Combination Therapy With Guselkumab and Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Pharmacokinetics, Immunogenicity and Drug-Drug Interactions.

A proof-of-concept study with the combination of guselkumab and golimumab in patients with ulcerative colitis (UC) has shown that the combination therapy resulted in greater efficacy than the individual monotherapies. The current analysis evaluated the pharmacokinetics (PK) and immunogenicity of guselkumab and golimumab in both the combination therapy and individual monotherapies. Blood samples were collected to evaluate serum concentrations and immunogenicity of guselkumab and golimumab. Population PK (PopPK) models were developed to assess the effects of combination therapy and other potential covariates on the PK of guselkumab and golimumab. The guselkumab PK was comparable between monotherapy and combination therapy, whereas golimumab concentrations were slightly higher with combination therapy. The anti-guselkumab antibody incidence was low with both monotherapy and combination therapy, and guselkumab immunogenicity did not impact the clearance. Conversely, the anti-golimumab antibody incidence with combination therapy was lower than that for monotherapy. PopPK analysis suggested that the slightly higher golimumab concentrations with combination therapy were partially due to lower immunogenicity and thus lower clearance with combination therapy. C-reactive protein (CRP) was also a significant covariate on golimumab clearance. The greater improvement of inflammation with combination therapy, as shown by reductions in CRP, may have also contributed to the higher golimumab concentrations. Combination therapy slightly decreased the clearance of golimumab, but not guselkumab clearance, in patients with UC. Lower immunogenicity and greater improvement of inflammation with combination therapy were potential mechanisms for slightly increased golimumab concentrations with combination therapy as compared with golimumab monotherapy.

Qualitative and psychometric evaluation of the PROMIS®-Fatigue SF-7a scale to assess fatigue in patients with moderately to severely active inflammatory bowel disease.

BACKGROUND: This study evaluated the content validity and psychometric properties of the Patient-Reported Outcomes Measurement Information System® (PROMIS)-Fatigue Short Form 7a (SF-7a) v1.0 scale to determine its suitability in clinical trials to assess fatigue in patients with moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A qualitative interview assessed patients' experience living with CD (N = 20) and UC (N = 19). The contents of the SF-7a scale were cognitively debriefed to evaluate content validity. A psychometric evaluation was performed using data from clinical trials of patients with CD (N = 360) and UC (N = 214). Correlations with Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn's Disease Activity Index (CDAI; CD only), and Mayo score (UC only) determined validity. The Patient Global Impression of Change (PGIC) was used to evaluate reliability and responsiveness to change. Using PGIC as an anchor, a preliminary threshold for clinically meaningful change was identified to define fatigue response in both CD and UC patients. RESULTS: All patients reported fatigue as a common symptom. Patients confirmed SF-7a items were relevant to assessing fatigue, instructions and response options were clear, and its 7-day recall period was appropriate. Higher SF-7a scores were associated with higher disease activity (CDAI and Mayo score) and lower health-related quality of life (IBDQ), confirming known groups validity. The correlation of the SF-7a scale was higher with fatigue-related items. (rs ≥ -0.70) than with items not directly associated with fatigue. Test-retest reliability was moderate to good (0.54-0.89) among patients with stable disease, and responsiveness to change in disease severity was demonstrated from baseline to Week 12. A ≥7point decrease was identified as a reasonable threshold to define clinically meaningful improvement. CONCLUSION: The SF-7a scale is a valid, reliable, and sensitive measure of fatigue in patients with moderately to severely active IBD and can be used to evaluate treatment response.

Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial.

BACKGROUND: Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy. METHODS: We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542. FINDINGS: Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group). INTERPRETATION: Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. FUNDING: Janssen Research and Development.

Latent variable indirect response modeling of clinical efficacy endpoints with combination therapy: application to guselkumab and golimumab in patients with ulcerative colitis.

Accurate characterization of longitudinal exposure-response of clinical trial endpoints is important in optimizing dose and dosing regimens in drug development. Clinical endpoints are often categorical, for which much progress has been made recently in latent variable indirect response (IDR) modeling with single drugs. However, such applications have not yet been used for trials employing multiple drugs administered concurrently. This study aims to demonstrate that the latent variable IDR approach provides a convenient longitudinal exposure-response modeling framework to assess potential interaction effects of combination therapies. This is illustrated by an application to the exposure-response modeling of guselkumab, a monoclonal antibody in clinical development that blocks the interleukin-23p19 subunit, and golimumab, a monoclonal antibody that binds with high affinity to tumor necrosis factor-alpha. A Phase 2a study was conducted in 214 patients with moderate-to severe active ulcerative colitis for which longitudinal assessments of disease severity based on patient-reported measures of rectal bleeding, stool frequency, and symptomatic remission were evaluated as categorical endpoints, and fecal calprotectin as a continuous endpoint. The modeling results suggested independent pharmacodynamic guselkumab and golimumab effects on fecal calprotectin as a continuous endpoint, as well as interaction effects on the categorical endpoints that may be explained by an additional pathway of competitive interaction.

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.

Pancreatitis Incidence in the Exenatide BID, Exenatide QW, and Exenatide QW Suspension Development Programs: Pooled Analysis of 35 Clinical Trials.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for treatment of type 2 diabetes mellitus; however, there have been concerns that GLP-1RA treatment may be associated with an increased incidence of pancreatitis. This study aimed to evaluate the incidence of pancreatitis in a pooled population of type 2 diabetes trials from the clinical development program of the GLP-1RA exenatide as well as to describe patient-level data for all reported cases. METHODS: The primary analysis examined pooled data among patients with type 2 diabetes from the controlled arms of 35 trials (ranging from 4 to 234 weeks' duration) in the integrated clinical databases for exenatide twice daily, once weekly, and once-weekly suspension, excluding comparator arms with other incretin-based therapies. The exposure-adjusted incidence rate (EAIR) of pancreatitis was calculated for exenatide and non-exenatide (non-incretin-based therapy or placebo) treatment groups. Patient-level data were described for all pancreatitis incidences. RESULTS: The primary analysis included 5596 patients who received exenatide and 4462 in the non-exenatide group. The mean duration of study medication exposure for the exenatide and non-exenatide treatment groups was 57.0 and 47.9 weeks, respectively. Pancreatitis was diagnosed in 14 patients (exenatide, n = 8; non-exenatide, n = 6), of whom 13 recovered with or without sequelae. The pancreatitis EAIR was 0.1195 events per 100 patient-years [95% confidence interval (CI), 0.0516-0.2154] in the exenatide group versus 0.1276 events per 100 patient-years (95% CI 0.0468-0.2482) in the non-exenatide treatment group. The EAIR ratio for the exenatide versus non-exenatide treatment group was 0.761 (95% CI 0.231-2.510). CONCLUSION: In this pooled analysis of 10,058 patients among studies comparing exenatide with other glucose-lowering medications or placebo, pancreatitis was rare. The EAIRs of pancreatitis were low and similar between exenatide and non-exenatide treatment groups. No evidence of an association between exenatide and pancreatitis was observed. FUNDING: Bristol-Myers Squibb and AstraZeneca. Plain language summary available for this article.

Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes.

AIMS: To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). MATERIALS AND METHODS: This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 µg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. RESULTS: A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2 ; diabetes duration, 8.5 years) received either exenatide QWS-AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by -1.4% and -1.0%, respectively (least-squares mean difference, -0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS-AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS-AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS-AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. CONCLUSIONS: Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

A Systematic Review and Pooled Analysis of Select Safety Parameters Among Normal Healthy Volunteers Taking Placebo in Phase 1 Clinical Trials.

A systematic review of the Bristol-Myers Squibb normal healthy volunteers (NHVs) database identified phase 1 trials that included NHVs administered placebo with the aim of characterizing normal inter- and intraindividual safety parameter variability. Twenty-five single and multiple ascending dose studies, median duration 28 (2 to 63) days, were included in the pooled analysis (355 NHVs). Laboratory evaluations, vital signs, electrocardiograms, and adverse events were assessed. The most commonly occurring adverse event was headache (28 [7.9%] NHVs; 519.5 events/100 person-years). During the dosing period (on placebo), evaluations showed 5.1 events/100 measures of alanine aminotransferase and 7.3 events/100 measures of creatine kinase 1× above the upper limit of normal. Alanine aminotransferase and creatine kinase elevations occurred in 28 (7.9%) and 39 (11.0%) NHVs, respectively; 105 (30.3%) NHVs had low and 46 (13.3%) had high diastolic blood pressure. This analysis may inform future study designs and provide a context for interpretation of safety signals in early phase clinical trials.

Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: The DURATION-NEO-2 randomized clinical study.

AIMS: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors treat type 2 diabetes through incretin-signaling pathways. This study compared the efficacy and safety of the glucagon-like peptide-1 receptor agonist exenatide once-weekly (Miglyol) suspension for autoinjection (QWS-AI) with the dipeptidyl peptidase-4 inhibitor sitagliptin or placebo. MATERIALS AND METHODS: In this open-label, multicentre study of patients with type 2 diabetes who had suboptimal glycaemic control on metformin monotherapy, 365 patients were randomized to receive exenatide 2.0 mg QWS-AI, sitagliptin 100 mg once daily or oral placebo (3:2:1 ratio). The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to 28 weeks. RESULTS: At 28 weeks, exenatide QWS-AI significantly reduced HbA1c from baseline compared to sitagliptin (-1.13% vs -0.75% [baseline values, 8.42% and 8.50%, respectively]; P = .02) and placebo (-0.40% [baseline value, 8.50%]; P = .001). More exenatide QWS-AI-treated patients achieved HbA1c <7.0% than did sitagliptin- or placebo-treated patients (43.1% vs 32.0% and 24.6%; both P < .05). Exenatide QWS-AI and sitagliptin reduced fasting plasma glucose from baseline to 28 weeks (-21.3 and -11.3 mg/dL) vs placebo (+9.6 mg/dL), with no significant difference between the 2 active treatments. Body weight decreased with both active treatments (-1.12 and -1.19 kg), but not with placebo (+0.15 kg). No improvement in blood pressure was observed in any group. The most common adverse events with exenatide QWS-AI were gastrointestinal events and injection-site reactions. CONCLUSIONS: This study demonstrated that exenatide QWS-AI reduced HbA1c more than sitagliptin or placebo and was well tolerated.

Changes in Fasting and Prandial Gut and Adiposity Hormones Following Vertical Sleeve Gastrectomy or Roux-en-Y-Gastric Bypass: an 18-Month Prospective Study.

BACKGROUND: Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) produce substantial weight loss, both primarily through gastric restriction but with potentially different hormonal signaling. This prospective, observational study compared changes in gut-derived hormones in VSG, RYGB, and weight-stable participants at 6 and 18 months post-surgery. METHODS: Sixty-four obese, non-diabetic women, including 18 VSG, 23 RYGB, and 23 weight-stable controls completed assessments at baseline and 6 months, before and after consuming a mixed-nutrient meal; blood sampling occurred for 180 min post-meal. Fifty-one participants completed the 18-month outcome. Change from baseline in post-prandial area under the curve (over 180 min) for GLP-1, PYY3-36, ghrelin, and leptin was measured at 6 and 18 months post-surgery. RESULTS: At 18 months, VSG and RYGB participants lost a mean (±SEM) of 25.5 ± 2.3% and 34.2 ± 4.2% of initial weight, respectively (p < 0.156), which both differed (p < 0.001) from the +1.7 ± 1.0% gain in the control group. Fasting ghrelin declined significantly more in VSG than RYGB participants at both months 6 (p = 0.0199) and 18 (p = 0.0003). In response to the mixed-nutrient meal, GLP-1 and PYY3-36 demonstrated an exaggerated post-prandial response that was significantly greater in RYGB than VSG at 6 months (p < 0.0001 and p = 0.0062, respectively) but not 18 months (p = 0.0296 and p = 0.1210). CONCLUSIONS: VSG and RYGB both produced substantial weight losses at 18 months. The data suggest a role of gastrointestinal hormones as mediators of weight loss.

Effect of an intensive lifestyle intervention on atrial fibrillation risk in individuals with type 2 diabetes: the Look AHEAD randomized trial.

BACKGROUND: Obesity is associated with higher risk of atrial fibrillation (AF), but the impact of behavioral weight loss interventions on atrial fibrillation (AF) risk in persons with diabetes is unknown. We addressed this question in the Look AHEAD randomized trial. METHODS AND RESULTS: A total of 5,067 overweight or obese individuals 45 to 76 years old with type 2 diabetes without prevalent AF were randomized to either an intensive lifestyle intervention (ILI) designed to achieve and maintain weight loss through caloric reduction and increased physical activity or a diabetes support and education usual care group. Atrial fibrillation was ascertained from electrocardiograms at study examinations and hospitalization discharge summaries. Multivariable Cox models were used to estimate the intention-to-treat effect of the intervention adjusting for baseline covariates. During a mean follow-up of 9.0 years, 294 incident AF cases were identified. Rates of AF were comparable in the ILI and diabetes support and education groups (6.1 and 6.7 cases per 1,000 person-years, respectively, P = .42). The intervention did not affect AF incidence (multivariable hazard ratio [HR] 0.99, 95% CI 0.77-1.28). Similarly, neither weight loss nor improvement in physical fitness during the first year of the intervention was significantly associated with AF incidence: multivariable hazard ratio (95% CI) comparing top versus bottom quartile was 0.70 (0.41-1.18) for weight loss and 0.88 (0.55-1.43) for physical fitness improvement. CONCLUSION: In a large randomized trial of overweight and obese individuals with type 2 diabetes, an ILI that induced modest weight loss did not reduce the risk of developing AF.

Long-term virologic outcomes following bariatric surgery in patients with HIV.

The management of morbid obesity and its metabolic complications among HIV-infected patients requires a multi-disciplinary approach, with surgical interventions as one option. We sought to assess the long-term durability of ART among HIV-infected patients undergoing bariatric procedures for the management of morbid obesity. During the study period, 7 patients underwent a bariatric surgery procedure for the management of morbid obesity: 3 patients underwent sleeve gastrectomy, 2 patients underwent laparoscopic banding, and 2 patients underwent Roux-en-Y gastric bypass surgery. Overall, the proportion of undetectable HIV viral load levels did not change after the bariatric procedures, although 2 patients did require temporary cessation of medications due to procedure-related complications. Sleeve gastrectomy and Roux-en-Y gastric bypass were safe and effective among morbidly obese HIV-infected patients in our clinic population.

Effects of a 2-year behavioral weight loss intervention on sleep and mood in obese individuals treated in primary care practice.

OBJECTIVE: To examine the effect of weight loss on sleep duration, sleep quality, and mood in 390 obese men and women who received one of three behavioral weight loss interventions in the Practice-based Opportunities for Weight Reduction trial at the University of Pennsylvania (POWER-UP). METHODS: Sleep duration and quality were assessed at baseline and months 6 and 24 by the Pittsburgh Sleep Quality Index (PSQI) questionnaire and mood by the Patient Health Questionnaire-8 (PHQ-8). Changes in sleep and mood were examined according to treatment group and based on participants' having lost ≥5% of initial weight vs. <5%. RESULTS: There were few significant differences between treatment groups in changes in sleep or mood. At month 6, however, mean (±SD) min of sleep increased significantly more in participants who lost ≥5% vs. <5% (21.6 ± 7.2 vs. 1.2 ± 6.0 min, P = 0.0031). PSQI total scores similarly improved (declined) more in those who lost ≥5% vs. <5% (-1.2 ± 0.2 vs. -0.4 ± 0.2, P < 0.001), as did PHQ-8 scores (-2.5 ± 0.4 vs. -0.1 ± 0.3, P < 0.0001). At month 24, only the differences in mood remained statistically significant (P < 0.05). CONCLUSION: Losing ≥5% of initial weight was associated with short-term improvements in sleep duration and sleep quality, as well as favorable short- and long-term changes in mood.

GLP-1 plays a limited role in improved glycemia shortly after Roux-en-Y gastric bypass: a comparison with intensive lifestyle modification.

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin(9-39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.

Bioequivalence of saxagliptin/dapagliflozin fixed-dose combination tablets compared with coadministration of the individual tablets to healthy subjects.

Saxagliptin and dapagliflozin are individually indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The bioequivalence of saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg fixed-dose combination (FDC) tablets compared with coadministration of the individual tablets and the food effect on both strengths of saxagliptin/dapagliflozin FDCs were evaluated in this open-label, randomized, single-dose crossover study. Healthy subjects were randomized to saxagliptin 2.5 mg + dapagliflozin 5 mg fasted, 2.5/5 mg FDC fasted, 2.5/5 mg FDC fed (Cohort 1) or saxagliptin 5 mg + dapagliflozin 10 mg fasted, 5/10 mg FDC fasted, 5/10 mg FDC fed (Cohort 2). Serial blood samples for pharmacokinetics of saxagliptin and dapagliflozin were obtained predose and up to 60 h postdose. Bioequivalence of FDC tablets versus individual components was concluded if the 90% CIs for FDC to individual component geometric mean ratios of C max, AUC 0-T, and AUC inf of both analytes were between 0.80 and 1.25. Seventy-two subjects were randomized; 71 (98.6%) completed the study. Saxagliptin/dapagliflozin 2.5/5 mg and 5/10 mg FDC tablets were bioequivalent to the individual tablets administered concomitantly. Food had no clinically meaningful effect on saxagliptin or dapagliflozin overall systemic exposure. Saxagliptin/dapagliflozin FDC tablets were bioequivalent to coadministration of the individual components in healthy subjects under fasted conditions and food had no clinically meaningful effect on bioavailability.

Nutritional management of type 2 diabetes mellitus and obesity and pharmacologic therapies to facilitate weight loss.

Diet plays an integral role in the treatment of type 2 diabetes mellitus (T2DM). Unfortunately, many patients with T2DM do not have access to a registered dietitian or certified diabetes educator, and rates of physician counseling about diet remain low. This article provides an overview of the current recommendations for the nutritional management of T2DM, which are endorsed by the American Diabetes Association (ADA). Medical nutrition therapy, which provides a flexible and individualized approach to diet, emphasizes the total number (rather than the type) of carbohydrate consumed. Because fat intake also affects glycemia and cardiovascular risk, a reduction in daily mono- and polyunsaturated fat intake is recommended for most patients with T2DM. Weight loss plays an important adjunct role in treating patients with T2DM, because the majority of individuals with T2DM are overweight or obese. Patient lifestyle modification, which encompasses diet, physical activity, and behavioral therapy, can be used to facilitate weight loss in conjunction with several different dietary approaches. These include low-carbohydrate, low-fat, low-glycemic index, and Mediterranean diets. Studies have demonstrated that modest weight loss (5%-10% of body weight) is associated with significant improvements in patient measures of glycemic control, lipids, blood pressure, and other cardiovascular risk factors. Furthermore, a modest weight loss of as little as 4.5 kg can result in reducing the glycated hemoglobin level by approximately 0.5%. Pharmacologic agents, when combined with these approaches, may further augment weight loss. Familiarity with these principles can help physicians provide dietary counseling to their patients with T2DM and obesity.

Attitudes about the safety and efficacy of bariatric surgery among patients with type 2 diabetes and a body mass index of 30-40 kg/m2.

BACKGROUND: Despite increasing awareness within the medical community about the benefits of bariatric surgery for type 2 diabetes mellitus (T2DM), little is known about patients' attitudes toward bariatric surgery as a treatment for T2DM. The objective of this study was to investigate the attitudes of individuals with T2DM and a body mass index of 30 to 40 kg/m(2) concerning bariatric surgery for the treatment of T2DM. METHODS: Patients identified from the Pennsylvania Integrated Clinical and Administrative Research Database (PICARD) were surveyed about perceptions of the safety profile and efficacy of bariatric surgery as a treatment for obesity and T2DM and their willingness to be randomly assigned to receive a surgical procedure. RESULTS: A total of 130 individuals of 513 (25.3%) responded. Respondents had a median (interquartile range) age of 58.0 (range 51.0-63.0) years and self-reported body mass index of 32.9 (range 30.9-35.2) kg/m(2). Roughly half (66 of 130) were female. Overall, only 20.3% of respondents had positive views of bariatric surgery, with few reporting that it is a safe (14.3%) and effective (28.5%) treatment for T2DM. Less than 20% of respondents were willing to be randomly assigned to undergo a surgical procedure for the treatment of diabetes (16.1%) or obesity (17.5%). CONCLUSIONS: Few obese individuals with T2DM who responded to the survey had positive views about bariatric surgery. Patients' concerns about the procedure's safety profile and efficacy must be addressed to improve the acceptability of bariatric surgery as well as the feasibility of randomized, controlled trials of bariatric surgery for these individuals.

Comparison of Bariatric Surgical Procedures for Diabetes Remission: Efficacy and Mechanisms.

Bariatric surgery induces a mean weight loss of 15-30% of initial body weight (depending on the procedure), as well as a 45-95% rate of diabetes remission. Procedures that induce greater weight loss are associated with higher rates of diabetes remission. Improvements in glucose homeostasis after bariatric surgery are likely mediated by a combination of caloric restriction (followed by weight loss) and the effects of altered gut anatomy on the secretion of glucoregulatory gut hormones.

Lifestyle modifications and surgical options in the treatment of patients with obesity and type 2 diabetes mellitus.

This article reviews recent developments in the behavioral and surgical treatment of obesity and type 2 diabetes mellitus (T2DM). Randomized controlled trials of comprehensive lifestyle-modification programs, which include dietary interventions, physical activity, and behavioral therapy, have shown weight losses of 7% to 10% of initial body weight within 4 to 6 months after treatment. These programs also reduce the likelihood of developing T2DM by 58% for individuals with impaired glucose tolerance. Long-term maintenance of these improvements requires continued implementation of the program diet, physical activity, and self-regulatory behaviors. This can be successfully facilitated by continued patient-provider contact, which is frequently delivered by phone, mail, email, or online. However, these benefits may have less impact on those with extreme obesity or more significant health problems. For these individuals, bariatric surgery may be a more appropriate treatment. Bariatric surgical procedures induce mean weight losses of 15% to 30% of initial body weight (depending on the procedure) within 2 years after surgery, as well as a 45% to 95% rate of diabetes remission. Familiarity with these developments can help physicians and patients to determine which combinations of behavioral, medical, and surgical interventions are appropriate for the treatment of obesity and T2DM.

Physicians' attitudes about referring their type 2 diabetes patients for bariatric surgery.

BACKGROUND: Despite increasing evidence about the beneficial effects of bariatric surgery, little is known about physicians' attitudes toward it as a treatment of type 2 diabetes. Our objective was to investigate physicians' attitudes about referring patients with type 2 diabetes for bariatric surgery. METHODS: Physicians were identified from the Pennsylvania Integrated Clinical and Administrative Research Database and other databases. Physicians at an academic medical center (n = 142) and community-based physicians (n = 197) in the Philadelphia area in specialties likely to treat type 2 diabetes were sent a survey about their perceptions of the safety and efficacy of bariatric surgery as a treatment for obesity and type 2 diabetes. RESULTS: Of the physicians, 93 returned the survey, for a combined response rate of 27.4%. Respondents reported having positive impressions of bariatric surgery as a treatment for obesity and type 2 diabetes (79.6% and 67.4%, respectively). Only 20.8% of respondents indicated that they would be likely to refer their patients with type 2 diabetes with a body mass index of 30-34.9 kg/m(2) to a randomized research trial of bariatric surgery. CONCLUSION: In general, physicians who treat patients with type 2 diabetes had favorable impressions about bariatric surgery as a treatment for obesity and type 2 diabetes. However, only a few were willing to refer their patients with type 2 diabetes and a body mass index of 30-34.9 kg/m(2) to randomized research trials of bariatric surgery. This reluctance to refer patients represents an important barrier to the successful completion of studies of the efficacy of bariatric surgery for those with type 2 diabetes and a body mass index <35 kg/m(2).