GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is a 36-center unmasked, parallel treatment group, randomized controlled trial evaluating four diabetes medications added to metformin in people with type 2 diabetes (T2DM). We report baseline characteristics and compare GRADE participants to a National Health and Nutrition Examination Survey (NHANES) cohort. RESEARCH DESIGN AND METHODS Participants were age ‡30 years at the time of diagnosis, with duration of T2DM <10 years, HbA 1c 6.8-8.5% (51-69 mmol/mol), prescribed metformin monotherapy, and randomized to glimepiride, sitagliptin, liraglutide, or insulin glargine. RESULTS At baseline, GRADE's 5,047 randomized participants were 57.2 6 10.0 years of age, 63.6% male, with racial/ethnic breakdown of 65.7% white, 19.8% African American, 3.6% Asian, 2.7% Native American, 7.6% other or unknown, and 18.4% Hispanic/ Latino. Duration of diabetes was 4.2 6 2.8 years, with mean HbA 1c of 7.5 6 0.5% (58 6 5.3 mmol/mol), BMI of 34.3 6 6.8 kg/m 2 , and metformin dose of 1,944 6 204 mg/day. Among the cohort, 67% reported a history of hypertension, 72% a history of hyperlipidemia, and 6.5% a history of heart attack or stroke. Applying GRADE inclusion criteria to NHANES indicates enrollment of a representative cohort with T2DM on metformin monotherapy (NHANES cohort average age, 57.9 years; mean HbA 1c , 7.4% [57 mmol/mol]; BMI, 33.2 kg/m 2 ; duration, 4.2 6 2.5 years; and 7.2% with a history of cardiovascular disease). CONCLUSIONS The GRADE cohort represents patients with T2DM treated with metformin requiring a second diabetes medication. GRADE will inform decisions about the clinical effectiveness of the addition of four classes of diabetes medications to metformin. The optimal medication management of hyperglycemia in type 2 diabetes (T2DM) is not established. In addition to lifestyle intervention, metformin is the recommended initial medication in T2DM due to its glycemic effectiveness, lack of associated hypoglycemia or weight gain, low cost, and evidence of long-term benefit and safety

ImportanceType 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.ObjectiveTo evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.Design, Setting, and ParticipantsA randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023.InterventionsAddition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control.Main Outcomes and MeasuresChronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat.ResultsOf the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was −2.03 (95% CI, −2.20 to −1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, −1.92 (95% CI, −2.08 to −1.75) mL/min/1.73 m2 per year; liraglutide, −2.08 (95% CI, −2.26 to −1.90) mL/min/1.73 m2 per year; and insulin glargine, −2.02 (95% CI, −2.19 to −1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment.Conclusions and RelevanceIn this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control.Trial RegistrationClinicalTrials.gov Identifier: NCT01794143

Background: Type II diabetes mellitus is a chronic medical condition affecting societies worldwide. The duration of hyperglycemia is a strong predictor of adverse outcomes and imposes immense clinical and public health concerns. The best way to prevent complications and reduce the economic burden is by capturing asymptomatic individuals early in the disease process.Local problem: Patients at a large urban academic medical center were not consistently identified as having a high risk of hyperglycemia. Methods:The project used a pretest-posttest design. Retrospective data on new-onset hyperglycemia incidence were compared for all individuals seeking primary care services 6 weeks before and after the intervention.Intervention: Patients without a known hyperglycemia history were provided the screening tool to determine risk status. Additional screening measures were implemented for patients identified as high risk on the initial screening.Results: A total of 52 (61.6%) of the 84 individuals who met inclusion criteria during the intervention period were diagnosed with new-onset chronic hyperglycemia. In contrast, 20 (22.5%) of the 89 individuals identified during the retrospective period resulted in a statistically significant difference (p < .001) in the frequency and accuracy of patients diagnosed with hyperglycemia between groups. Conclusion:A diabetes risk assessment tool is quick and reliable in capturing high-risk individuals who would benefit from additional screening measures.

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