title: Efficacy and safety of linagliptin in subjects with long-standing type 2 diabetes mellitus (>10 years): evidence from pooled data of randomized, double-blind, placebo-controlled, phase III trials.
abstract: OBJECTIVE
  Long duration of type 2 diabetes mellitus (T2DM) is associated with progressive β-cell loss and may pose a challenge to maintenance of good glycemic control. This study aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in an understudied population of patients with long-standing T2DM.
  
  
  METHODS
  Data from 202 individuals with T2DM for >10 years were pooled from 2 randomized, placebo-controlled, Phase III trials. Participants received either linagliptin 5 mg once daily (n = 122) or placebo (n = 80) for 24 weeks as an add-on to their current glucose-lowering therapy.
  
  
  RESULTS
  Long-standing T2DM was associated with older age (mean [SD], 69.1 [10.0] years) and a high prevalence of diabetes-related complications (78% with diabetic kidney disease and 83% with macrovascular disease). The mean baseline glycosylated hemoglobin (HbA1c) level was 8.22% (1.08%), and mean baseline fasting plasma glucose level was 161.8 (49.2) mg/dL. Linagliptin significantly improved glycemic control after 24 weeks, with a placebo-adjusted mean change in HbA1c from baseline of -0.66% (95% CI, -0.95 to -0.38; P < 0.0001). This change was accompanied by a significant reduction in fasting plasma glucose, with a placebo-adjusted mean change from baseline of -15.5 mg/dL (95% CI, -29.6 to -1.3; P = 0.0323) at week 24. Overall, linagliptin was well tolerated, with drug-related adverse events in 21.3% and 16.3% of the linagliptin and placebo groups, respectively. Investigator-reported hypoglycemia occurred more often with linagliptin (25.4%) compared with placebo (12.5%). However, no severe hypoglycemic events were reported with linagliptin. Moreover, in patients not receiving concomitant sulfonylureas, the incidence of hypoglycemia with linagliptin (12.5%) was similar to that with placebo (12.2%). Patients' mean weight remained unchanged in both groups.
  
  
  CONCLUSIONS
  This pooled analysis found that linagliptin was well tolerated and significantly improved hyperglycemia in a clinically challenging population of patients with long-standing T2DM (>10 years). Although T2DM is commonly associated with diminished β-cell function, the extent of glucose lowering was similar to that in linagliptin trials, which largely included patients in earlier stages of the disease. Thus, this observation supports the hypothesis that regulation of glucagon release from pancreatic α cells may be of particular relevance for improving hyperglycemia in patients with long-term T2DM (NCT01194830 and NCT01084005).
authors.affiliation: Diabetes America, Plano, Texas. Electronic address: rlajara@diabetesamerica.com.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Lajara
authors.affiliation: Diabetes Nation, Sisters, Oregon.
authors.forename: Richard
authors.initials: R
authors.lastname: Aguilar
authors.affiliation: Boehringer Ingelheim, Pharma GmbH & Co KG, Ingelheim, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hehnke
authors.affiliation: Boehringer Ingelheim, Pharma GmbH & Co KG, Ingelheim, Germany.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut.
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Eynatten
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000378:metabolism; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005934:Glucagon / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000069476:Linagliptin / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005934:Glucagon; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D013453:Sulfonylurea Compounds
keywords: DPP-4 inhibitor; HbA(1c); linagliptin; type 2 diabetes mellitus