Role of SGLT2 Inhibitors in Type 2 Diabetes Management
SGLT2 inhibitors should be considered a preferred second-line therapy after metformin for patients with type 2 diabetes, particularly for those with established cardiovascular disease, heart failure, or chronic kidney disease due to their proven benefits in reducing mortality, cardiovascular events, and renal disease progression. 1, 2
Mechanism of Action
SGLT2 inhibitors work through a unique insulin-independent mechanism:
- Inhibit sodium-glucose cotransporter 2 in the proximal renal tubules 3
- Reduce reabsorption of filtered glucose, lowering the renal threshold for glucose
- Increase urinary glucose excretion
- Deliver sodium to the distal tubule, increasing tubuloglomerular feedback and reducing intraglomerular pressure 3
- Promote diuretic and natriuretic effects, reducing preload and afterload 2
Clinical Benefits Beyond Glycemic Control
Cardiovascular Benefits
- Reduce all-cause mortality compared to usual care (high certainty of evidence) 1
- Reduce major adverse cardiovascular events (MACE) by 14% (moderate to high certainty of evidence) 1, 2
- Reduce heart failure hospitalizations by 27-35% 2
- Empagliflozin specifically reduces cardiovascular death by 38% (HR: 0.62; 95% CI: 0.49-0.77) 2
Renal Benefits
- Reduce progression of chronic kidney disease (high certainty of evidence) 1
- Reduce the risk of end-stage kidney disease, doubling of serum creatinine 3
- Slow GFR loss through mechanisms independent of glycemia 1
- Reduce oxidative stress in the kidney by >50% and blunt increases in angiotensinogen 1
Other Benefits
- Reduce serious adverse events and severe hypoglycemia compared to insulin or sulfonylureas (high certainty of evidence) 1
- Promote weight loss and blood pressure reduction 4, 5
- Improve lipid profile and reduce hyperuricemia 5
Patient Selection
SGLT2 inhibitors are particularly beneficial for patients with:
- Established cardiovascular disease 1, 2
- Heart failure (especially with reduced ejection fraction) 2
- Chronic kidney disease 1, 2
- Need for weight loss or blood pressure reduction 2
Dosing Considerations Based on Renal Function
| SGLT2 Inhibitor | Standard Dosing | eGFR 45-59 mL/min/1.73m² | eGFR 30-44 mL/min/1.73m² | eGFR <30 mL/min/1.73m² |
|---|---|---|---|---|
| Canagliflozin | 100 mg daily | 100 mg daily max | Not for glycemic control | Not recommended |
| Dapagliflozin | 10 mg daily | 10 mg daily | Not for glycemic control | Contraindicated |
| Empagliflozin | 10 mg daily | 10 mg daily | Not for glycemic control | Not recommended |
Note: While not recommended for glycemic control at lower eGFR levels, some SGLT2 inhibitors may still be used for cardiovascular and renal benefits in patients with advanced CKD. 1, 2
Safety Considerations
Common Adverse Effects
- Genitourinary infections 4, 5
- Volume depletion/dehydration 2
- Euglycemic diabetic ketoacidosis (rare but serious) 5
Monitoring Requirements
- Regular assessment of volume status, especially in elderly patients 2
- Renal function monitoring, particularly in patients with baseline renal impairment 2
- Signs/symptoms of ketoacidosis 2
Contraindications and Precautions
- Severe renal impairment (eGFR <30 mL/min/1.73m²) for initiating therapy 2
- History of serious hypersensitivity to SGLT2 inhibitors 2
- Caution in elderly patients at risk for volume depletion 2
- Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 2
Comparative Effectiveness
- SGLT2 inhibitors and GLP-1 receptor agonists both reduce all-cause mortality and MACE compared to usual care 1
- SGLT2 inhibitors are superior to DPP4 inhibitors, insulin, and sulfonylureas for reducing mortality and MACE 1
- SGLT2 inhibitors are particularly effective for reducing heart failure hospitalization and CKD progression 1
- GLP-1 receptor agonists are more effective for reducing stroke 1
Practical Prescribing Algorithm
- First-line therapy: Metformin (unless contraindicated)
- Add SGLT2 inhibitor as second-line if patient has:
- Established cardiovascular disease
- Heart failure
- Chronic kidney disease with albuminuria
- Need for weight loss or blood pressure reduction
- Consider GLP-1 receptor agonist instead if:
- Patient has high stroke risk
- SGLT2 inhibitors are contraindicated
- eGFR <30 mL/min/1.73m²
- Adjust other medications when adding SGLT2 inhibitor:
- Consider reducing insulin or sulfonylurea doses to prevent hypoglycemia 1
SGLT2 inhibitors have transformed the management of type 2 diabetes by providing benefits beyond glycemic control, making them a cornerstone therapy for patients with cardiorenal complications.