Similarities and differences between patients included and excluded from a randomized clinical trial of vitamin d supplementation for improving glucose tolerance in prediabetes: interpreting broader applicability

BACKGROUND: Randomized Clinical Trial (RCT) designs range from highly selective resulting in lack of external validity to more inclusive, requiring large sample sizes to observe significant results. Few publications, however, have compared excluded to enrolled participants. We aimed to assess our trial’s design based on the effectiveness versus efficacy continuum using the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) tool and to compare included and excluded patients. METHODS: Fifteen members of endocrinology section completed PRECIS for DIVA (D-Vitamin Intervention in VA) trial; an RCT evaluating vitamin D supplementation in improving dysglycemia in patients with prediabetes. Retrospective chart review compared subjects excluded (OUT) to those included (IN) in RCT. Student’s t and Chi-square tests were used to compare continuous and categorical variables. Additionally, multiple logistic regression was completed. RESULTS: PRECIS scores were nearly universally pragmatic. 178 patients enrolled in DIVA trial were compared with 178 randomly selected patients excluded from study involvement. There was no significant difference between IN and OUT for the majority of the continuous and all of the categorical variables. Multivariate logistic regression identified only the A1c, HDL and Charlson Index as significant predictors of a participant’s inclusion or exclusion. There was higher HDL (51.3(13.9) versus 44.6(10.1), P = 0.001) and Charlson Index (2.85(1.6) versus 2.2(1.17), P = 0.001) for OUT versus IN groups. Subanalysis of excluded patients in A1c range 5.7 to 6.9, had lower BMI (30.7(3.4) versus 32(2.7), P = 0.002) but higher HDL (mg/l: 49.7(11.8) versus 44.6(10.1), P = 0.001) and Charlson index (2.85(1.6) versus 2.2(1.17), P = 0.001) than included participants. Additionally, there was a trend towards higher rates of cancer (22.9 % versus 12.9 %, P = 0.033) but less psychiatric problems (56.2 % versus 72.5 %, P = 0.026) and thiazide diuretic use (18.1 % versus 29.8 %, P = 0.034). CONCLUSION: DIVA trial design appears to favor broad clinical applicability. The majority of objectively compared variables did not different between patients included and excluded from this RCT. Advice based on the evidence from this RCT may be applicable to a larger group of patients than those fitting inclusion/exclusion criteria alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT01375660 (registered 15 June 2011). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-015-0812-0) contains supplementary material, which is available to authorized users

Obesity and insulin sensitivity effects on cardiovascular risk factors: Comparisons of obese dysglycemic youth and adults

Background: Obesity and pubertal insulin resistance worsen cardiovascular (CV) risk factors in youth. It is unclear how the relationships of obesity and insulin resistance with CV risk compare to adults. Subjects and Methods: We evaluated 66 pubertal youth (mean ± SD: age 14.2 ± 2.0 years, body mass index [BMI] 36.6 ± 6.0 kg/m2, hemoglobin A1c [HbA1c] 38.5 ± 6.1 mmol/mol) and 355 adults with comparable BMI (age 52.7 ± 9.4 years, BMI 35.1 ± 5.1 kg/m2, HbA1c 39.8 ± 4.2 mmol/mol) participating in a multicenter study. Insulin sensitivity was quantified using hyperglycemic clamps. Assessment of CV risk factors was standardized across sites. Regression analyses compared the impact of insulin sensitivity and CV risk factors between youth and adults. Results: Obese pubertal youth were more insulin resistant than comparably obese adults (P \u3c.001), but with similar slopes for the inverse relationship between insulin sensitivity and obesity. The impact of obesity on CV risk factors was explained by insulin sensitivity (P = NS after adjustment for sensitivity). The two age groups did not differ in relationships between insulin sensitivity and diastolic blood pressure, total cholesterol, and low-density lipoprotein (LDL) cholesterol, after adjusting for obesity. However, while systolic blood pressure (SBP) and high-density lipoprotein (HDL) cholesterol exhibited the expected direct and inverse relationships, respectively with insulin sensitivity in adults, these slopes were flat in youth across the range of insulin sensitivity (P ≤.05 for group differences). Conclusions: Effects of obesity on CV risk factors were attributable to insulin sensitivity in both groups. The relationships between insulin sensitivity and CV risk factors were similar in obese youth and adult groups except for SBP and HDL cholesterol. Clinical Trial Registration: The RISE consortium studies are registered through Clinicaltrials.gov as NCT01779362 (Adult Medication Study); NCT01763346 (Adult Surgery Study); and NCT01779375 (Pediatric Medication Study). Clinical trial registration numbers: NCT01779362, NCT01779375 and NCT01763346 at clinicaltrials.gov

OGTT Glucose Response Curves, Insulin Sensitivity, and β-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve β-Cell Function

We examined the glucose response curves (biphasic [BPh], monophasic [MPh], incessant increase [IIn]) during an oral glucose tolerance test (OGTT) and their relationship to insulin sensitivity (IS) and β-cell function (βCF) in youth versus adults with impaired glucose tolerance or recently diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: This was both a cross-sectional and a longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose response curves to hyperglycemic clamp-measured IS and βCF at baseline and the change in glucose response curves 12 months after randomization were assessed. RESULTS: At randomization, the prevalence of the BPh curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose response curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (P < 0.05). βCF was lowest in IIn versus MPh and BPh in youth and adults (P < 0.05), yet compared with adults, youth had higher βCF in BPh and MPh (P < 0.005) but not IIn. At month 12, the change in glucose response curves did not differ between youth and adults, and there was no treatment effect. CONCLUSIONS: Despite a twofold higher prevalence of the more favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose response curves in youth compared with adults. Moreover, the typical β-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of β-cell dysfunction in youth with this least favorable glucose response curve

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

The Effect of Probiotic Yogurt on Glycemic Control in Type 2 Diabetes or Obesity: A Meta-Analysis of Nine Randomized Controlled Trials

Probiotic yogurt is suggested as a nutritional approach in type 2 diabetes (T2D) and obesity. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating the effects of probiotic yogurt on glycemic outcomes in T2D or obesity. The databases used to search for RCTs included Medline and Scopus. The RCTs were eligible if outcomes included selected glycemic markers. In nine eligible trials, 237 and 235 subjects were in treatment (probiotic yogurt) and control (mostly conventional yogurt) groups, respectively. There was no significant difference for pooled unstandardized mean difference (USMD) hemoglobin A1c (HbA1c) by probiotic yogurt compared with the control in T2D (USMD: &#8722;0.366; 95% CI: &#8722;0.755, 0.024, p = 0.066) and obesity (USMD: 0.116, 95% CI: &#8722;0.007, 0.238, p = 0.065). Similarly, there were no effects of probiotic yogurt on fasting blood glucose, fasting insulin, or insulin resistance (estimated by homeostatic model assessment of insulin resistance (HOMA-IR)) in either T2D or obesity. In conclusion, the present meta-analysis has not demonstrated the benefits of consuming probiotic compared with conventional yogurt for improving glucose control in patients with diabetes or obesity. Larger trials are needed to verify the benefits of probiotic and/or conventional yogurt or other probiotic fermented milk (e.g., kefir) on glycemic markers in patients with diabetes and obesity

Oxytocin is lower in African American men with diabetes and associates with psycho-social and metabolic health factors.

ObjectiveRecently, it has been suggested that oxytocin (OT) has a role in metabolism and neuropsychiatry health and disease, and therefore, it may represent a potential therapeutic target. The current study aimed to investigate relationships between OT and glycemic status along with psycho-social and behavioral factors.Design and methodsA total of 92 obese or overweight, African American, male subjects were enrolled in the study. Biometric and biochemical data were collected including oral glucose tolerance testing and urinary OT (measured by ELISA). Subjects also completed questionnaires on social and lifestyle factors.ResultsOT levels were found to be significantly lower in subjects with type 2 diabetes mellitus (T2DM) compared to normal glucose tolerance (pConclusionsIn this unique population, OT was found lower in subjects with diabetes but higher with better renal function, cigarette smoking and use of psychiatric medications. Future studies are needed to confirm these findings and examine the potential therapeutic role of OT

Predictors of Obesity among Gut Microbiota Biomarkers in African American Men with and without Diabetes

Gut microbiota and their biomarkers may be associated with obesity. This study evaluated associations of body mass index (BMI) with circulating microbiota biomarkers in African American men (AAM) (n = 75). The main outcomes included fecal microbial community structure (16S rRNA), gut permeability biomarkers (ELISA), and short-chain fatty acids (SCFAs, metabolome analysis). These outcomes were compared between obese and non-obese men, after adjusting for age. The results showed that lipopolysaccharide-binding protein (LBP), the ratio of LBP to CD14 (LBP/CD14), and SCFAs (propionic, butyric, isovaleric) were higher in obese (n = 41, age 58 years, BMI 36 kg/m2) versus non-obese (n = 34, age 55 years, BMI 26 kg/m2) men. BMI correlated positively with LBP, LBP/CD14 (p &lt; 0.05 for both) and SCFAs (propionic, butyric, isovaleric, p &lt; 0.01 for all). In the regression analysis, LBP, LBP/CD14, propionic and butyric acids were independent determinants of BMI. The study showed for the first time that selected microbiota biomarkers (LBP, LBP/CD14, propionic and butyric acids) together with several other relevant risks explained 39%&ndash;47% of BMI variability, emphasizing that factors other than microbiota-related biomarkers could be important. Further research is needed to provide clinical and mechanistic insight into microbiota biomarkers and their utility for diagnostic and therapeutic purposes

Photochemische Wasserbehandlung mit einem KrCl*-Excimer-UV-Rundrohrstrahler in einem Flachbettreaktor

The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health.A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior.The study subjects had prevalent overweight/obesity (78%), T2D (50%) and co-morbid psychiatric (65%) and opioid use (45%) disorders. In the analysis of microbiota, the data showed interactions of opioids, T2D and metformin with Bifidobacterium and Prevotella genera. The differential analysis of Bifidobacterium stratified by opioids, T2D and metformin, showed significant interactions among these factors indicating that the effect of one factor was changed by the other (FDR-adjusted p [q] < 0.01). In addition, the pair-wise comparison showed that participants with T2D not taking metformin had a significant 6.74 log2 fold increase in Bifidobacterium in opioid users as compared to non-users (q = 2.2 x 10-8). Since metformin was not included in this pair-wise comparison, the significant 'q' suggested association of opioid use with Bifidobacterium abundance. The differences in Bifidobacterium abundance could possibly be explained by opioids acting as organic cation transporter 1 (OCT1) inhibitors. Analysis stratified by lower and higher leptin and oxytocin (divided by the 50th percentile) in the subgroup without T2D showed lower Dialister in High-Leptin vs. Low-Leptin (p = 0.03). Contrary, the opposite was shown for oxytocin, higher Dialister in High-Oxytocin vs. Low-Oxytocin (p = 0.04).The study demonstrated for the first time that Bifidobacterium and Prevotella abundance was affected by interactions of T2D, metformin and opioid use. Also, in subjects without T2D Dialister abundance varied according to circulating leptin and oxytocin