Longitudinal Effects of Glucose-Lowering Medications on β-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial

Neda Rasouli, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, and VA Eastern Colorado Health Care System, Aurora, CO.
Naji Younes, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Alokananda Ghosh, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Jeanine Albu, Icahn School of Medicine, Mount Sinai Morningside, New York, NY.
Robert M. Cohen, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine and Cincinnati VA Medical Center, Cincinnati, OH.
Ralph A. DeFronzo, University of Texas Health Science Center, San Antonio, TX.
Elsa Diaz, VA San Diego Healthcare System, San Diego, CA.
Laure Sayyed Kassem, Department of Endocrinology, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH.
José A. Luchsinger, Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, New York, NY.
Janet B. McGill, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO.
William I. Sivitz, Department of Internal Medicine, University of Iowa, Iowa City, IA.
William V. Tamborlane, Yale School of Medicine, New Haven, CT.
Kristina M. Utzschneider, Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle.
Steven E. Kahn, Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle.

Document Type

Journal Article

Publication Date

4-1-2024

Journal

Diabetes care

Volume

47

Issue

4

DOI

10.2337/dc23-1070

Abstract

OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of β-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of β-cell function, the nature of the change in β-cell responses reflected those in β-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and β-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of β-cell function in the progression of type 2 diabetes.

Department

Biostatistics and Bioinformatics

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