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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

This paper aimed to investigate the effect of rosmarinic acid (RA; 10, 75, 250 µmol/g protein) addition on silver carp myofibrillar protein (MP) oxidation under MetHemoglobin (MetHb) catalyzed doco...

The 2008 ICSH guideline was proposed to bring uniformity in bone marrow reporting among pathologists worldwide. The objective was to study the usefulness of on-site procedural information in routine marrow reporting. The nature of marrow aspirate, gross appearance, and core length of iliac crest trephine biopsies from 174 consecutive subjects (109 males, 65 females, mean age 47.5 ± 19.2 years) were reviewed by a pathologist blinded to the final diagnosis. The nature of aspirate had a significant correlation with a positive diagnostic yield among 149/176 (84.6%) cases (P = 0.03). Among cytopenic subjects, megaloblastic anemias (MA) (N = 27) and aplastic anemias (AA) (N = 14) had richly particulate and greasy/fat rich aspirates, respectively (P

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.

Aims This pooled analysis of the DEPICT-1 and -2 trials aimed 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, 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. This article is protected by copyright. All rights reserved.

Summary 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.

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.

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.

BACKGROUND One of the most common forms of central nervous tuberculosis is tubercular meningitis and has high morbidity and mortality. The natural course of TBM is subacute in nature; hence, the symptoms may persist for weeks before diagnosis. The diagnosis of tuberculosis is based on clinical presentation and cerebrospinal fluid analysis. GeneXpert is a reliable and rapid diagnostic modality for diagnosing pulmonary tuberculosis. Various studies have shown various sensitivity patterns of GeneXpert in TBM. This study aims to find the utility of GeneXpert in TBM. METHODS All adult patients who presented with signs and symptoms of meningitis were included in the study. Detailed history was recorded and physical examination done. All patients were subjected to routine blood investigations, chest X ray, brain imaging along with lumbar puncture for cerebrospinal fluid (CSF) analysis. Apart from routine CSF analysis for cell type, cell count, and biochemical analysis, 3-5 ml of CSF was sent for GeneXpert to intermediate reference laboratory at Government Hospital for Chest Diseases, Pondicherry. On the basis of clinical history, examination, and investigations, composite gold standard for the diagnosis of TBM was defined. The composite gold standard included definite case of TBM, highly probable case of TBM, probable case of TBM and definitely not TBM. Sensitivity and specificity were calculated for GeneXpert for the composite gold standard. RESULTS 100 patients were included in the study. 64 were males and 36 were females. TBM was detected in 22 cases. Mean age for TBM was 42 ± 19.2 years. Among 22 cases of TBM, only one case was categorized as definite TBM, and the rest 21 were either highly probable TBM (7) or probable TBM cases (14). Common clinical signs and symptoms on presentation were headache (87%), fever (78%), neck rigidity (69%), seizure (52%) and altered sensorium (74%). GeneXpert and CSF culture was positive in only one case with sensitivity of 14% and specificity of 100%. Adenosine deaminase (ADA) was high in 13 cases with sensitivity of 60% and specificity of 100%. CONCLUSIONS The utility of GeneXpert in diagnosing tubercular meningitis is very insignificant. Negative GeneXpert in CSF analysis does not rule out TBM as sensitivity is 14% but positive GeneXpert has 100% specificity. In the absence of reliable diagnostic test, clinician should look for specific signs and symptoms of meningitis along with routine CSF analysis and CSF ADA level.

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

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.

OBJECTIVE Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in exenatide-treated and placebo-administered participants and MTC incidence in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring. RESEARCH DESIGN AND METHODS EXSCEL participants were randomized 1:1 to once-weekly exenatide 2 mg or placebo. Serum calcitonin was measured at baseline (with trial medication discontinued if >40 ng/L) and annually thereafter (with trial medication discontinued if ≥50 ng/L). Median calcitonin concentrations were calculated at each time point, and thyroid malignancies were collected prospectively. Data regarding follow-up after an elevated calcitonin were collected retrospectively. RESULTS At baseline, 52 (30 exenatide and 22 placebo) participants had calcitonin >40 ng/L, and during follow-up an additional 23 participants (15 exenatide and 8 placebo) had calcitonin ≥50 ng/L in the intention-to-treat population. Median calcitonin concentrations were similar between treatment groups at baseline with no increase over time. Confirmed MTC occurred in three participants (2 exenatide and 1 placebo), all of whom had significantly elevated baseline calcitonin values (413, 422, and 655 ng/L). CONCLUSIONS During a median 3.2 years’ follow-up, no change in serum calcitonin was seen with exenatide therapy. The three confirmed cases of MTC all occurred in participants with markedly elevated baseline calcitonin levels, measured prior to trial medication administration. Regular calcitonin monitoring identified no additional cases of MTC, suggesting no benefit of routine calcitonin monitoring during exenatide treatment.

Aims To investigate the glycemic efficacy, effects on cardiovascular risk factors, and safety of exenatide once weekly (QW) in patients with type 2 diabetes over 7 years in the DURATION-1 study. Methods Patients were initially randomized to exenatide QW 2 mg or exenatide twice daily for 30 weeks, after which they received open-label, open-ended treatment with exenatide QW 2 mg for up to 7 years. Efficacy analyses included changes from baseline in glycated hemoglobin (HbA1C) and cardiovascular risk factors. Results Of 295 patients in the intention-to-treat population, 122 (41%) completed 7 years of treatment. Patients in the 7-year completer population showed sustained glycemic improvements from baseline (7-year least-squares mean [LSM] change in HbA1C, −1.53%) and significant improvements in several cardiovascular risk factors, including body weight, diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Seven-year completers who received no additional glucose-lowering therapies (n = 65 [53%]) had similar improvements in HbA1C, and numerically greater reductions in body weight (7-year LSM change, −6.46 kg vs −3.87 kg), compared with the overall cohort. There were no unexpected safety findings. Conclusions Treatment with exenatide QW for 7 years was associated with sustained improvements in glycemic control and several cardiovascular risk factors.

Five-year clinico-laboratory data from 99 (one HIV seropositive) adults (mean age = 41.3 ± 20.4 years) who underwent bone marrow examination for fever persisting for ≥ 1 week were analysed and correlated with microbiological characteristics. Infections, reactive marrow changes and haematolymphoid malignancies were most commonly associated with fever. A high concordance rate of 71% was noted between aspiration and trephine biopsies. Bone marrow granulomas (BMG) were seen exclusively on sections and were most commonly of tubercular and typhoidal in origin (two Salmonella Typhi, one Salmonella Paratyphi A). The common aetiologies associated with fever and cytopenia(s) were BMG, acute leukaemia and haemophagocytic lymphohistiocytosis (HLH; n = 3). The yield from bone marrow culture was inferior compared to other body fluids. In conclusion, bone marrow histology is superior to smears in the evaluation of prolonged fever. Marrow culture may not be useful in immunocompetent individuals other than if Salmonellosis is suspected.

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) (HR(adj) 4.83, 95% CI 3.94–5.92), prior foot ulcer (HR(adj) 2.16, 95% CI 1.63–2.87), prior amputation (HR(adj) 2.00, 95% CI 1.53–2.64), current smoking (HR(adj) 2.00, 95% CI 1.54–2.61), insulin use (HR(adj) 1.86, 95% CI 1.52–2.27), coronary artery disease (HR(adj) 1.67, 95% CI 1.38–2.03), and male sex (HR(adj) 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 6-96 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.

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.

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 P 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.

BACKGROUND Metabolic syndrome is an important risk factor for cardiovascular disease and type 2 diabetes mellitus. According to International Diabetes Federation, the risk factor associated with metabolic syndrome are central obesity, hypertension, increased fasting glucose, triglyceride level and decreased HDL. Recent studies also found that hyperuricaemia is also associated with insulin resistance and increased cardiovascular disease related morbidity. A cross-sectional study was conducted at Pondicherry Institute of Medical Sciences with an objective to find the prevalence of hyperuricaemia among patients with metabolic syndrome and also to find the association of risk factor of metabolic syndrome with serum uric acid level. MATERIALS AND METHODS 103 patients (49 males and 54 females) who fulfilled the inclusion criteria were included in the study. Detailed medical history and physical examination including height, weight, BMI, waist circumference and blood pressure were recorded. Five millilitre of fasting blood sample was taken for lipid profile, serum uric acid and fasting blood glucose. Chi-square test was done to find out the association between metabolic syndrome and risk factors of hyperuricaemia with ‘p’ value of 0.05). Exercise had negative influence on uric acid level in both gender, 41% less in males and 14% less in females. Diet also had positive influence on uric acid levels in both male and female. CONCLUSION The prevalence of hyperuricaemia among males is higher than females. The risk factors of metabolic syndrome like obesity, hypertension and increased cholesterol level are associated with hyperuricaemia.

Background EXSCEL is a randomized, double-blind, placebo-controlled trial examining the effect of exenatide once-weekly (EQW) versus placebo on time to the primary composite outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) in patients with type 2 diabetes mellitus (DM) and a wide range of cardiovascular (CV) risk. Methods Patients were enrolled at 688 sites in 35 countries. We describe their baseline characteristics according to prior CV event status and compare patients with those enrolled in prior glucagon-like peptide-1 receptor agonist (GLP-1RA) outcomes trials. Results Of a total of 14,752 participants randomized between June 2010 and September 2015, 6,788 (46.0%) patients were enrolled in Europe; 3,708 (25.1%), North America; 2,727 (18.5%), Latin America; and 1,529 (10.4%), Asia Pacific. Overall, 73% had at least one prior CV event (70% coronary artery disease, 24% peripheral arterial disease, 22% cerebrovascular disease). The median (IQR) age was 63 years (56, 69), 38% were female, median baseline HbA1c was 8.0% (7.3, 8.9) and 16% had a prior history of heart failure. Those without a prior CV event were younger with a shorter duration of diabetes and better renal function than those with at least one prior CV event. Compared with prior GLP-1RA trials, EXSCEL has a larger percentage of patients without a prior CV event and a notable percentage who were taking a dipeptidyl peptidase-4 inhibitor at baseline (15%). Conclusions EXSCEL is one of the largest global GLP-1RA trials, evaluating the safety and efficacy of EQW with a broad patient population that may extend generalizability compared to prior GLP-1RA trials (ClinicalTrials.gov number, NCT01144338).

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose3.0 mmol/l (54 mg/dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event.

OBJECTIVEDipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy.RESEARCH DESIGN AND METHODSWe studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.RESULTSAt baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] 300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was −19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR 6.0 mg/dL, were similar as well.CONCLUSIONSTreatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.

We previously reported that dapagliflozin versus placebo as add-on to saxagliptin plus metformin resulted in greater reductions in glycated haemoglobin (A1C), fasting plasma glucose (FPG) and body weight (BW) after 24 weeks of treatment in patients with type 2 diabetes (T2D). Here we report results after 52 weeks of treatment. Patients stabilized on open-label metformin and saxagliptin 5 mg/day for 8-16 weeks were randomized to placebo or dapagliflozin 10 mg/day plus open-label saxagliptin plus metformin for 52 weeks. Changes from baseline to week 52 were greater with dapagliflozin versus placebo in A1C (−0.74% vs. 0.07%), FPG (−27 vs. 10 mg/dL) and BW (−2.1 vs. −0.4 kg). More patients achieved A1C

Aims Greater reductions in glycated haemoglobin (HbA1c) with saxagliptin, a dipeptidyl peptidase-4 inhibitor, versus placebo add-on in patients with type 2 diabetes who had inadequate glycaemic control with dapagliflozin 10 mg/d plus metformin were demonstrated after 24 weeks of treatment. Results over 52 weeks of treatment were assessed in this analysis. Materials and methods Patients (mean baseline HbA1c 7.9%) receiving open-label dapagliflozin 10 mg/d plus metformin were randomized to double-blind saxagliptin 5 mg/d or placebo add-on. Results The adjusted mean change from baseline to week 52 in HbA1c was greater with saxagliptin than with placebo add-on −0.38% vs 0.05%; difference −0.42% (95% confidence interval −0.64, −0.20)]. More patients achieved the HbA1c target of

Introduction Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). The recommended dose of the dipeptidyl peptidase-4 inhibitor saxagliptin is 2.5 mg in patients with moderate or severe renal impairment (creatinine clearance ≤50 mL/min). In this post hoc analysis, we assessed the effect of saxagliptin 2.5 and 5 mg/day versus placebo on glycemic measures in patients with T2D and estimated glomerular filtration rate 45–60 mL/min/1.73 m2. Methods Efficacy and safety data were pooled from nine 24-week, randomized, placebo-controlled clinical trials. Results The majority (56–61%) of patients were women aged

OBJECTIVE To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement RESULTS At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.

Background We investigated the association of electrocardiographic (ECG) abnormalities with markers of insulin resistance and pancreatic beta-cell dysfunction in a cross-sectional study of type 2 diabetes patients. Methods Electrocardiographic criteria were evaluated in the Penn Diabetes Heart Study participants (n = 1671; 64% male; 61% Caucasian), including a sub-sample (n = 710) that underwent oral glucose tolerance testing. The Matsuda Insulin Sensitivity Index and homeostasis model assessment of insulin resistance (HOMA-IR) estimated insulin sensitivity; Insulinogenic Index and homeostasis model assessment of beta-cell function assessed beta-cell function. Multivariable regression modelling was used to analyse associations of ECG changes with these indices. Results In unadjusted analyses, subjects in the highest quartile of Matsuda index had the lowest prevalence of Q-waves (6.3% versus 15.3%, p = 0.005). In adjusted models, an inverse association was seen between Q-waves and log Matsuda index [one standard deviation increase; OR = 0.59 (95% CI 0.43-0.87 p = 0.001)]. In the full Penn Diabetes Heart Study, there was a direct association between Q-waves and HOMA-IR [one standard deviation increase; OR = 1.43 (95% CI 1.13-1.81, p = 0.003)]. In adjusted models, left ventricular hypertrophy also was inversely associated with Matsuda index and directly with HOMA-IR. Higher Insulinogenic Index scores were associated with a lower prevalence of nonspecific ST changes [OR = 0.78 (95% CI 0.62-0.98, p = 0.032)]. Conclusions In type 2 diabetic patients, both oral glucose tolerance testing-derived and HOMA-derived measures of insulin resistance were associated with pathologic Q-waves and left ventricular hypertrophy on ECGs. Copyright © 2016 John Wiley & Sons, Ltd.

Background Dapagliflozin, a highly selective sodium–glucose cotransporter 2 inhibitor, reduces hyperglycemia, body weight, and blood pressure in patients with type 2 diabetes (T2D). Methods This randomized double-blind placebo-controlled parallel-group 24-week study assessed the efficacy, safety, and tolerability of dapagliflozin added to metformin in Asian patients with inadequately controlled T2D (HbA1c 7.5%–10.5%). Patients were randomized to receive placebo (n = 145) or dapagliflozin 5 (n = 147) or 10 mg (n = 152). Results Most participants were Chinese (86.0%), with a mean age of 53.8 years and mean T2D duration of 4.9 years; 92.1% completed the study. Adjusted mean HbA1c changes from baseline at Week 24 (primary endpoint) were −0.23%, −0.82%, and −0.85% in the placebo, dapagliflozin 5 and 10 mg groups, respectively, resulting in dapagliflozin 5 and 10 mg versus placebo differences of −0.59% and −0.62%, respectively (both P

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.

Background: Intracerebral hemorrhage (ICH) accounts for around 10% to 20% of all stroke cases worldwide. It is one of the most fatal and disabling subtype of strokes. Volume of hemorrhage is well documented risk factor for mortality. Aims and Objectives: The objectives of this study is to find whether the location of ICH is an independent risk factor for morbidity and mortality. Material and Methods: It is a prospective cohort study involving adult patients with age more than 18 years presenting with ICH. All patients satisfying inclusion criteria were subjected to CT scan brain. The location of hemorrhages and volume were noted. The four independent variables – gender, presence of hypertension, location and volume of bleed were documented. Their association with modified Rankin scale was calculated using chi – square test, the significance was calculated with P < 0.05. Result: Eighty patients were recruited in the study. 72.5% were male and 27.5% were female. Mean age was 56.25 + 14.3 years. Hypertension was one of the commonest risk factor for ICH (80%). Volume of bleed more than 60 cc was associated with 100% mortality. The majority of the patients presented with ganglio – capsular hemorrhage (64%). Cerebellar and lobar hemorrhage had mortality of 66.7% and 100% respectively. The volume of bleed had odds ratio of 1.2 (P < 0.05). The logistic regression analysis adjusting location of bleed for volume was not significant (P = 0.47). Conclusion: Hypertension is one of the commonest risk factor for ICH. The volume of bleed is an independent predictor of mortality irrespective of location of hemorrhage, gender and other co-morbidity.

Background: EXSCEL was a multinational, randomized, blinded, placebo-controlled, pragmatic CV outcome trial of once-weekly exenatide on the background of usual care. We report exenatide’s impact on estimated glomerular filtration rate (eGFR), new macroalbuminuria and 2 renal composites from a prespecified analysis plan. Methods: Opportunistic local laboratory data were collected. Overall least squares mean difference (LSMD) eGFR (95% confidence interval [95% CI]) was calculated for 13844 patients with baseline and ≥1 follow-up value. Effect on new macroalbuminuria was estimated with a Cox regression model. Effects on renal composites were estimated with interval censored time to event models, with and without covariate adjustment (demographics and disease characteristics). Results: Intention-to-treat analyses showed no significant difference in eGFR levels with exenatide (LSMD +0.21 [-0.27, 0.70] mL/min.1.73m2, p=0.39). New macroalbuminuria occurred in 2.2% and 2.5% of the exenatide and placebo groups (p=0.19). There was a 15% lower renal composite 2 adjusted risk with exenatide (p=0.027) (Table). Conclusions: A composite of 40% eGFR decline, renal replacement, renal death or new macroalbuminuria was significantly reduced in an adjusted analysis by the addition of exenatide in a broad range of people with type 2 diabetes. Other renal outcomes were numerically but not statistically improved with exenatide. Disclosure M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. R.J. Mentz: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. P. Merrill: None. J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck & Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company. S.G. Goodman: Research Support; Self; Amgen Inc.. Consultant; Self; Amgen Inc.. Research Support; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; Bayer AG. Consultant; Self; Bayer AG. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Bristol-Myers Squibb Company. Consultant; Self; Bristol-Myers Squibb Company. Research Support; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation. Research Support; Self; Pfizer Inc.. Consultant; Self; Pfizer Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Consultant; Self; Regeneron Pharmaceuticals, Inc.. Research Support; Self; CSL Behring. N. Iqbal: Employee; Self; AstraZeneca. N. Jakuboniene: None. B.G. Katona: Employee; Self; AstraZeneca. Y. Lokhnygina: None. R.D. Lopes: Consultant; Self; Bayer AG, Boehringer Ingelheim GmbH. Other Relationship; Self; Bristol-Myers Squibb Company. Consultant; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; GlaxoSmithKline plc., Medtronic. Consultant; Self; Merck & Co., Inc.. Other Relationship; Self; Pfizer Inc.. A.P. Maggioni: None. P.K. Ohman: Employee; Self; AstraZeneca. N.R. Poulter: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc.. Research Support; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc., Servier. Other Relationship; Self; International Society of Hypertension. A. Ramachandran: None. T. Tankova: None. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott. A.F. Hernandez: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. Consultant; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. R.R. Holman: Research Support; Self; AstraZeneca, Merck & Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck & Co., Inc.. Other Relationship; Self; AstraZeneca.

Incidence of genital tract infections (GTIs), a common adverse event during SGLT2 inhibitor therapy, may be modified by concomitant DPP-4 inhibitor treatment. We evaluated GTI incidence across randomized trials of dapagliflozin (DAPA) ± saxagliptin (SAXA) as add-on to metformin (MET). Safety data were pooled from seven randomized phase 3 trials; patients with type 2 diabetes (N=3134) receiving DAPA 5/10 mg, SAXA 5 mg or DAPA 5/10 mg + SAXA 5 mg as add-on to MET for 24-52 weeks were included. Data from patients with 52 weeks of follow-up across five of the studies were pooled separately (long-term [LT]-study pool; N=1719). In the 7-study pool, GTI incidence was lower with add-on DAPA 10 mg + SAXA 5 mg to MET vs. add-on of DAPA 10 mg alone (3.6% vs. 6.6%); the most common events in both groups were vulvovaginal mycotic infections (DAPA + SAXA, 1.5%; DAPA, 2.0%) and balanoposthitis (DAPA + SAXA, 0.9%; DAPA, 1.8%) (Table). This finding was confirmed in the individual studies with the exception of one study comparing GTI incidence with low-dose DAPA 5 mg + SAXA 5 mg (3.1%) vs. DAPA 5 mg (1.4%). With LT treatment, GTI incidence decreased over time with DAPA 10 mg + SAXA 5 mg and DAPA 10 mg (month 6, 3.1% and 5.3%; month 12, 0.9% and 2.1%). In conclusion, add-on of DAPA 10 mg + SAXA 5 mg to MET led to lower GTI incidence than with DAPA 10 mg alone; this effect was maintained after 12 months of treatment. Disclosure S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott. E.K. Johnsson: Employee; Self; AstraZeneca. R. Garcia-Sanchez: Employee; Self; AstraZeneca. C. Morgan: Employee; Self; AstraZeneca. P. Sartipy: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca, Novo Nordisk A/S. R. Kurlyandskaya: Employee; Self; AstraZeneca. N. Iqbal: Employee; Self; AstraZeneca. C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott.

Background To assess the efficacy and tolerability of saxagliptin and C-peptide secretion in patients with diagnosed type 2 diabetes classified as glutamic acid decarboxylase antibody (GADA)-positive or GADA-negative. Methods Post hoc analysis of data pooled from five randomized, placebo-controlled, 24-week phase 3 studies (n = 2709) was conducted. We evaluated mean change from baseline at week 24 in HbA1c, fasting plasma glucose, postprandial plasma glucose, fasting and postprandial C-peptide, and HOMA2-%β and the proportion of patients achieving HbA1c

OBJECTIVE To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment. RESEARCH DESIGN AND METHODS Patients receiving treatment with stable metformin (stratum A) (screening HbA1c level 8.0–11.5% [64–102 mmol/mol]) or stable metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (stratum B) (HbA1c 7.5–10.5% [58–91 mmol/mol]) for ≥8 weeks received open-label saxagliptin 5 mg/day and metformin for 16 weeks (stratum A) or 8 weeks (stratum B) (saxagliptin replaced any DPP-4 inhibitor). Patients with inadequate glycemic control (HbA1c 7–10.5% [53–91 mmol/mol]) were randomized to receive placebo or dapagliflozin 10 mg/day plus saxagliptin and metformin. The primary end point was the change in HbA1c from baseline to week 24. Secondary end points included fasting plasma glucose (FPG) level, 2-h postprandial glucose (PPG) level, body weight, and proportion of patients achieving an HbA1c level of RESULTS Treatment with dapagliflozin add-on to saxagliptin plus metformin resulted in a greater mean HbA1c reduction than placebo (−0.82 vs. −0.10% [−9 vs. −1.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA1c level of CONCLUSIONS Triple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy.