The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial.

AIM: To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population-specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial. METHODS: Individual participant data were pooled and analysed in subgroups according to population-specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed-effect models were used. RESULTS: A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (Pheterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95). CONCLUSIONS: The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population-specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial.

Maternal and neonatal outcomes of women with gestational diabetes and without specific medical conditions: an Australian population-based study comparing induction of labor with expectant management.

BACKGROUND/AIMS: To evaluate maternal birth and neonatal outcomes among women with gestational diabetes mellitus (GDM), but without specific medical conditions and eligible for vaginal birth who underwent induction of labour (IOL) at term compared with those who were expectantly managed. MATERIALS AND METHODS: Population-based cohort study of women with GDM, but without medical conditions, who had a singleton, cephalic birth at 38-41 completed weeks gestation, in New South Wales, Australia between January 2010 and December 2016. Women who underwent IOL at 38, 39, 40 weeks gestation (38-, 39-, 40-induction groups) were compared with those who were managed expectantly and gave birth at and/or beyond the respective gestational age group (38-, 39-, 40-expectant groups). Multivariable logistic regression analysis was used to assess the association between IOL and adverse maternal birth and neonatal outcomes taking into account potential confounding by maternal age, country of birth, smoking, residential location, residential area of socioeconomic disadvantage and birth year. RESULTS: Of 676 762 women who gave birth during the study period, 66 606 (10%) had GDM; of these, 34799 met the inclusion criteria. Compared with expectant management, those in 38- (adjusted odds ratio (aOR) 1.11; 95% CI, 1.04-1.18), 39- (aOR 1.21; 95% CI, 1.14-1.28) and 40- (aOR 1.50; 95% CI, 1.40-1.60) induction groups had increased risk of caesarean section. Women in the 38-induction group also had an increased risk of composite neonatal morbidity (aOR 1.10; 95% CI, 1.01-1.21), which was not observed at 39- and 40-induction groups. We found no difference between groups in perinatal death or neonatal intensive care unit admission for births at any gestational age. CONCLUSION: In women with GDM but without specific medical conditions and eligible for vaginal birth, IOL at 38, 39, 40 weeks gestation is associated with an increased risk of caesarean section.

Comparison of a subcutaneous versus intravenous insulin protocol for managing hyperglycemia following antenatal betamethasone in women with diabetes: a pilot randomized controlled trial.

INTRODUCTION: Evaluate the safety and efficacy of a subcutaneous insulin (SC-I) versus intravenous insulin (IV-I) protocol for optimizing maternal blood glucose levels (BGLs) post-betamethasone administration. METHODS: Randomized controlled in-patient pilot study in pregnant women with diabetes, excluding type 1 diabetes, receiving betamethasone ≥24 weeks' gestation. Interventions were stratified SC-I and IV-I protocols, titrated to hourly BGLs (IV-I) or predicted maternal hyperglycemia and 2-4 hourly BGLs (SC-I). Primary outcome was percentage at-target BGL 4.0-8.0 mmol/L over 48 h post-betamethasone. Secondary outcomes were rates of maternal hyperglycemia (>8.0 mmol/L), hypoglycemia (<4.0 mmol/L) and neonatal hypoglycemia (≤2.5 mmol/L). RESULTS: 19 women (3 with type 2 diabetes [T2DM], 4 with gestational diabetes [GDM]-diet, 12 GDM-insulin) were randomized to a SC-I (n = 13) or IV-I (n = 6) protocol in a 9-month period. There was a non-significant trend for higher mean percentage at-target BGLs with SC-I vs IV-I (87% vs 81%; p = .055); this was significant when the cohort was restricted to women with GDM (89% vs 81%; p = .04). Maternal hyperglycemia (85% vs 100%; p = .31) and hypoglycemia (54% vs 33%; p = .41) were not significantly different, but there were no BGLs <3.8 mmol/L with IV-I (vs 4 women with SC-I; p = .13). The rate of neonatal hypoglycemia was not different between groups. CONCLUSION: A SC-I or IV-I protocol controls maternal BGLs following betamethasone, but SC-I appears safe and minimizes labor intensive IV-I in GDM. An adequately powered RCT to assess superiority of SC-I is planned.

A Novel Early Pregnancy Risk Prediction Model for Gestational Diabetes Mellitus.

INTRODUCTION: Accurate early risk prediction for gestational diabetes mellitus (GDM) would target intervention and prevention in women at the highest risk. We evaluated novel biomarker predictors to develop a first-trimester risk prediction model in a large multiethnic cohort. METHODS: Maternal clinical, aneuploidy and pre-eclampsia screening markers (PAPP-A, free hCGß, mean arterial pressure, uterine artery pulsatility index) were measured prospectively at 11-13+6 weeks' gestation in 980 women (248 with GDM; 732 controls). Nonfasting glucose, lipids, adiponectin, leptin, lipocalin-2, and plasminogen activator inhibitor-2 were measured on banked serum. The relationship between marker multiples-of-the-median and GDM was examined with multivariate regression. Model predictive performance for early (< 24 weeks' gestation) and overall GDM diagnosis was evaluated by receiver operating characteristic curves. RESULTS: Glucose, triglycerides, leptin, and lipocalin-2 were higher, while adiponectin was lower, in GDM (p < 0.05). Lipocalin-2 performed best in Caucasians, and triglycerides in South Asians with GDM. Family history of diabetes, previous GDM, South/East Asian ethnicity, parity, BMI, PAPP-A, triglycerides, and lipocalin-2 were significant independent GDM predictors (all p < 0.01), achieving an area under the curve of 0.91 (95% confidence interval [CI] 0.89-0.94) overall, and 0.93 (95% CI 0.89-0.96) for early GDM, in a combined multivariate prediction model. CONCLUSIONS: A first-trimester risk prediction model, which incorporates novel maternal lipid markers, accurately identifies women at high risk of GDM, including early GDM.

Recruitment Strategies for a Randomised Controlled Trial Comparing Fast Versus Slow Weight Loss in Postmenopausal Women with Obesity-The TEMPO Diet Trial.

Current research around effective recruitment strategies for clinical trials of dietary obesity treatments have largely focused on younger adults, and thus may not be applicable to older populations. The TEMPO Diet Trial (Type of Energy Manipulation for Promoting optimal metabolic health and body composition in Obesity) is a randomised controlled trial comparing the long-term effects of fast versus slow weight loss on body composition and cardio-metabolic health in postmenopausal women with obesity. This paper addresses the recruitment strategies used to enrol participants into this trial and evaluates their relative effectiveness. 101 post-menopausal women aged 45⁻65 years, with a body mass index of 30⁻40 kg/m² were recruited and randomised to either fast or slow weight loss. Multiple strategies were used to recruit participants. The total time cost (labour) and monetary cost per randomised participant from each recruitment strategy was estimated, with lower values indicating greater cost-effectiveness and higher values indicating poorer cost-effectiveness. The most cost-effective recruitment strategy was word of mouth, followed (at equal second place) by free publicity on TV and radio, and printed advertorials, albeit these avenues only yielded 26/101 participants. Intermediate cost-effective recruitment strategies were flyer distribution at community events, hospitals and a local tertiary education campus, internet-based strategies, and clinical trial databases and intranets, which recruited a further 40/101 participants. The least cost-effective recruitment strategy was flyer distribution to local health service centres and residential mailboxes, and referrals from healthcare professionals were not effective. Recruiting for clinical trials involving postmenopausal women could benefit from a combination of recruitment strategies, with an emphasis on word of mouth and free publicity via radio, TV, and print media, as well as strategic placement of flyers, supplemented with internet-based strategies, databases and intranets if a greater yield of participants is needed.

Changing environment of hyperglycemia in pregnancy: Gestational diabetes and diabetes mellitus in pregnancy.

The diagnosis and treatment of gestational diabetes mellitus (GDM) have been in a state of flux since the World Health Organization accepted and endorsed the International Diabetes and Pregnancy Study Group's diagnostic pathway and criteria in 2013. These new diagnostic criteria identify an increasing number of women at risk of hyperglycemia in pregnancy (HGiP). Maternal hyperglycemia represents a significant risk to the mother and fetus, in both the short and long term. Controversially, metformin use for the treatment of GDM is increasing in Australia. This article identifies the multiple and varied presentations of HGiP, of which GDM is the most commonly encountered. The degree of maternal hyperglycemia experienced affects the outcomes for both the mother and neonate, and specific diagnosis determines the appropriate treatment for the pregnancy. Given the increasing incidence of women with dysglycemia and those developing HGiP, this is an important area for research and clinical attention for all health professionals.

A first trimester prediction model for gestational diabetes utilizing aneuploidy and pre-eclampsia screening markers.

OBJECTIVE: We examined whether first trimester aneuploidy and pre-eclampsia screening markers predict gestational diabetes mellitus (GDM) in a large multi-ethnic cohort and the influence of local population characteristics on markers. METHODS: Clinical and first trimester markers (mean arterial pressure (MAP), uterine artery pulsatility index (UtA PI), pregnancy associated plasma protein A (PAPP-A), free-ß human chorionic gonadotropin (free-hCGß)) were measured in a case-control study of 980 women (248 with GDM, 732 controls) at 11 to 13 + 6 weeks' gestation. Clinical parameters, MAP-, UtA PI-, PAPP-A-, and free-hCGß-multiples-of-the-median (MoM) were compared between GDM and controls; stratified by ethnicity, parity, and GDM diagnosis <24 versus ≥24 weeks' gestation. GDM model screening performance was evaluated using AUROC. RESULTS: PAPP-A- and UtA PI-MoM were significantly lower in GDM versus controls (median ((IQR) PAPP-A-MoM 0.81 (0.58-1.20) versus 1.00 (0.70-1.46); UtA PI-MoM 1.01 (0.82-1.21) versus 1.05 (0.84-1.29); p < .05). Previous GDM, family history of diabetes, south/east Asian ethnicity, parity, BMI, MAP, UtA PI, and PAPP-A were significant predictors in multivariate analysis (p < .05). The AUC for a model based on clinical parameters was 0.88 (95%CI 0.85-0.92), increasing to 0.90 (95%CI 0.87-0.92) with first trimester markers combined. The combined model best predicted GDM <24 weeks' gestation (AUC 0.96 (95%CI 0.94-0.98)). CONCLUSIONS: Addition of aneuploidy and pre-eclampsia markers is cost-effective and enhances early GDM detection, accurately identifying early GDM, a high-risk cohort requiring early detection, and intervention. Ethnicity and parity modified marker association with GDM, suggesting differences in pathophysiology and vascular risk.

Approaches to obesity management.

This review will provide an overview of the currently available approaches to obesity management available in Australia, including the various approaches to lifestyle intervention, in addition to evaluating the safety and efficacy of adjuvant therapies, including pharmacotherapy and bariatric surgery.

First trimester prediction of gestational diabetes mellitus: A clinical model based on maternal demographic parameters.

AIM: Develop a first trimester risk prediction model for GDM based on maternal clinical characteristics in a large metropolitan multi-ethnic population and compare its performance to that of other recently published GDM prediction models and clinical risk scoring systems. METHODS: A retrospective case control study of 248 women who developed GDM and 732 controls who did not. Maternal clinical parameters were prospectively obtained at 11-13+6 weeks' gestation. A predictive multivariate regression model for GDM was developed, evaluated using areas under the receiver-operating characteristic (AUC) curve. The performance of this model was then compared with other published GDM prediction models applied to our cohort and our existing clinical risk scoring system. RESULTS: Previous GDM, family history of diabetes, age, south/east Asian ethnicity, parity and body mass index (BMI) were significant predictors for GDM. The AUC of our multivariate regression model was 0.88 (95% Confidence Interval 0.85-0.92). This performed better than other predictive models applied to our cohort (AUCs 0.77-0.82). CONCLUSION: A multivariate model based on weighted maternal clinical risk factors accurately predicts GDM in early pregnancy and performs better than other proposed multivariate and clinical risk scoring models in a multiethnic cohort.

Baseline HbA1c to Identify High-Risk Gestational Diabetes: Utility in Early vs Standard Gestational Diabetes.

Context: The increasing prevalence of gestational diabetes mellitus (GDM) necessitates risk stratification directing limited antenatal resources to those at greatest risk. Recent evidence demonstrates that an early pregnancy glycated hemoglobin (HbA1c ≥5.9% (41 mmol/mol) predicts adverse pregnancy outcomes. Objective: To determine the optimal HbA1c threshold for adverse pregnancy outcomes in GDM in a treated multiethnic cohort and whether this differs in women diagnosed <24 vs ≥24 weeks' gestation (early vs standard GDM). Design and Setting: This was a retrospective cohort study undertaken at the Royal Prince Alfred Hospital Diabetes Antenatal Clinic, Australia, between 1991 and 2011. Patients and Interventions: Pregnant women (N = 3098) underwent an HbA1c (single-laboratory) measurement at the time of GDM diagnosis. Maternal clinical and pregnancy outcome data were collected prospectively. Main Outcome Measure: The association between baseline HbA1c and adverse pregnancy outcomes in early vs standard GDM. Results: HbA1c was measured at a median of 17.6 ± 3.3 weeks' gestation in early GDM (n = 844) and 29.4 ± 2.6 weeks' gestation in standard GDM (n = 2254). In standard GDM, HbA1c >5.9% (41 mmol/mol) was associated with the greatest risk of large-for-gestational-age (odds ratio [95% confidence interval] = 2.7 [1.5-4.9]), macrosomia (3.5 [1.4-8.6]), cesarean section (3.6 [2.1-6.2]), and hypertensive disorders (2.6 [1.1-5.8]). In early GDM, similar HbA1c associations were seen; however, lower HbA1c correlated with the greatest risk of small-for-gestational-age (P trend = 0.004) and prevalence of neonatal hypoglycemia. Conclusions: Baseline HbA1c >5.9% (41 mmol/mol) identifies an increased risk of large-for-gestational-age, macrosomia, cesarean section, and hypertensive disorders in standard GDM. Although similar associations are seen in early GDM, higher HbA1c levels do not adequately capture risk-limiting utility as a triage tool in this cohort.

Gestational Diabetes Mellitus in Early Pregnancy: Evidence for Poor Pregnancy Outcomes Despite Treatment.

OBJECTIVE: Recent guidelines recommend testing at <24 weeks of gestation for maternal dysglycemia in "high-risk" women. Evidence to support the early identification and treatment of gestational diabetes mellitus (GDM) is, however, limited. We examined the prevalence, clinical characteristics, and pregnancy outcomes of high-risk women with GDM diagnosed at <24 weeks of gestation (early GDM) and those with pre-existing diabetes compared with GDM diagnosed at ≥24 weeks of gestation, in a large treated multiethnic cohort. RESEARCH DESIGN AND METHODS: Outcomes from 4,873 women attending a university hospital antenatal diabetes clinic between 1991 and 2011 were examined. All were treated to standardized glycemic targets. Women were stratified as pre-existing diabetes (n = 65) or GDM diagnosed at <12 weeks of gestation (n = 68), at 12-23 weeks of gestation (n = 1,247), or at ≥24 weeks of gestation (n = 3,493). RESULTS: Hypertensive disorders in pregnancy including pre-eclampsia, preterm delivery, cesarean section, and neonatal jaundice (all P < 0.001) were more prevalent in women with pre-existing diabetes and early GDM. Macrosomia (21.8% vs. 20.3%, P = 0.8), large for gestational age (39.6% vs. 32.8%, P = 0.4), and neonatal intensive care admission (38.5% vs. 39.7%, P = 0.9) in women in whom GDM was diagnosed at <12 weeks of gestation were comparable to rates seen in women with pre-existing diabetes. CONCLUSIONS: Despite early testing and current best practice treatment, early GDM in high-risk women remains associated with poorer pregnancy outcomes. Outcomes for those in whom GDM was diagnosed at <12 weeks of gestation approximated those seen in pre-existing diabetes. These findings indicate the need for further studies to establish the efficacy of alternative management approaches to improve outcomes in these high-risk pregnancies.

Pharmacotherapy for the treatment of obesity.

The recognition of the complex counter-regulatory hormonal, metabolic and neurochemical mechanisms that promote weight regain following weight loss and the conceptualisation of obesity as a chronic disease requiring long-term management has led to increasing focus on the role of adjunctive therapies for obesity, particularly pharmacotherapy. Currently available pharmacotherapy achieves a weight loss intermediate between that commonly attained by lifestyle intervention and bariatric surgery, however its accessibility, compared to bariatric surgery increases its appeal. Despite the poor history of obesity pharmacotherapy, novel agents that are in development appear to have several advantages over predecessors. They are generally more selective in their mechanism of action, thereby potentially minimising adverse sequelae and improving the risk-benefit ratio of pharmacotherapy. Another approach has been to use combined pharmacotherapy to better counteract the multiple counter-regulatory neuroendocrine mechanisms which promote weight regain, as well as allowing lower constituent doses of the combined monotherapy agents, which improves the safety and tolerability of these agents that are usually required long-term for chronic weight maintenance. This review will provide an overview of past, present and future pharmacotherapy for obesity. The efficacy and safety profile of currently available pharmacotherapy will be discussed in the setting of stringent regulatory review processes now in place given the fraught history of pharmacological interventions for obesity. Potential novel therapies that seek to better target the multiple complex counter-regulatory mechanisms promoting weight regain while improving the efficacy/safety profile, will also be examined.

Management of obesity and cardiometabolic risk - role of phentermine/extended release topiramate.

The US Food and Drug Administration (FDA) recently approved lorcaserin and the combination of phentermine and extended release topiramate (phentermine/topiramate ER) for the treatment of obesity in conjunction with a lifestyle intervention, expanding the therapeutic options for long-term obesity pharmacotherapy, which was previously limited to orlistat. Combination phentermine/topiramate ER is associated with greater weight loss compared to its constituent monotherapy, with a more favorable adverse effect profile. Phentermine/topiramate ER also appears to have beneficial effects on cardiometabolic risk, although longer-term cardiovascular safety data are required. While there are no head-to-head studies among the currently available obesity pharmacotherapy agents, phentermine/topiramate ER appears to have a superior weight loss profile. This review will discuss the epidemiology, natural history, and cardiometabolic risk associated with obesity, provide an overview on current obesity pharmacotherapy, and summarize the recent clinical efficacy and safety data underpinning the FDA's approval of both phentermine/topiramate ER and lorcaserin as pharmacotherapy for a long-term obesity intervention.