Pfizer Research Articles

138-LB: A Retrospective Algorithm to Identify Meal Intakes from CGM Time Series

The accurate assessment of dietary behavior in clinical trials, including number and size of meal intakes, is essential to evaluate participants’ metabolic health which, in turn, might reflect an increased risk for developing diabetes. Traditional dietary assessments leverage handwritten/digital food logs, which are error-prone and time-consuming for both users and investigators. Instead, glucose timeseries unobtrusively collected by CGM could provide objective measures of meals’ consumption. Here we present a new algorithm to retrospectively identify meal intakes using CGM data only. In the Geriatric Anorexia Study (NCT04858932), 50 healthy individuals (26 females, mean±SD age: 72.26±5.02 years, BMI: 24.96±3.33 kg/m2) were monitored in free-living conditions for 2 weeks with the Abbott FreeStyle Libre Pro, and recorded meal intakes using the Renpho Smart Food Scale. After removal of days with <2 meals recorded, a total of 1132 meals over 365 days were available for analysis. To identify meal intakes, the proposed algorithm scans CGM data, identifies local maxima, and measures their prominence, i.e., the relative height with respect to a neighborhood window of length L. Peaks with prominence higher than Pmin are labeled as meals. Subject data was divided into a ~70% training set (n=31, 775 meals), where L and Pmin are tuned, and ~30% test set (n=12, 357 meals), where the algorithm is evaluated in terms of absolute percent error (APE) between number of recorded and detected meals. Across subjects, mean±sd daily APE is 25.1±9.70%. Similar values hold when considering only subjects with <3.5 meals/day (n=6, 144 meals, APE=24.5±13.2%) and ≥3.5 meals/day (n=6, 213 meals, APE=25.5±6.93%), demonstrating the reliability of the algorithm to identify the number of meals in subjects with different dietary behaviors. These results evidence the suitability of CGM for the automatic quantification of meal intakes. Further assessment of the algorithm should be performed using more controlled meal intake recordings. Disclosure N. Camerlingo: Employee; Pfizer Inc. A. Messere: None. M. Santamaria: None. C. Demanuele: None. D. Caouette: Employee; Pfizer Inc. K. C. Thomas: None. N. Shaafi kabiri: None. D. Psaltos: Employee; Pfizer Inc. F. Karahanoglu: None. S. Khan: None. I. Messina: Research Support; Pfizer Inc. M. Wicker: None. M. Kelly: Research Support; Pfizer Inc. H. Zhang: Employee; Pfizer Inc.

134-LB: Real-World Impact of Intermittently Scanned Continuous Glucose Monitoring on Hemoglobin A1c in People with Type 2 Diabetes in Canada That Use Basal Insulin—A Prospective Chart Review

The change in HbA1c after initiating FreeStyle Libre or FreeStyle Libre 2 Flash Glucose Monitoring System (FSL and FSL2) in adults with type 2 diabetes (T2D) in a real-world setting was evaluated over a 3-6 month period. Nine sites in Canada collected medical record data prospectively for adults who had started FSL or FSL2 in the last 3 months and with the following criteria: a basal insulin regimen with or without additional glucose lowering medications, and HbA1c 8.0-12.0%. Preliminary data were analysed from 79/138 medical records (n=138; 6 records ineligible, 53 no follow up, ineligible HbA1c or had stopped FSL or FSL2). Participants had the following baseline characteristics (mean±SD): HbA1c 8.9%±0.8, age 67.3±11.5 years (57% ≥65 years), BMI 30.1±6.2 (n=65), insulin use duration 5.3±3.9 years, and 54% were males. The most commonly used non-insulin glucose lowering medications included metformin (87.3%), sodium-glucose co-transporter-2 (SGLT2) inhibitors (62.0%) and sulphonylureas (46.8%). By the end of the study (3-6 months after the index date), mean HbA1c was reduced by 0.6%±1.1 to 8.3%±1.0 (p<0.0001). Observed changes in antihyperglycemic medications from baseline included increased use of GLP-1 agonists from 44.3% to 51.9% and decreased use of DPP4i from 24.1% to 16.5%. This prospective chart review study found that initiating intermittently scanned continuous glucose monitoring in individuals with T2D treated with basal insulin plus other glucose lowering medications was associated with significantly improved HbA1c over a 3-6 month period. Disclosure A. Abitbol: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Dexcom, Inc., Novo Nordisk Canada Inc., Janssen Pharmaceuticals, Inc., Research Support; Abbott Diabetes, Lilly Diabetes, Zucara Therapeutics, Novo Nordisk Canada Inc., Moderna, Inc., Senseonics, Speaker's Bureau; Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Amgen Canada, Dexcom, Inc., Novo Nordisk Canada Inc., HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi. A. B. Jain: Advisory Panel; Abbott, Amgen Canada, Dexcom, Inc., AstraZeneca, Novo Nordisk, Bayer Inc., Insulet Corporation, Takeda Canada, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Research Support; Abbott, Amgen Canada, Novo Nordisk, Speaker's Bureau; Abbott, Amgen Canada, Dexcom, Inc., AstraZeneca, Novo Nordisk, Bausch Health, Canada, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Pfizer Inc. M. Tsoukas: Speaker's Bureau; Novo Nordisk Canada Inc., Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Scientific Affairs, LLC, AstraZeneca, Sanofi. J. Sigalas: None. B. P. Galm: Advisory Panel; Abbott, Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Canada Inc., Pfizer Inc., Research Support; Abbott, Speaker's Bureau; Abbott, Dexcom, Inc., Pfizer Inc. J. Lee: Advisory Panel; Amgen Canada, Research Support; Novo Nordisk, Lilly, Abbott, Speaker's Bureau; Amgen Canada, Canadian Collaborative Research Network, AstraZeneca, Pfizer Inc. K. S. Qureshy: Advisory Panel; Novo Nordisk, Other Relationship; Novo Nordisk, Novo Nordisk, Research Support; Abbott Diagnostics, Novo Nordisk, Speaker's Bureau; AstraZeneca. C. Collins: None. V. C. Woo: Advisory Panel; Abbott, Speaker's Bureau; Dexcom, Inc. Funding Abbott Diabetes Care

13-LB: Treatment Patterns of Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease in Colombia

Aim: Describe treatment patterns of patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in outpatient setting from Colombia. Methods: We conducted a cross-sectional study characterizing treatment patterns of T2DM and CKD using the Audifarma S.A. drug dispensing database and included all patients with both diagnoses using ICD-10 codes and at least one disease-related prescription from April 1st 2019 to March 31st 2020. Sociodemographic variables, comorbidities, treatment received and combinations were evaluated. Drugs were classified as those for management of T2DM (oral antidiabetic agents, insulins, SGLT2i, GLP-1 analogs (GLP1a), dipeptidyl peptidase-4 inhibitors (DPP4i)), and others including renin angiotensin aldosterone system blockers (angiotensin converting enzyme inhibitors-ACEI, angiotensin receptor antagonists-ARBs) and mineralocorticoid receptor antagonists (MRAs). A descriptive analysis with frequencies and proportions, means and standard deviation was carried out. Results: Of a total of 194,023 patients with a primary diagnosis of T2DM, it was possible to identify that 14,722 (7.5%) had concomitant CKD, during the observation period. A total of 7513 (51%) were men, and the mean age was 74.7±10.9 years. The main comorbidities were hypertension (n=10665; 72.4%) and hypothyroidism (n=1138; 7.7%). The most used drugs were metformin (n=9901; 67.3%) alone or associated with some other antidiabetic, followed by 52.2% used DPP4i (n=7691), 17.0% an SGLT2i (n=2500), and 5.2% GLP-1a (n=766). Additionally, 67.2% (n=9895) of patients were under treatment with ARBs, 15.8% (n=2325) with ACEIs and 10.9% (n=1598) with MRAs. Conclusions: This contemporary study from Colombia further highlights the complexity and heterogeneity of treating patients with T2DM and CKD, which could be improved if the beneficial properties of newer agents that have shown positive anti-hyperglycemic and renal outcomes were implemented in the local treatment strategy. Disclosure M. Machado: Research Support; Bayer Inc., Pfizer Inc. A. Gaviria-mendoza: Employee; Audifarma S. A, Research Support; Bayer Inc., Pfizer Inc. J. S. Franco: Employee; Bayer Inc. M. D. R. Forero: Employee; Bayer Inc. D. Vizcaya: Employee; Bayer Inc. L. F. Valladales restrepo: Research Support; Bayer Inc., Pfizer Inc. J. E. Machado-alba: None. Funding Bayer AG

85-LB: CGM Outcomes and Hypoglycemia Duration with Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine U100 in Insulin-Naïve T2D—ONWARDS 1 Exploratory Analysis

In ONWARDS 1, a phase 3a, treat-to-target trial (NCT04460885) in insulin-naïve T2D randomized 1:1 to once-weekly icodec or once-daily glargine U100, time in, above and below range (TIR, TAR, TBR) and hypoglycemia duration were assessed with double-blinded CGM at pre-specified periods throughout the trial. TIR (70-180 mg/dL), TAR (>180 mg/dL), TBR (<70 and <54 mg/dL), median duration of hypoglycemia <70 mg/dL and the proportion of an episode spent <54 mg/dL were assessed at weeks (wks) 0-4, 22-26, 48-52, and 74-78. At wks 22-26, 48-52, and 74-78, mean TIR with icodec met the recommended target of >70%, and TIR and TAR were significantly improved with icodec vs glargine, with no significant difference between arms in TBR <54 mg/dL (table). There was a difference in favor of glargine in TBR <70 mg/dL at wks 48-52 and 74-78, but mean TBR <70 mg/dL and TBR <54 mg/dL were below recommended targets (4% and 1%, respectively) at all time periods for both arms. TIR, TBR and TAR did not differ significantly between arms at wks 0-4. Median duration of hypoglycemia <70 mg/dL and proportion of time <54 mg/dL were similar between arms at all time periods. In summary, TIR and TAR at wks 22-26, 48-52, and 74-78 were significantly improved with icodec vs glargine U100, with no significant difference in TBR <54 mg/dL and a similar duration of hypoglycemia <70 mg/dL between arms. Disclosure R. M. Bergenstal: Advisory Panel; Abbott Diabetes. Research Support; Abbott Diabetes. Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc. Research Support; Dexcom, Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Hygieia. Research Support; Insulet Corporation, Medtronic. Advisory Panel; Medtronic, Novo Nordisk. Research Support; Novo Nordisk. Consultant; Onduo LLC. Advisory Panel; Roche Diabetes Care. Research Support; Sanofi. Consultant; Sanofi. Research Support; UnitedHealth Group. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; Zealand Pharma A/S. S. K. Watt: Employee; Novo Nordisk. A. S. A. Matos: Employee; Novo Nordisk A/S. I. Lingvay: Advisory Panel; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Advisory Panel; Lilly Diabetes, Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc. Advisory Panel; Sanofi. Consultant; Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer. J. K. Mader: Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics. Research Support; A. Menarini Diagnostics, Abbott Diabetes. Advisory Panel; Abbott Diabetes. Speaker's Bureau; Abbott Diabetes. Advisory Panel; Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care. Research Support; Roche Diabetes Care. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Medtronic. Speaker's Bureau; Boehringer Ingelheim Inc., Becton, Dickinson and Company. Advisory Panel; Becton, Dickinson and Company. Speaker's Bureau; Ypsomed AG, Viatris Inc., Servier Laboratories. Research Support; Dexcom, Inc., Profusa, Inc. Stock/Shareholder; Decide Clinical Software GmbH. Advisory Panel; Pharmasense, embecta. Speaker's Bureau; Medtrust. T. Nishida: Employee; Novo Nordisk Pharma Ltd. Stock/Shareholder; Novo Nordisk A/S. J. Rosenstock: Advisory Panel; Applied Therapeutics Inc. Research Support; Applied Therapeutics Inc. Advisory Panel; Boehringer Ingelheim Inc. Research Support; Boehringer Ingelheim Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company, Merck & Co., Inc., Novartis. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Oramed Pharmaceuticals. Research Support; Pfizer Inc. Advisory Panel; Sanofi. Research Support; Sanofi. Advisory Panel; Zealand Pharma A/S, Intarcia Therapeutics, Inc. Research Support; Intarcia Therapeutics, Inc. Advisory Panel; Hanmi Pharm. Co., Ltd. Funding Novo Nordisk A/S

759-P: Changes in Liver Fat in Patients with Type 2 Diabetes by Presence of Genetic Hepatic Steatosis in the SURPASS-3 MRI Substudy

Patatin-like phospholipase 3 (PNPLA3) I148 genetic variant is highly associated with nonalcoholic fatty liver disease. Tirzepatide (TZP), a novel GIP/GLP-1 receptor agonist, significantly reduced liver fat content (LFC) vs insulin degludec (IDeg) in a subpopulation of patients in the SURPASS-3 phase 3 trial. This post-hoc analysis evaluated changes from baseline to Week 52 in LFC and cardiometabolic parameters by presence of PNPLA3 I148 allele (yes [genotype CG/GG] or no [genotype CC]). Insulin-naïve patients with type 2 diabetes inadequately controlled on metformin with/without SGLT-2i and fatty liver index ≥60 at baseline had an MRI scan performed prior to randomization (1:1:1:1) to once-weekly TZP (5, 10, 15 mg) or IDeg. LFC was assessed with MRI. Patients (mean baseline age, 56.2 years; diabetes duration, 8.3 years; HbA1c, 8.2%; weight, 94.4 kg; BMI, 33.5 kg/m2; 30% on SGLT-2i) experienced greater reductions in LFC, weight, HbA1c, and overall greater improvement in lipids profile and liver enzymes with all doses of TZP than with IDeg regardless of the presence of PNPLA3 I148 allele (Table). Findings with TZP were consistent in both subgroups. In summary, TZP led to clinically meaningful improvements in several cardiometabolic parameters in patients with type 2 diabetes regardless of the presence of PNPLA3 I148 allele. Disclosure K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns. A. Gastaldelli: Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Pfizer Inc. Consultant; Fractyl Health, Inc. Advisory Panel; Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH. Other Relationship; Pfizer Inc. Consultant; Merck Sharp & Dohme Corp. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M. Liu: Consultant; Eli Lilly and Company. A. Torcello-Gomez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Á. Rodríguez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

131-LB: Diabetes and Disparities in Continuous Glucose Monitoring in Community Health Care Settings

Federally qualified health centers (FQHCs) serve vulnerable DM patients in primary care in underserved settings. The state of DM (glycemic control, complications) may differ and utilization of technologies (e.g. continuous glucose monitoring [CGM]) may be essential. But the current state of DM and CGM is poorly characterized. Using EHR data from a national FQHC network (2015-2021) we examined baseline demographic characteristics, CGM prescriptions, and their association. We included 47,579 with DM: n=1630 with T1D [3%], n= 45,949 T2D [97%], 38% Hispanic, 34% Black (Table 1). Notably, T1D pts [mean age 43 SD 16], had poor glycemic control (HbA1c 9.4 SD 2.4) with elevated DM complications severity index scores [mean DSCI 2.3 SD 4.7]. Overall CGM prescriptions were extremely low; 9% in T1D and only 1% in T2D. Among T1D, those who were Hispanic [OR 0.39, (CI 0.23, 0.66), p < 0.001] or Black [OR 0.52, (CI 0.33, 0.81), p = 0.003] were less likely to have CGM prescribed than White adults, after adjustment. Among T2D, those who were Hispanic [OR 0.42, CI 0.33, 0.55, p < 0.001] or Black [OR 0.68, CI 0.54, 0.85, p = 0.001] were similarly less likely to have CGM. Non-private insurance was also a significant factor. DM severity (poor control, complications) is notable in FQHCs, yet CGM is exceptionally low. These findings underscore the major translation gap in standard of care for FQHCs and the critical need to understand inequities. Disclosure A. Wallia: Research Support; UnitedHealth Group, Novo Nordisk, Eli Lilly and Company. D. Bright: None. A. Eggleston: None. M. J. O'brien: None. S. Agarwal: Advisory Panel; Medtronic, Consultant; Beta Bionics, Inc., Research Support; Abbott Diabetes, Dexcom, Inc. A. L. Owen: None. E. L. Lam: None. K. Davis: None. S. Bailey: Advisory Panel; Gilead Sciences, Inc., Consultant; Lundbeck, Pfizer Inc., Research Support; Eli Lilly and Company, Merck Sharp & Dohme Corp., Gilead Sciences, Inc., Lundbeck, Pfizer Inc. S. E. Delacey: None. A. Pack: Consultant; Gilead Sciences, Inc., Research Support; Merck & Co., Inc., Pfizer Inc., Gordon and Betty Moore Foundation, RRF Foundation for Aging, Lundbeck, Eli Lilly and Company, Gilead Sciences, Inc. J. Espinoza: Consultant; Sanofi, Research Support; NIH - National Institutes of Health, FDA, Speaker's Bureau; Glooko, Inc. Funding Centers for Diabetes Translation Research (5P30DK020541, 472P30DK092949-11A); National Pilot and Feasibility Grant for Diabetes Research Centers; Center for Diabetes Translation Research

1380-P: Heterogeneity in the Association of Diet and Obesity in Asian, Pacific Islander, and Multiracial People

Background: Disaggregation of Asian, Pacific Islander (PI), and multiracial API people is needed to assess the subgroup-specific impact of diabetes. This study examined the association between diet quality and obesity. Methods: We used CVD case-control data from two integrated healthcare systems. Diet was measured using the Rapid Eating and Activity for Patient Survey. Results: Among all groups, Native Hawaiians had the lowest mean diet quality while Asian Indians had the highest diet quality (Table 1). Better diet was associated with lower odds of obesity in all groups except Japanese, Native Hawaiian, Other PI, and some multiracial groups after adjustment (Table 2). Conclusion: For some race groups better diet quality was associated with lower odds of obesity. Future work should examine groups where this was not the case. Disclosure S.L.Gibbs: None. A.M.Bacong: None. T.B.Frankland: Research Support; Pfizer Inc., Stock/Shareholder; AbbVie Inc., Pfizer Inc., CVS Health Corp, Regeneron Pharmaceuticals Inc. J.Li: None. Y.G.Daida: Research Support; GlaxoSmithKline plc. L.Palaniappan: None. S.P.Fortmann: Research Support; Pfizer Inc. Funding National Heart, Lung, and Blood Institute (R01HL126172)

Rationally Improving Doramectin Production in Industrial Streptomyces avermitilis Strains.

Avermectins (AVMs), a family of 16-membered macrocyclic macrolides produced by Streptomyces avermitilis, have been the most successful microbial natural antiparasitic agents in recent decades. Doramectin, an AVM derivative produced by S. avermitilis bkd- mutants through cyclohexanecarboxylic acid (CHC) feeding, was commercialized as a veterinary antiparasitic drug by Pfizer Inc. Our previous results show that the production of avermectin and actinorhodin was affected by several other polyketide biosynthetic gene clusters in S. avermitilis and Streptomyces coelicolor, respectively. Thus, here, we propose a rational strategy to improve doramectin production via the termination of competing polyketide biosynthetic pathways combined with the overexpression of CoA ligase, providing precursors for polyketide biosynthesis. fadD17, an annotated putative cyclohex-1-ene-1-carboxylate:CoA ligase-encoding gene, was proven to be involved in the biosynthesis of doramectin. By sequentially removing three PKS (polyketide synthase) gene clusters and overexpressing FadD17 in the strain DM203, the resulting strain DM223 produced approximately 723 mg/L of doramectin in flasks, which was approximately 260% that of the original strain DM203 (approximately 280 mg/L). To summarize, our work demonstrates a novel viable approach to engineer doramectin overproducers, which might contribute to the reduction in the cost of this valuable compound in the future.

1011-P: Humanistic and Economic Burden of Patients with Cardiorenal Metabolic Conditions—A Systematic Literature Review

Background: A comprehensive understanding of the burden of CRM conditions is needed to guide targeted interventions. Objective: This SLR assessed the humanistic and economic burden of T2D, CVD (including HF), and CKD. Methods: Following PRISMA guidelines, Embase and Medline databases were systematically searched to identify observational, RWE, and economic-model studies in populations ≥18 years old with CKD, T2D, and CVD. Outcomes of interest included humanistic (e.g., health related QoL, functional impairment, QALY) and economic burden. English-language studies from Jan 2011 to Jan 2022 were included. Relevant abstracts/posters also were identified from ACC, AHA, ASN, and ADA from the 2 previous years. Results: Of 22 studies identified (13 US; 9 non-US) and included, 1 Chinese study reported QoL data (depressive symptoms of CKD and T2D), 8 reported healthcare resource utilization (HCRU), 7 reported cost, and 6 reported HCRU and cost. Multimorbidity and advanced stages of CKD were associated with higher medical costs and HCRU for patients with CRM across all studies. Increasing age was associated with more comorbidities, leading to greater economic burden among patients ≥65 years old. Higher costs and HCRU were observed in patients with all 3 conditions (T2D, CVD, CKD) compared to those with fewer comorbidities. Higher healthcare expenditures and HCRU was observed among urban insured compared with uninsured populations. Black patients had lower odds of using healthcare services compared to patients who identified as White, Asian/Pacific Islander, or Hispanic ethnicity. Conclusions: This SLR identified a clear trend of increasing healthcare costs and HCRU commensurate with an increasing number of CRM comorbidities. Further research evaluating the economic and humanistic burden of CRM conditions, especially in patients from racial/ethnic groups, is needed. Disclosure K.Ferdinand: Consultant; Amgen Inc., Boehringer Ingelheim Inc., Novartis, Medtronic, Pfizer Inc. K.C.Norris: None. H.W.Rodbard: Advisory Panel; Merck Sharp & Dohme Corp., Pacira BioSciences, Inc., Research Support; Eli Lilly and Company, Medtronic, Sanofi, Novo Nordisk. J.Trujillo: Advisory Panel; Novo Nordisk, Sanofi. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

861-P: The Effect of Dual Amylin and Calcitonin Receptor Agonist Treatment on Spatial Memory in Rat Models of Metabolic Syndrome

Obesity and metabolic-related complications, especially insulin resistance, have been linked to cognitive dysfunction. Dual amylin and calcitonin receptor agonists (DACRAs) elicit beneficial effects on body weight, glucose control, and insulin action, making them novel candidates for treating obesity and related comorbidities. Whether DACRAs affect cognition has yet to be addressed. With these studies, we evaluated the effect of DACRA treatment on spatial learning and memory in rat models of metabolic syndrome. Spatial learning and spatial memory retention were evaluated by Morris Water Maze in ZDSD rats treated with KBP-336 (4.5 nmol/kg Q3D) for 7 months and ZSF1 rats treated with KBP-336 (4.5 nmol/kg Q3D) for 2 months. In the ZDSD study, rats performed 8 training trials with a hidden platform in a constant position and a 60 s probe without the platform. At the study end, rats performed a 60 s probe followed by 4 re-training trials and another probe. At study end of the ZSF1 study, rats performed 6 training trials with a hidden platform in a constant position followed by a 60 s probe without the platform. In both studies, KBP-336 treatment improved the overall metabolic status, including glucose control and insulin action. In ZDSD rats, KBP-336-treated rats spent more time and traveled longer distances in Whishaw's corridor than vehicle-treated rats during the probes at the study end. Together indicating a possible treatment improvement in spatial memory on KBP-336. In ZSF1 rats, KBP-336 treatment resulted in increased time spent in the platform quadrant and Whishaw's corridor, as well as increased distance, traveled in Whishaw's corridor during the probe. In both studies, the treatment did not affect the spatial learning evaluated as latency to reach the hidden platform during the training trials. Altogether, we found that the improved metabolic status obtained with KBP-336 treatment might have a beneficial effect on spatial memory in diabetic and obese rat models. Disclosure K.Mohamed: Employee; Nordic Bioscience. A.T.Larsen: Employee; Nordic Bioscience A/S. S.A.Melander: None. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. Funding Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)

809-P: The Effect of Various Degrees of Hepatic Impairment on the Pharmacokinetic Characteristics of Once-Weekly Insulin Icodec

Insulin icodec is a novel basal insulin being developed for once-weekly administration. This study investigated if the pharmacokinetic characteristics of icodec are affected by hepatic impairment. In an open-label, parallel-group trial, 25 individuals (13 females/12 males; mean±SD age 54±9 yrs, BMI 28.3±5.2 kg/m2) were allocated to four groups based on hepatic function: normal hepatic function (n=6), mild (Child-Pugh Classification grade A; n=6), moderate (Child-Pugh grade B; n=6), and severe (Child-Pugh grade C; n=7) hepatic impairment. Icodec was administered as a single s.c. dose (1.5 U/kg) followed by blood sampling for pharmacokinetics until 840 h (35 days) post-dose. Total exposure of icodec (AUC0-∞,SD) was greater for mild (by 13%) and moderate (by 15%) hepatic impairment vs normal hepatic function, while no difference was observed for severe hepatic impairment vs normal hepatic function (Figure). Maximum concentration of icodec was not affected by hepatic impairment after a single dose (Cmax,SD) or at simulated steady state (Cmax,SS). In conclusion, the slightly greater total exposure of icodec for mild and moderate hepatic impairment vs normal hepatic function is considered of limited clinical relevance as icodec should be dosed according to individual need. No specific dose adjustment of icodec is required in individuals with hepatic impairment. Disclosure H.Haahr: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. B.Cieslarova: None. A.M.Donatsky: Employee; Novo Nordisk. J.R.Joseph: None. N.R.Kristensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. V.Kupcová: None. J.R.Hingst: Employee; Novo Nordisk, Research Support; Pfizer Inc. Funding Novo Nordisk

612-P: The Effectiveness of Lifestyle, Metformin, or Dietary Supplements for the Prevention of Gestational Diabetes Mellitus (GDM) by Participant Characteristics—A Systematic Review and Meta-analysis

The GDM prevalence has been rising, affecting 7-28% of pregnancies worldwide. Prior systematic reviews examining the success of interventions for GDM prevention have presented results where some interventions have modest effect and others, no effect. The impact of individual characteristics on the efficacy of interventions has not been thoroughly investigated. To address this knowledge gap, we performed a systematic review of controlled trials of lifestyle (diet and exercise), metformin and dietary supplement interventions initiated in the preconception, prenatal or postpartum period to assess whether participant characteristics impact the interventions’ effectiveness in GDM prevention. Overall, 116 studies met inclusion criteria (lifestyle n=92, metformin n=13 and dietary supplements n=12). Lifestyle, metformin and dietary supplements reduced GDM risk by 24% (RR 0.76, 95% CI 0.69-0.83), 34% (RR 0.66, 95% CI 0.47-0.93), and 45% (RR 0.55, 95% CI 0.36-0.83). With lifestyle, lower risks of GDM was seen in individuals with overweight or obesity (n=33, RR 0.70, 95% CI 0.59-0.83), without PCOS (n=3, RR 0.62, 95% CI 0.47-0.82) and without a history of GDM (n=13, RR 0.63, 95% CI 0.53-0.70) (p<0.05). With metformin, lower GDM risks were achieved when commenced prior to conception (n=3, RR 0.22, 95% CI 0.11-0.45)(p<0.01). Dietary supplements resulted in lower GDM risks among individuals with normal weight (n=1, RR 0.42, 95% CI 0.24-0.72), with prediabetes (n=1, RR 0.08, 95% CI 0.02-0.31), and when initiated before 20 weeks’ gestation (n=10, RR 0.46, 95% CI 0.30-0.71) (p<0.05). Given the potentially greater effectiveness of these interventions in certain groups of individuals, future research on tailored recommendations in precision GDM prevention, replacing the current ‘one-size-fits-all’ approach, is needed. Disclosure S.Lim: None. R.Taylor: None. M.Pathirana: None. K.Liu: None. G.G.Ukke: None. M.P.Bonham: None. M.Chen: None. A.J.Fawcett: None. S.C.Chivers: None. J.L.Josefson: None. W.W.Takele: None. L.M.Redman: Research Support; Dexcom, Inc., Abbott Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, Stock/Shareholder; ABGIL, Teladoc Health. K.Vesco: Research Support; Pfizer Inc. J.A.Grieger: None. N.Habibi: None. A.Quinteros: None. G.Leung: None. S.J.Zhou: None.

123-LB: Implementing a Multidisciplinary Model of CGM Care in Real-World Pharmacy Practice—A Clinical Consensus for Canadian Pharmacists

Background: Continuous glucose monitoring (CGM) devices have transformed diabetes care, but there is a lack of guidance for pharmacists to follow when onboarding patients to begin using CGM systems. Our study aimed to develop a blueprint for best practices for pharmacists to support people living with diabetes (PWD) using CGM systems. Methods: We used a modified DELPHI process to gather insights from 11 Key Opinion Leaders (KOLs) across Canada, including two endocrinologists, one family physician, and eight pharmacists. Consensus was reached for each criterion when 75% agreement was achieved. Criteria for CGM device initiation, short-term or episodic CGM use, and best practices for CGM onboarding and monitoring were developed based on the results. Results: Amongst the ideal candidates for CGM use are PWD using insulin, those with type 1 diabetes, individuals not reaching their A1C target, those experiencing frequent hypoglycemia, pregnant individuals, and others at risk of hypoglycemia. Best practices for onboarding and monitoring included shared decision-making conversations, a comprehensive overview of cost and coverage options, customized alerts and alarms, and timely follow-up sessions. Discussion: The KOL group ensured a comprehensive and diverse perspective. The developed blueprint provides a valuable resource for pharmacists to improve the use of CGM devices and enhance diabetes management for their patients. Incorporating these best practices into clinical practice has the potential to transform diabetes care and improve outcomes. Disclosure A. S. Sihota: Consultant; Novo Nordisk Canada Inc., Other Relationship; Becton, Dickinson and Company. S. Sivapalan: Advisory Panel; Novo Nordisk, Pfizer Inc., AstraZeneca, Consultant; Pear Healthcare Solutions Inc., Other Relationship; Boehringer Ingelheim (Canada) Ltd., GlaxoSmithKline plc., Novo Nordisk, Bristol-Myers Squibb Company, Pfizer Inc., AbbVie Inc., Ferring Pharmaceuticals, AstraZeneca. T. Smith: Advisory Panel; Novo Nordisk Canada Inc., Dexcom, Inc., Emergent Biosolutions. I. Halperin: Advisory Panel; Sanofi, Speaker's Bureau; 3Boehringer Ingelheim Canada Ltd. /Ltée, Abbott Diabetes, Dexcom, Inc., Novo Nordisk. A. B. Jain: Advisory Panel; Abbott, Amgen Canada, Dexcom, Inc., AstraZeneca, Novo Nordisk, Bayer Inc., Insulet Corporation, Takeda Canada, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Research Support; Abbott, Amgen Canada, Novo Nordisk, Speaker's Bureau; Abbott, Amgen Canada, Dexcom, Inc., AstraZeneca, Novo Nordisk, Bausch Health, Canada, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Pfizer Inc. A. Chin: Other Relationship; Abbott Diabetes, BMO Bank of Montreal, Diabetes Canada, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care, Inc., Research Support; Novavax, Centricity Research. W. Chow: Advisory Panel; GlaxoSmithKline plc., Pfizer Inc., Speaker's Bureau; Abbott Diagnostics, AstraZeneca, Bayer Inc., Bausch Health, Canada, Boehringer Ingelheim (Canada) Ltd., Eisai Inc., Novo Nordisk. S. Jin: Advisory Panel; Dexcom, Inc., Eisai Inc., Novo Nordisk Canada Inc., Board Member; Wounds Canada, Consultant; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals Inc., Canadian Collaborative Research Network, Diabetes Canada, GlaxoSmithKline plc., HLS Therapeutics Inc., MDBriefcase, Novo Nordisk Canada Inc., AstraZeneca, Speaker's Bureau; Eisai Inc., Dexcom, Inc., Novo Nordisk Canada Inc. T. Molberg: None. S. Patil: None. R. Siemens: Consultant; Canadian Collaborative Research Network, Novartis Canada, AstraZeneca, Montmed, Sanofi, MDBriefcase, Other Relationship; Abbott Diabetes, Amgen Canada, Boehringer Ingelheim and Eli Lilly Alliance, GlaxoSmithKline plc., HLS Therapeutics, Novo Nordisk, Dexcom Canada, Diabetes Canada. Funding Dexcom Canada

1189-P: The Project Wellness Pilot Feasibility Randomized Controlled Trial, a Behavioral Physical Activity Intervention for Gestational Glucose Intolerance and Gestational Diabetes

Introduction: Animal evidence suggests that maternal exercise improves metabolic health in the offspring. The offspring of individuals with gestational glucose intolerance (GGI) or gestational diabetes mellitus (GDM) are at increased risk for large for gestational age, shoulder dystocia, obesity, and diabetes. Maternal physical activity (PA) is indicated for these pregnancies, though PA levels tend to be suboptimal and decline over pregnancy. This pilot feasibility randomized controlled trial explored the effects of a behavioral counseling intervention on late pregnancy maternal PA and neonatal anthropometrics. Methods: Twenty individuals with GGI or GDM were enrolled. Those randomized to the behavioral PA intervention met weekly with a lifestyle coach via Zoom for at least 5 sessions (10-20 minutes per session). Participants completed surveys and wore ActiGraph CentrePoint PA monitoring devices on their dominant wrist for a 7-day period, at both baseline and follow-up. The TwoRegressions algorithm estimated minute by minute metabolic equivalents of task (METs) for periods in which the devices were worn, and minutes per day at ≥ 3.0 METs, indicative of moderate to vigorous intensity PA (MVPA), were totaled. Neonatal measurements (n = 17) occurred within 3 days of birth. Results: Those in the PA intervention decreased MVPA less than controls [i.e., -4.0 minutes per day (95% CI -14.5, 6.5) vs. -23.5 minutes per day (95% CI -34.9, -12.1), P = .02]. Neonates born to those in the PA intervention were smaller than control neonates, however no difference attained statistical significance (e.g., weight, neonatal fat mass, total skinfolds). There was the suggestion of significant effect on subscapular skinfold (P = .07). Conclusion: A behavioral PA counseling intervention mitigated late pregnancy declines in PA in GGI or GDM, and could reduce upper-trunk adiposity in their neonates. Disclosure S.F.Ehrlich: None. B.G.Rand: None. N.Zite: Other Relationship; Merck & Co., Inc. K.B.Fortner: Other Relationship; Pfizer Inc. A.M.Paudel: None. S.E.Crouter: None. J.M.Maples: None. Funding National Institutes of Health (K01DK105106)

409-P: Post Hoc Analyses of Longitudinal Changes of Plasma Proteins Associated with Progression to End-Stage Kidney Disease in Type 2 Diabetes Patients with Chronic Kidney Disease Treated with GLP-1 Receptor Agonist Dulaglutide (AWARD-7)

The AWARD-7 clinical trial of patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) reported a slower decline in estimated glomerular filtration rate (eGFR) and decreased urinary albumin-to-creatinine ratio (UACR) in patients treated with dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, compared to insulin glargine over one year. Previous studies identified 21 circulating plasma risk proteins highly associated with progression to end stage kidney disease (ESKD) in patients with diabetes (Joslin Kidney Panel). The aim of this study was to determine the longitudinal changes of these proteins in AWARD-7 to evaluate their predictive performance as biomarkers of kidney disease progression. Plasma samples were obtained from patients with T2D and CKD stages 3-4 who received dulaglutide 1.5 mg (n=124) or insulin glargine as basal therapy (n=125) for 52 weeks. Using the Olink custom platform we measured the concentration of 21 proteins at baseline, 26-weeks, and 52-weeks of treatment. At baseline all 21 proteins were correlated with eGFR (r=-0.2 to -0.8; all p<0.0003) and UACR (r=0.2 to 0.6; all p<0.0001). After 26 weeks of treatment, 13 risk proteins significantly increased in glargine group (3 to 13%; all p<0.05) whereas no significant change was observed in dulaglutide group at 26 weeks. By 52 weeks, 5 proteins remained significantly elevated in the glargine group compared to dulaglutide. Several proteins were correlated with declining kidney function (change of eGFR) and increasing UACR in patients with glargine, but not in patients treated with dulaglutide. In this study, the increase of plasma risk proteins associated with ESKD was slowed in dulaglutide-treated patients and is consistent with the hypothesis that several proteins within the Joslin Kidney Panel can serve as predictive biomarkers of treatment efficacy. Disclosure B.E.Mcfarlin: Employee; Eli Lilly and Company. E.Satake: None. Z.Md dom: None. J.Ricca: None. A.V.Kechter: Employee; Eli Lilly and Company. J.M.Wilson: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. A.Krolewski: None.

1184-P: No Increased Risk of Gestational Diabetes Mellitus (GDM) Diagnosis after COVID-19 Vaccination

Background: Hyperglycemia and possible accelerated onset of de novo diabetes have been reported following COVID-19 vaccination in nonpregnant adults. The objective of this study was to examine the risk of GDM after COVID-19 vaccination in pregnancy. Methods: Using data from 8 integrated health care systems participating in the Vaccine Safety Datalink, we performed a retrospective analysis among 42,140 pregnancies resulting in livebirth from 1/27/21 -1/25/22. Diagnosis of GDM was defined as two outpatient or one inpatient ICD-10 codes for GDM at or beyond 22 weeks’ gestation. GDM diagnoses were compared between individuals who received one or two COVID-19 vaccine doses prior to 22 weeks’ gestation and those who did not receive a COVID-19 vaccine during pregnancy. We used generalized estimating equations with robust variance and inverse probability weighting to estimate the adjusted relative risk (aRR) and 95% Confidence Interval (CI) of GDM, accounting for baseline differences between vaccinated and unvaccinated individuals. Results: Of the 42,140 pregnancies, 38% identified as Hispanic, 33% non-Hispanic White, 15.6% non-Hispanic Asian, 8.8% non-Hispanic Black, and 4.4% other or unknown; 25.6% received one or more COVID-19 vaccine doses prior to 22 weeks’ gestation. Individuals who were vaccinated were older (mean age 32.0 ± 4.6 vs 29.5 ± 5.3 years) and more likely to be of non-Hispanic White (37.4% vs 31.7%) or Asian background (25.7% vs 12.1%) than those who were unvaccinated. The rate of GDM was 11.9 per 100 among those who received a COVID-19 vaccine and 10.6 per 100 among those who did not. There was no increased risk of GDM diagnosis associated with receipt of a COVID-19 vaccine during pregnancy, aRR 1.00 (95% CI 0.90-1.10). Conclusion: Data from this large cohort did not identify an increased risk of GDM associated with receipt of a COVID-19 vaccine prior to 22 weeks’ gestation. These results further support emerging evidence regarding the safety of COVID-19 vaccination in pregnancy. Disclosure K.K.Vesco: Research Support; Pfizer Inc. L.Jackson: None. J.Williams: None. T.G.Boyce: None. C.Fuller: Research Support; Pfizer Inc., Johnson & Johnson. G.Vazquez benitez: Research Support; AbbVie Inc., Sanofi. A.Denoble: None. H.S.Lipkind: Other Relationship; Pfizer Inc., Research Support; Centers for Disease Control and Prevention, Patient-Centered Outcomes Research Institute, National Institutes of Health. E.Kharbanda: None. M.B.Desilva: None. M.F.Daley: None. D.Getahun: None. O.Zerbo: None. A.Naleway: None. Funding Centers for Disease Control and Prevention (200-2012-53526)

840-P: Dual Amylin and Calcitonin Receptor Agonist Treatment Improves Blood Pressure and Glucose Control in ZSF1 Rats

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on both body weight, glucose control and insulin action. However, whether DACRAs affect hypertension, and diabetes-related cardiovascular complications remain unknown. In this study, the cardiovascular protective effect of the DACRA KBP-336 was evaluated in obese Zucker diabetic fatty-Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Obese ZSF1 rats were treated for 60 days with the KBP-336 (4.5 nmol/kg Q3D) and treatment efficacy on glucose control and blood pressure measured by tail cuff was evaluated. Furthermore, serum biomarkers of cardiovascular complications were evaluated. KBP-336 treatment significantly lowered fasting blood glucose levels compared to vehicle (P<0.001). This was also illustrated in the HbA1c levels at study end, where KBP-336 resulted in significantly (P<0.001) lower levels than vehicle. Importantly, KBP-336 significantly reduced both systolic (AUC levels reduced by 13.3%, P<0.001) and diastolic (AUC levels reduced by 17.0%, P<0.001) blood pressure compared to vehicle without affecting the heart rate. Notably, the beneficial effects on both glucose control and blood pressure were obtained independent of weight loss as KBP-336 only resulted in a small and transient weight reduction. Furthermore, serum levels of the marker of cardiovascular disease, rPRO-C6 (collagen type VI formation marker) were 6.4% lower in KBP-336 treated rats compared to vehicle, supporting improvement in cardiovascular parameters. In summary, we show for the first time that KBP-336 benefits blood pressure in a metabolic rat model suffering from hypertension. In addition, KBP-336 improved glucose control independent of weight loss. These data highlight KBP-336 as a promising candidate for treating obesity and related comorbidities including type 2 diabetes and hypertension. Disclosure S.A.Melander: None. A.T.Larsen: Employee; Nordic Bioscience A/S. K.Mohamed: Employee; Nordic Bioscience. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. Funding Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)

63-LB: Real-Time Continuous Glucose Monitoring (rtCGM) Is Associated with Improved Clinical and Psychosocial Health in People with Type 2 Diabetes on Basal Insulin (T2D-BI)

Background and Aims: Introduction of basal insulin (BI) can be an intimidating treatment escalation due to increased risk of hypoglycemia and weight gain for people with type 2 diabetes (T2D). There is growing evidence supporting the glycemic and quality of life benefits of rtCGM in T2D. We analyzed survey and rtCGM data for T2D-BI users of the Dexcom G6 rtCGM system to investigate the impact on sensor metrics, self-reported body weight, and psychosocial health. Methods: Three hundred T2D-BI Dexcom G6 users completed online surveys regarding their demographics and diabetes health. Participants’ sensor metrics were analyzed for duration of wear and glycemic changes from CGM initiation onwards (14-day time periods with ≥70% data available). Changes in variables were evaluated for clinical significance (weight loss ≥5%, transition to A1C <7%, ΔTIR ≥5%) and statistical significance (p<0.05 from paired t-tests). Results: Data from 150 CGM-naïve (prior to Dexcom G6 initiation) T2D-BI users were analyzed. Mean (IQR) age=60 years (53, 70), 45% female, 81% White, 50% reported annual household income <$75K. CGM duration was 11 months (4, 13). Body weight at baseline=235 pounds (190, 270), A1C=8.4% (7, 9.3), TIR= 69% (58, 86). Reported weight loss averaged 13 (-20, 0) pounds, A1C decrease averaged 1.6 (-2.5, 0) percentage points (both p<0.001) with no increase in hypoglycemia. Overall, 53 users experienced clinically significant weight loss (5% of total body weight), 48 improved their A1C to <7%, and 46 improved TIR by ≥ 5%. Participants reported healthier eating patterns, simplified diabetes management routines, and increased peace of mind using Dexcom G6. Conclusions: These real-world outcomes demonstrate clinically valuable improvements in T2D-BI on Dexcom G6 with respect to glycemic control, body weight, diabetes behaviors, and psychosocial health. Disclosure M. A. Crawford: Employee; Dexcom, Inc. C. Hicks: Employee; Dexcom, Inc. T. Zhou: Employee; Pfizer Inc. A. Kleinhanzl: Employee; Dexcom, Inc. H. Singh: Employee; Tandem Diabetes Care, Inc., Dexcom, Inc.

223-LB: Associations between Genetic Risk for Insulin Resistance and Measured Insulin Sensitivity Are Impacted by Race and BMI Status

African Americans (AA) are at greater risk for type 2 Diabetes (T2D) compared to European Americans (EA). This greater risk may derive in part from genetic factors. The genetic risk for insulin resistance (IR) has been linked to the failure to expand adipose tissue and is reflected in a genetic risk score (GRS) that is inversely associated with adiposity. In this study, we investigated whether associations between the GRS and measured insulin sensitivity (IS) differ by BMI status and/or race in a sample of 107 EA and AA adults without diabetes. IS was measured with the euglycemic clamp with an insulin dose of 120 µU/m²/min/kg lean body mass. In addition, surrogate indices of IS were calculated using glucose and insulin values obtained from an oral glucose tolerance test. Participants were classified as “high” or “low” BMI using the sample median (25.9 kg/m^2) as the cut-point. GRS were derived from imputed genotypes and weighted for clamp-derived IS. Multiple linear regression models were used to assess interactions between BMI status and GRS on measures of IS. Models were stratified by race and adjusted for percent body fat, sex, and age. In EA, associations of GRS with HOMA-IR and Matsuda differed by BMI status (pint=0.024 and pint=0.007, respectively), where GRS was inversely associated with IS in the high BMI group only (p=0.027 and p=0.010, respectively), suggesting that genetic risk for IR in EA is driven by greater adiposity. Conversely in AA, associations of GRS with IS from the clamp differed by BMI status (pint=0.083), but an inverse association was observed only in the low BMI group (p=0.035), suggesting that in AA, genetic risk for IR is associated with lower adiposity. Our results indicate that obesity status may differentially impact the link between genetic risk for IR and measured IS within and between races. Further, these results suggest that with a larger sample, a distinct phenotype may exist in AA where higher adiposity permits greater IS. Disclosure M. L. Yurchishin: None. L. A. Fowler: None. V. Parcha: None. P. Arora: None. W. Garvey: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Eli Lilly and Company, Merck & Co., Inc., Alnylam Pharmaceuticals, Inc., Fractyl Health, Inc. Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Pfizer Inc. Advisory Panel; Inogen. Research Support; Neurovalens. B. Gower: Consultant; Abbott.

260-LB: The Effect of LXR Activation on Liver Metabolism and Diet-Induced Steatohepatitis in Mice

While nonalcoholic fatty liver disease (NAFLD) affects approx. 30% of the US population, there is currently no approved pharmaceutical treatment to inhibit the progression of NAFLD to its more severe stage of nonalcoholic steatohepatitis (NASH). The liver X receptors (LXRs) are key regulators of cholesterol and fatty acid homeostasis in liver. However, the effects of LXR activation on liver metabolism in NASH pathogenesis are not well understood. We hypothesize that LXR activation might reduce NAFLD progression by augmenting lipid composition and metabolism in hepatocytes. To test this hypothesis, 8-week-old male wild type (WT) or obese, melanocortin-4 receptor knockout (Mc4r-/-) mice were placed on either chow or Western diet (WD) for 8 weeks. Half of the WD-fed mice were given WD supplemented with GW3965 (100mg/kg), a selective, orally active agonist for the LXRs. Animals fed GW3965-supplemented diet had increased gene expression of Abca1 and Lpcat3, both transcriptional targets of LXR action. LXR activation significantly decreased body mass of both WT and Mc4r-/- mice, which was correlated with reduction of subcutaneous fat. GW3965 supplementation greatly improved glucose homeostasis of Mc4r-/-. LXR activation significantly decreased hepatic triglycerides, cholesterol esters and ceramides content which was accompanied by decreased expression of lipogenic factors (Fasn, Dgat1 and 2, Fatp5, Elovl1 and 6) in Mc4r-/-. Contrary expression of genes involved in fatty acid β-oxidation together with pyruvate cycling fluxes (VPC, VPK+ME, VPEPCK) were elevated in Mc4r-/- fed diet supplemented with GW3965. These metabolic changes were related to decrease in hepatic fibrosis, expression of NF-κB pathway genes as well as inflammatory (Itgam, Cd274), oxidative (Sod2), and endoplasmic reticulum stress markers (Chop, Atf4 and 6). Taken together, these data suggest that LXR activation improves phenotype of genetically obese WD-fed animals and inhibits progression from NAFLD to NASH. Disclosure T. Bednarski: None. M. Rahim: None. N. Whittenbarger: None. A. J. Olichwier: None. J. Young: Consultant; Pfizer Inc. Stock/Shareholder; Metalytics, Inc. Consultant; Metalytics, Inc. Research Support; Merck Sharp & Dohme Corp. Funding National Institutes of Health (R01DK106348); Vanderbilt University; University of Nebraska-Lincoln Nutrition and Health Sciences Fund