title: Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials.
abstract: BACKGROUND
  Guidelines for type 2 diabetes (T2D) recommend reducing HbA1cthrough lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial.
  
  
  METHODS
  A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia.
  
  
  RESULTS
  A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39).
  
  
  CONCLUSIONS
  There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.
authors.affiliation: Cardiology department, CHU de Poitiers, 2, rue de la Milétrie, 86000 Poitiers, France. Electronic address: michaela.rehman@gmail.com.
authors.forename: M B
authors.initials: MB
authors.lastname: Rehman
authors.affiliation: Department of General Practice, Faculty of Medicine, 6, rue de la Milétrie, 86000 Poitiers, France.
authors.forename: B V
authors.initials: BV
authors.lastname: Tudrej
authors.affiliation: Department of General Practice, Faculty of Medicine, 6, rue de la Milétrie, 86000 Poitiers, France.
authors.forename: J
authors.initials: J
authors.lastname: Soustre
authors.affiliation: Inserm, CIC1407, CHU Lyon, 69000 Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Buisson
authors.affiliation: Department of General Practice, Faculty of Medicine, 6, rue de la Milétrie, 86000 Poitiers, France.
authors.forename: P
authors.initials: P
authors.lastname: Archambault
authors.affiliation: Department of General Practice, University François Rabelais, 37000 Tours, France.
authors.forename: D
authors.initials: D
authors.lastname: Pouchain
authors.affiliation: Department of General Practice, Faculty of Medicine of Clermont-Ferrand University, 28, place Henri-Dunant, 63000 Clermont-Ferrand, France; Investigation Center, INSERM CIC 1401, Clermont-Ferrand University Hospital, 58, rue Montalembert, 63000 Clermont-Ferrand, France.
authors.forename: H
authors.initials: H
authors.lastname: Vaillant-Roussel
authors.affiliation: UMR 5558, laboratoire de biométrie et biologie évolutive, Claude-Bernard Lyon 1 University, CNRS, 69000 Lyon, France.
authors.forename: F
authors.initials: F
authors.lastname: Gueyffier
authors.affiliation: Inserm, CIC1407, CHU Lyon, 69000 Lyon, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Faillie
authors.affiliation: Inserm CIC-1402, CHU de Poitiers, 86021 Poitiers, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Perault-Pochat
authors.affiliation: Inserm, CIC1407, CHU Lyon, 69000 Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Cornu
authors.affiliation: Department of General Practice, Faculty of Medicine, 6, rue de la Milétrie, 86000 Poitiers, France.
authors.forename: R
authors.initials: R
authors.lastname: Boussageon
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors
keywords: DPP-4 inhibitors; Meta-analysis; Micro- and macrovascular complications; Mortality; Randomized clinical trials; Type 2 diabetes