What are the pharmacokinetics of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors?

Pharmacokinetics of SGLT2 Inhibitors

SGLT2 inhibitors have excellent pharmacokinetic profiles characterized by high oral bioavailability, long half-lives allowing once-daily dosing for most agents, minimal renal clearance, and limited drug-drug interactions, making them effective and convenient medications for diabetes management.

Mechanism of Action

SGLT2 inhibitors work through a unique insulin-independent mechanism:

• They inhibit sodium-glucose cotransporter 2 (SGLT2) proteins expressed in the proximal convoluted tubule of the kidneys 1, 2
• By inhibiting SGLT2, they reduce reabsorption of filtered glucose and lower the renal threshold for glucose, thereby increasing urinary glucose excretion 2, 3
• They also reduce sodium reabsorption and increase delivery of sodium to the distal tubule, which may influence several physiological functions 2
• This mechanism leads to reduced hyperglycemia while improving both insulin secretion by β-cells and peripheral insulin sensitivity 1

Absorption

• Maximum plasma concentration (Cmax) is usually attained within 1-2 hours under fasting state 2, 3
• Absolute oral bioavailability is excellent (approximately 65-78%) 2, 3
• Food effects:
  • High-fat meals may decrease Cmax by up to 50% and prolong Tmax by approximately 1 hour for dapagliflozin
  • However, food does not significantly alter overall drug exposure (AUC)
  • SGLT2 inhibitors can be administered with or without food 2, 4

Distribution

• SGLT2 inhibitors are highly protein-bound (approximately 91% for dapagliflozin) 2
• Protein binding is not altered in patients with renal or hepatic impairment 2

Metabolism

• Primary metabolism varies by agent:
  • Dapagliflozin is primarily metabolized by UGT1A9 with CYP-mediated metabolism as a minor pathway 2
  • Dapagliflozin is extensively metabolized to inactive metabolites, primarily dapagliflozin 3-O-glucuronide 2
• Most SGLT2 inhibitors do not have active metabolites that contribute significantly to their glucose-lowering effects 5

Elimination

• Half-life varies significantly between agents:
  • Dapagliflozin: approximately 12.9 hours 2
  • Canagliflozin: 10.6-13.1 hours for 100-300 mg doses 3
  • Ertugliflozin: approximately 16 hours 6
  • Remogliflozin: 2-4 hours 6
  • Sergliflozin: 1-1.5 hours 6
• Elimination pathways:
  • Primarily renal excretion for most agents
  • For dapagliflozin, following a single dose, 75% is excreted in urine and 21% in feces 2
  • Less than 2% of dapagliflozin is excreted unchanged in urine 2

Pharmacodynamics

• Dose-dependent decreases in renal threshold for glucose (RTG) and increases in urinary glucose excretion are observed 3
• Maximal suppression of RTG over 24 hours is seen with 300 mg daily dose of canagliflozin, reducing RTG to approximately 70-90 mg/dL 3
• Urinary glucose excretion increases by approximately 70-100 g/day in patients with type 2 diabetes 1, 3
• Effects on urinary glucose excretion approach baseline within approximately 3 days after discontinuation 2, 3
• No clinically meaningful prolongation of QTc interval has been observed, even at supratherapeutic doses 2, 3

Special Populations

Renal Impairment

• Drug exposure increases when estimated glomerular filtration rate (eGFR) declines, but the relationship is not clear-cut and the amplitude is moderate 7
• Urinary glucose excretion steadily declines with reduction in eGFR, explaining lower glycemic efficacy in advanced kidney disease 7
• SGLT2 inhibitors should be used with caution in patients with renal insufficiency (eGFR < 45 mL/min/1.73 m²) 1
• Most SGLT2 inhibitors are not recommended for initiation when eGFR is below 45 mL/min/1.73 m² 1
• Recent evidence suggests cardiovascular and renal benefits may extend to patients with eGFR as low as 30 mL/min/1.73 m² 1, 4

Hepatic Impairment

• No clinically relevant changes in pharmacokinetic parameters have been observed in patients with mild to moderate hepatic impairment 5

Comparative Pharmacokinetics

Based on half-life values, SGLT2 inhibitors can be ranked as follows:

• Ertugliflozin (16 h) > Canagliflozin (10.6-13.1 h) > Dapagliflozin (12.9 h) > Remogliflozin (2-4 h) > Sergliflozin (1-1.5 h) 6

This explains why ertugliflozin, canagliflozin, and dapagliflozin are suitable for once-daily dosing, while agents with shorter half-lives may require more frequent administration 6

Drug-Drug Interactions

• SGLT2 inhibitors generally have a limited propensity for drug-drug interactions 5
• They can be used without regard to diabetes duration or β-cell function 1
• When adding SGLT2 inhibitors to insulin or sulfonylureas, consider reducing sulfonylurea dose by 50% and total daily insulin dose by approximately 20% to prevent hypoglycemia 4

Clinical Implications and Pitfalls

• Important caveat: When initiating SGLT2 inhibitors in patients on diuretics, consider reducing diuretic doses to prevent volume depletion 4
• Common pitfall: Monitor for euglycemic diabetic ketoacidosis, especially in patients with reduced carbohydrate intake or acute illness 4
• Safety consideration: Be vigilant for genital mycotic infections and urinary tract infections, which are common side effects 4, 5

SGLT2 inhibitors represent a significant advancement in diabetes management with their unique mechanism of action, favorable pharmacokinetic profile, and additional cardiovascular and renal benefits beyond glycemic control.