The epidemic of type 2 diabetes (T2DM) that has affected the world's populations threatens to become this century's major public health problem. The enormous human and economic costs associated with the epidemic in the US (prevalence of ~25 million, incidence 1.9 million per year) are related primarily to the development of long-term complications including retinopathy, nephropathy, and neuropathy that cause more cases of blindness, renal failure, and amputations than any other disease. Cardiovascular disease (CVD) is increased 2-5 fold in T2DM and is the leading cause of premature death. High quality clinical trials have established the importance of lowering glycemia to reduce long-term complications. Progression of T2DM usually requires addition of a second agent to metformin, the accepted first line treatment. With the development of numerous new classes of glucose-lowering drugs, evidence to guide the choice of the second agent is lacking, prompting the proliferation of conflicting guidelines that acknowledge this deficiency. Moreover, while these agents are typically used for many years, data on long-term use are non-existent. Comparative effectiveness research is a high priority to improve public health and maximize cost-effectiveness in the treatment of T2DM. In addition, efforts to individualize T2DM therapy and determine whether selected therapies work better in some patients than others are needed, as are studies to understand differential effects of various therapies on metabolism over time. The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study will address these questions in a randomized, pragmatic clinical trial in 6000 patients with recent-onset (<5 years duration) T2DM. GRADE will compare the metabolic effects of four common glucose-lowering medications, the sulfonylurea glimepiride, DPP-4 inhibitor sitagliptin, GLP-1 agonist liraglutide, and basal insulin glargine, added to metformin, over a clinically meaningful duration, with a mean exposure of 4.5 (3-6) years. The primary outcome is the time to primary metabolic failure (hemoglobin A1c (A1C)>7%, subsequently confirmed).Other outcomes include mean A1C;time to a secondary metabolic outcome of A1C>7.5%, confirmed, after which basal insulin "rescue" therapy will be added;and adverse effects such as weight gain and hypoglycemia, effects on selected microvascular disease and CVD risk factors, tolerability and quality-of-life, and cost and cost-effectiveness. We will also examine the phenotypic characteristics and pathophysiologic factors associated with metabolic response to and/or failure of the drug combinations.

Public Health Relevance

T2DM, a chronic disease with long-term complications, affects 25 million persons in the US. Clinical trials have established the importance of lowering glucose levels to delay or prevent complications of diabetes that cause more vision loss, kidney failure and amputations than any other disease. Still, the medications most likely to maintain goal glucose levels over time are unknown thus the GRADE study will identify the most effective means of treating T2DM, comparing drug effects on glucose levels, adverse effects, diabetes complications, and quality of life, and will have major public health implications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK098246-02
Application #
8549237
Study Section
Special Emphasis Panel (ZDK1-GRB-B (J1))
Program Officer
Linder, Barbara
Project Start
2012-09-25
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$25,963,369
Indirect Cost
$1,230,273
Name
George Washington University
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Bebu, Ionut; Lachin, John M (2016) Large sample inference for a win ratio analysis of a composite outcome based on prioritized components. Biostatistics 17:178-87
Zhang, Yanqing; Fava, Genevieve E; Wang, Hongjun et al. (2016) PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Mol Ther 24:251-60
Cespedes, Elizabeth M; Hu, Frank B; Tinker, Lesley et al. (2016) Multiple Healthful Dietary Patterns and Type 2 Diabetes in the Women's Health Initiative. Am J Epidemiol 183:622-33
Lachin, John M (2016) Fallacies of last observation carried forward analyses. Clin Trials 13:161-8
Jackson, Sandra L; Long, Qi; Rhee, Mary K et al. (2015) Weight loss and incidence of diabetes with the Veterans Health Administration MOVE! lifestyle change programme: an observational study. Lancet Diabetes Endocrinol 3:173-80
Merjaneh, L; He, Q; Long, Q et al. (2015) Disposition index identifies defective beta-cell function in cystic fibrosis subjects with normal glucose tolerance. J Cyst Fibros 14:135-41
Berkowitz, Seth A; Meigs, James B; DeWalt, Darren et al. (2015) Material need insecurities, control of diabetes mellitus, and use of health care resources: results of the Measuring Economic Insecurity in Diabetes study. JAMA Intern Med 175:257-65
Phillips, Lawrence S; Barb, Diana; Yong, Chun et al. (2015) Translating What Works: A New Approach to Improve Diabetes Management. J Diabetes Sci Technol 9:857-64
Olson, Darin E; Zhu, Ming; Long, Qi et al. (2015) Increased cardiovascular disease, resource use, and costs before the clinical diagnosis of diabetes in veterans in the southeastern U.S. J Gen Intern Med 30:749-57
Lachin, John M; Bebu, Ionut (2015) Application of the Wei-Lachin multivariate one-directional test to multiple event-time outcomes. Clin Trials 12:627-33

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