodies of diabetics. Chronic hyperglycemia causes subclinical myocardial damage, whose structural proteins are subsequently exposed to the immune system's reaction. In the case of T1DM, the situation is worsened by increased immune reactivity to damaged cells, leading to the release of a large amount of CD4⁺ T lymphocytes and the formation of autoantibodies. This pro-inflammatory state leads to the development of myocarditis and also potentiates the development of vascular atherosclerotic changes.

Frequently present obesity provokes the development of heart dysfunction primarily through alteration of natriuretic peptide (NP) function. Under normal conditions, these act as a protective mechanism against heart volume overload and prevent ventricular remodeling. NPs also act on the kidneys, promoting diuresis and natriuresis and causing vasodilation.

Chronic hyperglycemia activates non-physiological metabolic pathways, whose products play a key role in the development of oxidative stress and damage to tissues and vascular endothelium.

Gradual progression of heart failure in patients with type 2 DM

The development of heart failure in diabetics can be divided into several stages. Stage I includes asymptomatic patients with normal left ventricular function. However, subclinical heart damage often already exists due to diabetic cardiomyopathy. With the gradual progression of the disease, the patient begins to be mildly limited during exertion, but the left ventricular ejection fraction (LVEF) remains normal, although concentric hypertrophy occurs. In Stage III, LVEF decreases due to eccentric hypertrophy, pulmonary hypertension develops, and the patient is limited in performance even with minimal exertion (NYHA III). The final stage of the disease is characterized by resting dyspnea and failure of both heart ventricles.

Lifestyle adjustments and medication for prevention

The development of heart failure in diabetics can be somewhat prevented by lifestyle changes and pharmacological control of diabetes and associated comorbidities. One of the most commonly used antidiabetic drugs is metformin, which can reduce the risk of cardiovascular complications. The same applies to incretin analogs − glucagon-like peptide 1 receptor agonists (GLP-1RAs). Another significant group includes sodium-glucose cotransporter 2 inhibitors (SGLT2i, i.e., gliflozins). Although these transporters are primarily expressed in the proximal tubules of the kidneys, these drugs also have significant systemic effects. Besides satisfactory glycemic control, their use can reduce the risk of cardiovascular events and improve the prognosis in patients with heart failure and chronic renal insufficiency.

Cardiogenic diabetes in patients with heart failure

Heart failure itself is a state of insulin resistance. The reduced response of tissues to insulin is associated with hyperactivity of the renin-angiotensin-aldosterone system (RAAS). The exact cause of insulin resistance associated with heart failure has not yet been clarified, but it may be related to oxidative stress, inflammatory processes, insulin receptor mutations, or mitochondrial dysfunction. The result is the failure of pancreatic beta cells and finally the development of cardiogenic diabetes mellitus.

Drugs used in patients with heart failure with reduced left ventricular ejection fraction (HFrEF) have rather different metabolic effects. Diuretics promote the development of insulin resistance and increase serum uric acid concentration, which can result in glucose tolerance abnormalities. On the other hand, the use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs, i.e., sartans) often slows the development of diabetes. A very good antidiabetic profile has been noted with the angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan, which improves peripheral tissue sensitivity to insulin and helps reduce glycated hemoglobin levels. Similarly favorable metabolic effects have been demonstrated in studies with the use of SGLT2i.

Conclusion

Diabetes mellitus and heart failure form significantly interconnected units with similar risk factors and interlinked pathogenesis. The most suitable drugs currently considered for the treatment of both type 2 diabetes and heart failure are SGLT2 inhibitors, i.e., gliflozins. The combination of sacubitril/valsartan (from the ARNI group) in patients with HFrEF is also coming to the forefront of interest. While the development of heart failure in diabetics is now carefully controlled, new cases of DM in patients with heart failure still occur with some delay. Findings and procedures for the optimal prevention and timely therapy of cardiogenic diabetes will undoubtedly be the subject of further research in the near future.

(kali)

Source: Triposkiadis F., Xanthopoulos A., Bargiota A. Diabetes mellitus and heart failure. J Clin Med 2021 Aug 19; 10 (16): 3682, doi: 10.3390/jcm10163682.