Bayer AG Research Articles

1282-P: Genetic Susceptibility of Dipeptidyl Peptidase-4 Inhibitor–Associated Bullous Pemphigoid in Chinese Patients with Type 2 Diabetes

Objective: The rare risk association of bullous pemphigoid (BP) with use of dipeptidyl peptidase-4 inhibitors (DPP-4i) had been reported including genetic association with HLA variants. We assessed genetic susceptibility of BP associated with DPP-4i use in patients with type 2 diabetes (T2D) . Methods: In a prospective cohort of 30,129 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register between 1995 to 2018, we curated multiple case-control cohorts with available genotype data to explore the genetic associations of major histocompatibility complex (MHC) region with DDP-4i-associated BP. Results: During a median follow period of 9 years, 60 patients developed BP (incidence of 2.cases per 10,000 patient-years) . 20 patient developed BP after DPP-4i use, with median exposure to DPP-4i of 1.7 years (incidence of 4.76 cases per 10,000 patient-years) and an adjusted odds ratio of 1.1 (95% CI 0.5-1.6) . 32 patients developed BP and were not exposed to DPP-4i (incidence of 2.87 cases per 10,000 patient-years) . In 1:2 matched case:control cohort of patients who tolerated DPP-4i and did not develop of BP, multiple variants in the second intron of HLA-DQB1 exhibited strong association with DPP4i-associated BP, including the well-reported HLA-DQB1*03: (OR 12.00; 95% CI 1.99-72.35; P-value 6.71e-03) and a novel single nucleotide polymorphism rs281863580 (OR 11.96; 95% CI 4.14-34.54; P-value 4.53e-06) . We additionally identified variants located in other HLA regions that were associated with BP in non-DPP4i users. Conclusion: Multiple genetic polymorphisms in the second intron of HLA-DQB1 were associated with increased susceptibility to incident BP in DPP-4i users. Further exploration of the extended MHC region beyond HLA alleles might identify a combination panel for assessing the genetic risk of BP rather than a single HLA allele. Disclosure M.Shi: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. E.S.Lau: None. C.H.Tam: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. M.Cheung: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. W.Chan: None. Funding The Hong Kong Government Research Grants Committee Theme-based Research Scheme (T12-402/13N) .2) Impact Research Impact Fund (R4012-18) .

1159-P: Associations of HOMA2 with Clinical Outcomes in Type 2 Diabetes

Background: In patients with type 2 diabetes (T2D) negative for glutamic acid decarboxylase antibodies (GADA-) , the prognostic significance of insulin deficiency (ID) and insulin resistance (IR) remained uncertain. Methods: In 4590 patients with T2D consecutively enrolled to the Hong Kong Diabetes Register in 1995-2012 followed up till 2019, we measured GADA and fasting C peptide (CP) in stored samples at baseline. Using the updated homeostasis model assessment (HOMA2) , we defined below-median HOMA2-%B as ID and above-median HOMA2-IR as IR. We defined incident insulin use as the first insulin prescription of at least 28 days and used ICD-9 codes to define cardiovascular-renal diseases, severe hypoglycemia event (SHE) and all-cause mortality. We used Cox regression model to examine the associations between HOMA2 and clinical outcomes. Results: Amongst 3198 GADA- patients with available HOMA2 data, the median of HOMA2-%B was 52.4 (33.1, 60.9) and that of HOMA2-IR was 1.6 (1.1, 1.8) . The ID group was more likely to initiate insulin treatment [adjusted HR (95%CI) 1.26 (1.11-1.42) ] but less likely to progress to chronic kidney disease (CKD) , end-stage kidney disease (ESKD) and all-cause mortality than the non-ID group. The IR group had increased risks of incident insulin therapy [HR 1.13 (1.00-1.27) ], CKD, ESKD, and all-cause mortality than the non-IR group. Compared with the ID-/IR- group, the ID/IR group had the highest hazard of incident insulin use [HR 1.59 (1.30, 1.94) ], SHE and cardiovascular-renal diseases with HRs ranging from 1.45 to 2.09, although the associations for complications became insignificant after adjusting for metabolic factors and baseline treatments. Conclusions: In GADA- patients with T2D, ID and IR contributed differently to clinical outcomes with the co-existence of ID and IR associated with the highest risk of insulin requirement and adverse clinical outcomes. The assessment of ID and IR using HOMA2 improved risk stratification to identify high risk people for individualized intervention. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund

934-P: Real-World Evidence of Glucose Lowering Drug Use, Glycemic Outcomes, and Severe Hypoglycemia in Hong Kong: Eighteen-Year Trends in 0.9 Million Adults with Diabetes

Introduction: Improvements in glycemic outcomes have stalled since 20in some international surveys. We examined the latest trends in drug use and glycemic outcomes following recent introduction of newer classes of glucose lowering drugs (GLDs) in a territory-wide analysis. Methods: Using data from the Hong Kong Diabetes Surveillance Database, we estimated age-specific trends in the proportion of patients reaching different glycemic targets, and rates of severe hypoglycemia (SH) in 963,612 patients between 2002-2019. We assessed patterns of GLDs use by age, sex, presence of atherosclerotic cardiovascular disease (ASCVD) and estimated glomerular filtration rate (eGFR) . Results: HbA1c improved most markedly between 2007-2014 but plateaued since 2014, with 53.1% patients achieving HbA1c <7% in 2019. The 20-44 age group had the highest proportion with HbA1c ≥9% (22.1% in 2002 and 16.8% in 2019) compared with the ≥75 age-group (14.9% in 2002 and 5.5% in 2019) . SH rates declined between 2002-20 and further in 2010-2014. Between 2002-2019, metformin use increased steadily from 41.1% to 58.7%, sulfonylurea use decreased from 52.2% to 31.1% while insulin use remained static. Use of dipeptidyl-peptidase 4 inhibitors (DPP4i) experienced rapid growth between 2007-20equally in all age groups, with a slower rise between 2011-2019. DPP4i remains the most widely prescribed newer oral GLDs (14.3%) compared with sodium glucose co-transporter 2 inhibitors (SGLT2is) (4.2%) and glucagon like peptide-1 receptor agonists (GLP1-RAs) (0.6%) in 2019. Compared with over 75s, higher proportions of the 20-44 age-group were treated with SGLT2is (6.4% versus 1.7%) and GLP-1RAs (1.5% versus 0.1%) and thiazolidinediones (8.1% versus 3.4%) in 2019, irrespective of ASCVD status. Conclusions: Following rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite the increasing use of SGLT2is and GLP-1RA in Hong Kong. Disclosure A.Yang: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. H.Wu: None. E.S.H.Lau: None. X.Zhang: None. M.Shi: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

865-P: Long-Term Ertugliflozin Treatment and Incidence of Hypoglycemia: Analyses from VERTIS CV

This analysis assessed the incidence and total events of hypoglycemia in VERTIS CV (NCT01986881) , the cardiovascular (CV) outcome trial for ertugliflozin (ERTU) in patients (pts) with type 2 diabetes and atherosclerotic CV disease. Hypoglycemia was categorized as level 1, a documented symptomatic event with plasma glucose (PG) ≤70 mg/dL (prespecified) ; level 2, a documented event with PG <54 mg/dL (post hoc) ; level 3, a severe event requiring assistance (prespecified) . Time to first HYPO-broad (levels 1+2+3) and HYPO-strict (levels 2+3) were analyzed by a Cox proportional hazards model. Kaplan-Meier estimates were plotted. Exposure-adjusted event rates for total (first + recurrent) HYPO-broad and -strict were analyzed. Overall, 8246 pts were randomized, mean follow-up was 3.5 yrs. The incidence rate (ERTU vs PBO) of first HYPO-broad was 14.3 vs. 16.2/100 pt-yrs; adjusted hazard ratio [aHR], 95% CI: 0.93 [0.85, 1.00] and HYPO-strict was 9.5 vs. 11.1/100 pt-yrs; aHR: 0.89 [0.81, 0.97] [Figure A]. Exposure-adjusted event rates were lower in ERTU vs PBO [Figure B]. The increase in percentage of insulin users (end of study vs. baseline) was less with ERTU (3.5% 5 + 15 mg) compared with PBO (6.2%) . In VERTIS CV, pts randomized to ERTU had a lower risk of hypoglycemia, including first and recurrent events, than PBO-treated pts. This may in part be due to the lesser increase in insulin users with ERTU vs. PBO. Disclosure S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. D.K.Mcguire: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, ESPERION Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. J.Liu: Employee; Merck & Co., Inc. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding This study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

18-OR: Discontinuation of Renin Angiotensin System Inhibitor and Cardiovascular-Renal Events in Advanced Diabetic Kidney Disease

Introduction: Whether angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) should be discontinued in advanced diabetic kidney disease (DKD) remains controversial. We examined the association of discontinuation of ACEi/ARBs when estimated glomerular filtration rate (eGFR) reached <30 ml/min/1.73m2 with risk of death, major adverse cardiovascular events (MACE) , and end-stage-kidney-disease (ESKD) defined as dialysis and/or eGFR <15/ml/min/1.73m2 in Chinese patients with type 2 diabetes (T2D) . Methods: We performed a prospective analysis of a register including 11,323 patients stratified by continuation of ACEi/ARBs within 6 months of reaching eGFR <30 ml/min/1.73m2 in 2002-2018 followed up until 2019. We used Cox model with time-dependent exposure and covariates to estimate the hazard ratio (HR) of outcomes in the overlap propensity score weighted cohort. Results: Of 11,323 ACEi/ARBs users with new-onset eGFR<30 ml/min/1.73m2, 2,055 (18.5%) discontinued ACEi/ARBs within 6 months whereas 9,268 (81.5%) had continuation of ACEi/ARBs. During a mean follow-up of 4.3 years, 13.5% and 28.4% had incident MACE and ESKD respectively, and 36.2% died. Compared to ACEi/ARBs continuation, discontinuation of ACEi/ARBs was associated with higher risk of MACE (HR=1.26, 95% CI: 1.15-1.39) and ESKD (HR=1.26, 95% CI: 1.14-1.40) , and neutral risk of death (HR=0.96, 95% CI: 0.89-1.04) . Results were consistent when modeling ACEi/ARBs as a time-dependent exposure using a marginal structural model. Conclusions: Discontinuation of ACEi/ARBs was associated with increased risk of cardiovascular-renal events in support of their continued use in patients with advanced DKD. Disclosure M.Shi: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.Yang: None. E.S.H.Lau: None. H.Wu: None. X.Zhang: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

1208-P: Age-Specific Association between Risk Factors and All-Cause and Cause-Specific Mortality in People with Type 2 Diabetes

Background: We aimed to examine age-specific association and population attributable fraction (PAF) of risk factors for all-cause and cause-specific mortality in people with type 2 diabetes. Methods: We used data from 360,202 people with type 2 diabetes who underwent metabolic assessment in 2000-20in Hong Kong. We included eight risk factors, including three baseline comorbidities: cardiovascular disease (CVD) , chronic kidney disease (CKD) and cancer; and five modifiable risk factors: suboptimal HbA1c (≥7.0%) , suboptimal blood pressure (SBP/DBP ≥140/90 mmHg) , suboptimal LDL-C (≥2.6 mmol/L) , smoking and suboptimal weight (BMI <24.0 or ≥28.0 kg/m2) . We used Cox regression models to compare the hazard ratios and PAFs of the risk factors for mortality risk across age groups (18-54, 55-64, 65-74, and ≥75 years) . Findings: During a median 6.0 years of follow-up, 44,396 deaths were documented, with cancer, pneumonia, and CVD being the most common causes of death. When stratified by age group, the strength of the associations between most risk factors and all-cause and cause-specific mortality was strongest in the youngest age group and diminished with increasing age. The eight risk factors explained more population burden of mortality in the youngest (PAF: 51.6%) than the oldest (PAF: 35.3%) age group. In the youngest age group, the strongest population attributable risk factor for all-cause mortality was suboptimal control of blood pressure, followed by CKD. In the oldest age group, CKD and CVD were the largest contributors. CKD contributed most to mortality from CVD and pneumonia in the overall population, while cancer had the greatest PAF for cancer mortality across all age groups. Conclusions: The contribution of each risk factor to mortality in people with type 2 diabetes showed a different pattern across age groups. Age-stratified prevention strategies targeting the major risk factors may have the potential to reduce premature mortality. Disclosure H.Wu: None. A.Luk: None. E.S.H.Lau: None. A.Yang: None. X.Zhang: None. B.Fan: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd.

73-LB: Ambulatory Glucose Profile Informs Better Treatment Decisions for Type 2 Basal-Insulin Patients

Healthcare providers (HCP) treating patients who are on basal insulin and have suboptimal glycemic control may benefit from understanding glucose patterns. The primary objective of this study is to evaluate whether a review of Ambulatory Glucose Profile (AGP) of the patient would enable the HCP to recommend a therapy change. The secondary objectives included evaluating HCPs’ understanding of their patients’ glycemic control and patients’ understanding of the rationale for the recommended treatment after reviewing the AGP with their physician. A total of 136 patients with HbA1c values of 7.0 - 10.0% for whom their HCP is unsure of the optimal course of treatment based on standard of care were enrolled in the study at 10 sites and used FreeStyle Libre Pro Sensors;105 patients had at least 7 days of sensor data to generate an AGP. All HCPs received training on AGP interpretation. Based on their AGP, 94.3% (99/105) of the patients were recommended a therapy change. In addition, HCPs found that sensor data were useful in understanding their patients’ glycemic control, provided new insights on overall glucose control, and helped to make better informed treatment decisions for their patients (Table 1) . Patients also had a better understanding of the recommended treatment after reviewing the AGP with their HCP, where 96.7% of the patients understood the rationale of their recommended treatment. Disclosure E. Huang: Employee; Abbott Diabetes. M. Nada: Employee; Abbott Diabetes. E. Wright: Advisory Panel; Abbott Diabetes, Bayer AG, Boehringer Ingelheim International GmbH, Gelesis, GlaxoSmithKline plc., Lilly Diabetes, MannKind Corporation, Medtronic, Sanofi-Aventis U. S., Consultant; Abbott Diabetes, Bayer AG, Bigfoot Biomedical, Inc., Boehringer Ingelheim International GmbH, Lilly Diabetes, Stability Health, Other Relationship; UpToDate, Speaker's Bureau; Abbott Diabetes, American Diabetes Association, Bayer AG, Boehringer Ingelheim International GmbH, Sanofi-Aventis U. S. Funding Abbott Diabetes Care

345-OR: Longitudinal Changes in Arterial Stiffness and Heart Rate Variability in Youth-Onset Type 1 vs. Type 2 Diabetes

Limited data exist examining arterial stiffness and heart rate variability (HRV) over time in young adults with youth-onset type 1 (T1D) and type 2 diabetes (T2D) . We compared arterial stiffness and HRV over time and by diabetes type and determined the risk factors associated with worsening arterial stiffness and HRV. Arterial stiffness (pulse wave velocity, augmentation index) and HRV (SDNN and PNN50) were measured twice (∼ 5 years apart) in the SEARCH for Diabetes in Youth Study. Linear regression models assessed risk factors overtime and with arterial stiffness and HRV at follow-up. Of 1159 participants studied, 949 had T1D (mean age 17.1 ± 4.7 years, 60.3% non-Hispanic White, 55% female) and 2had T2D (mean age 22.1 ± 3.5 years, 23.8% non-Hispanic White, 71% female) at initial assessment when diabetes duration was 7.9 years (both groups) . Participants with T2D vs. T1D had greater arterial stiffness and more abnormalities in HRV at initial and follow-up assessments (Figure) .For AIx and PNN50 T2D compared to T1D had a greater change over time (p<0.05) . Risk factors associated with worse arterial stiffness and HRV at follow-up in both T1D and T2D included higher BP, HbA1c, waist circumference, and triglycerides overtime, and longer diabetes duration. Arterial stiffness and HRV worsened over time with greater changes among those with T2D and features of the metabolic syndrome regardless of diabetes type. Disclosure A.S. Shah: None. R. Dagostino: Consultant; Aetion, Inc., AstraZeneca, Biogen, Bristol-Myers Squibb Company, Daiichi Sankyo, Merck & Co., Inc. L.M. Dolan: None. D. Dabelea: None. G. Imperatore: None. A.K. Mottl: Advisory Panel; Bayer AG. Board Member; Bayer AG. Research Support; Alexion Pharmaceuticals, Inc., Aurinia, Bayer AG, Boehringer Ingelheim International GmbH, Pfizer Inc. E. Lustigova: None. C. Pihoker: None. S.M. Marcovina: None. E.M. Urbina: Advisory Panel; Astellas Pharma Inc. Funding NIH and CDC

859-P: Effects of Ertugliflozin on Uric Acid and Gout-Related Outcomes: Post Hoc Analyses from VERTIS CV

The effect of ertugliflozin (ERTU) on serum uric acid (SUA) and gout-related outcomes in VERTIS CV (NCT01986881) was investigated. Patients with T2D and ASCVD were randomized to ERTU 5 mg (n=2752) , 15 mg (n=2747) (doses pooled for analyses) , placebo (PBO; n=2747) . Changes in SUA and composite of gout onset or initiation of anti-gout medication were assessed. LSM changes from baseline in SUA (mg/dL [95% CI]) at week 260 were −0. (−0.25, −0.13) and 0. (−0.02, 0.15) in the ERTU and PBO groups, respectively, nominal P<0.0 (Fig. 1) . The HR (95% CI) for the composite of gout-related outcomes was 0.76 (0.580, 1.002) , nominal P=0.052 (Fig. 2) . Treatment with ERTU was associated with reductions from baseline in SUA and a non-significant reduction in gout-related outcome events compared with PBO. Disclosure V.S.Sridhar: None. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. M.N.Essex: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. M.Maldonado: Employee; Merck & Co., Inc. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding The VERTIS CV study and this analysis were sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

556-P: The Relationship between Short-Chain Fermentable Carbohydrates (FODMAPs) , Gut Microbiome, and Glucose Intolerance: An Exploratory Analysis

Fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) are fermentable short-chain carbohydrates that include fructans, galactooligosaccharides (GOS) , lactose, excess fructose, mannitol and sorbitol. Low FODMAP diets in irritable bowel syndrome were associated with reductions in metabolically beneficial, short-chain fatty acids (SCFA) - producing bacteria. We examined the interactions between FODMAP, gut microbiota and glucose tolerance in this exploratory analysis. Twenty subjects underwent oral glucose tolerance tests (OGTT) with C peptide measurements. Ten were classified as normal glucose tolerant (mean ±SD 55±years, body mass index (BMI) 22.7­±2.5 kg/m2, 2-hour plasma glucose 5.7±1.0 mmol/L) and with impaired glucose tolerance (58±­5 years, BMI 23.5±2.9 kg/m2, 2-hour glucose 9.0±0.9 mmol/L) . FODMAPs and macronutrients were assessed from 3-day food diaries. Fecal samples were collected for microbiome analysis. Total FODMAPs were positively correlated to presence of Dorea (r=0.49, p=0.027) . For individual FODMAP items, lactose was positively correlated with Akkermansia (r=0.54, p=0.013) , Bifidobacterium (r=0.42, p=0.037) and negatively correlated with Shigella (r=0.35, p=0.031) in both groups. GOS were positively correlated with Lactobacillus (r= 0.21, p=0.006) and negatively with Shigella (r=0.28, p=0.043) . In the whole group, lower insulin resistance as shown by homeostasis model assessment HOMA2-IR was associated with higher abundance of Bifidobacterium logum (r=0.48, p=0.01) . HOMA2-beta showed correlation with Dorea (r=0.43, p=0.056) . FODMAPs increased the health-promoting microbiota (e.g. Dorea, Lactobacillus, Akkermansia, and Bifidobacterium) . These SCFA promoting microbiota were associated with lower insulin resistance and improved beta-cell function while suppressing the growth of opportunistic pathogens, such as Escherichia spp. Disclosure N. Chu: None. J. He: None. R.C. Ma: Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH. A.P. Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd. Research Support; Boehringer Ingelheim. Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi. Stock/Shareholder; Aptorum Group Limited. Other Relationship; AstraZeneca, Novo Nordisk. J.C. Chan: Board Member; Asia Diabetes Foundation. Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc. Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories. Stock/Shareholder; GemVCare Ltd. E. Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc. Speaker's Bureau; Novartis AG, Sanofi. Funding Health Medical Research Fund (17180431) Hong Kong College of Physicians Young Investigator's Research Grant

290-OR: A Randomized Controlled Trial to Alleviate Carbohydrate Counting in Type 1 Diabetes with Automated Fiasp and Pramlintide Closed-Loop Delivery

We conducted a non-inferiority randomized crossover trial to alleviate carbohydrate counting (CC) in people with diabetes using automated dual-pump delivery of faster aspart (Fiasp) and pramlintide. Adults (N=15, 9 F, 39 ± 14 years, A1c 7.2 ± 0.9%) and adolescents (N=15, 8 F, 16 ± 1 years, A1c 8.4 ± 0.9%) used (i) Fiasp and placebo with CC, (ii) Fiasp and pramlintide with meal announcement (MA) , and (iii) Fiasp and placebo with MA for 2 weeks. Fiasp and pramlintide were delivered at a fixed 1 U:µg ratio to mimic a co-formulation. MA arms delivered fixed, user-specific priming meal boluses, independent of carbohydrate content. Prior to the first arm, participants had a 1-week run-in with automated Fiasp (single pump) delivery and CC, with mean time in range (70-180 mg/dL) of 71% in adults and 64% in adolescents. In adults, mean time in range was 65% on Fiasp and placebo with CC, 71% on Fiasp and pramlintide with MA, and 64% on Fiasp and placebo with MA; non-inferiority with a pre-defined 6.25% margin was achieved in both MA arms with pramlintide and placebo (difference -6 [95% CI -12.6, 0.5]; 1 [-3.0, 4.6]) . In adolescents, mean time in range was 51%, 55%, and 46% in the three respective arms; non-inferiority was only achieved on Fiasp and pramlintide with MA (-4 [-9.0, 1.7]) . We conclude that automated Fiasp and pramlintide delivery may alleviate CC without degrading glucose control. Disclosure E.Cohen: None. E.Palisaitis: Other Relationship; Eli Lilly and Company. J.Rutkowski: None. L.Legault: Advisory Panel; Abbott Diabetes, Insulet Corporation, Novo Nordisk A/S, Other Relationship; Eli Lilly and Company, Research Support; AstraZeneca, Merck & Co., Inc. A.Haidar: Consultant; Eli Lilly and Company, Research Support; ADOCIA, Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. J.E.Von oettingen: None. J.Yale: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Canada Inc., Sanofi, Research Support; Bayer AG, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Dexcom, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi. N.Garfield: None. M.Vallis: Advisory Panel; Bausch Health, Canada, Novo Nordisk Canada Inc., Consultant; Abbott Diabetes, LifeScan, Speaker's Bureau; AbbVie Inc., Bausch Health, Canada, LifeScan, Novo Nordisk, Novo Nordisk A/S. N.Gouchie-provencher: None. A.Jafar: None. M.Ghanbari: None. Funding Juvenile Diabetes Research Foundation International (2-SRA-2018-654-M-B) , Canada Research Chairs

96-OR: Adverse Micro- and Macrovascular Outcomes in Youth-Onset Type 1 and Type 2 Diabetes: The SEARCH and TODAY Studies

We sought to determine incidence rates for micro- and macrovascular events in youth-onset type 1 (T1D) and type 2 (T2D) diabetes in the SEARCH (T1D: N=564; T2D: N=149) and TODAY (T2D: N=495) studies. At study visits, we ascertained self-reported ophthalmologic, kidney, neuropathy, cardiac, and peripheral and cerebrovascular events , obtained medical records for these events, and adjudicated each event using predetermined standardized and harmonized criteria. Data were available from more than 6,000 person-years in T1D and more than 8,000 person-years in T2D. Incidence rates (events per 10,000 person-years) were calculated. As shown in the table, despite similar mean diabetes duration of 10-13 years and mean HbA1c >9%, the incidence of reported complications was higher in the youth with T2D than those with T1D, with rates 2.5-fold higher for microvascular and 4.0-fold higher for macrovascular disease. These data support the aggressive nature of youth-onset T2D. Disclosure A.K.Mottl: Advisory Panel; Bayer AG, Board Member; Bayer AG, Research Support; Alexion Pharmaceuticals, Inc., Aurinia, Bayer AG, Boehringer Ingelheim International GmbH, Pfizer Inc. S.Isom: None. J.B.Tryggestad: None. R.Gubitosi-klug: None. L.M.Dolan: None. R.Dagostino: Consultant; Aetion, Inc., AstraZeneca, Biogen, Bristol-Myers Squibb Company, Daiichi Sankyo, Merck & Co., Inc. K.Drews: None. Funding National Institutes of Health DK061230; R01DK127208 Center for Disease Control

1186-P: The Effect of Age on the Risk Relationship between Prediabetes and Mortality and Major Adverse Clinical Events

Background: Prediabetes is associated with increased risk of cardiovascular disease (CVD) , kidney disease and death but the extent to which the risk associations between prediabetes and clinical events are modified by age is not known. Methods: We conducted a retrospective analysis of a territory-wide diabetes surveillance dataset from the Hong Kong Hospital Authority including 2,692,880 individuals with at least one glycaemic measurement between 2000 and 2019. Prediabetes was defined according to the American Diabetes Association criteria. Proportional Cox regression was used to derive hazard ratios (HR) and 95% CI of prediabetes vs. normoglycaemic for incident CVD, end-stage kidney disease (ESKD) , all-site infection and all-cause death, stratified by baseline age categories (20-39, 40-59, 60-79 and ≥80 years) . Results: Compared with people with normoglycaemia, people with prediabetes had greater hazards for clinical events in all age groups but the effect size attenuated with ascending age. In the youngest and in the oldest age categories, the respective HRs (95% CI) of prediabetes vs. normoglycaemia were 1.93 (1.71-2.17) and 1. (1.01-1.12) for CVD, 1.72 (1.42-2.08) and 1. (1.03-1.17) for ESKD, 1.48 (1.36-1.62) and 1. (1.00-1.08) for all-site infection, and, 1.52 (1.33-1.73) and 1. (1.04-1.10) for all-cause death. The associations remained after excluding people who later developed diabetes and after adjusting for metabolic factors. Conclusion: Prediabetes increases the risk of major clinical events and death independent of subsequent development of diabetes and metabolic factors. The risk relationships between prediabetes and clinical events are stronger in young than older people. Disclosure X.Zhang: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. A.Luk: None. H.Wu: None. E.S.H.Lau: None. M.Shi: None. B.Fan: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd.

380-P: Burden of Low Interstitial Fluid Glucose Levels among Type 2 Diabetes Patients with Chronic Kidney Disease and Its Associated Variables

Background: Type 2 diabetes (T2D) patients with chronic kidney disease (CKD) are at high risk of hypoglycemia due to decreased renal gluconeogenesis and clearance of diabetes medications. This study aims to quantify the burden of hypoglycemia in this population, and identify potential risk factors. Methods: Outpatient T2D subjects with CKD (eGFR <60ml/min per 1.73m2) were recruited to wear a Freestyle Libre-Pro sensor for 2 weeks. Collected data was analyzed for low interstitial fluid glucose (IFG) burden. IFG values of less than 72mg/dL and 50mg/dL that persisted for at least 15 minutes were defined as ‘low sensor glucose (LSG) ’ and ‘very low sensor glucose (VLSG) ’ respectively. Occurrence of VLSG events were correlated with patient-reported symptoms. Univariate analysis with Poisson regression was performed to look for predictive factors for LSG and VLSG events. Results: A total of 77 subjects with CKD were included in the study, 46 (59.7%) male and 31 (40.3%) female. The subjects were 67.9 ± 8.9 years old with duration of diabetes of 22.0 ± 12.1 years and HbA1c of 8.1 ± 1.9%. The subjects wore the sensor for 14.3 ± 1.6 days. Sixty-five subjects (84.4%) experienced a total of 612 LSG events (mean number of events per subject 8.0 ± 8.6) with total duration of 1834 ± 2812 minutes while 44 subjects (57.1%) experienced a total of 244 VLSG events (mean number of events per subject 5.6 ± 5.9) with total duration of 1080 ± 1838 minutes. Majority of subjects who experienced VLSG events (90.9%) did not report associated symptoms. Lower HbA1c and lower mean glucose were associated with LSG (rate ratio of 0.79 (0.70 - 0.89) and 0.71 (0.66 - 0.76) respectively with p values <0.05) . Similar results were found for VLSG events. Interestingly, the degree of renal impairment did not predict for LSG or VLSG events. Conclusion: Clinicians must consider what appropriate glycemic targets should be for T2D patients with CKD as this modifiable risk factor is highly predictive of hypoglycemic events. Disclosure K.Tian: None. L.C.Ang: None. S.Goh: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Sanofi. Y.Bee: None. J.Choo: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Novartis AG, Consultant; AstraZeneca, Nitto Denko Asia Technical Centre, Novartis AG, Research Support; AstraZeneca, Nitto Denko Asia Technical Centre, Speaker's Bureau; Abbott, Bayer AG. M.M.Teh: None.

896-P: Dapagliflozin Cost Offsets in Chronic Kidney Disease for Commercial U.S. Payers

One in 7 adults have chronic kidney disease (CKD) , which is associated with high mortality and costly healthcare resource utilization (HCRU) . Data from a US employer-sponsored health insurance plan show rising per-member-per-year costs for treatment of cardiac and renal complications associated with CKD. A cost-offset model (COM) was deployed to quantify the predicted clinical and economic benefits of treatment with dapagliflozin. The COM used real-world cost and member count data from a US employer-sponsored commercial payer and the phase 3 DAPA-CKD (NCT03036150) clinical trial event rates for outcomes, including ≥ 50% decline in estimated glomerular filtration rate (eGFR) , end-stage kidney disease (ESKD) , and hospitalization for heart failure (HHF) . HCRU cost-offsets were calculated over a 3-year time horizon in a population of 130 members with CKD stages 2-4 who were modeled for treatment with either dapagliflozin plus standard of care (SOC) or SOC alone. Over a 3-year period, 9 instances of ≥ 50% decline in eGFR were estimated for treatment with dapagliflozin versus (vs.) 15 with SOC (6 fewer events; number needed to treat [NNT]: 20) , amounting to estimated cumulative cost-offsets of $0.57 million (M) . Similarly, 6 ESKD events were avoided with dapagliflozin vs. SOC (8 vs. 14; NNT: 24) , resulting in $1.92 M in cumulative cost-offsets. Dapagliflozin use also avoided 20 HHF events compared with SOC (13 vs. 33; NNT: 7) , totaling $0.79 M in cumulative cost-offsets. Overall, better clinical outcomes translated into total cumulative HCRU cost-offsets of $3.89 M (36.6% reduction in favor of dapagliflozin + SOC vs. treatment with SOC alone) . Results of our COM estimate that dapagliflozin greatly decreases HCRU costs in plan members with CKD by reducing cardiac and renal clinical events over a 3-year period. Modeling these outcomes for members with CKD with and without type 2 diabetes demonstrates that dapagliflozin can be a cost-effective way to reduce HCRU costs associated with CKD for commercial payers. Disclosure R.Chang: Employee; AstraZeneca, UnitedHealth Group. J.Huang: Employee; AstraZeneca. D.Reck: None. J.Hurst: Employee; AstraZeneca. K.Wolf khachatourian: Consultant; Bayer AG, Xcenda. M.H.Shannon: Consultant; Bayer AG, Speaker's Bureau; Bayer AG, Novo Nordisk A/S. Funding AstraZeneca

21-OR: Optimization of Albuminuria Lowering Treatment by Crossover Rotation to Four Different Drug Classes

Introduction: Renin-angiotensin system (RAS) inhibitors decrease urinary albumin:creatinine ratio (UACR) and are guideline recommended drugs for kidney protection but are ineffective in lowering UACR in up to 40% of cases. We hypothesized that rotation to another drug class overcomes resistance to RAS inhibition and tested this hypothesis in a randomized cross-over trial. Methods: We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR ≥30 and ≤500 mg/g to 4-week treatment periods with telmisartan 80 mg, empagliflozin mg, linagliptin 5 mg, and baricitinib 2 mg in random order, separated by 4-week wash-out periods. Participants were then re-exposed for 4-weeks to the individual drug that induced the largest UACR reduction. Primary outcome was the difference in UACR response between the first and second exposure to the best performing drug, versus the difference in UACR response between the best performing drug and the other three drugs. Results: There was substantial between person variation in the best performing drug: telmisartan was best performing in 33 (52%) participants, followed by empagliflozin and linagliptin in (17%) participants each, and baricitinib in 8 (13%) participants. The individual best performing drug changed UACR during the first exposure by -39.6% (95%CI -44.8, -33.8, p<0.001) and by -22.4% (95%CI -29.7, -12.5, p<0.001) at re-exposure (between exposure difference: 22.1% [95%CI 12.5, 30.8; p<0.001]) . The difference in UACR response between the individual best performing drug and the other three drugs was -40.5% (95%CI -45.9, -34.6, p<0.0vs. between exposure difference) . The correlation in UACR response of the best performing drug at exposure and re-exposure was r=0.389, p=0.017. Conclusion: We demonstrated a large and reproducible variation in UACR lowering responses to different drug classes reinforcing the need for personalized therapy approaches to overcome therapy resistance to guideline recommended treatment. Disclosure V.Rotbain curovic: None. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.Y.A.Kroonen: None. N.Jongs: None. T.Sen: None. E.Zobel: Employee; Novo Nordisk. T.W.Hansen: Stock/Shareholder; Novo Nordisk A/S. G.D.Laverman: Advisory Panel; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Vifor Pharma Management Ltd., Research Support; AstraZeneca, Lilly Diabetes, Sanofi, Vifor Pharma Management Ltd. A.Kooy: Advisory Panel; Bayer AG, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk, Speaker's Bureau; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk. F.Persson: Advisory Panel; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.

47-OR: Efficacy, Durability, and Safety of Faricimab in Diabetic Macular Edema: Two-Year Results from the Phase 3 YOSEMITE and RHINE Trials

Diabetic macular edema (DME) is a major cause of vision loss for people with diabetes. Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for DME; however, there is an unmet need for new strategies that address the multifactorial nature of DME, reduce treatment burden, and optimize patient outcomes. Angiopoietin-2 and VEGF-A synergistically drive vascular instability in DME; therefore, dual pathway inhibition with faricimab, the first bispecific antibody designed for intraocular use, may promote vascular stability and durable efficacy beyond current anti-VEGF therapies. YOSEMITE (NCT03622580) and RHINE (NCT03622593) were randomized, double-masked, active comparator-controlled, phase 3 trials designed to assess the efficacy, durability, and safety of faricimab in patients with DME (YOSEMITE, N = 940; RHINE, N = 951) . Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W) after 6 initial every-4-week (Q4W) doses, faricimab 6.0 mg per personalized treatment interval (PTI) after 4 initial Q4W doses, or aflibercept 2.0 mg Q8W after 5 initial Q4W doses. The PTI algorithm was a protocol-driven treat-and-extend regimen, with dosing intervals extended, maintained, or reduced (from Q4W up to every 16 weeks [Q16W]) based on prespecified vision and anatomic criteria. Efficacy and safety endpoints were assessed at Q4W study visits through week 100. At 1 year, faricimab Q8W or per PTI offered durable vision gains that were noninferior to aflibercept Q8W and were achieved with Q16W dosing in > 50% of patients in the PTI arms. Faricimab Q8W or per PTI demonstrated anatomic improvements versus aflibercept Q8W and was well tolerated, with low rates of intraocular inflammation. Year 2 results from YOSEMITE/RHINE will be presented at the meeting, and will examine whether early vision gains, anatomic improvements, and extended (up to Q16W) dosing with faricimab are maintained over 2 years. Disclosure C.J. Danzig: Advisory Panel; Genentech, Inc. Consultant; Adverum Biotechnologies, Genentech, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc. Research Support; Adverum Biotechnologies, Genentech, Inc., Kodiak Pharmaceuticals, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals. Speaker's Bureau; Novartis Pharmaceuticals Corporation. J.A. Wells: Advisory Panel; Genentech, Inc. Research Support; Adverum, Alimera, Bayer AG, DRCR Retina Network, Genentech, Inc., Gyroscope, Iveric, Kodiak, Lowy Medical institute, Regeneron Pharmaceuticals Inc. D. Eichenbaum: Consultant; Genentech, Inc., Regeneron Pharmaceuticals Inc. Research Support; Bayer AG, Genentech, Inc., Regeneron Pharmaceuticals Inc. Speaker's Bureau; Bayer AG, Genentech, Inc. J.I. Lim: Consultant; Cognition, Eyenuk, Genentech, Inc., Iveric Bio, Novartis AG, Quark, Santen, Luxa, Veridian, Aura, Unity. Research Support; Aldeyra, Chengdu Pharmaceuticals, Regeneron Pharmaceuticals Inc., Stealth, NGM. K. Asik: None. Z. Haskova: Employee; Genentech, Inc. S. Mohan: None. D. Silverman: Employee; Roche Pharmaceuticals. Y. Tang: Employee; Genentech, Inc. H. Lin: Employee; Genentech, Inc. Funding F. Hoffmann-La Roche Ltd. (Basel, Switzerland)

984-P: Incidence of Cardiovascular Disease, Kidney Disease, and Death in Youth-Onset Type 2 Diabetes Before the Age of 20 Years: Eight-Year Follow-Up of Territory-Wide Surveillance in Hong Kong

Background: Few studies reported incidence rates of late-stage complications in people with youth-onset type 2 diabetes. We compared the clinical characteristics and incidence of cardiovascular disease (CVD) , end-stage kidney disease (ESKD) and death in a cohort of Chinese youth with type 2 and type 1 diabetes. Method: We performed a retrospective analysis of 1221 people with type 2 diabetes and 641 with type 1 diabetes diagnosed at age <20 years who underwent metabolic and complication assessment in Hong Kong Hospital Authority between 2000-2019, followed for incident CVD, ESKD and all-cause death until 2019. Cox regression models were used to determine the hazards of complications in type 2 versus type 1 diabetes. Result: At baseline, people with youth-onset type 2 diabetes were older at diagnosis (16 [14-18] vs. [8-15] years, p<0.01) but had similar diabetes duration (6 [2-15] vs. 6 [2-13] years, p=0.32) to those with type 1 diabetes. People with type 2 diabetes had higher frequency of obesity (71.3% vs. 14.6%) , hypertension (48.3% vs. 21.0%) , dyslipidemia (58.8% vs 24.1%) and albuminuria (29.8% vs. 11.2%) (p<0.01) . Over a median follow-up of 6.7-7.8 years, incidence rates (per 1000 person-year [95% CI]) , were 5.3 (3.9-7.0) vs. 1.4 (0.6-2.9) for CVD, 8.1 (6.4-10.1) vs. 2.4 (1.3-4.2) for ESKD, and 6.9 (5.4-8.7) vs. 2.6 (1.4-4.4) for death in people with type 2 and type 1 diabetes, respectively (p<0.01) . With reference to type 1 diabetes, the risks of CVD (HR [95% CI] 2.6 [1.1-6.2]) and ESKD (HR 2.4 [1.2-4.5]) but not death (HR 1.6 [0.8-2.9]) were higher in type 2 diabetes, adjusted for age at diagnosis, diabetes duration and sex. The increased hazard for ESKD but not CVD remained after further adjustment for smoking, glycaemic and metabolic control. Conclusion: People with youth-onset type 2 diabetes had 2-fold increased risk of CVD and ESKD, in part driven by greater burden of obesity and other metabolic risk factors in this group. Disclosure Y.Fan: None. E.S.H.Lau: None. H.Wu: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. A.Luk: None.

856-P: Cardiovascular (CV) and Kidney Outcomes with Canagliflozin (CANA) According to Type 2 Diabetes (T2D) Treatment Targets at Baseline (BL) : Data from the CANVAS Program and CREDENCE

In T2D, treatment targets include maintaining HbA1c ≤7.0%, LDL-C <2 mmol/L (<77 mg/dL) , and BP <130/80 mmHg. It is also recommended to improve urinary albumin:creatinine ratio (UACR) , a marker of renal damage and CV risk. We examined effects of CANA vs. placebo on CV and kidney outcomes in patients with T2D and high CV risk and/or chronic kidney disease according to BL treatment targets and risk factors. Pooled data from the CANVAS Program (N=10,142) and the CREDENCE trial (N=4401) were analyzed according to treatment target achievement and by number of targets achieved at BL. Hazard ratios and 95% CIs were estimated using Cox regression models. Of 14,432 participants at BL, 3683 (26%) had achieved 0, 5851 (41%) had achieved 1, 3680 (25%) had achieved 2, and 1218 (8%) had achieved either 3 or 4 targets. At BL, 8415 (58%) participants had UACR >2 mg/mmol. CANA consistently reduced risk of MACE, HHF/CV death, and ESKD or doubling of serum creatinine vs. placebo, regardless of whether BL targets were met or if UACR was elevated (Figure) . The number of uncontrolled targets at BL did not impact the beneficial effect of CANA on CV and kidney outcomes (all P interaction >0.17) . In conclusion, CANA demonstrated consistent CV and renal benefits in patients with T2D, regardless of risk factor control. Disclosure V.C.Woo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Speaker's Bureau; Janssen Pharmaceuticals, Inc. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. S.Tobe: Other Relationship; Bayer AG, Speaker's Bureau; AstraZeneca, Otsuka Pharmaceutical Co., Ltd. A.Slee: Consultant; Alydia Health, Elixir Medical , IHP Therapeutics , iLumen Scientific, Intuitive Surgical, Janssen Global Services, LLC, Laborie, Providence Medical, Pulse Biosciences, SonoMotion. W.Rapattoni: Employee; Janssen Pharmaceuticals, Inc. F.Ang: Employee; Bristol-Myers Squibb Company, Janssen Pharmaceuticals, Inc. 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. D.C.Wheeler: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Global Services, LLC, Merck Sharp & Dohme Corp., Mundipharma, Tricida, Inc., Vifor Pharma Management Ltd., Consultant; AstraZeneca, Speaker's Bureau; Amgen Inc., Astellas Pharma Inc. Funding Janssen Inc., Toronto, ON, Canada

1211-P: Associations of C-peptide, HOMA2, and GADA with Insulin Initiation and Risk of Hypoglycemia in Type 2 Diabetes

Background: In patients with type 2 diabetes (T2D) and non-ketotic presentation, low C-peptide (CP) and positivity for glutamic acid decarboxylase antibodies (GADA+) indicate early insulin requirement. In GADA- patients, the associations of CP with insulin use, glycemic response and severe hypoglycemia event (SHE) are unknown. Methods: We measured fasting CP and GADA in 4590 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register in 1995-2012 followed up till 2019. The updated homeostasis model assessment (HOMA2) was derived from fasting CP and plasma glucose. We defined incident insulin use as the first insulin prescription of at least 28 days, glycemic response as HbA1c reduction at one year after insulin initiation, and SHE using ICD-9 codes. Linear and Cox regression models were applied for association analyses. Results: At enrolment, 32% had low CP (<250 pmol/L) and 5% were GADA+. In the low CP group, 7% were GADA+. In the GADA+ group, 50% had low CP. During a mean follow-up of 10.8 years, 58.6% were started on insulin after a median of 6.5 years. The GADA+ group was more likely to initiate insulin [adjusted HR (95% CI) 1.55 (1.26-1.91) ] and experienced SHE [HR 1.45 (1.08-1.95) ] than the GADA- group. In the GADA- group, low CP had lower hazards of insulin use [HR 0.86 (0.77-0.97) ] than high CP especially in patients with HOMA2-IR (insulin resistance) above median. The low CP group had higher HR of 1.34 (1.13-1.59) of SHE than the high CP group. In the GADA+ group, low CP was associated with increased risk of SHE [HR 1.81 (1.25, 2.62) ] but not in patients with high CP (P interaction= 0.01) . Both CP and GADA did not predict glycemia response after controlling for baseline HbA1c. Conclusions: In patients with T2D, CP interacted with GADA to influence disease progressions including early insulin therapy and SHE. C-peptide might be correlated with IR in patients with GADA-. These subphenotypes allowed more precise classification of beta cell function to guide personalized treatment. Disclosure B.Fan: None. A.Luk: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.S.H.Lau: None. H.Wu: None. M.Shi: None. A.Yang: None. C.K.P.Lim: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. Funding The HKG Health Medical and Research Fund and RGC Research Impact Fund