What is the comprehensive overview of Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

From the Guidelines

SGLT2 inhibitors are a crucial treatment approach for reducing cardiovascular disease and heart failure outcomes in people with diabetes, and should be used to prevent the development of incident heart failure in individuals with type 2 diabetes and increased cardiovascular risk or established cardiovascular disease. According to the most recent guidelines, people with type 2 diabetes and established ASCVD or established kidney disease should be treated with an SGLT2 inhibitor as part of their comprehensive cardiovascular risk reduction and/or glucose-lowering treatment plans 1. The benefits of SGLT2 inhibitors in reducing heart failure hospitalizations and cardiovascular mortality have been consistently demonstrated in several studies, including the EMPA-REG OUTCOME trial, the CANVAS Program, and the DAPA-HF study 1.

Some key points to consider when using SGLT2 inhibitors include:

• They work by preventing glucose reabsorption in the proximal tubule of the kidney, causing glucose to be excreted in urine, which lowers blood sugar levels independent of insulin.
• Common SGLT2 inhibitors include empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana), and ertugliflozin (Steglatro), typically dosed once daily.
• Side effects include genital mycotic infections, urinary tract infections, volume depletion, and rare but serious diabetic ketoacidosis.
• These medications should be used cautiously in patients with renal impairment, and are contraindicated during pregnancy and breastfeeding.
• Patients should be advised to maintain adequate hydration, practice good genital hygiene, temporarily discontinue during acute illness or surgical procedures, and monitor for symptoms of ketoacidosis, especially if insulin doses are reduced.

The most recent guidelines recommend using SGLT2 inhibitors with demonstrated cardiovascular benefit to reduce the risk of major adverse cardiovascular events and/or heart failure hospitalization in people with type 2 diabetes and established ASCVD, multiple ASCVD risk factors, or chronic kidney disease (CKD) 1. In people with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD, combined therapy with an SGLT2 inhibitor with demonstrated cardiovascular benefit and a GLP-1 RA with demonstrated cardiovascular benefit may be considered for additive reduction of the risk of adverse cardiovascular and kidney events. Overall, SGLT2 inhibitors are a valuable treatment option for reducing morbidity, mortality, and improving quality of life in people with diabetes.

From the FDA Drug Label

1. 1 Mechanism of Action Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2 By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. INDICATIONS AND USAGE JARDIANCE is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.

SGLT2 Inhibitors Overview

• SGLT2 inhibitors, such as empagliflozin, work by inhibiting the sodium-glucose co-transporter 2 (SGLT2) in the kidneys, reducing renal reabsorption of filtered glucose and increasing urinary glucose excretion.
• Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• It is also indicated to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease 2, 2.
• The mechanism of action and indications of empagliflozin are well-established, but the drug label does not provide a comprehensive overview of SGLT2 inhibitors as a class.

From the Research

SGLT2 Inhibitors: Mechanism and Benefits

• SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, have been shown to reduce hyperglycemia in patients with type 2 diabetes 3.
• These agents also have positive effects on nonglycemic variables, including reductions in body weight and blood pressure, which may confer additional health benefits 3, 4.
• SGLT2 inhibitors have been associated with renal-protecting benefits and a substantial reduction in major adverse cardiovascular outcomes, as demonstrated in the EMPA-REG OUTCOME trial 3, 4.

Clinical Implications and Recommendations

• SGLT2 inhibitors should be considered in patients with established cardiovascular disease, usually in combination with other glucose-lowering medications, when satisfactory glycemic control has not been achieved 4.
• The dose of insulin or sulfonylureas may need to be lowered when used with SGLT2 inhibitors to reduce the risk of hypoglycemia 4.
• A clinical practice guideline recommends the use of SGLT2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes, with risk-stratified recommendations 5.

Cost-Effectiveness and Comparisons

• Empagliflozin has been shown to be cost-effective compared to canagliflozin, dapagliflozin, and standard of care in patients with type 2 diabetes and established cardiovascular disease 6.
• A comparison of SGLT2 inhibitors and GLP-1 receptor agonists found that these agents generally reduce overall death and incidence of myocardial infarctions, and end-stage kidney disease or kidney failure 5.

Adverse Events and Considerations

• SGLT2 inhibitors are associated with an increased risk of genital mycotic infections, as well as the potential risk for serious adverse events such as dehydration, development of diabetic ketoacidosis, serious urinary tract infections, and bone fractures 3, 4.
• Genitourinary infections can occur with SGLT2 inhibitors in a small proportion of people, and it may be prudent to use empagliflozin rather than canagliflozin in people with osteoporosis or prior amputation 4.