Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: dose association with all-cause mortality, cardiovascular events and cancer.
OBJECTIVE
To evaluate the association between insulin exposure and all-cause mortality, incident major adverse cardiovascular events (MACE) and incident cancer in people with type 2 diabetes treated with insulin monotherapy.


METHODS
For this retrospective study, people with type 2 diabetes who progressed to insulin monotherapy from the year 2000 were identified from the UK Clinical Practice Research Datalink. The risks of progression to serious adverse outcomes were compared using Cox proportional hazards models. In the main analysis, insulin exposure was introduced into the model as prescribed international units per kilogram per day, as a cumulative, continuous, annually updated, time-dependent covariable.


RESULTS
A total of 6484 subjects with type 2 diabetes who progressed to treatment with insulin monotherapy from the year 2000 onwards were followed for a mean of 3.3 years. The event numbers were as follows: deaths, n = 1110; incident MACE, n = 342; incident cancers, n = 382. Unadjusted event rates were 61.3 deaths per 1000 person-years, 26.4 incident MACE per 1000 person-years and 24.6 incident cancers per 1000 person-years. The adjusted hazard ratios in relation to 1-unit increases in insulin dose were 1.54 [95% confidence interval (CI) 1.32-1.78] for all-cause mortality, 1.37 (95% CI 1.05-1.81) for MACE and 1.35 (95% CI 1.04-1.75) for cancer.


CONCLUSIONS
There was an association between increasing exogenous insulin dose and increased risk of all-cause mortality, MACE and cancer in people with type 2 diabetes. The limitations of observational studies mean that this should be further investigated using an interventional study design.
Cochrane Institute of Primary Care and Public Health, School of Medicine, Cardiff University, The Pharma Research Centre, Cardiff Medicentre, Cardiff, UK.
S E
SE
Holden
S
S
Jenkins-Jones
C Ll
CL
Morgan
G
G
Schernthaner
C J
CJ
Currie
D000368:Aged; D002318:Cardiovascular Diseases / Q000150:complications / Q000453:epidemiology* / Q000401:mortality / Q000517:prevention & control; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D003925:Diabetic Angiopathies / Q000453:epidemiology* / Q000401:mortality / Q000517:prevention & control; D058065:Diabetic Cardiomyopathies / Q000453:epidemiology* / Q000401:mortality / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D057286:Electronic Health Records; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015994:Incidence; D007328:Insulin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009369:Neoplasms / Q000150:complications / Q000453:epidemiology* / Q000401:mortality; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012306:Risk; D006113:United Kingdom / Q000453:epidemiology
D007004:Hypoglycemic Agents; D007328:Insulin
all-cause mortality; cancer; dose; epidemiology; insulin; major adverse cardiovascular events; type 2 diabetes