bluuebunny/crossref_metadata_2025_split huggingface dataset:
NOD1 Mediates Insulin Resistance in Response to Circulating Free Fatty Acids
Authors: RIVERS SYDNEY L. , YEUNG LUCY SHU NGA , CHAN KENNY L. , MORI YUSAKU , PHILPOTT DANA , KLIP AMIRA , GIACCA ADRIA 
Published: June 2018

Insulin resistance (IR) in type 2 diabetes (T2D) is associated with chronic low-grade inflammation. We have shown that nucleotide binding oligomerization domain (NOD)1, an intracellular pattern recognition receptor for bacterial wall peptidoglycans, is a factor linking the innate immune system to the development of high fat diet-induced IR. Although high fat diet may result in NOD1 activation via increased intestinal absorption of bacterial products, NOD1 has also been shown to be activated by saturated fatty acids in intestinal cells and adipocytes. We hypothesize that NOD1 plays a role in IR caused by chronic high levels of circulating free fatty acids (FFA) as found in obesity and T2D. Wild type (WT) and NOD1-/- mice were infused with ethylpalmitate (resulting in raised circulating palmitate) or ethanol vehicle as a control, for 48 hours to model prolonged elevation of circulating FFA in vivo. Hyperinsulinemic-euglycemic clamp with tracer methodology was then used to assess peripheral and hepatic insulin sensitivity. WT mice treated with ethylpalmitate had decreased peripheral and hepatic insulin sensitivity expressed as stimulation of glucose utilization (Control= 123%±30 and Ethylpalmitate= 25%±25, p&lt;.05) and suppression of glucose production (Control= 51%±10 and Ethylpamitate= 22%±2, p&lt;.05). NOD1-/- mice were protected from palmitate induced IR, showing no difference in stimulation of glucose utilization (Control= 289%±27 and Ethylpalmitate= 352%±64) and suppression of glucose production (Control= 63%±16 and Ethylpalmitate= 95%±25) with or without palmitate. Thus, our data provide compelling evidence that NOD1 activation via elevated plasma FFA contributes to the development of peripheral and hepatic IR.

Disclosure
S.L. Rivers: None. L. Yeung: None. K.L. Chan: None. Y. Mori: None. D. Philpott: None. A. Klip: None. A. Giacca: None.
Association between Diabetes Mellitus and Urinary Incontinence in Elderly Patients
Authors: VU HUYEN T. 
Published: June 2018

Background and Aim: Urinary incontinence (UI) has been known as a problem associated with diabetes, especially in elderly. The aging process and geriatric syndromes contribute to the incidence of UI. The aim of the study was to assess UI and related factors in elderly diabetic patients.
Materials and Methods: We conducted a cross-sectional study on 322 diabetic patients aged ≥ 60 years, who were admitted to the National Geriatric Hospital from December 2016 to December 2017. The 3 Incontinence Questions (3IQ) was used to identify the prevalence of UI and its classification. Information on socio-demography, medical history, glycaemic control [fasting plasma glucose (FPG) and HbA1c], co-morbidities (Charlson index), polypharmacy, and cognitive impairment were assessed to investigate the relationship of diabetes mellitus and UI.
Results: Three hundred twenty two patients were recruited. Age of subjects was ranging between 60 and 96 years old (average age: 74.8 ± 8.28 years). The prevalence of UI among patients with diabetes was 65.2%. The prevalence of urge, stress, overflow and mixed incontinence were 36.7%, 36.2%, 17.6% and 9.5%, respectively. Advanced age and overweight status were associated with UI (p&lt;0.05). The level of FPG and HbA1c among the incontinence diabetic patients were significantly higher than those in the continence diabetic patients (p&lt;0.05). Multiple logistic regressions revealed risk factors for UI including: age &gt; 70 years old (OR: 1.7, 95% CI: 1.1-2.7, p&lt;0.05); history of pelvic surgery (OR:4.5, 95% CI: 1.6-12.8, p&lt;0.05); long duration of diabetes (OR:2.8, 95% CI:1.6-4.9, p&lt;0.001); Charlson index (OR: 2.7, 95% CI: 1.7-4.3, p&lt;0.001); polypharmacy (OR: 2.9, 95% CI: 1.4-5.7, p&lt;0.05); cognitive impairment (OR:40.5, 95% CI: 5.0-329.9, p=0.001).
Conclusion: Advanced age, long duration of diabetes, the level of FPG and HbA1c, comorbidities, polypharmacy and cognitive impairment were associated with increased risk of urinary incontinence in elderly diabetic patients.

Disclosure
H.T. Vu: None.
Acute Increase in Creatinine after Starting ACE Inhibitor and Vascular Events and Premature Death in Patients with Type 2 Diabetes—The ADVANCE Trial
Authors: OHKUMA TOSHIAKI , JUN MIN , WOODWARD MARK , CHALMERS JOHN , PERKOVIC VLADO , RODGERS ANTHONY 
Published: June 2018

Background: An acute increase in serum creatinine (AICr) after starting ACE inhibitor is frequently observed, and consideration of discontinuation has been recommended if creatinine values increased 30% or more. However, the long term effect of continuation or discontinuation of that therapy is unclear.
Objective: To examine the association of AICr after starting a fixed combination of perindopril-indapamide and its continuation or discontinuation, with clinical outcomes using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.
Research Design and Methods: A total of 11,140 diabetes patients were randomly assigned to a fixed combination of perindopril-indapamide or placebo after a 6-week active run-in period. These analyses included 11,066 patients with 2 measurements of serum creatinine, before and during the active run-in period (3 weeks apart). AICr was determined using these 2 measurements, classified into 4 groups: &lt;10%, 10-19%, 20-29%, and ≥30%.
Results: AICr after starting perindopril-indapamide in the run-in period was subsequently associated with an increased risk of a composite of major macrovascular events, new or worsening nephropathy, all-cause mortality, in both randomized groups (P for trend &lt;0.for each). However, a consistent benefit of randomized treatment for the outcome was observed across subgroups defined by AICr, with no heterogeneity in the magnitude of the effects (P for heterogeneity = 0.94). Similar results were observed for major macrovascular events alone, new or worsening nephropathy alone, and all-cause mortality alone.
Conclusions: AICr after starting ACE inhibitor was associated with an increased risk of clinical outcomes, irrespective of continuation or discontinuation of the therapy. However, randomized treatment effects are consistent and beneficial across subgroups defined by AICr.

Disclosure
T. Ohkuma: None. M. Jun: None. M. Woodward: None. J. Chalmers: Research Support; Self; Servier. Other Relationship; Self; Servier. V. Perkovic: Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Consultant; Self; AbbVie Inc.. Advisory Panel; Self; Janssen Global Services, LLC.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novartis Pharmaceuticals Corporation, AstraZeneca, Gilead Sciences, Inc.. Consultant; Self; Servier. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. A. Rodgers: Other Relationship; Self; George Health Enterprises.
Increased Cardiovascular Risk in Patients with Diabetes, Statin-Controlled LDL Cholesterol, and Residual Hypertriglyceridemia
Authors: NICHOLS GREGORY , PHILIP SEPHY , GRANOWITZ CRAIG B. , REYNOLDS KRISTI , FAZIO SERGIO 
Published: June 2018

High triglyceride (TG) levels are common in type 2 diabetes (T2D). We evaluated T2D patients at high risk for CV events who had statin-controlled LDL cholesterol (LDLc) to determine whether the presence of high TG levels contribute to residual CV risk. We combined data from the Southern California and Northwest regions of Kaiser Permanente to identify adults on statin therapy with LDLc 40-100 mg/dL, no other lipid therapies, and with T2D and a prior diagnosis of myocardial infarction, ischemic stroke, peripheral artery disease or at least one other CV risk factor. Patients were grouped into high (200-499 mg/dL, n=5,542) or normal (&lt;150 mg/dL, n=22,411) TGs in 2010 and followed them through December 2016 to compare the adjusted incidence rates and rate ratios of first non-fatal MI, non-fatal stroke, unstable angina, coronary revascularization, death, and their composite. Models were adjusted for demographic and clinical characteristics using generalized linear models with Poisson errors. Over mean follow-up of 5 years, patients with high TG were at increased risk of CV outcomes (Table). High TG levels independently increase CV risk in T2D patients with statin-controlled LDLc. The ongoing CV outcome trial, REDUCE-IT, will determine if high dose pure prescription eicosapentaenoic acid reduces CV risk among statin users with persistently high TG levels, including T2D patients.

Disclosure
G. Nichols: Research Support; Self; Boehringer Ingelheim GmbH, Amarin Corporation, Janssen Pharmaceuticals, Inc., Sanofi. S. Philip: Stock/Shareholder; Self; Amarin Corporation. Employee; Self; Amarin Corporation. C.B. Granowitz: Employee; Self; Amarin Corporation. K. Reynolds: Research Support; Self; Amarin Corporation, Novartis Pharmaceuticals Corporation, Amgen Inc., CSL Behring. S. Fazio: Consultant; Self; Amarin Corporation, Akcea Therapeutics, Amgen Inc., Kowa Pharmaceuticals America, Inc..
Impact of Prior Coronary Artery Disease (CAD) and Glucose Tolerance Status (GTS) on Incident CAD in Japanese Men
Authors: KITAZAWA MASARU , FUJIHARA KAZUYA , HARADA MAYUKO , ISHIZAWA MASAHIRO , YAMAMOTO MASAHIKO , KANEKO MASANORI , OSAWA TAEKO , YAMADA TAKAHO , MATSUBAYASHI YASUHIRO , SONE HIROHITO 
Published: June 2018

Despite a decade of historical debate and the recent rebuttal regarding “diabetes mellitus (DM) as a CAD risk equivalent”, few studies have evaluated the impact of prediabetes (preDM) separately. Thus, it is still possible that the impact of DM has been underestimated unless preDM is excluded from the nondiabetic category and independently assessed along with normal glucose tolerance (NGT) and DM. To clarify the independent risk of NGT, preDM and DM with and without prior CAD for incident CAD, we analyzed data using a nationwide claim-based database that included 138,162 men (NGT 78,230; preDM 45,610; DM 14,322) aged 18-72 y in Japan. Multivariate Cox analysis showed that the impact of preDM on CAD was modest compared to DM even with prior CAD (Model 1, Table) whereas prior CAD confers a 5-8-fold excess risk for CAD regardless of GTS (Model 2, Table). The hazard ratio (HR) of CAD in NGT individuals with prior CAD was much higher than in DM individuals without prior CAD (HR 3.08(95% CI 2.08-4.54)). The HR in those with both DM and prior CAD was 15.7(11.8-21.0) compared to NGT without prior CAD.
In conclusion, DM alone is not prior CAD risk-equivalent even if the influence of preDM is eliminated. Prior CAD confers a far higher risk for subsequent CAD regardless of GTS. Necessity of intense intervention for the secondary prevention of CAD is implied considering the enormously high risk in those with both DM and prior CAD.

Disclosure
M. Kitazawa: None. K. Fujihara: None. M. Harada: None. M. Ishizawa: None. M. Yamamoto: None. M. Kaneko: None. T. Osawa: None. T. Yamada: None. Y. Matsubayashi: None. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..
Sex Differences in Coronary Artery Disease Patients With and in Those Without Type 2 Diabetes
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN DANIELA , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ 
Published: June 2018

Life-term cardiovascular risk is high also in women, and women with coronary artery disease (CAD) or with type 2 diabetes (T2DM) are at a particularly high risk. In this prospective cohort study, we addressed sex differences in CAD patients with as well in those without T2DM. We recorded cardiovascular events in an unselected consecutive series of 1472 patients with angiographically proven CAD over 7.5±2.9 years. T2DM prevelance was similar in men (n=1060) and women (27.3 vs. 30.1%; p=0.277). Among nondiabetic CAD patients women were older than men (68±9 vs. 63±11 years; p&lt;0.001), had higher LDL cholesterol (138±42 vs. 130±38 mg/dl; p=0.022) and HDL cholesterol (63±16 vs. 51±14 mg/dl; p&lt;0.001) and a lower prevelance of smoking (35.5 vs. 69.6%; p&lt;0.001) and of prior myocardial infarction (20.6 vs. 31.2%; p=0.001). Among those with T2DM, women also were older (69±9 vs. 64±10 years; p&lt;0.001), had higher HDL cholesterol (53±14 vs. 46±13 mg/dl; p&lt;0.001) and a lower prevalence of smoking (28.6 vs. 80.1%; p&lt;0.001); further among those with T2DM the prevelance of hypertension (79.9 vs. 70.7%; p=0.049) and of statin use (66.9 vs. 48.3%; p&lt;0.001) was higher in women. Prospectively, sex did not predict cardiovascular events in CAD patients without nor in those with T2DM, with adjusted hazard ratios of 0.96 [0.73-1.26]; p=0.757 and 0.82 [0.55-1.22]; p=0.329, respectively. We conclude that baseline risk factors both among CAD patients without and among those with T2DM differ between women and men, whereas irrespective of diabetes status sex does not affect the incidence of future cardiovascular events in this population.

Disclosure
C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin: None. B. Larcher: None. A. Mader: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
Comparative Cardiovascular Effectiveness of SGLT2 Inhibitors vs. Liraglutide in Routine Care
Authors: PATORNO ELISABETTA , EVERETT BRENDAN M. , SCHNEEWEISS SEBASTIAN , GLYNN ROBERT J. , LIU JUN , KIM SEOYOUNG C. 
Published: June 2018

Both SGLT2 inhibitors (canagliflozin and empagliflozin) and liraglutide have shown cardiovascular (CV) benefits in CV outcome trials. Whether these agents are associated with differential CV effects in routine care remains unexplored. In a large commercial U.S. health insurance database (4/2013-9/2015), we assessed the comparative CV risk of SGLT2 inhibitors (SGLT2i) vs. liraglutide in patients with type 2 diabetes. We used 1:1 propensity score (PS) matching to balance over 100 baseline characteristics. We estimated the hazard ratio (HR) of a combined CV outcome (hospitalization for myocardial infarction (MI) or stroke) and heart failure hospitalization (HHF). Secondary outcomes included an expanded combined CV outcome (hospitalization for MI, stroke, unstable angina, or coronary revascularization) and individual MI or stroke hospitalization. Over 30 months, SGLT2i initiators had no significant difference in the risk of the combined CV outcome (HR= 1.01 [95% CI 0.76-1.34]) or other secondary CV outcomes, but had an approximately 30% decrease in the risk of HHF (HR= 0.68 [0.52-0.88]), compared with liraglutide (Table). Subgroup analyses in patients with and without baseline CV disease produced largely consistent results.
In conclusion, this study rules out large differences in atherosclerotic CV risk between SGLT2i and liraglutide, but supports larger benefits of SGLT2i vs. liraglutide for HHF.

Disclosure
E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim GmbH, GlaxoSmithKline plc. B.M. Everett: Research Support; Self; Roche Diagnostics Corporation, Novartis Pharmaceuticals Corporation. Consultant; Self; Roche Diagnostics Corporation, Abbott Laboratories, Novartis Pharmaceuticals Corporation, U.S. Food and Drug Administration, UpToDate. Other Relationship; Self; American College of Cardiology. S. Schneeweiss: Consultant; Self; WHISCON, LLC. Other Relationship; Self; Aetion, Inc.. Research Support; Self; Genentech, Inc., Bayer AG, Boehringer Ingelheim GmbH, U.S. Food and Drug Administration, Patient-Centered Outcomes Research Institute. R.J. Glynn: Research Support; Self; Pfizer Inc., Novartis AG, Kowa Pharmaceuticals America, Inc.. J. Liu: None. S.C. Kim: None.
Epigenetic Link between Statin Use and Diabetes
Authors: OCHOA-ROSALES CAROLINA , PORTILLA-FERNANDEZ ELIANA , WILSON RORY , NANO JANA , GHANBARI MOHSEN , RUEDA-OCHOA OSCAR L. , LEHTIMÄKI TERHO , GAO XU , LEHNE BENJAMIN , VOORTMAN TRUDY , FRANCO OSCAR , MUKA TAULANT 
Published: June 2018

Current evidence associates statin use with increased risk of type 2 diabetes (T2D). Mechanism are unclear. Statins may impact DNA methylation, a key regulator in gene expression. We conducted an epigenome-wide association study among 8313 Europeans (7163 never users and 1150 current statin users) from 7 cohorts to assess the association of statin use and DNA methylation in blood. After replication we found genome-wide associations of methylation sites annotated to DHCR24 (cg17901584, cg10177197), SC4MOL (cg05119988), and ABCG1 (cg06500161, cg27243685), which are involved in cholesterol, insulin and lipoprotein lipase pathways. Cg06500161 hypermethylation was related to decreased ABCG1 expression in two probes (P = 5 x 10-12 and 9 x 10-13), lower high density lipoprotein cholesterol (HDL, P = 0.002) and higher triglycerides (P = 1 x 10-4). Mendelian Randomization suggested that HDL and triglycerides might be a consequence of cg06500161 rather than a cause. Lower methylation of cg17901584 was associated with higher insulin (P = 0.006). Prevalent T2D was related to all sites except cg27243685 (P from 6 x 10-10 to 9 x 10-4). Only cg06500161 independently predicted incident T2D (P = 6 x 10-7), implicating that ABCG1 may be a causal factor for T2D as suggested by Mendelian Randomization (Figure 1). Our study is the first to provide evidence of DNA methylation as potential mechanism by which statin use can lead to adverse metabolic alterations and subsequently T2D.

Disclosure
C. Ochoa-Rosales: None. E. Portilla-Fernandez: None. R. Wilson: None. J. Nano: None. M. Ghanbari: None. O.L. Rueda-Ochoa: None. T. Lehtimäki: None. X. Gao: None. B. Lehne: None. T. Voortman: None. O. Franco: None. T. Muka: Employee; Self; Novo Nordisk A/S.
Screening Patients for Diabetes in a Large, National Clinical Database
Authors: STEMPNIEWICZ NIKITA , CUDDEBACK JOHN K. , RATTELMAN CORI R. , CIEMINS ELIZABETH L. 
Published: June 2018

Objective: To characterize diabetes screening patterns among eligible patients per ADA Standards of Medical Care in Diabetes using a large, geographically diverse clinical dataset.
Study Design: Retrospective descriptive analysis conducted in a clinical database containing over 25 million patient records. Population Studied: A total of 5.1 million patients aged 18-75 in 23 health care organizations (HCOs) with at least one outpatient visit in the study period (7/2016-6/2017), no prior diagnosis of diabetes mellitus, and no prior diabetes medication prescriptions (except metformin).
Principal Findings: Among 5.1 million patients, 74% were eligible for screening and 55% were screened according to guidelines. Adequate screening ranged from 47%-76% across 23 HCOs. Adults 65 and older were most likely to be adequately screened (61%; P &lt; .01). Least likely to be screened were patients with low-income insurance types (P &lt; .01); non-white race (P &lt; .01) or lower education by zip code (P &lt; .01). Of 1.7 million patients screened, 2.8% and 36.5% had evidence of diabetes and prediabetes, respectively. Diabetes/prediabetes was identified in 30% of patients aged 35-44 and 48% of patients 65 and older. Patients with lower education were less likely to be adequately screened, but yielded greater rates of diabetes/prediabetes, 47% to 39% from least to most educated (P &lt; .01). More African Americans (46%) screened positive for diabetes/prediabetes compared to other race/ethnicities (42%) (P &lt; .01).
Conclusions: Screening practices vary greatly, mostly within and across HCOs. Patients least likely to be adequately screened were often those with highest yields of diabetes/prediabetes. The identification of inadequately screened, low-income, lower education, or race/ethnic minority populations may facilitate targeted efforts to decrease disparities in screening practices. Identification of organizations with the highest net yield may also provide insight into strategies for efficient screening practices.

Disclosure
N. Stempniewicz: None. J.K. Cuddeback: Research Support; Self; Novo Nordisk Inc.. Other Relationship; Self; Johnson & Johnson Diabetes Institute, LLC., Merck & Co., Inc., Sanofi US, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. C.R. Rattelman: None. E.L. Ciemins: None.
Heterogeneity between Pharmacoepidemiological Studies Using the Clinical Practice Research Datalink (CPRD)
Authors: KOECHLIN ALICE , BOYLE PETER , AUTIER PHILIPPE 
Published: June 2018

The CPRD has been collecting medical data among UK patients since 1987. Many studies on the risk of cancer associated with prescription of antidiabetic drugs have used the CRPD database. The objective was to compare methods and results of studies on the same exposure and outcome combination based on the CPRD.A systematic Pubmed search of articles on diabetes and cancer based on the CPRD was performed. Articles were grouped into common exposure and outcome combinations. Methods and results were compared, especially in case of diverging results between studies, with a focus on study design and statistical methods. Forty-six studies were identified. Five of them studied colorectal cancer (CRC) occurrence in diabetic patients prescribed with metformin. All studies consistently found no significant increased or decreased CRC risk associated with metformin prescription. Five studies examined the risk of bladder cancer in relation to pioglitazone prescription. Two studies found a significantly increased risk of bladder cancer, one based on the analysis of the full dataset and one based on a nested case-control design using conventional matching procedures. The three other studies found no association, all of which used propensity score matched cohort design. Four studies investigated the risk of breast cancer among insulin glargine users. The three studies that included diabetic subjects who were prescribed glargine or another insulin therapy for the first time (i.e., the new user design) found no association. The study that included past and new users of glargine and of another insulin found a significantly increased risk. Despite the use of the same data source, studies on the same exposure and outcome may arrive at markedly different conclusions. Studies using propensity scores for matching subjects or including past users in cohorts may obtain results substantially different than studies using conventional statistical approaches.

Disclosure
A. Koechlin: None. P. Boyle: Other Relationship; Self; Sanofi. P. Autier: Other Relationship; Self; Sanofi.