# SGLT2 Inhibitors in Nephrology: Mechanism, Trials, and Clinical Application

## Mechanism of Action: How SGLT2i Work

### Normal Proximal Tubule Glucose Reabsorption

- **Glomerular filtration**: ~125 mL/min × 1-2 mmol/L glucose = ~180 mmol/day filtered
- **SGLT2 transporters** (proximal tubule S1 segment): Reabsorb ~90% of filtered glucose
- **GLUT2 transporters** (exit across basolateral membrane)
- **Result**: Glucose normally absent in urine

### SGLT2 Inhibition Mechanism

- **Block SGLT2 cotransporter** in proximal tubule epithelium
- **Prevent glucose reabsorption** → glucosuria (spillage into urine)
- **Additional effects**: ↑ Urinary sodium excretion (natriuresis)

### Hemodynamic Consequences: The “Tubulo-Glomerular Feedback Hypothesis”

**Normal glomerular-tubular feedback**: - Proximal tubule reabsorbs NaCl → reduced delivery to macula densa - Macula densa senses low NaCl → ↓ renin release, ↑ afferent arteriolar vasodilation - Result: Maintains GFR

**With SGLT2i**: 1. SGLT2 blockade → ↑ Na+ delivery to macula densa (not reabsorbed with glucose) 2. Macula densa senses “high NaCl” → ↑ renin release, **afferent arteriolar vasoconstriction** 3. **Reduces intraglomerular pressure** → ↓ GFR initially (expected, not harmful) 4. **Net effect**: Glomerular pressure drops → proteinuria ↓, sclerosis prevented

Key Point

**eGFR “dip” with SGLT2i**: Expect 10-30% initial decline in eGFR within days-weeks. This is **expected and reflects pressure reduction, not true renal injury**. The dip improves outcomes by preventing glomerulosclerosis.

------------------------------------------------------------------------

## Pharmacology & Approved Agents

### SGLT2i Approved for Renal/Cardiometabolic Indication

| Agent | Dose (Nephrology) | Plasma t½ | Renal Clearance | FDA Approval (Renal) |
|----|----|----|----|----|
| **Empagliflozin (Jardiance)** | 10 mg daily | 13.1 hr | \<10% | EMPA-KIDNEY (2022) |
| **Dapagliflozin (Farxiga)** | 10 mg daily | 12.9 hr | \<0.1% | DAPA-CKD (2020) |
| **Canagliflozin (Invokana)** | 100 mg daily (with caution) | 10.6 hr | 33% renal excretion | CREDENCE (CKD + T2DM) |

### Dosing Adjustments

- **eGFR \<30**: Most agents can be used, but ↓ efficacy for glucose control
- **Empagliflozin 10 mg**: Minimal dose adjustment
- **Dapagliflozin 10 mg**: No dose adjustment needed

------------------------------------------------------------------------

## Landmark Trials: The Evidence Base

### CREDENCE Trial (2019) — Canagliflozin in CKD + T2DM

**Design**: T2DM + albuminuria; randomized canagliflozin vs. placebo \[1\]

**Primary outcome**: ESRD, doubling Cr, CV death

**Results**: - **33% ↓ ESRD/doubling Cr** (p \<0.001) - **↓ CV death** (especially HF-related) - Proteinuria ↓ 27% at 30 weeks

**Clinical impact**: First SGLT2i to show renal benefit; established class effect

### DAPA-CKD Trial (2020) — Dapagliflozin in CKD (±T2DM)

**Design**: CKD stage 3b-4 (eGFR 25-75) + albuminuria; **NOT limited to diabetics** \[2\]

**Primary outcome**: Composite of ≥50% eGFR decline, ESRD, kidney death, CV death, hospitalization for HF

**Results**: - **39% ↓ composite outcome** (p \<0.001) - **Benefit seen in both diabetic and non-diabetic patients** - Dapagliflozin reduced risk across eGFR ranges (even eGFR 25-40) - Proteinuria ↓ 35% by month 2

**Clinical impact**: Establishes SGLT2i benefit in NON-DIABETIC CKD (IgAN, FSGS, etc.); not just T2DM

### EMPA-KIDNEY Trial (2022) — Empagliflozin in CKD (±T2DM)

**Design**: CKD stage 2-4 (eGFR \>20) + albuminuria; similar broad population \[3\]

**Primary outcome**: Kidney disease progression (ESKD, sustained eGFR \<10, sustained ≥40% eGFR decline, or renal death) or CV death

**Results**: - **28% ↓ composite outcome** (13.1% vs 16.9%; HR 0.72, 95% CI 0.64–0.82; p \<0.001) - Empagliflozin 10 mg also ↓ all-cause hospitalization (HR 0.86, 95% CI 0.78–0.95) - Benefits consistent across diabetes status and eGFR subgroups

**Clinical impact**: Broadest indication yet; effective even with eGFR 20-30

### EMPEROR-Reduced, EMPEROR-Preserved (2020-2021) — HF Phenotypes

**Design**: HFrEF (EMPEROR-Reduced) \[5\] and HFpEF (EMPEROR-Preserved) \[4\]

**Results**: - **Empagliflozin 10 mg ↓ CV death + HF hospitalization — 21% in HFpEF (HR 0.79) and 25% in HFrEF (HR 0.75)** - Benefit seen in HFpEF (traditionally challenging to treat) - Renal function stable/improved

**Clinical impact**: Expands SGLT2i use beyond CKD to HF-CKD phenotype

------------------------------------------------------------------------

## Indications for SGLT2i in Nephrology

### PRIMARY INDICATION: CKD with Albuminuria (Non-Diabetic & Diabetic)

- **eGFR 20-75 mL/min/1.73m²** + **albuminuria** (UACR \>30 mg/g or proteinuria ≥0.5 g/day)
- **Baseline proteinuria**: Even \>3 g/day benefit demonstrated
- **Diabetes status**: Benefit in BOTH diabetic and non-diabetic CKD
- **Disease**: CKD from any cause (IgAN, FSGS, diabetic, lupus, hypertensive, etc.)

### SECONDARY INDICATION: HFrEF ± CKD

- **HFrEF** (LVEF \<40%) → dapagliflozin or empagliflozin for symptom relief + mortality reduction
- **Independent of diabetes status**
- Often used even without significant albuminuria if HF

### TERTIARY INDICATION: HFpEF ± CKD

- **HFpEF** (LVEF \>50%) + albuminuria → empagliflozin favored (EMPEROR data)
- Emerging indication; data maturing

### NOT INDICATED (Or Use with Caution)

- **Non-albuminuric CKD** (UACR \<30, no proteinuria): Limited data; reserved for high-risk subgroups
- **Type 1 diabetes (off-label)**: Some benefit seen in T1DM + CKD, but FDA indication T2DM
- **eGFR \<20** (but EMPA-KIDNEY included eGFR ≥20; limited data if \<20)

------------------------------------------------------------------------

## Clinical Dosing & Efficacy

### Dosing for Renal Indication

- **Dapagliflozin 10 mg**: Once daily, morning or evening (no food interaction)
- **Empagliflozin 10 mg**: Once daily, morning preferred (no food interaction)
- **Canagliflozin 100 mg**: Once daily, before first meal

### Expected Renal Outcomes

| Outcome | Timeline | Expected Change |
|----|----|----|
| **Proteinuria** | 2-4 weeks | 30-50% reduction |
| **eGFR dip** | Days-weeks | 10-30% initial decline (expected; reversible) |
| **Stabilization** | 6-12 weeks | eGFR stabilizes; trajectory flattened |
| **ESRD/doubling Cr** | 2-3 years | 25-39% risk reduction |

Clinical Pearl

**Expected eGFR dip doesn’t mean kidney damage**: The initial 10-30% decline in eGFR within first 4-8 weeks reflects hemodynamic changes (reduced intraglomerular pressure), NOT tubular toxicity. Most stabilize or improve by 12 weeks. Don’t discontinue based on initial dip.

------------------------------------------------------------------------

## Mechanism of Benefit: Beyond Glycosuria

### 1. Hemodynamic: Reduced Intraglomerular Pressure

- SGLT2i → afferent arteriolar vasoconstriction (via macula densa)
- ↓ Glomerular hyperfiltration → ↓ proteinuria
- Protective against glomerulosclerosis

### 2. Natriuresis & Volume Reduction

- ↑ Urinary sodium excretion → mild volume depletion
- Sympathetic nervous system activation (modest)
- Effective for edema management in nephrotic patients

### 3. Metabolic Effects

- **Improved insulin sensitivity**: ↓ HbA1c by 0.5-1.0% if diabetic
- **Weight loss**: 2-3 kg over months (from glycosuria caloric loss)
- **Lipid improvement**: ↓ triglycerides, ↑ HDL
- **Uric acid reduction**: ↓ serum UA (relevant for gout-prone patients)

### 4. Direct Renal Cellular Effects (Emerging)

- **Reduced inflammation**: ↓ tubular TNF-α, IL-6
- **Improved mitochondrial function**: Enhanced ATP production (cells shift toward oxidative metabolism)
- **Anti-fibrosis**: ↓ TGF-β signaling (anti-sclerotic)
- **Potential podocyte protection**: Direct effects on podocyte cytoskeleton

------------------------------------------------------------------------

## Adverse Effects & Safety Monitoring

### Euglycemic Diabetic Ketoacidosis (euDKA)

**Rare but serious**: ~0.1-0.4 cases per 1000 patient-years

**Risk factors**: - Acute illness (infection, surgery, dehydration) - Insulin-dependent diabetes - Recent change in insulin dosing

**Presentation**: Normal or mildly elevated glucose (\<250 mg/dL) + severe metabolic acidosis (pH \<7.25) - Symptoms: Nausea, vomiting, abdominal pain, dyspnea

**Prevention**: - Counsel patients: Hold SGLT2i during acute illness, surgery, fasting - Monitor for symptoms - Check VBG/ABG if vague abdominal symptoms in diabetic patient on SGLT2i

**Treatment**: IV insulin, fluid resuscitation, electrolyte correction; restart SGLT2i after recovery if no contraindication

High-Yield Board Point

**euDKA screening**: Any T2DM patient on SGLT2i with nausea/vomiting/abdominal pain → check VBG for acidosis. Can occur at normal glucose levels, making diagnosis challenging.

### Urinary Tract & Genital Infections

**Frequency**: 5-10% (more common in women)

**Mechanism**: Glucosuria promotes bacterial growth (especially Candida in genital areas)

**Management**: - Counsel: Hygiene, regular voiding, adequate hydration - Treat infections promptly (antibiotics for UTI, topical/oral antifungals for candida) - Consider discontinuation if recurrent/severe infections

### Volume Depletion & Hypotension

**Mechanism**: Natriuresis; mainly seen with loop diuretics or severe baseline volume depletion

**Risk factors**: Concomitant diuretic use, GFR \<30, heart failure

**Prevention**: - Monitor BP standing + sitting - Assess volume status at baseline - Adjust other diuretics if volume depleted (decrease dose)

**Management**: Usually mild; rehydrate; resume after volume repletion

### Amputation Risk (Canagliflozin Only)

**CANVAS Trial**: ↑ lower-extremity amputation risk with canagliflozin (↑ 97% vs. placebo) - Mechanism: Unclear (volume depletion? pressure-related?) - Increased risk: Peripheral arterial disease, prior amputation, foot ulcer history - Management: **Canagliflozin use restricted** in high-risk patients; preferred agents: dapagliflozin, empagliflozin

### Renal-Related Side Effects

| Side Effect | Frequency | Mechanism | Management |
|----|----|----|----|
| **Transient eGFR dip** | 50-80% | Hemodynamic (expected) | Monitor; don’t discontinue |
| **Acute kidney injury (rare)** | \<1% | Volume depletion | Rehydrate; assess volume status |
| **Hyperkalemia** | \<1% (even in CKD) | Net K+ loss (glucosuria) | Monitor baseline + 4 weeks; rare in CKD |

------------------------------------------------------------------------

## Drug Interactions & Contraindications

### Contraindications

- **Type 1 diabetes**: Not approved (↑ DKA risk); SGLT2i less effective (no β-cell reserve)
- **Acute kidney injury**: Hold SGLT2i until stabilized
- **Severe volume depletion**: Hold until rehydrated
- **Active UTI/candida**: Treat infection first; restart after resolution

### Key Interactions

- **Diuretics**: Risk volume depletion; coordinate dosing
- **ACE-I/ARB**: Additive renal hemodynamic effects; benefit, but monitor K+ and Cr
- **NSAIDs**: Risk AKI (avoid); use acetaminophen instead
- **Certain contrast dyes**: Hold SGLT2i 48 hours before contrast, restart 48 hours after

------------------------------------------------------------------------

## Clinical Pearls & Pitfalls

Clinical Pearl

**SGLT2i benefit independent of baseline glucose control**: Even well-controlled T2DM patients gain renal/cardiac benefit. Don’t reserve SGLT2i only for poorly controlled diabetes; use in all CKD + albuminuria if no contraindication.

High-Yield Board Point

**Initial eGFR dip is EXPECTED and BENEFICIAL**: Don’t panic or discontinue SGLT2i if eGFR drops 15-20% in first month. This reflects pressure reduction and is associated with BETTER long-term outcomes. Continue therapy; reassess at 8-12 weeks.

Key Point

**SGLT2i in non-diabetic CKD**: DAPA-CKD and EMPA-KIDNEY proved benefit in IgAN, FSGS, lupus, and other non-diabetic kidney diseases. Use SGLT2i in ALL albuminuric CKD, not just diabetes.

Clinical Pearl

**Canagliflozin amputation risk**: Use dapagliflozin or empagliflozin preferentially in patients with peripheral arterial disease, prior amputation, foot ulcers, or Charcot joint. Risk with canagliflozin outweighs benefits in this population.

Key Point

**SGLT2i + ACE-I/ARB synergy**: Combination therapy more effective than either alone for proteinuria reduction. Use together (if no contraindication) for maximal effect.

------------------------------------------------------------------------

## Special Populations

### CKD Stage 5 (eGFR \<15)

- **Limited data**: DAPA-CKD excluded eGFR \<25; EMPA-KIDNEY allowed eGFR ≥20
- **Recommendation**: Can use if eGFR 15-20 (dapagliflozin, empagliflozin); avoid if \<15 or on dialysis (no benefit, glucose spill not filtered)
- **Transition to dialysis**: Consider discontinuation (no renal filtration; no efficacy)

### Dialysis-Dependent ESRD

- **NOT indicated**: Kidneys not filtering glucose; no hemodynamic benefit
- **Discontinue**: Before dialysis initiation

### HFpEF + CKD

- **Emerging indication**: Empagliflozin reduces HF hospitalization even in HFpEF
- **Target**: Albuminuric CKD + HFpEF; empagliflozin 10 mg preferred (EMPEROR-Preserved)

### Post-Kidney Transplant

- **Limited data**: Some use off-label if proteinuria/CKD post-transplant; minimal trials
- **Caution**: Risk of volume depletion in transplant recipients; coordinate with transplant team

------------------------------------------------------------------------

## Monitoring Checklist

| Timepoint | Labs/Assessments | Rationale |
|----|----|----|
| **Baseline** | Cr, eGFR, UACR, K+, glucose, VBG | Baseline safety assessment |
| **Week 1-2** | BP standing/sitting | Screen for hypotension |
| **4 weeks** | Cr, eGFR, K+ | Monitor eGFR dip; ensure safe |
| **8-12 weeks** | Cr, eGFR, proteinuria, symptoms | Assess stabilization; expect eGFR recovery |
| **6-12 months** | Cr, eGFR, UACR, K+ | Long-term monitoring |
| **Annually** | CBC, CMP, UA | Routine surveillance for adverse effects |

------------------------------------------------------------------------

## Landmark Trials (Full Citations)

\[1\] **CREDENCE Trial** (2019): Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. *N Engl J Med.* 2019;380(24):2295–2306. PMID: 30990260

\[2\] **DAPA-CKD Trial** (2020): Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. *N Engl J Med.* 2020;383(15):1436–1446. PMID: 32970396

\[3\] **EMPA-KIDNEY Trial** (results 2022): The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, et al. Empagliflozin in patients with chronic kidney disease. *N Engl J Med.* 2023;388(2):117–127. PMID: 36331190

\[4\] **EMPEROR-Preserved** (2021): Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. *N Engl J Med.* 2021;385(16):1451–1461. PMID: 34449189

\[5\] **EMPEROR-Reduced** (2020): Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. *N Engl J Med.* 2020;383(15):1413–1424. PMID: 32865377

------------------------------------------------------------------------

## Related Resources

- CKD Comprehensive Management Pathways
- DAPA-CKD & Cardioprotection
- Drug Dosing in CKD Quick Reference
- SGLT2i in T1DM Report

------------------------------------------------------------------------

**Last reviewed:** 2026-02-28 \| **Next update due:** 2026-08-28


---

[Website version](https://urinenephrology.org/student-resources/pharmacology/sglt2i-nephrology-student-handout.html) · Markdown synchronized October 3, 2026.