Uses
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Diabetes Mellitus
Linagliptin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Linagliptin also is used as initial therapy in combination with metformin hydrochloride as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Linagliptin also is used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [ thiazolidinedione]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with oral antidiabetic agent monotherapy.
While metformin generally is the preferred antidiabetic agent for initial therapy in patients with type 2 diabetes mellitus, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) suggests a DPP-4 inhibitor as one of several alternative antidiabetic agents for initial monotherapy in patients with a contraindication to metformin (e.g., renal disease, hepatic disease, GI intolerance, risk of lactic acidosis). DPP-4 inhibitors are also recommended by AACE/ACE as part of combination therapy, particularly when both postprandial and fasting plasma glucose concentrations are elevated.
Linagliptin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
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Linagliptin Monotherapy
Efficacy of linagliptin as monotherapy for the management of type 2 diabetes mellitus has been established in 2 double-blind, placebo-controlled studies of 18 or 24 weeks' duration. Linagliptin (5 mg once daily) improved glycemic control as evidenced by reductions in glycosylated hemoglobin (HbA1c) as well as in fasting and 2-hour postprandial plasma glucose concentrations. HbA1c was reduced by a mean of 0.4% (from a mean baseline concentration of about 8%) in patients receiving linagliptin 5 mg daily, compared with an increase in HbA1c of 0.1-0.3% in those receiving placebo.
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Combination Therapy
Efficacy of linagliptin in combination with metformin, a sulfonylurea, or a thiazolidinedione in the management of type 2 diabetes mellitus has been established in several randomized, placebo- or active-controlled, double-blind studies. In these studies, the addition of linagliptin (5 mg once daily) to therapy with metformin and/or a sulfonylurea or to pioglitazone therapy improved glycemic control as evidenced by reductions in HbA1c as well as in fasting and/or 2-hour postprandial plasma glucose concentrations.
Efficacy of the combination of linagliptin and metformin as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise is supported by results of a 24-week, randomized, double-blind trial. In this trial, concurrent therapy with linagliptin and metformin hydrochloride improved glycemic control (as evidenced by reductions in HbA1c and fasting plasma glucose) compared with linagliptin or metformin hydrochloride monotherapy or placebo. Reductions in HbA1c were 1.2 or 1.6% with linagliptin 2.5 mg plus metformin hydrochloride 0.5 or 1 g twice daily, respectively; 0.5% with linagliptin 5 mg once daily; 0.6 or 1.1% with metformin hydrochloride 0.5 or 1 g twice daily, respectively; and 0.1% with placebo.
In a 24-week study in patients receiving metformin hydrochloride monotherapy (>=1.5 g daily), add-on therapy with linagliptin resulted in a reduction of 0.5% in HbA1c compared with an increase of 0.15% in patients receiving metformin hydrochloride and add-on placebo. In a 104-week, active-controlled, noninferiority study in patients receiving metformin hydrochloride monotherapy (>=1.5 g daily), add-on therapy with linagliptin was noninferior at 52 weeks and resulted in a reduction of 0.4% in HbA1c from baseline, compared with a reduction of 0.6% from baseline in patients receiving add-on therapy with glimepiride (initiated at 1 mg daily and titrated over 12 weeks to a maximum dosage of 4 mg daily [ mean dosage: 3 mg daily]). At 104 weeks, add-on therapy with linagliptin resulted in a reduction of 0.2% in HbA1c from baseline, compared with a reduction of 0.4% from baseline in those receiving add-on glimepiride therapy. Patients receiving add-on linagliptin therapy had a mean decrease in body weight (loss of 1.1 kg), while those receiving add-on glimepiride had a mean increase in body weight (gain of 1.4 kg).
In a 24-week study in patients receiving pioglitazone monotherapy (30 mg daily), add-on linagliptin or placebo resulted in a reduction of 1.1 or 0.6%, respectively, in HbA1c.
In an 18-week study in patients receiving a sulfonylurea antidiabetic agent (sulfonylurea not specified), add-on therapy with linagliptin resulted in a reduction of 0.5% in HbA1c compared with a reduction of 0.1% in patients receiving add-on placebo.
In a 24-week study in patients receiving metformin and a sulfonylurea (generally glimepiride, glyburide [glibenclamide], or gliclazide [not commercially available in the US]), add-on therapy with linagliptin or placebo resulted in a reduction of 0.7 or 0.1%, respectively, in HbA1c.
Efficacy of linagliptin in combination with insulin in patients with type 2 diabetes mellitus inadequately controlled with insulin (with or without oral antidiabetic agents) is supported by the results of a 24-week randomized, placebo-controlled trial. In this trial, addition of linagliptin (5 mg once daily) to existing stable therapy with insulin resulted in improvements in HbA1c and fasting plasma glucose concentrations at week 24 compared with addition of placebo. Mean reductions in HbA1c were 0.6% in patients receiving linagliptin and 0.1% in those receiving placebo.
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