Mechanisms of Cardioprotective Effects of SGLT2 Inhibitors

SGLT2i – Substances with a Unique Mechanism of Action

By inhibiting SGLT2, the reabsorption of glucose in the proximal tubule of the kidneys is blocked. A significant portion of the filtered glucose is thus lost through the urine, resulting in lowered blood glucose levels and thereby reducing energy loss. The feared risk of hypoglycemia is very low with these medications, as their effect is dependent on the glucose level – the higher the glucose level, the greater the effect of SGLT2i.

Renoprotection and Cardioprotection

Inhibiting SGLT2 in the proximal tubule of the kidneys has a significant glycosuric and natriuretic effect. Natriuresis influences, among other things, the tubuloglomerular feedback, and the resulting vasoconstriction of the afferent arterioles helps reduce intraglomerular hypertension. This process is one of the bases of the long-term renoprotective influence of SGLT2i in patients with T2DM.

Osmotic diuresis leads to a reduction in sodium content within body tissues and also – due to water loss – to hemoconcentration. The reduction in plasma volume and the increase in red blood cell mass have a very positive effect on myocardial function in patients with heart failure. Hence, SGLT2 inhibitors contribute to the improvement of diastolic filling of the left ventricle. Studies conducted so far have demonstrated this protective mechanism only with SGLT2, not with other medications that also have a diuretic effect. Other studies have suggested that the change in plasma volume may also lead to a reduction in blood pressure and improvement in endothelial function.

Improvement of Myocardial Energy Metabolism

SGLT2 inhibitors also contribute to improving myocardial energy metabolism. The metabolic flexibility of the cardiac muscle is somewhat limited, especially in patients with T2DM. This is due to the increased utilization of free fatty acids as a substrate for ATP synthesis. Intermediates of these reactions can lead to lipotoxicity, affect the function of the sarcoplasmic reticulum, and promote the development of myocardial diastolic dysfunction.

SGLT2i moderately increases the production of β-hydroxybutyrate. According to some hypotheses, this molecule is preferentially used by the myocardium as an energy source. Additionally, ketone bodies may improve the mechanical function of the cardiac muscle. With increased consumption of ketone bodies, the utilization of glucose and lactate production in the myocardium may decrease. Interfering with glucose and ketone body metabolism alters acetyl-CoA levels, which according to some studies, can lead to reduced hyperacetylation of mitochondrial enzymes and thus increased ATP production.

Impact on the Na⁺/H⁺ Exchanger

Recent studies have indicated a possible direct impact of SGLT2 inhibitors on the Na⁺/H⁺ antiporter NHE1 located in the myocardium. Increased activation of NHE1 was observed in experimental models of heart failure. Inhibition of this antiporter leads to reduced cytoplasmic sodium and calcium content, while simultaneously increasing calcium levels in mitochondria. A similar type of Na⁺/H⁺ pump (NHE3) is located in the proximal tubules of the kidneys. Their activity is also increased in patients with heart failure. Inhibition of NHE3 increases natriuresis, supporting the cardioprotective effect of SGLT2i.

Acting Against the Development of Fibrosis

Structural remodeling of the myocardium is very often associated with chronic heart failure. According to recently discovered experimental data, SGLT2i may significantly influence myocardial fibrosis development. One possible pathway is the activation of M₂ macrophages, inhibition of myofibroblast differentiation, and the resulting suppression of collagen synthesis.

Further Research Needed to Confirm Hypotheses

Despite the very promising findings regarding the protective effects of SGLT2 inhibitors, many biological and metabolic mechanisms remain unconfirmed. Another question is whether they can reverse already existing structural and functional changes in the myocardium. Answers may be provided by ongoing or future studies. What is certain, however, is that the use of SGLT2i will help improve treatment outcomes in terms of cardiovascular morbidity and mortality in patients with T2DM.

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Sources:
1. Verma S., McMurray J. J. V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018; 61 (10): 2108–2117, doi: 10.1007/s00125-018-4670-7.
2. Švihovec J., Bultas J., Anzenbacher P. et al. (eds.). Pharmacology. Grada, Prague, 2018.