What is the recommended treatment approach for an adult patient with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or high risk of cardiovascular events using Jardiance (empagliflozin)?

Jardiance (Empagliflozin) for Type 2 Diabetes with Cardiovascular Disease

Empagliflozin 10 mg once daily is the recommended first-line glucose-lowering agent for adults with type 2 diabetes and established cardiovascular disease, with dose escalation to 25 mg if needed for additional glycemic control. 1

Primary Indication and Cardiovascular Benefits

Empagliflozin carries a Class I, Level A recommendation from the European Society of Cardiology to reduce cardiovascular death in patients with type 2 diabetes and established cardiovascular disease. 2, 3

The landmark EMPA-REG OUTCOME trial demonstrated:

• 38% reduction in cardiovascular death (HR 0.62; 95% CI 0.49-0.77) 2, 3
• 32% reduction in all-cause mortality (HR 0.68; 95% CI 0.57-0.82) 2, 4
• 35% reduction in hospitalization for heart failure 2
• 14% reduction in major adverse cardiovascular events (MACE: CV death, non-fatal MI, or non-fatal stroke; HR 0.86; 95% CI 0.74-0.99) 5, 4

These benefits appear within months of initiation and are independent of baseline HbA1c levels, suggesting the mechanism extends beyond glucose lowering. 6, 5

Dosing and Administration

Start empagliflozin 10 mg once daily in the morning, with or without food. 1

• Increase to 25 mg once daily if additional glycemic control is needed 1
• Both doses showed similar cardiovascular benefits in clinical trials 2, 7
• Expected HbA1c reduction: 0.5-0.8% from baseline 6, 4

Renal Function Requirements and Monitoring

Assess estimated glomerular filtration rate (eGFR) before initiating empagliflozin. 1

Critical thresholds:

• Do not initiate if eGFR <45 mL/min/1.73 m² 1
• Discontinue if eGFR falls persistently below 45 mL/min/1.73 m² 1
• Cardiovascular and mortality benefits persist in patients with chronic kidney disease (eGFR 30-60 mL/min/1.73 m²), though glucose-lowering efficacy diminishes 7

In patients with prevalent kidney disease at baseline (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 hospitalization for heart failure by 39% (HR 0.61; 95% CI 0.42-0.87). 7

Combination Therapy Strategy

In patients with peripheral arterial disease (PAD) and type 2 diabetes, empagliflozin is recommended as the foundational glucose-lowering agent, with metformin and GLP-1 receptor agonists added as necessary for glycemic control. 2

Among PAD patients in EMPA-REG OUTCOME (20.8% of trial population):

• 43% reduction in cardiovascular death (HR 0.57; 95% CI 0.37-0.88) 2
• 38% reduction in all-cause mortality (HR 0.62; 95% CI 0.44-0.88) 2
• Non-significant reduction in limb amputation risk (HR 0.84; 95% CI 0.54-1.32) 2

When combining with DPP-4 inhibitors, use sitagliptin rather than saxagliptin, as saxagliptin increases heart failure hospitalization risk. 8, 3

Safety Precautions and Contraindications

Absolute contraindications: 1

• History of serious hypersensitivity reaction to empagliflozin
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• End-stage renal disease or dialysis

Volume status assessment before initiation is mandatory, particularly in: 1

• Elderly patients
• Patients with eGFR 30-60 mL/min/1.73 m²
• Patients with low systolic blood pressure
• Patients on diuretics

Discontinue empagliflozin at least 3 days before planned surgery to prevent postoperative euglycemic ketoacidosis. 8

Ketoacidosis Risk Management

Monitor for signs of diabetic ketoacidosis regardless of blood glucose level, as empagliflozin can cause euglycemic DKA. 1

High-risk scenarios requiring temporary discontinuation:

• Prolonged fasting or reduced oral intake 1
• Acute illness with volume depletion 1
• Perioperative period 8, 1

If metabolic acidosis is suspected, discontinue empagliflozin immediately, evaluate, and treat promptly. 1

Hypoglycemia Prevention

Empagliflozin has no intrinsic hypoglycemia risk when used alone or with metformin. 9, 4

When combining with insulin or insulin secretagogues (sulfonylureas), reduce the dose of these agents to minimize hypoglycemia risk. 1

Common Adverse Effects

The most frequent adverse reactions (≥5% incidence): 1

• Urinary tract infections
• Female genital mycotic infections (straightforward to manage with topical antifungals) 5

Less common but important:

• Volume depletion (especially in elderly or those on diuretics) 1
• Increased LDL-C (monitor and treat as appropriate) 1
• Urosepsis and pyelonephritis (evaluate and treat promptly if suspected) 1

Special Populations

Elderly patients have higher incidence of adverse reactions related to volume depletion and reduced renal function. 1

Pregnancy: Advise females of potential fetal risk, especially during second and third trimesters. 1

Lactation: Empagliflozin is not recommended when breastfeeding. 1

Clinical Pitfalls to Avoid

• Do not withhold empagliflozin based solely on HbA1c levels – cardiovascular benefits occur independently of glycemic control 10, 6
• Do not discontinue empagliflozin when eGFR falls below the glycemic efficacy threshold (45-60 mL/min/1.73 m²) if the patient tolerates it, as cardiorenal benefits persist 8
• Do not combine with thiazolidinediones (pioglitazone, rosiglitazone) due to increased heart failure risk 3
• Avoid using canagliflozin as an alternative in PAD patients due to increased amputation risk in the CANVAS trial (though not confirmed in CREDENCE) 2