The Association Between Baseline Insulin Treatment and Cardiovascular Events

A Meta-Analysis

Joanna E. Khatib; Yixue Shao; Lizheng Shi; Vivian A. Fonseca


J Endo Soc. 2021;5(2) 

In This Article

Abstract and Introduction


Objective: We conducted a meta-analysis to compare major adverse cardiovascular events (MACEs) in recent diabetes type 2 drugs cardiovascular outcome trials (CVOTs) in the subgroups that used insulin at baseline to the subgroups that did not.

Methods: English publications from 2010 to 2019 were searched in PubMed and Google Scholar. We searched published clinical trials for CVOTs with new drugs for type 2 diabetes and found 12 publications, of which 8 provided outcomes according to insulin use. We compared the event rate of the primary outcome in the group taking insulin with the one not taking insulin. Data were extracted by 2 investigators independently, including CVOT drug, publication year, sample size, duration of diabetes, mean glycated hemoglobin A1c, mean age, and number of patients in each treatment group. We included 8 trials in the analysis: DECLARE, EMPA-REG, EXSCEL, HARMONY, LEADER, SUSTAIN-6, EXAMINE, and SAVOR-TIMI. The pooled relative risk was 1.52 (95% CI, 1.43 ~ 1.62) when comparing the treatment group with insulin at baseline with the treatment group of patients without insulin use.

Results: In recent CVOTs, patients on insulin regimen along with the new antidiabetic drug had a higher risk ratio of cardiovascular events than patients who used the new antidiabetic drug alone.


In 2016, statistics from the Centers for Disease Control and Prevention showed that 23 million adults in the United States were diagnosed with diabetes.[1] Diabetes carries a 2- to 3-fold increase in atherosclerotic disease both in men and women, including intermittent claudication, congestive heart disease, and coronary artery disease.[2] Multiple studies have confirmed that patients with diabetes have higher mortality rates due to cardiovascular disease compared to patients who did not have diabetes.[3–6]

In 2008, the Food and Drug Administration mandated sponsors of new type 2 diabetes agents prove that therapy would not cause increased cardiovascular risk beyond a specified threshold based on findings of the RECORD trial.[7,8] There were 12 published cardiovascular outcome clinical trials (CVOTs) comparing the new drugs for type 2 diabetes to placebo from 2013. These trials included 3 sodium-glucose cotransporter 2 inhibitors (SGLT-2), 6 glucagon-like peptide-1 receptor agonists (GLP-1), and 3 dipeptidyl peptidase-4 inhibitors (DPP-4).

The CVOTs for SGLT-2 inhibitors and GLP-1 agonists showed that patients who were treated with these drugs had a lower risk of cardiovascular events than patients treated with placebo,[9–16] whereas CVOTs of patients treated with DPP-4 inhibitors did not show cardiovascular benefit or harm.[17–19]

Most recent CVOTs have focused on cardiovascular outcomes when patients were taking the drugs vs placebo or compared different diabetes drugs; it is unclear how the cardiovascular health is affected when the patient regimen included insulin and other type 2 diabetes drugs. This is a very popular regimen and is often clinically used. Cosmi et al analyzed data to determine whether patients who used insulin had worse outcomes among heart failure patients, concluding that insulin was associated with higher risks of death and hospitalizations in heart failure patients.[20] Mendez et al conducted a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) database to evaluate the relationship between insulin use and clinical outcomes including mortality, major cardiovascular outcome (MACE), and diabetic kidney disease (DKD).[21] They concluded that insulin use was associated with higher mortality, MACE, and DKD in patients who had higher insulin resistance.[21]

The CVOTs for the new type 2 diabetes drugs had good follow-up of participants and adjudication of events, and the trials included many patients taking insulin at baseline, which allowed us to examine the outcome when patients received the new diabetes agents along with insulin at baseline. To our knowledge, there has not been any previous analysis of CVOTs to examine the effect of an insulin and diabetes drug combination on cardiovascular events. This is a meta-analysis to assess the effect of combining new diabetes type 2 agents with insulin on cardiovascular outcomes among diabetes population in the CVOTs.