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We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0\u201330 min) and total (0\u2013120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c \u22657% [53 mmol\/mol] and secondary outcome HbA1c &gt;7.5% [58 mmol\/mol]) and examined differential treatment responses.<\/jats:p>\n <\/jats:sec>\n \n RESULTS<\/jats:title>\n 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 &lt; 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome.<\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS<\/jats:title>\n Insulin sensitivity and \u03b2-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.<\/jats:p>\n <\/jats:sec>","DOI":"10.2337\/dc23-1059","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T21:07:56Z","timestamp":1704748076000},"page":"571-579","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":9,"title":["Impact of Insulin Sensitivity and \u03b2-Cell Function Over Time on Glycemic Outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): Differential Treatment Effects of Dual Therapy"],"prefix":"10.2337","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4924-196X","authenticated-orcid":false,"given":"Kristina M.","family":"Utzschneider","sequence":"first","affiliation":[{"name":"1VA Puget Sound Health Care System and Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8913-0340","authenticated-orcid":false,"given":"Naji","family":"Younes","sequence":"additional","affiliation":[{"name":"2The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Butera","sequence":"additional","affiliation":[{"name":"2The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2093-5201","authenticated-orcid":false,"given":"Ashok","family":"Balasubramanyam","sequence":"additional","affiliation":[{"name":"3Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-5584","authenticated-orcid":false,"given":"Richard M.","family":"Bergenstal","sequence":"additional","affiliation":[{"name":"4International Diabetes Center, HealthPartners Institute, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7044-4166","authenticated-orcid":false,"given":"Joshua","family":"Barzilay","sequence":"additional","affiliation":[{"name":"5Department of Endocrinology, Kaiser Permanente of Georgia, Duluth, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6660-0568","authenticated-orcid":false,"given":"Cyrus","family":"DeSouza","sequence":"additional","affiliation":[{"name":"6Division of Diabetes, Endocrinology and Metabolism, University of Nebraska and Omaha VA Medical Center, Omaha, NE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-6273","authenticated-orcid":false,"given":"Ralph A.","family":"DeFronzo","sequence":"additional","affiliation":[{"name":"7Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Elasy","sequence":"additional","affiliation":[{"name":"8Vanderbilt University Medical Center, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Krakoff","sequence":"additional","affiliation":[{"name":"9Division of General Internal Medicine and Public Health, Southwestern American Indian Center, Phoenix, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7307-9002","authenticated-orcid":false,"given":"Steven E.","family":"Kahn","sequence":"additional","affiliation":[{"name":"1VA Puget Sound Health Care System and Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1269-3580","authenticated-orcid":false,"given":"Neda","family":"Rasouli","sequence":"additional","affiliation":[{"name":"10Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, and VA Eastern Colorado Health Care System, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willy M.","family":"Valencia","sequence":"additional","affiliation":[{"name":"11Geriatric Research Education and Clinical Center, Bruce W. 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