Can Glyxambi (empagliflozin/linagliptin) be added to metformin and/or Trulicity (dulaglutide) in patients with type 2 diabetes?

From the Guidelines

Yes, Glyxambi (empagliflozin/linagliptin) can be added to metformin and/or Trulicity (dulaglutide) in patients with type 2 diabetes, as this combination therapy is often used when patients need additional glycemic control beyond what they're achieving with their current medication regimen. When adding Glyxambi, the typical starting dose is one tablet (10 mg empagliflozin/5 mg linagliptin) once daily, taken in the morning. The dose can be increased to 25 mg empagliflozin/5 mg linagliptin if needed for better glucose control. Patients should be monitored for hypoglycemia when combining these medications, especially during the initial adjustment period. Adequate hydration should be maintained as empagliflozin increases urination. This combination makes pharmacological sense as each medication works through different mechanisms:

• metformin decreases hepatic glucose production and improves insulin sensitivity,
• Trulicity (a GLP-1 receptor agonist) increases insulin secretion and decreases glucagon,
• while Glyxambi combines an SGLT2 inhibitor (empagliflozin) that increases glucose excretion in urine with a DPP-4 inhibitor (linagliptin) that increases incretin levels to stimulate insulin release, as supported by the KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease 1. Additionally, the 2021 standards of medical care in diabetes also recommend a patient-centered approach to choosing pharmacologic treatment of blood glucose, considering factors such as efficacy, comorbidities, hypoglycemia risk, effects on body weight, side effects, cost, and patient preferences 1. It's also important to consider the dose adjustments for patients with reduced estimated glomerular filtration rates (eGFR), as outlined in the 2022 consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) 1. Overall, the decision to add Glyxambi to metformin and/or Trulicity should be based on individual patient needs and factors, with careful monitoring and adjustment as needed. Key points to consider include:
• The patient's current glycemic control and targets
• The presence of any comorbidities, such as chronic kidney disease or heart failure
• The patient's risk of hypoglycemia and ability to monitor and manage it
• The potential benefits and risks of the combination therapy
• The patient's preferences and values regarding their treatment plan. As recommended by the management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 1.

From the FDA Drug Label

Empagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers

Glyxambi (empagliflozin/linagliptin) can be added to metformin in patients with type 2 diabetes, as the pharmacokinetics of empagliflozin were similar with and without coadministration of metformin.

• However, there is no direct information on the use of Glyxambi with Trulicity (dulaglutide) in the provided drug label. 2

From the Research

Combination Therapy with Glyxambi

Glyxambi (empagliflozin/linagliptin) is a fixed-dose combination therapy that can be used as an add-on to diet and exercise to improve glycemic control in adults with type 2 diabetes. The following points highlight the potential of combining Glyxambi with metformin and/or Trulicity (dulaglutide):

• Glyxambi combines 10mg or 25mg empagliflozin with 5mg linagliptin, with different, complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes 3.
• Empagliflozin/linagliptin has been shown to improve 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 4.
• A study evaluating the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin found that the combination therapy significantly reduced HbA1c compared to the individual components and was well tolerated 5.

Addition to Metformin

The addition of Glyxambi to metformin has been studied, with results indicating:

• Empagliflozin/linagliptin improved glycaemic control significantly more than linagliptin or empagliflozin when administered as an add-on therapy to metformin 4.
• The combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin resulted in significant reductions in HbA1c 5.

Addition to Trulicity (Dulaglutide)

There is limited direct evidence on the addition of Glyxambi to Trulicity (dulaglutide). However:

• Glyxambi and Trulicity have different mechanisms of action, with Glyxambi combining an SGLT2 inhibitor and a DPP-4 inhibitor, and Trulicity being a GLP-1 receptor agonist.
• The safety and efficacy of combining these medications would need to be evaluated in clinical trials to determine the potential benefits and risks 3, 4, 6, 7, 5.

Safety and Efficacy

The safety and efficacy of Glyxambi have been evaluated in several studies, with results indicating:

• Glyxambi is generally well tolerated in patients with type 2 diabetes, with a low risk of hypoglycaemia and no reports of exacerbations of, or hospitalizations for, heart failure during the trials 4.
• The combination of empagliflozin and linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and was well tolerated 5.