The Efficacy and Safety of Myo-inositol Supplementation for the Prevention of Gestational Diabetes Mellitus in Overweight and Obese Pregnant Women: A Systematic Review and Meta-Analysis.

Background: Myo-inositol has emerged as one of the preventive therapies for the development of gestational diabetes mellitus in at-risk populations. This systematic review and meta-analysis was conducted to determine the efficacy and safety of myo-inositol in decreasing the incidence of gestational diabetes in overweight and obese pregnant women. Methodology: This meta-analysis was conducted using the standard Cochrane methodology and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. Inclusion criteria were randomized controlled trials (RCTs) that enrolled overweight and obese pregnant women and used myo-inositol supplementation. The primary outcome was the incidence of gestational diabetes mellitus at 24-28 weeks. Secondary outcomes included cesarean section rate, the incidence of pregnancy-induced hypertension, macrosomia and preterm delivery. Risk ratios (RRs) and 95% confidence intervals (CIs) were used for dichotomous data. Results: Six RCTs were included. Compared to standard micronutrient supplementation, standard dose of myo-inositol (4 g) may reduce the incidence of GDM (RR 0.54; CI [0.30, 0.96]; n = 887 women), but the certainty of evidence is low to very low. With low-dose myo-inositol however, evidence is uncertain about its benefit on the incidence of gestational diabetes mellitus in overweight and obese women with RR 0.71; CI [0.14, 3.50]. No adverse effects were noted. For the secondary outcomes, standard dose myo-inositol appears to reduce the incidence of pregnancy-induced hypertension and preterm delivery, but the certainty of evidence is low to very low. Conclusion: Current evidence is uncertain on the potential benefit of myo-inositol supplementation in overweight and obese pregnant women. While studies show that 4 g myo-inositol per day may decrease the incidence of GDM, pregnancy-induced hypertension and pre-term birth with no associated risk of serious adverse events, the certainty of evidence is low to very low. Future high-quality trials may provide more compelling evidence to support practice recommendations.

The effect of myo-inositol supplementation on the prevention of gestational diabetes in overweight pregnant women: a randomized, double-blind, controlled trial.

BACKGROUND: This study strove to investigate the hypothesis that a low dosage of myo-inositol supplementation might decrease the likelihood of gestational diabetes in overweight, pregnant women. METHODS: A randomized, double-blind, controlled trial was performed on 60 eligible overweight, pregnant women, at 12-14 weeks of gestation, at two Iranian obstetric clinics. The participants were divided into two groups based on blocked randomization. The myo-inositol group received 2000 mg plus 400 µg folic acid daily and the control group received 400 µg of folic acid daily from 14-24 gestational weeks. The occurrence of gestational diabetes was determined based on 75-g 2-hour oral glucose tolerance test (OGTT) at 24-28 gestational weeks, which was the primary outcome of the study. The secondary outcomes were: the evaluation of insulin therapy, insulin resistance and lipid profile, gestational weight gain, and fetal and maternal outcomes. RESULTS: The incidence of gestational diabetes in myo-inositol group was noticeably minimized compared to that in the control group (RR=0.29, 95% CI: 0.09-0.94, P=0.037). There were no differences between the two groups in terms of fasting blood sugar, fasting insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), insulin therapy, and triglyceride. There was no report of severe adverse drug reactions. CONCLUSIONS: The absolute risk reduction and the number-needed-to-treat for gestational diabetes were 26.8% (95% CI: 5.6-48) and 3.7 (95% CI: 2.1-18.0), respectively. Hence, it can be concluded that approximately one out of every four overweight pregnant women receiving myo-inositol benefitted from its daily intake.

Myo-Inositol Moderates Glucose-Induced Effects on Human Placental 13C-Arachidonic Acid Metabolism.

Maternal hyperglycemia is associated with disrupted transplacental arachidonic acid (AA) supply and eicosanoid synthesis, which contribute to adverse pregnancy outcomes. Since placental inositol is lowered with increasing glycemia, and since myo-inositol appears a promising intervention for gestational diabetes, we hypothesized that myo-inositol might rectify glucose-induced perturbations in placental AA metabolism. Term placental explants (n = 19) from women who underwent a mid-gestation oral glucose-tolerance-test were cultured with 13C-AA for 48 h in media containing glucose (5, 10 or 17 mM) and myo-inositol (0.3 or 60 µM). Newly synthesized 13C-AA-lipids were quantified by liquid-chromatography-mass-spectrometry. Increasing maternal fasting glycemia was associated with decreased proportions of 13C-AA-phosphatidyl-ethanolamines (PE, PE-P), but increased proportions of 13C-AA-triacylglycerides (TGs) relative to total placental 13C-AA lipids. This suggests altered placental AA compartmentalization towards storage and away from pools utilized for eicosanoid production and fetal AA supply. Compared to controls (5 mM glucose), 10 mM glucose treatment decreased the amount of four 13C-AA-phospholipids and eleven 13C-AA-TGs, whilst 17 mM glucose increased 13C-AA-PC-40:8 and 13C-AA-LPC. Glucose-induced alterations in all 13C-AA lipids (except PE-P-38:4) were attenuated by concurrent 60 µM myo-inositol treatment. Myo-inositol therefore rectifies some glucose-induced effects, but further studies are required to determine if maternal myo-inositol supplementation could reduce AA-associated pregnancy complications.

Role of phospholipase C in catecholamine-induced increase in myocardial protein synthesis.

The activation of the α1-adrenoceptor-(α1-AR) by norepinephrine results in the G-protein (Gqα) mediated increase in the phosphoinositide-specific phospholipase C (PLC) activity. The byproducts of PLC hydrolytic activity, namely, 1,2-diacylglycerol and inositol-1,4,5-trisphosphate, are important downstream signal transducers for increased protein synthesis in the cardiomyocyte and the subsequent hypertrophic response. In this article, evidence was outlined to demonstrate the role of cardiomyocyte PLC isozymes in the catecholamine-induced increase in protein synthesis by using a blocker of α1-AR and an inhibitor of PLC. The discussion was focused on the α1-AR-Gqα-PLC-mediated hypertrophic signalling pathway from the viewpoint that it may compliment the other ß1-AR-Gs protein-adenylyl cyclase signal transduction mechanisms in the early stages of cardiac hypertrophy development, but may become more relevant at the late stage of cardiac hypertrophy. From the information provided here, it is suggested that some specific PLC isozymes may potentially serve as important targets for the attenuation of cardiac hypertrophy in the vulnerable patient population at-risk for heart failure.

Differences in levothyroxine action on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity between metformin- and myo-inositol-treated women with autoimmune subclinical hypothyroidism.

WHAT IS KNOWN AND OBJECTIVE: Insulin resistance impairs the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity. Both metformin and myo-inositol were found to improve insulin sensitivity and to reduce thyrotropin levels in individuals with hypothyroidism. The aim of the present study was to compare the effect of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity between women receiving metformin and myo-inositol. METHODS: The study included two groups of women with autoimmune hypothyroidism, treated for at least 6 months with either metformin (group A; n = 25) or myo-inositol (group B; n = 25). Both groups were matched for age, insulin sensitivity, hormone levels and antibody titers. For the following 6 months, all women received levothyroxine. Plasma levels of glucose, insulin, thyrotropin, free thyroid hormones, prolactin, 25-hydroxyvitamin D and high-sensitivity C-reactive protein (hsCRP), as well as titers of thyroid peroxidase and thyroglobulin antibodies were assessed at the beginning and at the end of the study. RESULTS AND DISCUSSION: At baseline there were not differences between the study groups. Although levothyroxine reduced thyrotropin levels, increased free thyroid hormone levels and decreased antibody titers in both study groups, these effects were more pronounced in group A than group B. Only in group A, levothyroxine increased 25-hydroxyvitamin D, decreased hsCRP and improved insulin sensitivity. The impact of levothyroxine on thyrotropin and free thyroid hormones correlated with treatment-induced changes in insulin sensitivity, antibody titers, 25-hydroxyvitamin D and hsCRP. WHAT IS NEW AND CONCLUSION: The present study suggests that the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity is stronger in women receiving metformin than in women treated with myo-inositol.

Combinatory lung tumor inhibition by myo-inositol and iloprost/rapamycin: association with immunomodulation.

Although both preclinical and clinical studies have suggested that myo-inositol (MI) may be a safe and effective lung cancer chemopreventive agent, its efficacy is moderate. To test whether the chemopreventive agents iloprost (IL) or rapamycin enhance the lung tumor inhibitory effects of MI, A/J mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and, beginning one week after the end of NNK treatment, given MI, IL, rapamycin, MI + IL or MI + rapamycin for 17 weeks. Analyses of the number and size of tumors on the surface of the lung have indicated that MI, IL, rapamycin, MI + IL and MI + rapamycin reduced the multiplicity of NNK-induced lung tumors by 41, 34, 46, 79 and 67%, respectively, and larger tumors (lung tumors with a diameter of 1-2 or >2 mm) were absent in the MI + IL and MI + rapamycin groups. These results clearly indicated that MI + IL and MI + rapamycin are more effective than MI alone in inhibiting the formation and growth of lung tumors. Assessment of the immunomodulatory effects of the drugs showed that whereas MI + rapamycin and MI + IL increased the infiltration of lung tumors by CD4+ and CD8+ T cells, MI + rapamycin reduced the expression of the immune checkpoint protein programmed-death ligand-1 (PD-L1). Moreover, all treatments, except IL, increased apoptosis, whereas cell proliferation was markedly suppressed in all treated groups. In summary, these results suggest that IL and rapamycin could enhance the efficacy of MI in lung cancer chemoprevention trials.

Inositol Alleviates Pulmonary Fibrosis by Promoting Autophagy via Inhibiting the HIF-1α-SLUG Axis in Acute Respiratory Distress Syndrome.

The effective remission of acute respiratory distress syndrome- (ARDS-) caused pulmonary fibrosis determines the recovery of lung function. Inositol can relieve lung injuries induced by ARDS. However, the mechanism of myo-inositol in the development of ARDS is unclear, which limits its use in the clinic. We explored the role and mechanism of myo-inositol in the development of ARDS by using an in vitro lipopolysaccharide- (LPS-) established alveolar epithelial cell inflammation model and an in vivo ARDS mouse model. Our results showed that inositol can alleviate the progression of pulmonary fibrosis. More significantly, we found that inositol can induce autophagy to inhibit the progression pulmonary fibrosis caused by ARDS. In order to explore the core regulators of ARDS affected by inositol, mRNA-seq sequencing was performed. Those results showed that transcription factor HIF-1α can regulate the expression of SLUG, which in turn can regulate the key gene E-Cadherin involved in cell epithelial-mesenchymal transition (EMT) as well as N-cadherin expression, and both were regulated by inositol. Our results suggest that inositol activates autophagy to inhibit EMT progression induced by the HIF-1α/SLUG signaling pathway in ARDS, and thereby alleviates pulmonary fibrosis.

Caffeinated energy drinks in the Canadian context: health risk assessment with a focus on cardiovascular effects.

In Canada, caffeinated energy drinks (CEDs) currently sold under Temporary Marketing Authorizations must meet strict eligibility criteria. These criteria, which include compositional and labelling requirements, were developed based on the outcome of a health risk assessment conducted by Health Canada (HC) in 2013. HC updated its assessment by reviewing new information with the focus on potential cardiovascular effects associated with the consumption of CEDs available for sale in Canada. Due to limited data on CED consumption among Canadians to derive accurate exposure information, the composition of a typical CED was characterized to assess the potential effects of single ingredients and synergistic interactions between ingredients on the cardiovascular system. Surveillance data on potential adverse effects related to CED consumption was also analyzed. After extensive review, HC's updated assessment confirms the current risk management approach for CEDs is health protective for Canadian consumers, including the potential for cardiovascular effects. The available evidence supports that moderate consumption (up to 500 mL per day) of a typical CED authorized for sale in Canada is safe for the general population of healthy adults and adolescents. It also re-confirms that vulnerable sub-populations (i.e., children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals) should not consume CEDs. Novelty: Consumption up to 500 mL per day of a typical CED is not associated with an increased risk of cardiovascular effects. Children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals should not consume CEDs.

The use of D-chiro-Inositol in clinical practice.

OBJECTIVE: D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this molecule acts through two different mechanisms, with potentially different outcomes. On the one hand, under a metabolic perspective, D-chiro-Inositol improves insulin signaling, thus restoring physiological insulin levels in resistant subjects. On the other hand, at a cellular level, it downregulates the expression of steroidogenic enzyme aromatase, which is responsible for the conversion of androgens to estrogens. MATERIALS AND METHODS: We reviewed current literature in different databases, searching for D-chiro-Inositol in relation with one of the following keywords: myo-inositol, PCOS, infertility, insulin resistance, aromatase, androgen and inositol, testosterone, estrogen and inositol, estradiol, hypogonadotropic hypogonadism, fat tissue, estrogens and cancer, anovulation, uterine myoma, endometriosis, endometrial hyperplasia. RESULTS: D-Chiro-Inositol treatment may be helpful in restoring physiological hormonal levels in various clinical disorders. However, D-Chiro-Inositol intervention should be carefully designed to avoid possible undesired side effects stemming from its multiple mechanisms of action. CONCLUSIONS: We evaluated the optimal D Chiro-Inositol administration for different pathologies, defining dosages and timing. Even though further studies are required to validate our preliminary results, this paper is primarily intended to guide researchers through some of the pathways of D-Chiro-Inositol.

The effect of voglibose on metabolic profiles in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of clinical trials.

OBJECTIVE: The effect of voglibose on metabolic homeostasis is not well characterized. Therefore, we conducted a systematic review and meta-analysis of clinical trials assessing the effect of voglibose on metabolic profile in patients with type 2 diabetes mellitus (T2DM). METHODS: Systematic searches were conducted in PubMed, Scopus, Embase, Google Scholar, Web of Science and Cochrane Library to identify clinical trials assessing the effects of voglibose supplementation on cardio-metabolic profile from incept up to 29 July 2019. Data was pooled using fixed- or random-effect models and weighted mean difference (WMD) as the effect size. RESULTS: Eight clinical trials from 1094 reports, were eligible for inclusion. Pooled findings identified significant reductions in hemoglobin A1c (HbA1c) (WMD= -0.27; 95 %CI -0.49 to -0.05; P = 0.01; I2 = 64.8 %) and an increase in LDL-cholesterol levels (WMD=5.97 mg/dl, 95 % CI 0.88, 11.06, P = 0.02; I2 = 0.0 %). However, no evidence of effect for voglibose intake on T2DM patients was observed for: fasting blood sugar (FBS) (WMD -7.43 mg/dl; 95 %CI -16.56 to 1.71; P = 0.110; I2 = 69.3 %), serum insulin (WMD= -0.15 µU/mL; 95 %CI -0.89 to 0.60; P = 0.70; I2 = 0.0 %), total-cholesterol (WMD=2.82 mg/dl, 95 %CI -2.36 to 8.01, P = 0.70; I2 = 49.7 %), triglycerides (WMD= -7.07 mg/dl, 95 %CI -21.76 to 7.62, P = 0.34; I2 = 0.0 %), HDL-cholesterol levels (WMD= -2.10 mg/dl, 95 %CI -4.48 to 0.27, P = 0.08; I2 = 0.0 %,), body mass index (BMI) (WMD=0.09 kg/m2, 95 %CI -0.70 to 0.87; P = 0.87; I2 = 0.0 %), body weight (WMD= -0.42 kg, 95 %CI -0.84 to 0.00; P = 0.05; I2 = 0.0 %), and adiponectin levels (WMD = 0.32 µg/mL, 95 %CI -0.74 to 1.38; P = 0.55; I2 = 0.0 %). CONCLUSIONS: The current meta-analysis identified a decrease in HbA1c and an increase in LDL-cholesterol with administration of voglibose. However, no significant effect was observed on FBS, insulin, bodyweight, BMI, adiponectin, triglycerides, total- and HDL-cholesterol levels.

Effects of sitagliptin on exercise capacity and hemodynamics in patients with type 2 diabetes mellitus and coronary artery disease.

Sitagliptin attenuates left ventricular (LV) dysfunction and may improve oxygen uptake in animals. The effects of sitagliptin on oxygen uptake (VO2) and exercise hemodynamics have been unclear in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). Thirty patients with T2DM and CAD were randomized into a sitagliptin (50 mg/day) or voglibose (0.6 mg/day) group. Patients underwent maximal cardiopulmonary exercise testing. VO2 and hemodynamics were evaluated at rest, anaerobic threshold and peak exercise. Resting LV diastolic function (E', peak early diastolic mitral annular velocity) and geometry were evaluated by echocardiography, and endothelial function by reactive hyperemia peripheral arterial tonometry. A total of 24 patients (69 ± 9 years) completed 6 months of intervention. Peak VO2 in the sitagliptin and voglibose groups (25.3 ± 7.3 vs. 24.0 ± 7.4, 22.7 ± 4.8 vs. 22.1 ± 5.2 ml/kg/min) was slightly decreased after 6 months (time effect p = 0.051; group × time effect p = 0.49). No effects were observed on LV ejection fraction, E', or reactive hyperemia index in either group. Heart rate during exercise was unaffected in both groups. Systolic blood pressure was unchanged by sitagliptin at rest and during exercise, but slightly lowered by voglibose at anaerobic threshold and peak exercise. In patients with T2DM and CAD, sitagliptin had little effect on resting LV and arterial function, exercise capacity, or exercise hemodynamics. Further studies need to be conducted with more patients as the number of the patients in this study was limited.

Myoinositol in the Prevention of Gestational Diabetes Mellitus: Is It Sensible?

Gestational diabetes mellitus (GDM) is a complication that increasingly affects pregnant women. Due to the risk of adverse outcomes in the mother as well as in the fetus which is caused by GDM, appropriate diagnosis and treatment is very essential. Nevertheless, it is important to find new, effective ways of prevention of GDM to avoid side effects. A promising example of such an action may be supplementation of myoinositol. As shown in studies, myoinositol may reduce the risk of developing gestational diabetes mellitus by improving insulin sensitivity.

A Prospective Study Evaluating the Effects of a Nutritional Supplement Intervention on Cognition, Mood States, and Mental Performance in Video Gamers.

Cognitive function is critical for successful prolonged performance in eSports. This double-blind placebo-controlled study examined the effect of an inositol-enhanced arginine silicate oral supplement on cognitive performance and energy in eSports athletes. Sixty healthy men and women who spent 5 or more hours a week playing video games were randomly assigned to take supplement or placebo for 7 days. On day 1 and 7, before and 15 min after dosing, subjects completed the Trail Making Test (TMT), Parts A and B; Stroop Test; and Profile of Mood States (POMS) questionnaire, and then played a video game for 60 min. Immediately after, cognitive tests were repeated. Self-reported energy levels increased, anger decreased, and TMT-B test errors decreased in the supplement group compared to placebo (p < 0.05). Fatigue, TMT-B time, and TMT B-A score improved in the supplement group compared to baseline (p < 0.05). After 60 min of gaming, supplementation decreased Stroop Test errors and TMT-A time (p < 0.05). Adverse events were minimal and not different between groups. These data appear to support the use of the studies product (nooLVL®) in eSports gamers looking to improve their accuracy, decision making, and reaction time during gaming.

Inositol and antioxidant supplementation: Safety and efficacy in pregnancy.

Pregnancies complicated by diabetes have largely increased in number over the last 50 years. Pregnancy is characterized by a physiologic increase in insulin resistance, which, associated with increased oxidative stress and inflammations, could induce alterations of glucose metabolism and diabetes. If not optimally controlled, these conditions have a negative impact on maternal and foetal outcomes. To date, one can resort only to diet and lifestyle to treat obesity and insulin resistance during pregnancy, and insulin remains the only therapeutic option to manage diabetes during pregnancy. However, in the last years, in a variety of experimental models, inositol and antioxidants supplementation have shown insulin-sensitizing, anti-inflammatory, and antioxidant properties, which could be mediated by some possible complementary mechanism of action. Different isomers and multiple combinations of these compounds are presently available: Aim of the present review article is to examine the existing evidence in order to clarify and/or define the effects of different inositol- and antioxidant-based supplements during pregnancy complicated by insulin resistance and/or by diabetes. This could help the clinician's evaluation and choice of the appropriate supplementation regimen.

Alpha-glucosidase inhibitors for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus.

BACKGROUND: Alpha-glucosidase inhibitors (AGI) reduce blood glucose levels and may thus prevent or delay type 2 diabetes mellitus (T2DM) and its associated complications in people at risk of developing of T2DM. OBJECTIVES: To assess the effects of AGI in people with impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. The date of the last search of all databases was December 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs), with a duration of one year or more, comparing AGI with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with IFG, IGT, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles or records, assessed quality and extracted outcome data independently. One review author extracted data, which were checked by a second review author. We resolved discrepancies by consensus or involvement of a third review author. For meta-analyses we used a random-effects model with assessment of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall quality of the evidence by using the GRADE instrument. MAIN RESULTS: For this update of the Cochrane Review (first published 2006, Issue 4) we included 10 RCTs (11,814 participants), eight investigating acarbose and two investigating voglibose, that included people with IGT or people "at increased risk for diabetes". The trial duration ranged from one to six years. Most trials compared AGI with placebo (N = 4) or no intervention (N = 4).Acarbose reduced the incidence of T2DM compared to placebo: 670 out of 4014 people (16.7%) in the acarbose groups developed T2DM, compared to 812 out of 3994 people (20.3%) in the placebo groups (RR 0.82, 95% CI 0.75 to 0.89; P < 0.0001; 3 trials; 8008 participants; moderate-certainty evidence). One trial including participants with coronary heart disease and IGT contributed 64% of cases for this outcome. Acarbose reduced the risk of T2DM compared to no intervention: 7 out 75 people (9.3%) in the acarbose groups developed T2DM, compared to 18 out of 65 people (27.7%) in the no-intervention groups (RR 0.31, 95% CI 0.14 to 0.69; P = 0.004; 2 trials; 140 participants; very low-certainty evidence).Acarbose compared to placebo did not reduce or increase the risk of all-cause mortality (RR 0.98, 95% CI 0.82 to 1.18; P = 0.86; 3 trials; 8069 participants; very low-certainty evidence), cardiovascular mortality (RR 0.88; 95% CI 0.71 to 1.10; P = 0.26; 3 trials; 8069 participants; very low-certainty evidence), serious adverse events (RR 1.12, 95% CI 0.97 to 1.29; P = 0.13; 2 trials; 6625 participants; low-certainty evidence), non-fatal stroke (RR 0.50, 95% CI 0.09 to 2.74; P = 0.43; 1 trial; 1368 participants; very low-certainty evidence) or congestive heart failure (RR of 0.87; 95% CI 0.63 to 1.12; P = 0.40; 2 trials; 7890 participants; low-certainty evidence). Acarbose compared to placebo reduced non-fatal myocardial infarction: one out of 742 participants (0.1%) in the acarbose groups had a non-fatal myocardial infarction compared to 15 out of 744 participants (2%) in the placebo groups (RR 0.10, 95% CI 0.02 to 0.53; P = 0.007; 2 trials; 1486 participants; very low-certainty evidence). Acarbose treatment showed an increased risk of non-serious adverse events (mainly gastro-intestinal events), compared to placebo: 751 of 775 people (96.9%) in the acarbose groups experienced an event, compared to 723 of 775 people (93.3%) in the placebo groups (RR 1.04; 95% CI 1.01 to 1.06; P = 0.0008; 2 trials; 1550 participants). Acarbose compared to no intervention showed no advantage or disadvantage for any of these outcome measures (very low-certainty evidence).One trial each compared voglibose with placebo (1780 participants) or diet and exercise (870 participants). Voglibose compared to placebo reduced the incidence of T2DM: 50 out of 897 participants (5.6%) developed T2DM, compared to 106 out of 881 participants (12%) in the placebo group (RR 0.46, 95% CI 0.34 to 0.64; P < 0.0001; 1 trial; 1778 participants; low-certainty evidence). For all other reported outcome measures there were no clear differences between voglibose and comparator groups. One trial with 90 participants compared acarbose with diet and exercise and another trial with 98 participants reported data on acarbose versus metformin. There were no clear differences for any outcome measure between these two acarbose interventions and the associated comparator groups.None of the trials reported amputation of lower extremity, blindness or severe vision loss, end-stage renal disease, health-related quality of life, time to progression to T2DM, or socioeconomic effects. AUTHORS' CONCLUSIONS: AGI may prevent or delay the development of T2DM in people with IGT. There is no firm evidence that AGI have a beneficial effect on cardiovascular mortality or cardiovascular events.

A randomized controlled trial comparing lifestyle intervention to letrozole for ovulation in women with polycystic ovary syndrome: a study protocol.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects between 8 and 18% of women and is the leading cause of female anovulatory infertility. Unfortunately, common treatments for women trying to conceive can be ineffective as well as disruptive or harmful to patients' quality of life. Despite evidence that women with PCOS have expressed the need for alternative fertility treatments, lifestyle interventions incorporating a nutritional plan with supplementation, increased physical activity, and techniques for stress management have not been combined as a program and studied in this population. Literature suggests that each of these individual components can positively influence reproductive hormones and metabolic health. METHODS/DESIGN: This is a randomized controlled trial which will include 240 women diagnosed with PCOS, according to the Rotterdam criteria, who are trying to conceive. Participants will be randomized to either a comprehensive lifestyle intervention program or prescribed an oral fertility medication, letrozole. These two groups will be further randomized to consume either myo-inositol or a placebo. Participants will be between the ages of 18 and 37 years. Exclusion criteria include women who have already begun fertility treatment, who are currently using myo-inositol or have taken it within the past 3 months, or who are being treated for, or have a history of, an eating disorder. The primary outcome will be the ovulation rate, the secondary outcome will be conception. Other outcomes include miscarriage rates, validated rating measures of overall quality of life (including social, relational, mind/body and emotional sub-categories) and mental health scores (depression, anxiety, and stress). DISCUSSION: This trial will determine the effectiveness of a structured lifestyle-based comprehensive intervention program for women with PCOS experiencing infertility. In addition, it will determine whether supplementing with myo-inositol provides any further benefit. The objective of this study is to assess a possible non-pharmacological solution to ovulatory dysfunction in these patients and perhaps improve other associated features of PCOS. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02630485 . Registered on 15 December 2015.

Effects of Myo-inositol on Type 1 Retinopathy of Prematurity Among Preterm Infants <28 Weeks' Gestational Age: A Randomized Clinical Trial.

Importance: Previous studies of myo-inositol in preterm infants with respiratory distress found reduced severity of retinopathy of prematurity (ROP) and less frequent ROP, death, and intraventricular hemorrhage. However, no large trials have tested its efficacy or safety. Objective: To test the adverse events and efficacy of myo-inositol to reduce type 1 ROP among infants younger than 28 weeks' gestational age. Design, Setting, and Participants: Randomized clinical trial included 638 infants younger than 28 weeks' gestational age enrolled from 18 neonatal intensive care centers throughout the United States from April 17, 2014, to September 4, 2015; final date of follow-up was February 12, 2016. The planned enrollment of 1760 participants would permit detection of an absolute reduction in death or type 1 ROP of 7% with 90% power. The trial was terminated early due to a statistically significantly higher mortality rate in the myo-inositol group. Interventions: A 40-mg/kg dose of myo-inositol was given every 12 hours (initially intravenously, then enterally when feeding; n = 317) or placebo (n = 321) for up to 10 weeks. Main Outcomes and Measures: Type 1 ROP or death before determination of ROP outcome was designated as unfavorable. The designated favorable outcome was survival without type 1 ROP. Results: Among 638 infants (mean, 26 weeks' gestational age; 50% male), 632 (99%) received the trial drug or placebo and 589 (92%) had a study outcome. Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks' postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%-11%]; adjusted relative risk, 1.66 [95% CI, 1.14-2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%). Conclusions and Relevance: Among premature infants younger than 28 weeks' gestational age, treatment with myo-inositol for up to 10 weeks did not reduce the risk of type 1 ROP or death vs placebo. These findings do not support the use of myo-inositol among premature infants; however, the early termination of the trial limits definitive conclusions.

Effects of myo-inositol on glucose variability in women with gestational diabetes.

OBJECTIVE: Myo-inositol supplementation prevents gestational diabetes (GDM) in women at risk and reduces insulin resistance in women with GDM. No data are available about its effect on glucose variability. The aim of this study was to evaluate the effects of a supplementation of myo-inositol on glucose variability in women with GDM. PATIENTS AND METHODS: Myo-inositol effect on glucose variability was studied in a pilot case-control study involving 12 consecutive pregnant women (median age 34 years, 25.0% insulin-treated) with GDM. Six women received myo-inositol 2 g plus 200 mg folic acid twice a day, the others received only folic acid. Information on side effects was collected. A continuous glucose monitoring system was wore before and at the beginning of the supplementation. Mean amplitude of glucose excursion (MAGE), standard deviation (SD) and variability coefficient were the indexes of glucose variability. RESULTS: Myo-inositol lowered glucose levels in the first days after the treatment was started. However, pre-post supplementation overall mean glucose difference was similar between groups (-4.8 vs. 5.0 mg/dL for controls and treated, respectively; p = 0.79). Pre-post differences in SD (13.7 vs. 6.0; p < 0.001), MAGE (3.5 vs.-1.5; p < 0.001) and variability coefficient (0.14 vs. 0.02; p < 0.001) were improved in myo-inositol group. No side effects were recorded. CONCLUSIONS: Myo-inositol is effective in reducing glucose variability in women with GDM. It could be a useful strategy for treating GDM.

Pharmacodynamic effects of voglibose administered alone, administered with metformin, and administered with metformin in a fixed-dose combination in healthy Korean subjects
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OBJECTIVE: This study aimed at exploring the effects of metformin on the pharmacodynamics of voglibose, while investigating the pharmacodynamics between a fixed-dose combination (FDC) of voglibose/metformin and coadministered doses of voglibose and metformin tablets in healthy Korean subjects. MATERIALS AND METHODS: A randomized, open-label, 2×3×3 crossover study with a 9-day washout period was conducted in 30 healthy subjects. All subjects received orally administered voglibose alone, individual voglibose and metformin tablets, or FDC 3 times daily for 5 days. Oral sucrose was administered on day -1 (pretreatment) and at 10 minutes after the morning dose of the study drug on day 5 of each period. Plasma glucose and serum insulin were measured over the course of 2 hours following sucrose loading. RESULTS: 21 subjects completed the study. The geometric mean ratios (GMR) of ΔCmax and the AUC of glucose for voglibose plus metformin vs. voglibose alone were 0.995 (90% CI, 0.800 - 1.237) and 0.969 (90% CI, 0.949 - 0.990), respectively; the GMRs for individual tablets vs. FDC were 1.118 (90% CI, 0.930 - 1.344) and 1.010 (90% CI, 0.974 - 1.048), respectively. A relatively smaller number of subjects experienced adverse events when receiving voglibose alone compared to those administered FDC or metformin and voglibose. There were no significant differences in adverse events between individual voglibose and metformin tablets and FDC. CONCLUSION: Coadministered metformin did not have statistically or clinically significant effects on the pharmacodynamics of voglibose in healthy subjects. Glucose levels following sucrose loading seem not to be clinically different between FDC and individual tablets of voglibose and metformin.
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