bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality Risk of Noninsulin Glucose-Lowering Drugs in Type 2 Diabetes—A Network Meta-analysis of Observational Trials
Authors: BONGAERTS BRENDA , LINDNER LENA M. , HOYER ANNIKA , KUSS OLIVER , HERDER CHRISTIAN , AL-HASANI HADI , MÜSSIG KARSTEN , RODEN MICHAEL , RATHMANN WOLFGANG 
Published: June 2018

Given the short-comings of randomized controlled trials, such as low numbers of patients and events, we aimed to perform a network meta-analysis of observational trials on the effects of non-insulin glucose-lowering drugs on all-cause and cardiovascular mortality in type 2 diabetes.
We searched MEDLINE and EMBASE through August 2017. From the 38 eligible studies, we extracted patient characteristics, exposure, outcome, confounder-adjusted effect measures, and risk of bias. All-cause and cardiovascular mortality risk were assessed with random-effects network meta-analysis.
In 32 studies reporting on all-cause mortality (1,661,945 persons) and in 11 studies on cardiovascular mortality (358,784 persons), 119,591 (7.2%) and 9,221 (2.6%) persons, respectively, died during follow-up. Compared to metformin, sulfonylurea drugs (SU) increased all-cause mortality risk (HR: 1.42 (95% CI: 1.29-1.56)). Dipeptidyl peptidase-4 inhibitors (DDP4i) added to metformin significantly decreased all-cause mortality risk compared to metformin monotherapy (HR: 0.76 (0.63-0.93)), any other drug class as monotherapy, and SU + metformin dual therapy (HR: 0.69 (0.60-0.79)). DPP-4i + metformin dual therapy was associated with even larger reductions in risk of cardiovascular mortality; HR: 0.40 (0.21-0.79) when compared to metformin monotherapy, and HR: 0.41 (0.23-0.74) when compared to SU + metformin dual therapy. Glucagon-like-peptide-1 receptor agonists + metformin dual therapy tended to, but did not significantly, decrease mortality risk when compared to metformin monotherapy (all-cause mortality, HR: 0.88 (0.53-1.47); cardiovascular mortality, HR: 0.74 (0.30-1.82)).
In conclusion, this large network meta-analysis evidently confirmed that SU, compared to metformin, increased all-cause mortality risk. DPP-4i + metformin dual therapy, compared to other treatments, resulted in a consistent risk reduction of both all-cause and cardiovascular mortality.

Disclosure
B. Bongaerts: None. L.M. Lindner: None. A. Hoyer: None. O. Kuss: None. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company. H. Al-Hasani: None. K. Müssig: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. W. Rathmann: Advisory Panel; Self; AstraZeneca. Research Support; Self; Novo Nordisk A/S.
Accuracy of Daily Foot Temperature Monitoring for Patients with Recently Healed Diabetic Foot Ulcers or History of Amputation
Authors: GORDON IAN L. , NOUVONG AKSONE , NAJAFI BIJAN , ROTHENBERG GARY M. , PETERSEN BRIAN , BLOOM JONATHAN D. , FRYKBERG ROBERT 
Published: June 2018

Diabetic foot ulcers (DFU) result in significant morbidity, mortality, and healthcare costs. Fortunately, recent data suggest as many as 75% of DFU and 60% of lower extremity amputations (LEA) may be preventable. Clinical practice guidelines recommend evidence-based foot temperature monitoring (thermometry) for preventing DFU and its complications in high-risk patients. Despite this, several authors have noted that thermometry is not commonly practiced. This is potentially due to lack of evidence on the accuracy of thermometry in some of the highest-risk cohorts, including those with a recently-healed DFU or with history of LEA. The former may present with ipsilateral inflammation as part of normal healing, while the latter may lack the anatomy required for direct contralateral comparison of temperatures. Whether these concerns affect the accuracy of thermometry needs to be assessed. A recent study suggests that a novel thermometric mat may address some barriers to adoption. The mat was found to predict as many as 97% of non-traumatic plantar DFU with an average lead time of five weeks in a cohort with history of DFU. In the current investigation, we hypothesized no difference in the predictive accuracy of thermometry in two subgroups: those who healed from a DFU fewer than three months before enrolling, and those with a history of partial LEA (Syme amputation or more distal). Of the 129 subjects studied, 31% had recently-healed DFU and 56% had history of LEA. Although no difference in DFU incidence was found in the LEA subgroup, we found significantly higher incidence in those with recently-healed DFU (0.88 vs. 0.63 DFU/subject/year). Importantly, we found no differences in accuracy or lead time in either cohort. These data suggest thermometry is appropriate for monitoring both recently-healed DFU or partial LEA patients. Utilization of thermometry in these high-risk patients may significantly reduce morbidity, mortality, and resource utilization.

Disclosure
I.L. Gordon: None. A. Nouvong: None. B. Najafi: None. G.M. Rothenberg: Consultant; Self; Podimetrics. B. Petersen: Employee; Self; Podimetrics, Inc.. Stock/Shareholder; Self; Podimetrics, Inc. J.D. Bloom: Employee; Self; Podimetrics, Inc. Board Member; Self; Podimetrics, Inc. Stock/Shareholder; Self; Podimetrics, Inc. R. Frykberg: None.
A Pooled Analysis of the Efficacy and Safety of Ertugliflozin as Add-On Therapy to Metformin
Authors: CALLE ROBERTO A. , LIU JIE , HUYCK SUSAN , WU LARRY , PONG ANNPEY , MANCUSO JAMES P. , TERRA STEVEN , LAURING BRETT 
Published: June 2018

Ertugliflozin (ERTU) is a highly selective sodium-glucose cotransporter 2 inhibitor in development for treatment of patients with type 2 diabetes mellitus (T2DM). This pooled analysis characterized the efficacy and safety of ERTU when used as add-on therapy to metformin (MET).
Pooled data from 2 randomized, double-blind, placebo-controlled Phase 3 studies with similar design and patient population (NCT02033889 [VERTIS MET], NCT02036515 [VERTIS SITA2]) were analyzed. Adult patients with T2DM inadequately controlled on MET (± sitagliptin) with A1C ≥7.0 to ≤10.5% were randomized to placebo (PBO), ERTU 5 mg or 15 mg for 26 weeks.
Mean baseline (BL) characteristics of patients (N=1083) were similar across pooled treatment groups (age 57.7 years; T2DM duration 8.6 years; A1C 8.1%; body weight [BW] 85.7 kg; systolic blood pressure [SBP] 130.6 mmHg; estimated glomerular filtration rate 89.4 mL/min/1.73 m2). Changes in A1C, BW and SBP after 26 weeks are shown in the Table. Relative to PBO, more patients receiving ERTU had A1C &lt;7.0%, BW reduction of ≥5%, or SBP &lt;130 mmHg (among patients with BL SBP ≥130 mmHg) at Week 26. ERTU had an overall similar safety profile to PBO, except for a higher incidence of adverse events (AEs) of genital mycotic infections and of AEs related to osmotic diuresis.
Addition of ERTU to MET (± sitagliptin) provides reductions in A1C, BW and SBP, resulting in more patients achieving metabolic treatment goals.Table. Changes from baseline in A1C, BW and SBP at Week 26Placebo (n=362)Ertugliflozin 5 mg (n=363)Ertugliflozin 15 mg (n=358)Least squares mean change from baseline in A1C at Week 26 (95% CI), % Placebo-adjusted difference–0.1 (–0.2, 0.0) ––0.8 (–0.8, –0.7) –0.7 (–0.8, –0.6)–0.9 (–1.0, –0.8) –0.8 (–1.0, –0.7)Patients with A1C &lt;7.0% at Week 26, n (%)59 (16.3)123 (33.9)143 (39.9)Least squares mean change from baseline in BW at Week 26 (95% CI), kg Placebo-adjusted difference–1.3 (–1.6, –1.0) ––3.2 (–3.4, –2.9) –1.8 (–2.3, –1.4)–3.0 (–3.3, –2.7) –1.7 (–2.1, –1.2)Patients with BW reduction ≥5% at Week 26, n (%)39 (10.8)115 (31.7)103 (28.8)Least squares mean change from baseline in SBP at Week 26 (95% CI), mmHg Placebo-adjusted difference–0.8 (–2.0, 0.5) ––4.1 (–5.3, –2.9) –3.4 (–5.1, –1.7)–4.9 (–6.1, –3.7) –4.1 (–5.8, –2.4)Patients with baseline SBP ≥130 mmHg (N) and with SBP &lt;130 mmHg (n) at Week 26, n/N (%)32/171 (18.7)70/192 (36.5)71/189 (40.7)

Disclosure
R.A. Calle: Employee; Self; Pfizer Inc.. J. Liu: None. S. Huyck: Employee; Self; Merck & Co., Inc.. L. Wu: None. A. Pong: None. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc. S. Terra: Employee; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc..
Increased Rates of Readmission, Reoperation, and Mortality following Open Reduction and Internal Fixation of Ankle Fractures Are Associated with Diabetes Mellitus
Authors: LIU JENNIFER , AHN JUNHO , RASPOVIC KATHERINE M. , WUKICH DANE 
Published: June 2018

The purpose of this large-scale retrospective study was to calculate the increased risk for postoperative unplanned readmission, unplanned reoperation, and mortality after ankle fracture ORIF in patients with diabetes mellitus (DM). Patients who underwent ORIF for ankle fractures from 20to 2015 were identified in ACS-NSQIP database. Patient demographics and 30-day postoperative readmission, reoperation, and mortality rates were compared in 2,044 patients with DM and 15,420 patients without DM. Adjusted odds ratios controlling for age differences were calculated for each parameter with a 95% confidence interval. Patient factors and pre-operative laboratory statistics are summarized in Figure D, and the distribution of ankle fractures for each group are shown in Figure A and B. Comparing patients with DM vs. without DM, the rate of readmission was 4.35% vs. 1.50%, rate of reoperation was 2.30% vs. 0.75%, and rate of mortality was 0.73% vs. 0.21%. As shown in Figure C, patients with DM had a 2.66 times increased risk of readmission, a 2.76 increased risk of reoperation, and a 2.34 increased risk of mortality. Interestingly, we also found a 22.increased risk of amputation, though the rate of amputation in both groups was very small. Ankle fractures requiring ORIF in patients with DM are serious events and associated with substantial morbidity.

Disclosure
J. Liu: None. J. Ahn: None. K.M. Raspovic: None. D. Wukich: None.
Tofogliflozin and Pemafibrate Combination Therapy Prevents Nonalcoholic Steatohepatitis (NASH) Development of Novel Metabolic Syndrome–Related NASH Model Mice
Authors: SASAKI YUSUKE , ASAHIYAMA MASATO , KAMIYA WAKANA , SAKAI JURO , KODAMA TATSUHIKO , TANAKA TOSHIYA 
Published: June 2018

Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and widely defined by the presence of steatosis with inflammation and progressive fibrosis that causes to the liver transplantation and hepatocellular carcinoma (HCC). Here, we developed a novel NASH/HCC model represented metabolic syndrome like phenotypes (obesity, hyperglycemia, and glucose intolerance), and evaluated the therapeutic potential of Tofogliflozin and Pemafibrate combination therapy on NASH development. Male C57BL/6J mice were injected multiple low dose STZ (40 mg/kg) for 5 days and fed high-fat diet (HFD). These mice revealed hyperglycemia and higher body weight gain, and glucose intolerance compared with wild type mice. In addition, novel NASH/HCC model shows sequential histological changes from fatty liver to NASH (20 weeks), and all mice developed hepatocellular carcinoma after 52-week HFD feeding. Using our NASH/HCC model, we conducted the prevention study of Tofogliflozin and Pemafibrate (mono-therapy or combination therapy) against NASH development. The combination therapy has significantly prevented body weight gain from 3 weeks after treatment and this effect was persisted throughout study. While Tofogliflozin or Pemafibrate treatment markedly decreased blood glucose and triglyceride levels, the combination therapy showed the synergistic effect compared to mono-therapy groups. Histological analysis revealed Tofogliflozin or combination therapy group markedly suppressed ER-TR7 (fibroblast) and ballooning degeneration. Furthermore, these treatment groups significantly improved NAS score (NAFLD activity score). These results suggested that Tofogliflozin/Pemafibrate combination therapy would be a beneficial for NASH/NAFLD treatment.

Disclosure
Y. Sasaki: Employee; Self; Kowa Company, Ltd. M. Asahiyama: Employee; Self; Kowa Company, Ltd.. Employee; Spouse/Partner; Kowa Company, Ltd.. W. Kamiya: None. J. Sakai: None. T. Kodama: Consultant; Self; Kowa Company, Ltd. T. Tanaka: Research Support; Self; Kowa Company, Ltd..
SGLT2i Dual Therapy with Metformin (Met) for Type 2 Diabetes Mellitus (T2DM)—Systematic Literature Review and Network Meta-analysis (NMA)
Authors: MCNEILL ANN MARIE , DAVIES GLENN M. , KRUGER ELIZA , REASON TIMOTHY , EJZYKOWICZ FLAVIA , HANNACHI HAKIMA , CATER NILO B. , MCLEOD EUAN 
Published: June 2018

Objective: Indirectly compare the efficacy and safety of ertugliflozin (ertu) from the VERTIS MET and FACTORIAL trials to other SGLT2i as an add-on to MET.
Methods: Pubmed, EMBASE and Cochrane databases were searched through to end 2016 for RCTs of 24-26 weeks duration in T2DM patients with uncontrolled A1C on MET. Comparators to ertu 5mg and 15mg were low and high doses of SGLT2i licensed in Europe and USA: canagliflozin (cana), dapagliflozin (dapa) and empagliflozin (empa). Included outcomes vs. placebo at 24-26 weeks were change in A1C, weight, systolic blood pressure (SBP), A1C &lt;7% and safety outcomes (urinary tract infections [UTIs], genital mycotic infections [GMIs], hypoglycemic events and patients with ≥1 adverse event [AE]). Evidence synthesis used both fixed effect (FE) and random effects (RE) Bayesian NMA, with model selection informed by guidelines. Credible intervals (CrI), analogous to 95% confidence intervals, were used to determine significance.
Results: The NMA included 7 RCTs. Ertu was significantly more effective in reducing A1C than dapa doses (ertu 5mg vs. dapa 5mg mean difference (MD): -0.22%, CrI -0.42, -0.02; ertu 15mg vs. dapa 10mg MD:-0.26%, CrI -0.46, -0.06) and ertu 15mg was superior to empa 25mg (MD: -0.23%, CrI -0.44, -0.03). There were no further significant differences between ertu and other SGLT2i for change in A1C, SBP, weight, A1C &lt;7%, UTIs or ≥1 AEs. Limited number of hypoglycemic and GMI events in placebo comparators resulted in non-convergence for these networks. The impact of heterogeneity was tested, but potential confounding due to differences in factors such as study design and patient population may remain.
Conclusions: Although reliant upon indirect comparison rather than head to head RCTs, ertu 5 and 15mg were superior to dapa 5 and 10mg, respectively, and ertu 15mg was superior to empa 25mg. Across remaining outcomes, both ertu doses added to MET were comparable to other SGLT2i.

Disclosure
A. McNeill: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc. G.M. Davies: Employee; Self; Merck & Co., Inc. E. Kruger: Employee; Self; QuintilesIMS. T. Reason: None. F. Ejzykowicz: Employee; Self; Merck Sharp & Dohme Corp. H. Hannachi: Employee; Self; Merck & Co., Inc. N.B. Cater: Employee; Self; Peter Sheehan Diabetes Care Foundation, Inc. E. McLeod: Employee; Self; Pfizer Inc..
Effect of SGLT2 Inhibition on Body Water Distribution and Its Relevance to Body Composition Measures
Authors: NAKAYAMA HITOMI , IWATA SHIMPEI , OHKI TSUYOSHI , NAGAYAMA AYAKO , YAMADA KENTARO , TAJIRI YUJI , NOMURA MASATOSHI 
Published: June 2018

Many studies have reported the effect of SGLT2 inhibition on body composition. However, its effect on water distribution and the resultant influence on body composition measures are still unclear. The subjects of this study consisted of 29 tofogliflozin (TOFO) -treated type 2 diabetic inpatients aged 48±14 years with BMI of 29.4±6.3 kg/m2, and 29 age- and BMI-matched type 2 diabetic inpatients treated with other therapies. TOFO was administered for 7 days at a dose of 20 mg/day without changing the dose of other drugs. Average glucose levels assessed by CGM decreased from 188±43 to 142±32 mg/dL. Body composition and fluid status were estimated using a multifrequency BIA. The TOFO and the control groups lost 1.64±0.95 and 0.80±0.74 kg body weight, together with 1.31±1.02 and 0.38±0.87 kg body fat, respectively. The reduction of skeletal muscle was not statistically significant due to large variation in either group (0.21±0.84 and 0.39±1.03 kg, respectively). Thus we further analyzed factors associated with the skeletal muscle reduction. Although the change in skeletal muscle mass was correlated with changes in both body fat and body water, a multiple regression analysis showed that the change in intracellular water was the independent factor. Intracellular water was decreased in the TOFO group by 0.29±0.61 kg, but not in the control group. Extracellular water was not changed in either group. Serum sodium concentration was increased in the TOFO group (140.0±1.9 to 141.0±2.7 mEq/L) but not in the control group. The reduction in intracellular water was strongly correlated with that in skeletal muscle in the TOFO group (r=0.863), although there was an inverse correlation in the control group (r=-0.469). These observations indicate that SGLT2 inhibition results in the decrease of intracellular water likely due to increased osmotic diuresis despite plasma glucose reduction. The altered water distribution may affect the assessment of skeletal muscle by BIA.

Disclosure
H. Nakayama: Speaker's Bureau; Self; Medtronic, MSD K.K.. S. Iwata: None. T. Ohki: None. A. Nagayama: None. K. Yamada: Speaker's Bureau; Self; MSD K.K., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc.. Y. Tajiri: None. M. Nomura: None.
Changing Glucose Tolerance during Pregnancy—Implications for Diagnosis of Gestational Diabetes Mellitus (GDM)
Authors: KNOWLER WILLIAM C. , DREWS KIMBERLY , REDMAN LEANNE , JOSHIPURA KAUMUDI J. , ARTEAGA S. SONIA , PI-SUNYER XAVIER , HORN LINDA VAN , WING RENA R. , KLEIN SAMUEL ,   LIFE-MOMS RESEARCH GROUP
Published: June 2018

Background: ADA recommends testing for GDM at 24-28 weeks gestation. This recommendation is based on the assumption that glucose tolerance worsens during pregnancy and, therefore, testing earlier in pregnancy will miss many cases that develop only later. We tested this assumption in the LIFE-Moms consortium.
Methods: LIFE-Moms was a consortium of randomized clinical trials of lifestyle interventions aimed at limiting gestational weight gain compared with standard care in 1,150 pregnant women with BMI ≥25 kg/m2 recruited from different racial/ethnic groups in the U.S. Women with known or probable diabetes preceding this pregnancy were excluded. As previously reported, the lifestyle interventions modestly reduced excessive gestational weight gain (the primary outcome) but had no significant effect on the prevalence of GDM at 24-31 weeks. We report here results of 75 g 2-hour OGTTs performed sequentially during pregnancy in a subset of 296 women tested at &lt;16 weeks (mean 12.6 weeks) gestation and again at 24-31 weeks. Tests were interpreted by the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria.
Results: Plasma or serum glucose declined from the early to later tests by a mean of 2.5 mg/dl (fasting), 10.9 mg/dl (1-hr), and 9.3 mg/dl (2-hr), each p&lt;0.0001. The prevalence of GDM by IADPSG criteria declined from 20% at &lt;16 weeks gestation to 15% at 24-31 weeks (p=0.04). Only 9% of women without GDM at &lt;16 weeks gestation developed it by 24-31 weeks, whereas 65% of those meeting GDM criteria at &lt;16 weeks gestation did not meet GDM criteria at follow-up. None of the changes in glucose or GDM prevalence differed significantly by treatment group.
Conclusions: In pregnant women with BMI ≥25 kg/m2 who are otherwise healthy, glucose tolerance improves on average rather than deteriorates during gestation. Testing for GDM early in pregnancy is needed to understand pregnancy effects on glycemia and the clinical implications of earlier detection of GDM.

Disclosure
W.C. Knowler: None. K. Drews: None. L. Redman: None. K.J. Joshipura: None. S. Arteaga: None. X. Pi-Sunyer: None. L. Van Horn: None. R.R. Wing: None. S. Klein: Stock/Shareholder; Self; Aspire Bariatrics. Consultant; Self; Pfizer Inc.. Research Support; Self; Merck & Co., Inc., Johnson & Johnson Services, Inc., REMD Biotherapeutics.
What Is the Role of A1C in Comorbidities?
Authors: PERLMAN JORDAN E. , ROSENBAUM JENNIFER L. , MCNULTY BRIDGET K. , HIRSCH IRL B. 
Published: June 2018

The ADAG Study Group defined the relationship between average blood glucose (AG) and A1C. They derived an equation valid across diabetes types but excluded comorbidities known to impact A1C. The goal of this study is to examine the relationship between AG and A1C in patients omitted from prior analyses. A retrospective chart review was performed of downloaded glucose data from patients prescribed insulin at the UW Diabetes Center between 1/2011-10/2017. Patients were identified who had either 1) documentation and/or laboratory confirmation of anemia; 2) CKD; or 3) NAFLD. Eligible charts required: 1) 2 weeks of fingerstick glucose (SMBG) data with ≥14 checks or 1 month of CGM with ≥14 complete days and, 2) an A1C measured within 1 month of the encounter. The SMBG and CGM means were obtained from downloads. An AG was extrapolated from the A1c using the ADAG equation. The downloaded data and A1C-derived AGs were compared. There was a linear correlation between AG and A1C (R2=0.48) in anemic patients regardless of etiology. Non-anemic patients (N=220) had better ADAG agreement (70% of AGs inside 15% of predicted) than anemic patients (55% of AGs, N=123, p=0.006). Normal GFR yielded 71% of AGs inside 15% of ADAG estimation (N=440). This decreased to 59% if limited to anemic patients (N=83, p&lt;0.001). ADAG agreement decreased as a function of renal impairment. The impact of anemia was only significant in CKD stage 3A (N=49, p=0.02). In CKD stage 4/ESRD there was no correlation between AG and A1C (N=14, R2=0.0004). Abnormal LFTs did not affect ADAG agreement. In NAFLD there was no correlation between AG and A1C (N=14, R2=0.03) but 64% of AGs were inside 15% of ADAG projection. For many, SMBG and CGM data provide an important confirmatory assessment of A1C. However, in certain conditions there is significant discordance between AG and A1C. There is a complete lack of correlation between AG and A1C in advanced renal dysfunction and NAFLD as measured by our lab. These findings suggest glucose downloads are a better assessment of diabetes control in several common comorbidities.

Disclosure
J.E. Perlman: None. J.L. Rosenbaum: None. B.K. McNulty: None. I.B. Hirsch: Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Abbott, Bigfoot Biomedical, Roche Diabetes Care Health and Digital Solutions, ADOCIA.