What is the role of Empagliflozin (Jardiance) in treating a patient with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD), including myocardial infarction (MI), stroke, or peripheral artery disease (PAD), with consideration for impaired renal function?

Empagliflozin for Type 2 Diabetes with Established Cardiovascular Disease

Empagliflozin is strongly recommended for patients with type 2 diabetes and established cardiovascular disease (including MI, stroke, or PAD), as it reduces cardiovascular death by 38% and all-cause mortality by 32%, with benefits maintained even in patients with impaired renal function down to eGFR ≥30 mL/min/1.73 m².

FDA-Approved Indications

Empagliflozin (Jardiance) is FDA-approved specifically to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease, in addition to its glucose-lowering indication 1.

Cardiovascular Benefits in High-Risk Patients

Primary Cardiovascular Outcomes

The EMPA-REG OUTCOME trial enrolled 7,020 patients with type 2 diabetes and established atherosclerotic cardiovascular disease (99% had established ASCVD), with mean age 63 years and 57% having diabetes duration >10 years 2, 3. The trial demonstrated:

• Cardiovascular death reduction of 38% (HR 0.62; 95% CI 0.49-0.77) 4, 2
• All-cause mortality reduction of 32% (HR 0.68; 95% CI 0.57-0.82) 2
• Heart failure hospitalization reduction of 35% (HR 0.65; 95% CI 0.50-0.85) 4, 2
• 3-point MACE reduction of 14% (HR 0.86; 95% CI 0.74-0.99) for the composite of cardiovascular death, non-fatal MI, or non-fatal stroke 4, 2, 3

Mechanism of Cardiovascular Protection

The cardiovascular benefits appear independent of glucose-lowering effects and likely result from empagliflozin's additional mechanisms including diuresis, natriuresis, weight loss, and systolic blood pressure reduction 2. The mortality benefit emerged rapidly (within months), consistent with hemodynamic effects rather than prevention of atherosclerotic complications 5.

Use in Impaired Renal Function

Efficacy Across Renal Function Levels

Empagliflozin maintains cardiovascular and renal benefits even with impaired kidney function 6:

• In patients with prevalent kidney disease (eGFR <60 mL/min/1.73 m² and/or urine albumin-creatinine ratio >300 mg/g), empagliflozin reduced cardiovascular death by 29% (HR 0.71; 95% CI 0.52-0.98) and all-cause mortality by 24% (HR 0.76; 95% CI 0.59-0.99) 6
• Effects were consistent across eGFR categories including <45-<60-<90, and ≥90 mL/min/1.73 m² 6
• Heart failure hospitalization was reduced by 39% (HR 0.61; 95% CI 0.42-0.87) in patients with baseline kidney disease 6

Glucose-Lowering Efficacy by Renal Function

While cardiovascular benefits persist, glucose-lowering efficacy diminishes with declining renal function 1:

• eGFR 60 to <90 mL/min/1.73 m²: HbA1c reduction of -0.6%
• eGFR 45 to <60 mL/min/1.73 m²: HbA1c reduction of -0.5%
• eGFR 30 to <45 mL/min/1.73 m²: HbA1c reduction of -0.2%
• eGFR <30 mL/min/1.73 m²: No discernible glucose-lowering effect 1

Dosing Recommendations with Renal Impairment

Empagliflozin 25 mg provided statistically significant HbA1c reduction in patients with mild to moderate renal impairment (eGFR 30 to <90 mL/min/1.73 m²) 1. The drug is not recommended for initiating therapy in patients with eGFR <30 mL/min/1.73 m² for glucose control, though cardiovascular benefits may still apply 1.

Renal Protection Benefits

• Incident or worsening nephropathy reduced by 39% (HR 0.61) 2
• Progression to macroalbuminuria reduced by 38% (HR 0.62) in the overall population 2
• In patients with heart failure, progression to macroalbuminuria reduced by 50% (HR 0.50; 95% CI 0.33-0.75) 7
• eGFR stabilized over time with empagliflozin versus gradual decline with placebo 7

Guideline Recommendations

The 2025 American Diabetes Association Standards of Care state that in people with type 2 diabetes and established ASCVD, multiple ASCVD risk factors, or CKD, an SGLT2 inhibitor with demonstrated cardiovascular benefit (specifically empagliflozin) is recommended to reduce the risk of major adverse cardiovascular events and/or heart failure hospitalization 4.

Safety Considerations

Common Adverse Effects

• Genital mycotic infections are the most common adverse effect but are typically straightforward to manage 8, 9
• Volume depletion and hypotension can occur, especially with concomitant diuretics or antihypertensive drugs 5
• Diabetic ketoacidosis risk, though rare 5

Renal Safety

The adverse event profile in patients with eGFR <60 mL/min/1.73 m² was consistent with the overall trial population 6. Kidney-related adverse event rates were comparable between empagliflozin and placebo groups 7.

Important Distinction from Other SGLT2 Inhibitors

Unlike canagliflozin, empagliflozin has not been associated with increased risk of amputation or bone fractures 8.

Clinical Algorithm for Use

For patients with T2DM and established CVD (MI, stroke, or PAD):

1. Add empagliflozin regardless of baseline HbA1c or current glucose control 2, 3
2. Check baseline eGFR:
   • eGFR ≥30 mL/min/1.73 m²: Initiate empagliflozin 10 mg daily, may increase to 25 mg 1
   • eGFR <30 mL/min/1.73 m²: Consider for cardiovascular benefits despite limited glucose-lowering effect 1
3. Monitor for volume depletion if patient is on diuretics or has eGFR 30-60 mL/min/1.73 m² 5
4. Maintain stable background antidiabetic therapy for first 12 weeks, then adjust as needed 1
5. Continue empagliflozin even if eGFR declines during treatment, as cardiovascular and renal benefits persist 6, 7