A systematic literature review on the efficacy-effectiveness gap: comparison of randomized controlled trials and observational studies of glucose-lowering drugs

Aim: To identify a potential efficacy–effectiveness gap and possible explanations (drivers of effectiveness) for differences between results of randomized controlled trials (RCTs) and observational studies investigating glucose-lowering drugs. Methods: A systematic literature review was conducted in English language articles published between 1 January, 2000 and 31 January, 2015 describing either RCTs or observational studies comparing glucagon-like peptide-1 analogs (GLP-1) with insulin or comparing dipeptidyl peptidase-4 inhibitors (DPP-4i) with sulfonylurea, all with change in glycated hemoglobin (HbA1c) as outcome. Medline, Embase, Current Content, and Biosis were searched. Information on effect estimates, baseline characteristics of the study population, publication year, study duration, and number of patients, and for observational studies, characteristics related to confounding adjustment and selection- and information bias were extracted. Results: From 312 hits, 11 RCTs and 7 observational studies comparing GLP-1 with insulin, and from 474 hits, 16 RCTs and 4 observational studies comparing DPP-4i with sulfonylurea were finally included. No differences were observed in baseline characteristics of the study populations (age, sex, body mass index, time since diagnosis of type 2 diabetes mellitus, and HbA1c) or effect sizes across study designs. Mean effect sizes ranged from −0.43 to 0.91 and from −0.80 to 1.13 in RCTs and observational studies, respectively, comparing GLP-1 with insulin, and from −0.13 to 2.70 and −0.20 to 0.30 in RCTs and observational studies, respectively, comparing DPP-4i and sulfonylurea. Generally, the identified observational studies held potential flaws with regard to confounding adjustment and selection- and information bias. Conclusions: Neither potential drivers of effectiveness nor an efficacy–effectiveness gap were identified. However, the limited number of studies and potential problems with confounding adjustment, selection- and information bias in the observational studies, may have hidden a true efficacy-effectiveness gap

Assessment of channeling bias among initiators of glucose-lowering drugs: A UK cohort study

Mikkel Z Ankarfeldt,1,2 Brian L Thorsted,1 Rolf HH Groenwold,2,3 Erpur Adalsteinsson,1 M Sanni Ali,2–4 Olaf H Klungel2,3 1Novo Nordisk A/S, Bagsvaerd, Denmark; 2Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; 3Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands; 4Nuffield Department of Orthopaedics, Rheumatology, Musculoskeletal Sciences, University of Oxford, Oxford, UK Background: Channeling bias may occur when a newly marketed drug and an established drug, despite similar indications, are prescribed to patients with different prognostic characteristics (ie, confounding).Aim: To investigate channeling bias and its impact on relative effectiveness of glucagon-like peptide-1 (GLP-1) analogs versus basal insulin and dipeptidyl peptidase-4 inhibitors (DPP-4i) versus sulfonylurea.Methods: In the UK Clinical Practice Research Datalink, patients with type 2 diabetes initiating treatment between 2006 and 2015 were included. Analyses were stratified by years since first prescription of GLP-1 and DPP-4i, respectively. The characteristics of GLP-1 versus insulin and DPP-4i versus sulfonylurea initiators were compared over time. After propensity score matching, the relative effectiveness regarding 6-month changes in glycated hemoglobin (HbA1c) and body weight was estimated.Results: In total, 8,398 GLP-1, 14,807 insulin, 24,481 DPP-4i, and 33,505 sulfonylurea initiators were identified. No major channeling was observed. Considerable overlap in distributions of characteristics allowed for propensity score-matched analyses. Relative effectiveness was similar across time. The overall relative effect of GLP-1 versus insulin showed no difference for HbA1c and relative increase in body weight (3.57 kg [95% confidence interval {CI}: 3.21, 3.92]) for insulin. The overall relative effect of DPP-4i versus sulfonylurea showed relative decrease in HbA1c (–0.34% [95% CI: –0.38, –0.30]) and increase in body weight (1.58 kg [95% CI: 1.38, 1.78]) for sulfonylurea.Conclusion: No major channeling was identified in the investigated glucose-lowering drugs. Relative effectiveness could be estimated already in the first year after launch and was consistent in the years thereafter. Keywords: channelling bias, channeling bias, glucose-lowering drugs, DPP-4i, GLP-1, type 2 diabetes, observational study, relative effectivenes

Assessment of channeling bias among initiators of glucose-lowering drugs: A UK cohort study [Corrigendum]

Ankarfeldt MZ, Thorsted BL, Groenwold RHH, et al. Clin Epidemiol. 2017;9:19–30. On page 23, Figure 1 Notes section was marked incorrectly. The correct Notes should read as follows:Figure 1 Propensity score over time for GLP-1 versus basal insulin initiators.Notes: Blue: insulin, red: GLP-1.Abbreviation: GLP-1, glucagon-like peptide-1 analogs. On page 24, Figure 2 Notes section was marked incorrectly. The correct Notes should read as follows:Figure 2 Propensity score over time for DPP-4i versus sulfonylurea initiators.Notes: Blue: sulfonylurea, red: DPP-4i.Abbreviation: DPP-4i, dipeptidyl peptidase-4 inhibitors. On Page 3 of Supplementary materials, Figure S2 caption was shown incorrectly. The correct caption should read as follows:Figure S2 Histograms of propensity score over time. Intention-to-treat and perprotocol cohorts of all identified initiators of GLP-1 and insulin, and DPP-4i and sulfonylurea, respectively. Blue: insulin and sulfonylurea initiators, respectively. Red: GLP-1 and DPP-4i initiators, respectively. Despite the above corrections, the interpretation of these figures in the published proof and the Supplementary materials was correct. Read the original articl