Volume XV No. IV July/August 2012 Marcia J. Wyman, Pharm.D., BCPS Drug Information Pharmacist Linagliptin: An Alternative Dipeptidyl Peptidase-4 Inhibitor Editor By: Anna Powichrowski, Pharm.D. Mandy C. Leonard, Pharm.D., BCPS System Director, Drug Use Policy and Introduction: Diabetes mellitus affects Food and Drug Administration (FDA) Formulary Management 26 million people in the United States or approved three DPP-4 inhibitors: si- Editor 1 ® about 8.3% of the population. Key risk tagliptin (Januvia ; Merck Company, Meghan K. Lehmann, Pharm.D., BCPS factors for type 2 diabetes include fam- Inc), saxagliptin (Onglyza™; Bristol– Drug Information Specialist ily history, excess weight, lack of regu- Myers Squibb Company), and lina- Editor lar exercise, dyslipidemia, and hyper- gliptin (Tradjenta™; Boehringer tension. 2 Uncontrolled diabetes is asso- Ingelheim Pharmaceuticals, Inc). 4 Amy T. Martin, Pharm.D., BCPS Drug Information Pharmacist ciated with significant morbidity includ- Linagliptan, the newest DPP-4 inhibi- Associate Editor ing chronic kidney disease, retinopathy, tor was approved by the FDA on May neuropathy, amputations, and acute or- 2, 2011. The DPP-4 inhibitors are ap- Marigel Constantiner, MSc, BCPS, CGP, CPh gan failure. Clinical management of proved as an adjunct therapy to diet Drug Information Specialist Associate Editor patients with type 2 diabetes is intended and exercise to improve glycemic to reach and maintain patient-specific control in adults with type 2 diabetes Christopher Snyder, R.Ph. glycemic goals. According to the mellitus. 5-7 Sitagliptin and saxagliptin In this Issue Drug Information Pharmacist American Diabetes Association (ADA), have been evaluated for use as mono- Associate Editor a desirable treatment target for most therapy or in combination with other Katie L. Stabi, Pharm.D., BCPS patients with diabetes is a hemoglobin antidiabetic agents, including met- Drug Information Pharmacist A1C (A1C) level lower than 7%, as long formin and thiazolidinediones when a Associate Editor as the level can be accomplished safely single agent does not provide ade- while minimizing the risk of hypoglyce- quate control. 6,7 In addition, Scott Knoer, MS, Pharm.D., FASHP Chief Pharmacy Officer mia. The American Association of saxagliptin has been evaluated for use Clinical Endocrinologists (AACE) and with sulfonylureas. 7 The ADA ex- In This Issue: American College of Endocrinology cludes DPP-4 inhibitors from the two • Linagliptan Overview (ACE), have a similar A1C target of tiers of preferred agents in their treat- • Formulary Update 6.5% or lower for most patients. 3 First- ment algorithm due to limited data • Frequently Asked Questions 2 line treatment options in type 2 diabetes and high expense of these agents. On involve lifestyle modifications including the other hand, AACE/ACE recom- exercise, meal planning, and weight mends consideration of DPP-4 inhibi- loss. 2,3 However, pharmacotherapy to tors for use with metformin in patients achieve treatment goals is often re- requiring dual therapy especially Drug Information Service (216) 444-6456, option #1 quired. Initial pharmacologic therapy when experiencing hypoglycemia with metformin (Glucophage ®) is rec- and/or weight gain with the other 3 Comprehensive information about ommended, but may not be sufficient to agents. achieve adequate glycemic control. 2,3 medications, biologics, nutrients, and drug therapy Intensification of therapy often involves Mechanism of Action: Linagliptin an addition of an agent from a different inhibits DPP-4, an enzyme that de- Formulary Information pharmacologic class. Dipeptidyl pepti- grades incretin hormones, glucagon- dase-4 (DPP-4) inhibitors are consid- like peptide-1 (GLP-1) and glucose- Medication Inservices ered a reasonable second-line pharma- dependent insulinotropic polypeptide 2,3 5 cologic option after metformin. The (GIP). This activity increases the plasma concentrations of active incretin hormones, thereby stimulating the release of insulin in a glucose-dependent man- ner and decreasing circulating levels of glucagon. Glucagon-like peptide-1 and GIP are involved in physiological regula- tion of glucose homeostasis. Both hormones increase the biosynthesis of insulin and its secretion from pancreatic beta cells in the presence of normal or elevated levels of blood glucose. Glucagon-like peptide-1 also decreases glucagon se- cretion from pancreatic alpha-cells, resulting in a reduction in glucose output from the liver. Pharmacokinetics: Linagliptin has a time to peak concentration following oral administration of 1.5 hours. 5 Its bioavail- ability is 30%. Plasma protein binding is concentration-dependent; however, the percentage of plasma protein binding is not altered in patients with hepatic or renal dysfunction. Its elimination half-life is 12 hours and major route of elimina- tion is enterohepatic excretion as unchanged drug. Select Clinical Trials: Prato and colleagues conducted a trial to investigate the effect of linagliptin monotherapy on gly- cemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes.8 This multicenter, randomized, double-blind trial was conducted between February 15, 2008, and May 6, 2009, at 66 sites in 11 countries. The objective was to investigate the efficacy and safety of linagliptin 5 mg versus placebo administered as monotherapy to patients with type 2 diabetes who were either treatment-naïve or who had received one oral antidiabetic drug. The in- clusion criteria consisted of participants between 18 and 80 years with type 2 diabetes, body mass index (BMI) 2 ≤ 40 kg/m , and with either an A1C of 6.5% to 9.0% and were treated with not more than one antidiabetic agent (excluding thiazolidinediones) or an A1C of 7.0% to 10.0% and were treatment naïve. Key exclusion criteria included participants who had a myocardial infarction, stroke, or transient ischemic attack within 6 months prior to randomization, impaired hepatic function, hypersensitivity to the product, treatment with more than one antidiabetic agent within 10 days, or current treatment with systemic steroids. Prior to study initiation, individuals with an A1C 6.5% to 9.0% had to un- dergo a 6-week washout period of previous antidiabetic medications; afterwards a 2-week placebo run-in period was initi- ated. Treatment-naïve patients with an A1C 7.0% to 10.0% directly entered the 2-week placebo run-in period. An A1C of 7.0% to 10.0% was required by both groups at the start of placebo run-in period. Metformin could be utilized as a res- cue medication only during the randomization period in patients with a confirmed glucose level > 13.3 mmol/L after an overnight fast. Randomization was stratified by A1C < 8.5% versus ≥ 8.5% and by whether or not patients had previously received an oral antidiabetic drug. Following the placebo run-in period, patients were randomized to linagliptin 5 mg once daily or placebo. The primary endpoint was the change from baseline in A1C after 24 weeks. Table 1 contains study outcomes and results. A significantly smaller portion of patients receiving linagliptin required metformin rescue therapy (10.2%) compared with placebo (20.9%) with OR=0.3 (p=0.0002). Overall, 98 patients (58.7%) reported adverse events in the placebo group and 176 patients (52.4%) reported adverse events in the linagliptin group. Mean trough levels of linagliptin over time were comparable between patients with normal renal function and those with mild or moderate renal impairment. Linagliptin dose adjustments may not be required in patients with renal impairment. Both body weight and waist circumference did not differ significantly from baseline in both groups validating that linagliptin is weight neutral. The authors concluded that a clinically relevant reduction in A1C, fasting plasma glucose (FPG), and change in 2-hour postprandial glucose (2h-PPG) from baseline to week 24 were observed with linagliptin compared with placebo. Prato and colleagues conducted a multicenter, randomized, double-blind trial between August 2008 and August 2010 at 53 sites in seven countries. 9 The objective of the trial was to examine the efficacy, safety, and tolerability of linagliptin compared with placebo in patients with type 2 diabetes who were intolerant to metformin therapy or for whom metformin was contraindicated. Participants were included if they were 18 to 80 years of age with type 2 diabetes, BMI ≤ 40 kg/m 2, had intolerability or contraindication to metformin, had an A1C 7.0% to 10.0% and were drug naïve or had an A1C 6.5% to 9.0% and were previously treated with one oral antidiabetic for at least 10 weeks. In order to start in the placebo run-in period patients in both groups needed an A1C of 7.5% to 11.0%. Patients naïve to diabetic treatment directly started in the 2-week placebo run-in period. Select exclusion criteria included those with a myocardial infarction, stroke, or transient ischemic attack within 6 months, impaired hepatic function, severe renal impairment, and treatment with rosiglitazone or pioglitazone, GLP-1 analogs, insulin, or antiobesity drugs in the past 3 months. Following the placebo run-in period, pa- tients were randomized to linagliptin 5 mg once daily or placebo. The primary endpoint was the change from baseline in A1C after 18 weeks. Table 1 contains study outcomes and results. The rate of adverse events was comparable between both groups with 40.4% in the linagliptin group and 48.7% in the placebo group. The mean changes in weight and waist circumference