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Markers of ?-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes.

ABSTRACT: To assess whether clinical characteristics and simple biomarkers of ?-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes.We prospectively studied 620 participants with type 2 diabetes and HbA1c ?58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with ?-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change.Reduced glycemic response to GLP-1RAs was associated with longer duration of diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine C-peptide-to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P ? 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide ?0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change -5.2 vs. -15.2 mmol/mol [-0.5 vs. -1.4%], P = 0.005; C-peptide <0.25 nmol/L, mean change -2.1 vs. -15.3 mmol/mol [-0.2 vs. -1.4%], P = 0.002). These markers were predominantly present in insulin-treated participants and were not associated with weight change.Clinical markers of low ?-cell function are associated with reduced glycemic response to GLP-1RA therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1RA therapy in insulin-treated diabetes.

SUBMITTER: Jones AG

PROVIDER: S-EPMC4894547 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Markers of β-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes.

Jones Angus G AG McDonald Timothy J TJ Shields Beverley M BM Hill Anita V AV Hyde Christopher J CJ Knight Bridget A BA Hattersley Andrew T AT

Diabetes care 20150804 2

<h4>Objective</h4>To assess whether clinical characteristics and simple biomarkers of β-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes.<h4>Research design and methods</h4>We prospectively studied 620 participants with type 2 diabetes and HbA1c ≥58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the ass ...[more]

PMID: 26242184

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Project description:BackgroundPatients with diabetes have increased risk of infections and wound complications after total knee arthroplasty (TKA). Glycemic markers identifying patients at risk for complications after TKA have not yet been elucidated.Questions/purposesWe aimed to determine the correlations among four commonly used glycemic markers and to identify the glycemic markers most strongly associated with the occurrence of surgical site infections and postoperative wound complications in patients with diabetes mellitus after undergoing TKA.MethodsOur retrospective study included 462 patients with diabetes, who underwent a total of 714 TKAs. Blood levels of glycemic markers, including preoperative fasting blood glucose (FBG), postprandial glucose (PPG2), glycated hemoglobin (HbA1c), and levels obtained from random glucose testing on postoperative days 2, 5, and 14, were collected on all patients as part of a medical clearance program and an established clinical pathway for patients with diabetes at our center. Complete followup was available on 93% (462 of 495) of the patients. Correlations among markers were assessed. Associations between the markers and patient development of complications were analyzed using multivariate regression analyses of relevant cutoff values. We considered any of the following as complications potentially related to diabetes, and these were considered study endpoints: surgical site infection (superficial and deep) and wound complications (drainage, hemarthrosis, skin necrosis, and dehiscence). During the period of study, there were no fixed criteria applied to what levels of glycemic control patients with diabetes needed to achieve before undergoing arthroplasty, and there were wide ranges in the levels of all glycemic markers; for example, whereas the mean HbA1c level was 7%, the range was 5% to 11.3%.ResultsThere were positive correlations among the levels of the four glycemic markers; the strongest correlation was found between the preoperative HbA1c and PPG2 levels (R = 0.502, p < 0.001). After controlling for potential confounding variables using multivariate analysis, the HbA1c cutoff level of 8 (odds ratio [OR], 6.1; 95% confidence interval [CI], 1.6-23.4; p = 0.008) and FBG 200 mg/dL or higher (OR, 9.2; 95% CI, 2.2-38.2; p = 0.038) were associated with superficial surgical site infection after TKA.ConclusionsIn general, there is a positive correlation among the various available glycemic markers among patients with diabetes undergoing TKA, and patients undergoing surgery with HbA1c ? 8 and/or FBG ? 200 mg/dL were associated with superficial surgical site infection. These findings should be considered in patient selection and preoperative counseling for patients with diabetes undergoing TKA.Level of evidenceLevel III, prognostic study.

Project description:ContextNovel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide.ObjectiveExplore mechanisms of glucose control by tirzepatide.DesignPost hoc analyses of fasting biomarkers and multiple linear regression analysis.SettingForty-seven sites in 4 countries.Patients or other participantsThree hundred and sixteen subjects with type 2 diabetes.InterventionsTirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo.Main outcome measuresAnalyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks.ResultsHomeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively.ConclusionsTirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

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Markers of ?-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes.

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Markers of β-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes.

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