The effects of dual-therapy intensification with insulin or dipeptidylpeptidase-4 inhibitor on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A retrospective cohort study.
To compare time to a composite endpoint of non-fatal acute myocardial infarction, non-fatal stroke or all-cause mortality in patients with type 2 diabetes mellitus who had their treatment intensified with a dipeptidylpeptidase-4 inhibitor or insulin following dual-therapy (metformin plus sulfonylurea) failure.



A retrospective cohort study was conducted on 5238 patients newly treated with either a dipeptidylpeptidase-4 inhibitor or insulin following dual-therapy failure (2007-2014). Data were sourced from UK General Practices. The risk of the composite outcome was compared between two treatment groups: metformin + sulfonylurea + insulin ( n = 1584) and metformin + sulfonylurea + dipeptidylpeptidase-4 inhibitor ( n = 3654), while adjusting for baseline covariates. Follow-up was for up to 5 years. Propensity score matching analysis and Cox proportional hazard models were employed.



Overall, 123 and 171 composite outcome events occurred among patients who added insulin versus dipeptidylpeptidase-4 inhibitor, respectively (44.5 vs 14.6 events per 1000 person-years). Addition of insulin was associated with a significantly higher hazard ratio versus the addition of a dipeptidylpeptidase-4 inhibitor (adjusted hazard ratio = 2.6, 95% confidence interval: 1.9-3.4; p < 0.01), an effect that was more pronounced in obese (body mass index: 30-34.9 kg/m2) patients (corresponding adjusted hazard ratio 3.6, 95% confidence interval: 2.3-5.6; p < 0.01).



In routine clinical practice, intensification of metformin + sulfonylurea therapy by adding insulin is associated with increased risk of cardiovascular events and death compared with adding a dipeptidylpeptidase-4 inhibitor. These findings are in line with suggestions from previous studies regarding the cardiovascular safety of insulin in type 2 diabetes mellitus, but should be interpreted with caution.
1 Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
Mamza
M
Jil
2 Research Design Services East Midlands, School of Medicine, University of Nottingham, Nottingham, UK.
Mehta
M
Rajnikant
1 Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
Donnelly
D
Richard
1 Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, UK.
Idris
I
Iskandar
D000328:Adult; D000368:Aged; D002423:Cause of Death; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D057216:Propensity Score; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D008687:Metformin
Insulin; cardiovascular; gliptins; intensification