Abnormal regulation of glycemia (dysglycemia) has an extremely long time course, from its earliest stage, labeled pre-diabetes, to the onset of Type 2 diabetes (T2D), 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, in preventing or delaying the onset of diabetes mellitus over a 3-year period in a high-risk population (n=3234). The DPP also described the role of phenotypic and genotypic risk factors associated with diabetes development, the factors that influenced the success of the interventions and health economic implications of diabetes prevention. On the basis of these results, the DPP lifestyle program has been widely implemented. The DPP Outcomes Study (DPPOS) explored the longer-term effects of T2D prevention, bridging the period between pre-diabetes and T2D over 11 years of follow-up, to examine outcomes that required more time to develop than the relatively brief 3 years of DPP (n=2776). 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. Although the aggregate microvascular outcome was not significantly reduced by either active intervention, those in whom T2D was prevented had a 28% lower risk of developing microvascular complications compared with those who developed T2D. The risk of complications was associated with T2D duration and HbA1c levels. The proposed project (DPPOS Follow-up), 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=2776), including ~1500 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 early in the course of dysglycemia. DPPOS Follow-up will examine outcomes that are of increasing public health concern in an aging population with pre-diabetes and T2D, including the development of CVD, cancer, and concomitant quality of life. The overarching goals of DPPOS Follow-up are to examine efficiently: 1) the putative benefits of metformin therapy begun early in the prediabetic phase on risk for CVD and cancer; 2) the very long-term effects of T2D prevention with ILS and MET by intention-to-treat on further development of diabetes, and on traditional and more recently recognized complications of dysglycemia; and 3) the modern day clinical course of dysglycemia and its associated complications, based on both categorical diagnoses (pre-diabetes vs. diabetes) as well as a continuum, including a careful analysis of interactions with DPP interventions as well as 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 estimated at $245 billion in 2012. 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 - 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 #
2U01DK048489-22
Application #
8852883
Study Section
Special Emphasis Panel (ZDK1-GRB-N (J1))
Program Officer
Teff, Karen L
Project Start
1994-08-20
Project End
2016-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
22
Fiscal Year
2015
Total Cost
$2,142,786
Indirect Cost
$589,752
Name
George Washington University
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
de Groot, Mary; Marrero, David; Mele, Lisa et al. (2018) Depressive Symptoms, Antidepressant Medication Use, and Inflammatory Markers in the Diabetes Prevention Program. Psychosom Med 80:167-173
Kim, Catherine; Aroda, Vanita R; Goldberg, Ronald B et al. (2018) Androgens, Irregular Menses, and Risk of Diabetes and Coronary Artery Calcification in the Diabetes Prevention Program. J Clin Endocrinol Metab 103:486-496
Crandall, Jill P; Mather, Kieren; Rajpathak, Swapnil N et al. (2017) Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. BMJ Open Diabetes Res Care 5:e000438
Luchsinger, José A; Ma, Yong; Christophi, Costas A et al. (2017) Metformin, Lifestyle Intervention, and Cognition in the Diabetes Prevention Program Outcomes Study. Diabetes Care 40:958-965
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
O'Sullivan, John F; Morningstar, Jordan E; Yang, Qiong et al. (2017) Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes. J Clin Invest 127:4394-4402
Sylvetsky, Allison C; Edelstein, Sharon L; Walford, Geoffrey et al. (2017) A High-Carbohydrate, High-Fiber, Low-Fat Diet Results in Weight Loss among Adults at High Risk of Type 2 Diabetes. J Nutr 147:2060-2066
Kim, Catherine; Dabelea, Dana; Kalyani, Rita R et al. (2017) Changes in Visceral Adiposity, Subcutaneous Adiposity, and Sex Hormones in the Diabetes Prevention Program. J Clin Endocrinol Metab 102:3381-3389
Alzahrani, Saud; Nelson, Jason; Moss, Steven F et al. (2017) H. pylori seroprevalence and risk of diabetes: An ancillary case-control study nested in the diabetes prevention program. J Diabetes Complications 31:1515-1520

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