title: Drug-related risk of severe hypoglycaemia in observational studies: a systematic review and meta-analysis.
abstract: BACKGROUND
  Diabetes mellitus (DM) leads to multiple complications, including severe hypoglycaemia events (SHEs). SHEs can impact a patient's quality of life and compliance and may directly result in additional costs to the health care system. The aim of this review was to evaluate the risk of severe hypoglycaemia in patients with type 1 (T1) and 2 (T2) DM as observed in everyday clinical practice for various drug regimens.
  
  
  METHODS
  We conducted a systematic review of observational (retrospective or prospective) studies in the MEDLINE, Embase, and Cochrane Library databases that covered at least 100 children or adults with T1/T2 DM. In T1 DM, basal-bolus/pre-mix insulin (human or analogue) and insulin pump were reviewed, and in T2 DM, basal-bolus/pre-mix insulin (human or analogue), oral antidiabetic drugs supported with basal insulin (human or analogue), sulfonylureas in monotherapy, and combined oral treatment were reviewed. In order to estimate SHE rates, we extracted data on the time horizon of the study, number of patients, number of SHEs, and number of patients experiencing at least one SHE. We used a random effects model to estimate the annual SHE rate. We considered the risk for other antidiabetic medications in T2 DM to be negligible and the results of our main review yielded no observational data for premixes in T1 DM so they were assessed based on relative rates taken from additional systematic reviews. The study, being a desk research, did not involve any human subjects (including human material or human data) and no ethical committee approval was asked for. For the same reason there was no need to collect informed consent for participation in the study.
  
  
  RESULTS
  We identified 76 observational studies encompassing 707,722.30 patient-years. The estimated annual SHE rate varied from 0.168 (95 % CI 0.123-0.237) for insulin pump up to 1.628 for biphasic human insulin in T1 DM patients, and from 0.0035 for oral antidiabetic drugs up to 0.554 (95 % CI 0.157-7.534) for basal-bolus with human insulin in T2 DM patients.
  
  
  CONCLUSIONS
  Our review indicates that SHE rates differ between patients depending on treatment regimen. However, SHEs are also driven by other factors. Proper modelling techniques are needed to use various types of information in published studies.
authors.affiliation: Novo Nordisk Pharma sp. z o.o, Warsaw, Poland. mcze@novonordisk.com.|Department of Pharmacoeconomics, Medical University of Warsaw, Warsaw, Poland. mcze@novonordisk.com.|Business School, Warsaw University of Technology, Warsaw, Poland. mcze@novonordisk.com.
authors.forename: Marcin
authors.initials: M
authors.lastname: Czech
authors.affiliation: HealthQuest spółka z ograniczoną odpowiedzialnością Sp. K, Warsaw, Poland. elzbieta.rdzanek@healthquest.pl.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Rdzanek
authors.affiliation: HealthQuest spółka z ograniczoną odpowiedzialnością Sp. K, Warsaw, Poland. justyna.paweska@gmail.com.
authors.forename: Justyna
authors.initials: J
authors.lastname: Pawęska
authors.affiliation: HealthQuest spółka z ograniczoną odpowiedzialnością Sp. K, Warsaw, Poland. olga.adamowicz-sidor@healthquest.pl.
authors.forename: Olga
authors.initials: O
authors.lastname: Adamowicz-Sidor
authors.affiliation: Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland. maciej.niewada@gmail.com.
authors.forename: Maciej
authors.initials: M
authors.lastname: Niewada
authors.affiliation: Decision Analysis and Support Unit, Warsaw School of Economics, Al. Niepodległości 162, 02-554, Warsaw, Poland. michal.jakubczyk@sgh.waw.pl.
authors.forename: Michał
authors.initials: M
authors.lastname: Jakubczyk
mesh_terms: D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced*; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D011379:Prognosis; D012307:Risk Factors
chemical_list: D007004:Hypoglycemic Agents