Systematic review and meta-analysis of head-to-head trials comparing sulfonylureas and low hypoglycaemic risk antidiabetic drugs.

BACKGROUND: Safety of sulfonylurea drugs in the treatment of Type 2 Diabetes is still under debate. The aim of this study was to compare the all-cause mortality and cardiovascular adverse events of sulfonylureas and drugs with a low risk for hypoglycaemia in adults with type 2 diabetes. METHODS: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: MEDLINE (PubMed, OVID), Embase, Cochrane Central Register of Controlled Trials, CINAHL, WOS and Lilacs. STUDY SELECTION: Randomised controlled head-to-head trials that compared sulfonylureas with active control with low hypoglycaemic potential in adults (≥ 18 years old) with type 2 diabetes published up to August 2015. The drug classes involved in the analysis were metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. OUTCOMES: The primary endpoint was all-cause mortality. The secondary endpoints were MACE, cardiovascular events and severe hypoglycaemia. SYNTHESIS OF RESULTS: Two reviewers checked study eligibility, independently extracted data and assessed quality with disagreements resolved through discussion. We assessed the risk of bias of the included studies using the Cochrane risk of bias tool for randomized trials v2. Pooled odds ratios (ORs) were estimated by using fixed effects model. The study is registered on PROSPERO (26/05/2016 CRD42016038780). RESULTS: Our final analysis comprised 31 studies (26,204 patients, 11,711 patients given sulfonylureas and 14,493 given comparator drugs). In comparison to drugs with low hypoglycaemic potential, sulfonylureas had higher odds for all-cause mortality (OR 1.32, 95% CI 1.00-1.75), MACE (OR 1.32, 95% CI 1.07-1.61), myocardial infarction (fatal and non-fatal) (OR 1.67, 95% CI 1.17-2.38) and hypoglycaemia (OR 5.24, 95% CI 4.20-6.55). Subsequent sensitivity analysis revealed differences in the effect of sulfonylureas, with an increased risk of all-cause mortality with glipizide but not the other molecules. CONCLUSION: Our meta-analysis raises concern about the safety of SUs compared to alternative drugs involved in current analysis. Important differences may exist within the drug class, and glimepiride seems to have best safety profile.

Association of FTO rs1421085 with obesity, diet, physical activity, and socioeconomic status: A longitudinal birth cohort study.

BACKGROUND AND AIMS: Fat mass and obesity-associated protein (FTO) variants are among genetic variants frequently associated with obesity. We analyzed the association between FTO rs1421085 polymorphism and obesity, dietary intake, cardiorespiratory fitness (CRF), physical activity, and socioeconomic status (SES) from the age of 9-25 years. METHODS AND RESULTS: The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between FTO rs1421085 and obesity, dietary intake, CRF, physical activity, and SES from the age of 15-25 years was assessed using linear mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, and 25 years were assessed by one-way ANOVA. Male C-allele carriers had significantly (p < 0.05) higher body mass index (BMI), sum of 5 skinfolds, body fat percentage, and hip circumference from the age of 15-25 years. Findings were similar at the age of 9 years. In female subjects, waist-to-hip ratio was significantly greater in CC homozygotes. Interestingly, female CC homozygotes had a greater decrease in the rate of change in daily energy intake and lipid intake per year and higher physical activity score at every fixed time point. Moreover, in females, an effect of FTO × SES interaction on measures of obesity was observed. CONCLUSION: The FTO rs1421085 polymorphism was associated with obesity and abdominal obesity from childhood to young adulthood in males, and with abdominal obesity from adolescence to young adulthood in females. This association is rather related to differences in adipocyte energy metabolism than lifestyle.

Is low platelet MAO activity associated with antisocial behavior? evidence from representative samples of longitudinally observed birth cohorts.

Lower platelet monoamine oxidase (MAO) activity has been associated with problem behaviors, including criminal behavior, but not all studies agree. We have examined platelet MAO activity and antisocial behavior involving police contact in a longitudinal birth cohort study. The sample included both birth cohorts (original n = 1238) of the Estonian Children Personality Behavior and Health Study. Platelet MAO activity was measured at ages 15, 18 and 25 radioenzymatically with ß-phenylethylamine as the substrate. Police contacts were self-reported in an interview and drug use in a questionnaire filled in during a laboratory visit. In cross-sectional analyses, males with the record of antisocial behavior had lower platelet MAO activity. In longitudinal mixed-effect regression models, this association was found to be independent of smoking. Furthermore, including smoking in the model revealed lower platelet MAO activity also in females with past antisocial behaviour. A further exploratory regression analysis with antisocial behavior at two levels of frequency and consideration of self-reported use of illicit drugs either in a single occasion or repeatedly demonstrated some "dose-dependency" in the relationship of antisocial behavior and platelet MAO activity. Platelet MAO activity was lower in male but not female subjects with basic education level as compared to secondary and higher education, but it was not related to non-verbal intelligence. Neither was platelet MAO activity associated with socio- economic status. In conclusion, antisocial behavior as occurring in general population is associated with low platelet MAO activity that probably reflects low capacity of the serotonergic system.

Association between platelet MAO activity and lifetime drug use in a longitudinal birth cohort study.

RATIONALE: Platelet monoamine oxidase (MAO) activity, a marker of central serotonergic capacity, has been associated with a variety of problem behaviours. However, studies on platelet MAO activity and addictive drugs have not consistently linked MAO activity with addiction or reported to predict illicit substance use initiation or frequency. OBJECTIVES: Platelet MAO activity and illicit drug use was examined in a longitudinal birth cohort study. METHODS: The sample included both birth cohorts (original n = 1238) of the Estonian Children Personality Behaviour and Health Study. Longitudinal association from age 15 to 25 years between platelet MAO activity and lifetime drug use was analysed by mixed-effects regression models. Differences at ages 15, 18 and 25 were analysed by t-test. Cox proportional hazard regression analysis was used to assess the association between platelet MAO activity and the age of drug use initiation. RESULTS: Male subjects who reported at least one drug use event had lower platelet MAO activity compared to nonusers, both in cross-sectional and longitudinal analyses. Males with low platelet MAO activity had started to use drugs at a younger age. Moreover, in male subjects who had experimented with illicit drugs only once in lifetime, low platelet MAO activity was also associated with higher risk at a younger age. In females, platelet MAO activity was not associated with drug use. CONCLUSION: In males, low platelet MAO activity is associated with drug abuse primarily owing to risk-taking at early age.

Neuropeptide Y gene variants in obesity, dietary intake, blood pressure, lipid and glucose metabolism: A longitudinal birth cohort study.

OBJECTIVE: Neuropeptide Y affects several physiological functions, notably appetite regulation. We analysed the association between four single nucleotide polymorphisms (SNP) in the NPY gene (rs5574, rs16147, rs16139, rs17149106) and measures of obesity, dietary intake, physical activity, blood pressure, glucose and lipid metabolism from adolescence to young adulthood. METHODS: The sample included both birth cohorts of the Estonian Children Personality Behaviour and Health Study at ages 15 (n = 1075 with available complete data), 18 (n = 913) and 25 (n = 926) years. Linear mixed-effects regression models were used for longitudinal association between NPY SNP-s and variables of interest. Associations at ages 15, 18 and 25 were analysed by ANOVA. RESULTS: Rs5574 CC-homozygotes had a greater increase per year in waist-to-hip ratio (WHR) and a smaller decrease in daily energy intake and carbohydrate intake from age 15-25 years; fasting glucose and cholesterol were higher in rs5574 CC-homozygotes. Rs16147 TT-homozygotes had higher body weight and a greater increase in sum of 5 skinfolds, waist circumference, WHR and waist-to-height ratio; however, they had lower carbohydrate intake throughout the observation period. Rs16147 TT-homozygotes and both rs16139 and rs17149106 heterozygotes had higher triglyceride levels. All NPY SNP-s were associated with blood pressure: rs5574 TT-and rs16147 CC-homozygotes had a smaller increase in diastolic blood pressure, while rs16139 and rs17149106 heterozygous had lower blood pressure throughout the study. CONCLUSION: Variants of the NPY gene were associated with measures of obesity, dietary intake, glucose and lipid metabolism and blood pressure from adolescence to young adulthood.

The role of reward sensitivity in obesity and its association with Transcription Factor AP-2B: A longitudinal birth cohort study.

OBJECTIVE: One factor potentially contributing to obesity is reward sensitivity. We investigated the association between reward sensitivity and measures of obesity from 9-33 years of age, paying attention to the inner structure of reward sensitivity. METHODS: The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between reward sensitivity and measures of obesity was assessed using mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, 25 and 33 (older cohort) years were analyzed by one-way ANOVA. The indirect effect of the gene encoding transcription factor 2 beta (TFAP2B) on obesity through reward sensitivity was tested using mediation analysis. RESULTS: According to linear mixed effects regression models, an increase in scores of Insatiability by Reward and both of its components, Excessive Spending and Giving in to Cravings, significantly increased body weight, body mass index, sum of five skinfolds, waist circumference, hip circumference and waist-to-height ratio from 15 to 25 years of age. Findings were similar at age 9 and 33 years. In contrast, no association between obesity and Openness to Rewards or its facets was observed. The TFAP2B genotype was also associated with fixation to rewards in females, but not with striving towards reward multiplicity. CONCLUSION: Our results suggest that reward sensitivity is associated with obesity by its reward fixation component. The heterogeneity of the reward sensitivity construct should be taken into account in studies on body composition.