Is it safe to combine Janumet (sitagliptin and metformin) with Jardiance (empagliflozin) for patients with type 2 diabetes?

Combining Janumet with Jardiance for Type 2 Diabetes

Yes, combining Janumet (sitagliptin/metformin) with Jardiance (empagliflozin) is safe and effective for patients with type 2 diabetes, representing a rational triple therapy approach that addresses multiple pathophysiologic defects without increasing hypoglycemia risk. 1

Rationale for This Combination

This triple combination targets three distinct mechanisms:

• Metformin reduces hepatic glucose production and improves insulin sensitivity 2
• Sitagliptin (DPP-4 inhibitor) enhances glucose-dependent insulin secretion and reduces glucagon secretion 2
• Empagliflozin (SGLT2 inhibitor) increases urinary glucose excretion independent of insulin 3

The European Society of Cardiology guidelines explicitly state that SGLT2 inhibitors (empagliflozin, canagliflozin, or dapagliflozin) are recommended in patients with T2DM and CVD, or at very high/high CV risk, to reduce CV events, and that DPP-4 inhibitors sitagliptin and linagliptin have a neutral effect on risk of HF and may be considered 1. This directly supports using both drug classes together.

Evidence Supporting Triple Combination

• A 24-month study of drug-naïve patients using metformin, sitagliptin, and empagliflozin demonstrated 72.5% achieved HbA1c <7.0% at 12 months and 61.7% at 24 months, with significant improvements in beta-cell function, insulin resistance, body composition, and albuminuria—all without serious adverse events including ketoacidosis 4

• Initial combination therapy with empagliflozin and metformin showed HbA1c reductions of -1.9 to -2.1% over 24 weeks, with weight loss of -2.8 to -3.8 kg and no hypoglycemic events requiring assistance 5

• Pharmacokinetic studies confirm no drug-drug interactions between empagliflozin and metformin 3

Safety Profile

The combination is well-tolerated with complementary safety profiles:

• Hypoglycemia risk remains minimal because both sitagliptin and empagliflozin work through glucose-dependent mechanisms 2, 5, 4
• Weight is reduced or neutral, not increased—empagliflozin causes weight loss while sitagliptin is weight-neutral 3, 5
• Blood pressure reduction occurs with empagliflozin without additional risk 3
• Adverse event rates in combination studies (56.7-66.3%) were similar across treatment groups 5

Cardiovascular and Renal Benefits

Empagliflozin provides mortality and morbidity benefits beyond glycemic control:

• Empagliflozin is recommended to reduce the risk of death in patients with T2DM and CVD 1
• SGLT2 inhibitors are recommended to lower risk of HF hospitalization 1
• SGLT2 inhibitors are recommended to reduce progression of diabetic kidney disease 1

The EMPA-REG OUTCOME trial demonstrated that empagliflozin combined with metformin may be used in patients with established cardiovascular disease or heart failure 3.

Clinical Implementation Algorithm

When to use this combination:

1. After metformin monotherapy fails to achieve glycemic targets (HbA1c >7% for most patients) 1
2. In patients with established CVD or high CV risk where empagliflozin provides mortality benefit 1
3. In patients with heart failure or CKD where empagliflozin reduces hospitalization and slows kidney disease progression 1
4. When avoiding hypoglycemia and weight gain are priorities 1

Dosing approach:

• Start with metformin (already in Janumet) at 1000-2000 mg daily 2
• Sitagliptin 100 mg daily (in Janumet 50/500,50/850, or 50/1000 mg twice daily) 2, 6
• Add empagliflozin 10-25 mg once daily 3, 5

Critical Monitoring Points

Monitor these parameters at 3-month intervals:

• HbA1c to assess glycemic efficacy 7
• Renal function (eGFR) because both metformin and empagliflozin have renal contraindications—metformin should be used cautiously if eGFR <45 mL/min/1.73m² and empagliflozin is less effective below eGFR 45 1, 3
• Genital mycotic infections (more common with SGLT2 inhibitors) 7
• Vitamin B12 levels with long-term metformin use 7
• Volume status in elderly or those on diuretics (SGLT2 inhibitors cause osmotic diuresis) 3

Common Pitfalls to Avoid

Do not use empagliflozin in patients with:

• Severe renal impairment (eGFR <30 mL/min/1.73m²) where it is ineffective and metformin is contraindicated 3
• History of diabetic ketoacidosis or type 1 diabetes 4
• Recurrent genital or urinary tract infections without addressing underlying causes 7

Avoid saxagliptin (different DPP-4 inhibitor) instead of sitagliptin in patients with high risk of heart failure, as saxagliptin is specifically not recommended in this population 1. Sitagliptin has a neutral effect on HF risk 1.

Do not add more medications before optimizing adherence to current therapy and reinforcing lifestyle modifications including dietary carbohydrate management and regular physical activity 7.