Acute and long-term effects of saxagliptin on a set of cardiovascular targets measured at fasting and post-prandially in obese patients with impaired glucose tolerance: A placebo-controlled study.

BACKGROUND AND AIMS: Studies of dipeptidyl peptidase inhibitors (DPP4is) report heterogeneous effects on cardiovascular targets in type 2 diabetes. This study aimed to investigate, in patients with impaired glucose tolerance (IGT), whether saxagliptin, a DPP4i, had beneficial cardiovascular effects at fasting and during the post-prandial state. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind, single-center pilot exploratory study, we included obese individuals with IGT. Twenty-four individuals (BMI 36.8 ± 4.8 kg/m2) were randomized to receive for 12 weeks either saxagliptin 5 mg a day or placebo. They were explored before and after a standardized breakfast for biological markers; microcirculatory blood flow at baseline and after transcutaneous administration of acetylcholine (Periflux System 5000® PERIMED); post-occlusive digital reactive hyperhemia (Endopat2000®); pulse wave velocity, augmentation index, central pulse pressure and subendocardial viability ratio (Sphygmocor®); cardiac hemodynamic parameters and cardiovascular autonomic nervous system activity (Task force monitor®). The results of all the investigations were similar after breakfast in the two groups at Visit 1 (acute post-prandial effects, after the first tablet) and Visit 2 (long-term post-prandial effects), and at fasting at Visit 1 and 2 (long-term effects, after 12 weeks of treatment). Only at Visit 2 the decrease in cardiac vagal activity occurring after breakfast was more sustained in the saxagliptin group than in the placebo group (interaction between treatment and time effect: p = 0.016). CONCLUSION: In obese patients with IGT, the effects of saxagliptin on the large set of cardiovascular parameters measured are neutral, except for a more marked post-prandial depression of vagal activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT01521312.

Acute and long-term effects of saxagliptin on post-prandial glycemic response in obese patients with impaired glucose tolerance.

BACKGROUND AND AIMS: Dipeptidyl-peptidase inhibitors might be useful in type 2 diabetes prevention. ACCES (ACute and Chronic Effects of Saxagliptin) was a randomized, placebo-controlled, double-blind, controlled phase 2, pilot study aiming to examine in obese patients with impaired glucose tolerance (IGT) the acute effects and the effects after 12 weeks of treatment by saxagliptin on glucose levels at fasting and postprandially after a standard breakfast, and on glucose tolerance. METHODS AND RESULTS: We included 24 obese patients with IGT. Patients were randomized to receive saxagliptin 5 mg or placebo in the morning. The treatment was taken on Visit 1 before breakfast, then continued for 12 weeks. Biochemical measurements were performed before, one, two and three hours after a standard breakfast including 75 g of carbohydrates, during Visit 1 and Visit 2 (12 weeks). Glucose variability (GV) was evaluated at Visit 1 from 24-h continuous glucose monitoring including the breakfast. A second OGTT was performed at Visit 3 (3-5 days after Visit 2). Compared with placebo-treated patients, saxagliptin-treated patients had lower 1 h and 2 h post-meal plasma glucose levels at Visit 1 and similar changes at Visit 2 (p < 0.01 to p < 0.004), with lower GV indexes after breakfast at Visit 1. At Visit 3, all patients but one in saxagliptin group and only 4 patients in placebo group turned to normal glucose tolerance. Lower glucose response to breakfast at Visit 1 was predictive of recovery of glucose tolerance. CONCLUSION: Saxagliptin has metabolically beneficial effects in glucose-intolerant obese patients by significantly lowering postprandial blood glucose levels. CLINICAL TRIAL REGISTRATION NUMBER: NCT01521312: https://clinicaltrials.gov/ct2/show/NCT01521312.

Glycation gap is associated with macroproteinuria but not with other complications in patients with type 2 diabetes.

OBJECTIVE: We investigated whether glycation gap (G-Gap), an index of intracellular glycation of proteins, was associated with diabetes complications. RESEARCH DESIGN AND METHODS: We measured concomitantly HbA1c and fructosamine in 925 patients with type 2 diabetes to calculate the G-Gap, defined as the difference between measured HbA1c, and fructosamine-based predicted HbA1c. Patients were explored for retinopathy, nephropathy, peripheral neuropathy, cardiac autonomic neuropathy (n = 512), and silent myocardial ischemia (n = 506). RESULTS: Macroproteinuria was the only complication that was associated with G-Gap (prevalence in the first, second, and third tertile of G-Gap: 2.9, 6.2, and 11.0%, respectively; P < 0.001). The G-Gap was higher in patients with macroproteinuria than in those without (1.06 ± 1.62 vs. 0.03 ± 1.30%; P < 0.0001). Because HbA1c was associated with both G-Gap (HbA1c 7.0 ± 1.4, 7.9 ± 1.4, and 10.1 ± 1.8% in the first, second, and third G-Gap tertile, respectively; P < 0.0001) and macroproteinuria (HbA1c 8.8 ± 2.2% if macroproteinuria, 8.3 ± 2.0% if none; P < 0.05), and because it could have been a confounder, we matched 54 patients with macroproteinuria and 200 patients without for HbA1c. Because macroproteinuria was associated with lower serum albumin and fructosamine levels, which might account for higher G-Gap, we calculated in this subpopulation albumin-indexed fructosamine and G-Gap; macroproteinuria was independently associated with male sex (odds ratio [OR] 3.2 [95% CI 1.5-6.7]; P < 0.01), hypertension (2.9 [1.1-7.5]; P < 0.05), and the third tertile of albumin-indexed G-Gap (2.3 [1.1-4.4]; P < 0.05) in multivariate analysis. CONCLUSIONS: In type 2 diabetic patients, G-Gap was associated with macroproteinuria, independently of HbA1c, albumin levels, and confounding factors, suggesting a specific role of intracellular glycation susceptibility on kidney glomerular changes.

Cardiovascular risk prediction is improved by adding asymptomatic coronary status to routine risk assessment in type 2 diabetic patients.

OBJECTIVE: To evaluate if silent myocardial ischemia (SMI) and silent coronary artery disease (CAD) provide significant additional value to routine cardiovascular risk assessment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We followed up to a first cardiovascular event 688 subjects (322 men, aged 59 ± 8 years) out of 731 consecutive asymptomatic type 2 diabetic patients with ≥1 additional risk factor who had been prospectively screened between 1992 and 2006 for SMI by stress myocardial scintigraphy and for silent CAD by coronary angiography. RESULTS: SMI was found in 207 (30.1%) patients and CAD in 76 of those with SMI. Of the patients, 98 had a first cardiovascular event during a 5.4 ± 3.5 (range: 0.1-19.2) year follow-up period. Cox regression analysis considering parameters predicting events but not SMI and CAD ("routine assessment") showed in univariate analyses that macroproteinuria (hazard ratio [HR] 3.33 [95% CI 1.74-6.35]; P < 0.001), current multifactorial care (0.27 [0.15-0.47]; P < 0.001), and peripheral/carotid occlusive arterial disease (PCOAD; 4.33 [2.15-8.71]; P < 0.001) independently predicted cardiovascular events. When added into the model, SMI (HR 1.76 [1.00-3.12]; P = 0.05) and CAD (2.28 [1.24-4.57]; P < 0.01) were also independently associated with events. SMI added to the prediction of an event in the following 5 years above and beyond routine assessment risk prediction (c statistic with or without SMI 0.788 [0.720-0.855] and 0.705 [0.616-0.794], respectively). CONCLUSIONS: Although screening for SMI and silent CAD should not be systematic, these complications are predictive of cardiovascular events in type 2 diabetic patients in addition to routine risk predictors, especially represented by PCOAD, macroproteinuria, and nonintensive management.

Comparison of field methods to estimate fat mass in children.

BACKGROUND: Reliable field methods to measure fat mass (FM) in children may contribute to primary prevention of childhood obesity. AIM: The objective was to compare the accuracy of existing field methods (skinfold thickness (SF), leg-to-leg bioelectrical impedance analysis (BIA), anthropometrics for FM measurement in prepubertal European children. SUBJECTS AND METHODS: Reference FM was measured in 55 French children (30 boys, 25 girls; mean age 8.7 years) using a three-compartment model: body volume (BV) was assessed by air displacement plethysmography (ADP) and total body water (TBW) was assessed by deuterium dilution. Agreement between field methods and the reference method was assessed using Bland-Altman analyses. Since field methods for FM measurement are reported to be population-dependent, adjustment to the study population was performed using stepwise multiple linear regressions modelling. RESULTS: Even after adjustment, field methods exhibited a high correlation (R(2) = 0.71-0.84) but a moderate agreement (+/-3.32 to +/-4.47 kg for fat mass) with the reference model. Methods based on BIA or SF performed slightly better than those based on anthropometry. CONCLUSIONS: Field methods for FM measurement may be recommended for epidemiological applications, but not for individual follow-up. New field equipment is required to improve accuracy of FM measurement in children and make individual follow-up possible.