Abstract A23: Cancer outcomes in the diabetes prevention program outcomes study
Authors: Heckman-Stoddard Brandy M. , Crandall Jill P. , Edelstein Sharon L. , Hamman Richard F. , Prorok Philip C. , Ryan Anne , Dabelea Dana , Hazuda Helen P. , Horton Edward , Hoskin Mary A. , Jeffries Susan , Knowler William C. , Mather Kieren J. , Shapiro Susana M. , Walcott Farzana L. , Ford Leslie G. 
Published: October 2015

Numerous observational studies have reported decreased cancer incidence and cancer-related mortality in patients with diabetes receiving standard doses of metformin. A recent meta-analysis of these studies suggested a 31% reduction in overall cancer incidence, summary relative risk (0.69; 95% confidence interval, 0.52-0.90), in subjects taking metformin as compared with other antidiabetic drugs. Separate meta-analyses of studies that adjusted for BMI or time-related bias suggested an attenuation of this signal, but still showed a significant reduction in cancer incidence. However, studies published to date are limited by the observational nature of the data and the randomized controlled trials that have been used to examine metformin's potential as an anti-cancer agent in patients with diabetes have had insufficient follow-up for cancer endpoints. These data also do not address the cancer risk in non-diabetic populations, in which the cancer preventive potential of metformin is unknown.

The Diabetes Prevention Program (DPP) was a national multi-center, randomized, placebo-controlled clinical trial, which enrolled 3234 participants between 1996 and 1999, designed to investigate whether intensive lifestyle modification or treatment with metformin (850mg twice a day) delayed or prevented the onset of type 2 diabetes in a high risk population. The DPP and its follow up study, the Diabetes Prevention Program Outcomes Study (DPPOS), provide a unique opportunity to examine the role of metformin and lifestyle intervention in reducing cancer incidence in an overweight adult population with impaired glucose regulation, before the onset of diabetes. The National Cancer Institute Division of Cancer Prevention, in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the DPPOS investigators, proposed a study to examine the hypothesis that metformin and/or lifestyle intervention can modify total cancer incidence and/or obesity-related cancer incidence (breast, colorectal, endometrium, pancreas, lower esophagus, gall-bladder, and kidney) in DPP/DPPOS participants.

The DPPOS protocol and consent were modified to allow collection of data to support the inclusion of cancer incidence as an endpoint of interest in the study. Participants complete a cancer risk questionnaire that includes family history of cancer, cancer screening activities, and use of aspirin and NSAIDs including dose and frequency. The participants who previously reported a cancer diagnosis, through the SAE reporting process and/or an annual questionnaire, or during a subsequent follow-up visit, are asked to provide physician information to obtain medical records for case adjudication. This protocol will allow for the examination of the effect of metformin and lifestyle intervention on cancer incidence in an initially pre-diabetic population potentially through a median of 20 years of follow-up.

Data from this study will compare incidence of total and obesity-related cancers between the original treatment groups; assess cancer (total and obesity-related) incidence by metformin exposure across all treatment groups, using a “met-years” variable, and explore subgroups to investigate effect modification by sex, age group, race/ethnicity, diabetes status, or weight loss at 1 year or mean weight loss since study baseline.

Citation Format: Brandy M. Heckman-Stoddard, Jill P. Crandall, Sharon L. Edelstein, Richard F. Hamman, Philip C. Prorok, Anne Ryan, Dana Dabelea, Helen P. Hazuda, Edward Horton, Mary A. Hoskin, Susan Jeffries, William C. Knowler, Kieren J. Mather, Susana M. Shapiro, Farzana L. Walcott, Leslie G. Ford. Cancer outcomes in the diabetes prevention program outcomes study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A23.