bluuebunny/crossref_metadata_2025 huggingface dataset:
747-P: Insulin Therapy Deintensification with iGlarLixi (IDEAL) Randomized Controlled Trial—CGM-Related Outcomes
Authors: NOVODVORSKY PETER , THIEME LENKA , LANKOVA IVANA , VESELÁ ALICA , ZAHUMENSKY EMIL , EDELSBERGER TOMAS , LÖBLOVÁ MARIE , HRUBÝ FILIP , MRAZ MILOS , HALUZIK MARTIN
Published: June 2024

Introduction: The IDEAL RCT examined the efficacy and safety of MDI de-intensification into once-daily administered iGlarLixi in people with type 2 diabetes (PwT2D) and showed that it provides comparable glycemic control with the benefits of reduction of body weight, total daily insulin dose and number of insulin injections. Here we report CGM outcomes from the trial.

Methods: IDEAL was a 5-centre, open-label, parallel-group, phase 4 RCT with a 24-week active treatment period. Participants were randomized in a 1:1 fashion into iGlarLixi or continuation with MDI and were applied professional CGM (Freestyle Libre Pro iQ) before the onset (BL) and for the last 2 weeks of the treatment period (W24). Participants in whom ≥ 72 hours of CGM data were available were included in the analysis.

Results: Altogether 73/91 (80.2%) of IDEAL participants were analyzed. Median (IQR) %TIR increased in the iGlarLixi group (70 [57 - 88] at BL vs 80 [61 - 92] at W24, p = 0.039), but remained unchanged in the MDI group (78 [67 - 89] vs 82 [64 - 89], p = 0.728). In the iGlarLixi group reductions in %TAR (26 [11 - 44] vs 13 [6 - 35], p = 0.04), % of time in level 2 hyperglycemia (2 [1 - 9] vs 1 [0 - 4], p = 0.019), mean glucose (8.6 [7.4 - 10.1] vs 7.7 [6.9 - 9.2] mmol/L, p = 0.012) and glycemia risk index (GRI) (26 [10 - 46] vs 19 [8 - 35], p = 0.036) were detected. Median (IQR) %TBR (< 3.9 mmol/L) remained unchanged in iGlarLixi group (0 [0 - 1] vs 1 [0 - 2], p = 0.337) and MDI group (0.5 [0 - 2] vs 1 [0 - 3.75], p = 0.147). Statistically significant differences between the changes (BL - W24) in the following CGM metrics (iGlarLixi vs MDI) were observed: %CV (-0.8 [-3.4 - 0.75] vs 1.4 [-1.2 - 3.3], p = 0.016) and GRI (-3.2 [-22.4 - 2.4] vs 1.6 [-6.25 - 10.6], p = 0.045).

Conclusion: Insulin therapy de-intensification from MDI into iGlarLixi in PwT2D showed an improvement in CGM outcomes vs baseline (TIR, TAR, level 2 hyperglycemia, mean glucose and GRI) and vs continuation with MDI (glycemic variability and GRI) without increase of time spent in hypoglycemia.

Disclosure

P. Novodvorsky: Speaker's Bureau; Sanofi, Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Novo Nordisk A/S. Research Support; Sanofi. Speaker's Bureau; Abbott, Medtronic, Berlin-Chemie AG, Viatris Inc., Novartis AG. L. Thieme: None. I. Lankova: None. A. Veselá: None. E. Zahumensky: None. T. Edelsberger: None. M. Löblová: None. F. Hrubý: None. M. Mraz: None. M. Haluzik: Advisory Panel; Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Johnson & Johnson Medical Devices Companies. Consultant; Merck & Co., Inc., Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Johnson & Johnson Medical Devices Companies, Novatin. Research Support; Sanofi. Speaker's Bureau; Sanofi, Novo Nordisk.

Funding

Sanofi
778-P: Changes in HbA1c with GLP-1 Use in People with Type 1 Diabetes—Data from the T1D Exchange QI Initiative
Authors: LEVY CAROL J. , GILLIS MARGARET , PAT GALLAGHER MARY , BASINA MARINA , SHAH VIRAL N. , OSPELT EMMA L. , ROMPICHERLA SAKETH , BREIDBART EMILY , ZUPA MARGARET , EBEKOZIEN OSAGIE , COLLABORATIVE T1DX-QI
Published: June 2024

Background: Glucagon-like peptide 1 receptor agonists (GLP-1RA) are currently not approved for use in people with T1D (PwT1D). At present there is limited safety and efficacy data using these agents in PwT1D. We analyzed the association of GLP-1RA on HbA1c levels and weight in PwT1D.

Methods: Electronic medical record data from T1D Exchange Quality Improvement Collaborative, including 13 endocrinology clinics across the United States was subcategorized by age, race/ethnicity, gender, insurance type use as well as type of GLP-1RA prescribed. Analysis included PwT1D, 20 years of age or older with at least two prescriptions of the same GLP-1RA. BMI and HbA1c prior to GLP-1RA use and 6-12 months after the initiation of GLP-1RA were analyzed using t and chi square tests as appropriate (Table 1).

Results: The population consisted of 481 PwT1D using GLP1RA. Of these individuals, 53% were non-Hispanic White, 70% were female, and 90% were prescribed long acting GLP-1RA. There was a reduction in the mean HbA1c level from 7.5 to 7.3 (p=0.04). No significant differences were found in BMI or DKA events.

Conclusions: HbA1c levels decreased after 6-12 months on a GLP-1RA. Prospective research should further clarify use, optimal dosing, and potential benefits, including cardiovascular risk reduction, of GLP1-RA medication for PwT1D.

Disclosure

C.J. Levy: Research Support; Dexcom, Inc. Consultant; Dexcom, Inc. Research Support; MannKind Corporation, T1D Exchange, Tandem Diabetes Care, Inc., Abbott, Insulet Corporation. M. Gillis: None. M. Gallagher: None. M. Basina: None. V.N. Shah: Consultant; Dexcom, Inc., Insulet Corporation. Research Support; Insulet Corporation. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Sanofi, Medscape. Consultant; embecta, Tandem Diabetes Care, Inc. E.L. Ospelt: None. S. Rompicherla: None. E. Breidbart: None. M. Zupa: None. O. Ebekozien: Advisory Panel; Sanofi, Medtronic. Research Support; Vertex Pharmaceuticals Incorporated. Speaker's Bureau; Vertex Pharmaceuticals Incorporated. Research Support; Medtronic, Lilly Diabetes, Abbott, Dexcom, Inc.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
78-OR: Breath Acetone Correlates with Capillary Beta Hydroxybutyrate in Type 1 Diabetes
Authors: JONES KAI , PETERSEN MAX C. , MARKOV ALEXANDER M. , KRUTILOVA PETRA , MCKEE ALEXIS M. , BOHNERT KATHRYN L. , ADAMSON SAMANTHA E. , SALAM MAAMOUN , MCGILL JANET B.
Published: June 2024

Introduction: Prior work has shown a linear relationship between breath acetone (BrACE) and capillary blood beta hydroxybutyrate (BOHB) in persons without diabetes. This innovative study investigates the correlation between capillary BOHB and BrACE in T1D during usual care and while taking an SGLT2 inhibitor in both insulin-sufficient and -deficient states. The primary outcome of the study is the correlation of capillary BOHB and BrACE.

Methods: Participants provided written consent and were randomized to 2 weeks of usual care and 1 day of insulin withdrawal followed by 2 weeks of usual care plus dapagliflozin, 10 mg daily and 1 day of insulin withdrawal or the opposite sequence. Paired BOHB (Precision Xtra®, Abbott) and BrACE (Biosense®, Readout) were obtained 3X daily for 2 weeks, then hourly during supervised insulin withdrawal. Sick day rules were reviewed and insulin doses were minimally adjusted when taking dapagliflozin. The data was tested for normality and the Spearman’s test was utilized due to non-normally distributed data.

Results: Participant age was 48 ±18 years (mean ± SD), baseline A1c 7.0 ± 0.9%, and CGM time in range [70-180mg/dL] 61 ± 18%. During outpatient care, BrACE and BOHB were weakly correlated both without dapagliflozin (n=689 paired readings; Spearman’s ρ = 0.44; 95% CI: 0.37 to 0.50) and with dapagliflozin (n=718 paired readings; ρ = 0.32; 95% CI: 0.25 to 0.39). However, BrACE and BOHB were strongly correlated during supervised insulin withdrawal (n=246 paired values, ρ = 0.81; 95% CI: 0.77 to 0.85). In ROC analysis, BrACE of ≥ 5 demonstrated optimal sensitivity (93%) and specificity (87%) for detecting a capillary BOHB > 1.5 mmol/L. No serious adverse events occurred.

Conclusion: In adults with T1D, BrACE monitoring provides a noninvasive estimate of ambient ketone levels when compared to blood BOHB but is more useful under supervised conditions with greater range of ketone production and less potential for interference with volatile organic compounds than in typical outpatient settings.

Disclosure

K. Jones: None. M.C. Petersen: None. A.M. Markov: None. P. Krutilova: None. A.M. McKee: Advisory Panel; Medtronic, Novo Nordisk. Employee; Novo Nordisk. K.L. Bohnert: None. S.E. Adamson: None. M. Salam: None. J.B. McGill: Advisory Panel; Bayer Inc., Boehringer-Ingelheim, ClearNote Health, Lilly Diabetes, MannKind Corporation, Novo Nordisk. Research Support; Novo Nordisk.

Funding

JDRF DRCICTS
794-P: Effect of Liraglutide on Abdominal Fat Distribution and Glucose Metabolism in Chinese Patients with Obesity
Authors: DU MENGYANG , YUE JIANG , QI YICHENG , HE SHENGYUN , LU XIAOBING , YANG MINGLAN , WANG LIHUA , LU QING , MA JING
Published: June 2024

Introduction & Objective: Recent studies have shown that liver fat content (LFC) is associated with impaired glucose metabolism and insulin resistance in the obesity. It has been established that GLP-1RA could significantly reduce LFC in patients with T2DM. This study aimed to observe the effects of liraglutide on abdominal fat distribution and glucose metabolism in Chinese subjects with obesity for 12 weeks, and further explore the correlation between abdominal fat content and glucose profiles.

Methods: This study recruited 71 obese patients (BMI≥28 kg/m²). All the patients have received liraglutide monotherapy for 12 weeks, and received anthropometric measurement, OGTT (Oral glucose tolerance test) and MRI examination at baseline and after 12 weeks treatment. The association between the glycemic metabolism and abdominal fat content was further analysed.

Results: After 12 weeks of liraglutide monotherapy, body weight in the obese participants decreased significantly (P=0.014). Fasting blood glucose (FBG), 2h postprandial blood glucose (2hPBG), HbA1c, HOMA-IR were remarkably improved (all P<0.001). TC and LDL-c were sharply reduced (P=0.004, P=0.027 respectively). LFC was strikingly more in subjects with impaired glucose regulation (IGR) group compared to those with normal glucose tolerance (NGT) at baseline (P=0.002). The decreased LFC in IGR group was significantly greater after liraglutide treatment than those with NGT (P<0.001). Linear regression analysis showed that HOMA-IR at baseline was the independent marker for LFC reduction after liraglutide treatment (B: 0.634; 95%CI:0.100-1.168, P=0.021).

Conclusion: Liraglutide monotherapy for 12 weeks significantly reduced LFC in patients with obesity. The LFC reduction may serve as one of possible mechanisms of blood glucose improvement in obese patients.

Disclosure

M. Du: None. J. Yue: None. Y. Qi: None. S. He: None. X. Lu: None. M. Yang: None. L. Wang: None. Q. Lu: None. J. Ma: None.
808-P: Impact of Fasting on Adherence to Dosing Instructions and Efficacy of Oral Semaglutide during Ramadan in People with Type 2 Diabetes in Real-World Setting—O-SEMA-Fast Subanalysis
Authors: HASSANEIN MOHAMED , ALKADHIM IBRAHIM , ALY HAZEM , BAJAWI DALILA , CINAR TARHAN , DHANWAL DINESH , JABBAR ABDUL , KHADER SAID , KHUDADAH KHALED , MUZAFFAR TALAL , NGOME MARY , NAFACH JALAL , SHAGHOULI AMNA
Published: June 2024

Introduction & Objective: Oral semaglutide, a glucagon-like peptide 1 receptor agonist, should be administered in empty stomach, with up to 120 ml of water and with no food, beverages or any oral medications intake for a minimum of 30-min post administration to ensure optimal systemic absorption. These instructions could be cumbersome to follow during Ramadan when patients fast for longer duration. This O-SEMA-Fast sub-analysis assessed impact of fasting on adherence to oral semaglutide dosing instructions and subsequently on glycemic and body weight changes.

Methods: O-SEMA-Fast was a non-interventional, prospective study in people with T2D who fasted during Ramadan and on oral semaglutide treatment in United Arab Emirates, Saudi Arabia and Kuwait. Patients were followed up for a period of 20-weeks (end of study, EOS). HbA1c and body weight were measured at baseline and at EOS; changes were analyzed by mixed models for repeated measures.

Results: Of 257 patients in the full analysis set, 215 were eligible as they had recorded administration details in their diaries. Among these, 68.4% (n=147) were found to be adherent to oral semaglutide dosing instructions for ≥80% of days the diary was filled. At baseline, mean HbA1c was 6.69% and 7.0% in adherent and non-adherent (dosing instructions) people, respectively. At EOS, an estimated change in HbA1c from baseline was -0.33 (95% CI: -0.44, -0.23; p<0.0001) and -0.12 (95% CI: -0.36, 0.12; p=0.3138), respectively. Similarly, change in body weight was -3.22 kg (95% CI: -4.03, -2.40, p<0.0001) and -1.64 (95%CI: -2.45, -0.84, p=0.0001), in adherent and non-adherent people.

Conclusion: This O-SEMA Fast sub-analysis indicated that most people adhered to oral semaglutide administration instructions and experienced significant decrease in HbA1c and body weight, making oral semaglutide as a suitable choice of drug for people who fast during Ramadan.

Disclosure

M. Hassanein: Research Support; Novo Nordisk A/S. Advisory Panel; Sanofi. Speaker's Bureau; Abbott, Boehringer-Ingelheim, Medtronic. Advisory Panel; Eli Lilly and Company. I. AlKadhim: Speaker's Bureau; Lilly Diabetes. Research Support; IQVIA Inc. Advisory Panel; Novo Nordisk. Speaker's Bureau; Boehringer-Ingelheim, AstraZeneca, Novo Nordisk. H. Aly: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. D. Bajawi: Consultant; Novo Nordisk, Boehringer-Ingelheim, AstraZeneca, Sanofi. T. Cinar: Employee; Novo Nordisk. D. Dhanwal: Research Support; Novo Nordisk A/S. A. Jabbar: Research Support; Novo Nordisk A/S. S. Khader: Research Support; IQVIA Inc., Novo Nordisk. K. Khudadah: None. T. Muzaffar: Other Relationship; Novo Nordisk. M. Ngome: Employee; Novo Nordisk. J. Nafach: None. A. Shaghouli: None.
809-P: Oral Semaglutide in Indian Type 2 Diabetes Mellitus patients (SOLID) Study—Twelve Months Follow-up
Authors: BHATTACHARYYA SUPRATIK
Published: June 2024

Background: The oral formulation of semaglutide, a GLP-1R agonist, has emerged as a promising treatment option for diabesity, demonstrating efficacy in both glycemic parameter improvement and weight management.

Materials and Methods: Following market launch in India in 2022, we conducted a prospective, observational cohort study across eight Indian centers to examine the initial utilization patterns of oral semaglutide in routine clinical practice. The present study enrolled subjects diagnosed with type 2 diabetes who possessed one year of follow-up data on oral semaglutide use.

Results: A multi-center, open-label, single-arm study evaluated the efficacy and safety of oral semaglutide monotherapy in 152 patients with type 2 diabetes mellitus. The mean age of the participants was 50.14 years, and the majority were male (59.86%). The baseline characteristics included a mean body mass index of 29.82 kg/m2, a mean body weight of 87.17 kg, and a mean HbA1c of 9.09%. A significant portion of the study population had comorbidities, including hypertension (46%), dyslipidemia (41%), and hypothyroidism (16%). At baseline, 81.7% of patients were initiated on the 3 mg dose of oral semaglutide. The primary outcome measures were the change in HbA1c and body weight from baseline to the follow-up visit after 1 year. The mean reduction in HbA1c and body weight was 1.81% and 5.03 kg, respectively (P < 0.0001 for both). The most common adverse events reported were generalized weakness, nausea, dryness of mouth, and diarrhea. Notably, no hypoglycemia, other serious adverse events, or discontinuations were observed.

Conclusions: Over a 12-month period, individuals with T2DM demonstrated significant improvements in key glycemic parameters, including HbA1c, and reduction in body weight, highlighting the potential of oral semaglutide as a first-line therapeutic option for this population.

Disclosure

S. Bhattacharyya: None.
810-P: Role of Glucagon-Like-Peptide-1 Agonists as an Adjunctive Treatment in Adults with Type 1 Diabetes Mellitus and Overweight/Obesity, Retrospective Cohort, Saudi Arabia 2023
Authors: HABEEB KHOLOOD , BREMA IMAD , ALMEHTHEL MOHAMMED , ALSHEHRI ALI
Published: June 2024

Introduction & Objective: Diabetes is a major public health problem, in 2021, Diabetes affect 537 million adults, and it is estimated to affect 643 million adults by 2030, associated with 6.7 million adult deaths in 2021(1). The Usefulness of Many non-insulin therapies has been investigated in type-1 diabetes like Metformin, and Sodium-Glucose co-transporter-2 inhibitors. Recent evidence on Semaglutide in early Type-1 diabetes shows a promising effect. The study aimed to determine whether Glucagon-Like Peptide-1 Receptor agonist (GLP-1) added to Insulin in Adults with Type-1 Diabetes Mellitus is effective and safe.

Methods: A retrospective cohort was conducted (Jan 2022-Feb 2023) among all adults with Type-1 Diabetes on GLP-1 agonists and overweight/Obesity, attending the Diabetes or Obesity clinic in King Fahad Medical City through an Electronic system records review. Excluding those on other non-insulin Diabetes medications, or obesity interventions. Many variables were evaluated to assess the efficacy and safety: Hga1c, CGM data, Weight, biochemical profile, retinal exam, hypoglycemia, and DKA incidence. Student T test Chi-square and linear mixed modeling were used for statistical analysis.

Result: 32 patients on GLP-1 agonists were recruited, with a mean age of 30 years, 87% were on Semaglutide (0.5mg or 1mg), while the rest were on Liraglutide (1.2mg-3mg), Estimated Hga1c reduction was 0.84% after 8 months from baseline, p-value <0.001. TIR improved by 15% p value <0.001. 31% of the patients achieved 5% TBWL and 12.5% achieved 15% TBWL p-value <0.001. A significant reduction in insulin total daily dose was observed more in bolus insulin. No Significant hypoglycemia, Retinopathy, or DKA episodes.

Conclusions: GLP-1 agonist as adjunctive therapy to insulin shows a significant Improvement in Glycemic control, weight reduction, and insulin requirement in patients with Type-1 diabetes.

Disclosure

K. Habeeb: None. I. Brema: None. M. Almehthel: None. A. Alshehri: None.
812-P: Safety and Efficacy of Early Initiation of GLP1RA and SGLT2 inhibitors, in Post–Kidney Transplant Patients with Type 2 Diabetes
Authors: ACOSTA FRANCISCA M. , TODD BYRON , HU BEVERLY , FRAUSTO PAOLA , NICHOLS JESSICA , ESCOBAR VASCO MARIA , SOLIS-HERRERA CAROLINA
Published: June 2024

Introduction: DKD is the most common cause of ESKD. Among kidney transplant recipients (KTRs), 40% have DM. Anti-rejection therapies worsen DM and have increased CV mortality >50%. To date, we do not know what the best early therapy is to treat post-transplant patients with type 2 diabetes (T2D). The use of SGLT2i or GLP1-RA, as early anti-diabetic therapy, could improve glucose, weight, cardiovascular and renal function in these patients.

Methods: Retrospective, observational, single-center study using EMR. Inclusion-criteria included KTR with T2D. After 6 months post-transplant, GLP1RA or combination therapy was initiated. A1c, lipids, eGFR, and weight were taken as major outcomes to determine efficacy. Outcomes were measured before and after 18 months of therapy. SE and SAE were recorded.

Results: Twenty-six patients KTR with T2D; 55±2 years-old, A1c 6.8%+/-0.5; BMI 30.2 +/- 1.4 were included. Five subjects were on SGLT2i+GLP1RA and 21 subjects on GLP1RA. There were no significant differences between groups at baseline. The A1c levels in the combination group decreased (-0.14%±0.4) and the GLP1-group (-0.06%±0.4). LDL (-51mg/dL ± 23 vs +0.2mg/dL±8.3), p=0.009. Triglycerides (-10.8mg/dL±10.8 vs -64.8mg/dL±15.7), p=0.05. eGFR (+1.2mL/min vs +6.3mL/min) p=0.25. Weight (-7.8kg±3 vs -4.6kg±2) p=0.2. No patients discontinued the medication due to side effects.

Conclusion: This single-center retrospective analysis showed that both groups treated with either GLP1RA, or its combination with SGLT2i, are safe and effective after 18 months without significant SE. These novel drugs should be considered as a safe early therapy in KTR patients with T2D. As our numbers are small in this real-world data, further randomized studies are necessary to confirm these findings.

Disclosure

F.M. Acosta: None. B. Todd: None. B. Hu: None. P. Frausto: None. J. Nichols: None. M. Escobar Vasco: None. C. Solis-Herrera: Advisory Panel; Novo Nordisk, Bayer Inc.
820-P: Faster-Acting Insulin Aspart vs. Insulin Aspart for Adults with Type 1 Diabetes Treated with Insulin Pump and Continuous Glucose Monitoring
Authors: RANJAN AJENTHEN G. , SCHMIDT SIGNE , ANDERSEN HANNE-CHARLOTTE , NØRGAARD KIRSTEN
Published: June 2024

Objective: To evaluate efficacy and safety of faster-acting insulin aspart (Fiasp) compared to insulin aspart (Iasp) in adults with type 1 diabetes using non-automated insulin pump and continuous glucose monitoring (CGM).

Methods: In this double-blinded crossover trial participants were randomly assigned to start with Fiasp or Iasp for 16 weeks and then switch to the alternate therapy for another 16 weeks following a 3-week washout period. Insulin pump settings were adjusted every 3 weeks based on CGM and insulin pump data. Primary outcome was the between-treatment difference in time in range (TIR: 3.9-10.0 mmol/L) from week 14 to 16. Secondary outcomes included other CGM metrics and HbA1c. Safety outcomes included injection site reactions.

Results: Forty adults (20 males) with a median (IQR) age of 54 (44-61) years, type 1 diabetes duration of 27 (20-34) years, HbA1c 59 (55-65) mmol/mol or 7.5 (7.2-8.1) %, BMI 25.7 (24.5-30.3) kg/m2 and total daily insulin dose 37 (29-52) IE completed both study arms. At 16 weeks, TIR was (mean ± SD) 60.6 ± 12.1% for Iasp and 62.5 ± 12.3% for Fiasp, p = 0.24; time above range (>10.0 mmol/L) was 31.5 ± 12.6% for Iasp and 30.1 ± 11.3% for Fiasp, p=0.30; and time below range (<3.9 mmol/L) was 7.8 ± 5.5% for Iasp and 7.5 ± 6.1% for Fiasp, p=0.89. The coefficient of variation was significantly higher with Iasp compared to Fiasp (35.9 ± 4.9% vs 34.0 ± 3.7%, p=0.03). At week 16, HbA1c was 58.0 ± 6.6 mmol/mol with Iasp and 57.5 ± 6.9 mmol/mol with Fiasp (p= 0.43). No differences were observed in SAE including severe hypoglycemia and diabetes ketoacidosis. Fiasp had numerically more events of burning sensation at injection site than Iasp.

Conclusion: At 16 weeks, after frequent adjustments of insulin pump settings, no differences between Fiasp and Iasp treatment were observed in TIR, TAR, TBR and HbA1c in adults with type 1 diabetes using insulin pump and CGM. However, Fiasp significantly reduced glycemic variability compared to Iasp.

Disclosure

A.G. Ranjan: None. S. Schmidt: Employee; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. H. Andersen: None. K. Nørgaard: Research Support; Dexcom, Inc., Medtronic. Advisory Panel; Medtronic, Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Advisory Panel; Convatec. Research Support; Zealand Pharma A/S.

Funding

Steno Diabetes Center Copenhagen is the sponsor of this investigator-initiated trial. Novo Nordisk provided financial support to the conduct of the study and supplied the study medication.
83-OR: Metabolic Dysfunction–Associated Steatotic Liver Disease and Nonalcoholic Fatty Liver Disease Have Similar Clinical Profiles and Mortality
Authors: YOUNOSSI ZOBAIR , PAIK JAMES M. , GOLABI PEGAH , ONG JANUS , HENRY LINDA , ALQAHTANI SALEH , NADER FATEMA
Published: June 2024

Introduction & Objective: Metabolic dysfunction associated steatotic liver disease (MASLD) has recently replaced the term nonalcoholic fatty liver disease (NAFLD). Concern remains whether evidence generated under NAFLD definition is fully applicable to MASLD. We compared the clinical profile and outcomes of NAFLD to MASLD using population-based data.

Methods: National Health and Nutrition Examination Survey (NHANES-III) with the linked Mortality file (through 2019) were used to compare groups defined as NAFLD and MASLD. Hazard ratios (HRs) of MASLD/NAFLD on all-cause mortality were calculated by cox-regression models.

Results: Among 2,736 NHANES participants with NAFLD (age 47.80 years, 52.48% male, 47.66% obese, 18.26% T2D, 94.71% ≥ 1 cardiometabolic criteria), only 5.29% patients did not meet MASLD criteria. The clinical profile of MASLD was similar except for age (48.56 years) and presence of cardiometabolic risks (50.32% obese, 19.28% T2D, 100% ≥ 1 cardiometabolic criteria). There was excellent concordance between NAFLD and MASLD definitions (Cohen’s kappa coefficient=0.968 [95% CI: 0.962-0.973]). After a median follow-up of 22.83 years, there were no mortality rate differences between MASLD and NAFLD (p-values ≥ 0.05). Adjusting for socio-demographic factors, lack of healthy eating and physical activity, MASLD had a higher all-cause mortality risk (Hazard Ratio (HR)=1.15 [1.05-1.25]). However, after further adjustment for cardiometabolic risks, MASLD was not associated with increased all-cause mortality (p-value>0.80).

Conclusions: NAFLD and MASLD are similar except MASLD subjects are older with slightly higher mortality risk, potentially due to the inclusion of cardiometabolic risk factors. These data provide evidence that NAFLD and MASLD can be used interchangeably.

Disclosure

Z. Younossi: Consultant; Gilead Sciences, Inc., Bainan Biotech, AbbVie Inc., Bristol-Myers Squibb Company, Abbott, Novo Nordisk, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Siemens Healthcare Diagnostics, Intercept Pharmaceuticals, Inc. J.M. Paik: None. P. Golabi: None. J. Ong: None. L. Henry: None. S. Alqahtani: Consultant; AbbVie Inc., Bristol-Myers Squibb Company, Merck & Co., Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. F. Nader: None.
838-P: Impact of Age on the Efficacy and Safety of Once-Weekly Insulin Icodec vs. Once-Daily Insulin in Type 2 Diabetes (ONWARDS 1–5)
Authors: VIANNA ANDRE G.D. , DESOUZA CYRUS , LAUGESEN CHRISTIAN , FRAGÃO MARQUES MARIANA , HØJLUND NIELSEN PERNILLE , SHAIKH SHEHLA S. , LINGVAY ILDIKO
Published: June 2024

Introduction & Objective: This post hoc analysis assessed the treatment effects of once-weekly insulin icodec (icodec) vs once-daily (OD) basal insulin comparators across different age groups in adults with T2D.

Methods: Efficacy outcomes and hypoglycemia rates for icodec vs OD comparators across three age subgroups (<55, 55-64 and ≥65 years) were assessed, by trial, in insulin-naïve (ONWARDS 1, 3, 5) and insulin-treated (ONWARDS 2, 4) adults with T2D.

Results: There were no statistically significant treatment by subgroup interactions for change in A1C from baseline to planned end of treatment (EOT) (Figure). A larger reduction in A1C with icodec was seen across age subgroups in ONWARDS 1-5, except for individuals ≥ 65 years in ONWARDS 4, where the opposite trend was seen. Overall, rates of clinically significant and severe hypoglycemic episodes were low in both treatment arms across age subgroups. In ONWARDS 1-5, the proportions of individuals achieving A1C <7% without clinically significant or severe hypoglycemic episodes at planned EOT were higher for icodec vs OD comparators irrespective of age, except for individuals < 55 and ≥ 65 years in ONWARDS 4; no statistically significant difference was seen in the treatment by subgroup interaction across different age subgroups.

Conclusion: Overall, efficacy and hypoglycemia outcomes were consistent for icodec vs OD comparators irrespective of age.

Disclosure

A.G.D. Vianna: Board Member; Abbott, Lilly Diabetes, Novo Nordisk, Medtronic. Speaker's Bureau; AstraZeneca, Novo Nordisk. Research Support; Novo Nordisk, Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Research Support; Servier Laboratories. C. Desouza: Advisory Panel; Novo Nordisk, Bayer Inc., Madrigal Pharmaceuticals, Inc. Other Relationship; ADA/ACC Diabetes by Heart Program. Advisory Panel; Asahi Kasei. C. Laugesen: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. M. Fragão Marques: None. P. Nielsen: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. S.S. Shaikh: None. I. Lingvay: Consultant; Altimmune, Astra Zeneca, Bayer, Biomea, Boehringer-Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/J&J, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Sanofi. Research Support; NovoNordisk, Sanofi, Mylan, Boehringer-Ingelheim. Consultant; TERNS Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma.

Funding

Novo Nordisk A/S
842-P: Improvement in Time in Range after Smart Insulin Pen Initiation in Austria
Authors: MADER JULIA K. , HARTVIG NIELS V. , KAAS ANNE , KNUDSEN NIKOLINE N. , WINHOFER YVONNE
Published: June 2024

Introduction & Objectives: A prior multinational study showed improved time in range (TIR; 70-180 mg/dL) in people living with type 1 or type 2 diabetes (PLWD) after smart pen initiation for their bolus insulin. To understand country-specific experiences with smart pen use, this study replicated the analysis, focusing on PLWD in Austria.

Methods: Real-world data (RWD) were collected from adults in Austria on a multiple daily insulin regimen who were already using a continuous glucose monitoring (CGM) device and initiating a smart pen. Days were included if an individual had ≥1 data upload (pen to app) within the last 14 days and ≥15% time covered by CGM sensor readings. Key glycemic outcomes were TIR and time below range (TBR; <3.9 mmol/L).

Results: Data from 1336 adults (mean 49.1 years) were analyzed (101 394 days with CGM data and recorded bolus injections). Mean TIR increased by 4.0% at month 3 (95% CI 3.0, 5.1; p < 0.001) and was sustained at month 6 (95% CI 2.7, 5.2; p < 0.001) (Figure). TBR decreased significantly from baseline by month 3, but was not statistically significant at month 6. The percentage of participants with TIR >70% increased from 35% at baseline to 42% at 6 months (p < 0.001).

Conclusion: RWD from Austria shows a clear glycemic improvement after smart pen initiation. Analyzing country-specific experiences is important to understand the potential impact of smart pen use and how PLWD and physicians can most benefit from this technology.

Disclosure

J.K. Mader: Advisory Panel; Becton, Dickinson and Company. Speaker's Bureau; Becton, Dickinson and Company, A. Menarini Diagnostics, Boehringer-Ingelheim, diaTribe. Other Relationship; Diabetes UK. Stock/Shareholder; decide Clinical Software GmbH. Advisory Panel; embecta. Speaker's Bureau; embecta, Viatris Inc., Eli Lilly and Company. Advisory Panel; Eli Lilly and Company, Medtronic. Speaker's Bureau; Medtrust. Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Advisory Panel; PharmaSens, Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care. Board Member; Sanofi-Aventis Deutschland GmbH. Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Sanofi, Dexcom, Inc., Viatris Inc. Advisory Panel; Viatris Inc. Speaker's Bureau; Ypsomed AG. Research Support; European Union. Stock/Shareholder; elyte Diagnostics GmbH. Other Relationship; elyte Diagnostics GmbH. Board Member; European Association for the Study of Diabetes. Research Support; European Union Aviation Safety Agency. N.V. Hartvig: Stock/Shareholder; Novo Nordisk A/S. Employee; Novo Nordisk A/S. A. Kaas: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. N.N. Knudsen: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Y. Winhofer: None.

Funding

Novo Nordisk A/S
849-P: Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of an Optimized Dual GLP-1/GIP Receptor Agonist (BGM0504) in Healthy Subjects—A Phase Ia, Randomized, Double-Blind, Placebo-Controlled, Ascending Dose Study
Authors: YUAN JIANDONG , HUANG YANGQING , DING HAIFENG , JIANG XIAOHUI
Published: June 2024

Background: BGM0504 is an optimized dual GIP and GLP-1 receptor agonist with greater in vitro potency, and similar GLP-1R/GIPR activity ratio as Tirzepatide. Here we report the results of a phase Ia study of BGM0504 in healthy subjects (CTR20230120).

Methods: In a clinical study of 40 healthy subjects, four initially received a single 2.5 mg subcutaneous injection of BGM0504. The remaining 36 were divided into three groups, each receiving two weekly injections at escalating doses: 2.5/5 mg, 5/10 mg, and 10/15 mg, respectively. In each group, 10 subjects were randomly assigned to BGM0504, and 2 received a placebo. The primary endpoints were safety and tolerability. The secondary endpoints included PK and PD.

Results: In the study with 40 healthy subjects, gastrointestinal adverse events like decreased appetite, nausea, abdominal distension, vomiting, and diarrhea were most common, all mild to moderate. The concentration of BGM0504 peaked between 24 to 72 hours post-dosing, with a mean half-life of approximately 4 days, supporting a weekly dosing schedule. BGM0504 showed dose-proportional PK within the tested range, with slightly higher exposures (Cmax and AUC) than Tirzepatide at equivalent doses. Subjects experienced a dose-dependent weight loss ranging from 3.24% to 8.30% by study end, with no significant changes in other PD markers like glycemia, C-peptide, and insulin.

Conclusions: BGM0504 was well tolerated with favorable PK profile and led to evident body weight loss. These data support further clinical developments of BGM0504 for T2DM and obesity. The phase II clinical trials for both T2DM and obesity are ongoing, and available results will be presented.

Disclosure

J. Yuan: Other Relationship; BrightGene Bio-Medical Technology Co., Ltd. Y. Huang: Employee; BrightGene Bio-Medical Technology Company Ltd. H. Ding: Employee; BrightGene Bio-Medical Technology Company Ltd. X. Jiang: Consultant; BrightGene Bio-Medical Technology Co Ltd.
850-P: Trends in GLP-1RA Use among Individuals with Type 2 Diabetes (T2D) and/or Obesity—Insights from a Nationwide Electronic Health Record System, 2010–2023
Authors: LI PIAOPIAO , SAM VARGHESE JITHIN , SHAH MEGHA K. , PASQUEL FRANCISCO J. , HARDING JESSICA L. , JIAO TIANZE , SHAO HUI , ALI MOHAMMED K.
Published: June 2024

New evidence highlights GLP-1 RAs' significant benefits in blood glucose and weight control for those with T2D and/or obesity, yet their real-world use and related disparities are unexplored. We conducted a pooled cross-sectional study using electronic health records from the Epic Cosmos database (2010-2023), an integrated database covering 176 million patients across 50 US states. We examined trends in GLP1-RA use among three groups: T2D-only, obesity-only, and T2D with obesity. The trend was also examined by socio-demographic factors in each group. The study included a sample of 67.9 million individuals. A gradual increase in GLP-1RA use was observed across all groups from 2010 to 2016, followed by a pronounced and accelerated uptake since 2016 (Figure). In the obesity-only population, females exhibited a 1.47 times faster uptake rate than males, measured by the annual rate of increase. Similarly, those with education beyond college showed a 1.76 times faster uptake rate than their counterparts. The utilization rate for individuals under 19 years with T2D and obesity, which remained at 0% from 2010 to 2017, surged to 35.3% in 2023. We found an upward trend in GLP-1 RA utilization since 2016 when FDA approval occurred, though use was disproportionate among some groups, raising concerns about inequitable access.

Disclosure

P. Li: None. J. Varghese: None. M.K. Shah: None. F.J. Pasquel: Research Support; Tandem Diabetes Care, Inc., Insulet Corporation, Dexcom, Inc., Ideal Medical Technologies, Novo Nordisk. Consultant; Dexcom, Inc., Medscape. J.L. Harding: None. T. Jiao: None. H. Shao: Consultant; Eli Lilly and Company. M.K. Ali: Advisory Panel; Eli Lilly and Company.
852-P: Effect of Metformin on Intestinal Flora in Patients with Polycystic Ovary Syndrome
Authors: XU LAN , JIE JIANG CHEN
Published: June 2024

Objective: To analyze the characteristics of the intestinal flora of patients with polycystic ovary syndrome (PCOS) in reproductive age, and to explore the effect of metformin on the intestinal flora of PCOS patients.

Methods: Thirty-six PCOS patients attending Wuxi People's Hospital affiliated to Nanjing Medical University from 2019 to 2021 were selected as the study group and 35 healthy women of childbearing age during the same period as the control group, and metformin treatment was given to the PCOS patients for 6 months, and blood and fecal specimens were collected before and after treatment. 16S rDNA was used to identify the intestinal flora of the fecal specimens.

Results: (1) The α and β diversity of the intestinal flora was lower in the study group, and the abundance of Bacteroidaceae, Oscillospiraceae, Rikenellaceae, and Clostridiaceae UCG-014 was lower than that of the control group, while Enterobacteriaceae was more abundant, and after correction for BMI, there was still a significant difference between Bacteroidaceae and Enterobacteriaceae. (2) After metformin treatment, and the abundance of Bacteroidaceae in the study group increased, while the abundance of Peptostreptococcaceae and Clostridiaceae decreased. (3) Correlation analyses showed that the abundance of Bacteroidaceae was negatively correlated with testosterone, antimüllerian hormone, and lipids; the abundance of Enterobacteriaceae was positively correlated with testosterone, antimüllerian hormone, blood glucose and insulin. (4) Changes in the abundance of Bacteroidaceae before and after treatment with metformin in the study group were negatively correlated with changes in total cholesterol; changes in the abundance of Peptostreptococcaceae were positively correlated with changes in total cholesterol and low-density lipoprotein cholesterol.

Conclusion: Intestinal flora disorders exist in PCOS patients, and metformin has an ameliorating effect on intestinal flora disorders in PCOS patients.

Disclosure

L. Xu: None. C. Jiang: None.
859-P: ALN-KHK, an Investigational RNA Interference Therapeutic, Successfully Targets Hepatic Ketohexokinase in a Single Ascending Dose Study of Overweight to Obese Adults
Authors: MARATOS-FLIER ELEFTHERIA , NANDI TIRTHA , BOYLE KATHERINE , LI XINGYU , WU YUANFENG , NOETZLI LEILA , KAJBAF FARSHAD , MORELLI GAETANO
Published: June 2024

Introduction & Objective: Rising obesity rates are attributed in part to high dietary sugar consumption, including fructose, which is linked to development of hepatosteatosis and type 2 diabetes. ALN-KHK is an investigational RNA interference therapeutic designed to decrease hepatic ketohexokinase (KHK) expression, thus reducing fructose metabolism by targeting its initial step and potentially decreasing hepatic lipogenesis. The objectives of this Phase 1/2 Part A single ascending dose study (NCT05761301) were to evaluate safety, tolerability, and pharmacology of ALN-KHK in overweight to obese adults.

Methods: Healthy adults with a BMI of 27-34.9 kg/m2 were randomized 3:1 to receive a single subcutaneous dose of ALN-KHK or placebo. Five dose cohorts (25, 75, 150, 300, and 600 mg) were evaluated over a 3-month period with follow up for up to 9 months. The primary endpoint assessed safety and tolerability. Secondary endpoints characterized pharmacokinetics and pharmacodynamics of ALN-KHK after a fructose tolerance test (FTT) prior to dosing and on Days 29, 57, 85, and 169.

Results: Forty participants enrolled (N=30, ALN-KHK; N=10, placebo; mean (SD) age, 45.4 (11.5) years; mean (SD) BMI, 29.7 (1.7) kg/m2; 67.5% male). By data cutoff, all adverse events were mild, non-serious, and resolved. Increasing doses of ALN-KHK were generally associated with dose- and time-dependent increases in serum fructose area under the curve (AUC) and urinary fructose fraction excreted after FTT. Preliminary data showed a mean (SD) increase from baseline of 178.0% (84.4%) in serum fructose AUC with 300 mg at Day 85. Reduction of fibroblast growth factor 21 after FTT was also observed.

Conclusion: Interim results of this first clinical study of ALN-KHK demonstrate an encouraging safety and tolerability profile with target engagement in overweight to obese adults, supporting its further evaluation in patients with type 2 diabetes.

Disclosure

E. Maratos-Flier: Employee; Alnylam Pharmaceuticals. T. Nandi: None. K. Boyle: Employee; Alnylam Pharmaceuticals, Inc. X. Li: None. Y. Wu: Employee; Alnylam Pharmaceuticals, Inc. L. Noetzli: Employee; Alnylam Pharmaceuticals, Inc. Stock/Shareholder; Alnylam Pharmaceuticals, Inc. F. Kajbaf: Employee; Alnylam Pharmaceuticals, Inc. G. Morelli: None.

Funding

Alnylam Pharmaceuticals, Inc.
865-P: Metformin Reduces Insulin Dose and Visceral Fat Accumulation, and Increases GDF15 without Reducing Insulin Resistance in Adults with Type 1 Diabetes—A 26-Week, Randomized, Double-Blind Placebo-Controlled Trial (INTIMET)
Authors: SNAITH JENNIFER R. , OLSEN NICHOLAS D. , KOWALSKI GREG M. , BRUCE CLINTON , EVANS JENNIFER L. , JANUSZEWSKI ANDRZEJ S. , JENKINS ALICIA , BREIT SAMUEL N. , HOLMES-WALKER JANE , GREENFIELD JERRY
Published: June 2024

Insulin resistance is a cardiovascular (CV) risk factor in type 1 diabetes (T1D). The effect of metformin on liver and muscle insulin resistance has not been studied in adults with T1D. We recruited 40 adults with T1D (HbA1c 7.5±0.9% [58±10mmol/mol], diabetes duration 22.9±8.9 years, age 37.4±8.8 years, 60% male, BMI 26.4±3.8 kg/m2). Twenty age, gender and BMI matched controls without diabetes were studied at baseline only. Subjects with T1D were randomized to metformin XR 1500mg daily or placebo for 26 weeks. At baseline and end of treatment, subjects completed two-step hyperinsulinemic-euglycemic clamps with 6,6-2H2 glucose to measure insulin sensitivity at liver (endogenous glucose production during low dose insulin infusion; EGP) and muscle (glucose infusion rate during high dose insulin infusion; GIR). Arterial stiffness (augmentation index; AIx), body composition (DXA, MRI), continuous glucose monitoring (CGM) and growth differentiation factor 15 (GDF15) were measured. Adults with T1D displayed insulin resistance in muscle (GIR 29% lower) and liver (EGP 64% higher). After 26 weeks, metformin reduced total daily insulin dose (estimated treatment difference [ETD] -6.5 units/day [95% CI -11.4 to -1.7]; p=0.009) and visceral fat (p=0.04), and increased serum GDF15 levels (ETD 382 pg/mL [59 to 704]; p<0.001). Metformin did not improve EGP, GIR, AIx, body composition, HbA1c or CGM time in range vs placebo. Metformin reduced insulin dose and visceral fat, and increased GDF15, without improving insulin resistance. This insulin dose difference was previously associated with a 6% CV risk difference. This study: 1) Implicates insulin resistance-independent actions of metformin; 2) Highlights reducing insulin dose as a possible mediator of metformin’s cardioprotection; and 3) Postulates that metformin’s effects in adults with T1D may involve GDF15.

Disclosure

J.R. Snaith: None. N.D. Olsen: Stock/Shareholder; Pfizer Inc. G.M. Kowalski: None. C. Bruce: None. J.L. Evans: None. A.S. Januszewski: None. A. Jenkins: Research Support; Abbott, Viatris Inc. Advisory Panel; Abbott. Research Support; Medtronic. Board Member; Insulin for Life. Research Support; Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), Jaeb Center for Health Research, National Institutes of Health, National Health and Medical Research Council Australia. S.N. Breit: Other Relationship; Novo Nordisk A/S, Aveo Pharmaceutical, Roche Diagnostics. J. Holmes-Walker: None. J. Greenfield: Other Relationship; Novo Nordisk.

Funding

Diabetes Australia; St Vincent's Clinic Foundation; UNSW Cardiac, Vascular and Metabolic Medicine Theme; National Health and Medical Research Council (NHMRC)
869-P: Gastrin Reduces Incidence of Type 1 Diabetes through Reducing Inflammation and Preserving ß-Cell Mass in Animal Model
Authors: MIAO LYNN N. , GU ANGEL S. , HUSSEINY MOHAMED I. , RAWSON JEFFREY , MARES JACOB , ORR CHRIS , DHAWAN SANGEETA , SHIH BEN , KU HSUN T. , KANDEEL FOUAD R.
Published: June 2024

Introduction: Progressive destruction of insulin-producing β-cells by autoimmunity is a primary feature of type 1 diabetes (T1D). Therapies that block immune attacks on islet cells and preserve or restore the functional β-cell mass are needed to halt or reverse disease progression. Here, we tested the therapeutic effects of GAST-17, an analogue of the natural gastric hormone that is produced by intestinal G cells and fetal islets, on preservation and restoration of β-cell mass in the NOD mice.

Methods: Normoglycemic female NOD mice were injected intraperitoneal with GAST-17 (300 or 600ug/kg/day) or saline (control) for 14-weeks. At end of the experiment, an intraperitoneal glucose tolerance test (IPGTT) was performed. Pancreatic tissues were examined for islets number, endocrine cell mass and inflammatory cell infiltration.

Results: GAST-17 treated animals had lower rates of diabetes incidents in a dose-dependent manner. Animals treated with 600 ug/kg/day of GAST-17, prevented diabetes in 70-80% compared to 20-57% in control, and area under the curve in IPGTT test was also lower compared to control (p<0.05). Islet morphology was not different among the diabetic mice, but GAST-17 treated nondiabetic mice had lower inflammatory cell infiltration (p<0.004), higher number of islets (p<0.01) and larger endocrine cell mass/islet than nondiabetic controls (p<0.01).Smaller (<10026uM2) but not larger islets showed higher ratios of insulin to glucagon and insulin per islet area when compared to controls(p<0.005). All normoglycemic animals had larger numbers of small islets, compared to larger islets that were closer to the ducts.

Conclusion: GAST-17 treatment protected NOD mice from the development of diabetes by reducing islet inflammatory cell invasion, preserving beta cell mass and likely augmenting islet neogenesis from a ductal origin. Lineage tracing experiments are ongoing.

Disclosure

L.N. Miao: None. A.S. Gu: None. M.I. Husseiny: None. J. Rawson: None. J. Mares: None. C. Orr: None. S. Dhawan: None. B. Shih: None. H.T. Ku: None. F.R. Kandeel: Advisory Panel; Vertex Pharmaceuticals Incorporated.
883-P: Brain-Directed AAV-FGF21 Gene Therapy Reverses Type 2 Diabetes, Obesity, and Cognitive Decline
Authors: BOSCH FATIMA , SACRISTAN VICTOR , RIBERA ALBERT , MARCÓ COSTA SARA , JAMBRINA CLAUDIA , JIMENEZ VERONICA , CASANA ESTEFANIA , LEON XAVIER , ELIAS GEMMA , FERRE TURA , FRANCKHAUSER SYLVIE , ELIAS IVET
Published: June 2024

Introduction: Type 2 Diabetes (TD2) and obesity are closely related metabolic diseases with an increasing worldwide prevalence. TD2 and obese patients have high risk of developing cognitive decline in the long-term. Fibroblast growth factor 21 (FGF21) has become a promising therapeutic agent for the treatment of obesity and T2D. It has been reported that FGF21 can act in different brain regions to regulate whole body metabolism.

Methods: Two-month-old C57Bl6 mice were fed either a chow or a HFD. Ten weeks later, mice were intra-cerebrospinal fluid (CSF) administered with adeno-associated viral (AAV) vectors encoding FGF21 (AAV-FGF21) and remained in HFD up to 14 months. Body weight, metabolic parameters and behavioral changes were determined at different time points after treatment.

 Results: Intra-CSF administration of AAV-FGF21 allowed specific overexpression of FGF21 in the CNS, without an increase in FGF21 circulating levels. Brain FGF21 expression resulted in normalization of body weight, adiposity, adipose tissue inflammation and hepatic steatosis and fibrosis. Moreover, AAV-FGF21 treatment counteracted HFD-induced insulin resistance, glucose intolerance and islet hyperplasia. This was parallel to enhanced energy expenditure resulting from FGF21 signaling in the CNS. Moreover, brain FGF21 expression also counteracted obesity-associated cognitive decline, prevented short-term and long-term memory loss, improved learning capacity and decreased anxiety-like behavior.

Conclusion: All these results underscore the potential of brain-directed AAV-FGF21 gene therapy to treat obesity, insulin resistance, T2D, and associated cognitive decline.

Disclosure

F. Bosch: None. V. Sacristan: None. A. Ribera: None. C. Jambrina: None. V. Jimenez: None. E. Casana: None. X. Leon: None. G. Elias: None. T. Ferre: None. S. Franckhauser: None. I. Elias: None.