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Blood Glucagon Levels Predict the Hemoglobin A1c Response to Saxagliptin in Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

ABSTRACT: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as second-option medications when metformin fails. Variance of the glycated hemoglobin (HbA1c) response to DPP-4 inhibitions in patients with type 2 diabetes mellitus (T2DM) has been observed, but the characteristics which predict the response to DPP-4 inhibitor therapy are unclear. The aim of this study was to investigate the characteristics of ?- and ?-cell functions which might predict the efficacy of saxagliptin and facilitate personalization of treatment.We studied 60 patients with T2DM who had inadequate glycemic control [HbA1c7.0-13.0% (53-119 mmol/mol)) with metformin alone. The patients were treated with saxagliptin (5 mg, daily) and metformin (1000-2000 mg as former) for 12 weeks. Oral glucose tolerance tests were carried out at baseline and endpoint to evaluate ?- and ?-cell functions, and blood C-peptide, insulin, glucagon levels were tested. Blood glucose, HbA1c and weight were also observed.Significant reduction of weight, HbA1c and glucagon was observed after 12-week treatment, while C-peptide, insulin and homeostasis model assessment-? increased (P < 0.05). Linear regression and receiver operating characteristic analysis showed that baseline HbA1c and 30 min-glucagon were correlated with the HbA1c response to saxagliptin, while the weight loss was correlated with gender, age and fasting-insulin level. Further analysis showed the 30 min-glucagon of 49.1 pmol/L was the optimal cutoff value to predict the efficacy of saxagliptin.Saxagliptin added to metformin significantly improved glycemic control and ?- and ?-cell function. Blood glucagon level was a good predicting factor for the HbA1c response to saxagliptin, and it will help appropriate patient selection.Chinese Clinical Trial Register identifier, ChiCTR-PPR-15007045.

SUBMITTER: Liu H

PROVIDER: S-EPMC5118238 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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Blood Glucagon Levels Predict the Hemoglobin A1c Response to Saxagliptin in Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

Liu Hao H Hu Yun Y Li Feng-Fei FF Liu Bing-Li BL Su Xiao-Fei XF Ma Jian-Hua JH

Diabetes therapy : research, treatment and education of diabetes and related disorders 20161012 4

<h4>Background</h4>Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as second-option medications when metformin fails. Variance of the glycated hemoglobin (HbA1c) response to DPP-4 inhibitions in patients with type 2 diabetes mellitus (T2DM) has been observed, but the characteristics which predict the response to DPP-4 inhibitor therapy are unclear. The aim of this study was to investigate the characteristics of α- and β-cell functions which might predict the efficacy of saxagliptin and ...[more]

PMID: 27734321

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Project description:ContextExercise guidelines for individuals with diabetes include both aerobic and resistance training although few studies have directly examined this exercise combination.ObjectiveTo examine the benefits of aerobic training alone, resistance training alone, and a combination of both on hemoglobin A(1c) (HbA(1c)) in individuals with type 2 diabetes.Design, setting, and participantsA randomized controlled trial in which 262 sedentary men and women in Louisiana with type 2 diabetes and HbA(1c) levels of 6.5% or higher were enrolled in the 9-month exercise program between April 2007 and August 2009.InterventionForty-one participants were assigned to the nonexercise control group, 73 to resistance training 3 days a week, 72 to aerobic exercise in which they expended 12 kcal/kg per week; and 76 to combined aerobic and resistance training in which they expended 10 kcal/kg per week and engaged in resistance training twice a week. Main Outcome Change in HbA(1c) level. Secondary outcomes included measures of anthropometry and fitness.ResultsThe study included 63.0% women and 47.3% nonwhite participants who were a mean (SD) age of 55.8 years (8.7 years) with a baseline HbA(1c) level of 7.7% (1.0%). Compared with the control group, the absolute mean change in HbA(1c) in the combination training exercise group was -0.34% (95% confidence interval [CI], -0.64% to -0.03%; P = .03). The mean changes in HbA(1c) were not statistically significant in either the resistance training (-0.16%; 95% CI, -0.46% to 0.15%; P = .32) or the aerobic (-0.24%; 95% CI, -0.55% to 0.07%; P = .14) groups compared with the control group. Only the combination exercise group improved maximum oxygen consumption (mean, 1.0 mL/kg per min; 95% CI, 0.5-1.5, P < .05) compared with the control group. All exercise groups reduced waist circumference from -1.9 to -2.8 cm compared with the control group. The resistance training group lost a mean of -1.4 kg fat mass (95% CI, -2.0 to -0.7 kg; P < .05) and combination training group lost a mean of -1.7 (-2.3 to -1.1 kg; P < .05) compared with the control group.ConclusionsAmong patients with type 2 diabetes mellitus, a combination of aerobic and resistance training compared with the nonexercise control group improved HbA(1c) levels. This was not achieved by aerobic or resistance training alone.Trial registrationclinicaltrials.gov Identifier: NCT00458133.

Project description:Dysfunctional insulin signaling may affect brain metabolism or amyloid deposition. We investigated the associations of type 2 diabetes with amyloid accumulation measured using (11)C-Pittsburgh compound B ((11)C-PiB) and brain hypometabolism measured using (18)F-FDG PET.We studied a sample of nondemented participants from the population-based Mayo Clinic Study of Aging. All subjects underwent MR imaging, amyloid PET, and (18)F-FDG PET. Alzheimer disease (AD) signature and region-of-interest (ROI) measures for (11)C-PiB retention ratio and (18)F-FDG ratio were measured. Diabetes was assessed from the Rochester Epidemiology Project medical records linkage system.Among 749 participants (median age, 79.0 y; 56.5% men, 81.0% cognitively normal; 20.6% diabetic individuals), (18)F-FDG hypometabolism ((18)F-FDG ratio < 1.31) in the AD signature meta-ROI was more common in diabetic individuals (48.1%) than in nondiabetic individuals (28.9%; P < 0.001). The median (18)F-FDG ratio was lower in diabetic individuals than in nondiabetic individuals in the AD signature meta-ROI (1.32 vs. 1.40, P < 0.001) and in the angular (1.40 vs. 1.48, P < 0.001) and posterior cingulate gyri ROIs (1.63 vs. 1.72, P < 0.001). The odds ratio (OR) for abnormal AD signature (18)F-FDG hypometabolism was elevated (2.28; 95% confidence interval [CI], 1.56-3.33) in diabetic individuals versus nondiabetic individuals after adjustment for age, sex, and education and after additional adjustment for apolipoprotein ?4 allele, glycemic level, and cognitive status (OR, 1.69; 95% CI, 1.10-2.60). However, the AD signature (11)C-PiB retention ratio was similar in diabetic individuals versus nondiabetic individuals (OR, 1.03; 95% CI, 0.71-1.51; P = 0.87). In post hoc analyses in nondiabetic individuals, a 1% increase in hemoglobin A1c was associated with greater AD signature hypometabolism in cognitively normal subjects (OR, 1.93; 95% CI, 1.03-3.62; P = 0.04) and in the total cohort (OR 1.59; 95% CI, 0.92-2.75; P = 0.10).Diabetes and poor glycemic control in nondiabetic individuals may enhance glucose hypometabolism in AD signature regions. These factors should be investigated in longitudinal studies for their role in detecting onset of symptoms in AD.

Project description:BackgroundManagement of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.MethodsThis was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.ResultsA total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg).ConclusionsDapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.Trial registrationClinicalTrials.gov: NCT00528879.

Project description:To assess safety and efficacy of saxagliptin in older patients with type 2 diabetes mellitus (T2DM).This was a post hoc analysis of pooled data from older patients (?65 years of age) from five 24-week phase III trials: three studies of saxagliptin versus placebo as an add-on therapy to metformin, glyburide, or a thiazolidinedione; and two studies of saxagliptin versus placebo as monotherapy in drug-naïve patients. Separate analyses were conducted on one study of initial combination therapy with saxagliptin plus metformin versus metformin monotherapy in drug-naïve patients. The safety analysis population for the five-study pool included 428 patients ? 65 years of age with baseline glycated hemoglobin (HbA(1c)) 7.0% to 10.5% who received saxagliptin 2.5 or 5 mg or placebo, and for the study of initial combination therapy included 69 patients ? 65 years of age with baseline HbA(1c) 8.0% to 12.0% who received saxagliptin 5 mg in combination with metformin or metformin monotherapy. The primary efficacy endpoint was change from baseline HbA(1c).In the five-study pool, the differences in the adjusted mean change from baseline HbA(1c) among older patients receiving saxagliptin versus placebo were -0.60% (95% confidence interval [CI], -0.99% to -0.21%) for saxagliptin 2.5 mg and -0.55% (-0.97% to -0.14%) for saxagliptin 5 mg; in the initial combination study, the difference was -1.22% (-2.27% to -0.17%) among older patients receiving saxagliptin 5 mg plus metformin versus metformin monotherapy. The results were generally similar in older and younger patients. Saxagliptin was well tolerated; the incidence and types of adverse events were similar for saxagliptin and comparators. Hypoglycemia was reported in 3.0% to 9.4% of patients receiving saxagliptin (0%-8.0% for comparators) and was confirmed (finger stick glucose ? 50 mg/dL, with associated symptoms) in 0% to 0.7% (0%-0.7% for comparators); hypoglycemic episodes did not vary by age category and did not require medical intervention.Saxagliptin was effective and well tolerated, with a low risk of hypoglycemia, when used as monotherapy, add-on therapy, or initial combination therapy with metformin in older patients with T2DM.

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Blood Glucagon Levels Predict the Hemoglobin A1c Response to Saxagliptin in Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

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Blood Glucagon Levels Predict the Hemoglobin A1c Response to Saxagliptin in Patients with Type 2 Diabetes Inadequately Controlled with Metformin.

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