Perspectives in weight control in diabetes - SGLT2 inhibitors and GLP-1-glucagon dual agonism.

Treatment of people with type 2 diabetes mellitus (T2D) and obesity should include glycemic control and sustained weight loss. However, organ protection and/or risk reduction for co-morbidities have also emerged as important goals. Here, we define this combined treatment approach as 'weight loss plus' and describe it as a metabolic concept where prolonged periods of energy consumption is central to outcomes. We suggest there are currently two drug classes - sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1)-glucagon dual agonists - that can facilitate this 'weight loss plus' approach. We describe evidence supporting that both classes address the underlying pathophysiology of T2D and facilitate normalization of metabolism through increased periods with a catabolic type of energy consumption, which effect other organ systems and may facilitate long-term cardio-renal benefits. These benefits have been demonstrated in trials of SGLT2is, and appear, to some degree, to be independent of glycemia and substantial weight loss. The combined effect of caloric restriction and metabolic correction facilitated by SGLT2i and GLP-1-glucagon dual agonists can be conceptualized as mimicking dietary restriction and physical activity, a phenomenon not previously observed with drugs whose benefits predominantly arise from absolute weight loss, and which may be key to achieving a 'weight loss plus' approach to treatment.

Joint longitudinal and time-to-event modelling compared with standard Cox modelling in patients with type 2 diabetes with and without established cardiovascular disease: An analysis of the EXSCEL trial.

AIM: To demonstrate the gain in predictive performance when cardiovascular disease (CVD) risk prediction tools (RPTs) incorporate repeated rather than only single measurements of risk factors. MATERIALS AND METHODS: We used data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to compare the quality of predictions of future major adverse cardiovascular events (MACE) with the Cox proportional hazards model (using single values of risk factors) compared to the Bayesian joint model (using repeated measures of risk factors). The risk of MACE was calculated in patients with type 2 diabetes with and without established CVD. We assessed the predictive ability of the following cardiovascular risk factors: glycated haemoglobin, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, estimated glomerular filtration rate, low-density lipoprotein cholesterol (LDL-C), total cholesterol, and systolic blood pressure (SBP) using the time-dependent area under the receiver-operating characteristic curve (aROC) for discrimination and the time-dependent Brier score for calibration. RESULTS: In participants without history of CVD, the aROC of SBP increased from 0.62 to 0.69 when repeated rather than only single measurements of SBP were incorporated into the predictive model. Similarly, the aROC increased from 0.67 to 0.80 when repeated rather than only single measurements of both SBP and LDL-C were incorporated into the predictive model. For all other investigated cardiovascular risk factors, the measures of discrimination and calibration both improved when using the joint model as compared to the Cox proportional hazards model. The improvement was evident in participants with and without history of CVD but was more pronounced in the latter group. CONCLUSIONS: The analysis demonstrates that the joint modelling approach, considering trajectories of cardiovascular risk factors, provides superior predictive performance compared to standard RPTs that use only a single timepoint.

Dapagliflozin or Saxagliptin in Pediatric Type 2 Diabetes.

BACKGROUND: Incidence of type 2 diabetes (T2D) in children and adolescents is increasing, but treatment options are limited. METHODS: This was a 26-week, phase 3 trial with a 26-week extension among patients (10 to 17 years of age) with uncontrolled T2D (A1C 6.5 to 10.5%) receiving metformin, insulin, or both. Participants were randomly assigned 1:1:1 to 5 mg of dapagliflozin (N=81), 2.5 mg of saxagliptin (N=88), or placebo (N=76). Patients in active treatment groups with A1C ≥7% at week 12 were further randomly assigned 1:1 at week 14 to continue the dose or up-titrate to a higher dose (10 mg of dapagliflozin or 5 mg of saxagliptin). The primary end point was change in A1C at week 26. Safety was assessed over 52 weeks. RESULTS: At week 26, the difference versus placebo in adjusted mean change in A1C was −1.03 percentage points (95% confidence interval [CI], −1.57 to −0.49; P<0.001) for dapagliflozin and −0.44 percentage points (95% CI, −0.93 to 0.05; P=0.078) for saxagliptin. Adverse events (AEs) and serious AEs occurred in 72.8% and 8.6% of patients receiving dapagliflozin, 69.3% and 8.0% of patients receiving saxagliptin, and 71.1% and 6.6% of patients receiving placebo. Severe hypoglycemia occurred in 4.9%, 4.5%, and 7.9% of patients in each group, respectively. Over 52 weeks, the most common AE was headache (dapagliflozin 14.8%; placebo 5.3%). Most events were mild and none was considered serious or resulted in discontinuation. CONCLUSIONS: Dapagliflozin, but not saxagliptin, showed significant improvement in A1C compared with placebo. Nonserious headaches were more common in participants treated with dapagliflozin than in those receiving placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03199053.)

Long-term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104-week extension to a 52-week randomized, phase 3 study and liver fat MRI substudy.

AIM: To report the results of a 104-week extension to a 52-week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin. MATERIALS AND METHODS: This extension to a 52-week global, multicentre, parallel-group, active-controlled, double-blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1-6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5-91.3 mmol/mol [7.5%-10.5%]), and a body mass index of 20.0 to 45.0 kg/m2 , and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy. RESULTS: Overall, 382 participants entered and 338 completed the 104-week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156-week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39-0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23-3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least-squares mean difference from GLIM+MET -4.89%, -0.41 L and -0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents. CONCLUSIONS: Overall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D.

Predicting major adverse limb events in individuals with type 2 diabetes: Insights from the EXSCEL trial.

AIMS: Although models exist to predict amputation among people with type 2 diabetes with foot ulceration or infection, we aimed to develop a prediction model for a broader range of major adverse limb events (MALE)-including gangrene, revascularization and amputation-among individuals with type 2 diabetes. METHODS: In a post-hoc analysis of data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, we compared participants who experienced MALE with those who did not. A multivariable model was constructed and translated into a risk score. RESULTS: Among the 14,752 participants with type 2 diabetes in EXSCEL, 3.6% experienced MALE. Characteristics associated with increased risk of MALE were peripheral artery disease (PAD) (HRadj 4.83, 95% CI: 3.94-5.92), prior foot ulcer (HRadj 2.16, 95% CI: 1.63-2.87), prior amputation (HRadj 2.00, 95% CI: 1.53-2.64), current smoking (HRadj 2.00, 95% CI: 1.54-2.61), insulin use (HRadj 1.86, 95% CI: 1.52-2.27), coronary artery disease (HRadj 1.67, 95% CI: 1.38-2.03) and male sex (HRadj 1.64, 95% CI: 1.31-2.06). Cerebrovascular disease, former smoking, age, glycated haemoglobin, race and neuropathy were also associated significantly with MALE after adjustment. A risk score ranging from 6 to 96 points was constructed, with a C-statistic of 0.822 (95% CI: 0.803-0.841). CONCLUSIONS: The majority of MALE occurred among participants with PAD, but participants without a history of PAD also experienced MALE. A risk score with good performance was generated. Although it requires validation in an external dataset, this risk score may be valuable in identifying patients requiring more intensive care and closer follow-up.

Long-term (52-week) efficacy and safety of dapagliflozin as an adjunct to insulin therapy in Japanese patients with type 1 diabetes: Subgroup analysis of the DEPICT-2 study.

AIM: To examine the long-term efficacy and safety of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor used to treat type 1 diabetes, in the Japanese subpopulation of the DEPICT-2 study. MATERIALS AND METHODS: Patients with type 1 diabetes were randomized to dapagliflozin 5 mg (n = 55), dapagliflozin 10 mg (n = 41) or placebo (n = 58) plus insulin for a 24-week, double-blind period followed by a 28-week, single-blind extension phase. RESULTS: From baseline to 24 weeks, dapagliflozin reduced HbA1c compared with placebo (mean change of -0.58% and -0.80% for 5 and 10 mg, respectively), and an HbA1c reduction was observed up to 52 weeks. Compared with placebo, dapagliflozin 5 and 10 mg increased the proportion of patients achieving HbA1c reductions of 0.5% or more without severe hypoglycaemia events and reduced glycaemic variability assessed via continuous glucose monitoring. Both dapagliflozin doses decreased body weight and total daily insulin dose at 24 weeks compared with placebo; these reductions were maintained up to 52 weeks. Diabetic ketoacidosis occurred in both dapagliflozin groups (one and two cases, respectively) but not with placebo. CONCLUSIONS: Efficacy and safety results from the Japanese subpopulation of the DEPICT-2 study were generally consistent with those from the overall population, indicating that long-term dapagliflozin adjunct to insulin therapy improves glycaemic control without an increased risk of hypoglycaemia but with a risk of diabetic ketoacidosis in Japanese patients with type 1 diabetes.

Measuring Software Maintainability with Naïve Bayes Classifier.

Software products in the market are changing due to changes in business processes, technology, or new requirements from the customers. Maintainability of legacy systems has always been an inspiring task for the software companies. In order to determine whether the software requires maintainability by reverse engineering or by forward engineering approach, a system assessment was done from diverse perspectives: quality, business value, type of errors, etc. In this research, the changes required in the existing software components of the legacy system were identified using a supervised learning approach. New interfaces for the software components were redesigned according to the new requirements and/or type of errors. Software maintainability was measured by applying a machine learning technique, i.e., Naïve Bayes classifier. The dataset was designed based on the observations such as component state, successful or error type in the component, line of code of error that exists in the component, component business value, and changes required for the component or not. The results generated by the Waikato Environment for Knowledge Analysis (WEKA) software confirm the effectiveness of the introduced methodology with an accuracy of 97.18%.

Melioidosis: distinctive clinico-epidemiological characteristics in southern India.

As it is increasingly being reported from India, we carried out a prospective study of patients with culture-proven melioidosis from south India, examining clinical, laboratory features, epidemiological data, risk factors, treatments, outcomes at three and six months, and factors associated with mortality.Between 2014 and 2018, 31 cases were identified. Diabetes (83.9%) and alcohol abuse (58.1%) were common risk factors. Musculoskeletal, skin and soft tissue manifestations together constituted 48.4% of presentations, while 29% had pneumonia. During the intensive phase, 74.2% received one of three recommended antibiotic regimes, but 51.6% did not receive continuation treatment. Pneumonia and lack of continuation treatment were independently associated with a high mortality of 25.8%. Hot spots for melioidosis exist in India, and there is considerable diversity of presentation, including skin, soft tissue, musculoskeletal and neurological involvement. High rates of bacteraemia are shown.

Simulated Randomized Controlled Trial to Learn Critical Appraisal (SiRCA): A Randomized Controlled Study of Effectiveness Among Undergraduate Medical Students.

INTRODUCTION: The ideal method to teach evidence-based medicine (EBM) to medical students is unclear. We determined the effectiveness of a simulated randomized controlled trial (RCT) in improving critical appraisal and EBM skills among medical students compared to traditional training. METHODS: One hundred and eighteen medical students were randomized into two groups. Sixty-one students (immersion arm) were trained in critical appraisal using a simulated RCT aimed at determining efficacy of a "brainy pill" on ability to crack puzzles. Fifty-seven students (traditional group) were trained using a journal club with a checklist. Primary outcome of change in knowledge and skills of critical appraisal and EBM was determined by comparing scores on pre- and post-intervention Fresno tests. RESULTS: Mean age of students was 21.76 (SD - 0.78) years. Seventy (59.3%) were females and 48 (40.7%) males. Mean pre-test scores of traditional and immersion groups were 8.0 (SD - 4.88) and 9.31 (SD - 5.49) respectively and post-test scores were 50.2 (SD - 16.2) and 68.12 (SD - 14.72) respectively (post-intervention mean difference - 17.92; 95% CI 12.26 - 23.57; p<0.0000001). Odds of achieving 65% or more in post-intervention Fresno test score was significantly higher in immersion group (29.8% vs 8.2%; OR 4.76; 95% CI 1.62-13.97; p = 0.001). Perceived competence regarding EBM skills improved significantly in immersion group. CONCLUSIONS: Simulated RCT is effective in imparting critical appraisal and EBM practice skills to medical students. Trainers should consider integrating and reinforcing this approach in EBM curriculum to make learning contextual and immersive.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies.

AIM: To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. RESULTS: Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. CONCLUSIONS: Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies.

Further improvement in glycemic control after switching from exenatide two times per day to exenatide once-weekly autoinjected suspension in patients with type 2 diabetes: 52-week results from the DURATION-NEO-1 study.

INTRODUCTION: Investigate the effects of switching from two times per day exenatide to once-weekly exenatide administered by autoinjector (exenatide once-weekly suspension by autoinjector (QWS-AI)) or treatment with exenatide QWS-AI for 1 year. RESEARCH DESIGN AND METHODS: In this phase III open-label study, adults with type 2 diabetes were randomized to receive exenatide QWS-AI (2 mg) or exenatide two times per day (5 mcg for 4 weeks, followed by 10 mcg) for 28 weeks. During a subsequent non-randomized 24-week extension, patients who received exenatide two times per day were switched to exenatide QWS-AI and those randomized to exenatide QWS-AI continued this treatment. Efficacy measures included changes from baseline in glycated hemoglobin (A1C), fasting plasma glucose (FPG), and body weight. RESULTS: In total, 315 patients (mean baseline A1C of 8.5%) completed the initial 28 weeks of randomized treatment with exenatide QWS-AI (n=197) or exenatide two times per day (n=118) and were included in the 24-week extension (mean A1C of 7.0% and 7.3%, respectively, at week 28). From weeks 28-52, patients who switched from exenatide two times per day to exenatide QWS-AI had additional A1C reductions of approximately 0.5% (mean A1C change from baseline of -1.4% at week 52) and further reductions from baseline in FPG. Patients who continued exenatide QWS-AI treatment for 52 weeks showed clinically relevant A1C reductions (mean A1C change from baseline of -1.3% at week 52). Body-weight reductions achieved through week 28 were sustained at week 52 in both groups. There were no unexpected safety concerns or changes in the safety profile among patients who switched from exenatide two times per day to exenatide QWS-AI or those who continued exenatide QWS-AI treatment for 52 weeks. CONCLUSIONS: Switching from exenatide two times per day to exenatide QWS-AI resulted in further A1C reductions and maintenance of earlier decreases in body weight, while continued therapy with exenatide QWS-AI for 52 weeks maintained A1C and body-weight reductions, without additional safety or tolerability concerns. TRIAL REGISTRATION NUMBER: NCT01652716.

Effect of dapagliflozin as an adjunct to insulin over 52 weeks in individuals with type 1 diabetes: post-hoc renal analysis of the DEPICT randomised controlled trials.

BACKGROUND: The DEPICT-1 and DEPICT-2 studies showed that dapagliflozin as an adjunct to insulin in individuals with inadequately controlled type 1 diabetes improved glycaemic control and bodyweight, without increase in risk of hypoglycaemia. We aimed to determine the effect of dapagliflozin on urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) using pooled data from the DEPICT studies. METHODS: In this post-hoc analysis, we used data pooled from both DEPICT studies (DEPICT-1 ran from Nov 11, 2014, to Aug 25, 2017; DEPICT-2 ran from July 8, 2015, to April 18, 2018), in which participants were aged 18-75 years, with inadequately controlled type 1 diabetes and with a baseline UACR of at least 30 mg/g. In the DEPICT studies, participants were randomly assigned (1:1:1) to receive dapagliflozin (5 mg or 10 mg) or placebo all plus insulin, for 24 weeks, with a 28-week long-term extension (ie, 52 weeks in total). In this post-hoc analysis, we assessed the percentage change from baseline in UACR and in eGFR, up to 52 weeks. UACR, eGFR, and safety were assessed in all eligible participants who had received at least one dose of study drug. HbA1c, bodyweight, and systolic blood pressure were assessed in all participants who received at least one dose of study drug during the first 24-week period, and who had a baseline and any post-baseline assessment for that parameter. The DEPICT trials were registered with ClinicalTrials.gov, NCT02268214 (DEPICT-1), NCT02460978 (DEPICT-2), and are now complete. RESULTS: 251 participants with albuminuria at baseline were included in this post-hoc analysis; of whom 80 (32%) had been randomly assigned to dapagliflozin 5 mg, 84 (33%) to dapagliflozin 10 mg, and 87 (35%) to placebo. Compared with placebo, treatment with both dapagliflozin doses improved UACR over 52 weeks. At week 52, mean difference in change from baseline versus placebo in UACR was -13·3% (95% CI -37·2 to 19·8) for dapagliflozin 5 mg and -31·1% (-49·9 to -5·2) for dapagliflozin 10 mg. No notable change from baseline was seen in eGFR, with a mean difference in change from baseline versus placebo of 3·27 mL/min per 1·73 m2 (95% CI -0·92 to 7·45) for dapagliflozin 5 mg and 2·12 mL/min per 1·73 m2 (-2·03 to 6·27) for dapagliflozin 10 mg. Similar proportions of participants in each treatment group had adverse events and serious adverse events, including hypoglycaemia and diabetic ketoacidosis; no new safety signals were identified in this population. INTERPRETATION: Treatment with dapagliflozin resulted in UACR reduction, which might provide renoprotective benefits in individuals with type 1 diabetes and albuminuria. Dedicated prospective studies are needed to confirm these findings as prespecified endpoints. FUNDING: AstraZeneca.

Benefit/risk profile of dapagliflozin 5 mg in the DEPICT-1 and -2 trials in individuals with type 1 diabetes and body mass index ≥27 kg/m2.

AIM: The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes who were receiving intensive insulin therapy. The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes. This post-hoc study investigated the safety and efficacy of dapagliflozin in individuals with BMI ≥27 kg/m2 to assess if the benefit/risk ratio associated with dapagliflozin treatment can be further improved than that observed in the overall DEPICT population. METHODS: Changes in glycated haemoglobin (HbA1c) and body weight, percentage change in daily insulin dose and proportion of participants achieving HbA1c reduction ≥0.5% without severe hypoglycaemia were evaluated at weeks 24 and 52. Changes in mean interstitial glucose, mean amplitude of glycaemic excursions and time in target glycaemic range were evaluated at week 24. Safety was assessed until week 56. RESULTS: Week-52 adjusted mean (SE) change from baseline for HbA1c was -0.26% (0.05) with dapagliflozin versus +0.08% (0.05) with placebo and for body weight was -2.74 kg (0.25) with dapagliflozin versus +0.81 kg (0.26) with placebo. Mean (SE) percentage change in daily insulin dose was -10.5% (1.23) with dapagliflozin versus -1.4% (1.36) with placebo. Time spent in target glycaemic range increased by 2.2 h/day versus placebo. Dapagliflozin was well tolerated, with fewer participants experiencing diabetic ketoacidosis (dapagliflozin, 1.7%; placebo, 1.0%) than dapagliflozin 5 mg receiving participants in the pooled DEPICT populations. CONCLUSIONS: Compared with the pooled DEPICT population, the benefit/risk profile of adjunct dapagliflozin therapy was more favourable in individuals with type 1 diabetes with body mass index ≥27 kg/m2 because of the reduced risk of diabetic ketoacidosis in this population.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial.

AIM: To investigate the long-term efficacy and safety of dapagliflozin as an adjunct to adjustable insulin in adults with type 1 diabetes (T1D) and inadequate glycaemic control. MATERIALS AND METHODS: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-2) was a placebo-controlled, double-blind, multicentre, phase III study of adults with T1D (HbA1c 7.5%-10.5%) randomized (1:1:1) to receive dapagliflozin 5, 10 mg, or placebo. The efficacy and safety of dapagliflozin over 52 weeks were exploratory endpoints in this extension to DEPICT-2. RESULTS: Of 813 participants randomized, 88.2% completed the study. From baseline to 52 weeks, dapagliflozin 5 and 10 mg were associated with reduction in HbA1c (difference [95% CI] vs. placebo: -0.20% [-0.34, -0.06] and -0.25% [-0.38, -0.11], respectively) and adjusted mean percentage change in body weight (difference [95% CI] vs. placebo: -4.42% [-5.19, -3.64] and -4.86% [-5.63, -4.08], respectively). Serious adverse events were reported in the dapagliflozin 5, 10 mg, and placebo groups (32 [11.8%], 19 [7.0%] and 16 [5.9%], respectively). The proportion of hypoglycaemic events was similar across groups; severe hypoglycaemia was uncommon. More participants with events adjudicated as definite diabetic ketoacidosis (DKA) were in the dapagliflozin 5 and 10 mg groups versus placebo (11 [4.1%], 10 [3.7%] and 1 [0.4%], respectively); the majority of events were mild or moderate in severity and all were resolved with treatment. CONCLUSIONS: Dapagliflozin led to long-term reductions in HbA1c and body weight in adults with T1D, but increased DKA risk compared with placebo.

The prognostic and predictive role of 21-gene recurrence scores in hormone receptor-positive early-stage breast cancer.

Over the past two decades, gene expression profiling of breast cancer has emerged as an important tool in early-stage breast cancer management. The approach provides important information on underlying biological mechanisms, breast cancer classification, future risk potential of developing recurrent metastatic disease, and provides beneficial clues for adjuvant chemotherapy in hormone receptor (HR) positive breast cancer. Of the commercially available genomic tests for breast cancer, the prognostic and predictive value of 21-gene recurrence score tests have been validated using both retrospective data and prospective clinical trials. In this paper, we reviewed the current evidence on 21-gene expression profiles for HR-positive HER2-negative early-stage breast cancer management. We show that current evidence supports endocrine therapy alone as an appropriate adjuvant systemic therapy for approximately 70% of women with HR-positive, HER2-negative, node-negative breast cancer. Evolving evidence also suggests that 21-gene recurrence scores have predictive values for node-positive breast cancer and that chemotherapy can be avoided in more than half of women with nodes 1 to 3 positive HR-positive breast cancer. Furthermore, retrospective data also supports the predictive role of 21-gene recurrence scores for adjuvant radiation therapy. A prospective trial in this area is ongoing.

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.

BACKGROUND: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. METHODS: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. RESULTS: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. CONCLUSIONS: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.

Microvascular and Cardiovascular Outcomes According to Renal Function in Patients Treated With Once-Weekly Exenatide: Insights From the EXSCEL Trial.

OBJECTIVE: To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS: Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS: EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI -0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70-1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74-0.98]). Retinopathy rates did not differ by treatment group or in the HbA1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m2 did not differ by group. Those with eGFR ≥60 mL/min/1.73 m2 had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58-0.93]; P for interaction = 0.035) and CV death (HR 1.08 [95% CI 0.85-1.38]; P for interaction = 0.031). CONCLUSIONS: EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m2 in analyses unadjusted for multiplicity.

Clinical Outcomes in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: Results From the EXSCEL Trial.

BACKGROUND: Recent trials have identified anti-diabetes mellitus agents that lower major adverse cardiovascular event (MACE) rates, although some increase rates of lower-extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of diabetes mellitus and risk for LEA, prompting this investigation of clinical outcomes in patients with diabetes mellitus and PAD in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering). METHODS: EXSCEL evaluated the effects of once-weekly exenatide (a GLP-1 [glucagon-like peptide-1] receptor agonist) versus placebo on the rates of the primary composite MACE end point (cardiovascular death, myocardial infarction, or stroke) among patients with type 2 diabetes mellitus. In this post hoc analysis, we assessed the association of baseline PAD with rates of MACE, LEA, and the effects of exenatide versus placebo in patients with and without PAD. RESULTS: EXSCEL included 2800 patients with PAD (19% of the trial population). These individuals had higher unadjusted and adjusted rates of MACE compared with patients without PAD (13.6% versus 11.4%, respectively) as well as a higher adjusted hazard ratio (adjusted hazard ratio, 1.13 [95% CI, 1.00-1.27]; P=0.047). Patients with PAD had higher all-cause mortality (adjusted hazard ratio 1.38 [95% CI, 1.20-1.60]; P<0.001) and more frequent LEA (adjusted hazard ratio 5.48 [95% CI, 4.16-7.22]; P<0.001). Patients treated with exenatide or placebo had similar rates of MACE and LEA, regardless of PAD status. CONCLUSIONS: EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates with exenatide versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Effect of Once-Weekly Exenatide in Patients With Type 2 Diabetes Mellitus With and Without Heart Failure and Heart Failure-Related Outcomes: Insights From the EXSCEL Trial.

BACKGROUND: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW's effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. METHODS: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. RESULTS: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77-0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80-0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85-1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68-0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71-0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89-1.29]; interaction P=0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68-0.99]; P=0.038). CONCLUSIONS: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Simulation-Based Training in Measurement of Blood Pressure: A Randomized Study of Impact in Real-Life Settings.

INTRODUCTION: Simulators are used for training competencies including blood pressure (BP) measurement. Whether such training translates to competency in real life is unclear. METHODS: We randomized 145 first-year undergraduate medical students to train on a BP simulator or arms of colleagues. After training, all students were assessed for accuracy (within 4 mm Hg above or below assessor's simultaneous recording) and methodology of BP recordings by an objectively structured clinical examination on real patients. RESULTS: Overall, 67 (46.2%) and 92 (63.4%) students accurately measured systolic and diastolic BP, respectively. Forty-three (58.1%) of 74 students in the conventional training recorded systolic BP accurately compared with 24 (33.8%) of 71 students in simulator training (P = 0.005). Diastolic BP was accurately recorded by 56 (75.7%) of 74 students in conventional group as against 36 (50.7%) of 71 students trained on simulator (P = 0.002). Median (interquartile range) objectively structured clinical examination score in conventional group was 8 (7-9) compared with 6 (5-7) in simulator group (P < 0.001). CONCLUSIONS: Simulator-based training did not translate to clinical competence in terms of accuracy and methodology of BP recordings in real-life settings. Notwithstanding its advantages, simulator-based BP training needs integration with human element to make it meaningful and relevant to clinical practice.