title: Clinical Effects and Safety of Direct-Acting Insulin Analogs in Patients with Type 1 Diabetes: A Nation-Wide Observational Cohort Study.
abstract: BACKGROUND
  Studies comparing direct-acting insulin analogs (DAIs) in terms of effectiveness and long-term safety are scarce. Our aim was to explore these variables in clinical practice among patients with type 1 diabetes, including the elderly and those with renal impairment.
  
  
  METHODS
  We linked four national registers in a population-based cohort study. Patients with type 1 diabetes and continuous use of all currently available DAIs (lispro, aspart, or glulisine) in 2005-2013 were monitored for up to 7.5 years. Inverse probability of treatment weighting was used to adjust for differences in baseline characteristics between treatment groups. Unadjusted mean HbA1c and weights were plotted. Hazard ratios and 95% confidence intervals of cardiovascular events (CVEs) and mortality were estimated using Cox proportional hazards regression models.
  
  
  RESULTS
  We included 41,165 patients-14,047 lispro, 26,813 aspart, and 305 glulisine users. At baseline, the mean age was highest among glulisine users (49.4 years), followed by 41.0 years for lispro users and 40.1 years for aspart users. A total of 9.2% of the patients were 65 years or older. Diabetes duration was shortest among glulisine users (11.6 years), followed by 15.4 years for aspart users and 19.5 years for lispro users. The mean HbA1c and weights during the follow-up period were similar. The numerical differences at baseline were subsequently adjusted for. There were no significant differences between groups regarding hyperglycemia requiring hospitalization, CVE, or mortality, while Cox regression suggested lower rates of hypoglycemia among glulisine users. Severe hypoglycemia was more common, and severe hyperglycemia was less common among patients aged 65 years or older, while severe hypoglycemia and hyperglycemia were more common in patients with low renal function (estimated glomerular filtration rate).
  
  
  CONCLUSIONS
  There were no pronounced differences in effectiveness and long-term cardiovascular safety and mortality between the DAIs, although there were some differences in clinical characteristics between patients using the three types of insulin. Severe hypoglycemia was more common among older patients, while severe hypoglycemia and hyperglycemia were more common among patients with impaired renal function.
  
  
  BACKGROUND
  Sanofi.
authors: Department of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Göteborg, Sweden. waiming.lak@gmail.com.
authors: Vincent
authors: http://orcid.org/0000-0002-7394-6812
authors: V
authors: Lak
authors: Center of Registers in Region Västra Götaland, Göteborg, Sweden.
authors: Ann-Marie
authors: AM
authors: Svensson
authors: Center of Registers in Region Västra Götaland, Göteborg, Sweden.
authors: Mervete
authors: M
authors: Miftaraj
authors: Center of Registers in Region Västra Götaland, Göteborg, Sweden.
authors: Stefan
authors: S
authors: Franzén
authors: Department of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Göteborg, Sweden.
authors: Björn
authors: B
authors: Eliasson
keywords: Cohort study; Effectiveness; Elderly; Insulin analogs; Insulin aspart; Insulin glulisine; Insulin lispro; Renal failure; Safety; Type 1 diabetes