From the Guidelines
SGLT2 inhibitors improve heart failure primarily by promoting sodium and glucose excretion in the urine, which leads to several beneficial cardiovascular effects, as demonstrated in the most recent study published in 2025 1. The main mechanisms are:
- Reduced fluid overload: By increasing urine output, SGLT2 inhibitors decrease blood volume and preload on the heart, reducing congestion and edema.
- Blood pressure lowering: The diuretic effect and sodium loss lead to a modest reduction in blood pressure, easing the workload on the heart.
- Improved cardiac metabolism: By shifting the heart's energy source from glucose to ketones and fatty acids, SGLT2 inhibitors may enhance cardiac efficiency.
- Reduced inflammation and fibrosis: These drugs appear to have anti-inflammatory effects and may reduce cardiac fibrosis, improving heart function.
- Decreased sympathetic nervous system activity: SGLT2 inhibitors may reduce overactivation of the sympathetic nervous system, which is often elevated in heart failure. Common SGLT2 inhibitors used for heart failure include dapagliflozin (10 mg daily) and empagliflozin (10 mg daily), which have been shown to reduce hospitalization for heart failure by 33-35% in people with type 2 diabetes and increased cardiovascular risk or established cardiovascular disease 1. These medications can be used in patients with heart failure regardless of whether they have diabetes, and have been found to reduce cardiovascular mortality and hospitalization for heart failure by 17% in the DAPA-HF study 1. Patients should be monitored for potential side effects such as genital infections and volume depletion, especially when initiating therapy, and the risk of diabetic ketoacidosis should be considered, particularly in patients with type 1 diabetes or those with a history of ketoacidosis 1. Understanding these mechanisms helps explain why SGLT2 inhibitors have shown significant benefits in reducing hospitalizations and mortality in heart failure patients, making them an important addition to standard heart failure therapy.
From the FDA Drug Label
By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.
The mechanism by which SGLT2 inhibitors, such as dapagliflozin, improve heart failure is by:
- Lowering pre- and afterload of the heart
- Downregulating sympathetic activity
- Decreasing intraglomerular pressure through increased tubuloglomerular feedback, which occurs as a result of:
- Reduced sodium reabsorption
- Increased delivery of sodium to the distal tubule 2
From the Research
Mechanism of SGLT2 Inhibitors in Improving Heart Failure
- The mechanisms by which SGLT2 inhibitors improve cardiovascular outcome appear not to be glucose-lowering or anti-atherosclerotic effects, but rather hemodynamic effects through osmotic diuresis and natriuresis 3
- SGLT2 inhibitors lower glycated hemoglobin (HbA1c) by 0.6-0.8% (6-8 mmol/mol) without increasing the risk of hypoglycemia and induce weight loss and improve various metabolic parameters including blood pressure, lipid profile and hyperuricemia 3
- Decrease in B-type natriuretic peptide and increase in plasma renin activity were significant in each group of SGLT2 inhibitors 4
- Plasma aldosterone concentration was significantly increased in the empagliflozin and canagliflozin groups, but not in the dapagliflozin group 4
- Plasma noradrenaline was significantly increased in the empagliflozin group, but not in the canagliflozin and dapagliflozin groups 4
Key Aspects of SGLT2 Inhibitors
- SGLT2 inhibitors provide significant beneficial effects on cardiorenal outcomes, including heart failure, regardless of type 2 diabetes status 5
- The benefits of SGLT2 inhibitors on clinical outcomes outweigh the risks, and recognition of this by physicians will result in the integration of SGLT2 inhibitors into clinical practice and lead to improved patient care and outcomes 5
- Recent randomized clinical trials have demonstrated important cardioprotective effects of SGLT2 inhibitors, independent of the presence of diabetes 6
- SGLT2 inhibitors have shown to have a beneficial effect on lowering cardiovascular death and lowering hospital admission, and have beneficial renal outcomes 7
Clinical Evidence
- Seven large-scale randomized controlled trials examined the benefit of SGLT2 inhibitors in patients with cardiovascular disease, irrespective of their diabetic status, and showed a beneficial effect in reducing cardiovascular mortality and morbidity in patients with type 2 diabetes mellitus 7
- The studies combined had a total sample population of 55,433, and the mean follow-up time was about four years 7
- SGLT2 inhibitors have been shown to improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes, especially in those with prior cardiovascular events, heart failure, or chronic kidney disease 3