Empagliflozin in Type 2 Diabetes: Evidence-Based Role
Empagliflozin is indicated as an adjunct to diet and exercise for glycemic control in adults with type 2 diabetes, and more importantly, to reduce cardiovascular death in patients with type 2 diabetes and established cardiovascular disease. 1
Primary Indications and Patient Selection
Cardiovascular Disease Reduction
- Empagliflozin should be prescribed for all patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) to reduce cardiovascular mortality and prevent heart failure hospitalization. 2, 3
- The EMPA-REG OUTCOME trial demonstrated a 38% reduction in cardiovascular death (HR 0.62; 95% CI 0.49-0.77) and a 14% reduction in the composite outcome of MI, stroke, and cardiovascular death (HR 0.86; 95% CI 0.74-0.99) over 3.1 years in 7,020 patients with established cardiovascular disease. 2, 3
- All-cause mortality was reduced by 32% (HR 0.68; 95% CI 0.57-0.82), representing one of the most robust mortality benefits demonstrated for any glucose-lowering agent. 3, 4
Heart Failure Prevention
- Empagliflozin reduces hospitalization for heart failure by 35% (HR 0.65; 95% CI 0.50-0.85) and should be used in patients with type 2 diabetes at risk for or with established heart failure. 2, 3
- This benefit occurs regardless of baseline heart failure status, making empagliflozin valuable for primary prevention in asymptomatic patients with type 2 diabetes and cardiovascular risk factors (stage B heart failure). 2, 5
- Only 10% of EMPA-REG OUTCOME participants had prior heart failure, yet the heart failure hospitalization benefit was consistent across all subgroups. 2
Chronic Kidney Disease Protection
- In patients with type 2 diabetes and chronic kidney disease (eGFR ≥30 mL/min/1.73 m²), empagliflozin reduces 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
- Empagliflozin reduced incident or worsening nephropathy by 39% (HR 0.61) and progression to macroalbuminuria by 38% (HR 0.62). 3
- These renal benefits occur independently of glucose-lowering effects and persist across all stages of chronic kidney disease studied. 6
Mechanism and Glycemic Efficacy
Pharmacologic Action
- Empagliflozin inhibits SGLT2 in the proximal renal tubule, reducing renal glucose reabsorption and lowering the renal threshold for glucose, thereby increasing urinary glucose excretion by approximately 64-78 grams per day. 1
- The mechanism is insulin-independent, conferring a low inherent risk of hypoglycemia when used as monotherapy. 7, 8
- Peak plasma concentrations occur at 1.5 hours post-dose with a terminal elimination half-life of 12.4 hours, supporting once-daily dosing. 1
Glucose-Lowering Effects
- Empagliflozin produces HbA1c reductions of 0.59-0.82% across phase 3 trials when used as monotherapy or add-on therapy. 4
- Important caveat: Glucose-lowering efficacy diminishes significantly in patients with eGFR <45 mL/min/1.73 m² due to decreased urinary glucose excretion, though cardiovascular and renal benefits persist. 1, 8, 9
Additional Cardiometabolic Benefits
- Empagliflozin reduces body weight by 2.1-2.5 kg through caloric loss via glucosuria. 4
- Systolic blood pressure decreases by 2.9-5.2 mmHg without compensatory increase in heart rate, likely due to osmotic diuresis and natriuresis. 3, 4
- These cardiovascular benefits are independent of glucose-lowering effects and occur regardless of baseline HbA1c levels. 2, 3
Dosing and Administration
- FDA-approved doses are 10 mg or 25 mg once daily. 1
- Empagliflozin may be administered with or without food, as food reduces AUC by only 16% and Cmax by 37%, which is not clinically significant. 1
- No dose adjustment is required for mild to moderate renal impairment, though efficacy for glucose lowering decreases with eGFR <45 mL/min/1.73 m². 1, 9
- Empagliflozin is contraindicated in patients with severe renal impairment, ESRD, or those receiving dialysis, as it is not expected to be effective. 1
Safety Profile and Adverse Events
Common Adverse Events
- Genital mycotic infections are the most common adverse event, occurring more frequently than placebo but generally straightforward to manage. 7, 8
- Urinary tract infections occur at increased rates compared to placebo. 1
- Volume depletion-related adverse reactions may occur, particularly in patients with baseline renal impairment, elderly patients, or those on diuretics. 1
Serious but Rare Risks
- Euglycemic diabetic ketoacidosis is a rare but serious risk that requires patient education and monitoring, particularly during acute illness, surgery, or periods of reduced food intake. 10
- Unlike canagliflozin, empagliflozin has not been associated with increased risk of lower-limb amputation or bone fractures, representing a safety advantage. 7
- The adverse event profile in patients with eGFR <60 mL/min/1.73 m² was consistent with the overall trial population. 6
Place in Treatment Algorithm
- Empagliflozin should be initiated early in the treatment course for patients with type 2 diabetes and established ASCVD, heart failure, or chronic kidney disease, independent of HbA1c levels and metformin use. 2, 10
- The American Diabetes Association recommends SGLT2 inhibitors as part of the glucose-lowering regimen for these high-risk populations based on cardiovascular and renal outcome benefits. 2
- Empagliflozin can be combined with GLP-1 receptor agonists for complementary cardiovascular and renal benefits, as these drug classes have different mechanisms of action. 10
Comparative Considerations
- Both empagliflozin and dapagliflozin demonstrate significant cardiovascular benefits, with empagliflozin showing a 35% reduction in heart failure hospitalization versus dapagliflozin's 27% reduction in respective trials. 5
- Empagliflozin's 38% reduction in cardiovascular death is particularly robust compared to other SGLT2 inhibitors. 5, 3
- Monthly costs are similar between SGLT2 inhibitors, with empagliflozin 25mg costing approximately $627 versus dapagliflozin 10mg at $621. 5