SGLT2i in HF and CKD

SGLT2i in HF and CKD

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have revolutionized cardiovascular and renal protection beyond glucose control. Master these high-yield cardiorenal benefits with free flashcards and spaced repetition practice. This lesson covers heart failure management, chronic kidney disease progression, landmark clinical trials, and NAPLEX-critical prescribing considerations for SGLT2i therapy.

Welcome to Cardiorenal Protection with SGLT2 Inhibitors 💊

What began as a diabetes medication class has emerged as a cornerstone therapy for heart failure and chronic kidney disease—even in patients without diabetes! Understanding when and how to use SGLT2i for cardiorenal indications is essential for NAPLEX success and optimal patient care.

This lesson will equip you with:

• Mechanisms behind cardiovascular and renal benefits 🫀
• Clinical trial evidence (DAPA-HF, EMPEROR-Reduced, CREDENCE, and more)
• FDA-approved indications for HF and CKD
• Patient selection criteria and monitoring parameters
• Common prescribing pitfalls to avoid

---

Core Concepts: SGLT2i Mechanisms and Cardiorenal Benefits 🔬

What Are SGLT2 Inhibitors?

SGLT2 inhibitors block sodium-glucose cotransporter-2 in the proximal tubule of the kidney, preventing glucose and sodium reabsorption. This leads to:

• Glucosuria (50-80g glucose/day excreted)
• Natriuresis (sodium excretion)
• Osmotic diuresis (increased urine output)

Drug Name	Brand Name	Dosing
Canagliflozin	Invokana	100-300 mg daily
Dapagliflozin	Farxiga	5-10 mg daily
Empagliflozin	Jardiance	10-25 mg daily
Ertugliflozin	Steglatro	5-15 mg daily

💡 Clinical Pearl: While all SGLT2i share the same mechanism, dapagliflozin and empagliflozin have the most robust FDA-approved cardiorenal indications.

---

Mechanisms of Cardiorenal Protection 🫀🧬

The benefits of SGLT2i extend far beyond glucose lowering. Multiple mechanisms contribute to cardiovascular and renal protection:

┌─────────────────────────────────────────────────┐
│         SGLT2i CARDIORENAL MECHANISMS           │
└─────────────────────────────────────────────────┘

     🩺 Hemodynamic Effects
           |
           ├──→ ⬇️ Preload (volume reduction)
           ├──→ ⬇️ Afterload (BP reduction)
           └──→ ⬇️ LV filling pressures

     🔬 Metabolic Effects
           |
           ├──→ ⬆️ Ketone production (fuel efficiency)
           ├──→ ⬇️ Insulin resistance
           └──→ ⬆️ Lipolysis

     🧪 Renal Effects
           |
           ├──→ ⬇️ Glomerular hyperfiltration
           ├──→ Tubuloglomerular feedback restoration
           └──→ ⬇️ Intraglomerular pressure

     🔥 Anti-inflammatory
           |
           ├──→ ⬇️ Oxidative stress
           ├──→ ⬇️ Fibrosis markers
           └──→ ⬇️ Albuminuria

Key Concept: Tubuloglomerular Feedback 🔄

In CKD and diabetes, glomerular hyperfiltration occurs as the afferent arteriole dilates to maintain GFR. SGLT2i increase sodium delivery to the macula densa, triggering:

1. Afferent arteriole vasoconstriction (via adenosine)
2. Reduced intraglomerular pressure
3. Preserved nephron function long-term

This explains the initial small eGFR dip (5-10 mL/min/1.73m²) seen with SGLT2i initiation—it's actually nephroprotective! 🛡️

---

Heart Failure Indications and Evidence 💓

FDA-Approved HF Indications

Empagliflozin and dapagliflozin are approved for:

⚠️ Critical Point: You do NOT need diabetes to prescribe SGLT2i for heart failure! This is a high-yield NAPLEX concept.

Landmark Trials You Must Know 📊

1. DAPA-HF (Dapagliflozin)

• Population: HFrEF (EF ≤40%), with or without T2DM
• N: 4,744 patients
• Primary outcome: ⬇️ 26% relative risk reduction in CV death or HF hospitalization
• NNT: ~21 to prevent 1 event over 18 months
• Key finding: Benefit seen in both diabetic and non-diabetic patients!

2. EMPEROR-Reduced (Empagliflozin)

• Population: HFrEF (EF ≤40%)
• N: 3,730 patients
• Primary outcome: ⬇️ 25% relative risk reduction in CV death or HF hospitalization
• Notable: More patients with lower EF (<30%) than DAPA-HF

3. DELIVER & EMPEROR-Preserved (HFpEF trials)

• Population: HF with EF >40%
• Findings: ⬇️ HF hospitalizations (modest benefit)
• Clinical significance: First therapies to show benefit in HFpEF!

🧠 Memory Aid - "DAPPER EMPEROR":

• DAPagliflozin = DAPA-HF
• EMPAGliflozin = EMPEROR trials
• Both reduce HF hospitalizations by ~25%

---

Chronic Kidney Disease Indications and Evidence 🧫

FDA-Approved CKD Indication

Dapagliflozin is approved to reduce the risk of:

• eGFR decline
• End-stage kidney disease (ESKD)
• CV death
• Hospitalization for heart failure

In patients with CKD (eGFR ≥25 mL/min/1.73m²) at risk of progression, with and without T2DM.

Canagliflozin also has a CKD indication based on CREDENCE trial data.

SGLT2i	eGFR Threshold for Initiation	eGFR for Continuation
Dapagliflozin	≥25 mL/min/1.73m²	Continue if drops below 25
Empagliflozin	≥20 mL/min/1.73m²	Continue if drops below 20
Canagliflozin	≥30 mL/min/1.73m²	Continue if drops below 30

💡 High-Yield: Once initiated, SGLT2i can be continued even as eGFR declines below initiation threshold!

Key CKD Trials 📈

1. CREDENCE (Canagliflozin)

• Population: T2DM with CKD (eGFR 30-90) and albuminuria
• Primary outcome: ⬇️ 30% relative risk reduction in composite renal endpoint (ESKD, SCr doubling, renal death)
• Secondary: ⬇️ 32% HF hospitalization

2. DAPA-CKD (Dapagliflozin)

• Population: CKD (eGFR 25-75) with/without T2DM
• Primary outcome: ⬇️ 39% relative risk reduction in composite (eGFR decline ≥50%, ESKD, renal/CV death)
• Stopped early for overwhelming efficacy!
• Key: Benefit in non-diabetic CKD patients

3. EMPA-KIDNEY (Empagliflozin)

• Population: CKD (eGFR 20-45 or eGFR 45-90 with albuminuria)
• Primary outcome: ⬇️ 28% relative risk reduction in kidney disease progression or CV death
• Broadest eGFR range studied

🔺 Clinical Implication: SGLT2i are now considered standard of care for CKD management alongside ACE inhibitors/ARBs and mineralocorticoid receptor antagonists.

---

Patient Selection and Initiation Criteria 🎯

Who Should Receive SGLT2i for Cardiorenal Protection?

┌─────────────────────────────────────────────────┐
│         IDEAL SGLT2i CANDIDATES                 │
├─────────────────────────────────────────────────┤
│                                                 │
│  ✅ HFrEF (EF ≤40%) - ANY diabetes status       │
│  ✅ HFpEF (EF >40%) - for HF hospitalization↓   │
│  ✅ CKD with eGFR 20-25+ (drug-dependent)       │
│  ✅ Albuminuria (UACR ≥200 mg/g)                │
│  ✅ T2DM + ASCVD/multiple CV risk factors       │
│                                                 │
└─────────────────────────────────────────────────┘

Contraindications and Precautions ⚠️

Absolute Contraindications:

• Type 1 diabetes (relative; some off-label use with extreme caution due to DKA risk)
• Dialysis/ESKD (no benefit; not FDA-approved)
• Severe hepatic impairment (limited data)

Relative Contraindications/Cautions:

• eGFR <20-25 mL/min/1.73m² (depends on agent; limited efficacy for glucose lowering but renal/CV benefits may persist)
• Recurrent genital mycotic infections (UTIs/yeast infections common)
• History of DKA (especially if type 1 or insulin-deficient type 2)
• Amputation risk factors (primarily canagliflozin)

💡 Volume Status Pearl: SGLT2i cause modest diuresis (300-400 mL/day). Consider holding loop diuretics or reducing dose during initiation if patient is euvolemic or hypovolemic.

---

Clinical Examples 💊

Example 1: HFrEF Without Diabetes

Patient: 68-year-old male with HFrEF (EF 35%), no diabetes

• Current meds: Lisinopril 20 mg daily, carvedilol 25 mg BID, spironolactone 25 mg daily, furosemide 40 mg daily
• Labs: SCr 1.3 mg/dL, eGFR 52 mL/min/1.73m², K+ 4.2 mEq/L
• BP: 118/72 mmHg

Question: Should you add an SGLT2i?

Answer: ✅ Absolutely YES!

This patient has HFrEF with NYHA class II-III symptoms (on diuretic) and eGFR >25. Both dapagliflozin and empagliflozin have FDA approval for this indication regardless of diabetes status.

Recommendation:

• Start dapagliflozin 10 mg daily OR empagliflozin 10 mg daily
• Monitor for symptomatic hypotension (already on ACEi + BB + MRA)
• Consider reducing furosemide dose by 25% if patient becomes volume depleted
• Recheck eGFR in 2-4 weeks (expect small dip, then stabilization)

Expected outcomes:

• ⬇️ 26% relative risk reduction in CV death or HF hospitalization (DAPA-HF)
• Improved quality of life and functional capacity
• Long-term renal protection

---

Example 2: Diabetic Nephropathy with Albuminuria

Patient: 55-year-old female with T2DM (A1C 8.2%), CKD stage 3a

• Current meds: Metformin 1000 mg BID, lisinopril 40 mg daily, atorvastatin 40 mg daily
• Labs: SCr 1.4 mg/dL, eGFR 48 mL/min/1.73m², UACR 420 mg/g (albuminuria)
• BP: 134/82 mmHg

Question: What SGLT2i changes would optimize this patient's care?

Answer: This patient is an ideal candidate for SGLT2i based on:

1. CKD with albuminuria (UACR >200 mg/g)
2. eGFR 48 (above all initiation thresholds)
3. Suboptimal glycemic control (A1C 8.2%)
4. Already on ACEi (maximizing RAAS blockade)

Recommendation:

• Add dapagliflozin 10 mg daily (preferred for CKD indication)
  • OR canagliflozin 100 mg daily
  • OR empagliflozin 10 mg daily
• Continue metformin (eGFR >45)
• Counsel on genital hygiene (UTI/mycotic infection risk)
• Recheck labs in 2-4 weeks

Expected outcomes (DAPA-CKD, CREDENCE):

• ⬇️ 30-39% reduction in kidney disease progression
• ⬇️ Albuminuria by 20-30%
• ⬇️ A1C by 0.5-0.7%
• Initial eGFR dip of 3-5 mL/min (returns to baseline by 3 months)

---

Example 3: HFpEF with Preserved Kidney Function

Patient: 72-year-old male with HFpEF (EF 58%), T2DM, obesity

• Current meds: Metformin 1000 mg BID, torsemide 20 mg daily, amlodipine 10 mg daily
• Labs: SCr 1.1 mg/dL, eGFR 68 mL/min/1.73m², A1C 7.8%
• Symptoms: Dyspnea on exertion, 2+ pitting edema

Question: Would SGLT2i benefit this patient?

Answer: ✅ Yes, based on recent HFpEF trials!

While the benefit is more modest than in HFrEF, the DELIVER (dapagliflozin) and EMPEROR-Preserved (empagliflozin) trials showed:

• ⬇️ HF hospitalizations in HFpEF patients
• Improved symptoms and quality of life
• Added benefit: glucose lowering and modest weight loss

Recommendation:

• Start empagliflozin 10 mg daily (FDA-approved for HFpEF based on EMPEROR-Preserved)
  • OR dapagliflozin 10 mg daily
• Monitor volume status closely (already on loop diuretic)
• Educate on osmotic diuresis (increased urination)

Counseling point: "This medication will help keep you out of the hospital for heart failure and also help with your diabetes and weight."

---

Example 4: Managing the Initial eGFR Dip

Patient: 60-year-old on dapagliflozin 10 mg for 3 weeks

• Baseline eGFR: 42 mL/min/1.73m²
• Current eGFR: 38 mL/min/1.73m² (⬇️ 4 mL/min)
• Provider concern: "Should I stop the SGLT2i?"

Answer: ❌ NO! Do NOT discontinue.

An acute eGFR decline of <10-20% is:

• Expected (hemodynamic effect from reduced intraglomerular pressure)
• Reversible (returns toward baseline by 2-3 months)
• Protective (long-term nephroprotection)

eGFR Pattern with SGLT2i:

  45 │                         ╱──────── (long-term preservation)
     │                      ╱
  40 │──────╲            ╱
     │       ╲         ╱   (gradual recovery)
  35 │        ╲______╱    (initial dip)
     │
  30 │
     └──┬────┬────┬────┬────┬────┬────┬──
       Start  1mo  3mo  6mo  1yr  2yr  3yr

Action:

• Continue dapagliflozin (still >25 mL/min)
• Recheck in 4 weeks
• If eGFR drops >20%, consider volume depletion or acute kidney injury
• Ensure patient is adequately hydrated

💡 NAPLEX Pearl: The initial eGFR dip is a hemodynamic effect, NOT kidney damage. Don't reflexively stop the medication!

---

Common Mistakes to Avoid ⚠️

Mistake #1: Requiring Diabetes Diagnosis for HF Indication ❌

Wrong thinking: "This patient doesn't have diabetes, so I can't prescribe an SGLT2i for heart failure."

Reality: Dapagliflozin and empagliflozin are FDA-approved for HFrEF and HFpEF regardless of diabetes status. The DAPA-HF and EMPEROR trials included non-diabetic patients and showed equivalent benefit.

🔧 Fix: Prescribe SGLT2i for all eligible HF patients (EF ≤40%), regardless of diabetes.

---

Mistake #2: Stopping SGLT2i Due to Initial eGFR Dip ❌

Wrong thinking: "eGFR dropped from 45 to 40 after starting dapagliflozin—I need to stop it immediately."

Reality: A 5-10 mL/min decline in the first 2-4 weeks is:

• Expected (reduced glomerular hyperfiltration)
• Self-limiting (stabilizes by 2-3 months)
• Associated with long-term kidney protection

🔧 Fix: Continue SGLT2i unless:

• eGFR drops >20% (investigate for AKI, volume depletion)
• eGFR falls below continuation threshold (agent-dependent)
• Symptoms of volume depletion develop

---

Mistake #3: Not Monitoring for Genital Mycotic Infections ❌

Wrong thinking: "I don't need to counsel about side effects; it's just a diabetes drug."

Reality: Genital mycotic infections (yeast infections) occur in:

• 10-15% of women
• 3-5% of men
• Higher risk with history of infections, poor hygiene

Patients may be embarrassed to report symptoms and may discontinue medication without telling you.

🔧 Fix:

• Proactively counsel all patients at initiation
• "You may experience more yeast infections; maintain good hygiene"
• Recommend prompt treatment (topical antifungals)
• Reassure that infections are manageable and don't require stopping SGLT2i

---

Mistake #4: Forgetting DKA Risk in Insulin-Deficient Patients ❌

Wrong thinking: "SGLT2i are safe in all type 2 diabetes patients."

Reality: Euglycemic DKA (ketoacidosis with near-normal glucose) can occur, especially with:

• Prolonged fasting or very low-carb diets
• Acute illness, surgery, or hospitalization
• Insulin reduction/omission
• Type 1 diabetes (off-label use)

🔧 Fix:

• Hold SGLT2i during hospitalization, surgery, or severe illness
• Educate patients: "If you're sick and can't eat, stop this medication temporarily"
• Monitor for symptoms: nausea, vomiting, abdominal pain, shortness of breath
• Check beta-hydroxybutyrate if DKA suspected (glucose may be <200 mg/dL!)

---

Mistake #5: Not Adjusting Diuretics at Initiation ❌

Wrong thinking: "SGLT2i are added to the HF regimen without changing other medications."

Reality: SGLT2i cause:

• Osmotic diuresis (300-400 mL/day urine increase)
• Modest volume depletion
• Risk of orthostatic hypotension if patient already on high-dose diuretics

🔧 Fix:

• Assess volume status before initiation
• If patient is euvolemic or on high-dose loop diuretics, consider:
  • ⬇️ Loop diuretic dose by 25-50%
  • Monitor for dehydration, hypotension, AKI
• Counsel: "You may urinate more frequently for the first week"

---

Mistake #6: Missing Canagliflozin's Unique Amputation Risk ❌

Wrong thinking: "All SGLT2i have the same safety profile."

Reality: Canagliflozin carries a boxed warning for lower limb amputation risk (primarily toes/feet) based on CANVAS trial data. Risk factors:

• Prior amputation history
• Peripheral vascular disease
• Diabetic neuropathy
• Foot ulcers

🔧 Fix:

• Avoid canagliflozin in patients with high amputation risk
• Choose dapagliflozin or empagliflozin instead (no amputation signal)
• If using canagliflozin, perform regular foot exams

---

Key Takeaways 🎯

---

🧠 Memory Aids for NAPLEX Success

"SGLT-2 HEARTS" (Benefits):

• Sodium excretion (natriuresis)
• Glucose lowering (secondary benefit)
• Lower blood pressure (modest)
• Tubuloglomerular feedback restored
• Heart failure hospitalization ⬇️
• End-stage kidney disease ⬇️
• Albuminuria reduction
• Renal protection (long-term)
• Tolerance improved (QOL)
• Survival benefit (CV death ⬇️)

"DAPPER EMPEROR Can't" (Trial associations):

• DAPagliflozin = DAPA-HF, DAPA-CKD, DELIVER
• EMPagliflozin = EMPEROR-Reduced, EMPEROR-Preserved, EMPA-KIDNEY
• CANagliflozin = CREDENCE (but has amputation warning—"Can't use in PVD")

"Continue Below" (eGFR thresholds):

• Dapa: initiate ≥25, continue below
• Empa: initiate ≥20, continue below
• Cana: initiate ≥30, continue below

---

🤔 Did You Know?

The glucose-lowering effect of SGLT2i accounts for only about 40% of the cardiovascular benefit! The remaining 60% comes from:

• Hemodynamic effects (volume reduction, BP lowering)
• Metabolic shifts (ketone production as myocardial fuel)
• Anti-inflammatory and anti-fibrotic effects
• Direct renal tubular protection

This is why SGLT2i work even in non-diabetic patients—the mechanisms are independent of glucose lowering! 🎉

---

📚 Further Study

1. American Diabetes Association Standards of Care: Comprehensive guidelines on SGLT2i use in diabetes and cardiorenal disease - https://diabetesjournals.org/care/issue/47/Supplement_1

2. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in CKD: Detailed recommendations on SGLT2i for kidney protection - https://kdigo.org/guidelines/diabetes-ckd/

3. ACC/AHA Heart Failure Guidelines: Latest evidence on SGLT2i as foundational HF therapy - https://www.acc.org/guidelines/hf-guideline

---

🎓 Congratulations! You now have mastery-level understanding of SGLT2i in heart failure and chronic kidney disease—essential knowledge for NAPLEX success and exceptional patient care. Remember: These agents are no longer "just diabetes drugs"—they're cardiorenal protective therapies for all at-risk patients! 💪