Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)
Deborah J Wexler, Heidi Krause-Steinrauf, Jill P Crandall, Hermes J Florez, Sophia H Hox, Alexander Kuhn, Ajay Sood, Chantal Underkofler, Vanita R Aroda, GRADE Research Group
Abstract
Objective: 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, HbA1c 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 ± 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 ± 2.8 years, with mean HbA1c of 7.5 ± 0.5% (58 ± 5.3 mmol/mol), BMI of 34.3 ± 6.8 kg/m2, and metformin dose of 1,944 ± 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 HbA1c, 7.4% [57 mmol/mol]; BMI, 33.2 kg/m2; duration, 4.2 ± 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.
Trial registration: ClinicalTrials.gov NCT01794143.
© 2019 by the American Diabetes Association.
Figures
References
- Nathan DM, Buse JB, Kahn SE, et al. .; GRADE Study Research Group . Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care 2013;36:2254–2261
- Nathan DM, Buse JB, Davidson MB, et al. .; American Diabetes Association; European Association for Study of Diabetes . Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203
- Kahn SE, Haffner SM, Heise MA, et al. .; ADOPT Study Group . Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427–2443
- Ekström N, Svensson AM, Miftaraj M, et al. . Durability of oral hypoglycemic agents in drug naïve patients with type 2 diabetes: report from the Swedish National Diabetes Register (NDR). BMJ Open Diabetes Res Care 2015;3:e000059
- Turner RC, Cull CA, Frighi V, Holman RR; UK Prospective Diabetes Study (UKPDS) Group . Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005–2012
- Brown JB, Conner C, Nichols GA. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care 2010;33:501–506
- Kuhn A, Park J, Ghazi A, Aroda VR. Intensifying treatment beyond monotherapy in type 2 diabetes mellitus: where do newer therapies fit? Curr Cardiol Rep 2017;19:25.
- American Diabetes Association 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018. Diabetes Care 2018;41(Suppl. 1):S73–S85
- Davies MJ, D’Alessio DA, Fradkin J, et al. . Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018;41:2669–2701
- Inzucchi SE, Bergenstal RM, Buse JB, et al. . Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140–149
- Inzucchi SE, Bergenstal RM, Buse JB, et al. .; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD) . Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379
- Sox HC, Greenfield S. Comparative effectiveness research: a report from the Institute of Medicine. Ann Intern Med 2009;151:203–205
- Herman WH, Pop-Busui R, Braffett BH, et al. .; DCCT/EDIC Research Group . Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med 2012;29:937–944
- Lachin JM. Statistical considerations in the intent-to-treat principle. Control Clin Trials 2000;21:167–189
- Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988-2012. JAMA 2015;314:1021–1029
- Centers for Disease Control and Prevention (CDC) , National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD, U.S. Department of Health and Human Services and Centers for Disease Control and Prevention, 2018
- Centers for Disease Control and Prevention. National Diabetes Statistics Report [Internet], 2017. Available from . Accessed 13 November 2017
- Selvin E, Parrinello CM, Sacks DB, Coresh J. Trends in prevalence and control of diabetes in the United States, 1988-1994 and 1999-2010. Ann Intern Med 2014;160:517–525
- UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) [published correction appears in Lancet 1998;352:1558]. Lancet 1998;352:854–865
- UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet 1999;354:602]. Lancet 1998;352:837–853
- Viberti G, Lachin J, Holman R, et al. .; ADOPT Study Group . A Diabetes Outcome Progression Trial (ADOPT): baseline characteristics of Type 2 diabetic patients in North America and Europe. Diabet Med 2006;23:1289–1294
- Cushman WC, Evans GW, Byington RP, et al. .; ACCORD Study Group . Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–1585
- Gerstein HC, Miller ME, Byington RP, et al. .; Action to Control Cardiovascular Risk in Diabetes Study Group . Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–2559
- Duckworth W, Abraira C, Moritz T, et al. .; VADT Investigators . Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–139
- Cefalu WT, Kaul S, Gerstein HC, et al. . Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? Reflections from a Diabetes Care editors’ Expert Forum. Diabetes Care 2018;41:14–31
- Iglay K, Hannachi H, Joseph Howie P, et al. . Prevalence and co-prevalence of comorbidities among patients with type 2 diabetes mellitus. Curr Med Res Opin 2016;32:1243–1252
- Yoon SS, Dillon CF, Illoh K, Carroll M. Trends in the prevalence of coronary heart disease in the U.S.: National Health and Nutrition Examination Survey, 2001-2012. Am J Prev Med 2016;51:437–445
- Perkovic V, Jardine MJ, Neal B, et al. . Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306
- Zelniker TA, Wiviott SD, Raz I, et al. . Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 2019;139:2022–2031
- Gerstein HC, Colhoun HM, Dagenais GR, et al. .; REWIND Investigators . Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121–130
- Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians . Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2012;156:218–231
- Toscano D. Market Brief – The Market for Type 2 Diabetes Therapeutics – Key Findings From a Recent Analysis of Global Drug Development Efforts. Drug Development and Delivery, November/December 2013 [Internet]. Available from . Accessed 4 June 2018
- Knowler WC, Barrett-Connor E, Fowler SE, et al. .; Diabetes Prevention Program Research Group . Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403
- Food and Drug Administration. Dialogues on diversifying clinical trials: Successful strategies for engaging women and minorities in clinical trials [Internet], 2011. Available from . Accessed 13 November 2017
- Food and Drug Administration. Collection of race and ethnicity data in clinical trials: Guidance for industry and Food and Drug Administration staff [Internet], 2016. Available from . Accessed 13 November 2017
- Suissa S. Lower risk of death with SGLT2 inhibitors in observational studies: real or bias? Diabetes Care 2018;41:6–10
Source: PubMed