bluuebunny/crossref_metadata_2025_split huggingface dataset:
768-P: MSDC-0602 Is a Direct Mitochondrial Pyruvate Carrier Inhibitor That Modulates Central Carbon Metabolism in Mice and Humans
Authors: RAUCKHORST ADAM J. , PAPE DANIEL J. , COLCA JERRY R. , TAYLOR ERIC B. 
Published: June 2021

Mitochondrial pyruvate carrier (MPC) disruption attenuates type 2 diabetes NAFLD in mice. MSDC-0602, a PPARγ-sparing, TZD-like molecule that inhibits the MPC, was recently tested in a phase 2B trial for treating NASH, which reported beneficial effects on glucose and insulin homeostasis. Yet, the broad, in vivo metabolomic effects of MSDC-0602 treatment have remained undefined. Here, we tested MSDC-062 metabolic mechanisms of action in vitro and in vivo, spanning from mitochondrial pyruvate uptake assays in isolated mouse mitochondria, through cultured mouse liver cells, in vivo in mice, and in humans participating in the EMMINENCE trial. First, we examined MSDC-0602’s effect in isolated mouse liver mitochondria: Pyruvate-oxidation was decreased by MSDC-0602, and 2.5 µM MSDC-0602 was sufficient to decrease mitochondrial pyruvate uptake by &gt;50%. We extended these findings to AML12 mouse liver cells and mouse liver in vivo. In AML12 cells, MSDC-0602 treatment increased pyruvate and lactate and decreased alanine. These results were comparable but not identical to results from parallel testing of the specific MPC inhibitor UK5099. 14-day treatment of NCD and HFD fed mice with MSDC-0602 decreased liver alanine and branched chain amino acids. As we previously observed with MPC liver-specific knockout mice, the HFD-induced liver TCA intermediate pool size expansion was mitigated by MSDC-0602. Accordingly, MSDC-0602-dependent metabolomic changes were more pronounced in HFD- versus NCD-fed mice. Human EMMINENCE trial participants receiving MSDC-0602 showed decreased circulating alanine, ketone bodies, and glucose. Similarly, circulating and liver glucose were decreased in HFD mice treated with MSDC-0602. Together, these data are consistent with MSDC-0602 modulating in vivo metabolism in a partially MPC-dependent manner and by additional mechanisms that remain to be understood.

Disclosure
A. J. Rauckhorst: None. D. J. Pape: None. J. R. Colca: Board Member; Self; Metabolic Solutions Development Company, LLC, Employee; Self; Cirius Therapeutics. E. B. Taylor: None.

Funding
American Diabetes Association (1-18-PDF-060 to A.J.R.); National Institute of Diabetes and Digestive and Kidney Diseases (DK104998); Cirius Therapeutics
778-P: SGLT2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors and Risk of All-Cause Hospitalization
Authors: LYU BEINI , GRAMS MORGAN , CHANG ALEX R. , INKER LESLEY A. , CORESH JOSEF , SHIN JUNG-IM 
Published: June 2021

Introduction: Clinical trials have shown cardiorenal benefits of SGLT2 inhibitors (SGLT2i). However, adoption of SGLT2i in clinical practice has been slow, perhaps in part due to safety concerns. We aimed to assess the association between SGLT2i and risk of all-cause hospitalization as the totality of severe adverse events and benefits, comparing to risks associated with DPP4 inhibitors (DPP4i) and GLP1 receptor agonists (GLP1RA).
Methods: We identified patients with type 2 diabetes who initiated SGLT2i (n=2492), DPP4i (n=4762) or GLP1RA (n=1982) between 2015 and 2018 in Geisinger and performed 1:1 propensity score matching on SGLT2i (n=2171) vs. DPP4i (n=2171) and SGLT2i (n=1605) vs. GLP1RA (n=1605). We examined all-cause hospitalization as the main outcome. We also considered two positive controls (major adverse cardiovascular event [MACE] defined as cardiovascular death, myocardial infarction, and stroke; and heart failure [HF] hospitalization), and a negative control (hospitalization due to major bleeding).
Results: Mean (SD) age was 58 (13) and 56 (13) years and 46% and 53% were women in the SGLT2i-DPP4i and SGLT2i-GLP1RA matched sample, respectively. During a median follow-up of 14 months, SGLT2i had similar risk of all-cause hospitalization compared with DPP4i (HR [95% CI] 0.85 [0.72-1.01]) or GLP1RA (HR 0.93 [0.77-1.13]). SGLT2i was associated with significantly lower risk of MACE and HF hospitalization compared with DPP4i (MACE: HR 0.70 [0.37, 0.98]; HF: HR 0.61 [0.38, 0.97]) but not with GLP1RA (MACE: HR 1.02 [0.50, 2.08]; HF: HR 0.72 [0.42, 1.23]). Risk of hospitalization due to bleeding was similar between SGLT2i vs. DPP4i or SGLT2i vs. GLP1RA.
Conclusions: In this real-world comparison of antidiabetes medications, SGLT2i may be as safe as DPP4i with significant cardiac benefits and have comparable risk-benefit profiles compared with GLP1RA. These results further encourage SGLT2i use in routine diabetes care, particularly among patients at high risk of MACE.

Disclosure
B. Lyu: None. M. Grams: None. A. R. Chang: Advisory Panel; Self; Reata Pharmaceuticals, Inc., Relypsa Inc., Research Support; Self; Novo Nordisk Inc. L. A. Inker: None. J. Coresh: Consultant; Self; Healthy. io, Research Support; Self; National Institutes of Health, National Kidney Foundation. J. Shin: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K01DK121825)
809-P: The Impact of High-Deductible Health Plans (HDHPS) and Out-of-Pocket (OOP) Costs on Access to Care in Diabetes
Authors: SZABO SHELAGH M. , KUTI EFFIE , FRIESEN MICHAEL , REARDON DEBORAH , JAYKUS ELIZABETH , COREPAL REKESH , DONATO BONNIE M.K. 
Published: June 2021

Background: HDHP use and high OOP costs are associated with decreased healthcare resource use (HCRU) and access to care, among those with lower incomes, or racial and ethnic minorities. The potential impact on diabetes care is a public health concern, given that regular access to medications is critical to avoid severe complications. The objective of this study was to characterize the impact of HDHPs and high OOP costs on access to care and HCRU among Americans with diabetes, and the interaction of race/ethnicity and income.
Methods: A systematic review was performed using Medline/EMBASE to identify records from the past 10 years, describing the impact of HDHPs, or high OOP costs or copayments, on access to care (e.g., not pursuing care because of cost) or HCRU (e.g., medication use, physician visits). The focus of the review was on Americans with diabetes; whether the impact of race/ethnicity and income was reported was also captured.
Results: From 2707 abstracts, 2 described the impact of HDHPs among those with diabetes and 9, high OOP/copayment costs. Four studies (36.4%) reported the impact of race/ethnicity: Black and non-Hispanic patients with diabetes tended to be at higher risk of non-adherence than white patients. Three studies (27.2%) reported the impact of income: Lower-income patients with diabetes were at higher risk of non-adherence and decreased HCRU, versus higher-income patients. Only one study reported on both race/ethnicity and income, but not the interaction of these.
Conclusions: These findings suggest that HDHP use and high OOP costs are associated with decreased HCRU and adherence among Americans with diabetes. This effect may be more pronounced among those of non-white race/ethnicity or with low income. Notably, no studies reported the impact of HDHPs and high OOP costs on access to care. Understanding how race/ethnicity and income interact will be important to fully recognize the impact of HDHPs and high OOP costs on outcomes among Americans with diabetes.

Disclosure
S. M. Szabo: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. E. Kuti: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. M. Friesen: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D. Reardon: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. E. Jaykus: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. R. Corepal: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. B. M. K. Donato: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc.

Funding
Boehringer Ingelheim
815-P: Cost-Effectiveness of Subcutaneous Semaglutide vs. Empagliflozin as Add-On Therapy for Type 2 Diabetes
Authors: ZUPA MARGARET , CODARIO RONALD , SMITH KENNETH J. 
Published: June 2021

Background: Efforts to reduce type 2 diabetes morbidity and mortality focus on reducing microvascular and macrovascular complications. Development of GLP-1 receptor agonists and SGLT2 inhibitors has furthered progress toward this goal. As these medication classes have distinct effects on complication risk, the optimal approach is not clear.
Methods: We evaluated the cost-effectiveness of 2 strategies to intensify treatment of patients with type 2 diabetes and cardiovascular disease: addition of 1 mg subcutaneous semaglutide weekly or 25 mg oral empagliflozin daily to usual diabetes treatment. A Markov decision model estimated the impact of each strategy; complications included nonfatal myocardial infarction, hospitalization for congestive heart failure, nonfatal stroke, new or worsening nephropathy, and death. The empagliflozin strategy also included possible genital mycotic infection. Complication rates were based on EMPA-REG and SUSTAIN-6 trials. Modeled cohorts began at age 66 and were followed for 3 years at 1 month intervals. Analyses took a healthcare perspective, discounting 3%/year. For the base case, all patients entered the model with no complications.
Results: Compared to empagliflozin, semaglutide gained 0.053 quality-adjusted life year (QALY) at a cost of $1,006, or $18,897 per QALY gained. In one-way sensitivity analysis, only a semaglutide cost &gt;$38/day (base case $18.04) resulted in empagliflozin being preferred at a willingness-to-pay threshold of $50,000/QALY. In probabilistic sensitivity analysis, semaglutide was preferred in 55% of model iterations at a $50,000/QALY threshold and in 57% at $100,000/QALY. When patients entered the model in complication states based on trial cohorts, semaglutide remained the preferred strategy at $23,518 per QALY gained.
Conclusion: For patients with type 2 diabetes mellitus with cardiovascular disease, semaglutide is likely more cost-effective than empagliflozin as an addition to usual treatment.

Disclosure
M. Zupa: None. R. Codario: None. K. J. Smith: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007052-45)
831-P: The Development of a New Computer Adaptive Test of Medication Adherence for People with Type 2 Diabetes Mellitus: Medication Adherence Item Bank
Authors: MITCHELL SUZANNE , KALLEN MICHAEL A. , BRAGG ALEXA , MOLDOVAN IOANA , HOWARD JESSICA M. , JACK BRIAN W. , MINER JENNIFER A. , GRAVES CHRISTOPHER M. , CARLOZZI NOELLE 
Published: June 2021

Over 27 million Americans have type 2 diabetes mellitus (T2DM), accounting for &gt;7.7 million hospital admissions. Social determinants of behavior, including medication adherence, play a critical role in their health outcomes. We developed a new patient-reported outcome (PRO) measure to evaluate medication adherence in people with T2DM, using established measurement development standards. An item pool was created that reflected important content related to medication adherence for people with T2DM. The item pool was then refined, using feedback from experts, a reading-level assessment (ensuring no &gt;5th grade reading-level content was included), a translatability review (e.g., to allow future measure translation into Spanish), and feedback from T2DM patients. Next, 225 people with T2DM completed 58 self-report medication adherence items. Exploratory factor analysis supported the item pool’s essential unidimensionality. Five items were excluded due to low item-rest correlations. Confirmatory factor analysis supported retaining 27 items. All items fit the graded response model, and no items had meaningful differential item functioning for the factors age, sex, education, or socioeconomic status. The final item bank is comprised of 27 items and can be administered as a computer adaptive test or 6-
item short form. Internal consistency reliability was excellent for all administration formats (α’s all ≥ .90). The new Medication Adherence item bank provides a reliable, content-relevant assessment of medication adherence for people with T2DM. It is part of the comprehensive Re-Engineered Discharge for Diabetes Computer Adaptive Test (REDD-CAT) measurement system, which is designed to capture important social determinants of behavior for people with T2DM. Work is underway to establish additional psychometric properties (e.g., test-retest reliability, validity) of this new measure.

Disclosure
S. Mitchell: Other Relationship; Self; See Yourself Health LLC, Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. M. A. Kallen: None. A. Bragg: None. I. Moldovan: None. J. M. Howard: None. B. W. Jack: None. J. A. Miner: None. C. M. Graves: None. N. Carlozzi: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R21DK121092)
832-P: Implementation of Depression Screening in a Pediatric Diabetes Clinic with Limited Mental Health Services
Authors: GURNURKAR SHILPA , VYAS NEHA V. , PATEL UNNATI , PIERCE JESSICA 
Published: June 2021

Objective: Depression is up to 3 times more common in adolescents with diabetes than in their healthy peers and is associated with higher A1c values, and increased rates of diabetes-related hospitalizations. The ADA standards of care recommend integration of psychosocial screening into comprehensive medical care, but this is challenging in settings with limited mental health services. Here, we describe our quality improvement (QI) process for implementing depression screening in a pediatric diabetes center with limited mental health services.
Methods: This QI project took place in a pediatric children’s hospital that includes 3 satellite clinics. Routine diabetes care does not include integrated social work or psychology providers. Our goal is to increase PHQ-9 screening from 0% to 80% over 2 years in patients with diabetes (T1 or T2D) &gt;11 yrs old across all 4 sites and to provide appropriate follow-up services for 100% of positive screens. We began our QI project in Dec. 2019 and present data through Oct. 2020. This includes 4 Plan-Do-Study-Act (PDSA) cycles ranging from trialing PHQ-9 screening with a single provider (Cycle 1) to implementing PHQ-9 screening across all providers and sites utilizing more efficient EMR processes (Cycle 4).
Results: Cycle 1 demonstrated a baseline screening average of 35.7%, of which 11.4% had a positive PHQ-9 screen. Screening rates improved by the end of Cycle 4 to 46-88% across the 4 sites. 100% of patients with positive screens were referred to Behavioral Health for further evaluation and treatment. Of note, screening rates decreased in April/May 2020 (Cycle 2), due to COVID and subsequent clinic closure.
Conclusions: Our QI methodology was effective in implementing depression screening in adolescent patients with rates of screening increasing over time and at all of our sites as more efficient methods were utilized. Continued efforts to screen and follow-up will focus on addressing barriers to evaluating and obtaining treatment for depression.

Disclosure
S. Gurnurkar: None. N. V. Vyas: None. U. Patel: None. J. Pierce: None.
865-P: Care Management Processes That Improve Diabetes Outcomes
Authors: PETERSON KEVIN A. , CARLIN CAROLINE , SOLBERG LEIF , EDER MILTON 
Published: June 2021

Although previous work suggests that high performing practices focus on proactive patient outreach, the specific care management processes (CMP) that improve diabetes outcomes remain unclear. We evaluated 60 CMP from a state-wide practice survey in 2017 and 2019. Previously validated, the survey included 586 practices in 2017 (71% response, N=415) and 627 practices in 2019 (71% response, N= 445). Electronic health record data for A1c, blood pressure (BP), and lipid management were extracted for all patients with type 1 or type 2 diabetes in the practices. The longitudinal data set included 395 practices providing care to 204,745 patients. We used a longitudinal Bayesian model to correlate CMPs with A1c, systolic/diastolic BP, and probability of taking a statin. Patient outcomes were controlled for age, sex, diabetes type, insurance, comorbidity, community-level race-ethnicity, wealth, education, and income. Practices were controlled for rurality, size, FQHC status, system size, and practice-level random effects. Significance was reduced to &lt;.01 for multiple comparisons. Although 7 CMPs significantly improved the overall diabetes performance measures for an average practice, CMPs affected individual outcomes differently. A1c improved by: 1) implementing a systematic approach to identifying and reminding patients when they were due for testing, and 2) having a nurse or care manager provide after visit follow up. BP was reduced by: 1, 2, and 3) tracking lab tests, 4) using checklists in the practice for required testing, and 5) guideline based reminders for preventive services. Statin use increased by: 5, and 6) screening for substance-abuse, and 7) a formal process for measuring performance. Together, CMPs with a statistically significant impact on performance measures accounted for a drop in average A1c in a practice from 7.39 to 7.25 (P&lt;.01) BP from 127/75 to 121/71 (P&lt;.01) and a 3.9% (P&lt;.01) statin use increase. CMP 1 and 2 exemplify specific proactive patient outreach processes proven to improve diabetes care delivery.

Disclosure
K. A. Peterson: Board Member; Self; Treatment.com International Inc. C. Carlin: None. L. Solberg: None. M. Eder: None.

Funding
National Institutes of Health (R18DK110732)
883-P: Evaluating Impact of the Physician-Pharmacist Collaborative Management (PPCM) Team Providing Diabetes Preventative Care Services
Authors: VASCIMINI ANGELINA , SULLIVAN TARA , SAKDIPANICHKUL SUTHIDA S. , DEREMER CHRISTINA E. 
Published: June 2021

Type 2 diabetes more than doubled in the last 20 years, putting an increase demand on the limited number of physicians practicing in rural areas. Implementing a physician-pharmacist collaborative management (PPCM) team, pharmacists can help increase access to care. The goal of this study is to determine if active PPCM patients have improved preventative care measures and associated drug therapy management. A single center retrospective chart review was conducted for patients seen by the PPCM team between March 2019 and December 2020. The comparator groups consisted of active PPCM patients (seen twice by the team in the last 12 months) versus inactive PPCM patients. The primary outcomes included annual foot exam, annual/biennial eye exam, blood pressure control, timely preventative care lab monitoring and appropriate therapy based on labs and atherosclerotic cardiovascular disease (ASCVD) risk. This project was approved by the institutional quality improvement performance registry process. Descriptive statistics, T test and Chi-square test were used for data analysis. Data was collected for 172 patients (92 active PPCM patients and 80 inactive PPCM patients). Baseline demographics were similar, however there were statistically more males in the inactive PPCM group. The primary outcome for annual foot exam (p value 0.0012), annual/biennial eye exam (p value &lt;.001) and annual UACR (p value &lt;.001) and lipid monitoring (p value 0.003) were statistically significant when comparing active PPCM patients to inactive PPCM patients. The other primary outcomes, appropriate drug therapy based on albuminuria and ASCVD risk and blood pressure control, were not statistically significant. Sample population data shows the PPCM team models improve preventative care measures, lab monitoring and may improve related drug therapy. When access to care is limited in rural areas, an effective PPCM team can extend the reach of the physician improving care for patients.

Disclosure
A. Vascimini: None. T. Sullivan: None. S. S. Sakdipanichkul: None. C. E. Deremer: Research Support; Self; Pfizer Inc., Speaker’s Bureau; Spouse/Partner; Pharmacy Times, Stock/Shareholder; Self; Portola Pharmaceuticals, Inc.
894-P: Monophasic Glucose Response Curve Is Associated with Increased C-Reactive Protein in Obese Adolescents
Authors: HOFFMAN ROBERT P. , CAZEAU RACHEL-MARIE , RAUCH LINDSEY , BAUER JOHN A. 
Published: June 2021

Three distinct glucose response curves, biphasic, monophasic and incessant increase, have been demonstrated in adults and adolescents during OGTT. Individuals with incessant increase and monophasic curves have increased risk of type 2 diabetes and decreased insulin sensitivity and secretion and thus are likely at increased risk for other cardiometabolic diseases. We, therefore, examined differences in traditional, and nontraditional cardiometabolic risk factors between obese adolescents with biphasic (n=9; age=12.6±0.9 yr, BMI=31.8±5.9 kg/m2; mean±SD) and monophasic (n=6; age=13.1±0.9; BMI=35.3±6.9) glucose response curves. Traditional risk factors were blood pressure and lipids while non-traditional risk factors included reactive hyperemia (RH), inflammatory markers [c-reactive protein (CRP), interleukin-6 (IL-6)], adiponectin, soluble intracellular adhesion molecule 1 (SICAM1), and insulin sensitivity and secretion (OGTT, Matsuda and insulinogenic indices). Systolic and diastolic blood pressure, triglycerides, HDL and LDL did not differ between groups. RH, Il-6 and Matsuda index also did not differ. Subjects with monophasic curves tended to have increased SICAM1 (260±33 vs. 184±21; mean±SE; p=0.087) and had significantly increased CRP levels (4.40±1.03 vs. 1.66±0.28 ng/ml; p=0.009) compared to subjects with biphasic curves. Adiponection (3570±450 vs. 2350±440 ng/ml; p=0.089) and insulin secretion (4.31±0.52 vs. 2.89±0.53 µU dl/mg ml; p=0.089) tended to be lower in subjects with monophasic curves. The difference in CRP remained significant when BMI was included as a covariate (p=0.02). Obese adolescents with monophasic glucose response curves to OGTT have increased inflammation compared to subjects with biphasic curves. Longitudinal studies are needed to determine whether this early phase of glucose intolerance causes increased inflammation or whether early inflammation reduces insulin secretion and causes early glucose intolerance.

Disclosure
R. P. Hoffman: Consultant; Self; Provention Bio, Inc., Other Relationship; Self; Medscape, Research Support; Self; Provention Bio, Inc. R. Cazeau: None. L. Rauch: None. J. A. Bauer: None.

Funding
National Center for Research Resources (UL1RR05755)