Gliflozins Successfully Treat Type 2 Diabetes Mellitus and Heart Failure

Cardiomyopathy and Heart Failure in Diabetics

Diabetic cardiomyopathy is defined as the presence of diastolic or systolic dysfunction in a patient diagnosed with DM2, in the absence of other possible causes of cardiomyopathy (ischemic heart disease, hypertension, valvular disease). Type 2 diabetics have approximately 2.5 times higher risk of developing heart failure than patients without DM2. The prevalence of DM2 in patients hospitalized for heart failure is approximately 44%. An increase in glycated hemoglobin (HbA_1c) by 1% increases the incidence of heart failure by up to 8%. Subclinical changes in heart function are apparent even before the full development of DM2 and are associated with insulin resistance. Chronic hyperglycemia and metabolic changes accompanying it can eventually result in remodeling of the heart chambers and subsequent systolic and diastolic dysfunction of the heart.

Gliflozins in Therapy for DM2 and Their Effect on the CV System

Sodium-glucose cotransporters 2 (SGLT2) in the proximal tubule of the kidney are responsible for the reabsorption of up to 90% of filtered glucose. Their activity in diabetics can additionally be increased, leading to further hyperglycemia. Utilizing gliflozins leads mainly to the blockade of SGLT2. The mechanism of action of these drugs is primarily to increase glucose excretion, accompanied by a natriuretic and diuretic effect. It is estimated that the use of gliflozins can lower HbA_1c levels by 5.5–11 mmol/mol.

The safety and benefits of using gliflozins in type 2 diabetics have been investigated in several clinical trial programs over the past few years (EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58). Their results showed a significant reduction in cardiovascular morbidity and mortality in these patients. The most promising effect of this new drug group was on the risk of hospitalization for heart failure. Regardless of the presence of other cardiovascular and other risk factors, this risk decreased by 37%. The effect was evident from the first month of observation and persisted throughout the study period. In addition to the effect on heart function, study results indicated a decrease in the incidence of chronic renal failure. Several other ongoing studies aim to further specify the groups of patients who will benefit the most from using gliflozins and to compare their efficacy and safety with other antidiabetic medications.

Hemodynamic and Metabolic Effects of Gliflozins

By increasing the excretion of sodium and water, preload is reduced, improving the function of heart chambers and hemodynamic status. Reducing plasma volume increases hematocrit and hemoglobin concentration in the blood, improving conditions for oxygen delivery to target tissues. According to some authors, the proportion of water expelled is higher with gliflozins than with so-called loop diuretics, which also result in the excretion of large amounts of electrolytes. Gliflozins primarily reduce interstitial fluid volume and therefore have less impact on blood volume, arterial filling, and organ perfusion. They can also lower serum uric acid levels without adversely affecting potassium homeostasis and glucose tolerance as is the case with other diuretics. Gliflozins lower blood pressure values by approximately 4/1.6 mmHg and improve endothelial function of blood vessels. The impact of gliflozins on cardiomyocyte metabolism is mainly represented by increased ATP production through the oxidation of fatty acids and glucose and ketogenesis.

Reducing glycemia is also crucial for reducing oxidative stress, resulting in fewer reactive oxygen species, preventing fibrosis and myocardial remodeling, improving coronary microcirculation function, and increasing myocardial contractility. Liver function and lipid profiles also improve, thus preventing liver steatosis. The anti-inflammatory and antifibrotic effects of gliflozins also have a positive impact on kidney function. Increased sodium excretion causes feedback vasoconstriction in the afferent arterioles, thus reducing blood pressure within the glomeruli.

Conclusion

The study results helped to clarify the connection between the occurrence of DM2 and cardiovascular disease. In addition to the usual approach and efforts for an ideal glycemic profile, attention must undoubtedly be given to reducing the incidence of cardiovascular complications. Due to their properties and safe use, gliflozins are becoming a very promising group of new oral antidiabetics.

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Source: Santos-Ferreira D., Gonçalves-Teixeira P., Fontes-Carvalho R. SGLT-2 inhibitors in heart failure and type-2 diabetes: hitting two birds with one stone? Cardiology 2020; 145: 311−320, doi: 10.1159/000504694.