Jardiance (Empagliflozin) in Patients with Diabetes Mellitus and Coronary Artery Disease
Jardiance (empagliflozin) is strongly recommended as a Class I, Level A therapy for patients with both diabetes mellitus and coronary artery disease to reduce cardiovascular death and major adverse cardiovascular events. 1, 2
Primary Indication and Evidence Base
Empagliflozin should be initiated in all patients with type 2 diabetes and established CAD unless contraindicated. 1, 2 The FDA has specifically approved empagliflozin to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease. 3
The landmark EMPA-REG OUTCOME trial demonstrated that empagliflozin, when added to standard care in 7,020 patients with type 2 diabetes and established atherosclerotic cardiovascular disease (76% had documented coronary artery disease), produced:
- 38% reduction in cardiovascular death (HR 0.62; 95% CI 0.49-0.77; p<0.001) 3, 4, 5
- 32% reduction in all-cause mortality (HR 0.68; 95% CI 0.57-0.82; p<0.001) 3, 4, 5
- 14% reduction in major adverse cardiovascular events (cardiovascular death, non-fatal MI, or non-fatal stroke; HR 0.86; 95% CI 0.74-0.99; p=0.04) 3, 4, 5
- 36% reduction in hospitalization for heart failure 5
The cardiovascular mortality benefit appeared within months of treatment initiation, suggesting mechanisms beyond glucose control alone. 6
Dosing and Initiation
Start empagliflozin at 10 mg once daily. 2 The dose can be increased to 25 mg daily if additional glycemic control is needed and the medication is well tolerated. 3
When initiating empagliflozin in patients with well-controlled HbA1c already on insulin, reduce total daily insulin dose by approximately 20% to prevent hypoglycemia. 1 Consider weaning or stopping sulfonylureas or glinides when starting empagliflozin to avoid hypoglycemic episodes. 1
Efficacy Considerations Based on Renal Function
The glucose-lowering efficacy of empagliflozin decreases with declining renal function:
- eGFR 60-90 mL/min/1.73 m²: HbA1c reduction of approximately 0.6% 3
- eGFR 45-60 mL/min/1.73 m²: HbA1c reduction of approximately 0.5% 3
- eGFR 30-45 mL/min/1.73 m²: HbA1c reduction of approximately 0.2% 3
- eGFR <30 mL/min/1.73 m²: No discernible glucose-lowering effect 3
However, cardiovascular and renal protective benefits persist even with reduced eGFR, so empagliflozin should not be discontinued solely based on declining renal function in patients with established CAD. 7, 1
Additional Cardiovascular Benefits
Beyond mortality reduction, empagliflozin provides:
- Reduction in worsening nephropathy (HR 0.61; 95% CI 0.53-0.70) 8
- Modest blood pressure reduction (systolic BP reduction of 2.9-5.2 mmHg) without compensatory heart rate increase 5
- Body weight reduction of approximately 2 kg 3, 5
Special Populations
Patients with Concurrent Heart Failure
If the patient has CAD, diabetes, and heart failure with LVEF ≤40%, empagliflozin receives a Class I recommendation to reduce cardiovascular death and heart failure hospitalization, regardless of diabetes status. 1
If the patient has CAD, diabetes, and heart failure with LVEF >40%, empagliflozin receives a Class IIa recommendation to decrease heart failure hospitalizations and improve quality of life. 1
Patients with Peripheral Artery Disease
In the EMPA-REG OUTCOME trial, 20.8% of patients had peripheral artery disease at baseline. 7 In this subgroup, empagliflozin reduced cardiovascular death (HR 0.57; 95% CI 0.37-0.88) and all-cause mortality (HR 0.62; 95% CI 0.44-0.88). 7 There was a non-significant trend toward reduced limb amputation (5.5% vs 6.3%; HR 0.84; 95% CI 0.54-1.32), contrasting with concerns raised about canagliflozin. 7, 9
Safety Monitoring and Precautions
Common Adverse Effects to Monitor
- Genital mycotic infections are the most common adverse effect, typically straightforward to manage 4, 10
- Volume depletion and hypotension, especially when combined with diuretics—consider reducing diuretic doses if signs of volume contraction develop 1
- Urinary tract infections occur at slightly higher rates than placebo 3
Critical Safety Measures
Discontinue empagliflozin at least 3 days before planned surgery to prevent postoperative diabetic ketoacidosis. 1 This is a critical safety measure as SGLT2 inhibitors can cause euglycemic diabetic ketoacidosis.
Monitor for diabetic ketoacidosis, particularly in patients with reduced insulin reserve, prolonged fasting, or acute illness. 6 Empagliflozin shares this risk with other SGLT2 inhibitors.
Assess renal function before initiation and periodically thereafter. 3 While empagliflozin provides renal protective effects, acute kidney injury can occur, particularly with concurrent use of nephrotoxic drugs or in volume-depleted states. 6
Integration with Comprehensive CAD Management
Empagliflozin should be part of a comprehensive treatment strategy:
- First-line: Empagliflozin (Class I, Level A) 1, 2
- Concurrent therapies: ACE inhibitors or ARBs (Class I), high-intensity statins targeting LDL-C <55 mg/dL with ≥50% reduction (Class I), and aspirin 75-160 mg daily (Class I) 2
- Additional glucose control: Add metformin and other glucose-lowering agents as necessary to achieve HbA1c <7% (53 mmol/mol) 7
- Consider GLP-1 receptor agonists (liraglutide or semaglutide) as complementary therapy for additional cardiovascular risk reduction 7, 2
Medications to Avoid
Do not use thiazolidinediones (pioglitazone, rosiglitazone) or saxagliptin in patients with CAD due to increased heart failure risk (Class III recommendation). 2
Clinical Context and Mechanism
The cardiovascular benefit of empagliflozin appears to extend beyond its glucose-lowering effects. 6 The rapid onset of mortality benefit (within months) and the diuretic effect suggest mechanisms related to hemodynamic improvements and heart failure prevention rather than prevention of atherosclerotic complications. 6 This explains why the reduction in cardiovascular death was substantial despite no significant difference in myocardial infarction or stroke rates individually. 6