Objective: Several Cardiovascular Outcome Trials (CVOTs) have demonstrated benefits compared to placebo. However, the patients included were heterogeneous, including several with long duration diabetes, insulin treatment may be a surrogate for duration and severity of disease. We conducted a meta-analysis to evaluate the impact of concurrent insulin treatment on the odds of meeting the primary outcome in recent CVOTs.

Methods: PubMed and google scholar were searched for CVOTs with new drugs for diabetes. We found 10 publications, of which 7 provided outcomes according to insulin use. We compared the risk ratio of the primary endpoint in the group taking insulin with those not taking insulin by extracting the number of events in both groups along with total number of patients. We also removed the 2 trials that used dipeptidyl peptidase 4 inhibitors, since none of the drugs had shown benefit in the trials. The I-square was used to assess between-study heterogeneity and all analyses were performed using STATA program version 15.1. Fixed effect models were used in these analyses due to low heterogeneity. This study was conducted in compliance with PRISMA guidelines.

Results: When all 7 trials were included in the meta-analysis (EXSCEL, SUSTAIN6, SAVORTIMI, EMPAREG, LEADER, EXAMINE, and DECLARE), the risk ratio of the primary outcome was significantly increased indicating that patients using insulin with drug are more likely to have the primary cardiovascular outcome than the group of patients using drug without insulin. The RR was 1.43 (95% confidence interval: 1.32, 1.55).

Conclusion: In recent CVOTs which have demonstrated a benefit of the study drug on the primary outcome compared to usual care, the concomitant use of Insulin along with the study drugs led to a higher risk of cardiovascular events than in patients who were on the drugs without insulin. The reason for this increased risk is unclear but may be related to the likely longer duration of diabetes and poorer antecedent control which led to the use of insulin.


J. Khatib: None. Y. Shao: None. L. Shi: None. V. Fonseca: Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Abbott, Asahi Kasei Corporation, Novo Nordisk Inc., Sanofi US, Takeda Pharmaceutical Company Limited. Research Support; Self; Bayer US. Stock/Shareholder; Self; Amgen Inc., BRAVO4HEALTH, Mellitus Health.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.