# Continuation of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study

> **NIH NIH U01** · GEORGE WASHINGTON UNIVERSITY · 2022 · $3,162,825

## Abstract

Project Summary
 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 ~28 million, incidence 1.4 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 ~5000 patients
with recent-onset (<10 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 follow-up of approximately 4.8 (4-7.5) 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.

## Key facts

- **NIH application ID:** 10474955
- **Project number:** 5U01DK098246-10
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Heidi Krause-Steinrauf
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,162,825
- **Award type:** 5
- **Project period:** 2012-09-25 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474955

## Citation

> US National Institutes of Health, RePORTER application 10474955, Continuation of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study (5U01DK098246-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10474955. Licensed CC0.

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