What are the clinical trials and dosing recommendations for Empagliflozin (Empagliflozin) in patients with type 2 diabetes?

Empagliflozin Clinical Trials Summary

Major Cardiovascular Outcomes Trials

Empagliflozin has demonstrated robust cardiovascular and mortality benefits across multiple landmark trials, most notably reducing cardiovascular death by 38%, hospitalization for heart failure by 35%, and all-cause mortality by 32% in high-risk patients with type 2 diabetes. 1

EMPA-REG OUTCOME Trial (2015)

• Study Design: Randomized, double-blind trial enrolling 7,020 patients with type 2 diabetes and established cardiovascular disease, followed for median 3.1 years 1
• Patient Characteristics: Mean age 63 years, 57% had diabetes >10 years, 99% had established cardiovascular disease, mean baseline A1C 8.1% 2
• Dosing: Empagliflozin 10 mg or 25 mg once daily versus placebo 1
• Primary Outcome: 3-point MACE (cardiovascular death, nonfatal MI, nonfatal stroke) occurred in 10.5% empagliflozin group vs 12.1% placebo (HR 0.86,95% CI 0.74-0.99, P=0.04) 1
• Key Secondary Outcomes:
  • Cardiovascular death: 3.7% vs 5.9% placebo (38% relative risk reduction) 1
  • Hospitalization for heart failure: 2.7% vs 4.1% placebo (35% relative risk reduction) 1
  • All-cause mortality: 5.7% vs 8.3% placebo (32% relative risk reduction) 1
  • Worsening nephropathy: 12.7% vs 18.8% placebo (HR 0.61) 3

EMPEROR-Reduced Trial

• Study Design: Enrolled 3,730 patients with heart failure with reduced ejection fraction (≤40%), NYHA class II-IV, approximately 50% with type 2 diabetes 4
• Dosing: Empagliflozin 10 mg daily versus placebo 4
• Primary Outcome: Composite of cardiovascular death or hospitalization for worsening heart failure reduced by 21% (HR 0.79,95% CI 0.69-0.90, P<0.001) 4
• Key Finding: Benefits were consistent regardless of diabetes status 4

EMPEROR-Preserved Trial

• Study Design: Randomized 5,988 adults with NYHA functional class I-IV chronic heart failure with preserved ejection fraction (LVEF >40%), approximately 50% with type 2 diabetes at baseline 2
• Dosing: Empagliflozin 10 mg daily versus placebo 2
• Follow-up: Median 26.2 months 2
• Primary Outcome: Composite cardiovascular death or hospitalization for heart failure reduced by 21% (HR 0.79,95% CI 0.69-0.90, P<0.001) 2
• Key Finding: Effects were consistent in patients with or without diabetes 2

Cardiovascular Risk Spectrum Analysis

Heart Failure Risk Stratification

• Risk Distribution: Among patients without baseline heart failure, 67.2% had low-to-average (<10%), 24.2% high (10-20%), and 5.1% very high (≥20%) 5-year heart failure risk using Health ABC HF Risk score 5
• Consistent Benefits: Empagliflozin reduced cardiovascular death and heart failure hospitalization across all risk groups: HR 0.71 (0.52-0.96) in low-to-average, 0.52 (0.36-0.75) in high, and 0.55 (0.30-1.00) in very high risk groups 5
• Highest Risk Patients: In patients with baseline heart failure and/or incident heart failure during trial (37.9% of overall CV deaths), empagliflozin showed HR 0.67 (0.47-0.97) for cardiovascular death 5

KDIGO Risk Categories

• Risk Distribution: 47% low, 29% moderately increased, 15% high, and 8% very high KDIGO risk categories 3
• Consistent Treatment Effect: Empagliflozin showed consistent risk reductions across all KDIGO categories for cardiovascular outcomes (P for interaction 0.26-0.85) and kidney outcomes (P for interaction 0.16-0.60) 3
• Renal Function: Benefits observed even in patients with eGFR as low as 30 mL/min/1.73 m² 3

TIMI Risk Score Analysis

• Risk Distribution: 12% low (≤2 points), 40% intermediate (3 points), 30% high (4 points), and 18% highest (≥5 points) estimated cardiovascular risk 6
• Event Rates: In placebo group, 3-point MACE occurred in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest risk, respectively 6
• Consistent Benefits: Relative reductions in cardiovascular death, all-cause mortality, 3-point MACE, and heart failure hospitalization were consistent across all TIMI risk categories (P>0.05 for interactions) 6

Glycemic Efficacy Trials

Phase 3 Clinical Program

• A1C Reductions: Empagliflozin demonstrated A1C reductions of -0.59% to -0.82% across phase 3 trials 7
• Body Weight: Moderate reductions of -2.1 to -2.5 kg observed 7
• Blood Pressure: Systolic blood pressure reductions of -2.9 to -5.2 mmHg without compensatory heart rate increase 7
• Hypoglycemia Risk: Low risk of hypoglycemia except when combined with insulin or insulin secretagogues 7
• Mechanism: Glucose-lowering independent of β-cell function, effective at any disease stage 7

Renal Function Considerations

Efficacy by Renal Function

• Mild-Moderate Impairment: Study included 195 patients with eGFR 60-90,91 patients with eGFR 45-60, and 97 patients with eGFR 30-45 mL/min/1.73 m² 8
• Diminished Glycemic Benefit: Glucose-lowering benefit of empagliflozin 25 mg decreased with worsening renal function 8
• Cardiovascular Benefits Maintained: In 1,819 patients with eGFR <60 mL/min/1.73 m², cardiovascular death findings were consistent with overall trial results 8
• Contraindication: Not expected to be effective in severe renal impairment, ESRD, or dialysis patients 8

Safety Profile

Common Adverse Events

• Genital Infections: Increased rate compared to placebo across all trials 3, 1
• Volume Depletion: Risk increased in patients ≥75 years (4.4% with empagliflozin 25 mg vs 2.1% placebo) 8
• Urinary Tract Infections: Increased in elderly patients ≥75 years (15.1-15.7% with empagliflozin vs 10.5% placebo) 8

Diabetic Ketoacidosis Risk

• Mechanism: Multiple pathways including reduced insulin doses, increased glucagon leading to lipolysis, and decreased renal clearance of ketones 2
• Trial Exclusions: Cardiovascular and heart failure outcomes trials excluded patients with type 1 diabetes and/or recent diabetic ketoacidosis history 2, 9
• High-Risk Situations: Insulin pump malfunctions, significant insulin dose reductions, prolonged fasting, or carbohydrate restriction 2

Special Populations

• Elderly: No dosage adjustment needed based on age, but diminished glycemic efficacy expected with renal impairment 8
• Pregnancy: Not recommended; empagliflozin crosses placenta and may affect fetal renal development 8
• Lactation: Not recommended while breastfeeding due to potential effects on postnatal renal development 8
• Hepatic Impairment: May be used without dose adjustment 8

Dosing Recommendations

Standard Dosing

• Type 2 Diabetes with CVD: 10 mg or 25 mg once daily 1
• Heart Failure: 10 mg daily regardless of diabetes status 4
• Renal Adjustment: Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²), ESRD, or dialysis 8

Clinical Implementation

• Initiation Timing: Can be initiated during heart failure hospitalization in stabilized patients 4
• Combination Therapy: Provides additive benefit to optimal guideline-directed medical therapy including ACE inhibitors, ARBs, beta-blockers, and mineralocorticoid receptor antagonists 4
• Insulin Management: Never reduce basal insulin doses when initiating in type 1 diabetes (off-label use) 9