Intercept Pharmaceuticals Research Articles

738-P: The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES) : Final 24-Month Patient-Reported Outcomes

Data on patient-reported outcome (PRO) measures in people living with T2D who initiate injectable glucagon-like peptide-1 receptor agonist (GLP-1 RA) medication in routine clinical practice are limited. Here we present final PRO data from the TROPHIES 24-month, prospective, non-comparative, observational study of adult patients with T2D in France, Germany and Italy who started their first injectable GLP-1 RA with either once-weekly dulaglutide (DU) or once-daily liraglutide (LIRA) . Patients’ scores on PRO questionnaires were assessed every 6 months. We present scores at 24 months compared with baseline values before starting DU or LIRA treatment. For each PRO measure, higher scores reflect better outcomes. Baseline characteristics (previously published) for patients prescribed DU (N=1,014) or LIRA (N=991) were similar between groups. Mean changes from baseline to 24 months in PRO scores indicate improvements in health outcomes in patients initiating DU or LIRA (Table) . In summary, among those patients still evaluable at 24 months we observed improvements in PRO scores from baseline in both groups, but with a more pronounced trend of improvement in the DU cohort for EQ-5D-5L VAS, IW-SP, DTSQs total, and DPM life and work productivity scores. Disclosure M.Fuechtenbusch: Advisory Panel; Berlin-Chemie AG, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Speaker's Bureau; AstraZeneca, Novo Nordisk. K.Boye: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. B.Guerci: Advisory Panel; Amgen Inc., Medtronic, Board Member; Abbott Diagnostics, AstraZeneca, Bayer AG, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Consultant; Boehringer Ingelheim International GmbH, Intercept Pharmaceuticals, Inc., Novo Nordisk. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. L.Garcia-perez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. E.Heitmann: None. J.Lebrec: Consultant; Eli Lilly and Company. A.Barrett: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Dib: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Orsini federici: Employee; Eli Lilly and Company.

178-OR: Prescription Patterns of Cardiovascular and Kidney Protective Therapies among Patients with Type 2 Diabetes

Background: Recent guidelines recommend use of SGLT2i and/or GLP1-RA in persons with type 2 diabetes (T2D) and CVD or CKD, regardless of glycemic control. The degree of adoption of these recommendations thus far is unclear Methods: Among T2D patients receiving care within the VA Health Care System, we evaluated the prevalence and correlates of SGLT2i and GLP1-RA prescription during 20 and 2020. Logistic regression was used to examine associations of atherosclerotic CVD (ASCVD) , heart failure, and CKD (defined by lab values and/or administrative codes) as well as predicted risks of ASCVD and end-stage kidney disease (ESKD) , with prescription of SGLT2i and GLP1-RA Results: Of 1,319,500 adults with T2D, 10% and 7% were prescribed SGLT2is and GLP1-RAs, respectively. Prescription prevalence of SGLT2i and GLP1-RA were 13% and 9% in patients with established ASCVD; 14% and 11% in those with heart failure; and 11% and 10% in those with CKD. In adjusted models, patients with severe albuminuria were less likely to be prescribed an SGLT2i or a GLP1-RA versus non-albuminuric patients with CKD: aOR (95% CI) = 0.89 (0.87, 0.91) and 0.95 (0.93, 0.98) , respectively. In patients with 10-year ASCVD risk >20% versus those with risk <5%, ASCVD risk was inversely associated with prescription: SGLT2i OR=0.70 (0.60, 0.80) and GLP1-RA OR=0.60 (0.50, 0.70) . Patients with 5-year ESKD risk >5% were less likely to be prescribed an SGLT2i: OR=0.61 (0.57, 0.66) , versus those with ESKD risk <1% Conclusions: Among a national VA cohort of patients with T2D, prescription of SGLT2i and GLP1-RA was pervasively low across conditions for which they are currently indicated to lower the risk of CVD and CKD progression. Furthermore, we observed a “risk-treatment paradox”, where patients with higher risk of adverse outcomes were less likely to receive these therapies. Intensive implementation efforts are needed to prioritize prescription of these medications to patients who would derive the largest benefit. Disclosure J.A. Lamprea Montealegre: Research Support; Bayer AG. E. Madden: None. S. Tummalapalli: Consultant; Bayer AG. Research Support; Scanwell Health. C. Chu: Research Support; Bayer AG. Y. Du: Employee; Bayer AG. Stock/Shareholder; Bayer AG. R. Singh: None. S. Kong: Employee; Bayer AG. D.S. Tuot: None. C. Peralta: Employee; Cricket Health, Inc. Research Support; American Heart Association, National Institutes of Health. M.G. Shlipak: Advisory Panel; TAI Diagnostics. Consultant; Cricket Health, Intercept Pharmaceuticals, Inc. Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH. M. Estrella: Research Support; Bayer AG. Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH.

830-P: The Pan-PPAR Agonist Lanifibranor Improves Nonalcoholic Steatohepatitis (NASH) and Glycemic Control

Lanifibranor therapy resulted in both NASH resolution and fibrosis reduction in the phase 2b NATIVE study in patients with non-cirrhotic NASH, compared to placebo. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D) . We evaluated the association between the effect of lanifibranor on glycemic control (GC) and NASH markers. Methods: NATIVE included 247 patients, randomized to lanifibranor 800, 1200 mg/d or placebo for 24 weeks of treatment; 228 patients completed the trial. Efficacy in NASH was measured with SAF score (primary endpoint) and NASH-CRN grading and fibrosis staging. Biomarkers for insulin resistance (IR) , GC, lipid metabolism, inflammation, liver enzymes and imaging of hepatic steatosis by continuous attenuation parameter (CAP) were analyzed at baseline (BL) and end of treatment (EOT) . Correlations between HbA1c (≤6, >6 - ≤7 and >7%) at BL and HbA1c change from BL to EOT with improvement in biomarkers and histologic features of NASH at EOT were assessed. Results: T2D was present in 103 (42%) patients. The composite endpoint of NASH resolution and fibrosis improvement in the overall and T2D group for lanifibranor (pooled data) versus (vs) placebo was 26% vs. 7% (p<0.001) , and 26% vs. 3% (p=0.003) , respectively. Irrespective of T2D status, lanifibranor improved fasting glucose (FG) , IR, lipid metabolism, C-reactive protein, and liver enzymes. In contrast to placebo, lanifibranor improved mean HbA1c from BL in the overall and T2D group, -0.41% and -0.66%, respectively. In the lanifibranor group, BL HbA1c correlated with BL NASH activity and fibrosis; HbA1c decrease at EOT correlated with improvement of FG, insulin, IR, liver enzymes, HDL-cholesterol, triglycerides, ApoB, ApoB/ApoA1, CAP and histologic improvement of steatosis and ballooning. Conclusion: GC correlates with NASH severity. The improvement of metabolic markers of NASH and hepatic steatosis with lanifibranor treatment is consistent with its beneficial effect on GC. Disclosure M.P.Cooreman: Employee; Inventiva Pharma. S.Francque: None. L.Dzen: Employee; Inventiva Pharma. P.Huot-marchand: Employee; Inventiva Pharma. J.L.Junien: None. P.Broqua: None. M.F.Abdelmalek: Advisory Panel; Akero Therapeutics, Inc., Bristol-Myers Squibb Company, Inventiva Pharma, Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Novo Nordisk, Consultant; Hanmi Pharm. Co., Ltd., Research Support; Akero Therapeutics, Inc., Allergan, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Celgene, DURECT Corporation, Enanta, Enyo Pharma, Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Inventiva Pharma, Madrigal Pharmaceuticals, Inc., NGM Biopharmaceuticals, Novo Nordisk, Poxel SA, TARGET PharmaSolutions, Inc., Viking Therapeutics.

726-P: The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Type 2 Diabetes Patients (TROPHIES) : Final 24-Month Clinical Characteristics and Treatment Pattern Analyses

TROPHIES was a 24-month, prospective, non-comparative, observational study in adult patients with T2D initiating their first injectable glucose-lowering treatment with once-weekly dulaglutide (DU; N=1,014) or once-daily liraglutide (LIRA; N=991) in France, Germany, and Italy. Secondary objectives included assessments of HbA1c, body weight and treatment patterns. Clinical characteristics of the DU and LIRA cohorts at 24 months are described in the Table. Most patients receiving DU (856/1,014) initiated treatment at 1.5 mg/week and, among 286 patients with a significant treatment change, 237 were still receiving 1.5 mg/week. In the LIRA cohort, most patients (809/991) initiated at the starting dose 0.6 mg/day and 45% increased dose to 1.2 mg/day by Day 90; however, 17% of patients were already receiving 1.8 mg/day by Day 90. At the first significant treatment change 285/448 patients in the LIRA cohort were receiving 1.2 mg/day. Insulin was initiated by 79 and 97 patients in the DU and LIRA cohorts, respectively. Both treatments showed clinically meaningful effectiveness on HbA1c and weight, maintained over the 24-month study period. Disclosure B. Guerci: Advisory Panel; Amgen Inc., Medtronic. Board Member; Abbott Diagnostics, AstraZeneca, Bayer AG, Eli Lilly and Company, Novartis Pharmaceuticals Corporation. Consultant; Boehringer Ingelheim International GmbH, Intercept Pharmaceuticals, Inc., Novo Nordisk. F. Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. Consultant; Lilly Diabetes, Sanofi. Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. K. Boye: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M. Fuechtenbusch: Advisory Panel; Berlin-Chemie AG. Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp. Speaker's Bureau; AstraZeneca, Novo Nordisk. E. Heitmann: None. J. Lebrec: Consultant; Eli Lilly and Company. A. Dib: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M. Orsini Federici: Employee; Eli Lilly and Company. M. Yu: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. L. Garcia-Perez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

A209 EXPERT CONSENSUS CRITERIA AND PRACTICAL RECOMMENDATIONS FOR PBC CARE IN THE COVID-19 ERA AND BEYOND

BackgroundPrimary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that can progress to liver fibrosis and cirrhosis, and requires timely diagnosis, optimal treatment, and risk stratification. Several guidelines for the management of PBC have been published, including the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL) Clinical Practice Guidelines, which include goals for standards of PBC care. However, recent audits have identified deficiencies in real-world PBC care. In addition, the global coronavirus (COVID-19) pandemic has generally reduced access to care, diminished healthcare resources and accelerated the use of remote patient management. There is therefore a need for simple, actionable guidance that physicians can implement in order to maintain standards of care in PBC in the new environment.AimsA working group of ten PBC specialists from Europe and Canada were convened by Intercept Pharmaceuticals in January 2020 with the aim of defining key criteria for the care of patients with PBC.MethodsFollowing the outbreak of the COVID-19 pandemic, based on these criteria, a smaller working group of six PBC specialists developed practical recommendations to assist physicians in maintaining standards of care and to guide remote management of patients.ResultsThe working group defined five key criteria for care in PBC, encompassing PBC diagnosis, initiation of first line therapy with ursodeoxycholic acid (UDCA), risk stratification on UDCA, symptom management, and initiation of 2L therapy. The group developed 21 practical recommendations for the management of patients with PBC in the COVID-19 environment including modality, frequency and timing of investigations and monitoring. (Figure 1).ConclusionsThe delivery of PBC care during the COVID-19 pandemic carries significant challenges. These consensus criteria and practical recommendations provide guidance for the management of PBC during the pandemic era and beyond. Funding AgenciesNoneIntercept Pharmaceutical

Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease.

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by chronic inflammation and accumulation of fat in liver tissue. Affecting estimated 35 million people globally, NASH is the most common chronic liver condition in Western populations, and with patient numbers growing rapidly, the market for NASH therapy is projected to rise to $27.2 B in 2029. Despite this clinical need and attractive commercial opportunity, there are no Food and Drug Administration (FDA)-approved therapies specifically for this disease. Many have tried and unfortunately failed to find a drug, or drug combination, capable of unravelling the complexities of this metabolic condition. At the time of writing this review, only Zydus Cadila’s new drug application for Saroglitazar had been approved (2020) for NASH therapy in India. However, it is hoped that this dearth of therapy options will improve as several drug candidates progress through late-stage clinical development. Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon. Here, we have performed an exhaustive review of the current therapeutic landscape for this disease and compared, in some detail, the fortunes of different drug classes (biologics vs small molecules) and target molecules. Given the complex pathophysiology of NASH, the use of drug combination, different mechanisms of actions and the targeting of each stage of the disease will likely be required. Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come.

752-P: LIVRQNac (AXA1125) Enhances Insulin Sensitivity in Primary Human Hepatocytes and in Subjects with NAFLD and T2D

Background: AXA1125, an investigational composition of 5 amino acids and n-acetyl-cysteine, targets multiple biologies relevant to NAFLD pathogenesis.Methods: Primary human hepatocytes (PHH) from multiple donors were pretreated with AXA1125 components (LIVRQNac), exposed to lipotoxic insult in the presence of LIVRQNac, incubated in high glucose insulin-free medium, followed by glucose-free medium±insulin. Human safety, tolerability, and biologic activity were evaluated in a 16-week, multicenter, randomized, placebo (Pbo)-controlled study (NCT04073368) in subjects with NAFLD±T2D. Results from Pbo and AXA1125 24 g twice daily dosing in subjects with T2D are reported.Results: In PHH, LIVRQNac reduced glucose output by ~50% (p <0.01) and enhanced insulin-dependent Akt phosphorylation by 80% (p<0.001). Clinically, AXA1125 showed greater reductions from BL at W16 vs. Pbo in metabolic and fibroinflammatory biomarkers (Table); both arms had similar baseline characteristics. AEs were mostly mild to moderate.Conclusions: This concordant multifactorial biologic activity, including the effects on glucose homeostasis, suggests a potential enhanced impact of AXA1125 in NAFLD subjects with diabetes that warrants further investigation.View largeDownload slideView largeDownload slide DisclosureS. Baum: Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. J. Zhao: Employee; Self; Axcella Health Inc., Stock/Shareholder; Self; Axcella Health Inc. M. Chakravarthy: None. M. Koziel: None. S. A. Harrison: Consultant; Self; Axcella Health Inc. N. T. Gunn: None. Z. Younes: Research Support; Self; Axcella Health Inc., Novo Nordisk. A. Kohli: Research Support; Self; Axcella Health Inc., Novo Nordisk. R. Patil: Speaker’s Bureau; Self; Intercept Pharmaceuticals, Inc. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. M. Hamill: Employee; Self; Axcella Health Inc. N. Daou: None.FundingAxcella Health Inc.

192-OR: Glycemic Control with Once-Weekly Basal Insulin Fc (BIF) in Persons with Type 2 Diabetes Mellitus (T2DM) Using Continuous Glucose Monitoring (CGM) in a Phase 2 Study

Basal insulin Fc (BIF; LY3209590) is a novel, once-weekly, long-acting IgG Fc-fusion protein assessed for the treatment of diabetes mellitus. A 32-week study evaluating the safety and efficacy of BIF vs. degludec in persons with T2DM previously treated with a basal insulin showed HbA1c non-inferiority of BIF vs. degludec with significantly fewer hypoglycemic events (≤70 mg/dL). Here we present CGM data derived by Dexcom G6, allowing a more detailed assessment of glycemic control of BIF vs. degludec. The study included 2 dosing algorithms for BIF with different fasting glucose (FG) targets: ≤140 mg/dL (BIF-A1) and ≤120 mg/dL (BIF-A2). Degludec was titrated to FG ≤100 mg/dL. Subjects were randomized to 1 of the 3 arms. Subject (N=399) mean age was 60.2 yrs and baseline HbA1c was 8.1%. For the entire 32 weeks, the percent of 24 hrs in range, hyperglycemia and hypoglycemia was similar for the 3 arms (Figure). At Week 32, total duration of hypoglycemia was similar across 7 days post-injection for BIF-A1 and A2, showing that duration of hypoglycemia is independent of day post-injection. CGM data confirm that BIF showed similar glycemic control vs. degludec despite higher FG targets and numerically lower time in hypoglycemia. The flat pharmacokinetic profile enables near peakless insulin concentrations without an increase in hypoglycemia risk at highest exposure. Disclosure C. M. Kazda: Employee; Self; Eli Lilly and Company. J. Chien: Stock/Shareholder; Self; Eli Lilly and Company. Q. Zhang: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. E. Chigutsa: Employee; Self; Eli Lilly and Company. W. Landschulz: Employee; Self; Lilly Diabetes, Employee; Spouse/Partner; Covance Inc., Stock/Shareholder; Self; Lilly Diabetes. P. Wullenweber: None. A. Haupt: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. Funding Eli Lilly and Company

101-OR: Efficacy and Safety of Once-Weekly Semaglutide 2.0 vs. 1.0 mg for Type 2 Diabetes: SUSTAIN FORTE Randomized Trial

Once-weekly (OW) subcutaneous semaglutide 0.5 and 1.0 mg are approved maintenance doses for type 2 diabetes (T2D) treatment. We hypothesized that a higher dose of 2.0 mg would provide additional glycemic control with more patients achieving treatment targets vs. 1.0 mg. SUSTAIN FORTE (NCT03989232) was a randomized, double-blind, phase 3b trial investigating the efficacy and safety of OW semaglutide 2.0 vs. 1.0 mg after 40 weeks of treatment in 961 adults with T2D in need of treatment intensification (HbA1c 8.0-10.0%) on stable metformin ± sulfonylurea. All participants initiated semaglutide treatment with the 0.25 mg dose, doubling every 4 weeks until target dose was reached. The primary objective was to establish superiority of semaglutide 2.0 vs. 1.0 mg on glycemic control; secondary objectives included comparison of the effect on body weight (BW) (confirmatory), safety and tolerability. Baseline characteristics and key results are shown in the Table. Superior HbA1c and BW reductions were shown with semaglutide 2.0 vs. 1.0 mg and a greater proportion of participants achieved HbA1c In conclusion, semaglutide 2.0 mg is superior to 1.0 mg in reducing HbA1c and BW, with a comparable safety profile. Disclosure J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. J. B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Fortress Biotch, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego Inc., Stability Health, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Research Support; Self; NovaTarg Therapeutics, Novo Nordisk, Sanofi, Tolerion, Inc., vTv Therapeutics, Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. P. Auerbach: Employee; Self; Novo Nordisk A/S. H. S. Bajaj: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., Sanofi, Tricida, Inc. Y. Fukushima: None. I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. S. Macura: Employee; Self; Novo Nordisk A/S. A. L. Sondergaard: Stock/Shareholder; Self; Novo Nordisk A/S, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Tankova: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Sanofi, Worwag Pharma, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Pharma Ltd., Sandoz International GmbH, Sanofi, Servier Laboratories. N. Tentolouris: None. Funding Novo Nordisk A/S

102-OR: Efficacy and Safety of Once-Weekly Efpeglenatide vs. Placebo as Monotherapy in Patients with Type 2 Diabetes (AMPLITUDE-M)

Efpeglenatide (Efpeg) is being developed as a long-acting GLP-1 receptor agonist for once weekly, subcutaneous administration. The efficacy and safety of Efpeg vs. placebo (PBO) was assessed in patients with type 2 diabetes (T2D) inadequately controlled with diet and exercise alone. In this double-blind, PBO-controlled, 30+26-week Phase 3 study, patients with T2D were randomized to Efpeg 2 mg (n=100), 4 mg (n=101), and 6 mg (n=103), or PBO (n=102). Endpoints were change from baseline in HbA1c at week 30 (primary) and other parameters of glycemic control, body weight (BW) and safety at weeks 30 and 56 (secondary). Baseline characteristics and key results are shown in the Table. All doses of Efpeg showed significantly greater reductions in HbA1c vs. PBO at weeks 30 and 56, and a greater proportion of patients achieved HbA1c In conclusion, Efpeg as monotherapy in patients with T2D was well tolerated and demonstrated significant improvements versus PBO in HbA1c and BW after 30 weeks of treatment. These improvements generally remained stable through 56 weeks of therapy. Disclosure S. Baek: Employee; Self; Hanmi Pharmaceutical. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. L. Popescu: Employee; Self; Sanofi. E. Niemoeller: Employee; Self; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Self; Sanofi. I. Muehlen-bartmer: Employee; Self; Sanofi-Aventis Deutschland GmbH. J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi.

665-P: Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg vs. 1.0 mg by Baseline HbA1c and BMI: SUSTAIN FORTE Subgroup Analyses

Once-weekly subcutaneous semaglutide 2.0 mg showed superior efficacy with similar safety vs. 1.0 mg in 961 participants with type 2 diabetes (HbA1c 8.0-10.0%) after 40 weeks in SUSTAIN FORTE. We assessed the effect of semaglutide 2.0 mg vs. 1.0 mg on HbA1c and body weight (BW) in prespecified baseline (BL) HbA1c (<9.0%, ≥9.0%) and BMI (<35, ≥35 kg/m2) subgroups.Mean BL HbA1c was 8.9% and BMI 34.6 kg/m2. For HbA1c and BW, estimated treatment differences favored semaglutide 2.0 mg vs. 1.0 mg across all BL HbA1c and BMI subgroups. Treatment-by-subgroup interactions were nonsignificant (HbA1c, p=0.55 and p=0.41; BW, p=0.40 and p=0.13; Figure A-D). Greater mean HbA1c reductions were observed for both doses in the higher vs. lower BL HbA1c subgroup (Figure A). Conversely, greater mean BW reductions were observed for both doses in the lower vs. higher BL HbA1c subgroup (Figure C). Similar mean HbA1c reductions were observed across BL BMI subgroups (Figure B), while greater mean BW reductions were observed for both doses in the higher vs. lower BL BMI subgroup Figure D). Overall, the incidence of adverse events was similar for both doses and across BL HbA1c and BMI subgroups with no new safety concerns identified.In line with the results in the overall population, semaglutide 2.0 mg provided consistently greater reductions in HbA1c and BW vs. 1.0 mg across BL HbA1c and BMI subgroups.View largeDownload slideView largeDownload slide DisclosureJ. B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Fortress Biotch, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego Inc., Stability Health, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Research Support; Self; NovaTarg Therapeutics, Novo Nordisk, Sanofi, Tolerion, Inc., vTv Therapeutics, Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. P. Auerbach: Employee; Self; Novo Nordisk A/S. H. S. Bajaj: Other Relationship; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., Sanofi, Tricida, Inc. Y. Fukushima: None. I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. S. Macura: Employee; Self; Novo Nordisk A/S. A. L. Søndergaard: Stock/Shareholder; Self; Novo Nordisk A/S, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Tankova: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Medtronic, Novartis AG, Sanofi, Wörwag Pharma, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Pharma Ltd., Sandoz International GmbH, Sanofi, Servier Laboratories. N. Tentolouris: None.FundingNovo Nordisk A/S

119-LB: Increased Adiponectin following Efruxifermin Treatment Is Associated with Improvements in Dyslipidemia, Glucose Metabolism, and Liver Health in a 16-Week, Randomized, Placebo-Controlled NASH Trial

FGF21, an endocrine hormone that regulates whole-body metabolism during energy imbalance, is a promising therapeutic target. Efruxifermin (EFX), an Fc-FGF21 analog, is a balanced FGFR1c, 2c, and 3c agonist under investigation as a potential treatment for nonalcoholic steatohepatitis (NASH). In a clinical trial in biopsy-confirmed NASH, EFX significantly reduced liver fat content (LFC), ALT, and AST, and increased adiponectin.1 Activating FGFR1c in adipose tissue increases circulating adiponectin; the aim of this analysis was to evaluate correlations between changes in adiponectin and markers of dyslipidemia, glucose metabolism and liver health following EFX treatment. Patients (N=80) were randomized to placebo or 28, 50, or 70mg EFX. Larger increases in adiponectin correlated with greater improvements in lipid profiles, including decreases in triglycerides and increases in HDL-C, as well as decreases in LFC (Table). Increases in adiponectin also correlated strongly with markers of improved glucose metabolism, and greater reductions in markers of liver injury and fibrosis. These data suggest adipose tissue-mediated effects of EFX contribute substantially to restoration of liver health, healthy lipoprotein profiles, insulin sensitivity and glucose tolerance.1 Harrison 2020 Hepatol 72 1S; 6AView largeDownload slideView largeDownload slide DisclosureJ. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. E. J. Tillman: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. R. Shringarpure: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. E. Fong: Employee; Self; Akero Therapeutics, Inc. B. De temple: Employee; Self; Akero Therapeutics, Inc. T. Rolph: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Pfizer Inc. A. Cheng: Employee; Self; Akero Therapeutics, Inc. K. Yale: Employee; Self; Akero Therapeutics, Inc. S. A. Harrison: Consultant; Self; Axcella Health Inc.

100-OR: ADA Presidents’ Select Abstract: Efficacy and Safety of Once-Weekly Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist vs. Placebo as Monotherapy in People with Type 2 Diabetes (SURPASS-1)

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist in development for type 2 diabetes (T2D). Efficacy and safety of TZP vs. placebo (PBO) was assessed in people with T2D inadequately controlled with diet and exercise alone. In this double-blind, PBO-controlled, 40-wk Phase 3 study, people with T2D (N=478; mean baseline [BL] HbA1c 7.94%; age 54.1 y; T2D duration 4.7 y; BMI 31.9 kg/m2) were randomized (1:1:1:1) to TZP (5, 10, 15 mg) or PBO. Primary efficacy measure was mean change in HbA1c from BL at 40 wk. Secondary measures were mean change in fasting serum glucose (FSG) and body weight (BW) and proportion achieving HbA1c and BW goals. TZP 5, 10 and 15 mg were superior to PBO in mean change in HbA1c at 40 wk (LSM treatment difference [95% CI]: -1.91% [-2.18, -1.63], -1.93% [-2.21, -1.65], -2.11% [-2.39, -1.83]; p In conclusion, TZP as T2D monotherapy demonstrated robust clinically meaningful reductions in HbA1c and BW without hypoglycemia (BG Disclosure J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi. C. H. Wysham: Other Relationship; Self; Abbott Laboratories, American Diabetes Association, Endocrine Society, Medscape Education, Novo Nordisk, Sanofi-Aventis, Research Support; Self; Eli Lilly and Company, Mylan N. V., Mylan N. V., Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc. J. P. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. S. Kaneko: Advisory Panel; Self; Novo Nordisk Pharma Ltd., Consultant; Self; Novo Nordisk Pharma Ltd., Research Support; Self; Eli Lilly Japan K. K., Novo Nordisk Pharma Ltd., Speaker’s Bureau; Self; AstraZeneca, Eli Lilly Japan K. K., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Pharma Ltd., Sumitomo Dainippon Pharma Co., Ltd. C. Lee: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. L. Fernandez lando: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. H. Mao: Employee; Self; Eli Lilly and Company. X. Cui: Employee; Self; Eli Lilly and Company. V. Thieu: None. Funding Eli Lilly and Company

116-LB: Efruxifermin Is Associated with Improved Glucose Metabolism in Patients with NASH and Type 2 Diabetes

A third of patients with type 2 diabetes (T2D) are estimated to have nonalcoholic steatohepatitis (NASH). There is a high unmet need for safe and effective therapies that can address liver health and metabolic comorbidities in NASH patients. Efruxifermin (EFX), a long-acting Fc-FGF21 fusion protein, demonstrated robust reductions in liver fat content, markers of liver injury and fibrosis, and improved lipid and glucose metabolism in patients with NASH and fibrosis stage 1-3.1Patients (N=80) were randomized to receive placebo or 28, 50, or 70mg EFX for 16 weeks, and continued on their existing antidiabetic medications. The aim of this analysis was to evaluate the effects of EFX on markers of glucose metabolism in patients with NASH and in the subgroup with T2D (N=41).Mean age, BMI and HbA1c at baseline were 52y, 37.6 kg/m2 and 6.3% in the overall study population, and 53y, 38.1 kg/m2, and 7.0% in the T2D subgroup. Clinically meaningful improvements in glycemic control were observed in the T2D subgroup (Table B), consistent with improvements in markers of glucose metabolism in the overall population (Table A), and with the insulin-sensitizing actions of EFX. Considering the prevalence of T2D in NASH, the ability to improve glycemic control over existing medications is a desirable attribute for future NASH therapies.1Harrison et. al. 2020. Hepatology, 72; 1S; 6AView largeDownload slideView largeDownload slide DisclosureJ. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. S. A. Harrison: Consultant; Self; Axcella Health Inc. R. Shringarpure: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. E. J. Tillman: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Akero Therapeutics, Inc. C. Hu: None. E. Fong: Employee; Self; Akero Therapeutics, Inc. B. De temple: Employee; Self; Akero Therapeutics, Inc. T. Rolph: Employee; Self; Akero Therapeutics, Inc., Stock/Shareholder; Self; Pfizer Inc. A. Cheng: Employee; Self; Akero Therapeutics, Inc. K. Yale: Employee; Self; Akero Therapeutics, Inc.

78-LB: Efficacy and Safety of Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist, Compared with Insulin Degludec in Patients with Type 2 Diabetes (SURPASS-3)

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist under development for the treatment of type 2 diabetes (T2D). The efficacy and safety of TZP vs. titrated insulin degludec (IDeg) were assessed in insulin-naive patients with T2D inadequately controlled on metformin with/without SGLT-2i. In this open-label, 52-week, Phase 3 study, 1444 patients with T2D were randomized (1:1:1:1) to once-weekly TZP (5, 10, 15 mg) or once-daily IDeg (mean baseline [BL] age, 57.4 years; T2D duration, 8.4 years; HbA1c, 8.17%; BMI, 33.5 kg/m2; 32% on SGLT-2i). The primary efficacy endpoint was mean change in HbA1c from BL to Week 52. Secondary efficacy endpoints included mean change in fasting serum glucose (FSG) and body weight (BW) and proportion of subjects achieving HbA1c and BW goals. All TZP doses were superior to IDeg in mean change from BL in HbA1c and BW, and in the proportion of patients achieving all HbA1c and BW goals at Week 52 (Table). Among patients taking TZP 15 mg, 48.4% achieved HbA1c Disclosure B. Ludvik: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Research Support; Self; Amgen Inc., Eli Lilly and Company, Novo Nordisk, Speaker’s Bureau; Self; MSD Corporation. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. E. Jodar: Other Relationship; Self; AstraZeneca, Lilly Diabetes, Mundipharma International, Novo Nordisk, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. J. Frias: Consultant; Self; 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CymaBay Therapeutics, Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi, Speaker’s Bureau; Self; Merck & Co., Inc., Sanofi. L. Fernandez lando: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. K. Brown: Employee; Self; Eli Lilly and Company. R. Bray: None. A. Rodriguez: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

718-P: Long-Term Safety of Intranasal Insulin (INI) in Insulin-Dependent Type 2 Diabetes (T2DM-IDDM): A Safety Substudy of Memory Advancement by Intranasal Insulin in Type 2 Diabetes (MemAID) Trial

INI has emerged as a potential treatment for T2DM-related functional decline and is safe in adults without T2DM. However, INI safety in T2DM-IDDM is unknown. We aimed to demonstrate safety of long-term INI use in T2DM-IDDM MemAID participants. We screened 86 participants with T2DM-IDDM, 14 were randomized (9 INI/5 Placebo), 9 started treatment (5 INI [60±14 years, 2 Female]; 4 Placebo [68±2 years, 1 Female]). Of those, 2-INI and 3-Placebo participants completed 24 weeks of treatment and 24 weeks of follow-up. Participants underwent one week of continuous glucose monitoring (CGM)(Medtronic IPro2) at baseline and after INI (Novolin® R ) or placebo initiation. HbA1c, fasting plasma and capillary glucose, and insulin were measured throughout the study. Insulin levels were unchanged across the study. In 2 INI-treated participants, HbA1c, fasting plasma and capillary glucose declined from baseline, but the average values were similar during treatment and follow up, and comparable to 3 placebo-treated participants. Both INI-treated participants had adjustments of IDDM regimens. Capillary glucose did not decline 2 hours after INI administration, and there were no interactions between INI and subcutaneous insulin. There were no INI-related serious adverse events. Of 13 hypoglycemia (HG) episodes across the study, 2 asymptomatic level-1 HG (15.4%) occurred in INI group and 7 (53.8%) in placebo group. There were 2 asymptomatic level-2 HG (15.4%) in both INI and placebo groups. INI therapy was not associated with serious adverse events or HG in older participants with T2DM-IDDM. This study may pave the way towards future larger studies evaluating the safety of concomitant administration of INI and subcutaneous insulin (NCT02415556). Disclosure L. Aponte becerra: None. B. Galindo mendez: None. F. Khan: None. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. V. Lioutas: Consultant; Self; QMetis. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. Memaid investigators (j. trevino): n/a. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

256-OR: Substantial Cardiovascular Risk Reduction with Icosapent Ethyl Regardless of Diabetes Status or BMI: REDUCE-IT BMI

Background: REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams daily or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p Methods: We evaluated if BMI modulated CV risk reduction with IPE in patients with or without DM. Results: In the full cohort, similar CV risk reduction was observed across the prespecified endpoint testing hierarchy (interaction p=ns for all), and relative safety between treatment groups was generally consistent. In persons with or without DM, similar reductions in the primary endpoint were observed across BMI categories (Figure), with similar findings in the key secondary endpoint (interaction p=ns for all). Conclusion: The significant cardiovascular risk reduction provided by IPE 4g/day is consistent across BMI in patients with and without DM. Disclosure D. L. Bhatt: Research Support; Self; Afimmune Limited, Amarin Corporation plc, Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Idorsia Pharmaceuticals Ltd, Lexicon Pharmaceuticals, Inc., PLx Pharma Inc., Sanofi-Aventis. C. M. Ballantyne: Advisory Panel; Self; Amarin Corporation plc, Arrowhead Pharmaceuticals, Inc., Pfizer Inc., Consultant; Self; Amgen Inc., CSL Behring, Intercept Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Regeneron Pharmaceuticals Inc., Research Support; Self; Abbott, Amgen Inc., Ionis Pharmaceuticals, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., Roche Diagnostic USA. E. A. Brinton: Consultant; Self; 89bio, Inc., DalCor Pharmaceuticals, Esperion, Novartis AG, Other Relationship; Self; Kowa Pharmaceuticals America, Inc., Speaker’s Bureau; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Amgen Inc., Esperion, Medicure. P. G. Steg: Consultant; Self; Amarin Corporation plc, Amgen Inc., AstraZeneca, Bristol-Myers Squibb Company, Novartis Pharmaceuticals Corporation, Research Support; Self; Bayer AG, Sanofi, Servier Laboratories. S. B. Ketchum: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. R. A. Juliano: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. L. Jiao: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. R. T. Doyle: Employee; Self; Amarin Corporation plc, Stock/Shareholder; Self; Amarin Corporation plc. C. Granowitz: Employee; Self; Amarin Corporation plc. J. Tardif: Other Relationship; Self; Amarin Corporation plc, DalCor Pharmaceuticals, DalCor Pharmaceuticals, Sanofi, Research Support; Self; AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, REGENXBIO Inc., Servier Laboratories.

719-P: Caloric Intake, Appetite, and Body Composition Outcomes of Long-Term Intranasal Insulin (INI) Administration: A Substudy of the Memory Advancement by INI in Type 2 Diabetes (MemAID) Study

Centrally administered insulin stimulates the reward system to reduce appetite in response to food intake in animal studies. Previous studies in humans have shown mixed results, suggesting INI may decrease appetite, body fat, and weight in non-obese and young males, but this hypothesis has not been tested in elderly with and without type 2 diabetes. This randomized, doubled blind trial consisted of 24 weeks of treatment with either 40 IU of INI (Novolin® R) or Placebo (sterile saline) once daily in elderly adults from MemAID. The primary outcome was the INI effect on food intake, and secondary outcomes included appetite, anthropometric measures, and body composition. In exploratory analyses, we tested the effect of INI on these outcomes when contrasting individuals by gender, BMI, and type 2 diabetes. Randomization included 121 participants, of which 89 (42 women, 53%; age 65±9 years; 46 INI, 52%; 38 diabetes, 43%) completed baseline and at least one intervention visit. Of those, 70 completed treatment (31 diabetes). There was no INI effect on caloric intake on any of the secondary outcomes. Sub-analyses comparing participants within the INI group also showed no differential effect on primary and secondary outcomes. We did not observe an overall INI effect on food intake, appetite, anthropometric measures, and body composition. However, whether insulin resistance may limit the effect of INI in participants without type 2 diabetes remains to be explored. Further research on the mechanisms underlying the potential effect of INI on appetite centrally is warranted (NCT02415556). Disclosure L. Aponte becerra: None. F. Khan: None. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Memaid collaborators (a. gavrieli, j. upadhyay): n/a. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

1174-P: Application of NIS4 Technology for Stand-Alone and Sequential Identification of At-Risk NASH or Advanced Fibrosis in Nondiabetic, Prediabetic, and Type 2 Diabetic Patients

Background: Type 2 diabetes (T2D) is an independent risk factor for the development of nonalcoholic steatohepatitis (NASH. However, there is a need for non-invasive tests (NIT) to identify at-risk NASH patients requiring intense lifestyle or clinical intervention. Aim: The aim of this study was to access clinical performance metrics of NIS4™ either alone or in combination with other NITs in patients characterized as nondiabetic, pre-diabetic and T2D and with either at-risk of NASH (NAS≥4 and F≥2) or advanced fibrosis (F≥3). Methods: Patients in the RESOLVE-IT DIAG cohort presented with one or more risk factors for NAFLD and had corresponding NIT data: NIS4™ (miR-34a-5p, α2M, YKL-40, HbA1c), Fibrosis-4 (FIB-4), NAFLD activity score (NFS), and FibroScan™ (FS). NIT data were used to simulate different testing strategies to identify patients with at-risk NASH or advanced fibrosis. Results: The 467 patients were divided into 3 subgroups with 200 (43%) non-T2D, 67 (14%) pre-diabetic and 200 (43%) T2D with a prevalence for at-risk NASH ranging 42-71%, 58-78% and 66-84%, respectively. The corresponding prevalence for advanced fibrosis in the same groups was 18-27%, 34-40%, 42-49%, respectively. Generally, the performance was impacted by variability in sample size and prevalence which mainly affected PPV and NPV. Under these circumstance NIS4™ together with FS or FIB-4 provided a strong overall balanced performance (Acc: 66-82%, Sen: 50-80%, Spe: 58-94%). Conclusion: In this cohort, the sequential use of NIS4™ together with another blood-based test FIB-4 or an imaging-based FibroScan™ test provided an overall more balanced performance for identification of at-risk NASH or advanced fibrosis for nondiabetic and T2D patients. Therefore, NIS4™ has the potential to be a valuable clinical tool for also identifying diabetic patients at higher risk of negative outcomes. Disclosure C. Rosenquist: Employee; Self; GENFIT. Y. Hajji: None. J. Magnanensi: Employee; Self; GENFIT. N. Stankovic-valentin: Employee; Self; GENFIT, Stock/Shareholder; Self; GENFIT. S. Hosmane: Stock/Shareholder; Self; GENFIT, Stock/Shareholder; Spouse/Partner; Vertex Pharmaceuticals Incorporated. A. J. Sanyal: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Akero Therapeutics, Inc., Alnylam Pharmaceuticals, Inc., Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Genentech, Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Inventiva Pharma, Lilly Diabetes, Lipocine Inc., Merck &amp; Co., Inc., NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Genetics Center, Siemens Corporation, Other Relationship; Self; AstraZeneca, UpToDate, Stock/Shareholder; Self; GENFIT, HemoShear Therapeutics, LLC, Indalo Therapeutics, Inc., Tiziana Life Sciences plc.

1055-P: The Machine Learning Prediction Model NASHmap Identifies Higher Insulin Resistance in Type 2 Diabetes Mellitus (T2DM) Patients at Risk for Nonalcoholic Steatohepatitis (NASH)

Background: Phenotypic methods such as elevated liver tests and/or the presence of obesity or hypertension are often used to identify patients with T2DM at risk for NASH. Machine learning (ML) models allow the prediction of outcomes with many interacting features and may be superior to phenotype in the context of NASH and T2DM. Here we present an intergroup comparison between patients with T2DM predicted as positive or negative for NASH by NASHmap, a ML model showing high prediction performance in real-word datasets. Methods: We evaluated a subgroup of patients from a large T2DM clinical trial database (2002-2012) who had data for 14 NASHmap parameters. These include clinical observations and routine laboratory parameters but not HOMA-IR. We compared the profile of patients predicted by NASHmap (NASH positive or negative) using 17 parameters (14 NASHmap and 3 additional parameters). We compared HOMA-IR values between NASHmap positive and negative patients in the subgroup where the values were available. Results: The clinical database had 23038 metabolically compensated T2DM patients without chronic liver disease of other etiologies. Data for all 14 NASHmap parameters were available in 4336 patients. NASHmap positive patients were younger, had higher HbA1c, liver enzymes, triglycerides, WBC, body mass index, platelets, and a higher rate for hypertension. Data for HOMA-IR were available in 1208 patients. Median HOMA-IR value was 4.2 in NASHmap positive group vs. 2.6 in NASHmap negative group. Patients in both groups had a similar median duration of diabetes. Conclusion: Overall, the patients identified as at risk for NASH by NASHmap showed a metabolically unfavorable phenotype indicated by the higher HOMA-IR values in this group that the ML algorithm is also able to detect. ML models may be an important tool in effectively identifying patients at risk for NASH in electronic health records and clinical care. Disclosure A. Tietz: Employee; Self; Novartis AG, Stock/Shareholder; Self; Novartis AG. G. Bader: Employee; Self; Novartis AG. M. Docherty: Employee; Self; ZS Associates. B. Reinhart: Employee; Self; ZS Associates. M. Balp: Employee; Self; Novartis AG. M. Pedrosa: Employee; Self; Novartis AG. S. K. Acharya: Employee; Self; Novartis Healthcare Pvt. Ltd., Employee; Spouse/Partner; Novartis Healthcare Pvt. Ltd. J. Loeffler: Employee; Self; Novartis AG, Stock/Shareholder; Self; Novartis AG. J. M. Schattenberg: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Boehringer Ingelheim, BMS, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Novartis, Novo Nordisk, Nordic Bioscience, Pfizer, Roche, Sanofi, Siemens Healthcare GmbH, Zydus, Bristol-Myers Squibb Company.