GI Dynamics Research Articles

7255 Tirzepatide Helps Achieve Glycemic Control and Lower Triglycerides in Seven Patients with Lipodystrophy

Abstract Disclosure: R. Meral: None. E.D. Frontera: None. M. Celik Guler: None. M.C. Foss de Freitas: None. N. Nachawi: None. D.T. Broome: Consulting Fee; Self; Tayco, Inc.. Research Investigator; Self; Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals. S.I. Taylor: None. E.A. Oral: Advisory Board Member; Self; Amryt, Regeneron Pharmaceuticals. Consulting Fee; Self; Regeneron Pharmaceuticals, Amryt, Third Rock Ventures. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt. Research Investigator; Self; Novo Nordisk, Fractyl, Ionis Pharmaceuticals Inc., GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt. Lipodystrophy encompasses a group of rare disorders associated with severe metabolic disease. These disorders are defined by abnormal distribution of fat, with near-total (generalized lipodystrophy, GL) or partial (partial lipodystrophy, PL; i.e. familial partial lipodystrophy, FPLD) absence of adipocyte mass leading to a decreased ability to store triglycerides safely. Excess triglycerides are more likely to be stored in ectopic tissues such as hepatocytes, which leads to the metabolic manifestations of the disease state. Patients with GL have near absent levels of leptin hormone and leptin replacement therapy leads to dramatic improvement, which has mainly been attributed to a reduction in caloric intake. Patients with PL are not as leptin deficient and their response to leptin replacement therapy has been variable. We hypothesized that the clinical use of tirzepatide in patients with lipodystrophy may lead to favorable outcomes through the reduction of caloric intake. We closely observed 7 patients who were prescribed tirzepatide for their diabetes with information presented respectively [Age: 44; 54; 34; 53; 44; 46; 38 years | Sex: F; F; F; F; F; M; F | Subtype: FPLD type 1; FPLD type 2; FPLD type 1; Acquired GL; FPLD type 2; FPLD type 1; FPLD type 3]. At baseline, all patients had poor control of their disease despite aggressive medical therapy (except patient #5). Follow-up durations varied due to the observational nature of the study [follow-up duration (months): 6; 12; 7; 3; 8; 9; 5]. Reductions in A1c, triglycerides, and body mass index (BMI) were observed [A1c (%): 13.4->7.1; 7.1->6.6; 7.6->5.2; 8.7->6.9; 5.4->5.1; 8.9->7.8; 9.7->7.1 | triglycerides (mg/dL): 539->339; 164->109; 367->NA; 151->113; 388->101; 459->319; 4081->259 | BMI (Kg/m2): 25.0->24.5; 30.6->28.3; 37.7->33.9; 22.8->20.9; 27.6->23.4; 40.1->37.9; 24.0->24.9]. Those who were on insulin had decreased daily requirements [total daily insulin requirement (units): 160->25; 82->18; not on insulin; 85->0; not on insulin; 280->200; 124->111]. All patients reported a reduction in their daily food intake. Treatment related complications were limited to known gastrointestinal issues which the patients rated as tolerable. Based on our results, a randomized controlled trial to test the efficacy of tirzepatide in patients with lipodystrophy may be warranted. Presentation: 6/3/2024

6989 Novel Use of Dual GIP/GLP-1 Receptor Agonist in HNF4A-MODY

Abstract Disclosure: A. Mehdi: None. M.C. Foss de Freitas: Advisory Board Member; Self; PTC Pharmaceuticals. Other; Self; Scientific presenter in a symposium funded by Amryt Pharmaceuticals. C.L. Martin: None. B.E. Gregg: None. N. Nachawi: None. E. Frontera: None. E.A. Oral: Consulting Fee; Self; Amryt Pharmaceuticals, Akcea Therapeutics, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals. Grant Recipient; Self; Amryt Pharmaceuticals (now part of Cheisi, manufacturer of metreleptin), Akcea Therapeutics, Ionis Pharmaceuticals Inc., Regeneron Pharmaceuticals, Novo Nordisk, Rhythm Pharmaceuticals, Fractyl Laboratories, GI Dynamics (now Morfic Medical. Other; Self; Royalty rights from the use of Metreleptin in lipodystrophy. W.H. Herman: Advisory Board Member; Self; Member of the Data Safety and Monitoring Board for Merck Sharp & Dohme, LLC, Memer of the Data Safety and Monitoring Board for Rivus Pharmaceuticals. Other; Self; Chair for the National Committee for Quality Assurance (NCQA) Healthcare Effectiveness Data and Information Set (HEDIS) Workgroup. D.T. Broome: Consulting Fee; Self; Tayco, Inc. Research Investigator; Self; Novo Nordisk, Fractyl Laboratories, Rhythm Pharmaceuticals, Inc. HNF4A-MODY (formerly MODY-1) is an autosomal dominant form of diabetes caused by a mutation in the transcription factor HNF4A[1],2. Affected patients are initially very sensitive to the anti-hyperglycemic effect of sulfonylureas, but become unresponsive to sulfonylureas at a rate of 1-4% per year3. Recently, the efficacy of glucagon-like peptide-1 receptor agonists has been demonstrated in HNF4A-MODY2, but there have been no reports on the use of dual gastric inhibitory polypeptide/glucagon-like peptide-1 receptor agonists (dual GIP/GLP-1 RA) in HNF4A-MODY. This report describes a patient with HNF4A-MODY who was treated with a dual GIP/GLP-1 RA. A 42-year-old White male with a pathogenic heterozygous mutation in Q268X was diagnosed with HNF4A-MODY at the age of 10 years (part of the RW pedigree)3. He was diagnosed with diabetes at age 20, treated with metformin from age 20 to age 30, and had glipizide extended release added at age 30. His dose of glipizide was titrated over 9-years to the maximum therapeutic dose. At the age of 40, when his HbA1c was no longer controlled, dulaglutide 1.5 mg once weekly was added. Thereafter, his HbA1c was well controlled between 5.5-7.0%, until it increased to 7.7%. He was then transitioned from dulaglutide to tirzepatide 5 mg once weekly for 4 weeks, 7.5 mg once weekly for 4 weeks, then 10 mg once weekly. He has been maintained on tirzepatide 10 mg once weekly, glipizide extended release 10 mg once daily, and metformin 1,000 mg twice daily without significant side effects. His HbA1c improved from 7.7% to 5.8% and he lost 7 lbs since transitioning from dulaglutide to tirzepatide (while on tirzepatide for 4 months in total). During his recent visit, he was without significant hyper- or hypoglycemia and his BMI was 31.2 kg/m2. (down from 32.32 kg/m2). To our knowledge, this is the first case report demonstrating preliminary efficacy of dual GIP/GLP-1 receptor agonist in HNF4A-MODY. While it is known that GIP and GLP-1 can cause glucose stimulated insulin secretion, and the mechanism of GLP-1 was previously described in MODY4, the differential effects and/or predominance of GIP or GLP-1 in MODY requires further investigation.

7380 Qualitative Interviews Describing the Patient Experience of Individuals with Generalized Lipodystrophy Enrolled in a Clinical Trial of Mibavademab

Abstract Disclosure: S. Martin: Other; Self; Employee of RTI Health Solutions, an independent nonprofit research organization retained by Regeneron Pharmaceuticals, Inc. to conduct this research. Compensis unconnected to the studies they work on. K. Kosa: Other; Self; Employee of RTI Health Solutions, an independent nonprofit research organization retained by Regeneron Pharmaceuticals, Inc. to conduct this research. Compensis unconnected to the studies they work on. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Garg: Consulting Fee; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals, Third Rock ventures, Kyttaro, Cello Health, Health Advances. Grant Recipient; Self; Aegerion Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Amryt, Ionis Pharmaceuticals Inc. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt Pharmaceuticals, Ionis Pharmaceuticals Inc., Gemphire Therapeutics. Other; Self; Amryt Pharmaceuticals, Novo Nordisk, Rhythm Pharmaceuticals, Fractyl Laboratories, GI Dynamics. I. Yildirim Simsir: None. R.J. Brown: Other; Self; Regeneron Pharmaceuticals. S. Ozen: None. O. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Srinivasan: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by near-total lack of adipose tissue and, consequently, low levels of serum leptin. Mibavademab (REGN4461) is an investigational human monoclonal agonist antibody of the leptin receptor. As part of the phase 2, randomized, double-blind, placebo-controlled study (NCT04159415) of mibavademab, we conducted exit interviews to gather patient experience data specific to GLD and changes experienced during the study. Methods: Between week 52-54, experienced interviewers conducted 45-minute in-depth, semi structured, qualitative phone interviews to understand their GLD-related symptoms/signs, perceptions of any improvements experienced during the study as well as the importance of these improvements. Results: Interviews were conducted with 5 females and 2 males, with a mean age of 19.4 (range:15-23). Most participants reported experiencing hunger-related symptoms (n=6), pain, extreme body temperature sensations (n=5 for each), and fatigue or sleep problems (n=4 for each) prior to them starting the study. While we were interested in symptoms, many participants also reported clinical signs, such as enlarged/fatty liver and hyperglycemia (n=5 for each). Pain was most frequently reported as the most bothersome symptom (n=3) prior to the study. All participants who reported having hunger, pain, extreme body temperatures, hyperglycemia, and fatigue before the study reported improvements after 52 weeks of treatment. Participants generally indicated more than a minimal amount of change. For example, of the 5 participants who reported hunger as a symptom prior to the study and who were asked about the amount of change, all reported either “some” (n=1) or “a lot” of improvement (n=4). Participants, overall, rated each improvement, except body temperature as “very important.” Improvements in extreme body temperature were generally rated by participants as “somewhat important.” When asked which of the reported improvements were most important, changes in hyperglycemia was most frequently reported (n=4) followed by improvements in enlarged or fatty liver (n=2) and pain and hunger (n=1 each). All participants reported they were satisfied (n=2) or very satisfied (n=5) with the study treatment. Conclusions: All participants who reported symptoms of hunger, pain, fatigue, and extreme body temperature, or the clinical biomarker of hyperglycemia before entering the study reported improvements in each of these after treatment. In addition, all participants reported being either satisfied or very satisfied with treatment. This qualitative research provides insight into the patient experience for individuals with GLD and provides an opportunity to further understand and complement the clinical trial results. Presentation: 6/1/2024

7654 Unusual Case of Lipodystrophy: A Novel Disease Phenotype?

Abstract Disclosure: M. Celik Guler: None. E.D. Frontera: None. K. Hoose: None. M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. Speaker; Self; Amryt. L. Douyon: None. E.A. Oral: Advisory Board Member; Self; Amryt, Regeneron Pharmaceuticals. Consulting Fee; Self; Regeneron Pharmaceuticals, Amryt, Third Rock Ventures. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt. Research Investigator; Self; Novo Nordisk, Ionis Pharmaceuticals Inc., Fractyl, GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt. Background: Lipodystrophy syndromes (LD) are rare disorders characterized by varying degrees of adipose tissue deficiency that can predispose individuals to severe metabolic complications. Although these syndromes are traditionally subclassified based on inheritance patterns and the degree of adipose tissue loss, patients may exhibit highly heterogeneous clinical presentations. In this context, we report a unique case of partial lipodystrophy with an unusual distribution of adipose tissue that likely represents a novel syndrome and challenges conventional phenotypes. Clinical Case: A 60-year-old Puerto Rican female patient with medical history of type 1 diabetes mellitus (DM), obesity, hyperlipidemia, irritable bowel syndrome, asthma, and coronary artery disease was referred to us for unexplained asymmetric distribution of adipose tissue. She had chronic left posterolateral hip pain and lipoatrophy in her left lower extremity. Her medical history showed that she was born approximately 7 lbs., with no evidence of trauma during delivery. Her mother was given an unknown medication for improving circulation to the placenta. She had a morphea like rash on the arms and chest wall more prominent on the left upper body at birth. In addition, a dimple on her hip was noticed by her mother during the early stages of infancy. Despite the normal progression of neurological development (walking/climbing stairs), she always had a very mild limp. Also, her right arm was always 2 inches larger than her left arm. When she gained weight, she also put on more asymmetric weight on the left side of the abdomen and left lower torso. She had been treated with insulin injections since she was diagnosed with diabetes at the age of 11. She never demonstrated any islet cell specific antibodies. She had a normal weight until pregnancy at the age of 27, during which she gained 20 lbs. Her weight continued to increase over time, and the maximum was 212 lbs. Her examination reveals a BMI of 41.46 kg/m² with excess fat in the right arm, mid-section, left thigh, and left mons pubis. Conversely, only the left leg appears to demonstrate specific fat atrophy, with a near-total loss of adipose tissue starting from the mid-gluteal region. The hip MRI result reported moderate osteoarthritis of the left hip. EMG revealed signs of length-dependent sensorimotor axonal polyneuropathy and long duration/large amplitude motor unit potentials isolated only in the left medial gastrocnemius muscle. Triglyceride level was 73 mg/dL, HbA1c level was 6.8%, with an average total insulin dosage of around 43 IU/day. There was no history of pancreatitis due to hypertriglyceridemia. Conclusion: Our case highlights the heterogeneity of the lipodystrophy spectrum with a novel presentation of lipodystrophy. In addition, there may be homeostatic control of deposition of fat to seek symmetry between upper versus lower and right versus left sided depots. Presentation: 6/1/2024

6889 Potential Impact of Parental Origin of Inheritance in Presentation of Familial Partial Lipodystrophy

Abstract Disclosure: D. Gilio: None. M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. Speaker; Self; Amryt. O. Besci: None. M. Celik Guler: None. A. Neidert: None. I. Yildirim: None. B. Akinci: Advisory Board Member; Self; Amryt. Consulting Fee; Self; Regeneron Pharmaceuticals, Alnylam Pharmaceuticals, Amryt, AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis Pharmaceuticals, Novo Nordisk, Sanofi-Aventis, Servier, Third Rock Ventures. E.A. Oral: Advisory Board Member; Self; Amryt, Regeneron Pharmaceuticals. Consulting Fee; Self; Regeneron Pharmaceuticals, Amryt, Third Rock Ventures. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt. Research Investigator; Self; Novo Nordisk, Fractyl, Ionis Pharmaceuticals Inc., GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt. Background: Familial partial lipodystrophy Type 2 (FPLD2) caused by autosomal dominant LMNA variants is characterized by partial loss of subcutaneous adipose tissue in the limbs, trunk, and gluteal region with accumulation in other parts of the body, such as the face and neck. It is usually associated with different degrees of insulin resistance and hypertriglyceridemia and body composition patterns. We wanted to know the contributing factors for the different metabolic abnormalities and body composition presentations of FPLD2. We hypothesized that parental inheritance line may be a contributory factor to the expression of the metabolic phenotype and body composition characteristics. Methods: We retrospectively collected clinical data of 77 FPLD2 cases from the Divisions of Metabolism and Endocrinology of 3 different sites: the University of Michigan, the University of São Paulo and The Turkish Lipodystrophy Study Group (TuLip). We further selected 53 published cases curated from 15 studies in the literature. For inclusion of the studies, we used web search tools including PubMed, OMIM and Google Scholar. Only patients where we could assess the genetic inheritance were included in this study. Data collected included demographic information, medical history and laboratory results. Results: 79 patients inherited the LMNA variant from the mother (Group 1; 18 males and 61 females), and 51 patients inherited it from the father (Group 2; 14 males and 37 females). The median age at lipodystrophy diagnosis was lower in Group 1 than in Group 2. Diabetes was reported in more than half of the groups; however, the prevalence rates were not significantly different. The mean age (± SEM) at first diagnosis of diabetes was 30 ± 15 years in Group 1 and 32 ± 11 years in Group 2; the microvascular complications were present in 8 patients with diabetes in Group 1 (36.3%) and in 5 patients in Group 2 (23.8%). Both groups' mean triglycerides levels were >150 mg/dL, with a trend of higher triglycerides in Group 2 than in Group 1. Episodes of acute pancreatitis were identified in 9 patients (19.5%) of Group 1 and 10 patients (31.2%) of Group 2; however, patients in Group 1 showed 1.7 episodes of pancreatitis per person while Group 2 showed 8.1 episodes per person on average. The fatty liver disease was the most common liver abnormality identified and it seemed to be more frequent in Group 2 than in Group 1. There was no difference between the two groups in relation to the body mass index (BMI) and the ratio of percent fat mass of the trunk to percent fat mass of the legs (FMR); however, the DEXA (dual x-ray absorptiometry) showed a higher total fat mass in Group 1 compared to Group 2 (22.2 versus 17.3 Kg, p=0.040) in the presence of comparable total lean mass. Conclusion: Our data suggest that there is a difference in body fat mass according to the genetic inheritance, however the metabolic impact is not completely clear and require more detailed analysis. Presentation: 6/1/2024

2541. Steady-state PK of Fixed Dose Dolutegravir+Rilpivirine in Hemodialysis

Abstract Background Fixed dose combination (FDC) dolutegravir (DTG) plus rilpivirine (RPV) is an approved antiretroviral treatment regimen for people with HIV. The steady-state PK of FDC DTG+RPV in those requiring hemodialysis (HD) has not been previously studied. Methods We performed a single-center, prospective evaluation of the steady-state PK of FDC DTG (50mg)+RPV(25mg) in HIV-negative adults either requiring HD (n=4; 2 men, 2 women) or with normal renal function, defined as CrCl ≥ 75mL/min (n=2; 1 man, 1 woman). All participants received DTG+RPV daily for 10-14 days with food before undergoing an intensive 24-hour PK evaluation (performed between dialysis days for those requiring HD). Plasma drug and metabolite concentrations were measured using a validated LC/MS/MS assay method (QTRAP 6500+LC-MS/MS system) with turboelectrospray source operating in both positive (confirmation) and negative (quantification) modes. We did not evaluate dialysis extraction of DTG+RPV. Descriptive PK parameters were calculated. Results No participant experienced serious or grade 3-4 adverse events; there were no study discontinuations. The 4 HD and 2 normal renal function participants were of similar ages (range, 50-60 vs 53-58 years) and BMI (range, 18.5-28.2 vs 20.3-24.0 kg/m2). The Table shows the PK parameters assessed in the study population for circulating plasma DTG, DTG-glucuronide (DTG’s primary metabolite), and RPV. Conclusion In this study, HD did not lead to clinically appreciable differential exposures to DTG and RPV; the markedly increased exposure to DTG-glucoranide (which is considered inert) in HD suggests increased UGT1A1 activation. All participants maintained exposures throughout the dosing interval greater than the reported IC90 efficacy values for DTG (64ng/mL) and RPV (12ng/mL). These data suggest no dosing modifications are needed for the FDC DTG+RPV regimen in HD. Disclosures Samir K. Gupta, MD, Gilead Sciences: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Allon Friedman, MD, Eli Lilly: Advisor/Consultant|Eli Lilly: Stocks/Bonds|GI Dynamics: Advisor/Consultant|Gila Therapeutics: Advisor/Consultant

FRI069 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Weight And Associated Comorbidities In Congenital Leptin Deficiency

Abstract Disclosure: E. Ozsu: None. L. Akin: None. M. Aydin: None. M. Berberoglu: None. D. Stein: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Altarejos: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron, Third Rock Ventures. Consulting Fee; Self; Third Rock ventures, Regeneron, Amryt Pharmaceuticals. Speaker; Self; Astra Zeneca, Lilly, MSD, Novartis, Novo Nordisk, Sanofi Aventis. E.A. Oral: Advisory Board Member; Self; Third Rock Ventures, Regeneron, Rejuveneate Bio. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron. Grant Recipient; Self; Regeneron, Novo Nordisk, GI Dynamics, Ionis Pharmaceuticals, Fractyl, Rhythm Pharmaceuticals. Other; Self; Amryt Pharmaceuticals. Background: Congenital leptin deficiency (CLD) is a form of extreme obesity caused by biallelic pathogenic variants in the leptin gene. Recombinant human leptin normalizes weight and neuroendocrine/metabolic abnormalities in CLD, however, daily dosing is required with a risk of immunogenicity. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. Case report: A Turkish male infant came to medical attention due to rapid weight gain at 2 months of age and work-up led to identification of homozygous variant in the leptin gene causing CLD. He was treated with Metreleptin for 11 months starting at age 2. When weight regain despite Metreleptin therapy was noted, neutralizing antibody (Nab) was found to be strongly positive. He continued to gain weight rapidly causing impaired mobility, and required nightly oxygen with BIPAP. He was hospitalized frequently with upper respiratory tract infections and needed ICU care four times during the 5th year of his life. At age 5 years and 9 months and body weight of 89.9 kg (BMI SD:5.7), the compassionate use application to use Mibavademab was approved by the local ethics board and the Ministry of Health. The patient received an intravenous loading dose of Mibavademab followed by weekly subcutaneous (SC) administration of Mibavademab. SC dose and diet intake were carefully adjusted based on drug levels, and intended vs. observed weight loss. Results: Weight reduction was first observed in the first week of treatment, which was rapid with an average velocity of 7.1 kg/month until month 7. Upon dose adjustment, velocity decreased to 3.1 kg/month. Weight stabilization was achieved at month 11 at a weight of 28.9 kg (BMI SD:1.0) while using Mibavademab every two weeks. Overall, drug levels were significantly higher than projected in the first 28 weeks and then brought to predicted stable levels upon dose adjustments. Despite the rapid weight loss, improved mobility and age-appropriate growth were observed. There were no signs of precocious puberty. Glucose tolerance, insulinemia, and liver parameters all improved favorably over treatment period and there were no safety signals. The patient discontinued BIPAP treatment and sleep assumed a normal pattern without hypoxia. Conclusions: Compassionate treatment with Mibavademab for up to 60 weeks was associated with improvements in body weight and metabolic parameters, and was well-tolerated in a young child with CLD and Nab against metreleptin. Substantial benefits in mobility, social engagement, and respiratory status were also noted without adverse events. Mibavademab represents a potential new therapeutic option for patients with CLD and this first experience will provide guidance for treatment of similar patients. Presentation: Friday, June 16, 2023

FRI057 Drug Concentrations And Dosing Considerations For Mibavademab, A Novel Leptin Receptor Agonist, In Individuals With Generalized Lipodystrophy

Abstract Disclosure: J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Y. Wang: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B.A. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Advisory Board Member; Self; Regeneron Pharmaceuticals. Consulting Fee; Self; Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Amryt Pharamceuticals, Ionis Pharmaceuticals Inc., Gemphire Theraputics. Research Investigator; Self; Regeneron Pharmaceuticals, Novo Nordisk, Rhythm pharmaceuticals, Fractyl Laboratories, GI Dynamics. Other; Self; Has IP rights to Metreleptin manufactured by Amryt Pharmaceuticals and receives royalty payments. R.J. Brown: Research Investigator; Self; Regeneron Pharmaceuticals. J. Davis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by deficiency of adipose tissue and, consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD causes metabolic abnormalities and complications that are often refractory to treatment with usual glucose/lipid-lowering agents. Mibavademab is a first-in-class human leptin receptor (LEPR) agonist monoclonal antibody that activates LEPR. We investigated baseline serum leptin in patients with GLD, pharmacokinetics (PK) of mibavademab, and soluble LEPR (sLEPR) levels from a phase 2 study. Methods: In this phase 2 trial (NCT04159415), patients with GLD (≥12 yrs old) underwent a single-blind placebo run-in, followed by 1:1 randomization to one of two fixed sequence arms: Treatment A (placebo for 8 weeks, then mibavademab low dose for 8 weeks, then mibavademab high dose for 20 weeks) or Treatment B (mibavademab low dose for 8 weeks, then mibavademab high dose for 28 weeks). A loading dose of intravenous mibavademab was administered before low-dose treatment. Mibavademab and sLEPR concentrations in serum were serially measured during mibavademab treatment using validated bioanalytical methods. Results: Sixteen patients were enrolled with median body weight (BW) of 51 kg, corresponding to the approximate BW cut point for mibavademab. Baseline serum leptin was below the lower limit of quantitation (0.078 mg/L) in 5 patients with a median concentration of 0.345 mg/L (n=15). Baseline sLEPR concentrations with Treatments A and B were 30.6 and 33.9 μg/L, respectively. At Week 8, mean (SD) mibavademab trough concentrations (Ctrough) with Treatments A and B were 0 (0) and 1.61 (1.71) mg/L, respectively. Low-dose PK were less than predicted from a first in human study in healthy volunteers with higher leptin levels, reflecting higher target mediated clearance in patients with GLD. At Week 16, Ctrough for Treatments A and B increased to 2.31 and 43.0 mg/L, respectively, but were still below predicted. At Week 36, Ctrough for Treatments A and B were 60 (35.3) and 67.7 (44.2) mg/L, respectively. Clinically meaningful metabolic benefit (i.e reflected by reductions in fasting triglycerides and glycated hemoglobin) was observed at Week 36 with both Treatments A and B. Conclusions: Mibavademab concentrations by Week 36 were associated with clinically meaningful improvement in metabolic parameters. Presentation: Friday, June 16, 2023

51-OR: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study of BI 456906 in People with Overweight/Obesity

Glucagon receptor (GCGR) agonism increases energy expenditure and glucagon-like peptide 1 receptor (GLP-1R) agonism reduces energy intake; thus, dual GCGR/GLP-1R agonists, such as BI 456906, may be more effective at treating obesity than mono GLP-1R agonists. This dose-finding study tested efficacy and safety of BI 456906 in participants (pts) with overweight/obesity. This double-blind, placebo (PBO)-controlled study (NCT04667377) randomised adults with BMI ≥27 kg/m2 to weekly subcutaneous BI 456906 (0.6, 2.4, 3.6, 4.8 mg) or PBO for 46 weeks (thereof 20-week (W) rapid, bi-weekly dose escalation; 26-W maintenance). Primary endpoint was bodyweight (BW) change (%) from baseline (BL) at W46. Secondary endpoints included proportion of pts reaching ≥5, ≥10 or ≥15% BW loss from BL at W46. In total, 387 pts were randomised (treated set [TS], N=386; full analysis set [FAS], N=384; n≈77 per arm). At BL (FAS) mean age was 49.1 years, BW 105.7 kg and BMI 37.1 kg/m2; 31.8% of pts were male. BI 456906 therapeutic benefit vs PBO was shown by a non-flat dose response curve of BW change (%) from BL at W46. Mean BW reduced with dose over 46 weeks (FAS; 0.6 mg, −6.2%; 2.4 mg, −12.5%; 3.6 mg, −13.2%; 4.8 mg, −14.9%; vs PBO, −2.8%). At W46, BW loss (FAS) of ≥5, ≥10 and ≥15% was reached by 82.8%, 68.8% and 54.7% of 4.8 mg BI 456906 pts and 25.9%, 11.1% and 5.6% of PBO pts, respectively. Pts reaching and staying on 4.8 mg BI 456906 achieved BW loss of 18.7% at W46. Adverse events (AEs) were reported by 90.9% of BI 456906 pts (TS; 0.6 mg, 90.9%; 2.4 mg, 89.7%; 3.6 mg, 92.2%; 4.8 mg, 90.9%) and 75.3% of PBO pts, mainly gastrointestinal (TS; 0.6 mg, 57.1%; 2.4 mg, 85.9%; 3.6 mg, 75.3%; 4.8 mg, 81.8%; PBO, 41.6%); 24.6% of BI 456906 pts and 3.9% of PBO pts stopped treatment, mainly during dose escalation. Serious AE incidence was similar in BI 456906 and PBO pts (TS; 0.6 mg, 1.3%; 2.4 mg, 2.6%; 3.6 mg, 7.8%; 4.8 mg, 5.2%; vs PBO, 6.5%). Over 46 weeks, BI 456906 showed substantial BW loss efficacy with no unexpected safety concerns. Disclosure C.Le roux: Advisory Panel; Novo Nordisk, Boehringer Ingelheim Inc., Lilly, Herbalife International of America, Inc., Johnson & Johnson, Medtronic, GI Dynamics, Keyron Ltd. O.Steen: None. K.J.Lucas: None. E.Startseva: Employee; Boehringer Ingelheim International GmbH. A.Unseld: None. A.M.Hennige: Employee; Boehringer Ingelheim International GmbH. Funding Zealand Pharma A/S; Boehringer Ingelheim

1708-P: Comparing 9- vs. 12-Month Implantation in the Worldwide EndoBarrier (EB) Registry

Uncertainty exists re risk: benefit of proximal intestinal exclusion with EB, a novel endoscopic duodenal jejunal liner device for obesity, both with and without diabetes. In view of this, during 2017, an independent, secure, on line registry was established under the auspices of the Association of British Clinical Diabetologists, for the collection of safety and efficacy data worldwide. As of December 2022, data had been entered on 1022 patients, of whom 195 (age 51.6±10.3 years, 53% male, 81% white ethnicity, BMI 39.9±6.9kg/m2) had both 9- and 12-month data entered. EB had considerable impact on weight and HbA1c (Table). There was no difference between the mean±SD reduction in HbA1c or weight at 9- vs 12-months (HbA1c: 1.39±1.67% vs 1.38±1.66% (p=0.98); weight: 11.7±8.3kg vs 12.0±8.3kg (p=0.44). The higher the HbA1c the greater the fall but again no difference between 9- and 12-months (Table). In the full registry, 43/1022 (4.2%) experienced serious adverse events (SAE). 15/43 (34.9%) SAE would have been avoided by removal at 9-months (9 liver abscess, 4 GI bleed, one cholecystitis). It was particularly noteworthy that 9/13 (69.2%) liver abscess SAEs would have been avoided by removal at 9-months. This international data from the EB registry suggests that the benefits of EB are achieved in 9-months and a reduction in the recommended implantation period from 12- to 9-months would reduce SAEs, especially the liver abscess SAE. Disclosure R.E.Ryder: Other Relationship; Novo Nordisk, Speaker's Bureau; GI Dynamics, BioQuest. J.J.Mcmaster: None. J.Chisholm: None. L.Kow: None. J.C.Mason: None. R.V.Cohen: Advisory Panel; GI Dynamics, Research Support; Medtronic, Johnson & Johnson Medical Devices Companies. P.Sen gupta: Other Relationship; Novo Nordisk. M.Yadagiri: None. L.Munro: None. H.Frydenberg: None. S.Fishman: None. J.P.Byrne: Advisory Panel; Oxford Medical Products, Join Embla, Stock/Shareholder; Join Embla. J.P.Teare: None. C.De jonge: None. J.Greve: Advisory Panel; GI Dynamics. Funding Association of British Clinical Diabetologists

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

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

313-OR: The Efficacy and Safety of Glucagon-Like-Peptide-1 Agonists in Patients with Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPLD) syndromes are a rare group of conditions with abnormal fat distribution and deposition of fat in ectopic tissues such as liver and muscle, leading to challenging metabolic abnormalities. Glucagon-like peptide-1 receptor agonists (GLP1R-A) are used for management of other metabolic dysfunction, but their efficacy in FPLD syndromes is not known. In this retrospective EMR review, we evaluate the effect of GLP1R-A for DM management in patients with FPLD for whom there are no approved treatments in the US. We collected data from 17 patients with FPLD (age 58 ± 12; 76.47 % females) and 17 patients with type 2 DM (age 58 ± 13; 71% females) before and 6 months after starting GLP1R-A. Only cases where the sole change was the addition of GLP1R-A were included in the analyses. Reduction in weight (p=0.002), BMI (p=0.001), HbA1c (p=0.02), and fasting glucose (p=0.04) (Figure 1A-D) were observed in patients with FPLD. Only the change in triglycerides after six months of treatment was greater in patients with FPLD compared to patients with DM (p=0.02, 95%CI: 13.6 to 215.8) (Figure 1E). Overall, there were no differences in changes in other parameters, and no serious events were reported. However, we observed acute pancreatitis in two cases with FPLD with longer therapy. Our study demonstrates the relative safety and effectiveness of GLP1R-A in patients with FPLD for the first time. Disclosure S.K.Imam: None. M.C.Foss-freitas: None. R.Meral: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. A.Dill gomes: None. F.Grissi: None.

989-P: Glycaemic Control, Hypoglycaemia Unawareness, and Diabetes-Related Distress in Middle-Old (75 to 85 Years), and Old-Old (>85) before and after Flash Glucose Monitoring in People Living with Diabetes—Association of British Clinical Diabetologist Study

Introduction: There are limited data on the effect of intermittently scanned flash glucose monitoring (isCGM) on glycaemic control, hypoglycaemia unawareness and diabetes-related distress in middle-old (75 to 85 years) and old-old (≥85) people living with diabetes Methods: Clinicians were invited to submit isCGM data to a secure web-based tool held within the National Health services N3 network. We collected baseline data before FSL initiation, such as patient demographics, glycated haemoglobin (HbA1c) values from the previous 12 months, Gold score and Diabetes Distress Screening scale (DDS2) score. We compared the baseline clinical characteristics across the age categories using a t-test. All the analyses were done in R 4.1.2. Results: The study consisted of 16997 people with Type 1 diabetes with baseline and follow-up data, of which 342 were classified as middle-old, and 50 were classified as old-old (94% T1D). The use of isCGM was associated with significant improvement in Gold score in both middle-old (3.54 at baseline vs 3.02 at follow-up, P=0.04) and old-old populations (4.04 at baseline vs 2.72 at follow-up, P=0.01). The use of isCGM was also associated with significant improvement in DDS2 scores in both middle-old (2.53 at baseline vs 2.02 at follow-up, P<0.001) and old-old populations (2.40 at baseline vs 1.73 at follow-up, P<0.01). However, there was no significant effect of isCGM on glycaemic control in middle-old (64.2 mmol/mol at baseline vs 65.2 mmol/mol at follow-up, P=0.45) and old-old populations (60.3 mmol/mol at baseline vs 66.6 mmol/mol at follow-up, P=0.05). Conclusion: The use of isCGM was associated with significant improvement in diabetes-related distress and hypoglycaemia unawareness in middle-old and old-old people living with diabetes but did not affect glycaemic control in this population. Disclosure H.Deshmukh: None. E.G.Wilmot: Advisory Panel; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Roche Diabetes Care, Embecta, Consultant; Springer Healthcare, Research Support; Abbott Diabetes, Diabetes UK, Insulet Corporation, Novo Nordisk, NIH - National Institutes of Health, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Ypsomed AG, Glooko, Inc. C.Walton: None. R.E.Ryder: Other Relationship; Novo Nordisk, Speaker's Bureau; GI Dynamics, BioQuest. T.Sathyapalan: Other Relationship; Novo Nordisk, Abbott Diabetes, Research Support; Abbott Diabetes, Novo Nordisk, Eli Lilly and Company.

907-P: Glycaemic Outcomes Associated with Omnipod DASH Use in the Real World—Results from the Association of British Clinical Diabetologists (ABCD) Omnipod Worldwide Audit

Introduction: The ABCD Omnipod® Worldwide Audit launched in 2021 with the aim of capturing routine clinical outcomes from users in the real-world. This analysis reports glucose outcomes, including comparisons between pump-naïve and established pump-users starting on Omnipod DASH® Insulin Management System. Methods: Individuals were included in the analysis if relevant baseline and follow-up data were available. Change in HbA1c, time-in-range (TIR, 70-180mg/dL), time below range (TBR, <70mg/dL) and total daily dose of insulin were assessed using paired T-tests. For glucose outcomes, stratified analyses were performed to compare the outcomes between those new to pump therapy (“new”) and those already established (“established”). Results: Over a median follow-up of 2.3years (IQR 1.2-3) we included 235 individuals from the UK with baseline mean±SD HbA1c 8.1±1.4%; age 36.0±16.5years; diabetes duration 21.7±14.9years; 34.0% (n=82/235) were new to pump therapy. Across the whole population HbA1c reduced by 0.3% (95%CI 0.1, 0.5; P<0.01). Stratified by previous therapy, HbA1c reductions were statistically significant in the “new” group (0.5%; 95%CI 0.1, 0.8; P=0.01). TIR, TBR and HbA1c levels were maintained in those in the “established” group. Total daily dose decreased from 41.4units to 36.9units (-4.4; 95%CI 0.8, 8.1; P=0.018) between baseline and follow-up. Of those asked to rate on a 7-point Likert scale, 82/84 (97.6%) stated Omnipod DASH had improved their quality of life and 83/86 (96.5%) would recommend the system to other people with diabetes. Conclusion: In individuals new to pump therapy, Omnipod DASH is associated with clinically meaningful reductions in HbA1c, reduced insulin requirements and improved quality of life. Individuals switching to Omnipod DASH from other pumps maintained previous HbA1c levels, TIR and TBR. Disclosure T.S.J.Crabtree: Speaker's Bureau; Abbott Diabetes, Novo Nordisk, Lilly, Sanofi, Insulet Corporation. E.G.Wilmot: Advisory Panel; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Roche Diabetes Care, Embecta, Consultant; Springer Healthcare, Research Support; Abbott Diabetes, Diabetes UK, Insulet Corporation, Novo Nordisk, NIH - National Institutes of Health, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Ypsomed AG, Glooko, Inc. M.Haq: None. N.Hasan: None. D.M.Williams: None. E.R.Gatdula: None. E.Chinnasamy: None. J.Varghese: None. G.Modgil: None. R.E.Ryder: Other Relationship; Novo Nordisk, Speaker's Bureau; GI Dynamics, BioQuest. Funding Insulet Corporation

193-LB: Refining Diabetes Risk for Individuals with Prediabetes

Rate of progression from prediabetes to diabetes varies greatly, and better risk stratification would help guide prevention efforts. We evaluated predictors of incident diabetes in the placebo arm (n=1212) of the vitamin D and type 2 diabetes (D2d) study. At baseline, participants met 2 or 3 ADA glycemic criteria for prediabetes (fasting glucose, FPG, 100-125mg/dL; 2-hour glucose during a 75-g OGTT, 2hPG, 140-199 mg/dL; HbA1c, 5.7-6.4%). Diabetes was diagnosed based on semiannual testing. After a median follow up of 2.5 years, 27% met criteria for diabetes. Among those who did and did not develop diabetes, mean BMI (±SD) was similar (32.1 kg/m2 ± 4.4), as well as other demographic factors including age, race, and ethnicity. More men than women developed diabetes (29% vs 23%, p=0.02). Incident diabetes rates differed by prediabetes subgroups (Figure); and those meeting all three prediabetes criteria at baseline (35.4%) were most likely to develop diabetes (log-rank p <0.001). There were no differences in the incident diabetes rate among those people meeting only 2 of the prediabetes criteria (Figure). Also, area under the receiver operator characteristic curves for incident diabetes at 36 months increased when all 3 criteria were used in the diagnosis (0.736) vs only FPG and HbA1c (0.686). We conclude that ‘prediabetes’ is heterogeneous, and the 2hPG may refine diabetes risk and guide intervention strategies in adults with high-risk prediabetes. Disclosure S. H. Kim: Advisory Panel; GI Dynamics, Consultant; Aligos, Research Support; Fractyl Health, Inc. D. S. Hsia: None. E. S. Leblanc: Other Relationship; Dexcom, Inc. M. Staten: None. R. Chatterjee montgomery: Research Support; Bristol-Myers Squibb Company, Epigenomics AG. N. Rasouli: Research Support; Novo Nordisk, Eli Lilly and Company, Somalogic. V. R. Aroda: Consultant; Applied Therapeutics Inc., Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Applied Therapeutics Inc., Eli Lilly and Company, Fractyl Health, Inc., Novo Nordisk, Sanofi. A. G. Pittas: None. Funding National Institutes of Health (U01DK098245)

372-OR: Long-Term Outcomes of Metabolic Surgery vs. Medical/Lifestyle Therapy on Nonalcoholic Fatty Liver Disease in Adults with Obesity and Type 2 Diabetes

Introduction: Data are lacking on the long-term effects of metabolic surgery vs medical intervention on NAFLD in patients with obesity and T2D. Methods: A multi-center, prospective, observational study was performed with adults enrolled in the Alliance of Randomized trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium. Patients with BMI 27-45 kg/m2 were randomized to medical therapy or surgery with gastric sleeve (GS), gastric band (GB), or Roux-en-Y gastric bypass (RYGB). The hepatic steatosis index (HSI), FIB-4 index, and AST-to-platelet ratio index (APRI) were calculated at baseline and follow-up at 6-15 years then compared by intention-to-treat analysis. Results: We enrolled 262 patients, 49.9±8.3 yrs, 68.3% female, 67.2% white, HbA1c 8.5±1.5%, BMI 36.4±3.5 kg/m2. Liver steatosis was 100% positive by HSI. Fibrosis was rare by FIB-4 (<1% advanced, 16.7% at-risk) and APRI (5.0% significant or severe). Steatosis and fibrosis rates did not differ between patients when randomized to medical (N=96) or surgical (N=166) therapies (GB N=36, GS N=41, RYGB N=89). At latest follow-up, the surgical group had greater decrease in weight (-20.1 vs -11.2 kg, p<0.001), HbA1c (-1.10% vs -0.50%, p<0.001), and greater diabetes remission (16.8% vs 2.2%, p<0.001). Steatosis scores improved in both groups but to a greater extent after surgery (-8.5 vs -4.9, p<0.001). Fibrosis scores were stable even though patients were 6-15 years older and values did not differ between surgical vs medical groups (FIB-4 -0.01 vs -0.02, p=0.77; APRI -0.04 vs -0.01, p=0.60). Conclusion: Hepatic steatosis scores improved more in patients with T2D randomized to metabolic surgery vs medical management. Fibrosis scores did not worsen as would be expected with aging, suggesting a protective effect of both surgical and medical interventions. These results support a continued role for weight loss interventions to prevent and treat NAFLD. Disclosure M.D.Lundholm: None. B.Hu: None. J.P.Kirwan: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. D.E.Cummings: None. S.Kashyap: Consultant; GI Dynamics, Research Support; Fractyl Health, Inc., Stock/Shareholder; Gila therapuetics. Armms-t2d consortium: n/a. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK114156)

1463-P: Heterozygous Variant in NFKB1 Presenting with Autoantibody-Negative (AbNeg) Insulin-Dependent Diabetes (IDDM)

Due to its uncertain etiology and clinical management, AbNeg IDDM is a phenotype of interest for the NIH-funded Rare and Atypical Diabetes Network (RADIANT), which aims to identify and characterize people with unknown forms of diabetes (DM). We report a case of childhood-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. A 17-year-old female presented with DM at age 7 with A1c 10.8%; random C-peptide 0.21 ng/ml; no diabetic ketoacidosis; negative GAD65, insulin, IA-2 and ZnT8 Ab; normal BMI%ile; no signs of insulin resistance; and negative genetic testing for monogenic DM. She has required continuous insulin therapy. Past medical history: IgA deficiency, vitamin D deficiency, orthostatic intolerance, neurocardiogenic pre-syncope and chronic migraine. Family history: Autoimmune adult-onset DM and hypothyroidism in mother, frequent upper respiratory infections in sisters, Addison’s disease in maternal grandfather, hemochromatosis in paternal grandmother and pericarditis at age 30 in paternal grandfather. Physical exam: Unremarkable. RADIANT Labs: Undetectable serum C-peptide. Negative Ab. Whole genome sequencing: Heterozygous likely pathogenic variant in NFKB1 impacting the canonical splice acceptor sequence (NM_003998.4:c.1753-1G>C). This is a case of youth-onset AbNeg IDDM found to have a likely pathogenic variant in NFKB1. Heterozygous loss-of-function variants in NFKB1 are associated with Common Variable Immunodeficiency (CVID) type 12 (OMIM #616576), characterized by incomplete penetrance and variable expressivity of immunodeficiency and autoimmunity, including features of IDDM. Immune dysregulation may explain lack of classic Ab. There are no prior reports of CVID first ascertained through a DM phenotype. Thus, this case represents a phenotype expansion of NFKB1-associated disease, and contributes to our understanding of the heterogeneity of AbNeg IDDM. Genetic testing of first-degree relatives is underway. Disclosure M.J.Redondo: None. A.Balasubramanyam: None. P.Liu: Other Relationship; Baylor Genetics. A.N.Alkanaq: None. M.Tosur: Advisory Panel; Provention Bio, Inc. N.Ram: None. R.J.Kreienkamp: None. E.A.Oral: Advisory Panel; Amryt Pharma Plc, Regeneron, Rejuvenate Bio, Third Rock Ventures, Consultant; Amryt Pharma Plc, Ionis Pharmaceuticals, Regeneron, Other Relationship; Amryt Pharma Plc, Research Support; Amryt Pharma Plc, Novo Nordisk, Fractyl Health, Inc., Ionis Pharmaceuticals, Regeneron, GI Dynamics, Rejuvenate Bio. C.Pihoker: None. J.Posey: None. Funding National Institutes of Health (U54DK118638)

Bariatric endoscopic antral myotomy: first-in-human proof of concept of a novel therapeutic method to delay gastric emptying and induce weight loss

Bariatric endoscopic antral myotomy: first-in-human proof of concept of a novel therapeutic method to delay gastric emptying and induce weight loss

1151-P: Improved Liver Steatosis Scores in T2DM after Randomization to Bariatric Surgery Related to Improvement in Insulin Sensitivity and Cardiometabolic Risk

NAFLD is common in T2DM, linked to insulin resistance and beta-cell dysfunction, and can be assessed with validated liver scores for steatosis and fibrosis. The longitudinal impact of weight loss with or without bariatric/metabolic surgery (BMS) on NAFLD in T2DM is not clear. Patients with T2DM (N=52, age 48±9 yrs, 30 (58%) female, BMI 36.3±2.9 kg/m2, T2DM duration of 8.3±5.0 yrs, A1c 9.7±1.7%) were randomized to intensive medical therapy (IMT, n=15) alone or IMT with laparoscopic Roux-en-Y gastric bypass (RYGB, n=18) or sleeve gastrectomy (SG, n=19) . The hepatic steatosis index (HSI) , NAFLD/liver fat score, FIB-4 index, and AST-to-platelet ratio index (APRI) were calculated at baseline and 24 months and correlated to baseline and change in weight, body fat percent (assessed with iDXA) , insulin sensitivity, beta-cell function (DI) and adipocytokine measurements during mixed meal tolerance testing. Baseline steatosis liver scores were abnormal in 52 patients (100%) by HSI and 38 (73%) by NAFLD/LFS. Abnormal liver scores at baseline were correlated with higher HOMA-IR, lower adiponectin levels, and higher blood pressure. At 24 months, HSI only normalized in 10/37 (27%) BMS patients (p=0.046) . NAFLD/LFS normalized in 21/27 (78%) BMS patients and 1/ (9%) medical patients (p=0.001) . Normalization of HSI and NAFLD/LFS were associated with weight and body fat reduction (p<0.001) . Normalization of HSI was associated with improvement in Disposition index (DI) (P = 0.08) , CRP (p=0.001) , and leptin levels (p=0.016) ; change in NAFLD/LFS was associated with HOMA-IR (p<0.001) . Liver steatosis was prevalent in all T2DM undergoing BMS and medical therapy and improved in a majority of subjects who underwent BMS but not IMT. Normalization of liver scores was associated with improvement in body weight, insulin sensitivity, beta-cell function, and markers of CVD risk. These data support the use of liver scores when assessing T2DM for BMS. Disclosure A.Kodali: None. M.D.Lundholm: None. R.Vangoitsenhoven: Speaker's Bureau; Boehringer Ingelheim International GmbH, Goodlife Pharma, Lilly, Mundipharma, Novo Nordisk, Sanofi. J.P.Kirwan: None. A.Aminian: Consultant; Medtronic, Research Support; Medtronic. P.Schauer: Advisory Panel; GI Dynamics, Keyron Ltd., Persona Nutrition, Consultant; Ethicon, Inc., Medtronic, Research Support; Ethicon, Inc., Medtronic, Pacira BioSciences, Inc., Stock/Shareholder; Mediflix, Inc., SE Healthcare LLC. S.Kashyap: Advisory Panel; Fractyl Health, Inc., GI Dynamics, Research Support; Janssen Pharmaceuticals, Inc.

1415-P: Risk–Benefit Data from the Worldwide EndoBarrier (EB) Registry

Uncertainty exists re risk:benefit of proximal intestinal exclusion with EB, a novel endoscopic duodenal jejunal liner device for obesity, both with and without diabetes. In view of this, during 2017, an independent, secure, on line registry was established under the auspices of the Association of British Clinical Diabetologists, for the collection of safety and efficacy data worldwide. As of December 2021, data had been entered on 10patients {age 52.1 ± 10.3 year, 53% male, 87% diabetes, BMI 41.1 ± 8.9 kg/m2} and showed many benefits (Table 1) . There were 43 (4.2%) SAEs and 139 (13.9%) less serious AEs (Table 2) . All SAE patients made a full recovery and most derived significant benefit. The benefits of EB therapy are likely to reduce the complications of diabetes. This international data from the EB registry suggests that the likely benefits of EB, far outweigh the risks Disclosure R.E.J. Ryder: None. J.P. Teare: None. A. Ruban: None. M. Haluzik: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Lilly Diabetes, Novartis AG. L. Munro: None. H. Frydenberg: None. J.J. McMaster: None. S. Fishman: None. R.V. Cohen: Advisory Panel; GI Dynamics. Research Support; Johnson & Johnson, Medtronic. C.M. Aboud: None. G.J. Holtmann: Research Support; AbbVie Inc., Allergan, Arena Pharmaceuticals, Inc., Bayer, Bristol Myers, Datapharm Australia Pty Ltd Commonwealth Laboratories, Pty Limited, Eli Lilly Australia Pty Limited, F.Hoffmann-La Roche Limited, Falk Foundation, Falk GmbH and Co Kg, GI Therapies Pty Ltd, Gilead Sciences Pty Limited, MedImmune Ltd Celgene Pty Limited, Mylan, Nestle Pty Ltd, Prometheus Laboratories, Quintiles Pty Limited, Servatus, Takeda Development Center Asia, Pty Ltd, Vital Food Processors Ltd. C. de Jonge: None. J. Greve: Advisory Panel; GI Dynamics. Other Relationship; Bariatric Solutions International, Ethicon, Inc. J.C. Mason: None. H. Sourij: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk. Research Support; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk. R. Drummond: Research Support; Fractyl Health, Inc. Speaker's Bureau; AstraZeneca, Bristol-Myers Squibb Company. B. McGowan: Advisory Panel; Johnson & Johnson, Lilly, Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; AstraZeneca, Novo Nordisk. Stock/Shareholder; Reset Health. S.A. Amiel: Advisory Panel; Medtronic, Novo Nordisk. Other Relationship; Sanofi. M. Yadagiri: None. P. Sen Gupta: None. K. Laubner: None. J. Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH. Research Support; Boehringer Ingelheim International GmbH. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. Funding Association of British Clinical Diabetologists