How do Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors decrease preload and afterload in patients with type 2 diabetes?

From the Guidelines

SGLT2 inhibitors decrease both preload and afterload in type 2 diabetes patients through multiple mechanisms related to their unique pharmacological actions, primarily by promoting osmotic diuresis and natriuresis, which decreases plasma volume and lowers filling pressures in the heart, as well as by lowering blood pressure and improving vascular function 1.

Mechanisms of Action

The medications, including empagliflozin, dapagliflozin, and canagliflozin, reduce preload by:

• Promoting osmotic diuresis and natriuresis, which decreases plasma volume and lowers filling pressures in the heart
• Blocking glucose reabsorption in the proximal tubule, leading to increased urinary glucose and sodium excretion without activating the sympathetic nervous system They reduce afterload by:
• Lowering blood pressure through their natriuretic effects
• Improving vascular function, decreasing arterial stiffness, and enhancing endothelial function, which reduces systemic vascular resistance

Clinical Benefits

These hemodynamic improvements explain why SGLT2 inhibitors have demonstrated significant cardiovascular benefits in clinical trials, including:

• Reduced heart failure hospitalizations
• Reduced cardiovascular mortality in patients with type 2 diabetes
• Reduced progression of chronic kidney disease As noted in the EMPA-REG OUTCOME trial, empagliflozin reduced MACEs by 14% and cardiovascular mortality by 38% 1.

Recommendations

The use of SGLT2 inhibitors is recommended to reduce the risk of major adverse cardiovascular events and/or heart failure hospitalization in patients with type 2 diabetes and established ASCVD, multiple ASCVD risk factors, or diabetic kidney disease 1. Key points to consider:

• SGLT2 inhibitors have been shown to reduce the risk of heart failure hospitalization and progression of kidney disease
• They should be considered as part of a comprehensive treatment plan for patients with type 2 diabetes and cardiovascular disease or risk factors
• The choice of SGLT2 inhibitor should be based on individual patient characteristics and clinical trial evidence 1.

From the FDA Drug Label

By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE) Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure.

The SGLT2 inhibitors, such as canagliflozin, decrease preload and afterload by:

• Increasing urinary glucose excretion, which leads to a decrease in blood volume and subsequently reduces preload.
• Increasing the delivery of sodium to the distal tubule, which increases tubuloglomerular feedback and reduces intraglomerular pressure, leading to a decrease in afterload. However, the exact mechanism of how SGLT2 inhibitors decrease afterload is not fully explained in the provided drug label. 2

From the Research

Mechanism of SGLT2 Inhibitors

• SGLT2 inhibitors work by reducing the reabsorption of glucose in the kidneys, leading to increased glucose excretion in the urine 3.
• This mechanism also leads to a reduction in plasma volume, which contributes to decreases in systolic and diastolic blood pressures 3.
• The reduction in plasma volume is a result of the osmotic diuretic effect of SGLT2 inhibitors, which increases urine production and leads to a decrease in blood volume 3.

Effect on Preload

• Preload is decreased due to the reduction in plasma volume, which leads to a decrease in cardiac preload 3.
• The decrease in cardiac preload reduces the amount of blood returning to the heart, which can lead to a decrease in cardiac output 3.
• SGLT2 inhibitors have been shown to reduce systolic blood pressure by 4-6 mmHg and diastolic blood pressure by 1-2 mmHg, which can also contribute to a decrease in preload 3.

Effect on Afterload

• Afterload is decreased due to the reduction in blood pressure, which leads to a decrease in the resistance against which the heart must pump blood 3.
• The decrease in afterload can lead to an increase in cardiac output, as the heart does not have to work as hard to pump blood 3.
• SGLT2 inhibitors have been shown to reduce blood pressure and improve cardiovascular outcomes, including a reduction in the risk of heart failure hospitalizations 4.

Clinical Implications

• SGLT2 inhibitors have been shown to have beneficial effects on both glycemic and nonglycemic outcomes, including reductions in body weight, blood pressure, and cardiovascular risk 5, 4, 6.
• The use of SGLT2 inhibitors may be particularly beneficial in patients with type 2 diabetes who have established cardiovascular disease or are at high risk of cardiovascular events 4.
• However, SGLT2 inhibitors are associated with an increased risk of genital mycotic infections and other adverse events, and should be used with caution in certain patient populations 7, 6.