Why are sodium‑glucose cotransporter‑2 (SGLT‑2) inhibitors contraindicated when estimated glomerular filtration rate (eGFR) is <30 mL/min/1.73 m² despite their renoprotective benefits?

Why SGLT2 Inhibitors Are No Longer Contraindicated Below eGFR 30 mL/min/1.73 m²

SGLT2 inhibitors are NOT contraindicated when eGFR falls below 30 mL/min/1.73 m²—this is an outdated restriction that has been revised based on compelling evidence showing cardiovascular and renal protection persists independent of glucose-lowering effects. 1

The Historical Misconception

The original restriction stemmed from a fundamental misunderstanding of how SGLT2 inhibitors work:

• Early prescribing guidelines focused exclusively on glucose-lowering efficacy, which does decline as eGFR decreases because there is less filtered glucose available for the drug to block from reabsorption 2
• Regulatory agencies initially restricted initiation to eGFR ≥60 mL/min/1.73 m² and mandated discontinuation at eGFR <45 mL/min/1.73 m² based solely on diminished glycemic effects 3
• This "glucocentric" approach completely missed the cardiovascular and renal protective mechanisms that operate independently of glucose control 2, 4

Why the Guidelines Changed: Mechanisms Beyond Glucose

SGLT2 inhibitors provide renoprotection and cardioprotection through multiple glucose-independent mechanisms that remain active even when eGFR is severely reduced 1, 2:

• Reduction in intraglomerular pressure and systemic blood pressure 1
• Decreased albuminuria through hemodynamic effects 1
• Reduction in oxidative stress and NLRP3 inflammasome activity in the kidney 1
• Blunting of angiotensinogen increases 1
• Continued modest effects on body weight and blood pressure even when glucose-lowering is minimal 2

Current Evidence-Based Thresholds

For Initiation:

SGLT2 inhibitors should be initiated in patients with type 2 diabetes and CKD when eGFR is ≥20 mL/min/1.73 m² 1:

• Strong recommendation (Grade A) for eGFR ≥20 mL/min/1.73 m² with albuminuria ≥200 mg/g creatinine 1
• Moderate recommendation (Grade B) for eGFR ≥20 mL/min/1.73 m² with albuminuria <200 mg/g creatinine 1
• The 2024 BMJ guideline notes that evidence below eGFR 20 mL/min/1.73 m² is insufficient, making recommendations less applicable to this group 1

For Continuation:

Once initiated, SGLT2 inhibitors should be continued even if eGFR falls below 30 mL/min/1.73 m², unless the patient starts dialysis or the drug is not tolerated 1:

• This represents a critical shift from "stop at eGFR <30" to "continue through progressive CKD" 1
• Recent pooled analysis of major trials showed that SGLT2 inhibitors reduced cardiovascular outcomes and mortality even in patients whose eGFR deteriorated to <25 mL/min/1.73 m² (and even <20 mL/min/1.73 m²) during follow-up 5
• The protective effects on heart failure hospitalization, cardiovascular mortality, and all-cause mortality were maintained regardless of severe eGFR deterioration 5

The Landmark Evidence That Changed Practice

The DAPA-CKD trial specifically enrolled patients with CKD and demonstrated renal and cardiovascular benefits in patients with eGFR as low as 25 mL/min/1.73 m², and these benefits occurred regardless of diabetes status 3:

• CREDENCE (canagliflozin) and DAPA-CKD (dapagliflozin) were dedicated renal outcome trials in patients with CKD and macroalbuminuria 3
• Meta-analyses confirmed cardiovascular and renal protection down to eGFR 30 mL/min/1.73 m², independent of glucose control 2, 3
• The 2020 KDIGO guideline elevated SGLT2 inhibitors to Grade 1A recommendation for patients with type 2 diabetes, CKD, and eGFR ≥30 mL/min/1.73 m² 1

Practical Algorithm for SGLT2 Inhibitor Use Across eGFR Ranges

eGFR ≥30 mL/min/1.73 m²:

• Initiate SGLT2 inhibitor as first-line therapy alongside metformin 1
• No dose adjustment required 2
• Monitor for expected initial eGFR dip of 3-5 mL/min/1.73 m² (hemodynamic, not pathological) 1

eGFR 20-29 mL/min/1.73 m²:

• Initiate SGLT2 inhibitor for cardiovascular and renal protection 1
• Expect minimal to no glucose-lowering effect 2
• If already on SGLT2 inhibitor when eGFR falls into this range, continue the drug 1
• Do not discontinue based on eGFR alone 1

eGFR <20 mL/min/1.73 m²:

• Evidence is insufficient to recommend initiation 1
• If already on SGLT2 inhibitor, continuation is reasonable until dialysis initiation 1
• Recent pooled data suggest benefit persists even at these levels 5

On Dialysis:

• Discontinue SGLT2 inhibitor 1

Critical Safety Considerations

Expected vs. Pathological eGFR Changes:

A reversible 3-5 mL/min/1.73 m² eGFR decline within 1-3 months of starting SGLT2 inhibitor is expected and hemodynamic—this is NOT an indication to stop therapy 1:

• This initial dip occurs in approximately 80% of patients with CKD stage 3b 6
• eGFR typically recovers toward baseline by 6 months 6
• However, a decline ≥10% (large IAD-eGFR) may predict subsequent renal function deterioration and is associated with high estimated daily salt intake 6

When to Withhold Temporarily:

Hold SGLT2 inhibitors during prolonged fasting, surgery, or critical illness due to ketosis risk 1:

• Volume depletion increases risk of acute kidney injury 1
• Consider reducing loop or thiazide diuretics before starting SGLT2 inhibitor 1
• Educate patients on symptoms of volume depletion 1

Drug Exposure and Safety:

Drug exposure increases modestly as eGFR declines, but this does not require dose reduction in mild-to-moderate CKD 2:

• The increase in drug exposure is moderate and not clearly related to CKD severity 2
• Safety profile in CKD patients is similar to those with normal renal function 3

Common Pitfalls to Avoid

The biggest barrier to appropriate SGLT2 inhibitor use is clinical inertia and outdated "glucocentric" thinking 4:

• Only 32.9% of eligible high-risk CKD patients receive SGLT2 inhibitors in real-world practice 4
• Older age (≥65 years) and recent hospitalization are negatively correlated with SGLT2 inhibitor initiation, despite these patients having the most to gain 4
• Clinicians must shift focus from glucose control to reducing cardiovascular and renal events 4

Do not discontinue SGLT2 inhibitors when eGFR falls below 30 mL/min/1.73 m²—this outdated practice deprives patients of ongoing cardiovascular and renal protection 1, 5.