In Type 1 Diabetes, Higher Insulin Doses Could Increase Cancer Risk

Wenjun Zhong, PhD

New research from an analysis of patient data from the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study suggests patients with type 1 diabetes with the highest doses of daily insulin were at an increased risk of developing cancer over 28 years follow-up.

Nearly 40 and 30 years after the launch of the DCCT and EDIC studies, results of the analysis provide evidence from 2 different multivariable-adjusted models suggesting those in the highest category of daily insulin dose was associated with a more than 4-fold increase in the incidence of cancer among patients with type 1 diabetes.

“This study showed that daily insulin dose was associated with cancer risk in type 1 diabetes. The HRs were significantly higher in the high-dose vs low-dose group,” wrote investigators.

Citing previous reports detailing an association between type 1 diabetes and increased incidence of cancer relative to the general population, Wenjun Zhong, PhD, a principal scientist in epidemiology at Merck, and Yuanjie Mao, MD, PhD, an assistant clinical professor of endocrinology at the Ohio University, sought to assess risk factors associated with cancer incidence among patients with type 1 diabetes. With this in mind, investigators designed the current study as an analysis of data from the DCCT and EDIC studies. Launched in 1983, the DCCT study enrolled more than 1400 patients from 29 centers in North America and followed them to assess the impact of glycemic control on event risk in diabetes.

At the conclusion, 1375 of the 1441 patients initially enrolled in the trial volunteered to continue in the EDIC follow-up study. Of these patients, 1303 participants who were free from cancer at enrollment in DCCT and had completed the annual cancer history update were identified for inclusion in the current study.

Of the 1303 patients included in the study, 7% had cancer diagnoses during a total of 33,813 person-years of follow-up, which corresponded to an incidence rate of 2.8 (95% CI, 2.2-3.3) per 1000 person-years. The mean age at first diagnosis was 50 years and the mean duration of diabetes at the time was 25 years.

The most commonly reported forms of cancer were skin, breast, reproductive, and digestive cancers. Among the 93 patients with cancer diagnoses, 61% were female, 9% developed cancer within 10 years, 33% developed cancer between 11-20 years, and 58% developed cancer between 21-28 years. For the purpose of analysis, investigators calculate cancer incidence using Cox proportional hazards regression models adjusted for age and sex. Investigators noted their first model included time-dependent variables and a second model was created with daily insulin dose used as a fixed variable. Based on reported insulin use, participants were classified into the low-, medium- or high-dose groups.

Upon analysis, results indicated both age (HR, 1.08 [95% CI, 1.05-1.12]) and female sex (HR, 1.74 [95% CI, 1.15-2.64]) were associated with an increased incidence of cancer. Inverse associations with risk of cancer were observed for exercising habits and high-density lipoprotein cholesterol. However, an association was observed between daily insulin dose and increased incidence of cancer, even after adjustment for age and sex. In the model assessing daily insulin dose as a time-dependent variable, results indicated use of a high daily dose of insulin was associated with a nearly 6-fold increase in cancer incidence (HR, 5.93 [95% CI, 1.21-29.06]; P =.03). In models assessing daily insulin dose as a fixed variable, results indicated use of a high daily dose of insulin was associated with a 4-fold increase in cancer incidence (HR, 4.13 [95% CI, 1.13-15.17]; P=.03).

When assessing cancer incidence per 1000 person-years based on what category of insulin dose level patients are categorized into demonstrated an incidence rate of 2.11, 2.87, and 2.91 per 1000 person-years in the low-, medium-, and high-dose grouper respectively. Before concluding their study, the authors cautioned clinicians to consider limitations within their study before overinterpretation of results.

“A limitation of this study is the relatively small sample size, which precluded analyses with specific cancer types and resulted in a wide confidence interval for daily insulin dose. Moreover, the association found may be subject to residual confounding and was not necessarily causal. Furthermore, larger studies in type 1 diabetes are needed to validate this association,” wrote investigators.

This study, “Daily Insulin Dose and Cancer Risk Among Patients With Type 1 Diabetes,” was published in JAMA Oncology.