What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in the treatment of type 2 diabetes?

Role of SGLT2 Inhibitors in Type 2 Diabetes Management

SGLT2 inhibitors should be used as a preferred treatment option in type 2 diabetes patients with established cardiovascular disease, heart failure, or chronic kidney disease, regardless of baseline HbA1c levels, due to their proven benefits in reducing cardiovascular events, heart failure hospitalizations, and progression of kidney disease. 1

Mechanism of Action and Glycemic Effects

• SGLT2 inhibitors work by blocking sodium-glucose cotransporters in the proximal tubule of the kidney, reducing glucose reabsorption and increasing urinary glucose excretion 1
• They provide moderate glycemic control, lowering HbA1c by approximately 0.6-0.8%, with minimal risk of hypoglycemia unless used with insulin or insulin secretagogues 2
• The glucose-lowering effect is more pronounced in hyperglycemic states and diminishes as blood glucose normalizes 1

Cardiovascular Benefits

• SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) have demonstrated significant reductions in major adverse cardiovascular events (MACE) in patients with established cardiovascular disease 1
• For patients with type 2 diabetes and established atherosclerotic cardiovascular disease, SGLT2 inhibitors are recommended to reduce MACE, heart failure hospitalizations, and cardiovascular death 1
• Empagliflozin specifically has shown a 38% reduction in cardiovascular death and a 35% reduction in heart failure hospitalizations in the EMPA-REG OUTCOME trial 1
• The FDA has approved empagliflozin "to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease" 3

Heart Failure Benefits

• SGLT2 inhibitors are strongly recommended for patients with heart failure (particularly with reduced ejection fraction) to reduce hospitalizations for heart failure, MACE, and cardiovascular death 1
• These benefits appear to be independent of glucose-lowering effects and are likely related to hemodynamic effects through osmotic diuresis and natriuresis 2
• For patients with or without established atherosclerotic CVD but with heart failure with reduced ejection fraction (HFrEF, EF <45%), SGLT2 inhibitors provide the greatest level of evidence for benefit 1

Renal Benefits

• SGLT2 inhibitors are recommended to prevent progression of chronic kidney disease (CKD), reduce heart failure hospitalizations, MACE, and cardiovascular death in patients with type 2 diabetes and CKD 1
• They are particularly beneficial for patients with eGFR 30-60 mL/min/1.73 m² and/or albuminuria (especially UACR >300 mg/g) 1
• Canagliflozin has specific FDA approval "to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria" 4
• Note that the glycemic benefits of SGLT2 inhibitors are reduced when eGFR is <45 mL/min/1.73 m² 1

Patient Selection Algorithm

1. First-line consideration: For patients with type 2 diabetes and established cardiovascular disease, heart failure (especially HFrEF), or CKD with albuminuria, SGLT2 inhibitors should be considered regardless of baseline HbA1c 1

2. Second-line consideration: For patients without established cardiovascular or kidney disease but with multiple risk factors, SGLT2 inhibitors can be considered as part of the treatment regimen 1

3. Special populations:

   • For patients with eGFR <30 mL/min/1.73 m², GLP-1 receptor agonists are preferred over SGLT2 inhibitors for glycemic management 1
   • For patients with foot ulcers or at high risk for amputation, careful shared decision-making is required before initiating SGLT2 inhibitors 1

Safety Considerations

• Common adverse effects include genitourinary tract infections, particularly genital mycotic infections 2, 5
• Rare but serious adverse events include euglycemic diabetic ketoacidosis, which requires careful monitoring 2
• Canagliflozin has been associated with increased risk of lower extremity amputation and bone fractures in some studies; empagliflozin may be preferred in patients with osteoporosis or prior amputation 6
• SGLT2 inhibitors should be used with caution in elderly patients and those at risk for volume depletion 3
• When initiating SGLT2 inhibitors in patients already on insulin or sulfonylureas, consider reducing the dose of these medications to minimize hypoglycemia risk 6

Dosing and Renal Function Considerations

• For empagliflozin: Do not initiate if eGFR is below 45 mL/min/1.73 m² and discontinue if eGFR falls persistently below this threshold 3
• For canagliflozin: Not recommended for glycemic control in patients with eGFR less than 30 mL/min/1.73 m² 4
• Assess renal function before initiating therapy and monitor periodically during treatment 3

SGLT2 inhibitors represent a significant advancement in type 2 diabetes management, offering benefits beyond glycemic control by addressing cardiovascular and renal outcomes that are critical determinants of morbidity and mortality in this population.