Impact of Insulin Sensitivity and β-Cell Function Over Time on Glycemic Outcomes in GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study): Differential Treatment Effects of Dual Therapy

Kristina M. Utzschneider, VA Puget Sound Health Care System and Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA.
Naji Younes, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Nicole M. Butera, The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Ashok Balasubramanyam, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX.
Richard M. Bergenstal, International Diabetes Center, HealthPartners Institute, Minneapolis, MN.
Joshua Barzilay, Department of Endocrinology, Kaiser Permanente of Georgia, Duluth, GA.
Cyrus DeSouza, Division of Diabetes, Endocrinology and Metabolism, University of Nebraska and Omaha VA Medical Center, Omaha, NE.
Ralph A. DeFronzo, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX.
Tom Elasy, Vanderbilt University Medical Center, Nashville, TN.
Jonathan Krakoff, Division of General Internal Medicine and Public Health, Southwestern American Indian Center, Phoenix, AZ.
Steven E. Kahn, VA Puget Sound Health Care System and Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA.
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.
Willy M. Valencia, Geriatric Research Education and Clinical Center, Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL.
William I. Sivitz, Department of Internal Medicine, Endocrinology and Metabolism, University of Iowa, Iowa City, IA.

Document Type

Journal Article

Publication Date

1-8-2024

Journal

Diabetes care

DOI

10.2337/dc23-1059

Abstract

OBJECTIVE: To compare the effects of insulin sensitivity and β-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. RESEARCH DESIGN AND METHODS: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0-30 min) and total (0-120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c ≥7% [53 mmol/mol] and secondary outcome HbA1c >7.5% [58 mmol/mol]) and examined differential treatment responses. RESULTS: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a greater initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test of heterogeneity, P = 0.009 HOMA2-%S, P = 0.018 early CP, P = 0.001 total CP) and risk of primary outcome (P = 0.005 HOMA2-%S, P = 0.11 early CP, P = 0.025 total CP) but lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome. CONCLUSIONS: Insulin sensitivity and β-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response in comparison with the glimepiride and liraglutide groups.

Department

Biostatistics and Bioinformatics

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