Abnormal regulation of glycemia (dysglycemia) has a very long time course, from its earliest stage, labeled pre-diabetes, to the onset of Type 2 diabetes (T2D), to the development of clinically detectable microvascular changes and measurable atherosclerosis, to clinically manifest complications with attendant morbidity and mortality. The Diabetes Prevention Program (DPP) focused on the pre-diabetes stage of dysglycemia and demonstrated powerful beneficial effects of lifestyle intervention (ILS) and metformin (MET), compared with placebo (PLBO), in preventing or delaying the onset of T2D over a 3-year period in a high-risk population (n=3234). The DPP also investigated and described the interventions, phenotypic and genotypic risk factors associated with T2D development, the effects of the interventions in the setting of these risk factors, the health economic implications of T2D prevention, and other outcomes of interest. Based on these results, the DPP lifestyle program has been widely implemented. The 11-year follow-up DPP Outcomes Study (DPPOS) explored the longer-term effects of T2D prevention, bridging the period between pre-diabetes and T2D, and examined outcomes that required more time to develop than the relatively brief 3-years of DPP. DPPOS showed longer-term salutary effects of the original interventions on T2D prevention and on cardiovascular disease (CVD) risk factors. Prevention was cost-saving with MET and cost-effective with ILS. Overall, the risk for microvascular disease was significantly greater in subjects who developed T2D and increased with longer duration and higher hemoglobin A1c (A1C). There were no significant differences by treatment group in the prevalence of the aggregate microvascular outcome; however, compared with PLBO and MET, ILS significantly reduced the risk of microvascular disease among women and those who had A1C ?6.5% at study end. The proposed DPPOS Phase 3 will study the DPPOS cohort for 10 more years, taking advantage of the long-term randomized exposure to MET and the densely phenotyped and genotyped DPPOS cohort (n=2778), which includes nearly 1600 patients with known T2D duration and ~1200 who have not developed T2D, to address yet unanswered questions about long-term exposure to MET and ILS initiated during pre-diabetes. DPPOS Phase 3 will examine outcomes that are of increasing public health concern in the aging population with pre-diabetes and T2D, including the putative benefits of MET on development of CVD and cancer. The main goals of DPPOS Phase 3 are to examine efficiently: 1) the long-term effects of metformin therapy begun in the pre-diabetic phase on risk for CVD and cancer; 2) the long-term effects by intention-to-treat of ILS and MET on further development of T2D and on traditional and more recently recognized complications of dysglycemia, and of their economic impact; and 3) the clinical course of dysglycemia, evaluated by categorical diagnoses (pre-diabetes vs diabetes) and as a continuum, and their associations with the development of complications, including analyses of interactions with DPP interventions and established and novel risk factors.

Public Health Relevance

Pre-diabetes and T2D affect >100,000,000 individuals in the U.S., with the total cost of T2D currently estimated at $245 billion. Understanding the effects of preventing or delaying T2D on human disease, the potential long-term benefits of lifestyle intervention and metformin, one of the most commonly used medications in the world, and the clinical course of pre-diabetes and T2D is critical if we are to apply prevention and treatment methods effectively and efficiently. The current proposal will examine the long-term effects of the early use - starting before diabetes develops - of metformin and lifestyle changes on development of significant morbidities such as cancer and cardiovascular disease, and help understand the clinical course of abnormal glucose levels from the pre-diabetic state through early and more advanced T2D.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK048406-24
Application #
9230824
Study Section
Special Emphasis Panel (ZDK1-GRB-N (O3)S)
Program Officer
Teff, Karen L
Project Start
1994-08-15
Project End
2021-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
24
Fiscal Year
2017
Total Cost
$347,532
Indirect Cost
$125,997
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
McCaffery, Jeanne M; Jablonski, Kathleen A; Franks, Paul W et al. (2017) Replication of the Association of BDNF and MC4R Variants With Dietary Intake in the Diabetes Prevention Program. Psychosom Med 79:224-233
Goldberg, Ronald B; Aroda, Vanita R; Bluemke, David A et al. (2017) Effect of Long-Term Metformin and Lifestyle in the Diabetes Prevention Program and Its Outcome Study on Coronary Artery Calcium. Circulation 136:52-64
Ceglia, Lisa; Nelson, Jason; Ware, James et al. (2017) Association between body weight and composition and plasma 25-hydroxyvitamin D level in the Diabetes Prevention Program. Eur J Nutr 56:161-170
Zhou, Kaixin; Yee, Sook Wah; Seiser, Eric L et al. (2016) Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet 48:1055-1059
Walford, Geoffrey A; Ma, Yong; Clish, Clary et al. (2016) Metabolite Profiles of Diabetes Incidence and Intervention Response in the Diabetes Prevention Program. Diabetes 65:1424-33
Aroda, Vanita R; Edelstein, Sharon L; Goldberg, Ronald B et al. (2016) Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab 101:1754-61
Goldberg, Ronald B; Temprosa, Marinella; Mele, Lisa et al. (2016) Change in adiponectin explains most of the change in HDL particles induced by lifestyle intervention but not metformin treatment in the Diabetes Prevention Program. Metabolism 65:764-75
Hall, Kathryn T; Jablonski, Kathleen A; Chen, Ling et al. (2016) Catechol-O-methyltransferase association with hemoglobin A1c. Metabolism 65:961-967
Hivert, Marie-France; Christophi, Costas A; Franks, Paul W et al. (2016) Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants. Diabetes 65:520-6
Rockette-Wagner, Bonny; Edelstein, Sharon; Venditti, Elizabeth M et al. (2015) The impact of lifestyle intervention on sedentary time in individuals at high risk of diabetes. Diabetologia 58:1198-202

Showing the most recent 10 out of 36 publications