Once-daily oral small-molecule glucagon-like peptide-1 receptor agonist lotiglipron (PF-07081532) for type 2 diabetes and obesity: Two randomized, placebo-controlled, multiple-ascending-dose Phase 1 studies.

AIM: To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity. MATERIALS AND METHODS: Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron. RESULTS: Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose-dependent reductions in mean daily glucose. The 180-mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (-1.61% [90% confidence interval {CI} -2.08, -1.14] vs. -0.61% [-1.56, 0.34] for placebo) and body weight (-5.10 kg [90% CI -6.62, -3.58] vs. -2.06 kg [90% CI -4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once-daily dosing. CONCLUSIONS: The profile of once-daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose-dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses. CLINICALTRIALS: gov identifier: NCT04305587, NCT05158244.

Identifying the Causes of Unexplained Dyspnea at High Altitude Using Normobaric Hypoxia with Echocardiography.

Exposure to high altitude results in hypobaric hypoxia, leading to physiological changes in the cardiovascular system that may result in limiting symptoms, including dyspnea, fatigue, and exercise intolerance. However, it is still unclear why some patients are more susceptible to high-altitude symptoms than others. Hypoxic simulation testing (HST) simulates changes in physiology that occur at a specific altitude by asking the patients to breathe a mixture of gases with decreased oxygen content. This study aimed to determine whether the use of transthoracic echocardiography (TTE) during HST can detect the rise in right-sided pressures and the impact of hypoxia on right ventricle (RV) hemodynamics and right to left shunts, thus revealing the underlying causes of high-altitude signs and symptoms. A retrospective study was performed including consecutive patients with unexplained dyspnea at high altitude. HSTs were performed by administrating reduced FiO2 to simulate altitude levels specific to patients' history. Echocardiography images were obtained at baseline and during hypoxia. The study included 27 patients, with a mean age of 65 years, 14 patients (51.9%) were female. RV systolic pressure increased at peak hypoxia, while RV systolic function declined as shown by a significant decrease in the tricuspid annular plane systolic excursion (TAPSE), the maximum velocity achieved by the lateral tricuspid annulus during systole (S' wave), and the RV free wall longitudinal strain. Additionally, right-to-left shunt was present in 19 (70.4%) patients as identified by bubble contrast injections. Among these, the severity of the shunt increased at peak hypoxia in eight cases (42.1%), and the shunt was only evident during hypoxia in seven patients (36.8%). In conclusion, the use of TTE during HST provides valuable information by revealing the presence of symptomatic, sustained shunts and confirming the decline in RV hemodynamics, thus potentially explaining dyspnea at high altitude. Further studies are needed to establish the optimal clinical role of this physiologic method.

Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Currently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration. Objective: To investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks. Design, Setting, and Participants: A phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions. Interventions: Participants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily. Main Outcomes and Measures: Change from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period. Results: Of 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of -1.16% (90% CI, -1.47% to -0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of -33.24 mg/dL (90% CI, -45.63 to -20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of -2.04 kg (90% CI, -3.01 to -1.07 kg) for the 80-mg twice daily group and -4.17 kg (90% CI, -5.15 to -3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting. Conclusions and Relevance: In adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action. Trial Registration: ClinicalTrials.gov Identifier: NCT03985293.

First-in-human, randomized dose-escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF-06480605 in healthy subjects.

AIMS: Human genetic, tissue expression, proteomics, transcriptomics and nonclinical studies implicate tumour necrosis factor α-like ligand 1A (TL1A) as a novel target in inflammatory bowel disease (IBD). PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, targets TL1A. This first-in-human, Phase 1, dose-escalation study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of intravenous (IV) and subcutaneous (SC) PF-06480605 in healthy subjects (NCT01989143). METHODS: Ninety-two subjects were randomized to single ascending doses (SAD), PF-06480605 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 600 mg or 800 mg IV, or multiple ascending doses (MAD), PF-06480605 3 × 500 mg IV, or 3 × 30 mg, 3 × 100 mg, or 3 × 300 mg SC every 2 weeks for three doses, or placebo. Safety, tolerability, pharmacokinetics, immunogenicity profiles and total TL1A, anti-drug antibody (ADA) and neutralizing antibody (NAb) levels were assessed at pre-determined times. RESULTS: PF-06480605 SAD up to 800 mg IV and MAD up to 300 mg ×3 SC and 500 mg ×3 IV were well tolerated. Overall, there were 45 and 44 treatment-emergent adverse events in SAD and MAD cohorts, respectively, and no deaths or serious adverse events. PF-06480605 exposure generally increased dose-dependently. ADA and NAb levels did not impact safety, pharmacokinetics, or pharmacodynamics at higher doses. Target engagement was demonstrated through dose-dependent differences in serum total soluble TL1A concentrations for PF-06480605 vs placebo cohorts. CONCLUSIONS: PF-06480605 was generally well tolerated, and binding of soluble TL1A was maintained throughout the dose interval, supporting further study of PF-06480605 in patients with IBD and other inflammatory conditions.

Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study.

OBJECTIVE: This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn's disease (CD). DESIGN: Eligible adults were aged 18-75 years, with active moderate-to-severe CD (Crohn's Disease Activity Index (CDAI) 220-450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12. RESULTS: In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating ß7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen. CONCLUSIONS: Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating ß7+ central memory T cells. TRIAL REGISTRATION NUMBER: NCT01276509; Results.

Dietary Patterns and Colorectal Cancer Risk: A Review of 17 Years of Evidence (2000-2016).

PURPOSE OF REVIEW: Colorectal cancer (CRC) is a global public health problem, with an estimated 1.4 million cases diagnosed worldwide in 2012. Evidence suggests that diet may be important for primary prevention. RECENT FINDINGS: The 2017 WCRF/AICR Continuous Update Project on colorectal cancer concluded that there is convincing evidence linking several individual dietary factors with CRC risk but the evidence for dietary patterns was limited and inconclusive. Also, previous reviews and meta-analyses have not critically synthesized various dietary patterns. This review synthesized data from dietary patterns studies over a 17-year period from 2000 to 2016. SUMMARY: We included 49 studies (28 cohort and 21 case-control) that examined the association of index-based and empirically-derived dietary patterns and CRC risk. A synthesis of food group components comprising the different index-based and empirically-derived patterns revealed two distinct dietary patterns associated with CRC risk. A "healthy" pattern, generally characterized by high intake of fruits and vegetables, wholegrains, nuts and legumes, fish and other seafood, milk and other dairy products, was associated with lower CRC risk. In contrast, the "unhealthy" pattern, characterized by high intakes of red meat, processed meat, sugar-sweetened beverages, refined grains, desserts and potatoes was associated with higher CRC risk. It is notable that the number of food groups, the intake quantity, the exact types of foods in each food group, differed between populations, yet the two dietary patterns remained consistent across regions, especially in empirically-derived patterns, an indication of the high reproducibility of these patterns. However, findings for CRC risk in both index-based and empirically-derived patterns, differed by sex, with stronger associations among men than women; study design, a higher proportion of case-control studies reported significant findings compared to prospective studies. Consuming a dietary pattern high in fruits and vegetables and low in meats and sweets is protective against CRC risk. However, important questions remain about mechanisms underlying differences by sex; life-course timing of exposure to dietary patterns; interaction of dietary patterns with the microbiome or with lifestyle factors including physical activity; and elucidation of subsite differences.

Pharmacist independent prescribing in critical care: results of a national questionnaire to establish the 2014 UK position.

OBJECTIVES: Clinical pharmacist practice is well established in the safe and effective use of medicines in the critically ill patient. In the UK, independent pharmacist prescribers are generally recognised as a valuable and desirable resource. However, currently, there are only anecdotal reports of pharmacist-independent prescribing in critical care. The aim of this questionnaire was to determine the current and proposed future independent prescribing practice of UK clinical pharmacists working in adult critical care. METHODS: The questionnaire was distributed electronically to UK Clinical Pharmacy Association members (closed August 2014). KEY FINDINGS: There were 134 responses to the questionnaire (response rate at least 33%). Over a third of critical care pharmacists were practising independent prescribers in the specialty, and 70% intended to be prescribers within the next 3 years. Pharmacists with ≥5 years critical care experience (P < 0.001) or worked in a team (P = 0.005) were more likely to be practising independent prescribers. Pharmacists reported significant positives to the use of independent prescribing in critical care both in patient care and job satisfaction. Independently, prescribing was routine in: dose adjustment for multi-organ failure, change in route or formulation, correction prescribing errors, therapeutic drug monitoring and chronic medication. The majority of pharmacist prescribers reported they spent ≤5% of their clinical time prescribing and accounted for ≤5% of new prescriptions in critical care patients. CONCLUSIONS: Most critical care pharmacists intend to be practising as independent prescribers within the next 3 years. The extent and scope of critical care pharmacist prescribing appear to be of relatively low volume and within niche prescribing areas.

Do food blogs serve as a source of nutritionally balanced recipes? An analysis of 6 popular food blogs.

OBJECTIVE: To determine whether sampled food blogs provide nutritionally balanced recipes. METHODS: Two entree recipes per season, per year (2010-2011) were selected from 6 highly ranked food blogs (n = 96). Food Processor Nutrition and Fitness software was used to analyze sodium, saturated fat, and energy content. Analysis was separated by protein type (vegetarian, poultry, red meat, and seafood). RESULTS: Recipes met energy recommendations but were excessive in saturated fat and sodium. Vegetarian and seafood recipes were significantly lower in risk nutrients compared with red meat and poultry recipes. Red meat recipes were not significantly different from poultry recipes for risk nutrients studied; poultry recipes were higher in sodium and energy compared with red meat recipes. CONCLUSIONS AND IMPLICATIONS: The public should be aware of the nutritional limitations of popular food blogs; dietitians could assist in modifying blog recipes for individuals and partner with bloggers to improve the nutritional profile of recipes.

Dietary Patterns and the Risk of Colorectal Cancer.

Diet and lifestyle play a significant role in the development of colorectal cancer, but the full complexity of the association is not yet understood. Dietary pattern analysis is an important new technique that may help to elucidate the relationship. This review examines the most common techniques for extrapolating dietary patterns and reviews dietary pattern/colorectal cancer studies published between September 2011 and August 2012. The studies reviewed are consistent with prior research but include a more diverse international population. Results from investigations using a priori dietary patterns (i.e., diet quality scores) and a posteriori methods, which identify existing eating patterns (i.e., principal component analysis), continue to support the benefits of a plant-based diet with some dairy as a means to lower the risk of colorectal cancer, whereas a diet high in meats, refined grains, and added sugar appears to increase risk. The association between colorectal cancer and alcohol remains unclear.

Methodology for adding glycemic index to the National Health and Nutrition Examination Survey nutrient database.

Generating valid estimates of dietary glycemic index (GI) and glycemic load (GL) has been a challenge in nutritional epidemiology. The methodologic issues may have contributed to the wide variation of GI/GL associations with health outcomes observed in existing literature. We describe a standardized methodology for assigning GI values to items in the National Health and Nutrition Examination Survey (NHANES) nutrient database using the new International Tables to develop research-driven, systematic procedures and strategies to estimate dietary GI/GL exposures of a nationally representative population sample. Nutrient databases for NHANES 2003-2006 contain information on 3,155 unique foods derived from the US Department of Agriculture National Nutrient Database for Standard Reference versions 18 and 20. Assignment of GI values were made to a subset of 2,078 carbohydrate-containing foods using systematic food item matching procedures applied to 2008 international GI tables and online data sources. Matching protocols indicated that 45.4% of foods had identical matches with existing data sources, 31.9% had similar matches, 2.5% derived GI values calculated with the formula for combination foods, 13.6% were assigned a default GI value based on low carbohydrate content, and 6.7% of GI values were based on data extrapolation. Most GI values were derived from international sources; 36.1% were from North American product information. To confirm data assignments, dietary GI and GL intakes of the NHANES 2003-2006 adult participants were estimated from two 24-hour recalls and compared with published studies. Among the 3,689 men and 4,112 women studied, mean dietary GI was 56.2 (men 56.9, women 55.5), mean dietary GL was 138.1 (men 162.1, women 116.4); the distribution of dietary GI was approximately normal. Estimates of population GI and GL compare favorably with other published literature. This methodology of adding GI values to an existing population nutrient database utilized systematic matching protocols and the latest comprehensive data sources on food composition. The database can be applied in clinical and survey research settings where there is interest in estimating individual and population dietary exposures and relating them to health outcomes.

Dietary patterns of women are associated with incident abdominal obesity but not metabolic syndrome.

Data on the relationship between empirical dietary patterns and metabolic syndrome (MetS) and its components in prospective study designs are limited. In addition, demographic and lifestyle determinants of MetS may modify the association between dietary patterns and the syndrome. We prospectively examined the relationship between empirically derived patterns and MetS and MetS components among 1146 women in the Framingham Offspring/Spouse cohort. They were aged 25-77 y with BMI ≥18.5 kg/m(2) and free of cardiovascular disease, diabetes, cancer, and MetS at baseline, and followed for a mean of 7 y. Five dietary patterns, Heart Healthier, Lighter Eating, Wine and Moderate Eating, Higher Fat, and Empty Calorie, were previously identified using cluster analysis from food intake collected using a FFQ. After adjusting for potential confounders, we observed lower odds for abdominal obesity for Higher Fat [OR = 0.48 (95% CI: 0.25, 0.91)] and Wine and Moderate Eating clusters [OR = 0.28 (95% CI: 0.11, 0.72)] compared with the Empty Calorie cluster. Additional adjustment for BMI somewhat attenuated these OR [Higher Fat OR = 0.52 (95% CI: 0.27, 1.00); Wine and Moderate Eating OR = 0.34 (95% CI: 0.13, 0.89)]. None of the clusters was associated with MetS or other MetS components. Baseline smoking status and age did not modify the relation between dietary patterns and MetS. The Higher Fat and Wine and Moderate Eating patterns showed an inverse association with abdominal obesity; certain foods might be targeted in these habitual patterns to achieve optimal dietary patterns for MetS prevention.

Associations of carotid artery intima-media thickness (IMT) with risk factors and prevalent cardiovascular disease: comparison of mean common carotid artery IMT with maximum internal carotid artery IMT.

OBJECTIVE: The goal of this study was to compare internal carotid artery (ICA) intima-media thickness (IMT) with common carotid artery (CCA) IMT as global markers of cardiovascular disease (CVD). METHODS: Cross-sectional measurements of the mean CCA IMT and maximum ICA IMT were made on ultrasound images acquired from the Framingham Offspring cohort (n = 3316; mean age, 58 years; 52.7% women). Linear regression models were used to study the associations of the Framingham risk factors with CCA and ICA IMT. Multivariate logistic regression models and receiver operating characteristic (ROC) curve analysis were used to compare the associations of prevalent CVD with CCA and ICA IMT and determine sensitivity and specificity. RESULTS: The association between age and the mean CCA IMT corresponded to an increase of 0.007 mm/y; the increase was 0.037 mm/y for the ICA IMT. Framingham risk factors accounted for 28.6% and 27.5% of the variability in the CCA and ICA IMT, respectively. Age and gender contributed 23.5% to the variability of the CCA IMT and 22.5% to that of the ICA IMT, with the next most important factor being systolic blood pressure (1.9%) for the CCA IMT and smoking (1.6%) for the ICA IMT. The CCA IMT and ICA IMT were statistically significant predictors of prevalent CVD, with the ICA IMT having a larger area under the ROC curve (0.756 versus 0.695). CONCLUSIONS: Associations of risk factors with CCA and ICA IMT are slightly different, and both are independently associated with prevalent CVD. Their value for predicting incident cardiovascular events needs to be compared in outcome studies.

Nutrient database development: a historical perspective from the Framingham Nutrition Studies.

Food frequency questionnaires (FFQs) are commonly used in nutritional epidemiology to assess habitual eating habits. Development of an appropriate food and nutrient database is required for translating information derived from FFQs into estimates of nutrient intake, dietary quality, or for absolute or rank-ordered nutritional risk assessment. We discuss the procedures used recently in designing a historical nutrient database to analyze an FFQ administered in 1984-1988 to Framingham Offspring-Spouse Study members. This systematic approach should inform other research in the field. The self-administered 145-item Framingham FFQ is semi-quantitative with seven nonoverlapping response categories to determine annual consumption frequency. The database development process included selection of the US Department of Agriculture's Nutrient Database for Standard Reference as the primary raw data source, expansion of the 145 FFQ line items to code individual foods to assign nutrient values, a selection process to match foods to appropriate nutrition codes for nutrient information, and a statistical model to calculate nutrient intakes. The historical database contains 449 foods and nutrient data for all 29 nutrients available in 1985. The adequacy with which an FFQ can provide reliable diet assessment data depends on the integrity of the underlying database. We outlined a systematic protocol to derive usual dietary intake from an FFQ using a robust nutrient database that is appropriate for the Framingham Offspring-Spouse Study FFQ and its assessment time-frame. The database can be updated to accommodate changes in the food supply and eating behaviors and creates a foundation for future nutrition research.