bluuebunny/crossref_metadata_2025 huggingface dataset:
751-P: Longer Time Spent in Glycemic Control after Initiating Tirzepatide vs. Comparators—Exploratory Analysis of SURPASS 1–5 Trials
Authors: ROSENSTOCK JULIO , GARVEY W. TIMOTHY , BATTERHAM RACHEL L. , LIU MINZHI , BERGMAN BRANDON , HEMMINGWAY ANDREA , THIEU VIVIAN
Published: June 2023

Conventional trials in people with T2D typically report HbA1c at study end as the primary outcome. In SURPASS 1-5 trials, 81-97% of adults with T2D treated with the GIP/GLP-1 receptor agonist tirzepatide (5, 10, or 15 mg) achieved an HbA1c <7.0% at the primary endpoint. Here we report the time spent in glycemic control throughout the duration of each trial. Participants were randomized to tirzepatide (5, 10, or 15 mg) or comparator (placebo in SURPASS 1 and 5, semaglutide 1 mg in SURPASS 2, insulin degludec in SURPASS 3, and insulin glargine in SURPASS 4), with primary treatment durations of 40 or 52 weeks (wks). Continuous time spent with HbA1c <7.0% was descriptively analyzed in all patients on treatment without rescue medication, with missing data imputed, in this post-hoc analysis. Participants on tirzepatide 5, 10, or 15 mg spent longer time with HbA1c <7.0% than comparators. In studies of 40 wks duration, median time spent with HbA1c <7.0% was 32 wks for all tirzepatide doses, 28 wks for semaglutide 1 mg, and 0 wks for placebo. In studies of 52 wks, this was up to 44 wks for tirzepatide, 32 wks for insulin degludec, and 12 wks for insulin glargine. Time spent with HbA1c <7.0% was generally similar across all tirzepatide doses in each study. To conclude, tirzepatide allowed greater continuous time spent with HbA1c <7.0% vs placebo, semaglutide 1 mg, and basal insulins.

Disclosure

J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. W.Garvey: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Eli Lilly and Company, Merck & Co., Inc., Alnylam Pharmaceuticals, Inc., Fractyl Health, Inc., Inogen, Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Pfizer Inc., Neurovalens. R.L.Batterham: Advisory Panel; Novo Nordisk, GlaxoSmithKline plc., Gila Therapeutics Ltd, Pfizer Inc., Consultant; Eli Lilly and Company, Novo Nordisk, Epitomee, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, GlaxoSmithKline plc. M.Liu: Consultant; Eli Lilly and Company. B.Bergman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Hemmingway: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. V.Thieu: None.

Funding

Eli Lilly and Company
752-P: Improved BMI Category Is Associated with Better Patient-Reported Outcomes (PROs) in Adults with T2D Treated with Tirzepatide
Authors: LEE CLARE , BOYE KRISTINA , THIEU VIVIAN , ALLEN SHERYL , DONG WENXIU , SAPIN HELENE
Published: June 2023

Treatment with tirzepatide, a first-in-class GIP/GLP-1 receptor agonist, resulted in statistically and meaningfully reduced HbA1c, and substantially reduced weight, in adults with T2D in the Phase 3 SURPASS studies. We explored the association between shift in BMI category and PROs in adults treated with tirzepatide 5, 10, or 15mg in SURPASS-1 to -5.

Data from all SURPASS-1 to -5 tirzepatide-treated participants with non-missing BMI were pooled, regardless of tirzepatide dose assigned. Participants with ‘improved’ (≥1 category lower vs. baseline), ‘stable’, or ‘worsened’ (≥1 category higher vs. baseline) BMI category at endpoint were assessed using weight-related PRO instruments at baseline and endpoint - Impact of Weight on Self-Perceptions (IW-SP), Impact of Weight on Quality of Life-Lite-Clinical Trials (IWQOL-Lite-CT), and Ability to Perform Physical Activities of Daily Living (APPADL).

All PRO scores were greater at endpoint than at baseline for tirzepatide-treated participants with ‘improved’ or ‘stable’ BMI category (Table). Changes were numerically greater across all PROs for participants with ‘improved’ BMI category compared with those whose BMI category remained ‘stable’ or ‘worsened’.

Improvements in PRO scores were greater in tirzepatide-treated adults with T2D with improved BMI category than in those with stable or worsened BMI category.

Disclosure

C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.Boye: Employee; Eli Lilly and Company. V.Thieu: None. S.Allen: None. W.Dong: Employee; TechData Service Company, Other Relationship; Eli Lilly and Company, AstraZeneca. H.Sapin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
76-LB: Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA)–Experienced Adults with Type 2 Diabetes (T2D) Switching to Once-Weekly (OW) Semaglutide in a Real-World Setting—SURE Program Post Hoc Analysis
Authors: RUDOFSKY GOTTFRIED , MENZEN MARKUS , POTIER LOUIS , CATARIG ANDREI-MIRCEA , CLARK ALICE , PRIYADARSHINI PRACHI , ABREU CRISTINA
Published: June 2023

Retrospective database studies have shown that switching between some GLP-1RAs may be associated with additional benefits on glycemic control and body weight (BW).

This prospective post hoc analysis of pooled data from the SURE real-world program (9 ~30 week studies in 10 countries) investigated outcomes associated with switching to OW semaglutide from another GLP-1RA in adults with T2D. Endpoints included change in HbA1c and BW from baseline to end of study, percentage achieving HbA1c <7% (when baseline HbA1c ≥7%) or BW change ≥5%, and safety. For change in HbA1c and BW, a random coefficient-adjusted mixed analysis for repeated measures was used, regardless of semaglutide treatment status.

In total 651 participants (mean age 60 years; 53% male) switched to OW semaglutide: 64% from liraglutide, 31% from dulaglutide. Significant changes were observed in HbA1c and BW (Figure); 33% of participants with baseline HbA1c ≥7% achieved HbA1c <7%, and 28% reduced BW by ≥5%. No new safety concerns were identified; 3% discontinued due to AEs, 2% reported ≥1 hypoglycemic episode (blood glucose <54 mg/dL) and 8/11 participants with ≥1 level 2 hypoglycemic episode were on insulin.

In adults with T2D previously treated with GLP-1RAs, switching to OW semaglutide may provide additional benefits with convenient OW dosing.

Disclosure

G. Rudofsky: Consultant; AstraZeneca, Eli Lilly and Company, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. M. Menzen: Advisory Panel; Boehringer Ingelheim Pharma GmbH&Co. KG, Novo Nordisk A/S, Ascensia Diabetes Care, Eli Lilly and Company, Novartis, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Santis, Boehringer Ingelheim Pharma GmbH&Co. KG, Novo Nordisk A/S, Bayer Inc., Eli Lilly and Company, Novartis. L. Potier: Consultant; Lilly Diabetes, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim Inc. A. Catarig: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. A. Clark: Employee; Novo Nordisk A/S. P. Priyadarshini: None. C. Abreu: Speaker's Bureau; Lilly, Novo Nordisk.

Funding

Novo Nordisk
766-P: Safety and Tolerability of Once-Weekly GL0034 (Utreglutide) in Healthy Individuals—A Multiple Ascending Dose Study
Authors: THENNATI RAJAMANNAR , BURADE VINOD S. , NATARAJAN MUTHUKUMARAN , SHAHI PRADEEP , NAGARAJA RAVISHANKARA , PANCHAL SATISH T. , AGRAWAL SUDEEP K. , JANDRAIN BERNARD , DUVAUCHELLE THIERRY , GARCIA-OCANA ADOLFO , RUTTER GUY A. , PRATLEY RICHARD E. , THORENS BERNARD , VILSBØLL TINA
Published: June 2023

GL0034 (GL) is being developed as a once-weekly, long-acting glucagon-like peptide 1 receptor agonist (GLP-1RA). This phase 1 study assessed the safety and tolerability of multiple ascending doses of GL. Healthy individuals (N=36) with BMI 18 to 28 kg/m2 were randomized (9:3) to subcutaneous GL or placebo. Two groups of nine individuals each received a fixed dose of 450 μg (cohort 1) or 680 μg (cohort 2) during four weeks; a third group was treated for eight weeks, with two weekly doses of 450 μg, followed by two doses of 900 μg and four doses of 1,520 μg (cohort 3). Safety biomarkers and key exploratory pharmacodynamic effects including fasting insulin and glucose, alanine transaminase and body weight were assessed. GL related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting and decreased appetite. Fasting insulin was decreased in cohort 2 and cohort 3 on day 23 and 51 respectively following treatment with GL with a corresponding reduction in homeostatic model assessment for insulin resistance (HOMA-IR). At day 51, alanine transaminase levels decreased from baseline in cohort 3 versus an increase in placebo. Dose-dependent decreases in body weight were measured in cohorts 1, 2 and 3, respectively, compared to baseline, and were sustained through days 50 and 78. In conclusion, GL was well tolerated and efficacious in healthy individuals with normal weight.

Disclosure

R.Thennati: None. A.Garcia-ocana: Consultant; Sun Pharmaceutical Industries Ltd. G.A.Rutter: Consultant; Sun Pharmaceutical Industries Ltd. R.E.Pratley: Other Relationship; Bayer Inc., Corcept Therapeutics, Dexcom, Inc., Gasherbrum Bio, Inc., Hanmi Pharm. Co., Ltd., Hengrui (USA) Ltd., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. B.Thorens: Advisory Panel; Sun Pharmaceutical Industries Ltd. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. V.S.Burade: None. M.Natarajan: None. P.Shahi: None. R.Nagaraja: None. S.T.Panchal: None. S.K.Agrawal: None. B.Jandrain: None. T.Duvauchelle: None.
771-P: Tirzepatide Reduces HbA1c and Body Weight Significantly More than Placebo or Semaglutide Irrespective of Baseline Beta-Cell Function—Post Hoc Analysis from SURPASS-1 and SURPASS-2
Authors: MALDONADO JUAN M. , DE BLOCK CHRISTOPHE , FRIAS JUAN P. , LEE CLARE , BROWN KATELYN , WANG HUI , THOMAS MELISSA K.
Published: June 2023

Tirzepatide (TZP), a once-weekly GIP/GLP-1 receptor agonist, achieved significantly greater HbA1c and body weight (BW) reductions with all doses (5, 10, 15 mg) vs placebo (SURPASS-1 [S-1]) and semaglutide (SEMA) 1 mg (SURPASS-2 [S-2]) in randomized Phase 3 trials in people with type 2 diabetes controlled by diet and exercise (S-1) or metformin (S-2). Exploratory post hoc analyses examined changes from baseline in HbA1c and BW in these studies at 40 weeks across HOMA2-B (C-peptide) and HOMA2-IR (insulin) quartiles (Q) from low (lower beta-cell function/insulin resistance) (Q1) to high (Q4) as assessed by mixed model repeated measures (MMRM). HbA1c reductions were greater with all TZP doses than placebo or SEMA within each HOMA2-B and HOMA2-IR baseline Q. HbA1c reductions were largest in people within HOMA-2B Q1, yet similar across all HOMA2-IR Qs (Fig). BW reductions were greater across Qs with all TZP doses (ranging from 6%-14%) than placebo (up to 2%) or SEMA (up to 7%). TZP was more efficacious than placebo or SEMA in reducing HbA1c and BW across a spectrum of pancreatic beta-cell function, notably achieving greater glycemic improvement in people with markers of diminished pancreatic beta cell function at baseline.

Disclosure

J.M.Maldonado: Employee; Eli Lilly and Company. C.De block: Advisory Panel; Abbott Diagnostics, Indigo Diabetes, Insulet Corporation, Eli Lilly and Company, Novo Nordisk, Research Support; Boehringer-Ingelheim, AstraZeneca, Indigo Diabetes, Eli Lilly and Company, Speaker's Bureau; Novo Nordisk. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.Brown: Employee; Eli Lilly and Company. H.Wang: None. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
78-LB: PK Studies in Rats and Minipigs of GB-7001, a Novel Monthly Microsphere Formulation Containing High Drug Content of Semaglutide
Authors: SEOL EUNYOUNG , KIM YEJIN
Published: June 2023

Semaglutide, a once-weekly GLP-1 receptor agonist, has been developed as a treatment for type 2 diabetes and obesity. Currently, the longest-acting GLP-1 product (including dulaglutide, semaglutide, and tirzepatide) is a weekly injection, and there are no approved once-monthly long-acting injectables. There is a need for a product that lasts up to 1 month to improve patient convenience. GB-7001 is a monthly injectable with high content of semaglutide under development with an improvement that reduces the side effect of existing microspheres. The goal of this study is to investigate the pharmacokinetics (PK) of GB-7001 in rats and minipigs. Pharmacokinetic evaluation in rats and minipigs was performed by a single subcutaneous injection, and semaglutide concentration in serum was analyzed by liquid chromatography-tandem mass spectrometry. GB-7001 had a spherical shape with a D50 value of 34.4 µm. The drug content of semaglutide was determined to be 18.0%. Regardless of the high drug content, the sustained release of GB-7001 was shown for up to 28 days without an initial burst and without a lag phase. Although the release rate of GB-7001 slows after 28 days, semaglutide was detected within the quantifiable range for up to 56 days.

In conclusion, GB-7001 is an improved 1-month semaglutide injectable that has shown promising results in PK studies in rats and minipigs. Further preclinical studies of the final formulation are scheduled, and GB-7001 is planned to apply for IND once the final formulation is selected.

Disclosure

E. Seol: None. Y. Kim: None.

Funding

Ministry of Health & Welfare, Republic of Korea (HI21C1732)
782-P: Efficacy of Tirzepatide in People with Young-Onset T2D in the SURPASS Program
Authors: ZEITLER PHILIP , GALINDO RODOLFO J. , DAVIES MELANIE J. , BERGMAN BRANDON , THIEU VIVIAN , NICOLAY CLAUDIA , ALLEN SHERYL , LEE CLARE
Published: June 2023

Young-onset T2D, defined as diagnosed before age 40, presents with a more aggressive disease course, faster beta-cell deterioration and reduced response to diabetes treatment compared to later-onset T2D. Tirzepatide (TZP), a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, was recently approved for the treatment of type 2 diabetes (T2D). This post-hoc analysis assessed the effect of tirzepatide on glycemic control, body weight (BW) and cardiometabolic markers in participants with young-onset T2D from the SURPASS program. Changes from baseline in mean HbA1c, BW, waist circumference (WC), and cardiometabolic markers including lipids, and blood pressure (BP) were compared in participants with young-onset (N=873, 20.5%) vs later-onset T2D (N=3394, 79.5%) at Week 40 (SURPASS-1, -2, -5) or Week 52 (SURPASS-3). No differential treatment effect was observed for participants with young- vs later-onset T2D. Tirzepatide treatment led to similar improvements in HbA1c and BW in both subgroups at Week 40/52 for all TZP doses (Figure). Furthermore, TZP (all doses) improved WC, lipids (triglycerides and HDL) and systolic BP similarly between the two groups. In conclusion, tirzepatide treatment led to similar improvements in HbA1c, BW and cardiometabolic markers (WC, lipids, SBP) in participants regardless of having young-onset or later-onset T2D.

Disclosure

P.Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson & Johnson. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. B.Bergman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. V.Thieu: None. C.Nicolay: Employee; Eli Lilly and Company. S.Allen: None. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
783-P: Baseline HOMA2-B Can Predict Tirzepatide Efficacy—Post Hoc Analysis of the SURPASS-1 and SURPASS-2 Studies
Authors: HSIA STANLEY H. , THOMAS MELISSA K. , MATHIEU CHANTAL , WANG HUI , PELESHOK JENNIFER
Published: June 2023

Tirzepatide (TZP) is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). In the SURPASS-1 (S-1) (monotherapy) and SURPASS-2 (S-2) (on metformin) Phase 3 trials, TZP substantially reduced HbA1c and body weight (BW) in people with T2D. Exploratory post hoc analyses examined the predictive value of HOMA2-IR (insulin) and HOMA2-B (C-peptide) by quartiles low (lower beta-cell function or insulin resistance) [Q1] to high [Q4] for achieving HbA1c (<5.7%, ≤6.5%) and BW reduction (≥10%, ≥15%) targets for those adherent to TZP treatment at Week 40. Odds ratios (OR) were calculated from logistic regression models using the overall mean as the reference. The results showed that TZP was equally likely to achieve BW and HbA1c targets in S-1 and S-2 regardless of baseline HOMA2-B and -IR quartiles, with the exception of S-2 where subjects with Q1 HOMA2-B (lowest beta-cell function) were significantly less likely and those with Q4 HOMA2-B (highest beta-cell function) were significantly more likely to reach HbA1c ≤6.5% (Figure). We conclude that baseline HOMA2-B, but not HOMA2-IR, may predict the likelihood of subjects achieving the HbA1c target ≤6.5% for patients enrolled in S-2 not controlled with metformin alone.

Disclosure

S.H.Hsia: Research Support; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. H.Wang: None. J.Peleshok: Employee; Eli Lilly and Company.

Funding

Eli Lilly and Company
786-P: Effects of Switching from Liraglutide or Dulaglutide to Subcutaneous Semaglutide on Metabolic Parameters in Older People with Type 2 Diabetes Mellitus—SWITCH-SEMA1 Subgroup Analysis
Authors: TAKAHASHI YUKA , NOMOTO HIROSHI , YOKOYAMA HIROKI , MIYA AIKA , MIYAZAKI ASUKA , KAMEDA HIRAKU , ATSUMI TATSUYA , NAKAMURA AKINOBU , MIYOSHI HIDEAKI
Published: June 2023

Background: Once-weekly treatment with the subcutaneous glucagon-like receptor-1 receptor agonist (GLP-1RA) semaglutide has been reported to have potent beneficial effects on metabolic abnormalities. However, little is known about the usefulness of switching from other GLP-1RAs to semaglutide, especially in older people with type 2 diabetes.

Methods: This study is a subgroup analysis of the SWITCH-SEMA1 study, a multicenter, prospective, open-label, parallel-group, randomized controlled study in which people with type 2 diabetes continued liraglutide or dulaglutide therapy or switched to semaglutide for 24 weeks (jRCTs1011200008). One hundred people enrolled in this study were divided into two groups: an aged group consisting of people 65 years or older (n = 49; 72.8 ± 4.4 years old) and a non-aged group (n = 51; 51.2 ± 6.8 years old). The changes of metabolic parameters between the two treatment arms (continuation vs switching to semaglutide) were compared between an aged and a non-aged group.

Results: At baseline, BMI, fatty liver index (FLI), C-peptide index (CPI), HOMA2-β, HOMA2-R, eGFR, and triglyceride levels were significantly lower in the aged group (all P < 0.05). After 24 weeks, switching to semaglutide significantly ameliorated HbA1c in both groups (aged: −0.7%, P<0.001; non-aged: −0.7%, P < 0.01). In the aged group, FLI; CPI; HOMA2-β; AST, γ-GTP, and uric acid (UA) levels; and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) score significantly improved after switching to semaglutide (all P < 0.05). The magnitude of changes in BMI and UA levels after switching to semaglutide was greater in the aged group than in the non-aged group (BMI: −1.1 vs. −0.5 kg/m2, P < 0.01; UA: −0.4 vs. −0.1 mg/dL, P <0.05).

Conclusions: The effects on metabolic parameters of switching from other GLP-1RAs to once-weekly semaglutide might be greater in aged people than in non-aged people.

Disclosure

Y.Takahashi: None. H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. H.Yokoyama: None. A.Miya: None. A.Miyazaki: None. H.Kameda: None. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. H.Miyoshi: Research Support; Abbott, LifeScan Diabetes Institute, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Kowa Company, Ltd., MSD Life Science Foundation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation.
787-P: Glucose and Weight Outcomes Associated with Oral Semaglutide in the Real-World—Initial Results from the Association of British Clinical Diabetologists’ (ABCD) Audit
Authors: CRABTREE THOMAS S.J. , ADAMSON KAREN , KRISHNASAMY SENTHILKUMAR , THIN KHINE MAY , DE PARIJAT , PETER RAJESH , RYDER ROBERT E.
Published: June 2023

Semaglutide is the first glucagon like peptide-1 receptor agonist (GLP1-RA) available in an oral preparation. Weight and HbA1c outcomes with injectable semaglutide in the real-world are well established. The aim of this analysis is to assess weight and HbA1c response to oral semaglutide.

Methods: Data were extracted from the secure online ABCD audit tool. Individuals were included if baseline and follow-up weight and/or HbA1c data were available. Change in HbA1c, body mass index (BMI) and weight from baseline was assessed using a multivariate linear regression model and change in the numbers achieving an endpoint HbA1c≤7.5% [58mmol/mol] were assessed using Chi2 tests in Stata 16.

Results: Data were available for 350 individuals with baseline mean±SD HbA1c 9.2%±1.7 [76.6mmol/mol±18.3], weight 101.8kg±21.9, BMI 34.3kg/m2±6.9, median diabetes duration 11years (IQR 6-16) and age 59 years (IQR 51-68); 63.0% were male and 79.7% were white. Median follow-up was 0.5years (IQR 0.3-0.8). Significant reductions in HbA1c of 0.7% (95%CI 0.4, 0.9; P<0.001) [7.4mmol/mol; 95%CI 4.7, 10.0; P<0.001] were observed. Weight decreased by 3.3kg (95%CI 2.3, 4.3; P<0.001) and BMI fell by 1.1kg/m2 (95%CI 0.6, 1.6; P<0.001). Twice as many people achieved a HbA1c≤7.5% at follow-up compared to baseline (28.6% [52/182] vs 14.3% [26/182]) - this change was statistically significant (P<0.001).

Conclusion: In the real-world, oral semaglutide is associated with statistically significant and clinically meaningful reductions in HbA1c, weight and BMI. The numbers achieving a HbA1c≤7.5% also increased. In the light of this, further data collection and analysis should be undertaken, including comparisons between oral and injectable GLP1-RAs and analysis of switches between them

Disclosure

T.S.J.Crabtree: Speaker's Bureau; Abbott Diabetes, Novo Nordisk, Lilly, Sanofi, Insulet Corporation. K.Adamson: None. S.Krishnasamy: Other Relationship; Novo Nordisk, Sanofi, Eli Lilly and Company, AstraZeneca. M.Khine: None. P.De: Speaker's Bureau; Novo Nordisk, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Takeda Canada, Daiichi Sankyo, Napp Pharmaceuticals Limited, Lilly Diabetes. R.Peter: None. R.E.Ryder: Other Relationship; Novo Nordisk, Speaker's Bureau; GI Dynamics, BioQuest.

Funding

Novo Nordisk
790-P: An Indirect Treatment Comparison of the Cardiovascular Protective Effect of Semaglutide vs. Liraglutide in Subjects with Type 2 Diabetes
Authors: CHUBB BARRIE , BØG MARTIN
Published: June 2023

Background: In the absence of head-to-head evidence, an indirect treatment comparison (ITC) using individual-level participant data was conducted to provide evidence of the comparative cardiovascular (CV) protective effect of liraglutide vs semaglutide in subjects with type 2 diabetes.

Methods: CV outcomes trials (CVOTs) were identified for comparators of interest. LEADER was a randomised controlled trial studying the CV protective effect of liraglutide vs placebo. Similarly, two CVOTs comparing semaglutide with placebo were identified: SUSTAIN 6 and PIONEER 6. Time to first 3-point major adverse CV events (3P-MACE) (adjudicated) was the primary outcome in all trials and was chosen as the primary outcome for the ITC. Potential effect modifiers (baseline indicators of prior CV disease, albumin:creatinine ratio, estimated glomerular filtration rate) were identified in the literature and adjusted for in the ITC. A fixed-effects ITC using individual participant data was conducted in a Bayesian setting. Missing data for potential effect modifiers were imputed using multiple imputation (20 imputations). Comparisons were summarised as cause-specific hazard ratios (HRs). Population-average relative treatment effects between liraglutide and semaglutide were reported for each of the three populations corresponding to the three studies.

Results: The ITC showed that the relative risk of semaglutide vs liraglutide for the occurrence of 3P-MACE in the LEADER population favoured semaglutide: HR 0.73 (95% credible interval [CrI]: 0.56;0.94); results also favoured semaglutide in the SUSTAIN 6 (HR 0.76 [95% CrI: 0.59;0.97]) and PIONEER 6 (HR 0.78 [95% CrI: 0.60;1.00]) populations.

Conclusion: The results demonstrated a risk reduction of CV events (3P-MACE) for semaglutide vs liraglutide of 22-27% depending on the population studied. These results may have implications for clinical practice.

Disclosure

B.Chubb: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. M.Bøg: Employee; Lundbeck, Novo Nordisk.
8-LB: Adipocyte-Derived ANGPTL2 Regulates Abnormal Lipid Metabolism and Inflammation through PirB in Diabetic Kidney Disease
Authors: YIN RUILI , YANG LONGYAN , ZHAO DONG
Published: June 2023

Diabetic kidney disease (DKD) is a disorder of glycolipid metabolism caused by diabetes mellitus, which leads to hemodynamic and inflammatory processes. The aim of this study is to investigate the mechanism of adipocyte-derived angiopoietin-like protein 2 (ANGPTL2) in promoting the progression of DKD. Patients with DKD were included, and plasma ANGPTL2 was detected by ELISA. Type 2 diabetic mouse model induced by HFD and STZ, systemic Angptl2 knockout mouse model and adipose-specific AAV-Angptl2 were constructed. HKC cells stimulated with high glucose and PA in vitro. ELISA was used to measure the levels of IL-6, IL-1β, TNF-α and ANGPTL2 in plasma. RT-qPCR and Western blot were used to detect PirB, lipid metabolism indicators and inflammation, and the proteomics of kidney was performed. HE, oil red O staining and inflammatory factor staining were used to evaluate the degree of renal lipid metabolism and inflammation. The plasma level of ANGPTL2 in DKD patients is significantly higher than that in normal controls. Compared with the normal mice, the DKD mice had increased lipid accumulation and severe inflammation in kidney tissues, with increased PirB, Cybb and pro-inflammatory factors, and decreased CD36 and FATP2 in kidney. Similarly, overexpression of adipose-derived ANGPTL2 in mice caused the same abnormal lipid metabolism and increased inflammation levels, while Angptl2 ko mice significantly improved lipid deposition and inflammation levels and fatty acid transport. Knockdown of ANGPTL2 in HKC cells also inhibited the reduction of CD36 and FATP2, the increase of its receptor PirB, and the increase of Cybb /Nox2-mediated inflammatory cytokines induced by high glucose and high lipid in HKC cells. Adipose-derived ANGPTL2 may play an important role in lipid metabolism and Cybb/ NOX2-regulated inflammatory through its receptor in DKD, suggesting that ANGPTL2 may serve as a potential treatment for preventing the progression of DKD.

Disclosure

R. Yin: None. L. Yang: None. D. Zhao: None.

Funding

National Natural Science Foundation of China (82170454)
804-P: Similar Hypoglycemia Duration with Once-Weekly Icodec vs. Degludec or Glargine U100 in Insulin-Treated T2D—A Post Hoc CGM Analysis from ONWARDS 2 and 4
Authors: BAJAJ HARPREET S. , ÁSBJÖRNSDÓTTIR BJÖRG , CARSTENSEN LISBETH , LANG LEHRSKOV LARS , MATHIEU CHANTAL , PHILIS-TSIMIKAS ATHENA , BATTELINO TADEJ
Published: June 2023

Once weekly (OW) icodec is a basal insulin in development. Hypoglycemia duration during the switch (weeks 0-4) and steady state (weeks 22-26) periods from two phase 3, randomized, treat-to-target trials in T2D was investigated, using double-blinded Dexcom G6 CGM. Insulin-treated individuals were randomized to OW icodec or once-daily (OD) degludec (ONWARDS 2), or OW icodec or OD glargine U100 with mealtime insulin aspart (ONWARDS 4). When switching, a one-time only additional 50% icodec dose was administered. Basal insulins were titrated weekly. Median hypoglycemia <70 mg/dL duration for episodes lasting ≥ 15 minutes and the proportion of such episodes spent <54 mg/dL were assessed. Median duration of hypoglycemia <70 mg/dL was similar between icodec and comparators during switch and at steady state (Figure), with no apparent clustering in either time-period. At steady state (icodec/degludec and icodec/glargine U100), of the episodes <70 mg/dL, 66.6/63.9% and 60.4/60.0% spent no time <54 mg/dL; 23.2/26.6% and 29.2/28.8% included episodes <54 mg/dL for ≥15 minutes; and 10.2/9.5% and 10.4/11.2% included episodes <54 mg/dL for <15 minutes, respectively. In insulin-treated T2D, the duration of hypoglycemic episodes <70 mg/dL was similar, with no apparent clustering, during switch and at steady state for OW icodec versus OD degludec or glargine U100.

Disclosure

H.S.Bajaj: Research Support; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Anji Pharmaceuticals, Eli Lilly and Company, Kowa Company, Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Tricida, Inc. B.Ásbjörnsdóttir: Employee; Novo Nordisk. L.Carstensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L.Lang lehrskov: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. T.Battelino: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Consultant; Indigo Diabetes, Research Support; Novo Nordisk, Sanofi, Medtronic, Novartis, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Dexcom, Inc.

Funding

Novo Nordisk A/S
808-P: Pharmacokinetic Properties of Once-Weekly Insulin Icodec in Individuals with Renal Impairment vs. Normal Renal Function
Authors: HAAHR HANNE , KRISTENSEN NIELS R. , LARSEN JONAS H. , WAGNER FRANK-DIETRICH H. , IGNATENKO STANISLAV
Published: June 2023

Insulin icodec is a once-weekly basal insulin in development. This trial investigated if renal impairment affects the pharmacokinetics (PK) of icodec. In an open-label, parallel-group trial, 58 individuals (39 males; mean±SD age 50±13 yrs, BMI 26.5±3.1 kg/m2) were allocated to five groups according to renal function based on measured glomerular filtration rate (GFR): normal renal function (NRF; ≥90 mL/min; N=12), mild (60 to <90 mL/min; N=12), moderate (30 to <60 mL/min; N=12), severe (<30 mL/min; N=12) renal impairment and end‑stage renal disease (N=10). A single s.c. icodec dose (1.5 U/kg) was administered and blood was sampled for PK until 840 h (35 days) post-dose. A minor increase was observed in total exposure (AUC0-840h,SD) with decreasing GFR, but the estimated effect of GFR on AUC0-840h,SD did not differ statistically significantly from zero (-0.069; 95% CI [-0.150;0.013]; p=0.099). Pairwise group comparisons showed numerically slightly higher AUC0-840h,SD and Cmax,SS for renal impairment vs NRF (Figure). AUC0-840h,SD was statistically significantly higher for moderate renal impairment vs NRF. In conclusion, icodec exposure trended to be slightly higher for renal impairment vs NRF. The clinical relevance is however limited as icodec should be dosed according to individual need. Thus, no specific dose adjustment of icodec is required in individuals with renal impairment.

Disclosure

H.Haahr: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. N.R.Kristensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. J.H.Larsen: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. F.H.Wagner: None. S.Ignatenko: None.

Funding

Novo Nordisk
811-P: Initiation of Once-Weekly (QW) Basal Insulin Fc (BIF) in Three Patient Populations in Phase 2 Studies Using a One-Time Loading Dose (LD) Minimizes Transient Hyperglycemia and Is Not Associated with Excess Hypoglycemia Risk vs. Degludec
Authors: BUE-VALLESKEY JULIANA M. , KAZDA CHRISTOF M. , ZHANG QIANYI , HAUPT AXEL , DAHL DOMINIK , FRIAS JUAN P.
Published: June 2023

BIF is a fusion protein combining a novel single chain insulin variant with a human IgG Fc domain.

The safety population from 3 randomized, open-label, phase 2 treat-to-target studies included 942 people with T2D previously treated with basal insulin (T2D-Switch) or new to insulin therapy (T2D-Naïve), or with T1D on multiple daily injections (T1D). QW BIF was compared to once daily (OD) DEG for 26 or 32 wks.

Given BIF's slow accumulation and extended PK profile, initiation of or transition from prior OD basal insulin to BIF was managed by “boosting” initial exposure with a one-time ~ 3-fold LD strategy to achieve therapeutic concentration more quickly. In the absence of a definitive mg to unit conversion factor, determination of the starting QW dose differed by study and was based on PK/PD modelling and individual patient characteristics. Fasting glucose and patient reported hypoglycemia <70 mg/dL were compared during the first 6 wks of treatment and showed no clinically significant differences between treatments (Table). T2D-Switch and T1D studies included CGM and data during first 6 wks of the study were reviewed; no severe hypoglycemia was reported during this time.

These data suggest that the BIF LD strategy is safe and effective in reducing transient hyperglycemia, especially in T2D.

Disclosure

J.M.Bue-valleskey: Employee; Eli Lilly and Company. C.M.Kazda: Employee; Eli Lilly and Company. Q.Zhang: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. D.Dahl: Research Support; Lilly, Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim Inc., Amgen Inc. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi.

Funding

Eli Lilly and Company
82-LB: Effectiveness of Coordinated and Centralized Care for Insulin Pump Users—A Multiple-Year Cohort Study
Authors: LATIF KASHIF , LI QINGFENG , SHAIKH YAHYA , CHEEMA FAISAL H. , HYDER ADNAN
Published: June 2023

Background: With >13000 children diagnosed with type 1 diabetes each year, it imposes a tremendous burden on US healthcare. However, data are scarce on management models for pump users.

Methods: In this observational cohort study, patients (pts) were systematically monitored for 4 years at our centralized & coordinated pump center. Data on both outcome measures (percentage of glycated hemoglobin, or A1C) & pt characteristics were routinely documented.

Results: For all study pts (n=219), a statistically significant reduction in A1C was observed (-0.4% A1C; 95% CI: -0.7-0.1%). And this is true for all three groups of pts disaggregated by initial A1C (7.5-10, 8.0-10, ≥10). The reduction was -0.6 (95% CI: -0.8-0.3) for ps with a starting A1C between 7.5-10; -0.8 (95% CI: -1.1-0.5) for pts with a starting A1C of 8.0-10; and -2.4 (95% CI: -3.4 -1.3) for pts with a starting A1C above 10. A majority of pts reached their target A1C levels, and most of them achieved that in first quarter after the installation of insulin pumps (See Fig 1).

Conclusions: Through centralized and coordinated care, a pump center is effective in assisting diabetes patients in properly using insulin pumps and quickly achieving their target A1C levels. Given the heavy burden of diabetes and large number of insulin pumps, the model of a pump center may be able to help confront the disease burden, and therefore needs to be made available to more patients.

Disclosure

K. Latif: Research Support; Medtronic, Senseonics. Board Member; Bigfoot Biomedical, Inc. Q. Li: None. Y. Shaikh: None. F. H. Cheema: None. A. Hyder: None.
84-OR: Structure–Function Analysis of p57KIP2 in the Human Pancreatic Beta Cell Reveals a Canonical Bipartite Nuclear Localization Sequence (NLS)
Authors: CHOLEVA LAURYN , WANG PENG , LIU HONGTAO , WOOD OLIVIA , LAMBERTINI LUCA , KARAKOSE ESRA , STEWART ANDREW F.
Published: June 2023

p57KIP2 is a canonical cell cycle inhibitor encoded by the CDKN1C gene on chromosome 11. Mutations in CDKN1C underlie multiple pediatric endocrine syndromes including Beckwith-Wiedemann Syndrome (BWS), the Focal Variant of Congenital Hyperinsulinism (FoCHI), Insulinoma, Russel-Silver Syndrome and IMAGe Syndrome. Despite this central role in disease, little is known about the function of p57KIP2 in any cell type, including the human pancreatic beta cell. We hypothesized that p57KIP2 has functions that extend beyond cell cycle control and are unique to the human beta cell. We prepared RIP1 insulin promoter-driven adenoviruses encoding deletions of multiple putatively important and disease-associated but unexplored regions of p57KIP2 (WTp57, p57ΔPAPA, p57ΔCDKI, p57ΔPCNA and p57ΔNLS), and performed the first comprehensive structure-function analysis of CDKN1C/p57KIP2 in the human beta cell. RT-PCR and immunoblot analyses confirmed p57KIP2 overexpression, construct size and beta cell specificity in human islets. By immunocytochemistry, all constructs demonstrated nuclear localization, with the exception of a deletion mutant removing a putative NLS at amino acids 278-281. Unexpectedly, we identified a second NLS at amino acids 312-316. Further analysis showed that each individual NLS is required for nuclear localization of p57KIP2, but neither alone is sufficient to permit nuclear localization of p57KIP2. Finally, constructs containing both the 278-281 and 312-316 sequences were necessary and sufficient to target heterologous proteins to the nucleus of human beta cells.

In summary, we discovered that p57KIP2 contains a classic bipartite NLS characterized by two clusters of positively charged amino acids 278KRKRS281 and 312RKRLR316 separated by a proline-rich linker region. Variants in the sequences encoding these two NLS sequences account for functional p57KIP2 loss and beta cell expansion seen in human disease.

Disclosure

L. Choleva: None. P. Wang: None. H. Liu: None. O. Wood: None. L. Lambertini: None. E. Karakose: None. A.F. Stewart: None.
842-P: Development of Long-Acting GLP-1 Receptor Antagonist for the Treatment of Congenital Hyperinsulinism
Authors: YUAN YUE , JIANG HAOWEN , MENG SHI , HAN DONGNA , ZHU QIUSHA , WANG MANCHEN , LI HUSHAN , LI JIA , LI CHANGHONG
Published: June 2023

Targeting beta-cell GLP-1 receptors has proven to be a viable strategy for the treatment of congenital hyperinsulinism (CHI), especially CHI due to loss of function mutations of KATP channels. Currently, Phase II clinical study of the GLP-1 receptor antagonist, Exendin-(9-39) has been successfully initiated. However, Exendin-(9-39) has a short half-life (less than 2 hrs), which limits its clinical applications. We are therefore trying to develop a long-acting GLP-1 receptor antagonist. AR-GLP1R-01 was synthesized based on chemical modification of Exendin-9-39. In order to test its efficacy in disease mouse models, SUR1 knockout mice was created by targeted deletion of abcc8 gene using CRISPR/Cas9. Exendin-9-39 and AR-GLP1R-01 were injected subcutaneously at doses of 216 nmol/kg. Plasma concentrations were determined by UPLC-MS at 30 min, 2 hrs and 10 hrs after injection. Plasma levels of Exendin-9-39 were 0.5 µM at 30 min after injection and were later undetectable at 2 and 10 hrs. In contrast, plasma levels of AR-GLP1R-01 were 2.0 µM at 30 min, peaked at 2 hrs, and remained at 2.9 µM after 10 hrs of injection. Compared to Exendin-(9-39), AR-GLP1R-01 has similar inhibitory effects in amino acid mixture-stimulated insulin secretion in perifused islets isolated from SUR1 knockout mice. In vivo experiments were performed by subcutaneous injection at a dosage of 216 nmol/kg twice a day at 10 am and 5 pm for 4 days. Similar to Exendin-9-39, AR-GLP1R-01 caused plasma glucose to increase 1 hr after injection. However, the glucose-increasing effects of AR-GLP1R-01 were maintained overnight before the 10 am injection for 4 days, while the effects of Exendin-9-39 failed to do so. In the separate experiments, the effects of AR-GLP1R-01 on glucose elevation can last for 24 hrs after a single dose injection. This early phase “proof of concept” study has shown that AR-GLP1R-01 is a long-acting GLP-1 antagonist and has potential to be developed into a once-a-day injection for the treatment of CHI.

Disclosure

Y.Yuan: Employee; Nanjing AscendRare Pharmaceutical Technology. H.Jiang: None. S.Meng: Employee; Nanjing AscendRare Pharmaceutical Technology. D.Han: Employee; Nanjing AscendRare Pharmaceutical Technology. Q.Zhu: Employee; Nanjing AscendRare Pharmaceutical Technology. M.Wang: Employee; Shandong Baixinyuan Pharmaceutical Co. LLC.. H.Li: Employee; Shandong Baixinyuan Pharmaceutical Co. LLC.. J.Li: None. C.Li: Employee; Hua Medicine, Nanjing AscendRare Pharmaceutical Technology.

Funding

Shandong Innovation Project (2019JZZY021012)
844-P: Lanifibranor Improves Markers of Cardiometabolic Health in Patients with NASH and Type 2 Diabetes, Correlated with Responses in Adiponectin Levels
Authors: GRIFFEL LOUIS H. , FRANCQUE SVEN , ABDELMALEK MANAL F. , HUOT-MARCHAND PHILIPPE , DZEN LUCILE , BAUDIN MARTINE , JUNIEN JEAN L. , BROQUA PIERRE , COOREMAN MICHAEL P.
Published: June 2023

Background: Lanifibranor, a pan-PPAR agonist, has shown efficacy on liver histology and metabolic-immune markers of NASH in the phase 2b NATIVE study. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D). Adiponectin (ADP) is a pleiotropic adipokine which improves insulin resistance (IR), lipid metabolism, inflammation and fibrosis; low ADP levels are associated with risk for cardiovascular disease and NASH.

Methods: NATIVE evaluated lanifibranor 800 and 1200 mg/d versus placebo in 247 patients with non-cirrhotic NASH for 24 weeks treatment. Of these 103 had T2D, 144 did not have T2D of whom 47 had prediabetes defined by fasting glucose levels (FGL) between 5.6 - 6.9 mmol/l. ADP serum levels, metabolic-immune and hepatic markers (glycemic control, IR, lipids, systemic inflammation) were measured at baseline (BL) and end of treatment (EOT). In each subgroup, we evaluated ADP at BL, ADP fold-change at EOT, and correlation between ADP change and response of markers.

Results: ADP levels were lower in patients with T2D compared to those with pre-DM or normal glycemic control (NGC) (mean 4.6, 5.5, and 5.6 ug/ml, respectively). More patients with T2D had ADP below 5 mg/ml compared to pre-DM or NGC (65% vs 62/54%). In lanifibranor-treated group, ADP folds were similar in the 3 groups, with mean 4.3 fold increase by EOT, versus no increase in the placebo-treated group. In the pooled lanifibranor arms, increase in ADP correlated with improvements in glycemic control, IR, lipid metabolism, and systemic inflammation, consistently in the 3 groups, with higher improvements in patients with T2D and prediabetes compared to the NGC group.

Conclusion: The pan-PPAR agonist lanifibranor significantly improves ADP levels and this improvement correlated with markers of cardiometabolic health in patients with T2D and prediabetes. Lanifibranor improves cardiovascular risk profile in patients with impaired glycemic control and NASH.

Disclosure

L.H.Griffel: Employee; Inventiva Pharma. S.Francque: None. M.F.Abdelmalek: Advisory Panel; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Inventiva Pharma, Novo Nordisk, Merck & Co., Inc., Sonic Incytes, NGM Biopharmaceuticals, Consultant; Hanmi Pharm. Co., Ltd., Research Support; Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Boehringer Ingelheim Inc., Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk, Poxel SA, DURECT Corporation, Enyo Pharma, Enanta, Genentech, Inc., Celgene, NGM Biopharmaceuticals, TARGET PharmaSolutions, Inc., Allergan. P.Huot-marchand: Employee; Inventiva Pharma. L.Dzen: Employee; Inventiva Pharma. M.Baudin: Employee; Inventiva Pharma. J.L.Junien: Consultant; Inventiva Pharma. P.Broqua: None. M.P.Cooreman: Employee; Inventiva Pharma.