Is it recommended to take Jardiance (Empagliflozin), Januvia (Sitagliptin), and Ozempic (Semaglutide) together?

Combination Therapy with Jardiance, Januvia, and Ozempic

Yes, combining Jardiance (empagliflozin), Januvia (sitagliptin), and Ozempic (semaglutide) is recommended and supported by current guidelines, particularly for patients with type 2 diabetes who have established cardiovascular disease or high cardiovascular risk and require intensive glycemic control. 1, 2, 3

Guideline Support for Triple Combination

The American Diabetes Association explicitly recommends combining SGLT-2 inhibitors (empagliflozin), DPP-4 inhibitors (sitagliptin), and GLP-1 receptor agonists (semaglutide) as appropriate combination therapy options when intensifying treatment beyond metformin. 1, 2 These three agents have complementary mechanisms of action that provide additive benefits for glycemic control and cardiovascular risk reduction. 3

Cardiovascular Benefits of This Combination

Empagliflozin (Jardiance)

• Carries a Class I recommendation to reduce cardiovascular death by 38% in patients with type 2 diabetes and established cardiovascular disease. 4, 3
• Reduces heart failure hospitalization risk by 30-35%. 4
• Provides renoprotective benefits with Class I recommendations to reduce progression of diabetic kidney disease. 4, 3

Semaglutide (Ozempic)

• Recommended by the American College of Cardiology for cardiovascular event reduction in patients with type 2 diabetes and cardiovascular disease or high cardiovascular risk. 3
• Typically lowers HbA1c by 1.1-1.5%. 3

Sitagliptin (Januvia)

• Demonstrates cardiovascular safety with neutral effects on major cardiovascular events and heart failure risk. 2
• Unlike saxagliptin, sitagliptin is not contraindicated in patients with heart failure. 2

Expected Glycemic Control

This triple combination provides robust HbA1c reduction through three distinct mechanisms: SGLT-2 inhibition (urinary glucose excretion), DPP-4 inhibition (incretin enhancement), and GLP-1 receptor agonism (insulin secretion, glucagon suppression, gastric emptying). 3, 5 The combination can achieve more substantial HbA1c reductions than any single agent or dual therapy. 3

Practical Implementation Strategy

Initiation Sequence

• Start with one agent first, then add the second after 3-4 weeks to better manage potential side effects, followed by the third agent. 3
• If the patient is on insulin or sulfonylureas, reduce the total daily insulin dose by approximately 20% if HbA1c is well-controlled at baseline when initiating empagliflozin. 4
• Consider weaning or stopping sulfonylureas or glinides to prevent hypoglycemia when initiating this combination. 4

Monitoring Requirements

• Assess HbA1c within approximately 3 months of therapy initiation or intensification. 1
• Monitor for hypoglycemia, especially if the patient is also on sulfonylureas or insulin. 3
• Monitor for additive effects on weight loss and blood pressure reduction. 3
• Consider reducing diuretic doses if signs of volume contraction develop when initiating empagliflozin. 4

Critical Safety Considerations

Empagliflozin-Specific Precautions

• Discontinue at least 3 days before planned surgery to prevent postoperative euglycemic ketoacidosis. 4, 2
• Stop immediately if symptoms of ketoacidosis develop (dyspnea, nausea, vomiting, abdominal pain). 2
• Genital mycotic infections are the most common adverse effect. 4
• Volume depletion and hypotension risk, particularly when combined with loop diuretics. 4

Renal Function Limitations

• Empagliflozin should not be used for glycemic control when eGFR <45 mL/min/1.73 m². 4
• Empagliflozin is contraindicated when eGFR <30 mL/min/1.73 m². 4
• Sitagliptin requires dose adjustment in renal impairment. 2

Semaglutide Considerations

• Gastrointestinal side effects (nausea, vomiting) are common initially but typically improve over time. 3

Optimal Patient Profile for This Combination

This triple combination is particularly beneficial for patients with:

• Type 2 diabetes with established cardiovascular disease or high cardiovascular risk. 1, 3
• Inadequate glycemic control on dual therapy. 1
• Heart failure with preserved ejection fraction (HFpEF) or diastolic dysfunction. 4
• Chronic kidney disease requiring renoprotection. 4, 3
• Need for weight loss in addition to glycemic control. 3

Common Pitfalls to Avoid

• Do not delay intensification: If HbA1c target is not achieved within 3 months, intensify therapy rather than allowing prolonged hyperglycemia. 1
• Avoid saxagliptin substitution: If the patient has heart failure, use sitagliptin instead of saxagliptin in this combination. 2
• Monitor surgical planning: Failure to discontinue empagliflozin before surgery can lead to postoperative ketoacidosis. 4
• Assess baseline renal function: Starting empagliflozin in patients with eGFR <45 mL/min/1.73 m² for glycemic control is inappropriate. 4