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Introduction: Obesity and its complications are associated with high morbidity/mortality and a significant healthcare cost burden in Spain. It is therefore essential to know the potential clinical and economic benefits of reducing obesity. The objective of this study is to predict the decrease in rates of onset of potential complications associated with obesity and the cost savings after a weight loss of 15% over 10 years in Spain., Methods: Data were combined in an adapted version of a weight loss benefit simulation model. Sources with demographic information on the Spanish population and the distribution of obesity and type 2 diabetes mellitus (T2DM) were used to obtain the data for the model. In addition, use was made of prevalence data on obesity-associated complications from a cohort of patients with obesity in the United Kingdom (UK). These data were combined by age and sex to create a Spanish synthetic cohort., Results: The simulation showed that, for a cohort of 100,000 individuals with a body mass index (BMI) of 30-50 kg/m 2 , a weight loss of 15% is estimated to lead to relevant relative risk reductions in obstructive sleep apnoea (OSA) (- 56.4%), T2DM (- 39.2%), asthma (- 20.2%) and arterial hypertension (- 18.7%). The estimated overall savings were €105 million for a cohort of 100,000 individuals, mainly resulting from the decrease in T2DM and arterial hypertension (23% and 22% of the total savings at year 10, respectively), as well as osteoarthritis and chronic kidney disease (CKD) (16% and 13%, respectively)., Conclusions: Sustained weight loss could significantly reduce the burden derived from future complications associated to obesity in Spain, as well as the excess economic cost associated with its treatment., Competing Interests: Declarations. Conflict of Interest: This study and manuscript have been promoted by Novo Nordisk Pharma SA. Alberto Martín-Lorenzo is an employee of Novo Nordisk Pharma SA and Volker Schnecke is an employee of Novo Nordisk A/S. Lluís Segú, Max Brosa, Ened Rodríguez-Urgellés and Miquel Sastre-Belío are employees in PharmaLex Spain, which have received a consulting fee from Novo Nordisk Pharma SA. María Dolores Ballesteros-Pomar have recieved honoraria or consultancy services from Novo Nordisk Pharma SA, Lilly, Bohringer, Fresenius Kabi, Nutricia Danone, Nestlé Healthcare, Vegenat and Abbott Nutrition. Nuria Vilarrasa have received honoraria for consultancy services from Novo Nordisk Pharma SA, Lilly, Boeringher-Ingelheim, Adventia Pharma and FAES Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Ethical Approval: The results presented in this manuscript are based on published studies. All procedures performed in those studies involving human participants were conducted in accordance with the ethical standards of the local Institutional Review Boards for each site and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in publication of these studies., (© 2025. The Author(s).)

Background: The Asia-Pacific (APAC) region includes a significant proportion of the global population currently living with overweight and obesity. This modelling analysis was conducted to quantify the incidence of obesity-related comorbidities and change in obesity-related costs over 10 years with a hypothetical 10% weight loss in Australia, South Korea, Thailand, and India., Methods: An epidemiological-economic model was used to describe current prevalence and direct medical costs of ten obesity-related comorbidities, including type 2 diabetes and hypertension, in adults aged 20-69 years living with obesity, and estimate incidence and costs over 10 years. Incidence reduction and the associated savings by 2032 were then estimated for a 10% weight-loss scenario., Results: The total estimated medical costs for the ten obesity-related comorbidities in 2022 were 2.9, 7.5, 10.2, and 23.3 billion USD in Australia, South Korea, Thailand, and India, respectively. Costs increase to 6.9, 18.4, 23.5, and 44.3 billion USD in 2032, if insufficient action is taken. A 10% weight reduction would result in estimated savings of 0.3, 1.2, 2.2, and 3.0 billion USD in Australia, South Korea, Thailand, and India, respectively, in 2032, with cumulative savings over the 10-year period of 1.8, 7.0, 13.0, and 17.4 billion USD. Incidence of comorbidities were estimated to rise less in the weight-loss scenario., Conclusions: The financial, societal, and health benefits of a substantial but achievable 10% weight loss in adults living with obesity, and the consequences of insufficient action, are pronounced in the APAC region. To achieve sustained weight loss in the real world, policy actions for addressing barriers to obesity management are required., Competing Interests: Declarations. Ethics approval and consent to participate: Ethics approval was not required as this modelling study used publicly available population-level data. No identifiable data were accessed and no interactions with participants were involved. Consent for publication: Not applicable. Competing interests: JY is the President of the Singapore chapter of the Professional Society for Health Economics and Outcomes Research (ISPOR) and reports funding from Novo Nordisk PHARMA GULF FZE for congress attendance. VS is an employee of Novo Nordisk A/S, Denmark. JRB and JGUR are employees of Novo Nordisk PHARMA GULF FZE. SK reports honoraria from Boehringer Ingelheim and Sanofi. GK reports payment for serving on advisory boards and honoraria or travel support received from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, and Reed Exhibitions. KK reports clinical trial contracts from Alvogen Korea, Amgen, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk PHARMA, consulting fees for Novo Nordisk PHARMA Korea, and honoraria for Alvogen Korea, Chong Kun Dang, and Novo Nordisk PHARMA Korea. VM reports acting as consultant and speaker and having received research or educational grants from Abbott, Alembic Pharmaceuticals Ltd., AstraZeneca, Boehringer Ingelheim, Biocon, Dr. Reddy’s Laboratories, Emcure Pharmaceuticals Ltd., IPCA Laboratories Ltd., Johnson & Johnson, LifeScan, Lilly, MSD, Novartis, Novo Nordisk, Roche Diabetes Care India Pvt. Ltd, Sanofi-Aventis, SunPharma, USV Private Limited, and Zydus Healthcare Ltd. JP reports honoraria from INova and Novo Nordisk. BO reports a clinical study grant, consulting fees and honoraria from Novo Nordisk PHARMA Malaysia. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Obesity-related comorbidities (ORCs) cause significant economic and clinical burdens for people with obesity and the US health care system. A reduction in weight at the population level may reduce incident ORC diagnoses and associated costs of treatment. The aim of this work is to describe obesity burden in the United States through the prevalence and direct treatment costs of ORCs, as well as the clinical and economic value of 15% weight loss in a population of adults with obesity. The IQVIA Ambulatory US electronic medical record database was used to create a cohort (7,667,023 individuals 20-69 years of age, body mass index of 30-50 kg/m 2 ), utilized to characterize the prevalence of 10 ORCs. Direct treatment costs were collected from literature reports. A risk model was leveraged to estimate the number and cost of additional ORC diagnoses over 5 years from baseline through two scenarios: stable weight and 15% lower body weight at baseline for all members of the population. Prevalence, incidence, and cost data were scaled down to a representative subset of 100,000 individuals. In 2022, the annual treatment costs for all 10 ORCs exceeded $918 million for the representative cohort. In a stable-weight scenario, these costs were estimated to increase to ≈$1.4 billion by 2027. With 15% lower body weight at baseline, $221 million in cumulative savings was estimated, corresponding to $2205 in savings/patient over 5 years. Consequently, weight loss in this population may correspond to significantly reduced numbers of incident ORC complications translating to substantial cost savings.

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. Risk of first hospitalization was analyzed in the HFpEF sample with negative binomial and Cox proportional hazards models, adjusted for baseline comorbidities., Results: Compared with controls without HF matched on BMI, age, sex, and year of BMI record, patients with HFpEF displayed worse kidney function, greater estimated plasma volume, and more cardiovascular comorbidities. Within the HFpEF cohort, patients with higher degree of obesity were younger and had fewer concomitant cardiovascular comorbidities than those with lower degree of obesity. The mean number of HF-related hospitalizations increased with higher degree of obesity (9.6 to 15.7/100 patient-years; P=.002), but higher degree of obesity was not associated with increased risk of non-HF-related hospitalizations., Conclusion: Among persons with obesity, increasing cardiorenal dysfunction and volume overload differentiate those with HFpEF. Among persons with established HFpEF, those with higher degree of obesity are younger and have fewer cardiovascular comorbidities but display a unique increased risk of HF-related hospitalizations, even as risk for other hospitalizations is not different., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

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 2 ) 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., Results: The impact of weight change on ORCs was generally dependent on baseline BMI. Four clear patterns were seen across the 13 outcomes. Pattern 1 showed greatest weight loss benefit for people with low baseline BMI (type 2 diabetes, sleep apnoea, hypertension and dyslipidaemia); Pattern 2 showed most weight loss benefit at lower baseline BMI but no significant weight loss effect at higher baseline BMI (asthma, hip/knee osteoarthritis and polycystic ovary syndrome); Pattern 3 showed benefit in most cardiovascular diseases with weight loss (chronic kidney disease, heart failure, atrial fibrillation and venous thromboembolism), but no additional benefit with >10% weight loss; Pattern 4 showed no clear relationship between weight change and unstable angina/myocardial infarction and depression. We found similar but opposite patterns for weight gain., Conclusions: Weight loss benefit is dependent on weight loss magnitude and initial BMI, and weight gain is associated with a similar risk increase. Four patterns of association were identified between degree of weight change, baseline BMI and 13 ORCs., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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. Furthermore, a meta-analysis found that overweight/obesity significantly worsened metabolic and reproductive outcomes in women with PCOS., Study Design, Size, Duration: Data were extracted from the UK Clinical Practice Research Datalink GOLD database. Patients included women aged 18-45 years with BMI ≥18.5 (Study 1) or ≥25 kg/m2 (Study 2) at time of PCOS diagnosis (index date). The primary outcome was the time to first pregnancy recorded during 36-months' follow-up, analysed with Cox proportional hazard models and presented as hazard ratios (HRs)., Participants/materials, Setting, Methods: Study 1 included 9955 women with PCOS. Study 2 included 7593 women with PCOS and median BMI of 34.0 kg/m2., Main Results and the Role of Chance: Higher BMI was associated with a lower chance of pregnancy in the 3 years following diagnosis. It was estimated that 41% of women with normal weight (18.5-24.9 kg/m2) would become pregnant compared to 17% of women with obesity class III (BMI ≥40.0 kg/m2) during follow-up. Furthermore, the chance of pregnancy for women with obesity class III was estimated to be 63% lower than for women with normal weight, with the same age and glycaemic status (HR 0.37, 95% CI 0.31-0.44; P < 0.0001). A significant inverse association was found between BMI change and chance of pregnancy: 10% weight loss was estimated to increase the chance of pregnancy by 68% for women with baseline BMI of 40 kg/m2 (HR 1.68, 95% CI 1.49-1.90)., Limitations, Reasons for Caution: Multiple factors influence the chance of pregnancy (the ability and willingness to become pregnant), which was addressed by exclusion criteria employed. The real-world nature of the study means that use of non-prescription contraceptives was not available. Bias may have been introduced by the fact that only around 40% of women with PCOS in the CPRD GOLD database had their BMI recorded during the year prior to PCOS diagnosis. BMI categories used in the analyses may not be applicable to women of all ethnicities. The study population was only representative of women in the UK and results may not be generalizable to other regions. PCOS diagnoses were based on codes entered into the system by primary care providers, and no information was available regarding the criteria used for diagnosis, although symptoms used to diagnose PCOS have not changed over time., Wider Implications of the Findings: Our observations provide further evidence of the benefits of weight loss in women with overweight/obesity and PCOS who are seeking to become pregnant., Study Funding/competing Interest(s): Novo Nordisk A/S. A.H.B. declares fees for consultancy from Novo Nordisk. P.N.L. and C.L.H. are employees of Novo Nordisk. V.S. and A.V. are employees of, and hold shares in, Novo Nordisk., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

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. To obtain model inputs, we conducted a systematic literature review (SLR) to identify data on the prevalence of obesity and its complications in Saudi Arabia, and surveyed specialist physicians and hospital administrators in public (governmental) and private healthcare sectors. We used combinations of age, sex, obesity and type 2 diabetes (T2D) rates in Saudi Arabia to sample a United Kingdom (UK) cohort, creating a synthetic Saudi Arabia cohort expected to be representative of the population., Results: The synthetic Saudi Arabia cohort reflected expected comorbidity prevalences in the population, with a higher estimated prevalence of T2D, hypertension and dyslipidaemia than the UK cohort in all age groups. For 100,000 people with body mass index 30-50 kg/m 2 , it was estimated that 15% weight loss would lead to a 53.9% reduction in obstructive sleep apnoea, a 37.4% reduction in T2D and an 18.8% reduction in asthma. Estimated overall cost savings amounted to 1.026 billion Saudi Arabian Riyals; the largest contributors were reductions in T2D (30% of total cost savings for year 10), dyslipidaemia (26%) and hypertension (19%)., Conclusions: Sustained weight loss could significantly alleviate the burden of obesity-related complications in Saudi Arabia. Adopting obesity reduction as a major policy aim, and ensuring access to support and treatment should form an important part of the transformation of the healthcare system, as set out under 'Vision 2030'., (© 2023. The Author(s).)

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 2 ) 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. Cox proportional hazard models were used to estimate the benefit of weight loss by preventing incident cases of 10 obesity-related outcomes., Results: In the study cohort ( n  = 314,079), the 30-34.9 BMI category contributed two-thirds of the cohort, and no gender differences were found in the age distribution of BMI categories. The elderly population had a higher prevalence of obesity-related outcomes, such as hypertension, osteoarthritis, and type 2 diabetes mellitus (T2DM). The baseline cost (2023) for treating these outcomes was USD 1.245 billion, which could double in 10 years. A 15% weight loss could save USD 1.295 billion over 10 years, with most savings due to T2DM (USD 430 million), given its higher prevalence (27.5%). The model was most sensitive to cost variability in T2DM, dyslipidemia, and hypertension., Limitations: The results should be interpreted within the bounds of the study cohort, and Nphies is in its early stages of implementation. The cost estimates may differ if repeated among adults with obesity only, potentially leading to increased cost savings with weight loss., Conclusions: Moderate weight loss of 5-15% over 10 years is associated with substantial cost savings in Saudi Arabia. For a 15% weight loss, 18.8% of incidence cases of obesity-related outcomes may be prevented, and slowed increases in T2DM, dyslipidemia, and hypertension may lead to considerable cost savings. The findings would help policymakers to implement weight loss programs in KSA.

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). They were categorised by their weight pattern between year 1 post-index and year 4 post-index (baseline period) as having stable weight (-5% to +5%) or weight loss (-25% to -10%, plus evidence of intervention or dietary advice to confirm intention to lose weight). For inclusion, individuals also required a BMI of 25.0-50.0 kg/m 2 at the start of the follow-up period, during which the occurrence of ten obesity-related outcomes was recorded. Cox proportional hazard models adjusted for BMI, comorbidities, age, sex and smoking status were used to estimate relative risks for weight loss compared with stable weight. Individuals in the weight-loss cohort had median 13% weight loss. Assuming a BMI of 40 kg/m 2 before weight loss, this resulted in risk reductions for T2D (41%), sleep apnoea (40%), hypertension (22%), dyslipidaemia (19%) and asthma (18%). Furthermore, weight loss was associated with additional benefits, with lower risk of T2D, chronic kidney disease, hypertension and dyslipidaemia compared with maintaining the corresponding stable lower BMI throughout the study. This study provides objective, real-world quantification of the effects of weight loss on selected outcomes, with the greatest benefits observed for the established CVD risk factors T2D, hypertension and dyslipidaemia.

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., Methods: Demographic data and diagnosis codes were extracted from the Clinical Practice Research Datalink GOLD database in January 2019. Adults registered for ≥ 3 years were grouped by BMI, with BMI 18.5-24.9 kg/m 2 as reference group. Associations between BMI and 12 obesity-related outcomes were estimated using Cox proportional hazard models, adjusted for age, sex, and smoking., Results: More than 2.9 million individuals were included in the analyses and were followed up for occurrence of relevant outcomes for a median of 11.4 years during the study period. Generally, there was a stepwise increase in risk of all outcomes with higher BMI. Individuals with BMI 40.0-45.0 kg/m 2 were at particularly high risk of sleep apnea (hazard ratio [95% confidence interval] vs. reference group: 19.8 [18.9-20.8]), T2D (12.4 [12.1-12.7]), heart failure (3.46 [3.35-3.57]), and hypertension (3.21 [3.15-3.26])., Conclusions: This study substantiates evidence linking higher BMI to higher risk of a range of serious health conditions, in a large, representative UK cohort. By focusing on obesity-related conditions, this demonstrates the wider clinical impact and the healthcare burden of obesity, and highlights the vital importance of management, treatment approaches, and public health programs to mitigate the impact of this disease., Competing Interests: Christiane L. Haase, Kirsten T. Eriksen, Sandra Lopes, Altynai Satylganova and Volker Schnecke are employees of Novo Nordisk A/S. Altynai Satylganova and Sandra Lopes are also shareholders of Novo Nordisk A/S. Phil McEwan is an employee of Health Economics and Outcomes Research Ltd. Phil McEwan did not receive funding for this collaboration. HEOR Ltd have received funding from Novo Nordisk A/S for work conducted on previous studies., (© 2020 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

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. Incident CKD subjects were selected from a prevalent population with diabetes (T2DM). Subjects from the UK Clinical Practice Research Data Link GOLD (CPRD) were followed from CKD diagnosis ( n  = 30,222) until heart failure (HF), myocardial infarction (MI), ischemic stroke (IS), or a composite end point including all 3 event types (MACE plus), mortality, database dropout, or end of study follow-up., Results: Both the updated eGFR slope and updated mean eGFR were associated with MACE plus and HF. Updated eGFR slope decline of > -3 ml/min/1.73 m 2 increased the risk for MACE plus (adjusted hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.26-1.67), HF (HR = 1.50; 95% CI, 1.27-1.76), and MI (HR = 1.39; 95% CI, 1.01-1.91)., Conclusions: This study strongly supports current evidence that CKD is an independent risk factor for CVD. From a clinical perspective, both rate of progression and cumulative status of CKD describe distinct aspects of the cardiorenal risk among persons with diabetes. This evidence is essential to enable more timely and improved use of treatments in this population., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

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., Methods: We determined the drive on PGD2 secretion by glucose and IL-1beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro. To test if metabolic control would be improved by antagonizing a hyperglycemia-driven increased PGD2 tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m2). The randomized, double-blind, placebo-controlled cross-over study consisted of two three-day treatment periods (AZD1981 or placebo) separated by a three-day wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose infusion (GGI) was performed at start and end of each treatment period. Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, GLP-1, and PGD2 pathway biomarkers were performed., Results: We found (1) that PGD2 is produced in human islet in response to high glucose or IL-1beta, but likely by stellate cells rather than endocrine cells; (2) that PGD2 suppresses both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. However, AZD1981 had no impact on neither glucose nor incretin dependent insulin secretion in humans (GGI AUC C-peptide 1-2h and MMTT AUC Glucose 0-4h LS mean ratios vs placebo of 0.94 (80% CI of 0.90-0.98, p = 0.12) and 0.99 (90% CI of 0.94-1.05, p = 0.45), despite reaching the expected antagonist exposure., Conclusion/interpretation: Pharmacological inhibition of the PGD2-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients., Trial Registration: ClinicalTrials.gov NCT02367066., Competing Interests: All authors apart from MH, LM and EW are employees or shareholders of AstraZeneca AB. MH, LM, and EW received funding as a contract research organization by AstraZeneca for the clinical study. EW is affiliated with ProSciento Inc. There are no patents, products in development, or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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 2 ] 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. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation., Results: Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 μmol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW., Conclusions: Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation., Funding: AstraZeneca.

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 1C (HbA 1c ) metrics and HF was estimated using adjusted proportional hazard models. In the overall cohort (n=94 332), the increased risk for HF per 1% (10 mmol/mol) increase in HbA 1c was 1.15 (95% CI 1.13 to 1.18) for updated mean HbA 1c , and 1.06 (1.04 to 1.07) and 1.06 (1.04 to 1.08) for baseline HbA 1c and updated latest HbA 1c , respectively. When categorised, the hazard risk (HR) for the updated mean HbA 1c in relation to HF became higher than for baseline and updated latest HbA 1c above HbA 1c levels of 9%, but did not differ at lower HbA 1c levels. The updated latest variable showed an increased risk for HbA 1c <6% (42 mmol/mol) of 1.16 (1.07 to 1.25), relative category 6-7%, while the HRs for updated mean and baseline HbA 1c showed no such J-shaped pattern., Conclusions: Hyperglycaemia is still a risk factor for HF in persons with T2D of similar magnitude as in earlier cohorts. Such a relationship exists for current glycaemic levels, at diagnosis and the overall level but the pattern differs for these variables., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

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. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI)., Results: Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients., Conclusions: Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.

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., and followed from diagnosis until event of MI or end of study in 2013. Two subcohorts were defined: an early cohort with those diagnosed from 1997 to 2004 and a recent cohort with those diagnosed from 2004 to 2011. Association between each of three HbA1c metrics and MI was estimated using adjusted proportional hazards models., Results: In the overall cohort (n = 101,799), the risk increase for MI per 1% (10 mmol/mol) increase in HbA(1c) was higher for updated latest and updated mean HbA(1c) of 1.11 (95% CI 1.09-1.13) and 1.15 (1.13-1.18) than for baseline HbA(1c) of 1.05 (1.03-1.06). In the early subcohort, the corresponding risk estimates were greater than those in the recent subcohort. When categorized, the updated latest variable showed an increased risk for HbA(1c) <6% (42 mmol/mol), relative category 6-7%, in the recent but not in the early subcohort, with hazard ratios of 1.23 (1.08-1.40) and 1.01 (0.84-1.22), respectively., Conclusions: The two time-updated HbA(1c) variables show a stronger relation with MI than baseline HbA(1c). The risk association between HbA(1c) and MI has decreased over time. In recently diagnosed patients with type 2 diabetes, an increased risk of MI exists at a current HbA(1c) of <6.0% (42 mmol/mol)., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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., Approach and Results: Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up., Conclusions: The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk., (© 2015 American Heart Association, Inc.)

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. In this short review, we will describe how structure-based approaches can be used in the pharmaceutical industry to work away from CYP inhibition, with a focus on the opportunities and challenges. We will show two examples from our own work where structural information on CYP2C9 and CYP3A4 inhibitor complexes have been successfully exploited in ongoing drug discovery projects., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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. An original singleton hit from a high-throughput screen with micromolar levels of potency was optimised to give compounds with nanomolar activities. Key steps in this success were the introduction of an extra side-chain, which increased potency, and changing the linking functionality from a thioether to an ether, which led to improved potency and lipophilic ligand efficiency. This also led to more stable compounds with improved profiles in biological assays., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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. Computational chemistry tools are used in this context to predict properties, cluster hits, design focused libraries and search for close analogues to explore the potential of hit series. At the end of hit-to-lead, the project must commit to one, or preferably a few, lead series that will be refined during lead optimization and hopefully produce a drug candidate. Striving for the best possible decision is crucial because choosing the wrong series is a costly one-way street.

Screening for potential ligands and docking them into the binding sites of proteins is one of the main tasks in computer-aided drug design. Despite the progress in computational power, it remains infeasible to model all the factors involved in molecular recognition, especially when screening databases of more than 100,000 compounds. While ligand flexibility is considered in most approaches, the model of the binding site is rather simplistic, with neither solvation nor induced complementary usually taken into consideration. We present results for screening different databases for HIV-1 protease ligands with our tool Slide, and investigate the extent to which binding-site conformation, solvation, and template representation generate bias. The results suggest a strategy for selecting the optimal binding-site conformation, for cases in which more than one independent structure is available, and selecting a representation of that binding site that yields reproducible results and the identification of known ligands.

The three key challenges addressed in our development of SPECITOPE, a tool for screening large structural databases for potential ligands to a protein, are to eliminate infeasible candidates early in the search, incorporate ligand and protein side-chain flexibility upon docking, and provide an appropriate rank for potential new ligands. The protein ligand-binding site is modeled by a shell of surface atoms and by hydrogen-bonding template points for the ligand to match, conferring specificity to the interaction. SPECITOPE combinatorially matches all hydrogen-bond donors and acceptors of the screened molecules to the template points. By eliminating molecules that cannot match distance or hydrogen-bond constraints, the transformation of potential docking candidates into the ligand-binding site and the shape and hydrophobic complementarity evaluations are only required for a small subset of the database. SPECITOPE screens 140,000 peptide fragments in about an hour and has identified and docked known inhibitors and potential new ligands to the free structures of four distinct targets: a serine protease, a DNA repair enzyme, an aspartic proteinase, and a glycosyltransferase. For all four, protein side-chain rotations were critical for successful docking, emphasizing the importance of inducible complementarity for accurately modeling ligand interactions. SPECITOPE has a range of potential applications for understanding and engineering protein recognition, from inhibitor and linker design to protein docking and macromolecular assembly.