Why does Jardiance (empagliflozin) cause an initial decrease in Glomerular Filtration Rate (GFR) in patients with type 2 diabetes mellitus?

Why Jardiance Causes an Initial GFR Dip

Jardiance (empagliflozin) causes an initial decrease in GFR of 3-5 mL/min/1.73 m² due to hemodynamic changes that reduce intraglomerular pressure—this is a reversible, protective mechanism that actually predicts better long-term kidney outcomes, not kidney injury. 1, 2

Mechanism of the Initial eGFR Dip

The initial GFR decline occurs through a specific hemodynamic pathway:

• SGLT2 inhibition blocks glucose and sodium reabsorption in the proximal tubule, leading to increased sodium delivery to the distal tubule and macula densa 2
• This triggers tubuloglomerular feedback, causing afferent arteriole vasoconstriction and reducing intraglomerular pressure 2
• The reduction in glomerular hyperfiltration manifests as a 3-5 mL/min/1.73 m² eGFR decline within the first 1-4 weeks of treatment 1, 3

This is fundamentally different from true kidney injury—it represents normalization of pathologically elevated intraglomerular pressure that drives progressive kidney damage in diabetes.

Timeline and Reversibility

The eGFR changes follow a predictable three-phase pattern:

• Initiation phase (baseline to week 4): Mean eGFR slope decreases by -0.77 mL/min/1.73 m² per week with empagliflozin versus +0.01 with placebo 2
• Chronic maintenance phase (week 4 onward): Annual eGFR slope becomes +0.23 mL/min/1.73 m² per year with empagliflozin versus -1.46 with placebo, demonstrating kidney function preservation 2
• Post-treatment phase: After drug cessation, eGFR increases by +0.56 mL/min/1.73 m² per week, returning toward baseline, confirming the hemodynamic (not structural) nature of the initial dip 2

Kidney function generally returns to baseline in the following weeks and remains stable during SGLT2 inhibitor therapy or until drug discontinuation. 1

Clinical Implications of the eGFR Dip

Contrary to initial concerns, the eGFR dip is actually a favorable prognostic marker:

• 28.3% of empagliflozin-treated patients experience an eGFR dip >10% versus 13.4% on placebo (odds ratio 2.7,95% CI 2.3-3.0) 3
• Patients experiencing an acute eGFR reduction >10% at 2 weeks had better long-term renal outcomes with slower subsequent eGFR decline (-1.58 vs -2.44 mL/min/1.73 m²/year) compared to those without an initial dip 3
• The initial eGFR dip did not diminish treatment effects on cardiovascular death, heart failure hospitalization, or kidney disease progression 3

Predictive Factors for Larger eGFR Dips

Certain patient characteristics predict a more pronounced initial decline:

• Diuretic use at baseline independently predicts a larger eGFR dip 3
• Higher KDIGO risk category (more advanced CKD) predicts a larger eGFR dip 3
• Patients with hypovolemia are more susceptible to these changes 4

However, cardiovascular and kidney benefits remain consistent regardless of these predictive factors—patients at higher risk for an eGFR dip still derive full benefit from treatment. 3

Practical Management Approach

Do not discontinue empagliflozin solely because of an initial eGFR decline of 3-10%. 1 This is the expected hemodynamic response.

Monitoring Protocol:

• Check eGFR within 1-2 weeks after initiation to document the expected dip 5
• Assess volume status before starting and correct any volume depletion 5, 4
• Renal function should be evaluated prior to initiation and monitored periodically thereafter, with more frequent monitoring in patients with eGFR <60 mL/min/1.73 m² 4

When to Investigate Further:

• If eGFR decreases >30% from baseline AND there are signs of hypovolemia, reduce diuretic doses first before considering drug adjustment 5
• Consider temporarily discontinuing in settings of reduced oral intake (acute illness, fasting) or fluid losses (gastrointestinal illness, excessive heat exposure) 4

Key Pitfall to Avoid:

The most common error is discontinuing empagliflozin when eGFR falls below 45 mL/min/1.73 m² during treatment. 5 While empagliflozin should not be initiated for glycemic control at eGFR <45 mL/min/1.73 m², cardiovascular and renal protective benefits persist even when glycemic efficacy is lost, so continuation is appropriate. 6, 7

Distinction from True Acute Kidney Injury

The initial eGFR dip must be distinguished from true acute kidney injury:

• Hemodynamic dip: Occurs predictably within 1-4 weeks, stabilizes, reverses upon discontinuation, and predicts better long-term outcomes 2, 3
• True AKI: Progressive decline, associated with volume depletion or concurrent nephrotoxins, does not reverse with continued therapy 4

Before initiating empagliflozin, consider factors that may predispose to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). 4