Insulin analogs as an add-on to metformin after failure to oral treatment in type 2 diabetic patients increase diastole duration. The INSUlin Regimens and VASCular Functions (INSUVASC) study.

BACKGROUND: Fast acting insulin analogues are known to improve arterial stiffness. The combination of metformin with insulin represents a widely used therapeutic strategy in diabetes. We hypothesized that insulin treatment in patients with type 2 diabetes (T2D) with long-acting, fast-acting or basal bolus insulin as an add-on to metformin would provide additional improvement of arterial stiffness. METHODS: The INSUlin Regimens and VASCular Functions (INSUVASC) study is a pilot, randomized, open label three-arms study that included 42 patients with type 2 diabetes (T2D) in primary prevention, after a failure to oral antidiabetic agents. Arterial stiffness measurements were performed at fasting and after a standardized breakfast. During the first visit (V1) pre-randomization, participants took only metformin to perform the tests. The same tests were repeated after 4 weeks of insulin treatment during the second visit (V2). RESULTS: Data were available for final analysis in 40 patients, with a mean age of 53.6±9.7 years and a mean duration of diabetes of 10.6±5.6 years. Twenty-one were females (52.5%), hypertension and dyslipidemia were present in 18 (45%) and 17 patients (42.5%), respectively. After insulin treatment, the metabolic control was associated to a decrease in oxidative stress and improvement of endothelial functions, with a post prandial diastole duration increased and a decrease of the peripheral arterial stiffness, with a better post prandial pulse pressure ratio and ejection duration after insulin. In hypertensive patients, insulin treatment provided positive effects by decreasing the pulse wave velocity and improving reflection time. CONCLUSIONS: A short time treatment by insulin in addition to metformin improved myocardial perfusion. Moreover, insulin treatment in hypertensive patients provides a better hemodynamic profile in large arteries.

The relationship between mortality and daily number of steps in type 2 diabetes.

BACKGROUND: Physical activity (PA) is an established modifiable factor for the prevention of cardiovascular disease. Our objective was to assess the association of PA with mortality rates in a national sample of patients with diabetes. METHODS: We analyzed a nationally representative sample from The National Health and Nutrition Examination Survey (NHANES, periods 2003-2004 and 2005-2006) that used PA Monitors. Individuals were matched for BMI, number of steps/per day and age. Three groups were created: subjects with less than 5000/steps per day (low), 5000-7500/steps per day (moderate) and more than 7500/steps per day (high levels of physical activity). All-cause mortality was ascertained through December 2015. RESULTS: A sample of 3072 individuals (1018 with diabetes) was analyzed. Patients with diabetes had 30% increased risk of mortality of all causes (RR: 1.298, 95% CI [1.162-1.451], P<0.001), higher levels of PA (>7500 steps/day) provided similar relative risk for subjects with diabetes compared to their controls (RR:1.256 [95% CI 0.910-1.732]). In a Poisson model adjusted for sex, history of previous cardiovascular event or cancer, ethnicity, Hb1ac, SBP, and total cholesterol to HDL ratio, patients with diabetes and moderate or high PA had an associated 44% to 80% lower risk of all-cause mortality compared to those with low PA. CONCLUSIONS: The subgroup of patients with diabetes and high PA had no excess of mortality compared to the general population. PA can reduce the gap for all-cause mortality, used as an index of cardiovascular fitness and a clinical tool for the assessment of mortality risk.

Comparing benefits from sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in randomized clinical trials: a network meta-analysis.

INTRODUCTION: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) were individually proven to reduce major adverse cardiovascular events (MACE) in type 2 diabetes mellitus (T2DM) patients, but the relative magnitude of benefits from these two drug classes is debated. We aimed to review current available data on GLP1-RA and SGLT2i in T2DM patients and compare their efficacy and safety in this population. EVIDENCE ACQUISITION: We systematically searched MEDLINE/PubMed, the Cochrane Library, Google Scholar, Embase, www.tctmd.com, www.clinicaltrials.gov, www.clinicaltrialresults.org, from inception to September 17, 2020 for randomized controlled trials (RCTs) comparing the effects of GLP1-RA vs. SGLT2i vs. optimal medical therapy (OMT) in adult T2DM patients. Three authors independently screened references and extracted data using a predefined data collection form. Outcomes were analyzed using an indirect comparison meta-analysis of aggregate study-level data. The primary combined efficacy outcome comprised cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary efficacy outcomes included all-cause mortality, cardiovascular mortality, non-fatal MI, non-fatal stroke, heart failure hospitalizations (HFH), and worsening renal function (WRF). EVIDENCE SYNTHESIS: Eleven RCTs enrolling a total of 98572 patients were included; 56004 (57%) patients were derived from GLP1-RA RCTs and 42568 (43%) from SGLT2i RCTs. At a median follow-up of 3.0±1.3 years, compared with OMT, both GLP1-RA and SGLT2i similarly reduced the rate of the composite primary outcome (risk ratio [RR] 0.88; 95% confidence interval [95% CI] 0.83-0.93 and RR 0.88, 95% CI: 0.82-0.95, respectively) with no difference between the drug classes (RR 1.00, 95% CI: 0.92-1.10). Both classes similarly reduced MI rate, cardiovascular and all-cause mortality compared with OMT; stroke reduction was only observed with GLP1-RA with no difference in the indirect comparison with SGLT2i; conversely, only SGLT2i were effective in preventing HFH. Both GLP1-RA and SGLT2i were protective against WRF, with a major efficacy of SGLT2i in the indirect comparison. CONCLUSIONS: This meta-analysis report that GLP1-RA and SGLT2i reduced with a similar efficacy not only MACE as MI, but also cardiovascular mortality and all-cause mortality at a median 3-year follow-up. SGLT2i were more protective in HFH and WRF than GLP1RA. These new data highlight the efficacy of SGLT2i not only in HF and chronic kidney disease (CKD) but also in ischemic heart diseases (IHD), with a homogeneity among the class, whereas the results observed with GLP1-RA are heterogenous. These findings will help clinical's decisions to optimize therapeutic strategies for diabetic patients.

How to fill the GAPS-I in secondary prevention: application of a strategy based on GLP1 analogues, antithrombotic agents, PCSK9 inhibitors, SGLT2 inhibitors and immunomodulators.

The continuous progress in cardiovascular risk prevention strategies has led to an impressive reduction in mortality and recurrent ischemic events in patients with coronary artery disease (CAD). However, the control of several cardiovascular risk factors remains suboptimal in many CAD patients, with a high rate of recurrent events, underlying the need for more new prevention strategies. The GAPS-I (glucagon-like peptide 1 analogues, antithrombotic agents, proprotein convertase subtilisin/kexin type 9 inhibitors, sodium glucose cotransporter type 2 inhibitors and immunomodulators) strategy offers a promising potential in patients with a high-residual cardiovascular risk, who are frequently encountered in daily practice, by offering an individualized and structured approach to addressing their individual risk factors. The current review summarizes the evidence to date on each of its components, with respect to clinical outcomes and economic feasibility. The current evidence points to an efficacy of GAPS-I in reducing major adverse cardiovascular events and mortality, without a compromise on safety, albeit with the need for longer follow-up data.

Social isolation but not deprivation involved in employment status after bariatric surgery.

An increase in employment rate was observed among individuals who underwent bariatric surgery. This study assessed the relationship between employment rate and weight loss, deprivation, and Bariatric Analysis and Reporting Outcome System (BAROS) scores after bariatric surgery in a deprived area. This retrospective study evaluated the employment rate at a mean period of 2.3±0.1 years after bariatric surgery among 133 individuals. The Evaluation of Deprivation and Inequalities in Health Examination Centers (EPICES score), satisfaction scale, and BAROS (self-esteem, physical activity, social life, work conditions, and sexual activity) questionnaires were used. The mean age of the participants was 45 (range: 19-67) years. Approximately 88% were women. The initial mean body mass index (BMI) was 42.7 kg/m2, and about 88% of the participants underwent sleeve gastrectomy. The mean decrease in BMI was 12 ± 0.5 kg/m2. The mean EPICES score (N<30), BAROS, and satisfaction scale (range: 1-5) scores were 31.9±18, 1.3±1.1, and 4.27±1.19, respectively. After surgery, 19 participants obtained a job. However, three were unemployed. Based on a multivariate analysis, employed and unemployed participants (77 vs 52) before surgery had a lower initial BMI and better BAROS and satisfaction scale scores. After surgery, there was no difference between participants who obtained a new job and those still did not have a job in terms of questionnaire responses. Obtaining a new job was not associated with BMI, sex, or age differences. However, there was a positive correlation between social life score and weight loss. Bariatric surgery increased an individual's chance of finding a job independently of deprivation status. Participants with a pre-operative job had a better perception of satisfaction and BAROS scores. Moreover, social isolation was correlated with unsuccessful weight loss.

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.

Lactose Sensitivity and Lactose Malabsorption: The 2 Faces of Lactose Intolerance.

BACKGROUND/AIMS: Self-reported lactose intolerance (LI) is frequent in patients with functional bowel disorders (FBD) that could be interpreted as irritable bowel syndrome (IBS). The present study aims to characterize the responses of patients with FBD, without small intestinal bacterial overgrowth (SIBO), and LI, in terms of lactose malabsorption (LM) and lactose sensitivity (LS) according to psychological and clinical features. METHODS: One hundred and fifty-eight consecutive FBD outpatients with LI, and no SIBO, were classified according to the Rome III questionnaire and filled Beck Depression Inventory, and State and Trait Anxiety questionnaires. They underwent a lactose tolerance test in which glycemia during 60 minutes and digestive symptoms for 3 hours were recorded. RESULTS: Abnormal lactose tolerance tests were found in 110 patients (70%), 44 (28%) with LM, 96 (61%) with LS, and 30 (19%) having both LM and LS. LM patients had a higher frequency of functional diarrhea (P = 0.040) and a lower frequency of dysphagia (P = 0.031). LS patients had a higher depression score (P = 0.007), higher frequency of globus (P = 0.042), irritable bowel syndrome (IBS) (P = 0.027) and mixed IBS (P = 0.049), and lower frequency of abdominal pain (P = 0.040). LS was significantly associated with a higher depression score (P = 0.002), and a higher frequency of globus (P = 0.046). CONCLUSIONS: Thirty percent of LI patients have normal lactose absorption and normal LS. In the other 70% of patients, LI could be associated with LM and/or LS.

Biopsychosocial Model and Perceived Constipation Severity According to the Constipation Phenotype.

PURPOSE: Constipation is a frequent complaint of patients with functional bowel disorders. The present study aimed to evaluate the relationship between the perceived constipation severity with demographics, clinical, physiological, and psychological parameters in constipated patients. PATIENTS AND METHODS: Four hundred seven constipated patients were included and had clinical, physiological, and psychological evaluation. The self-reported severity of constipation was analyzed using stepwise linear regression in the total population and within each clinical group. RESULTS: The patients were mainly of female gender (81%) and were 47.4 ± 16.5 years old. They complained of IBS (65%), and 62% had defecation disorders. The depression scale was abnormal in 200 patients (49%). The relationships of the constipation severity varied according to the Rome IV phenotype. In all phenotypes, it was positively associated with bloating severity, and negatively with Bristol stool form. In IBS patients, perceived constipation severity was also associated with abdominal pain severity. CONCLUSION: Our data support the hypothesis that perceived constipation severity is associated with clinical and physiological factors but not demographics and psychological factors. Besides, the relationships of perceived constipation severity with these factors vary according to clinical phenotypes.

COLIGENTA treatment of small intestinal bacterial overgrowth. Results of an open study.

PURPOSE: The treatment of small intestinal overgrowth (SIBO) varies according to the center. The present study aimed to evaluate the efficacy of COLIGENTA, an association of colimycin and gentamycin, on SIBO symptomatology and breath test normalization PATIENTS AND METHODS: In this prospective cross-sectional open study, 150 patients with functional bowel disorders and SIBO diagnosed by lactulose hydrogen breath test (LHBT) underwent COLIGENTA oral treatment. A new HLBT was performed 4 weeks after the first HLBT. RESULTS: The patients were mainly female (74%), with a mean age of 47.4 ±â€¯16.2 years and a body mass index of 26.2 ±â€¯5.9 kg/m². After treatment, a decrease of expired hydrogen concentration (P<0.001) was found in the entire population. Improvement of gastrointestinal symptoms was found in 129 patients (86%), while the breath test's normalization was found in 62 patients (42%). Logistic regression showed that normalization of bowel symptoms was not associated with demographics, clinical, or hydrogen breath concentration. In contrast, normalization of LHBT was associated with an increase of breath hydrogen concentration at time 100 min during the first test (P = 0.003; OR=1.072; 95%CI= [1.023-1.123]). CONCLUSION: The present study shows that 10-days of COLIGENTA treatment has a high SIBO clinical improvement rate and can be used as the first or second treatment line.

Data Mining Approach for the Characterization of Functional Bowel Disorders According to Symptom Intensity Provides a Small Number of Homogenous Groups.

BACKGROUND/AIMS: The aim of the present study is to evaluate if the intensity of the cardinal symptoms of functional bowel disorders could be used to identify homogenous groups of patients defined by the Rome criteria. METHOD: In this observational study, 1,729 consecutive outpatients (73% females) filled out the Rome III questionnaire and 10-point Likert scales for constipation, diarrhea, bloating (BL)/distension, abdominal pain (AP) during the week before the medical consultation. A Gaussian mixture model was used for clustering the patients according to the intensity of symptoms without a priori information, and a classification tree was constructed from this clustering. Data were analyzed using analysis of variance and logistic regression analysis. RESULTS: According to the intensity of symptoms, the patients are divided into 8 groups named according to their main symptomatology: "painful constipation" (PFC), "mild pain constipation" (MPC), "painful diarrhea" (PFD), "mild pain diarrhea" (MPD), "mixed transit" (MT), "BL," "AP," and "nonspecific" (NS). The study of the relationship between the Rome III classification and this new grouping shows that irritable bowel syndrome (IBS)-constipation is associated with PFC, IBS-diarrhea with PFD and MPD, SII-mixed with MT, SII-unspecified with BL, functional constipation with PFC and MPC, functional diarrhea with MPD and NS, BL with "BL" and NS, nonspecific functional bowel disorders (FBD) with NS, and functional AP with "BL" and AP (p < 0.01 for all associations). CONCLUSION: A symptom intensity-based classification of FBD patients could simplify clinical phenotype, give homogeneous groups of patients, and could eventually be used by nongastroenterologists and in clinical research.

Association Between Adherence To The French Dietary Guidelines And Lower Resting Heart Rate, Longer Diastole Duration, And Lower Myocardial Oxygen Consumption. The NUTRIVASC Study.

BACKGROUND: To investigate whether chronic adherence to the French Nutrition and Health Program (PNNS) guidelines was associated with better cardiovascular health. METHODS: A study nested within the SU.VI.MAX2 cohort was conducted on participants without cardiovascular risk factors. Long-term adherence to the PNNS guidelines was estimated using validated dietary scores from 2007 and 2012. Individuals who did (PNNS+) and did not (PNNS-) continuously adhere to the PNNS guidelines were included. Applanation tonometry, impedance cardiography, laser doppler flowmetry, heart rate, heart rate variability, endothelial function was used for the assessment of cardiovascular health. RESULTS: A total of 49 subjects (mean age 65.4 ± 5.6 years, 75.5% women) had been included. Those in the PNNS+ group (n=26) were older, had a higher BMI and fat mass than those in the PNNS- group, both groups had similar metabolic parameters. After adjusting for sex, age, and BMI, PNNS+ subjects were found to have a lower heart rate (60.2 ± 8.0 vs 64.3 ± 8.4 beats/min, p=0.042), a lower heart rate × systolic blood pressure product (7166 ± 1323 vs 7788 ± 1680 beats× mmHg/min, p = 0.009), a longer diastole duration (66.7 ± 3.1% vs 64.6 ± 4.1% of the cardiac cycle duration, p=0.049), and a shorter tension-time index (2145 ± 489 vs 2307 ± 428 ms * mmHg, p=0.018) compared to the PNNS- group. CONCLUSION: Long-term adherence to the PNNS guidelines had a favorable impact on heart rate, diastole duration, and myocardial oxygen consumption. CLINICAL TRIAL REGISTRATION NUMBER: NCT01579409.

Influence of Age and Body Mass Index on Total and Segmental Colonic Transit Times in Constipated Subjects.

BACKGROUND/AIMS: Discordant data are found in the literature for the relationships between total and segmental colonic transit time (CTT) and demographic parameters. The aim of this study is to examine the influence of age, and body mass index (BMI) on total and segmental CTT in constipated subjects. METHODS: We included 354 constipated patients on this cross-sectional study. According to the Rome III criteria, patients were classified as having irritable bowel syndrome with constipation, or functional constipation. All patients filled the Bristol stool form, and reported the severity of constipation, bloating, and abdominal pain on a 10-point Likert scale. Total and segmental CTT were measured using radiopaque markers. RESULTS: Females were 84% of patients, with a mean age of 46.0 ± 15.9 years. The association between total and segmental CTT with age and BMI was significant after adjustment for gender, clinical phenotype, the presence of defecation disorders, and abdominal pain or bloating intensity despite the severity of symptoms, and the frequency of defecation disorders were higher in irritable bowel syndrome with constipation than in functional constipation patients. By comparison with subjects less than 30 years, rectosigmoid transit time (RSTT) was lower in patients between 30 and 60 years. Age was negatively associated with RSTT (P = 0.004). By comparison with patients with normal BMI, RSTT and total CTT were lower in patients of the overweight group. BMI was negatively associated with RSTT (P < 0.001). The severity of constipation was correlated with total (P < 0.001), right (P = 0.002), and left CTT (P = 0.049). CONCLUSION: Age and BMI are both associated with RSTT in constipated patients.

Effects of insulin analogs as an add-on to metformin on cutaneous microcirculation in type 2 diabetic patients.

BACKGROUND: A single insulin injection was shown to improve microcirculatory blood flow. Our aim was to examine the effects of 4weeks of insulin therapy by three randomly assigned insulin analog regimens (Detemir, Aspart, and their combination) on cutaneous blood flow (CBF) and microcirculatory endothelial function as an add-on to metformin in type 2 diabetic patients poorly controlled on oral antidiabetic treatment. METHODS: Fourty-two type 2 diabetic patients with no history of cardiovascular disease in secondary failure to oral antidiabetic agents had CBF measurements before and after acetylcholine (Ach) iontophoretic administration. CBF measurements were performed at fasting and after a standardized breakfast during the post-prandial period. Before randomization (Visit 1, V1) during the tests, participants took only metformin. The same tests were repeated after 4weeks of insulin treatment (Visit 2, V2). RESULTS: Thirty-four patients had good quality recordings for both visits. During V1, CBF and CBF response to Ach increased in the post-prandial period. After 4weeks of insulin treatment, metabolic parameters improved. Compared to V1, CBF at fasting did not increase at V2 but there was an improvement in endothelial function at fasting after Ach iontophoresis, without difference across insulin regimens. Oxidative stress markers were not modified, and E-selectin and vascular cell adhesion molecule 1 levels decreased after insulin treatment, without differences between insulin groups. CONCLUSIONS: A strategy of improving glycemic control for 4weeks with insulin analogs improves microcirculatory endothelial reactivity and reduces endothelial biomarkers at fasting, whatever the insulin regimen used. Insulin therapy associated to metformin is able to improve fasting microvascular endothelial function even before complete metabolic control.