Can I add tirzepatide to Jardiance (empagliflozin) in an adult patient with type 2 diabetes who is already tolerating empagliflozin at a stable dose and has adequate renal function (estimated glomerular filtration rate ≥ 45 mL/min/1.73 m²)?

Adding Tirzepatide to Jardiance (Empagliflozin) in Type 2 Diabetes

Yes, you can and should add tirzepatide to Jardiance (empagliflozin) in an adult patient with type 2 diabetes who has adequate renal function (eGFR ≥45 mL/min/1.73 m²), as this combination provides complementary cardiovascular and renal protection through distinct mechanisms without requiring dose adjustment of either medication. 1

Rationale for Combination Therapy

• SGLT2 inhibitors (empagliflozin) and GLP-1 receptor agonists (tirzepatide) are both recommended as priority agents for patients with type 2 diabetes, independent of baseline HbA1c or need for additional glucose lowering. 1

• The 2018 American College of Cardiology guidelines explicitly recommend considering the addition of both an SGLT2 inhibitor and a GLP-1 receptor agonist in patients with type 2 diabetes and established atherosclerotic cardiovascular disease, as these agents provide demonstrated cardiovascular outcome benefits through different pathways. 1

• Empagliflozin reduces cardiovascular death by 38% (HR 0.62; 95% CI 0.49-0.77) and all-cause mortality by 32% (HR 0.68; 95% CI 0.57-0.82), while GLP-1 receptor agonists provide complementary benefits including a 36% reduction in new or worsening nephropathy. 1, 2

Renal Function Requirements

• Empagliflozin can be initiated and continued at 10 mg or 25 mg daily when eGFR ≥45 mL/min/1.73 m², with no dose adjustment required at this threshold. 1, 3

• Tirzepatide can be used across all stages of chronic kidney disease without dose adjustment, making it an ideal partner for empagliflozin even if renal function declines over time. 2

• If eGFR falls below 45 mL/min/1.73 m² while on empagliflozin, do not discontinue the medication solely for this reason, as cardiovascular and renal protective benefits persist down to eGFR of 30 mL/min/1.73 m². 3

Practical Implementation Algorithm

Step 1: Confirm Eligibility

• Verify eGFR ≥45 mL/min/1.73 m² for optimal empagliflozin efficacy (though cardiovascular benefits extend to eGFR ≥30 mL/min/1.73 m²). 3
• Assess volume status and correct any depletion before adding tirzepatide. 2
• Exclude contraindications: pregnancy, breastfeeding, personal or family history of medullary thyroid carcinoma, or multiple endocrine neoplasia syndrome type 2. 2

Step 2: Initiate Tirzepatide

• Start tirzepatide at 2.5 mg subcutaneously once weekly for 4 weeks, then increase to 5 mg weekly. 2
• Continue empagliflozin at the current stable dose (10 mg or 25 mg daily) without adjustment. 3
• If the patient is on insulin or sulfonylureas, reduce insulin dose by approximately 20% and consider discontinuing sulfonylureas to prevent hypoglycemia. 2, 4

Step 3: Monitor and Titrate

• Recheck eGFR within 1-2 weeks after adding tirzepatide; expect a transient eGFR dip of 2-5 mL/min/1.73 m² with empagliflozin, which is hemodynamic and reversible. 2, 4
• Monitor blood glucose closely for the first 2-4 weeks, especially if other glucose-lowering agents remain in use. 2
• Tirzepatide can be titrated up to 15 mg weekly after at least 4 weeks at each dose, based on glycemic response and tolerability. 2

Safety Considerations and Common Pitfalls

Volume Depletion Risk

• Both empagliflozin and tirzepatide can cause volume depletion; elderly patients (≥75 years) and those on concurrent diuretics require heightened vigilance. 2, 4
• Consider reducing loop or thiazide diuretic doses when adding tirzepatide to empagliflozin. 2, 4

Sick Day Management

• Instruct patients to withhold both empagliflozin and tirzepatide during acute illness with reduced oral intake, fever, vomiting, or diarrhea. 2, 4
• Stop empagliflozin at least 3 days before major surgery or procedures requiring prolonged fasting. 2

Hypoglycemia Prevention

• The combination of empagliflozin and tirzepatide has low intrinsic hypoglycemia risk when used without insulin or sulfonylureas. 2
• If baseline HbA1c is <8.5%, discontinue sulfonylureas completely and reduce insulin dose by 20% when adding tirzepatide. 2, 4

Gastrointestinal Tolerability

• Tirzepatide commonly causes nausea, vomiting, and diarrhea, especially during dose escalation; slow titration and taking the medication with food may improve tolerability. 2

Genital Mycotic Infections

• Empagliflozin increases the risk of genital mycotic infections (approximately 6% vs. 1% with placebo); counsel patients on daily hygiene measures. 2, 4

Critical Pitfalls to Avoid

• Do not discontinue empagliflozin when eGFR falls below 45 mL/min/1.73 m²; cardiovascular and renal benefits persist even when glucose-lowering efficacy diminishes. 3

• Do not stop empagliflozin in response to the expected early eGFR dip; this change is hemodynamic and reversible, not indicative of kidney injury. 2, 4

• Do not reduce the empagliflozin dose below 10 mg for cardiovascular or renal indications, even at lower eGFR levels; both 10 mg and 25 mg doses demonstrated cardiovascular benefit in the EMPA-REG OUTCOME trial. 3

• Do not withhold ACE inhibitors or ARBs when adding tirzepatide to empagliflozin; continue these agents unchanged as part of comprehensive cardiorenal protection. 2

Cardiovascular and Renal Protection Benefits

• Empagliflozin reduces heart failure hospitalization by 35% (HR 0.65; 95% CI 0.50-0.85) and slows progression of kidney disease, including a 44% reduction in doubling of serum creatinine. 3, 5

• GLP-1 receptor agonists like tirzepatide provide complementary cardiovascular protection through improved endothelial function, weight loss, and enhanced glycemic control. 2

• The combination addresses multiple pathophysiologic mechanisms in type 2 diabetes: empagliflozin reduces intraglomerular pressure and attenuates eGFR decline, while tirzepatide improves insulin sensitivity and reduces cardiovascular risk factors. 2, 5