title: Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial.
abstract: OBJECTIVE
  To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug (OAD).
  
  
  METHODS
  This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment.
  
  
  RESULTS
  Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin.
  
  
  CONCLUSIONS
  Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of β-cell function. The safety profile of linagliptin was comparable with that of placebo.
authors.affiliation: Department of Endocrinology and Metabolism, Section of Metabolic Diseases, University of Pisa, Pisa, Italy. s.delprato@ao-pisa.toscana.it
authors.forename: S
authors.initials: S
authors.lastname: Del Prato
authors.forename: A H
authors.initials: AH
authors.lastname: Barnett
authors.forename: H
authors.initials: H
authors.lastname: Huisman
authors.forename: D
authors.initials: D
authors.lastname: Neubacher
authors.forename: H-J
authors.initials: HJ
authors.lastname: Woerle
authors.forename: K A
authors.initials: KA
authors.lastname: Dugi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006442:Glycated Hemoglobin / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000627:therapeutic use*; D011687:Purines / Q000378:metabolism / Q000627:therapeutic use*; D011799:Quinazolines / Q000378:metabolism / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D010919:Placebos; D011687:Purines; D011799:Quinazolines