Type 2 diabetes (T2D) is progressive, often requiring additional medications to maintain glycemic control. We assessed baseline β-cell function and insulin sensitivity as predictors of worsening glycemia (HbA1c) in the GRADE Study. Adults with T2D <y and HbA1c 6.8-8.5% were randomized to glimepiride, sitagliptin, insulin glargine 100 U/mL or liraglutide added to metformin monotherapy. Complete baseline OGTT data were available for 4586 of 5047 participants (Mean±SD: Age 57±y, 64% male, 5.0±1.3 y f/up) . Insulin sensitivity (HOMA2S) and early (C-peptide index (CPI) : ΔCP/ΔG 0-30 min) and total (incAUC-CP/G 0-120 min) C-peptide responses were used in Cox proportional hazard models to predict time to 1° (HbA1c ≥7%) and 2° (HbA1c >7.5%) glycemic outcomes and tested for treatment interaction. Given the inverse relationship with insulin sensitivity, C-peptide responses were adjusted for HOMA2S. Values determined at baseline (mean±SD) were: CPI 0.8±.nmol/g, incAUC CP/G 1.0±0.6 nmol/mg, HOMA2S 35±68 %, fasting glucose 152±31 mg/dl. Higher C-peptide responses predicted lower risk of 1° (CPI: HR±SE per 1 unit change =0.74±0.03, p<0.001; incAUC-CP/G: HR=0.68±0.02, p<0.001) and 2° glycemic outcomes (CPI: HR=0.71±0.03, p<0.001; incAUC-CP/G: HR=0.60±0.03, p<0.001) . Risks did not differ by treatment. There was interaction for HOMA2S and treatment; a 5 unit change in HOMA2S predicted lower risk of 1° and 2° outcomes with glimepiride and sitagliptin (HR=0.97±0.for both 1° outcomes; HR=0.96±0.for 2° outcome with glimepiride, HR=0.95±0.for 2° outcome with sitagliptin; all p<0.05) . A mg/dL change in fasting glucose predicted greater risk of 1° outcomes for all treatments, lowest for insulin glargine (HR=1.05±0.01) and highest for sitagliptin (HR=1.11±0.01) . Conclusions: Impaired β-cell function based on an OGTT predicted higher risk of T2D progression regardless of assigned treatment. This approach may identify cases that may benefit from earlier more aggressive therapy.


K.Utzschneider: Consultant; Nevro Corp. T.A.Elasy: None. W.Valencia: None. C.Ma: None. N.Rasouli: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Allergan, Eli Lilly and Company, Novo Nordisk. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W.Sivitz: n/a. Grade research group: n/a. N.Younes: None. N.M.Butera: None. A.Balasubramanyam: None. C.Desouza: Advisory Panel; AstraZeneca, Bayer AG, Novo Nordisk A/S, Consultant; Asahi Kasei Corporation. J.Krakoff: None. J.I.Barzilay: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca. R.M.Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi.


National Institute of Diabetes and Digestive and Kidney Diseases (U01DK098246, U34-DK-088043)

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