Obesity, Cardiorenal Comorbidities, and Risk of Hospitalization in Patients With Heart Failure With Preserved Ejection Fraction.

Objective: To compare clinical features of patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) with those of patients with similar body mass index (BMI) but no HF and to examine the association between degree of obesity and risk for hospitalizations.

Methods: This was a retrospective analysis of 22,750 adults from a large US electronic health care data set (January 1, 2012, through July 31, 2019), including 4975 with HFpEF. Baseline characteristics were compared between patients with HFpEF and a control group matched on BMI, age, sex, and year of BMI record.

Weight change and risk of obesity-related complications: A retrospective population-based cohort study of a UK primary care database.

Aims: To examine associations between weight loss/gain and risk of developing 13 obesity-related complications (ORCs), stratified by baseline body mass index (BMI).

Materials And Methods: In this retrospective cohort study, we included adults with obesity (>30 kg/m ) from the UK Clinical Practice Research Datalink GOLD database with weight change (-50% to +50%) between Years 1 and 4 (N = 418 774 [median follow-up: 7 years]). Associations between weight change, baseline BMI and risk of developing ORCs during follow-up were assessed using Cox proportional hazard models.

Ten-year cost-consequence analysis of weight loss on obesity-related outcomes in privately insured adults with obesity in Saudi Arabia.

Aim: This study aimed to estimate the 10-year cost-consequence of weight loss on obesity-related outcomes in a sample of privately insured adults with obesity in Saudi Arabia (KSA).

Methods: We analyzed data of adults with obesity (BMI ≥ 30 kg/m) available in Nphies, the private health insurance platform of the Council of Health Insurance, KSA. A micro-costing analysis was used to obtain domestic cost estimates for obesity-related outcomes.

Association between body mass index, weight loss and the chance of pregnancy in women with polycystic ovary syndrome and overweight or obesity: a retrospective cohort study in the UK.

Study Question: What are the associations between baseline BMI (Study 1) and change in body weight (Study 2) with the likelihood of pregnancy in women with polycystic ovary syndrome (PCOS).

Summary Answer: In women with PCOS, higher baseline BMI was associated with a lower chance of pregnancy; however, weight loss was associated with an increased chance of pregnancy versus maintaining a stable weight or gaining weight.

What Is Known Already: Two studies in large cohorts of Danish women with the intention to become pregnant showed a decline in fecundability ratios with higher BMI.

Obesity Burden and Impact of Weight Loss in Saudi Arabia: A Modelling Study.

Background: Obesity and its complications are associated with morbidity, mortality and high economic cost in Saudi Arabia. Estimating this impact at the population level and potential benefits to be gained from obesity reduction is vital to underpin policy initiatives to prevent disease risks.

Methods: We combined data in an adapted version of the value of weight loss simulation model, to predict reductions in complication rates and cost savings achievable with 15% weight loss in Saudi Arabia over 10 years.

Body mass index and risk of obesity-related conditions in a cohort of 2.9 million people: Evidence from a UK primary care database.

Objective: Obesity rates in the United Kingdom are some of the highest in Western Europe, with considerable clinical and societal impacts. Obesity is associated with type 2 diabetes (T2D), osteoarthritis, cardiovascular disease, and increased mortality; however, relatively few studies have examined the occurrence of multiple obesity-related outcomes in the same patient population. This study was designed to examine the associations between body mass index (BMI) and a broad range of obesity-related conditions in the same large cohort from a UK-representative primary care database.

Weight loss and risk reduction of obesity-related outcomes in 0.5 million people: evidence from a UK primary care database.

High body mass index (BMI) is known to be associated with various conditions, including type 2 diabetes (T2D), osteoarthritis, cardiovascular disease (CVD) and sleep apnoea; however, the impact of intentional weight loss on the risk of these and other outcomes is not well quantified. We examined the effect of weight loss on ten selected outcomes in a population from the UK Clinical Practice Research Datalink (CPRD) GOLD database. Included individuals were >18 years old at the index date (first BMI value between January 2001 and December 2010).

Impact of CKD Progression on Cardiovascular Disease Risk in a Contemporary UK Cohort of Individuals With Diabetes.

Introduction: It remains unclear whether an increased progression rate of chronic kidney disease (CKD) adds predictive information regarding cardiovascular disease (CVD) risk. The aim of this study was to evaluate the association between CKD progression, based on estimated glomerular filtration rate (eGFR) slope estimates and the risk for CVD.

Methods: We compared the updated eGFR slope calculated over multiple overlapping 2-year periods and the updated mean eGFR.

Exploring the insulin secretory properties of the PGD2-GPR44/DP2 axis in vitro and in a randomized phase-1 trial of type 2 diabetes patients.

Aims/hypothesis: GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients.

A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss.

Introduction: The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes.

Methods: In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment.

Contemporary risk estimates of three HbA variables in relation to heart failure following diagnosis of type 2 diabetes.

Background: We evaluated the association between glycaemic control and the risk of heart failure (HF) in a contemporary cohort of persons followed after diagnosis of type 2 diabetes (T2D).

Methods And Results: Persons with T2D diagnosed between 1998 and 2012 were retrieved from the Clinical Practice Research Data Link in the UK and followed from diagnosis until the event of HF, mortality, drop out from the database due to any other reason, or the end of the study on 1 July 2015. The association between each of three different haemoglobin A (HbA) metrics and HF was estimated using adjusted proportional hazard models.

Association between renin and atherosclerotic burden in subjects with and without type 2 diabetes.

Background: Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D.

Methods: Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients.

Contemporary Risk Estimates of Three HbA1c Variables for Myocardial Infarction in 101,799 Patients Following Diagnosis of Type 2 Diabetes.

Objective: This study evaluated the risk of myocardial infarction (MI) by impaired glycemic control in a contemporary large cohort of patients with type 2 diabetes followed from diagnosis.

Research Design And Methods: Patients with type 2 diabetes diagnosed between 1995 and 2011 were retrieved from the Clinical Practice Research Datalink in the U.K.

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.

Objective: Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.

Structure-based ligand design to overcome CYP inhibition in drug discovery projects.

Cytochrome P450 (CYP) enzymes are key players in xenobiotic metabolism, and inhibition of CYPs can therefore result in unwanted drug-drug interactions. Within drug discovery, CYP inhibition can cause delays in the progression of candidate drugs, or even premature closure of projects. During the past decade, a massive effort in the pharmaceutical industry and academic research has produced a wealth of structural information in the CYP field.

The discovery of a novel series of glucokinase activators based on a pyrazolopyrimidine scaffold.

Glucokinase is a key enzyme in glucose homeostasis since it phosphorylates glucose to give glucose-6-phosphate, which is the first step in glycolysis. GK activators have been proven to lower blood-glucose, and therefore have potential as treatments for type 2 diabetes. Here the discovery of pyrazolopyrimidine GKAs is reported.

Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats.

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability.

Computational chemistry-driven decision making in lead generation.

Novel starting points for drug discovery projects are generally found either by screening large collections of compounds or smaller more-focused libraries. Ideally, hundreds or even thousands of actives are initially found, and these need to be reduced to a handful of promising lead series. In several sequential steps, many actives are dropped and only some are followed up.