What about Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

From the Guidelines

SGLT2 inhibitors are recommended for patients with type 2 diabetes and chronic kidney disease (CKD) with an estimated glomerular filtration rate (eGFR) ≥20 ml/min per 1.73 m² for kidney and cardiovascular protection.

Benefits of SGLT2 Inhibitors

• They have been shown to decrease all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke in individuals at high risk 1.
• SGLT2 inhibitors also have a positive effect on glucose control, with a greater reduction of HbA1c compared to other oral anti-hyperglycemic agents 1.
• They have been found to reduce the risk of major adverse cardiovascular events, renal events, and hospitalization rates for heart failure 1.

Usage and Precautions

• The choice of an SGLT2 inhibitor should prioritize agents with documented kidney or cardiovascular benefits and take eGFR into account 1.
• It is reasonable to withhold SGLT2 inhibitors during times of prolonged fasting, surgery, or critical medical illness, and to consider decreasing thiazide or loop diuretic dosages before commencement of SGLT2 inhibitor treatment 1.
• A reversible decrease in eGFR with commencement of SGLT2 inhibitor treatment may occur, but is generally not an indication to discontinue therapy 1.
• SGLT2 inhibitors can be used in patients with CKD, but should be administered with caution in patients with renal insufficiency (GFR < 45 mL/min/1.73 m²) 1.

Available SGLT2 Inhibitors

• Dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, and sotagliflozin are currently available SGLT2 inhibitors, which can be used in monotherapy or in addition to metformin 1.
• These medications have been shown to have beneficial effects on cardiovascular outcomes, including reduced mortality and hospitalization for heart failure, in patients with and without diabetes 1.

From the Research

Mechanisms of SGLT2 Inhibitors

• SGLT2 inhibitors are effective antidiabetic therapies that improve glycaemic control, reduce body mass and blood pressure, and have cardiovascular and renal benefits 2
• The possible mechanisms of benefit include early natriuresis, reduction in plasma volume, improved vascular function, and changes in tissue sodium handling 2
• Additional mechanisms may include reduction in adipose tissue-mediated inflammation, shift towards ketone bodies as metabolic substrate, reduced oxidative stress, and lowered serum uric acid level 2

Benefits of SGLT2 Inhibitors

• SGLT2 inhibitors have been shown to decrease hypertension, acute cardiac failure, and bradycardia in the cardiovascular system 3
• They also have benefits in the pulmonary system, including aid with acute pulmonary edema, asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) 3
• SGLT2 inhibitors may also affect the central nervous system, reducing reactive oxygen species, blood-brain barrier leakage, microglia burden, and acetylcholinesterase levels 3
• They have been shown to assist with non-alcoholic fatty liver disease, hepatotoxicity, and weight loss in the liver, and with diabetes and hyperglycemia in the pancreas 3, 4
• SGLT2 inhibitors may also aid in decreasing nephrotoxicity and stopping the progression of the glomerular filtration rate (GFR) decrease 3

Risks and Side Effects of SGLT2 Inhibitors

• SGLT2 inhibitors have notable adverse effects, including urinary tract infections, dehydration, orthostatic hypotension, postural dizziness, syncope, hypotension, hyperkalemia-induced cardiac arrest, and pancreatitis 3
• They may also cause genital tract infections, lower leg amputations, electrolyte disturbances, and bone fractures 4

Off-Target Effects of SGLT2 Inhibitors

• SGLT2 inhibitors may have off-target effects, including actions on sodium transporters and pathways not directly linked to tubular sodium handling 5
• These effects may contribute to the renal and cardiovascular benefits associated with SGLT2 inhibitors, but the evidence is not yet conclusive 5
• Further studies are needed to investigate the long-term effects of SGLT2 inhibitors on sodium balance and the pathways through which the natriuretic effect is expressed 5