Drug Information Question Question: What evidence is available on linagliptin (Tradjenta®) for the treatment of type 2 diabetes? Thomas Combahee, Pharm.D. Candidate, and Stacy L. Haber, Pharm.D., Associate Professor, Midwestern University College of Pharmacy-Glendale Answer: Introduction Diabetes mellitus is a condition characterized by physiological imbalance of glucose homeostasis, attributed most commonly to impaired insulin secretion and insulin resistance.1 Its most common form is type 2 diabetes mellitus (T2DM), which affects close to 250 million people worldwide as of 2011 and is expected to reach 380 million by 2025.2 It is traditionally known as adultonset, but recent rises in childhood obesity and changes in dietary habits have led to increasing numbers of juvenile-onset cases.3 Metformin is typically the first-line treatment for T2DM unless there is a contraindication; sulfonylureas (glipizide, glimepiride, glyburide) are often used in combination with metformin, but they have the unwanted side effects of hypoglycemia and weight gain.4 Pioglitazone is another option for add-on or monotherapy, but it may cause weight gain, increase the risk of heart failure, and be associated with bladder cancer and osteoporosis. If diabetic goals are not achieved with these medications, use of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide (GLP-1) agonists, and/or insulin injections would be considered.2,4 The DPP-4 inhibitors include sitagliptin, saxagliptin, and linagliptin. The DPP-4 enzyme degrades the hormone GLP-1, which is released in response to food ingestion for enhancing glucose-dependent insulin secretion. Although DPP-4 inhibitors do not reduce glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) as much as other agents, they do reduce postprandial glucose levels more, as their mechanism of action would suggest.1,5,6 The newest agent in this class is linagliptin, which was FDA-approved in May of 2011.7 In a search of Medline, four randomized controlled trials have investigated the safety and efficacy of linagliptin.8-11 Clinical Trials Linagliptin 5-mg monotherapy was evaluated in patients with inadequately controlled T2DM, using measurements of glycemic control and markers of β-cell function in a study by Del Prato et al.8 All patients were required to discontinue their current antidiabetic medications, go through a four-week washout, and follow that with a two-week placebo run-in. This trial randomized 336 patients to linagliptin and 167 to placebo from 66 sites in 11 countries. The primary endpoint was the change from baseline in HbA1c after 24 weeks. Secondary endpoints included the percentages of patients who reached a goal HbA1c of < 7.0% or < 6.5% and experienced a lowering of HbA1c of ≥ 0.5%, reduction of HbA1c over time, and change from baseline in FPG and 2hPPG. Other endpoints included homeostasis model assessment (HOMA) indices for insulin resistance and β-cell function and changes in body weight and lipids. HbA1c changed in the linagliptin group by -0.44% versus +0.25% in placebo (p<0.0001). FPG was changed by -0.5 mmol/L versus +0.8 30 • Arizona Journal of Pharmacy • Spring 2012 mmol/L in placebo (p<0.0001), and 2hPPG was changed by -1.9 mmol/L versus +1.4 mmol/L in placebo (p<0.0001). Statistically significant changes were reported for several biomarkers and indices that favored linagliptin versus placebo. More patients reached a goal HbA1c of < 7% or < 6.5% with linagliptin versus placebo (25.2% versus 11.6%, p=0.0006). Similar results were reported for lowering of HbA1c of ≥ 0.5%. One case of hypoglycemia was reported in both the linagliptin and placebo groups. Adverse events more common with linagliptin included headache (2.7% versus 1.2%), hypertension (3.6% versus 1.2%), and back pain (2.7% versus 1.8%). No differences were noted in laboratory values, vital signs, or renal function. Body weight and waist circumference did not differ significantly. This study concluded that linagliptin monotherapy effectively reduced laboratory markers of T2DM with limited adverse events. A trial by Forst et al. evaluated the safety and efficacy of linagliptin as add-on therapy to metformin.9 This trial randomized 333 patients to linagliptin 1, 5, or 10 mg, glimepiride, or placebo. Each group required concomitant use of metformin, either from continued use or from a twoweek run-in. Primary endpoints were similar to Del Prato et al., except this trial was done over 12 weeks, the minimum necessary to accurately acquire HbA1c values. Change from baseline in HbA1c was -0.40% for 1 mg (p=0.01), -0.73% for 5 mg (p<0.0001), -0.67% for 10 mg (p<0.0001), and -0.90% for glimepiride (p<0.0001). FPG changed by -1.1 mmol/L for 1 mg (p=0.002), -1.9 mmol/L for 5 mg (p<0.0001), and -1.6 mmol/L for 10 mg (p<0.0001); FPG was not evaluated in the glimepiride group. The percentages of patients who reached a goal HbA1c of < 7% or < 6.5% and experienced a lowering of HbA1c of ≥ 0.5% were not reported. No hypoglycemic events were reported for the linagliptin or placebo groups, but 5% of patients receiving glimepiride experienced hypoglycemia. The authors concluded that linagliptin was safe and effective for improving T2DM glycemic control in combination with metformin, but that the 5-mg dose was more effective than the 10-mg dose. Taskinen et al. also evaluated linagliptin as add-on therapy to metformin.10 Patients with T2DM must have already been taking metformin at a dose ≥ 1500 mg/day. This trial randomized 524 patients to linagliptin 5 mg and 177 to placebo. Study design, primary endpoints, and secondary endpoints were the same as the study by Del Prato et al., except FPG over time and the need for rescue medications were also evaluated. Linagliptin reduced HbA1c levels by 0.49% versus 0.15% with placebo (p<0.0001). For FPG, linagliptin resulted in a mean change of -0.6 versus +0.6 for placebo (p<0.0001), and for 2hPPG, it resulted in a mean change of -2.7 versus +1.0 for placebo (p<0.0001). Rate of change in HbA1c increased over time until about 18 weeks, when it leveled out. A similar pattern was seen in the rate of change in FPG. A goal HbA1c of < 7% was reached by 26% of patients in the linagliptin group versus 9% in the placebo group (p=0.0001). Similar results were reported for a goal of < 6.5%. The percentage of patients who experienced a lowering of