bluuebunny/crossref_metadata_2025 huggingface dataset:
80-OR: Association of Nonalcoholic Fatty Liver Disease and Liver Fibrosis with Cardiovascular Disease, All-Cause, and Cause-Specific Mortality in Individuals with Type 2 Diabetes
Authors: XU SHAOYONG , YOU QIQI , LIU LONGFU
Published: June 2024

Introduction & Objective: The presence of NAFLD has been shown to significantly increase the risk of CVD and mortality, but their clarity in individuals with T2DM remains unclear. We aim to explore whether NAFLD and liver fibrosis affect CVD risk, all-cause and cause-specific mortality in individuals with T2DM.

Methods: This population-based cohort analyzed data of 14,990 individuals with T2DM from the UK biobank. NAFLD was identified by fatty liver index (FLI), and liver fibrosis was identified by BARD, Fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS). Cox models were used to estimate the associations of NAFLD and liver fibrosis with CVD, all-cause and cause-specific mortality.

Results: Among 14,990 participants with T2DM (mean [SD] age, 58.7 [7.4] years; 8 237 [54.9%] men), there were 1,429 coronary heart disease, 985 heart failure, 595 stroke and 1,904 deaths. NAFLD was associated with an increased risk of coronary heart disease (HR: 1.65, 95% CI: 1.22-2.23), and a high FLI (quartile 4) was linked to a 110% higher risk of heart failure (95% CI: 1.52-2.90), a 91% higher risk of all-cause mortality (95% CI: 1.54-2.39), and an 83% higher risk of cancer mortality (95% CI: 1.30-2.59). Participants at high risk for fibrosis had a significantly higher risk of all-cause mortality than those at low risk for fibrosis (BARD, HR: 1.65, 95% CI: 1.14-2.38; FIB-4, HR: 1.68, 95% CI: 1.37-2.06; NFS, HR: 1.49, 95% CI: 1.29-1.73). A high risk for fibrosis determined by the NFS and FIB-4 was also linked with higher risks of mortality from CVD (HR: 1.59, 95% CI: 1.17-2.15) and cancer (HR: 1.53, 95% CI: 1.09-2.16), respectively.

Conclusion: These findings suggest that NAFLD and liver fibrosis are associated with elevated risks of major CVD, all-cause and cause-specific mortality in individuals with T2DM. Assessing individuals with T2DM for the presence and progression of NAFLD during clinical consultations is recommended.

Disclosure

S. Xu: None. Q. You: None. L. Liu: None.

Funding

This work was supported by the Key project of Hubei Natural Science Foundation Innovation and Development Joint Fund (Grant number 2023AFD031), and the Science and Technology Research Key Project of Education Department of Hubei Province China (Grant number D20212602).
806-P: Effectiveness of a Hybrid Weight Loss Program for Obesity and Prediabetes Using GLP-1 Medications
Authors: ZAKARIA HALA , CACCELLI MILENA , OZKAN CIGDEM , JAAFAR ZEINAB , SAID YOUSEF , ALEABOVA SOFIA , LABORTE REMIE IRENE A. , HASHEMI ALI , ALMARZOOQI IHSAN
Published: June 2024

Anti-obesity GLP-1 agonists have widely been used by providers without emphasis on behavioral modification due to the short term effectiveness of these medications. The misuse of these medications without any monitored guidance on lifestyle changes can lead to significant weight regain. In this study, we will evaluate newer hybrid care models involving continuous engagement by multidisciplinary care teams on weight loss among those with pre-diabetes.This is a retrospective observational study of medical records for Zone.Health, a 6 months hybrid medicated obesity program, prescribed with both GLP-1 medications and multidimensional lifestyle modification (n=112). Behavioral change aspects of the program, delivered digitally via an app, included an accountability coach, use of food logging, CGM, and involvement of a personal trainer. Anthropometric data were recorded at the beginning and at 3 months. Majority received tirzepatide (51.8%), followed by semaglutide (46.4%), and a 1.8% received liraglutide. 3 months through the program, a significant -7.89 kg (-8.24%) weight loss (p < 0.001) led to a 2.79-unit BMI decrease, including reduced fat mass (5.46 kg, p < 0.001), improved cholesterol, LDL cholesterol, and triglycerides. In pre-diabetic patients (n=33) significant improvements in HbA1c of 0.46% (p < 0.001) were observed leading to remission of all pre-diabetic patients. Weight loss was substantial at -6.85 kg (-6.8%) (p < 0.001), with reductions in fat mass (-5.26 kg, -12.5% p < 0.001). Total cholesterol levels decreased by -16.08 mg/dL (-8.3%) (p = 0.005). The hybrid program resulted in a 16.2% more reduction in weight compared to STEP-2 trial results which involved in-clinic only behavioral change advice.The use of GLP-1 medications delivered in a hybrid mode, demonstrated significant positive changes across all parameters, suggesting the potential of this approach for managing obesity and pre-diabetes using GLPs for more effective changes.

Disclosure

H. Zakaria: None. M. Caccelli: None. C. Ozkan: None. Z. Jaafar: None. Y. Said: None. S. Aleabova: None. R.A. Laborte: None. A. Hashemi: None. I. Almarzooqi: None.
807-P: GLP-1 Agonists and the Risk of Delayed Gastric Emptying in Elective Ophthalmic Procedures
Authors: COOPER AMELIA , LOPEZ ASHLEY , PACAS MIRANDA K. , STEVENS HENRY , MCKAY LISA A. , COOPER BLAKE
Published: June 2024

Introduction & Objective: Concerns arise over delayed gastric emptying with Glucagon-like peptide-1 (GLP-1) receptor agonists in elective procedures. This study, in line with American Society of Anesthesiologists (ASA) guidelines, assesses perioperative effects, including evaluations of ASA scores and surgical outcomes, to address limited evidence highlighted by the ASA Task Force on Preoperative Fasting.

Methods: A three-month prospective chart review of patients undergoing ocular surgery with conscious sedation and a retrobulbar block with specific ASA preoperative instructions. When possible, patients on oral doses were instructed to hold the medication for 24 hours before surgery, while those receiving subcutaneous weekly doses were required to hold medication for one week and adhere to a clear liquid diet for 24 hours before surgery and maintain NPO status after midnight. Independent variables, including preoperative instructions and patient compliance, along with dependent variables such as preoperative blood sugar levels and complications, were analyzed.

Results: The prospective research study involved 20 participants, 6 males (30%) and 14 females (70%), with an average age of 68 years (SD: 9, range 54 to 88). Preoperative instructions were provided to 14 participants (70%), and there was complete compliance among the patients. The mean ASA score was 2.7 (SD: 0.57, range 2 to 4), and average preoperative glucose levels were 122 (SD: 29.4, range 95 to 210). There were no documented cases of aspiration and no difference between individuals who received preoperative instructions and those who did not, concerning glucose levels, coughing, desaturations, and the need for a jaw thrust in both scheduled and emergent surgeries.

Conclusion: Adhering to preoperative ASA guidelines, our results reveal no instances of aspiration despite concerns about delayed gastric emptying, offering insights into the safety and compliance implications of GLP-1 use in this patient group.

Disclosure

A. Cooper: None. A. Lopez: None. M.K. Pacas: None. H. Stevens: None. L.A. McKay: None. B. Cooper: None.
811-P: Safety and Effectiveness of iGlarLixi in People with Type 2 Diabetes Mellitus (T2DM) in South Korea
Authors: KIM HUN-SUNG , MIN KYUNGWAN , SOO KIM SANG , SOOK KIM EUN , CHUNG YOON-SOK , CHUNG CHOON H. , YUN JAE-SEUNG , KIM WON , HAN KIM DONG , JIB YOO SOON
Published: June 2024

Introduction & Objective: The fixed ratio combination of insulin glargine and lixisenatide, iGlarLixi, was indicated as antihyperglycemic for people with T2DM and approved in November 2017 in South Korea. This post marketing surveillance (PMS) study aimed to evaluate the safety and effectiveness of iGlarLixi in clinical practice setting.

Methods: This study was a multicenter, prospective, single-arm, observational study conducted in Korean people with T2DM from August 2018 to August 2023. Primary endpoint was to investigate safety profile. Secondary endpoints included changes in HbA1c, FPG and 2-hour PPG from baseline to Week 12 and 24.

Results: Out of 743 people enrolled, 625 were included in safety evaluation and 519 in effectiveness evaluation. The mean age was 60.9 years and duration of T2DM was 13.6 years with equal proportions of male and female participants. Adverse events (AEs) and adverse drug reactions (ADRs) were reported in 120 (19.2%, 163 events) and 51 (8.2%, 63 events) participants, respectively. Most common AEs were gastrointestinal disorders (6.7%) such as nausea, decreased appetite, and vomiting. Significant reductions in HbA1c, FPG, 2-hour PPG were observed from baseline to Weeks 12 and 24 (Table).

Conclusion: In clinical practice, iGlarLixi has shown to be safe and well tolerated without new safety concerns improving clinical outcomes in people with T2DM in South Korea.

Disclosure

H. Kim: None. K. Min: None. S. Kim: None. E. Kim: None. Y. Chung: None. C.H. Chung: None. J. Yun: None. W. Kim: None. D. Kim: Employee; Sanofi, GlaxoSmithKline plc. S. Yoo: None.

Funding

Sanofi
813-P: Successful Use of Hybrid Closed Loop Insulin Pumps with GLP1 Agonists in Diabulimia and Disordered Eating in Type 1 Diabetes
Authors: BASAVARAJU NAVYA , JONES ANNAMARIE , MOULIK PROBAL
Published: June 2024

Introduction:We present two cases of T1D with binge eating disorder(BED) benefitted by GLP-1 agonists with Hybrid closed loop(HCL) insulin pump(CSII).

Case 1:35-year-old female with T1D, obesity had high diabetes distress score(DDS), fear of hypoglycaemia, and emotional eating. She was on non-HCL CSII (Tandem Diabetes Care t:slim X2™ Insulin Pump), later Dexcom G6® Continuous Glucose Monitoring(CGM) with Control-IQ™ Technology and insulin Lispro for binge eating hyperglycaemia. She was supported by motivational interviewing, commenced Dulaglutide injections. Her food cravings reduced, felt positive about diabetes self-management and insulin requirement reduced by 25%.

Case 2:42-year-old female with T1DM, obesity, poor compliance, multiple diabetic ketoacidosis (DKA), nephropathy, retinopathy, diabulimia, high DDS; was commenced on Dulaglutide injections with HCL CSII (MiniMed™ 780G system with SmartGuard™ technology and Guardian™ 4 CGM). Renal function, quality of life score improved; insulin requirement reduced by 32%

Discussion:GLP-1 agonists with HCL CSII improved patient satisfaction scores, metabolic profile, weight, HbA1c, insulin requirement, blood pressure with no increase in DKA or hypoglycaemia. GLP-1 agonists are beneficial in binge eating without diabetes. Larger studies for complex T1D, diabetes distress, diabulimia may be warranted.

Disclosure

N. Basavaraju: None. A. Jones: None. P. Moulik: None.
817-P: Demographic, Clinical, and Treatment Characteristics of Patients with Timely vs. Delayed Basal Insulin Initiation
Authors: BILLINGS LIANA K. , SHETH SUNNY T. , BRADY BRENNA , RICHARDS MEGAN , RAJPURA JIGAR R. , MITRI JOANNA
Published: June 2024

Introduction & Objective: Basal insulin is indicated for patients with uncontrolled type 2 diabetes (uT2D) after trials of glucose-lowering medications (GLMs). Despite its benefit, it remains underutilized and is often initiated after delay as a last resource. This study examined the demographic, clinical, and treatment characteristics of patients with timely vs delayed basal insulin initiation.

Methods: In the 2011-2018 MerativeTM Claims-EHR Database, adults with uT2D who were candidates for basal insulin (HbA1c>7%, ≥2 GLMs totaling ≥180 days’ supply, no new GLM class in the next 90 days) and newly initiated treatment were selected (index date=first basal insulin fill). Timely and delayed initiators started treatment <6 months and ≥6 months after meeting uT2D criteria, respectively. Patients had ≥12 months of pre- and post-enrollment, no claims for type 1 diabetes or pregnancy, and ≥1 claim for T2D. Demographic, clinical, and treatment characteristics were compared between cohorts.

Results: Among 1,054 (29.2%) timely and 2,561 (70.8%) delayed initiators, mean time from uT2D to basal insulin was 59±55 days and 741±504 days, respectively. Timely initiators were younger and more likely to be female. Delayed initiators used more GLM classes than timely initiators in both pre- and post-periods. Delayed initiators had more HbA1c results in the pre-period (2.1±1.5 vs 1.9±1.2), indicating possible increased monitoring prior to basal insulin initiation, while timely initiators had a significantly larger HbA1c decrease from the pre- to post-periods (-1.3±1.9 vs -1.0±1.8, p<0.001).

Conclusion: Although basal insulin use led to reductions in HbA1c in both cohorts, greater benefits were observed with timely initiation. Patterns of GLM use and HbA1c monitoring suggested delayed basal insulin initiation was associated with more attempts to manage T2D with other GLMs, potentially prolonging exposure to hyperglycemia and increasing lifetime disease management costs.

Disclosure

L.K. Billings: Advisory Panel; Novo Nordisk, Pfizer Inc. S.T. Sheth: Employee; Novo Nordisk. B. Brady: None. M. Richards: None. J.R. Rajpura: Employee; Novo Nordisk. J. Mitri: Advisory Panel; MannKind Corporation. Consultant; Novo Nordisk. Research Support; Kowa Pharmaceuticals America, Inc. Consultant; Lilly Diabetes, Dianomi-. Employee; sequelmedtech. Consultant; AbbVie Inc., beigene-spouse, cellectar-spouse, kite-spouse, Janssen Pharmaceuticals, Inc., loxo-spouse, AstraZeneca.

Funding

Novo Nordisk Inc.
824-P: No Evidence of Increased Physical Activity–Related Hypoglycemia with Once-Weekly Insulin Icodec vs. Once-Daily Basal Insulin in Type 1 Diabetes—ONWARDS 6
Authors: SOURIJ HARALD , BRACKEN RICHARD M. , ASONG MARISSE , CARSTENSEN LISBETH , WATT SARA K. , PHILIS-TSIMIKAS ATHENA
Published: June 2024

Introduction & Objective: ONWARDS 6 compared the efficacy and safety of once-weekly insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with T1D. This post hoc analysis examined physical activity-related hypoglycemia in ONWARDS 6.

Methods: During the trial, participants experiencing hypoglycemic episodes were asked to indicate any relationship to physical activity in a digital diary. Overall hypoglycemia rate was also assessed based on baseline physical activity level recorded using the International Physical Activity Questionnaire.

Results: The proportion of physical activity-related hypoglycemic episodes relative to overall hypoglycemic episodes was similar or lower for icodec vs degludec (Figure A); odds of having physical activity-related level 2 or level 3 hypoglycemia were similar between groups (OR: 1.04; 95% CI: 0.75-1.46; p = 0.8060). Most physical activity-related level 2 or level 3 hypoglycemic episodes did not lead to further hypoglycemic episodes within 24 hrs in either group (Figure B). Overall hypoglycemia rates (including those unrelated to physical activity) were comparable within each group regardless of baseline physical activity level (data not shown).

Conclusion: There was no evidence of increased risk of physical activity-related hypoglycemic episodes with icodec versus degludec in adults with T1D.

Disclosure

H. Sourij: Advisory Panel; Amarin Corporation. Speaker's Bureau; Amgen Inc., Amarin Corporation, Bayer Inc. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Novartis AG. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Sanofi. Speaker's Bureau; Sanofi. Consultant; K:Businesscom. R.M. Bracken: None. M. Asong: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. L. Carstensen: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. S.K. Watt: Employee; Novo Nordisk. A. Philis-Tsimikas: Advisory Panel; Dexcom, Inc., Lilly Diabetes, Novo Nordisk, Sanofi, Medtronic, Bayer Inc.

Funding

Novo Nordisk A/S
829-P: iGlarLixi vs. Basal-Bolus (BB) or Premixed Insulin in Older Adult Ethnic Minorities with Type 2 Diabetes (T2D)
Authors: UMPIERREZ GUILLERMO , GILL JASVINDER , HOOD DAVID , LI XUAN , NÚÑEZ ANA
Published: June 2024

Introduction & Objective: Ethnic minorities and older adults, who are disproportionately affected by T2D, are underrepresented in studies. This retrospective study assessed whether the fixed-ratio combination iGlarLixi improved outcomes vs complex insulin therapies in these populations.

Methods: Medicare claims data were used from African American, Asian, and Hispanic beneficiaries with T2D aged ≥65 years receiving basal insulin who newly initiated iGlarLixi, BB, or premixed insulin from Jan 1, 2019-Dec 31, 2021. Groups were propensity score matched (PSM) at baseline and followed for up to 12 months. The primary endpoint was treatment persistence. Secondary endpoints included treatment adherence and hypoglycemia event rates.

Results: PSM generated 1162 participants/group for iGlarLixi vs BB and 1160 vs premix. For iGlarLixi, persistence was statistically significantly higher, and adherence was numerically higher than BB or premixed insulin in the overall cohort. Hypoglycemia event rates were numerically lower for iGlarLixi vs BB or premixed insulin in the overall cohort. Similar findings were observed in African-American, Asian, and Hispanic groups (Table).

Conclusion: In minority populations with Medicare, iGlarLixi led to higher treatment persistence, numerically higher adherence, and lower hypoglycemia event rates compared to BB or premixed insulin.

Disclosure

G. Umpierrez: Research Support; Abbott, Bayer Inc., Dexcom, Inc., AstraZeneca. Advisory Panel; Dexcom, Inc. J. Gill: Employee; Sanofi-Aventis U.S. D. Hood: Employee; Pfizer Inc. X. Li: Employee; Sanofi. A. Núñez: None.

Funding

Sanofi US
839-P: Treatment Satisfaction and Time in Range (TIR) after 16 Weeks of iGlarLixi in Insulin-Naive Adults with Suboptimally Controlled Type 2 Diabetes
Authors: SHAH VIRAL N. , DEX TERRY A. , MENEGHINI LUIGI , RODRIGUES AMÉLIE , POLONSKY WILLIAM H.
Published: June 2024

Introduction & Objective: A 16-week open-label study (NCT05114590) using blinded continuous glucose monitoring in insulin-naive adults with type 2 diabetes suboptimally controlled on ≥2 oral antihyperglycemic drugs (OADs) ± glucagon-like peptide-1 agonist (GLP-1 RA) showed that once daily iGlarLixi significantly increased TIR (26.2%; P<0.001). We describe patient-reported treatment satisfaction.

Methods: Treatment satisfaction was assessed with the Diabetes Medication Treatment Satisfaction Tool (DM-SAT), a 16-item survey scored from 0 (not at all) to 10 (extremely satisfied) in 4 domains. Association of TIR and overall satisfaction (sum of all items) was also assessed.

Results: In total, 124 people (58.9% males; 70.2% Hispanic/Latino; mean age 55.6 y, A1C 10.2%) were enrolled. At Week 16, there was improvement in overall and all subdomain scores (Table). For individual items, improvement was high for glucose control (+2.9), avoiding glucose highs (+2.7), and feeling in control of diabetes (+2.7). Treatment satisfaction was positively correlated with TIR (r 0.142; 95% CI -0.057, 0.328).

Conclusion: In people with type 2 diabetes suboptimally controlled on ≥2 OADs ± GLP-1 RA, 16 weeks’ treatment with iGlarLixi significantly improved treatment satisfaction, which may be associated with increased TIR.

Disclosure

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. T.A. Dex: Stock/Shareholder; Pfizer Inc. Employee; Sanofi. Stock/Shareholder; Viatris Inc., Teva Pharmaceutical Industries Ltd. L. Meneghini: Employee; Sanofi. A. Rodrigues: Consultant; Sanofi. W.H. Polonsky: Research Support; Abbott Diagnostics, Dexcom, Inc. Consultant; Eli Lilly and Company, Sanofi. Advisory Panel; embecta. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; 9am Health.

Funding

Sanofi US
840-P: Efficacy and Safety of Once-Weekly Insulin Icodec vs. Once-Daily Basal Insulin in Type 2 Diabetes according to Baseline Glucagon-Like Peptide 1 Receptor Agonist Use—ONWARDS 1–5
Authors: VILSBØLL TINA , BANGSGAARD KATRINE O. , FU ARIEL , KELLERER MONIKA , SØGAARD STINNE B. , GOLDENBERG RONALD
Published: June 2024

Introduction & Objective: To assess the treatment effects of once-weekly (OW) insulin icodec (icodec) vs once-daily (OD) basal insulin comparators ± concomitant glucagon-like peptide-1 receptor agonist (GLP-1 RA) use in ONWARDS 1-5.

Methods: A post hoc analysis by trial of insulin-naïve (ONWARDS 1, 3, 5) and insulin-experienced (ONWARDS 2, 4) adults with type 2 diabetes (T2D).

Results: Participants on icodec vs OD comparators had larger or similar A1C reductions from baseline (BL) to end of treatment (EOT) irrespective of GLP-1 RA use; there was no statistically significant treatment by subgroup interaction in A1C changes (Table). Overall rates of clinically significant or severe hypoglycemia were low (<1 event/patient-year of exposure) across arms among ONWARDS 1-3 and 5 subgroups, with numerically lower rates among GLP-1 RA users vs non-users; in ONWARDS 4 (basal-bolus trial), the hypoglycemia rate was similar among GLP-1 RA users vs non-users in the icodec arm (Table). There was no statistically significant treatment by subgroup interaction in any trial for the attainment of A1C <7% without clinically significant or severe hypoglycemia, nor body weight change from BL to EOT.

Conclusion: The efficacy and safety of icodec vs OD comparators was generally consistent among adults with T2D, irrespective of baseline GLP-1 RA use.

Disclosure

T. Vilsbøll: Consultant; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Mundipharma. Advisory Panel; Novo Nordisk, Lilly Diabetes, Sanofi. Speaker's Bureau; Bayer Inc., Gilead Sciences, Inc. Advisory Panel; Sun Pharmaceutical Industries Ltd. Research Support; Lilly Diabetes. K.O. Bangsgaard: Employee; Novo Nordisk A/S. A. Fu: Employee; Novo Nordisk A/S, Novo Nordisk. M. Kellerer: Advisory Panel; Abbott. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Sanofi, GlaxoSmithKline plc, AstraZeneca, Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Novo Nordisk. S.B. Søgaard: Employee; Novo Nordisk A/S. R. Goldenberg: Speaker's Bureau; Bayer Inc., Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company, HLS Therapeutics Inc., Novo Nordisk, Sanofi.

Funding

Novo Nordisk A/S
845-P: The Menin Inhibitor Ziftomenib Induces Insulin Production and Improves Insulin Sensitivity in a Rat Model of Type 2 Diabetes Mellitus (T2DM)
Authors: MCCLOSKEY ASAKO , LIU YAHU A. , WANG XINGJUAN , BURROWS FRANCIS
Published: June 2024

Menin is an epigenetic scaffold protein known to regulate pathogenic gene expression in several cell types. Genetic menin loss (MEN1 Syndrome) is associated with insulinemia due to upregulated pancreatic β-cell proliferation. Ziftomenib is a potent and selective menin inhibitor currently in clinical trials for the treatment of acute leukemias. Zucker Diabetic Fatty rats were used to assess the antidiabetic activity of ziftomenib dosed orally once daily for 27 days. Ziftomenib treatment was well tolerated and rapidly reduced fasting blood glucose (FBG) levels, with normalization of FBG levels observed in most animals within 2 weeks. Ziftomenib also progressively reduced %HbA1C by an average of 1.49% by week 4 (FIG). Oral glucose tolerance tests demonstrated that ziftomenib-treated animals achieved significantly improved postprandial glucose control (P<0.0001). Ziftomenib induced a reduction in HOMA-IR within 1 week, suggesting that one of the effects of menin inhibition is acute sensitization of the animals to insulin. In addition, fasting insulin and c-peptide levels demonstrated that ziftomenib significantly stimulated insulin production at week 3-4 (FIG). These observations suggest that pharmacological targeting of menin may be a viable option to treat both insulin resistance and insulin insufficiency, the two main pathological features of T2DM.

Disclosure

A. McCloskey: None. Y.A. Liu: None. X. Wang: None. F. Burrows: None.
847-P: Berberine Ursodeoxycholate (HTD1801) Improves Key Glycemic and Cardiometabolic Parameters across the Type 2 Diabetes Mellitus Disease Spectrum
Authors: JI LINONG , MA JIANHUA , MA YUJIN , CHENG ZHIFENG , GAN SHENGLIAN , YUAN GUOYUE , LIU DEXUE , LI SHELI , LIU YU , XUE XIA , BAI JIE , WANG KUN , CAI HANQING , LI SHU , LIU KUI , YU MENG , LIU LIPING
Published: June 2024

Introduction: HTD1801 is a gut-liver anti-inflammatory metabolic modulator shown to improve key glycemic and cardiometabolic parameters. The aim of this study was to evaluate the effectiveness of HTD1801 across the T2DM disease spectrum.

Method: In a Ph2 study of treatment-naïve patients with T2DM 113 patients were randomized 1:1:1 to placebo (n=38), HTD1801 500 mg BID (n=37), and 1000 mg BID (n=38) for 12 weeks. Key inclusion criteria included T2DM (WHO criteria), HbA1c 7%-10.5% and FPG <13.9 mmol/L. The primary endpoint was change from baseline (BL) in HbA1c at Week 12. For this analysis, patients were assigned to high/low risk groups by BL HbA1c above/below 8.5%.

Result: At BL, 35% of patients had HbA1c ≥8.5%. BL characteristics were balanced between treatment groups and subgroups. Patients with elevated HbA1c had elevated glycemic and cardiometabolic parameters at BL. Treatment with HTD1801 for 12 weeks resulted in a dose dependent reduction across both subgroups (Table). Improvements with 1000 mg BID were significant vs placebo at Week 12. HTD1801 patients with higher HbA1c had more substantial reductions across all parameters compared to patients with lower HbA1c.

Conclusion: Regardless of BL disease severity, HTD1801 treatment resulted in significant improvements in key glycemic and cardiometabolic parameters. HTD1801 continues to be evaluated for T2DM in Ph3 studies.

Disclosure

L. Ji: None. J. Ma: None. Y. Ma: None. Z. Cheng: None. S. Gan: None. G. Yuan: None. D. Liu: None. S. Li: None. Y. Liu: None. X. Xue: None. J. Bai: None. K. Wang: None. H. Cai: None. S. Li: None. K. Liu: Employee; Shenzhen HighTide Biopharmaceutical Ltd. Stock/Shareholder; Shenzhen HighTide Biopharmaceutical Ltd. M. Yu: Employee; Shenzhen HighTide Biopharmaceutical Ltd. Stock/Shareholder; Shenzhen HighTide Biopharmaceutical Ltd. L. Liu: Employee; Shenzhen HighTide Biopharmaceutical Ltd. Stock/Shareholder; Shenzhen HighTide Biopharmaceutical Ltd.
861-P: Efficacy of Digital Intervention vs. Metformin for Women with Polycystic Ovary Syndrome—A Randomized Clinical Trial
Authors: QU SHEN , DILIMULATI DILIQINGNA , CAI MEILI , ZHANG YUQIN , ZHANG MANNA
Published: June 2024

Objective: To evaluate the efficacy of digital intervention versus metformin treatment for women with polycystic ovary syndrome (PCOS) with insulin resistance (IR).

Methods: A total of 80 women with PCOS with IR were randomly assigned to receive either digital intervention (n = 40) or metformin (n = 40) for 12 weeks. The primary outcomes were the changes in the homeostatic model assessment for insulin resistance (HOMA-IR). Anthropometric parameters, menstruation frequency, sex hormone levels, metabolic factors, body fat distribution, and questionnaires on diet, exercise, sleep, anxiety and depression were obtained.

Results: A total of 72 participants completed the follow-up (90% follow-up rate), including 35 and 37 from the digital intervention and metformin groups, respectively. The HOMA-IR of the digital intervention group was significantly improved after a 12-week of treatment, but no statistical difference was observed between the groups. Both digital intervention and metformin significantly improved menstruation, and reduced body weight and total fat mass. Furthermore, the digital intervention had a significant advantage over metformin in improving waist circumference (WC), waist-hip ratio (WHR), total fat mass, and dehydroepiandrosterone sulfate (DHEAS). In terms of safety, the main adverse events in the digital intervention and metformin groups were sensations of hunger (5%) and gastrointestinal adverse events (30%), respectively.

Conclusion: Our data suggest that digital intervention is an effective treatment option for patients with PCOS, with an efficacy comparable to that of metformin, which can also alleviate the negative effects of medications and make it easier and more efficient to adhere to lifestyle treatments.

Disclosure

S. Qu: None. D. Dilimulati: None. M. Cai: None. Y. Zhang: None. M. Zhang: None.
877-P: Effect of Lobeglitazone, a Novel Thiazolidinedione, on Liver Fat in Patients with Type 2 Diabetes and Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD)—A Randomized Controlled Trial (Lobe-MASLD Trial)
Authors: GADVE SHARVIL S. , GADVE SNEHA S. , GADVE SHRIYA , CHAVANDA KETKI S. , HANAMSHETTI SATISH
Published: June 2024

Objective: Thiazolidinediones reduce liver fat. Older thiazolidinediones including pioglitazone have concerns in use like impact on bone health. Data regarding the effect of lobeglitazone, a novel thiazolidinedione on human liver fat are limited. This study examined effect of lobeglitazone on liver fat in patients with T2DM & metabolic dysfunction-associated steatotic liver disease (MASLD) by using MRI-derived proton density fat fraction (MRI-PDFF).

Research Design & Methods: 80 patients with T2DM & MASLD were randomly assigned to either the lobeglitazone group (standard treatment for T2DM plus lobeglitazone 0.5 mg daily) or the control group (standard treatment without lobeglitazone) for 24 weeks. Patients using sglt2 inhibitors, glucagon-like peptide 1 receptor agonists were excluded. Change in liver fat was measured by MRI-PDFF. Secondary outcome measures were change in alanine transaminase (ALT), aspartate transaminase (AST), and γ-glutamyl transferase (GGT) levels, FIB-4 score.

Results: Lobeglitazone was significantly better at reducing liver fat (mean MRI-PDFF difference between the lobeglitazone and control groups -3.9 %; P = 0.004). Significant reduction was found in the end-of-treatment MRI-PDFF for the lobeglitazone group (15.9% to 12.1%; P = 0.002) and a nonsignificant change was found in the control group (16.0% to 15.4%; P = 0.091). Lobeglitazone group showed significant difference for change in serum ALT level (P = 0.004) and both groups showed nonsignificant differences for AST (P = 0.517) and GGT (P = 0.098) levels and FIB-4 score (P=0.62).

Conclusions: Lobeglitazone reduces liver fat and improves ALT levels in patients with T2DM and MASLD. This benefit was seen even in absence of concurrent use of sglt2 inhibitors or glucagon-like peptide 1 receptor agonists.

Disclosure

S.S. Gadve: None. S.S. Gadve: None. S. Gadve: None. K.S. Chavanda: None. S. Hanamshetti: None.
880-P: Gene Therapy for MODY3 Moving from Mice to Large Animals
Authors: CASANA ESTEFANIA , JIMENEZ VERONICA , GARCIA MIQUEL , LUISA JAÉN MARIA , CASELLAS ALBA , MORRÓ MERITXELL , PUJOL ANNA , FERRE TURA , SACRISTAN VICTOR , JAMBRINA CLAUDIA , LEON XAVIER , FRANCKHAUSER SYLVIE , BOSCH FATIMA
Published: June 2024

Introduction & Objective: Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcription factor hepatocyte nuclear factor 1A (Hnf1α) gene. We have developed a pancreas-directed adeno-associated viral vectors (AAV)-Hnf1α gene therapy, which counteracted hyperglycemia, improved glucose tolerance and enhanced insulin secretion in MODY3 mice. Here, we further explore the benefits of the AAV-Hnf1α treatment in MODY3 mice and the feasibility of the pancreas-mediated gene transfer in large animals for the future translation of this approach.

Methods: AAV-Hnf1α vectors were administered intraductally to MODY3 mice. Biodistribution of vector genomes and Hnf1α expression, and key metabolic parameters were analyzed in these mice. Transcriptomic analysis of islets was also performed. Moreover, healthy beagle dogs were also administered intraductally with AAV vectors, and the AAV biodistribution in the pancreas and other key tissues examined.

Results: Treatment of MODY3 mice with AAV-Hnf1α resulted in vector genome copy number in the pancreas but restricted Hnf1α expression to islets. Moreover, comparative transcriptomic analysis in isolated islets revealed the restoration of the MODY3 pathway genes in treated mice. As a first step towards translation, intraductal delivery of AAV vectors to Beagle dog resulted in efficient transduction of pancreas, including endocrine cells, in the absence of adverse events or toxicities.

Conclusion: These results provide strong evidence of the efficacy of AAV-Hnf1α to treat MODY3 in mice and pave the way moving to the clinic this approach to treat MODY3 patients in the future.

Disclosure

E. Casana: None. V. Jimenez: None. M. Garcia: None. M. Jaén: None. A. Casellas: None. M. Morró: None. A. Pujol: None. T. Ferre: None. V. Sacristan: None. C. Jambrina: None. X. Leon: None. S. Franckhauser: None. F. Bosch: None.

Funding

This work was performed with the support of the Fundació La Marató de TV3 (Project 201603-31-32-33) and by grants SAF2017-86266R funded by Ministerio de Economía, Industria y Competitividad (MINECO), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional(FEDER, EU), Programa Estatal de I+D+i Orientada a los Retos de la Sociedad; grant PID2020-113864RB-I00 funded by MCIN/AEI/10.13039/501100011033, and 2017 SGR 1508, ICREA Academia Award to F.B. from Generalitat de Catalunya, Spain
887-P: The impact of GABAA Positive Allosteric Modulator as Novel First-in-Class Approach for MASH Therapy
Authors: ROHBECK ELISABETH , KOESTER LEONIE , ECKEL JÜRGEN
Published: June 2024

Introduction & Objective: Chronic liver injury represents a pathological wound-healing process. However, there is no approved pharmacological therapy for liver fibrosis. Since GABAergic signaling has been suggested to play a beneficial role in cytotoxic liver injury, we aimed to investigate if the hepatoprotective positive allosteric modulator of the GABAA receptor, HK3, could also ameliorate fibrosis in a human 3D spheroid MASH model. Moreover, AI- and chemoinformatic-based next-generation GABAA modulators will be in our focus as MASH therapeutics.

Methods: Cryopreserved primary hepatocytes and non-parenchymal cells from MASH patients were clustered to spheroids and supplemented with 10 μg/ml insulin (control group) or 10 mg/ml insulin and 240 μM palmitic acid (PA)/ oleic acid (OA) (MASH group) at HepaPredict. The CellTiter-Glo Luminescent Assay kit was used to assess viability for up to two weeks with repeated exposure of HK3. Subsequently, the effects of HK3 (1, 3, and 10 µM) for 1 week on intracellular lipid content were quantified using AdipoRed Assay. Secreted cytokines (IL-6, IL-8) or pro-Collagen type 1α1 were measured in the supernatants using Magnetic Luminex Assay or ELISA. The discovery of new hits was performed through generative AI molecule design and virtual screening with AI and docking simulations.

Results: Acute exposure to HK3 did not result in hepatotoxicity at any concentration. HK3 reduced hepatic lipid content (48%, 46%, and 49%) or pro-COL1A1 levels (82%, 73%, and 64%) compared to MASH, respectively. Exposure to 3 µM HK3 led to a strong decrease in IL-6 (55%) and IL-8 (80%) secretion. Iterative, AI-based identification of new hits and their in-depth functional analysis will be presented.

Conclusion: Our thioacrylamide compound promotes the regression of hepatic fibrosis, besides reducing steatosis and inflammation in a human 3D spheroid system. Overall, GABAA receptor modulators represent a first-in-class approach for MASH therapy.

Disclosure

E. Rohbeck: None. L. Koester: None. J. Eckel: None.
894-P: Safety and Efficacy of Imeglimin in Patients with Metformin Intolerance—Prospective Observational Study
Authors: AGRAWAL PRABHAT K. , GAUTAM ASHISH , PURSNANI NIKHIL , YADAV ALKA
Published: June 2024

Introduction and Objectives: Metformin is the first line drug recommended for management of T2DM. Intolerable GI side effects of metformin leads to its discontinuation in 15-20% of patients leading to miss out of its multiple benefits. Imeglimin shares the insulin sensitizing MOA similar to metformin with and additional effect on insulin secretion without untoward side effects of metformin. Objective of this study was to observe efficacy and safety of Imeglimin in metformin intolerant participants.

Methods: Fifty-three subjects above their glycemic targets, on OHAs without metformin due to its intolerance were enrolled for this study. It was a prospective observational study. Imeglimin in a dose of 1 gm BD/day started in all participants for the 24 weeks without changing the existing regimen. HbA1c & weight was observed before and after the completion of study duration. Participants were asked to visit every week during observation period and sos if any side effects appeared.

Results: All participants completed the observation period. Male: female = 1:0.7, Average age was 46.7±7 years, Duration of diabetes was 4.1±3.1 years. Average HbA1c at start was 8.3±0.5 whereas after 24 weeks was 7.3±0.5 (The t-value is 9.95663. The p-value is < .00001. The result is significant at p < .05.). Average weight at start was 69±12.4 Kg whereas at completion was 69.5±12.5 Kg (The t-value is -0.21796. The p-value is .413944. The result is not significant at p < .05). Three out of 7 whereas 1 out of 10 subjects with BMI above and less than 28 respectively, observed weight reduction of >10% (The chi-square statistic is 1.4852. The p-value is .222969. The result is not significant at p < .05.) Side effects observed were: withdrawn Imeglimin 1 (1.8%), Bloating: 5, increased Stool frequency: 3, Burning abdomen: 1.

Conclusion: Imeglimin show better GI tolerability as compared to metformin and significant Hba1c reduction with no effects on weight.

Disclosure

P.K. Agrawal: None. A. Gautam: None. N. Pursnani: None. A. Yadav: None.
895-P: Testosterone Replacement Therapy in Men with Hypogonadism and Type 2 Diabetes—ABCD Worldwide Audit
Authors: JONES THOMAS H. , HAIDER AHMAD , SULTAN HAIDER KARIM , CULL MELISSA L. , RYDER ROBERT E.
Published: June 2024

Symptomatic testosterone deficiency is common affecting 40% of men with type 2 diabetes (T2D).1 Testosterone replacement therapy (TRT) has been shown to have benefits on reducing insulin resistance, improving glycemic control and relieving symptoms of hypogonadism.2,3,4 We present early data analysis from the Association of British Clinical Diabetologists (ABCD) Worldwide audit of Testosterone in men with T2D. The audit has already recruited 460 patients from 40 centres from 10 countries. Mean age 70.7+9.35 years, mean total testosterone 9.22+1.74nmol/l. TRT included parenteral lon-acting depot testosterone undeconoate and daily applied testosterone gels. All analysis by paired t-tests of parameters. HbA1c before and after TRT (1) 6 months 70.51 to 64.96 (n=163); (2) 12 months 70.82 to 61.06 (n=145) (3) 3 years 70.99 to 51.7 (n=125). Weight (kg) baseline 112.66kg at 3 years 107.15kg (p=0.61), Waist Circumference baseline 116.08cm to 115.12cm at 3 years (p=0.43). The Aging Male Symptom (AMS) Score is a marker of symptoms and quality of life. AMS score at baseline 40.83 after 12 months 21.93 (n=196) p<0.001. Early analysis has provided evidence that TRT for men with T2D is associated with a progressive reduction in HbA1c over 3 years. No significant reduction of weight or waist circumference was identified. Importantly patients had a very significant improvement in quality of life and symptoms of testosterone deficiency. No adverse cardiovascular events were reported in patients in the audit up to 3 years TRT. Evidence from this ongoing audit that men who have symptoms of testosterone deficiency should have a fasting testosterone checked and if they fulfil the guideline criteria that consideration to be offered a trial of TRT. 1Kapoor D et al. Diabetes Care 2007:30;911-17, 2Kapoor et al. Eur J Endocrinol 2006:154;899-906, 3Jones TH et al. Diabetes Care 2011:34;828-37, 4Dhindsa S. et al. Diabetes Care 2016:39;82-91

Disclosure

T.H. Jones: None. A. Haider: Research Support; Bayer Inc., Grünenthal. K. Haider: Research Support; Bayer Inc., Grünenthal. M.L. Cull: None. R.E. Ryder: Speaker's Bureau; Abbott, Besins Healtcare, BioQuest, GI Dynamics. Consultant; GI Dynamics. Other Relationship; Novo Nordisk.

Funding

Association of British Clinical Diabetologists (ABCD)
896-P: Duodenal Mucosal Recellularization via Pulsed Electric Field–Induced Electroporation (ReCET) in Type 2 Diabetes—First-in-Human Experience
Authors: O'NEAL DAVID N. , SARTORETTO ADRIAN , EKINCI ELIF I. , MANOS GEORGINA , HOLT BRONTE , CAMERON GEORGINA , CHANDRAN SUJIEVVAN , VAUGHAN RHYS , ABU DAYYEH BARHAM K.
Published: June 2024

Background: ReCET utilizing an endoscope administered non-thermal pulsed electric field to stimulate duodenal cellular regeneration may correct abnormal duodenal signaling in type 2 diabetes (T2D). We report updated results from a feasibility study of ReCET therapy in T2D.

Method: This multicenter, open-label, treatment-only study recruited 18-70 yr old; T2D ≤10 years; HbA1c 7.5%-11.0%; BMI 24 - 40 kg/m2; C-peptide ≥ 333 pmol/l; and on 1-4 non-insulin glucose-lowering medications (GLMs) which were unchanged post-procedure. Primary endpoint: Device/procedure-related serious adverse events (SAEs). Secondary endpoints: Changes in metabolic parameters at 24W.

Results: Participants received single energy application (Single Tx, n=12), double energy application (Double Tx, n=18), or the Gen 2 catheter (Gen 2, n=21)- (Figure 1). Procedure success was 100% with no related SAEs. Common AEs were sore throat (25/51) and transient diarrhea (11/51), and mostly (76%) mild. Glycemia improved post procedure with trends suggesting an energy-dose response (Figure 1). Mean (SD) HbA1c at 24 wks vs baseline was 7.2 (1.2%) vs. 8.8 (0.9)% (p<0.01) in the Gen 2 group. Gen 2 group follow up is ongoing. Durability of glycemic improvement was observed in Double Tx group at 48 wks.

Conclusions: ReCET therapy is feasible and safe. Glycemic observations support further research.

Disclosure

D.N. O'Neal: None. A. Sartoretto: Research Support; Endogenex, Erbe Electromedizin GmbH. Advisory Panel; Bariatek. Consultant; Boston Scientific Corporation, Intuitive Surgical. E.I. Ekinci: Advisory Panel; Lilly Diabetes. Research Support; Novo Nordisk, Boehringer-Ingelheim, Eli Lilly and Company. Board Member; Eli Lilly and Company. Advisory Panel; Abbott. Research Support; Endogenex, Versanis, AstraZeneca. G. Manos: None. B. Holt: None. G. Cameron: None. S. Chandran: None. R. Vaughan: None. B.K. Abu Dayyeh: Research Support; USGI Medical, Apollo Endosurgery. Consultant; Boston Scientific Corporation, Medtronic. Other Relationship; Endogenex. Research Support; ERBE.
90-OR: Neddylation Targets Cullin 3 to Regulate Adipocyte Differentiation
Authors: ZHOU HONGYI , CHEN WEIQIN
Published: June 2024

Introduction & Objective: The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue (AT). Abnormal adipocyte differentiation will result in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to target protein, termed neddylation, has been shown to mediate adipogenesis by targeting PPARγ. However, much remains unknown about its role in adipogenesis.

Methods: Adipocyte differentiation was studied in 3T3-L1 cells and human Stromal vascular cells with pharmacological inhibition and genetic deletion by CRISPR/Cas9 of neddylation enzymes and its targeted cullins. Adipogenic signaling was analyzed by Western Blot, RT-PCR, FACS, etc.

Results: We first reported that neddylation and its targets, the cullin (CUL) family members, are differentially regulated during mouse and human adipogenesis. Neddylation inhibition by MLN4924 blunts adipogenesis in both 3T3-L1 cells and human stromal vascular cells. CRISPR/Cas9-mediated NAE1 deletion, a subunit of the only NEDD8 E1 enzyme, suppresses neddylation and impairs adipogenesis. Further studies identified that neddylation inhibition does not alter cell cycle progression, as evidenced by unaltered mitotic cell expansion. Instead, it impairs CREB-C/EBPβ-PPARγ signaling essential for adipogenesis. Furthermore, among different neddylation-targeted CULs, deletion of CUL3, but not CUL1, CUL2, and CUL4A, largely recapitulates neddylation deficiency-induced adipogenesis defects.

Conclusion: Our data establishes an indispensable role for neddylation and its target CUL3 in adipogenesis and suggests they can be important therapeutic targets for obesity.

Disclosure

H. Zhou: None. W. Chen: None.

Funding

National Institutes of Health (1R56 DK135657 and 2R01HL132182)
900-P: A Real-World, Multicentre, Retrospective, Observational Study to Evaluate the Effectiveness and Safety of Lobeglitazone in Type 2 Diabetes Mellitus Patients in India (LODIAB INDIA)
Authors: BARKATE HANMANT V. , CHITNIS KRUTTIKA R. , PETARE ANUP U. , CHOUDHARI SANJAY Y. , BHUSHAN SUMIT , PATIL SAIPRASAD
Published: June 2024

Background: Lobeglitazone, a novel TZD was recently approved in India for T2DM, has limited real-world data. This study assessed the effectiveness and safety of Lobeglitazone 0.5 mg once daily in real-world settings.

Methods: Data was captured from the medical records of patients after obtaining independent ethics committee approval from 16 different sites across India. The primary outcome was % change in HbA1c at week 12. Secondary outcomes were changes in the fasting blood sugar (FBS), post-prandial blood sugar (PPBS), lipid, liver and renal parameters and treatment emergent adverse effects at week 12. Statistical analysis was performed using paired t-test.

Results: Records of N=544 patients (60.4% males and 39.6% females), with a mean age of 52.6 ± 11.8 years were analysed. Baseline mean HbA1c reduced from 8.82 ± 1.57% to 7.62 ± 1.3% (mean reduction: 1.2%, p-value<0.0001; Figure 1). Proportion of patients achieving HbA1c <7% was 31.6% at week12. Changes in glycemic, lipid, liver and renal parameters are depicted in Table 1. There were no significant changes in body weight (p=0.17). Increase and decrease in the body weight and pedal oedema were reported in 0.92%, 2.39% and 0.37% individuals respectively. There were no reports of hypoglycaemia or any cardiac events in the enrolled patients.

Conclusion: Lobeglitazone significantly improved glycemic parameters, Sr. creatinine, Sr. bilirubin and total cholesterol levels and was well tolerated in Indian Type 2 diabetes patients in the real world setting.

Figure 1: Graphical Representation of change in HbA1c% at week12Table 1: Changes in glycemic, lipid, liver and renal parameters from baseline to week12

Disclosure

H.V. Barkate: Employee; Glenmark Pharmaceuticals. K.R. Chitnis: None. A.U. Petare: Employee; Glenmark Pharmaceuticals. S.Y. Choudhari: Employee; Glenmark Pharmaceuticals, Sun Pharmaceutical Industries Ltd. S. Bhushan: None. S. Patil: Employee; Glenmark Pharmaceuticals.