PMID- 25015594 OWN - NLM STAT- MEDLINE DCOM- 20160321 LR - 20220419 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 36 IP - 8 DP - 2014 Aug 1 TI - Safety and Tolerability of Linagliptin in Patients With Type 2 Diabetes: A Comprehensive Pooled Analysis of 22 Placebo-controlled Studies. PG - 1130-46 LID - S0149-2918(14)00371-3 [pii] LID - 10.1016/j.clinthera.2014.06.008 [doi] AB - PURPOSE: Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin. METHODS: Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of 5 years; approximately 75% were receiving >/=1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels. IMPLICATIONS: This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin. CI - Copyright (c) 2014 The Authors. Published by EM Inc USA.. All rights reserved. FAU - Lehrke, Michael AU - Lehrke M AD - Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany. FAU - Marx, Nikolaus AU - Marx N AD - Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany. FAU - Patel, Sanjay AU - Patel S AD - Boehringer Ingelheim Ltd, Bracknell, United Kingdom. FAU - Seck, Thomas AU - Seck T AD - Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. FAU - Crowe, Susanne AU - Crowe S AD - Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. FAU - Cheng, Karen AU - Cheng K AD - Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. FAU - von Eynatten, Maximilian AU - von Eynatten M AD - Boehringer Ingelheim Inc, Ridgefield, Connecticut. FAU - Johansen, Odd Erik AU - Johansen OE AD - Boehringer Ingelheim Norway KS, Asker, Norway. Electronic address: odd-erik.johansen@boehringer-ingelheim.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140708 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Sulfonylurea Compounds) RN - 3X29ZEJ4R2 (Linagliptin) SB - IM EIN - Clin Ther. 2014 Nov 1;36(11):1705 MH - Aged MH - Body Weight MH - Diabetes Mellitus, Type 2/*drug therapy MH - Dipeptidyl-Peptidase IV Inhibitors/*adverse effects MH - Double-Blind Method MH - Drug Therapy, Combination/adverse effects MH - Female MH - Heart Failure/chemically induced/epidemiology MH - Humans MH - Hypoglycemia/chemically induced/*epidemiology MH - Hypoglycemic Agents/*adverse effects MH - Incidence MH - Linagliptin/*adverse effects MH - Male MH - Middle Aged MH - Neoplasms/chemically induced/epidemiology MH - Pancreatitis/chemically induced/epidemiology MH - Randomized Controlled Trials as Topic MH - Sulfonylurea Compounds/therapeutic use OTO - NOTNLM OT - DPP4-inhibitor OT - hypoglycemia OT - linagliptin OT - safety OT - type 2 diabetes mellitus EDAT- 2014/07/13 06:00 MHDA- 2016/03/22 06:00 CRDT- 2014/07/13 06:00 PHST- 2014/04/30 00:00 [received] PHST- 2014/05/15 00:00 [revised] PHST- 2014/06/11 00:00 [accepted] PHST- 2014/07/13 06:00 [entrez] PHST- 2014/07/13 06:00 [pubmed] PHST- 2016/03/22 06:00 [medline] AID - S0149-2918(14)00371-3 [pii] AID - 10.1016/j.clinthera.2014.06.008 [doi] PST - ppublish SO - Clin Ther. 2014 Aug 1;36(8):1130-46. doi: 10.1016/j.clinthera.2014.06.008. Epub 2014 Jul 8.