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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-B (J1))
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Linder, Barbara
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George Washington University
Biostatistics & Other Math Sci
Schools of Public Health
United States
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Zhang, Yanqing; Wu, Meifen; Htun, Wynn et al. (2017) Differential Effects of Linagliptin on the Function of Human Islets Isolated from Non-diabetic and Diabetic Donors. Sci Rep 7:7964
Valencia, Willy Marcos; Palacio, Ana; Tamariz, Leonardo et al. (2017) Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia 60:1630-1638
Jackson, Sandra L; Staimez, Lisa R; Safo, Sandra et al. (2017) Participation in a National Lifestyle Change Program is associated with improved diabetes Control outcomes. J Diabetes Complications 31:1430-1436
Jackson, Sandra L; Safo, Sandra; Staimez, Lisa R et al. (2017) Reduced Cardiovascular Disease Incidence With a National Lifestyle Change Program. Am J Prev Med 52:459-468
Mongraw-Chaffin, Morgana; LaCroix, Andrea Z; Sears, Dorothy D et al. (2017) A prospective study of low fasting glucose with cardiovascular disease events and all-cause mortality: The Women's Health Initiative. Metabolism 70:116-124
Kancherla, Vijaya; Elliott Jr, John L; Patel, Birju B et al. (2017) Long-term Metformin Therapy and Monitoring for Vitamin B12 Deficiency Among Older Veterans. J Am Geriatr Soc 65:1061-1066
Lachin, John M (2016) Fallacies of last observation carried forward analyses. Clin Trials 13:161-8
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
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
Zhang, Yanqing; Fava, Genevieve E; Wang, Hongjun et al. (2016) PAX4 Gene Transfer Induces ?-to-? Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Mol Ther 24:251-260

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