What is the effect of the Empagliflozin (Empa, Jardiance) and Linagliptin (Trajenta) combination?

From the Guidelines

Empagliflozin-linagliptin is a recommended combination therapy for type 2 diabetes, particularly for patients who require additional glycemic control and would benefit from the cardiovascular and renal protective effects of empagliflozin, as evidenced by the EMPA-REG OUTCOME trial 1.

Mechanism of Action and Benefits

The combination of empagliflozin (an SGLT-2 inhibitor) and linagliptin (a DPP-4 inhibitor) provides a dual mechanism of action, increasing glucose excretion through the kidneys and stimulating insulin release while reducing glucagon secretion. This combination is typically dosed as 10mg/5mg or 25mg/5mg taken once daily with or without food. The empagliflozin component has been shown to reduce the risk of major adverse cardiovascular events, including cardiovascular death, myocardial infarction, and stroke, as demonstrated in the EMPA-REG OUTCOME trial 1.

Key Considerations and Side Effects

Common side effects of empagliflozin-linagliptin include urinary tract infections, genital mycotic infections, and upper respiratory infections. It is essential to use this medication cautiously in patients with renal impairment and to monitor renal function, blood pressure, and ketones (if symptoms arise) regularly. The combination is contraindicated in patients with type 1 diabetes or diabetic ketoacidosis.

Clinical Evidence and Recommendations

Recent studies, including the EMPA-REG OUTCOME trial 1 and the CREDENCE trial 1, have consistently demonstrated the cardiovascular and renal benefits of SGLT-2 inhibitors, such as empagliflozin. The EMPEROR-Preserved trial 1 further supports the use of empagliflozin in patients with heart failure with preserved ejection fraction, showing a 21% reduction in the composite outcome of cardiovascular death or hospitalization for heart failure. Therefore, empagliflozin-linagliptin is a valuable treatment option for patients with type 2 diabetes who require comprehensive management of their disease, including glycemic control and cardiovascular risk reduction.

From the FDA Drug Label

In Combination with Linagliptin as Add-On to Metformin Therapy A total of 686 patients with type 2 diabetes participated in a double-blind, active-controlled study to evaluate the efficacy and safety of JARDIANCE 10 mg or 25 mg in combination with linagliptin 5 mg compared to the individual components Patients with type 2 diabetes inadequately controlled on at least 1500 mg of metformin per day entered a single-blind placebo run-in period for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10. 5% were randomized 1:1:1:1:1 to one of 5 active-treatment arms of JARDIANCE 10 mg or 25 mg, linagliptin 5 mg, or linagliptin 5 mg in combination with 10 mg or 25 mg JARDIANCE as a fixed dose combination tablet. At Week 24, JARDIANCE 10 mg or 25 mg used in combination with linagliptin 5 mg provided statistically significant improvement in HbA1c (p-value <0.0001) and FPG (p-value <0. 001) compared to the individual components in patients who had been inadequately controlled on metformin. Treatment with JARDIANCE/linagliptin 25 mg/5 mg or JARDIANCE/linagliptin 10 mg/5 mg daily also resulted in a statistically significant reduction in body weight compared to linagliptin 5 mg (p-value <0. 0001). There was no statistically significant difference in body weight compared to JARDIANCE alone.

The combination of empagliflozin and linagliptin is effective in improving HbA1c and FPG levels, and also results in a significant reduction in body weight compared to linagliptin alone, in patients with type 2 diabetes who are inadequately controlled on metformin 2. Key benefits of this combination include:

• Statistically significant improvement in HbA1c and FPG levels
• Statistically significant reduction in body weight compared to linagliptin alone
• Effective as an add-on therapy to metformin in patients with type 2 diabetes.

From the Research

Empagliflozin Linagliptin Combination

• The empagliflozin/linagliptin combination is a fixed-dose combination product that is approved in the USA as an adjunct to diet and exercise in adults with type 2 diabetes (T2D) when treatment with both empagliflozin and linagliptin is appropriate 3.
• Results of two randomized controlled trials demonstrated that empagliflozin/linagliptin improved glycaemic control significantly more than linagliptin when administered as initial therapy and significantly more than linagliptin or empagliflozin when administered as an add-on therapy to metformin 3.
• The combination of empagliflozin and linagliptin provided significant weight loss compared with linagliptin in both trials 3.
• A meta-analysis evaluated the efficacy and safety of empagliflozin + linagliptin combination compared with either monotherapy and found that the combination led to significantly greater reductions in glycated haemoglobin (HbA1c) and fasting plasma glucose 4.
• Patients with T2DM treated with the drug combination had more than three times higher likelihood of achieving HbA1c <7% than those on either monotherapy 4.
• The empagliflozin + linagliptin combination had superior efficacy and similar safety in achieving euglycaemia compared with either monotherapy 4, 5, 6.
• A systematic review of randomized controlled trials and observational studies found that the fixed-dose combination of empagliflozin plus linagliptin is effective, safe, tolerable, and rationale cost-effective compared to placebo and either drug alone for the management of T2DM 6.
• The combination is also available as a triple fixed-dose combination with metformin, which has been shown to be bioequivalent to the corresponding free combinations 7.

Efficacy and Safety

• The empagliflozin/linagliptin combination has been shown to be effective in improving glycaemic control and reducing weight in patients with T2D 3, 4, 5, 6.
• The combination has a low risk of hypoglycemia and is generally well tolerated in patients with T2D 3, 4, 5, 6.
• The safety profile of the combination is similar to that of the individual components 4, 5, 6.

Clinical Use

• The empagliflozin/linagliptin combination is a useful new option for patients with T2D who require treatment with both empagliflozin and linagliptin 3.
• The combination can be used as initial therapy or as an add-on therapy to metformin 3.
• The triple fixed-dose combination with metformin is also available for patients who require treatment with all three medications 7.