Doses of Insulin and Its Analogues and Cancer Occurrence in Insulin-Treated Type 2 Diabetic Patients

Abstract

OBJECTIVERecent epidemiological studies suggested that some insulin analogues could be associated with increased risk of cancer. The present study is aimed at assessing the long-term association of different insulin analogues with cancer incidence.RESEARCH DESIGN AND METHODSA nested case-control study dataset was generated from the cohort study dataset (n = 1,340 insulin-treated diabetic outpatients) by sampling control subjects from the risk sets. For each case subject, the control subjects (up to five) were chosen randomly from those members of the cohort who are at risk for the same follow-up time of the case subject. Five-year age classes, sex, and BMI classes (<18.5, 18.5–24.9, 25–29.9, and ≥30 kg/m2) were considered as additional categorical matching variables.RESULTSDuring a median follow-up of 75.9 months (interquartile range 27.4–133.7), 112 case subjects of incident cancer were compared with 370 matched control subjects. A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects (0.24 IU/kg/day [0.10–0.39] versus 0.16 IU/kg/day [0.12–0.24], P = 0.036). Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (odds ratio 5.43 [95% CI 2.18–13.53], P < 0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues.CONCLUSIONSThe possibility of association between cancer and higher glargine doses suggests that dosages should always be considered when assessing the possible association of insulin and its analogues with cancer.

Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies

“…Time-window bias was observed in two studies (18,22). In one of the two studies, despite matching on calendar time, time-window bias was potentially present because case and control subjects were not matched on diabetes duration (as depicted in Supplementary Fig.…”

“…Thirteen studies examined ever use of long-acting insulin analogs, which was defined as at least one prescription, compared with nonuse, other, human, or NPH insulin (5)(6)(7)(8)14,16,18,19,21,23,(25)(26)(27). One study examined duration of time since starting long-acting insulin analogs, and one examined mean daily dose (22,28). Four studies used time-dependent exposure definitions (15,17,20,24).…”

“…1). Following our inclusion criteria, 16 cohort and 3 case-control studies were included in this systematic review (5)(6)(7)(8)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). All studies evaluated insulin glargine, with four studies also investigating insulin detemir (15,17,25,28).…”

“…These studies raised important concerns but were also criticized for important methodological shortcomings (9)(10)(11)(12)(13). Since then, several observational studies assessing the association between longacting insulin analogs and cancer have been published but yielded inconsistent findings (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Such discrepancies may be due to methodological limitations, including inadequate durations of followup between insulin initiation and cancer incidence, protopathic bias, detection bias, the inclusion of prevalent users, and time-related biases such as immortal time bias, time-window bias, and time-lag bias (29).…”

Insulin, glucose and the increased risk of cancer in patients with type 2 diabetes

“…This has been highlighted by observational studies suggesting a protective effect on cancer outcomes for metformin [1][2][3][4] and glitazones [5], but on the other hand a potential increased cancer risk associated with exogenous insulin [2,4,6,7], insulin analogues [8,9] and sulfonylurea therapies [2,4,7].…”