Examples of SGLT2 Inhibitors
The main SGLT2 inhibitors currently available include empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin. 1, 2
Mechanism of Action
- SGLT2 inhibitors work by blocking the sodium-glucose co-transporter 2 proteins in the proximal renal tubules, reducing glucose reabsorption and increasing urinary glucose excretion 2
- These medications function by inhibiting approximately 90% of urinary glucose reabsorption, leading to glucosuria that is more pronounced in hyperglycemic states 1
- SGLT2 inhibitors act independently of insulin secretion or action, making them effective regardless of diabetes duration or beta-cell function 2, 3
- The glucosuric effect diminishes significantly as blood glucose normalizes, which contributes to their low risk of hypoglycemia when used as monotherapy 1, 2
Available SGLT2 Inhibitors
FDA-Approved SGLT2 Inhibitors
- Empagliflozin (Jardiance): An orally-active SGLT2 inhibitor with the chemical name D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S) 4
- Dapagliflozin (Farxiga): Chemically described as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1) 5
- Canagliflozin (Invokana): One of the first approved SGLT2 inhibitors with demonstrated cardiovascular benefits 1, 6
- Ertugliflozin (Steglatro): A more recently approved SGLT2 inhibitor also shown to reduce HbA1c levels 2, 7
Clinical Benefits
- SGLT2 inhibitors reduce HbA1c levels by approximately 0.5% to 1.0% 2, 6
- They promote weight loss of 1.5 to 3.5 kg due to caloric loss through glucosuria 2, 8
- These medications lower systolic blood pressure by 3 to 5 mmHg 2, 8
- Empagliflozin and canagliflozin have demonstrated reduction in major adverse cardiovascular events (MACE) and heart failure hospitalization 1
- Empagliflozin specifically has been FDA-approved to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease 1
- SGLT2 inhibitors show renoprotective effects with reduced progression of diabetic kidney disease 2, 1
Pharmacokinetic Properties
- These medications share excellent oral bioavailability and long half-lives allowing for once-daily administration 9
- They have low accumulation indices and renal clearance 9
- SGLT2 inhibitors generally lack active metabolites and have limited propensity for drug-drug interactions 9
Safety Considerations
- Common adverse effects include genital mycotic infections and urinary tract infections, though these are generally mild to moderate in intensity 6, 10
- SGLT2 inhibitors have a low risk of hypoglycemia when used as monotherapy 1, 2
- Dose adjustments are not typically required for patients with mild renal impairment 9, 10
- Dapagliflozin is not recommended for use in patients with eGFR <60 mL/min/1.73m², while canagliflozin is not recommended for those with eGFR <45 mL/min/1.73m² 10
- KDIGO guidelines recommend SGLT2 inhibitors for adults with CKD with eGFR ≥20 ml/min per 1.73 m² with urine albumin-to-creatinine ratio ≥200 mg/g, or for those with heart failure, irrespective of albuminuria level 1
Clinical Applications
- SGLT2 inhibitors can be used as monotherapy or as an add-on to other antidiabetic medications 8, 10
- They are particularly beneficial for patients with type 2 diabetes who also have established cardiovascular disease or chronic kidney disease 1
- These medications can be used at various stages of diabetes due to their insulin-independent mechanism 3
- Emerging research suggests potential benefits in heart failure with reduced ejection fraction, regardless of diabetes status 7