SGLT2 Inhibitors in Type 2 Diabetes with eGFR ≥45 mL/min/1.73 m²
Dosing
Start dapagliflozin 10 mg once daily, empagliflozin 10 mg once daily, or canagliflozin 100 mg once daily—these are fixed doses that require no titration for cardiovascular or renal protection. 1, 2
- For glycemic control alone (if eGFR ≥45 mL/min/1.73 m²): dapagliflozin may be started at 5 mg once daily and increased to 10 mg if additional glucose lowering is needed, though the 10 mg dose is standard for all indications. 1
- No dose adjustment is required based on age, hepatic impairment, or eGFR levels ≥45 mL/min/1.73 m². 3
- All three agents with proven cardiovascular and renal benefits (canagliflozin, dapagliflozin, empagliflozin) should be prioritized over other SGLT2 inhibitors lacking outcome trial data. 4
Contraindications
- Absolute contraindications: History of serious hypersensitivity reaction to the specific SGLT2 inhibitor, dialysis or end-stage renal disease, and type 1 diabetes mellitus. 2, 3
- Do not initiate dapagliflozin if eGFR <25 mL/min/1.73 m² (though it may be continued if already prescribed). 1, 3
- Withhold at least 3 days before major surgery or procedures requiring prolonged fasting to prevent euglycemic diabetic ketoacidosis. 4, 1
- Temporarily discontinue during acute illness with reduced oral intake, fever, vomiting, or diarrhea. 4, 1
Adverse Effects
- Genital mycotic infections occur in approximately 6% of patients (versus 1% with placebo); counsel on daily hygiene to mitigate risk. 4, 1, 2
- Urinary tract infections are more common; hygienic counseling is recommended. 4
- Euglycemic diabetic ketoacidosis is rare but serious—warn patients to seek immediate care for malaise, nausea, vomiting, or abdominal pain even when blood glucose is normal. 4, 1
- Volume depletion and hypotension may occur, particularly in elderly patients (≥65 years), those on loop diuretics, or those with baseline systolic BP <110 mmHg. 4, 3
- Reversible eGFR decline of 3–5 mL/min/1.73 m² typically occurs within the first 2–4 weeks; this hemodynamic dip should not prompt discontinuation. 4, 1
- Hypoglycemia risk increases when combined with insulin or sulfonylureas—reduce insulin dose by ~20% and discontinue or reduce sulfonylureas when starting an SGLT2 inhibitor. 4, 1, 2
- Bone fractures were reported in one trial of patients with eGFR 30–60 mL/min/1.73 m² (13 patients on dapagliflozin versus none on placebo), though this has not been consistently observed. 3
Monitoring Parameters
- Check eGFR before initiation and recheck 1–2 weeks after starting therapy to document the expected early dip. 4, 1
- Reassess eGFR every 3–6 months if eGFR is 45–59 mL/min/1.73 m², or annually if eGFR ≥60 mL/min/1.73 m². 1
- Assess volume status before initiation and at follow-up visits, especially in elderly patients or those on concurrent diuretics. 4, 1, 2
- Monitor blood glucose closely for the first 2–4 weeks if the patient is on insulin or sulfonylureas. 1
- Do not discontinue therapy solely because eGFR falls below 45 mL/min/1.73 m²—cardiovascular and renal benefits persist even when glucose-lowering efficacy declines. 4, 1
- Lipid panel, blood pressure, and body weight should be monitored as part of routine diabetes care, though SGLT2 inhibitors typically improve these parameters. 5, 6
Alternative Options
If SGLT2 inhibitors are not tolerated or contraindicated, GLP-1 receptor agonists with proven cardiovascular benefits (liraglutide, dulaglutide, semaglutide) are the preferred alternative. 4, 2
- GLP-1 receptor agonists reduce cardiovascular events and provide renal protection, with no eGFR-based restrictions for initiation (can be used at eGFR <20 mL/min/1.73 m²). 4, 1, 6
- DPP-4 inhibitors (e.g., linagliptin) can be used without dose adjustment at any eGFR level, though they lack the robust cardiorenal benefits of SGLT2 inhibitors and GLP-1 receptor agonists. 1
- Insulin remains fully effective regardless of renal function and can be used as the primary glucose-lowering agent when aggressive glycemic control is required. 1
- Sulfonylureas (e.g., gliclazide, glipizide) provide no cardiovascular or renal protection and increase hypoglycemia risk—they should be avoided or discontinued when SGLT2 inhibitors are started. 1
Key Clinical Considerations
- SGLT2 inhibitors should be prioritized as first-line therapy (alongside metformin) in patients with type 2 diabetes and chronic kidney disease (eGFR ≥20 mL/min/1.73 m² with UACR ≥200 mg/g), heart failure, or established cardiovascular disease, regardless of baseline HbA1c. 4, 1
- Cardiovascular and renal benefits are independent of glucose-lowering effects—SGLT2 inhibitors reduce cardiovascular death or heart failure hospitalization by 26–29% and kidney disease progression by 39–44%. 1
- Continue ACE inhibitors or ARBs unchanged when starting an SGLT2 inhibitor; the combination provides additive renal protection. 4, 1
- Consider reducing concurrent diuretic doses (especially loop diuretics) at initiation to prevent excessive volume depletion. 4, 1, 2
- Glucose-lowering efficacy declines as eGFR falls below 45 mL/min/1.73 m², but cardiovascular and renal protective effects persist down to eGFR 20 mL/min/1.73 m². 1, 7
Common Pitfalls to Avoid
- Do not discontinue SGLT2 inhibitors when eGFR falls below 45 mL/min/1.73 m²—cardiorenal benefits remain robust. 4, 1
- Do not stop therapy because of the expected early eGFR dip (2–5 mL/min/1.73 m²) in the first 2–4 weeks—this is hemodynamic and reversible. 4, 1
- Do not reduce the dose below 10 mg for dapagliflozin or empagliflozin (or 100 mg for canagliflozin) for cardiovascular or renal indications—all outcome trials used fixed doses. 1, 2
- Do not combine SGLT2 inhibitors with sulfonylureas without reducing or stopping the sulfonylurea—this combination increases hypoglycemia risk without additional cardiovascular benefit. 1
- Do not withhold ACE inhibitors or ARBs when starting an SGLT2 inhibitor—the combination is safe and provides additive renal protection. 4, 1