title: Second line initiation of insulin compared with DPP-4 inhibitors after metformin monotherapy is associated with increased risk of all-cause mortality, cardiovascular events, and severe hypoglycemia.
abstract: OBJECTIVE
  The objective of this nationwide study was to compare the risk of all-cause mortality, fatal and nonfatal cardiovascular disease (CVD), and severe hypoglycemia in patients with type 2 diabetes (T2D) on metformin monotherapy treatment starting second-line treatment with either insulin or dipeptidyl peptidase-4 inhibitor (DPP-4i).
  
  
  METHODS
  All patients with T2D in Sweden who initiated second-line treatment with insulin or DPP-4i after metformin monotherapy during 2007-2014 identified in the Swedish Prescribed Drug Register were followed for outcome in the Cause of Death and National Patient Registers. Insulin and DPP-4i patients were matched 1:1 using propensity-score matching. Comparisons between groups were performed using unadjusted Cox regression models. Additionally, multivariate adjusted survival models were used to test the results using the full population without matching.
  
  
  RESULTS
  Of 27,767 mono-metformin-treated patients, 55.7% started insulin and 44.3% a DPP-4i, and after matching both groups had 9278 patients each. Median follow-up (patients years) times were 3.84 (37,578) and 3.93 (37,983) for insulin and DPP-4i-groups, respectively. Insulin compared with DPP-4i was associated with higher risk of subsequent all-cause mortality, fatal and nonfatal CVD, and severe hypoglycemia; adjusted HR (95% CI): 1.69 (1.45-1.96); 1.39 (1.21-1.61); and 4.35 (2.26-8.35), respectively. When performing multivariate adjusted analyses on the full population similar results were found.
  
  
  CONCLUSIONS
  Initiation of insulin, compared with DPP-4i treatment, was associated with an increased risk of subsequent all-cause mortality, fatal and nonfatal CVD, and severe hypoglycemia. Results from randomized trials will be important to elucidate causal relationships.
authors.affiliation: Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research, Karolinska Institute, Södersjukhuset, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.affiliation: AstraZeneca Nordic-Baltic, Södertälje, Sweden. Electronic address: johan.bodegard@astrazeneca.com.
authors.forename: Johan
authors.initials: J
authors.lastname: Bodegard
authors.affiliation: Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research, Karolinska Institute, Södersjukhuset, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Nathanson
authors.affiliation: Statisticon AB, Uppsala, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Thuresson
authors.affiliation: Cardiology Unit, Department of Medicine, Solna, Karolinska Institute, Stockholm, Sweden; Capio S:t Görans Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Norhammar
authors.affiliation: Department of Medical Sciences, Clinical Diabetes and Metabolism, Uppsala University, Uppsala, Sweden.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
mesh_terms: D002318:Cardiovascular Diseases / Q000209:etiology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000401:mortality; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced*; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D013453:Sulfonylurea Compounds / Q000627:therapeutic use
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D008687:Metformin
keywords: Cardiovascular disease; Dipeptidyl peptidase-4 inhibitor; Hypoglycemia; Insulin; Outcome; Type 2 diabetes