Roche Pharma Research Articles

1615-P: Predicting End-Stage Kidney Disease in Type 1 Diabetes

Introduction: End-stage kidney disease (ESKD) is a life-threatening but preventable complication to diabetes and early detection of high-risk persons is essential. Our aim was to develop a prediction model for ESKD in type 1 diabetes (T1D). Materials and Methods: Detailed clinical- and lifestyle data from 5,460 Danish adults with T1D was linked to ESKD events and death recorded in the national registries. Median follow-up time was 10.4 years (Q1-Q3: 5.1-14.7), during which 303 (5.5%) developed ESKD and 764 (14.0%) died of non-ESKD related causes. To account for the competing risk of death, rate models for the two events (ESKD and death) were estimated separately using Poisson regression analysis, censoring for the other event, and subsequently combined to give the cumulative incidence function for ESKD. External validation of the model is ongoing. Results: The rate model for ESKD included age, male sex, diabetes duration, eGFR, albuminuria, urine albumin-to-creatinine ratio, systolic BP, HbA1c, haemoglobin, previous cardiovascular disease and retinopathy status. Model discrimination was excellent for up to 10-year risk of ESKD with C-statistics between 0.883 and 0.911 (Figure 1). Calibration was adequate for predicting up to 5-year risk of ESKD (P ≥ 0.166). Conclusion: This tool for ESKD risk assessment could be an essential support for the decision on initiation of preventive treatment in persons with T1D. However, external validation is needed. Disclosure D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. G.S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. A. Hulman: None. S. McGurnaghan: None. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. J. Henriksen: None. R.W. Thomsen: None. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. P. Rossing: Advisory Panel; Self; Sanofi. Consultant; Self; Astellas Pharma Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.

39-OR: Secular Trends in Glucose-Lowering Drug Utilization, Glycemic Control, and Severe Hypoglycemia in Adults with Diabetes between 2002 and 2016 in Hong Kong

Introduction: There has been a shift towards new classes of glucose lowering drugs (GLDs) in the past decade but no improvements in glycemic control or hospitalization rates due to severe hypoglycemia (SH) in previous surveys. We examined secular trends in GLDs utilization, glycemic control and rate of SH among people with diabetes, mainly type 2 diabetes, in Hong Kong which introduced a territory-wide, team-based diabetes care model since 2000. Methods: Using population-based data from the Hong Kong Diabetes Surveillance Database consisting mainly of Chinese living a westernized lifestyle, we estimated the annual age- and sex-standardized proportion of GLDs classes, mean hemoglobin A1c (HbA1c) levels and SH rates in 763,809 diabetes patients aged ≥20 years between 2002-2016. We used Joinpoint regression to examine secular trends over time. Results: In 2002-2016, use declined for sulfonylureas (50.7% to 28.9%) but increased for metformin (47.8% to 57.3%) and dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.01% in 2007 to 7.0%). The proportion of patients with HbA1c of 6.0-7.0% increased from 25.6% to 37.2% while the rate of SH declined from 4.4 to 1.7 per 100 person-years. The main improvement in annual mean HbA1c occurred between 2007 and 2014, decreasing from mean (SD) 7.8 (1.6)% to 7.4 (1.7)% (p<0·001). The 20-44 age group had the highest proportion of HbA1c>9% with rising proportions not treated with any GLDs (from 4.3% to 10.5%). Conclusion: Prescription of GLDs has changed dramatically in Hong Kong in the past 15 years in line with treatment guidelines and introduction of new drugs. The modest but important improvement in HbA1c since 2007 coincided with widening reform of diabetes services in primary care and introduction of DPP-4i. Poor glycemic control and low utilization of GLDs in the youngest age group calls for targeted treatment strategies and ongoing surveillance. Disclosure A. Yang: None. H. Wu: None. E.S. Lau: None. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. A.P. Kong: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Sanofi. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. W. So: None. A. Luk: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Roche Pharma. Other Relationship; Self; Merck Sharp & Dohme Corp. J.C. Chan: None. E. Chow: None. Funding Chinese University of Hong Kong

1582-P: Glycemic Change from Baseline in the First Large-Scale Longitudinal Nationwide Study on Management and Real-World Outcomes of Diabetes in India (LANDMARC)

Glycemic change from baseline to 6-months was examined across various subgroups during first 6-months observational period in this 3 year prospective study (LANDMARC; CTRI/2017/05/008452). Descriptive statistics was used to assess glycemic trends in adults with T2D controlled/uncontrolled on ≥2 antihyperglycemic medications. Of 6236 enrolled participants, 5703 completed 6-month follow-up (visit 2 [V2]). A significant (p<0.0001) decrease in all glycemic parameters was noted at V2 from mean (SD) baseline A1C (8.05% [1.59]), FPG (142.80 [50.35]) mg/dL, and PPG (205.70 [72.26]) mg/dL; however, only 18.9% had reached optimum glycemic control (A1C<7%) (Table). On A1C subgroup stratification, significant reduction in number of participants was seen in 8-8.9% and ≥9% groups with more participants entering the 7-7.9% group (Table). In the CV risk factor and complications subgroups, glycemic parameters worsened in participants with family history of coronary disease and history of stroke. Interestingly, only participants with heart failure had optimal glycemic control and showed maximum reduction in FPG and PPG (Table). Within 6 months of study initiation, there was a marked improvement in the glycemic parameters in people with T2D; however notably only few had reached optimum control levels. Disclosure R. Ghosh: Employee; Self; Sanofi. A.K. Das: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. A. Mithal: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Johnson & Johnson, Lilly Diabetes, Novo Nordisk A/S. S. Joshi: Advisory Panel; Self; Novo Nordisk A/S, Roche Pharma, Sanofi. K. Kumar: None. S. Kalra: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; Novo Nordisk A/S, Sanofi-Aventis. A. Unnikrishnan: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Eli Lilly and Company, Ipca Laboratories, Merck Sharp & Dohme Corp., Novartis AG. H. Thacker: None. B. Sethi: None. S. Mohanasundaram: Employee; Self; Sanofi. S.K. Menon: None. A. Nair: Employee; Self; Sanofi. N. Rais: None. S. Wangnoo: None. S. Chowdhury: Advisory Panel; Self; Novo Nordisk A/S. A.H. Zargar: None. Funding Sanofi India Limited

28-OR: How Early after Treatment Initiation Are the CV Benefits of Empagliflozin Apparent? A Post Hoc Analysis of EMPA-REG OUTCOME

In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes (T2D) with established atherosclerotic cardiovascular disease (ASCVD), empagliflozin reduced the risk of hospitalization for HF (HHF) by 35% (HR [95%CI] 0.65 [0.50-0.85]), CV death/HHF by 34% (0.66 [0.55-0.79]), and CV death by 38% (0.62 [0.49-0.77]) with an early separation of the cumulative incidence curves. We aimed to explore at what time point after randomization the benefits became apparent. Overall, 7020 patients were treated with empagliflozin 10, 25 mg or placebo. We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF and CV death based on Hazard Ratios (HRs) (95% CI), and calculated the HR on the day the effect reached significance using Cox proportional hazards models. The reduction in risk with empagliflozin vs. placebo reached significance at day 17 for HHF [0.10 [0.01, 0.87), p=0.0372], and day 27 for CV death/HHF [HR 0.28 (0.08, 0.97), p=0.0445], and sustained significant throughout follow-up (Figure). The benefit on CV death reached significance for the first time at day 59 [HR 0.28 (0.08, 0.96)]. HRs stabilized as the number of patients with events increased over time. The benefit of empagliflozin in reducing the risk of HHF, CV death/HHF and CV death emerged within weeks after treatment initiation in EMPA-REG OUTCOME. The earliest effect appears to be on HHF. Disclosure S. Verma: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Other Relationship; Self; AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Eli Lilly and Company, EOCI Pharmacomm, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi, Sanofi, Sun Pharmaceuticals, Toronto Knowledge Translation Working Group. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. M. Mattheus: None. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

1742-P: Targeting the Low Molecular Weight Protein Tyrosine Phosphatase for Obesity-Associated Diabetes Therapy

Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, acts as a critical regulator of insulin signaling by dephosphorylating the activation motif of the insulin receptor. Human genetics studies suggest that high LMPTP catalytic activity promotes diabetes and insulin resistance in obesity. We recently discovered that LMPTP is a critical promoter of insulin resistance in obesity through an action on the liver and that pharmacological inhibition of LMPTP reverses obesity-induced diabetes in mice. Here we report our progress in the development of a new chemical series of LMPTP inhibitors that is orally bioavailable and effective at treating disease in obese diabetic mice. Disclosure S.M. Stanford: None. M.A. Diaz: None. J.J. Zou: None. R.J. Ardecky: None. A. Pinkerton: None. N. Bottini: Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., Kyowa Hakko Kirin Co., Ltd., Roche Pharma. Funding American Diabetes Association/Pathway to Stop Diabetes (1-15-INI-13 to S.M.S.); National Institutes of Health (R01DK106233)

139-LB: The Redox Balance Predicts Both Cardiovascular (CV) and Renal Outcomes in CANVAS

We tested whether circulating metabolites reflecting cytosolic (lactate/pyruvate) or mitochondrial (β-hydroxybutyrate/acetoacetate [AcAc]) redox balance are associated with major clinical outcomes in patients with type 2 diabetes. The CANVAS study randomized participants to placebo (Plb) or canagliflozin (100mg or 300mg) (Tx) and followed them for up to 6 years. Metabolic markers were measured at baseline (2,373 in Tx [dose combined] and 1,185 in Plb), at year 1 (2,022 in Tx and 949 in Plb) and year 2 (1,793 in Tx and 834 in Plb). By linear mixed model analysis, plasma free fatty acids, AcAc, and β-hydroxybutyrate increased with Tx vs. Plb, whereas plasma pyruvate decreased with Tx while glycerol and lactate did not change significantly. Of note, these changes were independent of the background antihyperglycemic medication (metformin, sulfonylureas, insulin, or combinations thereof). The incidence of hospitalized heart failure or cardiovascular death (HHF/CVD) was 10.2%, the incidence of the renal composite endpoint (CombR; i.e., 40% reduction in eGFR or renal replacement/death) was 3.9%. In Cox models adjusting for sex, age, BMI, HbA1c, baseline systolic blood pressure, diabetes duration, smoking, baseline use of diuretics or statins, history of heart failure, prior CV disease, and Tx, baseline AcAc was a negative predictor of HHF/CVD (HR=0.83 [95%CI 0.75-0.94]), while baseline lactate was a positive predictor (HR=1.42 [95%CI 1.20-1.68]). Adding baseline ACR and eGFR to the same multivariate model for CombR as the outcome, AcAc was still a negative (HR=0.84 [95%CI 0.75-0.94]) and lactate still a positive predictor (HR=1.42 [95%CI 1.20-1.67]). For CV and renal outcomes, higher baseline plasma lactate is an independent positive risk marker potentially reflecting a reducing cytosolic redox shift, but higher baseline plasma AcAc is a protective factor, which may be related to efficient mitochondrial supply/usage of reducing equivalents. Further analysis is needed to test these hypotheses. Disclosure E. Ferrannini: Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Oramed Pharmaceuticals. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. S. Baldi: None. T. Scozzaro: None. F. Tesfaye: Employee; Self; Janssen Research & Development, LLC. W. Shaw: Employee; Self; Janssen Pharmaceuticals, Inc. N. Rosenthal: None. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. V. Perkovic: Other Relationship; Self; See Other Relationship field. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. Funding Janssen Research & Development, LLC

155-OR: ADA Presidents’ Select Abstract: Symptom Responses to Hypoglycemia Are Related to Connectivity Change between the Thalamus and Frontal Lobes

Neuroimaging studies highlight the importance of thalamic activation in response to hypoglycemia in people with and without type 1 diabetes (T1D). This activation is characteristically attenuated in impaired awareness of hypoglycaemia (IAH), a major risk factor for severe hypoglycemia. We investigated changes in connectivity of the thalamus with other brain regions during hypoglycemia. Methods: Fourteen people without diabetes (no diabetes, ND), 15 with T1D and normal awareness of hypoglycemia (NAH) and 22 with IAH, all right-handed, age, sex and gender matched, underwent a hyperinsulinemic glucose clamp during which we acquired blood oxygen level dependent fMRI at euglycemia (90mg/dL) and at onset of hypoglycemia (48mg/dL). Connectivity was studied using the CONN toolbox in SPM12. A thalamic seed was used in a seed-to-voxel analysis with and without the increase in symptoms at hypoglycemia as an explanatory regressor variable. Results: Symptom scores in response to hypoglycemia rose earliest and to the greatest levels in NAH (11.0 to 18.3, p= 0.029). The rise in symptom scores in ND was not significant at this timepoint (9.2 to 13.8, p= 0.057), whilst IAH showed no symptom change (10.5 to 9.8, p= 0.7). In ND, hypoglycemia increased thalamic connectivity with the right frontal pole (pFDR = 0.018). This did not occur in diabetes, either in NAH or IAH. The NAH group demonstrated a positive relationship between change in symptoms with change in connectivity of the thalamus and a left frontal pole region (pFDR = 0.035), whereas an overlapping area had a negative correlation in ND (pFDR = 0.001). There was no correlation in IAH. Conclusion: During hypoglycemia, those with T1D display aberrantly enhanced thalamic connectivity with brain regions responsible for complex behavior. Disruption of this network occurs in IAH and may be the mechanism for failure of perception of the onset of hypoglycemia and reduced hypoglycemia avoidance behaviors, increasing severe hypoglycemia risk. Disclosure P. Jacob: None. M. Nwokolo: Other Relationship; Self; Sanofi. O. ODaly: None. F.O. Zelaya: None. S.A. Amiel: Advisory Panel; Self; Medtronic, Novo Nordisk A/S, Roche Pharma. Other Relationship; Self; Diabetes UK. P. Choudhary: Advisory Panel; Self; Abbott, Eli Lilly and Company, Insulet Corporation, Medtronic. Research Support; Self; European Union, JDRF. Speaker’s Bureau; Self; Dexcom, Inc., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis. Funding JDRF (3-SRA-2017-484-S-B)

924-P: Exploring Potential Mediators of the Cardiovascular Benefit of Dulaglutide in REWIND

The REWIND trial showed that relative to placebo (PL), once weekly dulaglutide (DU) 1.5 mg reduced the incidence of a major adverse cardiovascular (CV) event (MACE; nonfatal myocardial infarction, nonfatal stroke, or CV death) in patients with T2D with and without established CV disease (hazard ratio (HR) 0.88, 95% CI [0.79, 0.99]; p=0.026). DU also significantly reduced A1C, body weight (BW), and systolic blood pressure (SBP) (Table). In this post-hoc assessment, a mediation analysis was used to estimate the degree to which the effect of DU on these risk factors could statistically account for its effect on MACE. Data were analyzed from 9901 patients who had 1257 first MACE events over 5.4 median yrs of observation. Those risk factors for which the updated mean on follow-up was significantly related to MACE were added to a separate Cox model that included DU allocation, the baseline [BL] value of the measurement and the updated mean of the variable as time dependent covariates. Only A1C satisfied this condition (Table), suggesting that BW and SBP did not mediate the effect of DU on MACE in this study population. The effect size of DU on the MACE outcome was attenuated by 36.1% after accounting for its effect on A1C (Table). In conclusion, the results suggest most of the CV benefit of DU on MACE is not attributable to the A1C, BW, or SBP-lowering effects of DU. Disclosure H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. C. Hasenour: Employee; Self; Eli Lilly and Company. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. K. Branch: Consultant; Self; Bayer AG. Research Support; Self; Bayer AG, Eli Lilly and Company. M. Konig: Employee; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. M. Lakshmanan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi.

1028-P: Real-World Effectiveness and Safety of Insulin Glargine 300 U/mL (gla-300) in Insulin-Naïve Patients with Type 2 Diabetes (T2DM): Interim Analysis of the ATOS Study

ATOS is a prospective, 12-month, observational study assessing real-world effectiveness of the second-generation basal insulin analog Gla-300 in emerging markets. Insulin-naïve adults (≥18 years) with T2DM, HbA1c >7-≤11 % and previously treated with ≥1 oral antihyperglycemic drug were recruited in 18 countries. An interim analysis was undertaken when ≥50% of participants had 6-months’ follow-up data (cut-off July 1, 2019); this included 4527 eligible patients (Eastern Europe: 1748; Egypt: 214; India: 1269; Latin America and Caribbean: 317; Western Asia: 882; Southeast Asia: 46; Taiwan: 51). Mean (SD) age was 57.2 (10.8) years, BMI was 29.4 (5.3) kg/m2, and duration of diabetes was 10.2 (6.2) years; 48.4% were male. Physician-set individualized HbA1c (%) goals at baseline were <7: 13.7%; 7-<7.5: 70.3%; 7.5-<8: 11.9%; ≥8: 4.2%. The proportion of evaluable patients achieving HbA1c goal at Month 6 (primary outcome) was 25.1% (95% CI: 23.6 to 26.6); HbA1c decreases are shown in Table. Hypoglycemia incidence was low (<2%). Treatment-emergent adverse events (TEAEs) were reported in 230 (5.0%) patients, with 47 (1.0%) serious TEAEs (included population). ATOS showed high baseline HbA1c, suggesting delayed insulin initiation; introduction of Gla-300 led to marked improvements in HbA1c with a good safety profile in a real-world setting. Disclosure G.R. Galstyan: None. A. Bhansali: None. H. Vargas-Uricoechea: Speaker’s Bureau; Self; Sanofi-Aventis. A. Tirosh: Advisory Panel; Self; Novo Nordisk Inc., Sanofi. G. Sun: None. M. Naqvi: Employee; Self; Sanofi. V. Pilorget: Employee; Self; Sanofi. M. Coudert: Employee; Self; Roche Pharma, Sanofi-Aventis. D. Cherkasov: None. N. Khan: None. Funding Sanofi (ATOS/NCT03703869)

26-OR: Acute Declines in EGFR during Treatment with Canagliflozin and Its Implications for Clinical Practice: Insights from CREDENCE

Background: Canagliflozin (CANA) slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its association with long-term eGFR trajectories and safety outcomes are unknown. Methods: This post-hoc study of the CREDENCE trial included 4289 patients with type 2 diabetes and CKD who had eGFR measured at both baseline and week 3. Participants were categorized by percentage decline in eGFR at week 3: >10%, ≤10% to >0%, and ≤0%. Baseline characteristics associated with acute eGFR declines >10% were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use. Results: More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p<0.001). A >30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO; p<0.001). In the CANA but not in the PBO group, older age (OR CANA 1.17, 95% CI 1.05-1.31; per 10 years) and history of heart failure (OR CANA 0.77, 0.59-0.99) were associated with a higher and lower likelihood of an acute eGFR decline >10%, respectively (both p for interaction <0.05). Following the initial eGFR change, long-term eGFR trajectories as well as overall safety profiles were similar across eGFR decline categories (all p values >0.05). Results were consistent when other decline thresholds (>20%) were used and in subgroup analysis by baseline eGFR (30-<45, 45-<60, and 60-<90 ml/min/1.73 m2). Conclusions: Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with placebo was observed regardless of the acute eGFR decline and safety profiles were similar. Disclosure M. Oshima: Research Support; Self; Japan Society for the Promotion of Science Program for Fostering Globally Talented Researchers. M.J. Jardine: Other Relationship; Self; See Other Relationship field. R. Agarwal: Other Relationship; Self; AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. C. Cannon: None. D.M. Charytan: Advisory Panel; Self; Allena Pharmaceuticals, AstraZeneca, Merck & Co., Inc., PLC Medical. Employee; Self; BAIM Institute. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. R. Edwards: Employee; Self; Janssen. T. Greene: Other Relationship; Self; Janssen, Durect, and Pfizer. A. Levin: Consultant; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support; Self; Diabetes Australia. Speaker’s Bureau; Self; AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship; Self; Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.C. Wheeler: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant; Self; AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. H. Zhang: Employee; Self; Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. V. Perkovic: Other Relationship; Self; See Other Relationship field. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC

2258-PUB: Impact of Cardiovascular (CV) Risk Factors during the Initial 6 Months of the First Large-Scale Longitudinal Nationwide Study on Management and Real-World Outcomes of Diabetes in India (LANDMARC)

Impact of cardiovascular (CV) risk factors in participants with T2D during the first 6-months of observational period were examined in this 3 year prospective study (LANDMARC; CTRI/2017/05/008452). CV risk factors (rate of hypertension, dyslipidemia, albuminuria, and family history of premature coronary disease) at baseline (V1) and 6 months (Visit 2 [V2]) were assessed and compared between subgroups. Overall, >50% of the participants who had A1C data available, had CV risks at both V1 (2385/4479; 53.2%) and V2 (2422/4479; 54.1%). More than half of the participants with obesity (BMI ≥25 kg/m2) had CV risks at V1 (2305/4150; 55.5%) and V2 (2340/4150; 56.4%). On comparing the insulin (N=1548) vs. insulin naïve (N=4688) subgroups, a higher proportion of participants on insulin had CV risks than those who were insulin naïve (V1: 60.1% vs. 50.1%; V2: 60.8% vs. 50.9%). At V2, hypertension and dyslipidemia were more predominant in those with BMI ≥23 kg/m2 than <23 kg/m2, with A1C ≥ 7% than <7%, and in men than women (Table). In India, CV risks may be increased in people with T2D who are overweight, have suboptimal glycemic control, or are men. The real-world trend of CV risks may offer insights and direction for risk factor modifications and treatment adjustments. Disclosure R. Ghosh: Employee; Self; Sanofi. A.K. Das: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. S. Joshi: Advisory Panel; Self; Novo Nordisk A/S, Roche Pharma, Sanofi. A. Mithal: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Johnson & Johnson, Lilly Diabetes, Novo Nordisk A/S. K. Kumar: None. S. Kalra: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; Novo Nordisk A/S, Sanofi-Aventis. A. Unnikrishnan: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Eli Lilly and Company, Ipca Laboratories, Merck Sharp & Dohme Corp., Novartis AG. H. Thacker: None. B. Sethi: None. S. Mohanasundaram: Employee; Self; Sanofi. S.K. Menon: None. A. Nair: Employee; Self; Sanofi. N. Rais: None. S. Wangnoo: None. S. Chowdhury: Advisory Panel; Self; Novo Nordisk A/S. A.H. Zargar: None. Funding Sanofi India Limited

356-OR: Effect of Dulaglutide on Kidney Function–Related Outcomes in Type 2 Diabetes: Post Hoc Analysis from the REWIND Trial

In participants with type 2 diabetes (T2D) in the REWIND trial, dulaglutide (DU) use for median follow-up of 5.4 years was associated with reduced composite renal outcomes, defined as the first occurrence of new macroalbuminuria, sustained decline in estimated glomerular filtration rate (eGFR) of ≥30%, or chronic renal replacement therapy. The objective of this post-hoc analysis was to evaluate the effect of dulaglutide on renal outcomes related to kidney function that are typically used in renal outcomes studies, defined as the composite endpoint of sustained eGFR decline ≥40%, end-stage renal disease (ESRD), or all-cause death. Participants with T2D at cardiovascular (CV) risk were randomized (1:1) to DU 1.5 mg once-weekly or placebo. This post-hoc analysis used Cox proportional hazards modeling for time to first event to determine the risk of renal outcomes. Sensitivity analyses were conducted by replacing the all-cause death component with CV or renal death, or renal death. At baseline, treatment groups had similar eGFR (mean±SD: DU=77.2±22.7; placebo=76.6±22.8). The incidence rate of the composite endpoint was significantly lower for the DU group compared with placebo (Table). Treatment with DU 1.5 mg was associated with a 17% risk reduction in kidney function-related outcomes, suggesting potential delay in progression of diabetic kidney disease in patients with T2D at CV risk. Disclosure J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi. Funding Eli Lilly and Company

1955-P: Interleukin-1ß Orchestrates Non–Glucose Dependent Cephalic Phase Insulin Release in Health and Obesity

The non-glucose dependent spike in insulin levels immediately following the beginning of a meal is called the cephalic or pre-absorptive phase of insulin secretion. Even though this early insulin response is of marked consequence for overall postprandial insulin release, its basic mechanisms remain largely unexplored. Here, we show that both genetic and pharmacologic blockade of interleukin-1β (IL-1β) leads to a pronounced reduction in cephalic phase insulin secretion (-0.65 [95%CI= -1.137 to -0.172]). Assessing mice fed a high-fat diet, we found that the cephalic phase insulin response was abolished in obesity. In a systematic review and meta-analysis of trials studying cephalic phase insulin release in healthy human volunteers, we found that this was equally the case in humans. In contrast, high-fat diet-fed mice pre-treated with a specific anti-IL-1β antibody once a week developed no such impairment. We therefore conclude, that dysregulation of physiologic IL-1β signaling, specifically during cephalic phase, may contribute to the overall pathology of metabolic disease. Thus, we identify cephalic phase inflammatory signaling as a novel and potentially modifiable target in the regulation of glucose metabolism. Disclosure S.J. Wiedemann: None. E. Dror: None. D.T. Meier: None. K. Trimigliozzi: None. J. Molina-Tijeras: None. F. Schulze: None. L. Rachid: None. S.P. Häuselmann: None. T.V. Rohm: None. H. Mereau: None. C. Magnan: None. M. Boeni-Schnetzler: None. M.Y. Donath: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Roche Pharma, Sanofi-Aventis.

303-OR: Effect of Dapagliflozin on Risk for Fast Decline in EGFR: Analyses from the DECLARE-TIMI 58 Trial

SGLT2 inhibitors may lead to short term decrease in eGFR, with later stabilization and long-term reduction in the risk for end stage kidney disease. Fast decline (FD) in eGFR can be defined as a reduction of ≥3 ml/min/1.73m2/year and is associated with poor long-term renal prognosis. In this post-hoc analysis we studied the effect of dapagliflozin (dapa) on the risk for FD in the DECLARE-TIMI 58 trial. In DECLARE-TIMI 58, 17,160 patients with T2D and established or increased risk for CVD, with mean baseline eGFR of 85.2 ml/min/1.73m2, were randomized to dapa vs. placebo and followed for a median of 4.2 years. The risk for FD was compared between treatment arms. In the time frame of 0.5 years (after stabilization) to 4 years, the proportion of patients with FD was reduced with dapa vs. placebo (26.8% vs. 37.1% respectively, p<0.0001). This observation was persistent in all subgroups assessed (Table). The mean (SD) reduction in eGFR per year was 6.3 (3.7) vs. 0.0 (2.5) ml/min/1.73m2/year in the FD (N=4,788) vs. non-FD (N=10,224) patients. The proportion of patients with FD during the entire study period (i.e., 0-4 years) was reduced with dapa vs. placebo as well (33.6% vs. 37.0% respectively, p<0.0001). Dapagliflozin reduced the risk for FD in eGFR in a broad population of patients with T2D and either established or increased risk for CVD, but relatively preserved renal function, irrespective of patients’ baseline characteristics.

922-P: LIRA-PRIME: A Randomized Trial in Primary Care Settings of Liraglutide vs. OAD for Glycemic Control in Patients with Type 2 Diabetes Not in Control on Metformin

Most patients with type 2 diabetes (T2D) are treated in primary care, but data to guide evidence-based, shared decision making in this setting are scarce. LIRA-PRIME (NCT02730377) was a randomized, open-label, active-controlled trial in a primary care setting, comparing efficacy and safety of liraglutide vs. an oral antidiabetic drug (OAD) in patients with T2D inadequately controlled with metformin. Patients aged ≥18 years, with A1C 7.5-9.0%, recruited from nine countries (219 sites), were randomized 1:1 using an interactive web response system to liraglutide or an OAD (α-glucosidase inhibitor, DPP-4i, meglitinide, SGLT2i, SU or TZD, chosen by their physician) on top of metformin, for up to 104 weeks. Primary endpoint: time to inadequate glycemic control, defined as A1C &amp;gt;7.0% at two consecutive visits after the first 26 weeks of treatment. Key secondary endpoints: time to premature treatment discontinuation, including for inadequate glycemic control, and occurrence of adverse events (AEs). From Mar 2016 to Aug 2017, patients were randomized to liraglutide (N=996) or OAD (N=995; 48% SGLT2i, 40% DPP-4i, 11% SU). Liraglutide significantly reduced the risk of inadequate glycemic control vs. OAD (416/996 [42%] vs. 547/995 [55%] patients, respectively; hazard ratio [95% CI] 0.58 [0.51;0.66]; p&amp;lt;0.0001) and of premature treatment discontinuation (532/996 [53%] vs. 624/995 [63%], respectively; p&amp;lt;0.0001). Median time to inadequate glycemic control (109 vs. 65 weeks; p&amp;lt;0.0001) and premature treatment discontinuation (80 vs. 52 weeks; p&amp;lt;0.0001) was longer with liraglutide vs. OAD. Rates of serious AEs and hypoglycemic episodes were similar, but more patients discontinued due to gastrointestinal AEs with liraglutide vs. OAD (54/980 [6%] vs. 9/984 [1%], respectively). Within global primary care settings, LIRA-PRIME demonstrated longer lasting glycemic control with liraglutide than with an OAD, when added to metformin. Disclosure J. Unger: Consultant; Self; Bayer. Research Support; Self; GlaxoSmithKline, Merck, Pfizer, Sanofi, Lilly, Janssen. Stock/Shareholder; Self; Tandem Diabetes. Other Relationship; Self; Abbott, Abbott Diabetes, Novo Nordisk. M. Kaltoft: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D. Kolhe: Employee; Self; Novo Nordisk. J. Panda: None. M. Sargın: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Pfizer Inc. B. Wolthers: Other Relationship; Self; Novo Nordisk. M. Zoghbi: Advisory Panel; Spouse/Partner; Janssen Pharmaceuticals, Inc., New Bridge. Advisory Panel; Self; Novartis AG. Advisory Panel; Spouse/Partner; Novartis AG. Advisory Panel; Self; Novo Nordisk A/S. Advisory Panel; Spouse/Partner; Pfizer Inc., Roche Pharma. Advisory Panel; Self; Sanofi. Funding Novo Nordisk A/S

2271-PUB: Rate of Diabetes Complications during the Initial 6 Months of the First Large-Scale Longitudinal Nationwide Study on Management and Real-World Outcomes of Diabetes in India (LANDMARC)

LANDMARC (CTRI/2017/05/008452) aims to evaluate the development and progression of diabetes complications over 3 years in Indian participants with T2D. Rate of diabetes complications was compared from baseline to 6 months (visit 2 [V2]) using McNemar’s test and Chi square test (when complications were stratified in subgroups). There was an increase in the rate of microvascular complications by V2 (Table). Microvascular complications were reported more commonly in participants with A1C≥7% than A1C&amp;lt;7%, with BMI≥23 kg/m2 than BMI&amp;lt;23 kg/m2, and in those with than without cardiovascular (CV) risk factors (Table). In case of macrovascular complications, 7 new cases of peripheral vascular disease, 2 new cases each of MI, stroke and ACS, but no new case of heart failure or unstable angina were reported at V2. Notably, neuropathy was the most common complication at 6 months. The real-world data on complications in LANDMARC may help in understanding disease progression and offer insights on treatment adjustments. Disclosure R. Ghosh: Employee; Self; Sanofi. A.K. Das: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. S. Joshi: Advisory Panel; Self; Novo Nordisk A/S, Roche Pharma, Sanofi. A. Mithal: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Johnson &amp; Johnson, Lilly Diabetes, Novo Nordisk A/S. K. Kumar: None. S. Kalra: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; Novo Nordisk A/S, Sanofi-Aventis. A. Unnikrishnan: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; Eli Lilly and Company, Ipca Laboratories, Merck Sharp &amp; Dohme Corp., Novartis AG. H. Thacker: None. B. Sethi: None. S. Mohanasundaram: Employee; Self; Sanofi. S.K. Menon: None. A. Nair: Employee; Self; Sanofi. N. Rais: None. S. Wangnoo: None. S. Chowdhury: Advisory Panel; Self; Novo Nordisk A/S. A.H. Zargar: None. Funding Sanofi India Limited

1497-P: Secular Trends in Incidence and One-Year Mortality Rates of Lower Extremity Amputation in People with Diabetes in Hong Kong between 2001 and 2016

Objective: Diabetes is a leading cause of nontraumatic lower extremity amputation (LEA). We describe the secular trends in incidence rates of LEA and one-year mortality rates after LEA in people with diabetes in Hong Kong between 2001 and 2016. Methods: The Hong Kong Diabetes Surveillance Database (HKDSD) is a territory-wide population-based diabetes cohort identified from the Hong Kong Hospital Authority electronic medical system. We identified LEA events using ICD-9 procedure codes and that of one-year mortality after LEAs from the linkage to the Hong Kong Death Registry. We used Joinpoint regression models to describe the trends in incidence of LEAs from 2001 to 2016 and one-year mortality rates after LEAs from 2001 to 2015. Results: Between 2001 and 2016, a total of 390,071 men and 380,007 women with diabetes aged 20 years or older were included in the HKDSD, among whom 6,113 LEAs in men and 4,149 LEAs in women were recorded. The event rates of minor LEAs declined by 48.6% (average annual percent change [AAPC]: -3.8, 95% CI -5.7, -1.9) from 14.0 to 7.2 per 10,000 in men and by 59.5% (AAPC: -6.3, 95% CI -10.6, -1.8) from 7.9 to 3.2 per 10,000 in women. The rates of major LEAs declined by 77.9% (AAPC: -8.0, 95% CI -9.6, -6.5) from 19.5 to 4.3 per 10,000 in men and by 79.3% (AAPC: -10.4, 95% CI -13.1, -7.6) from 11.6 to 2.4 per 10,000 in women. The one-year mortality rates after both minor and major LEAs remained constant during the surveillance period in both sexes. The AAPC for one-year mortality rates was 1.5 (95% CI -3.0, 6.1) in men and 0.6 (95% CI -4.7, 6.1) in women after minor LEAs, and was -2.1 (95% CI -4.8, 0.6) in men and 2.6 (-1.4, 6.7) in women after major LEAs. Conclusions: Although the event rates of LEAs have declined overall in people with diabetes in Hong Kong, there was no improvement in one-year mortality rates after LEAs. Urgent action to improve the quality of care and ongoing surveillance after LEAs in people with diabetes is needed. Disclosure H. Wu: None. A. Yang: None. E.S. Lau: None. R.C. Ma: Advisory Panel; Self; AstraZeneca. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Tricida Inc. A.P. Kong: Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Sanofi. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. E. Chow: None. W. So: None. J.C. Chan: None. A. Luk: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Roche Pharma. Other Relationship; Self; Merck Sharp &amp; Dohme Corp.

490-P: Renal Effects of Metformin in Type 1 Diabetes (T1D): The REMOVAL Trial

Aims: In REMOVAL (NCT01483560), metformin attenuated decline in estimated glomerular filtration rate (eGFR) using the creatinine-based Modified Diet in Renal Disease (MDRD) equation in adults with T1D. We now report the effects of metformin vs. placebo on: (i) eGFR by CKD-EPI; and (ii) microalbuminuria (albumin: creatinine ratio, ACR). Methods: In 428 participants (mean age 55 years; HbA1c 8.0%; BP 130/72mmHg; eGFR 92 ml/min/1.73m2, 69% on ACE inhibitors/ARBs), CKD-EPI was derived separately from creatinine and cystatin C (annual). ACR was measured on annual first morning void. Treatment effects were compared by ANCOVA for continuous data (adjusted for baseline) and Cox Regression for incident microalbuminuria. Results: Mean baseline eGFR by CKD-EPI was 90 ml/min/1.73m2 by creatinine and 96 ml/min/1.73m2 by cystatin C. Decline in eGFR over 3 years was attenuated by metformin vs. placebo when CKD-EPI was derived from creatinine and cystatin C. There was no effect on ACR but confidence intervals were wide (Table). Conclusions: Deriving eGFR from other biomarkers/equations does not alter the conclusion that metformin has a potentially beneficial effect on eGFR in T1D; its effect on ACR requires further study. Disclosure J.G. Timmons: None. N. Greenlaw: None. C.D. Stehouwer: None. M. Brouwers: None. N. Chaturvedi: Consultant; Self; AstraZeneca. A.D. Hughes: Advisory Panel; Spouse/Partner; AstraZeneca. I. Hramiak: Consultant; Self; Medtronic, Novo Nordisk Inc. Research Support; Self; Eli Lilly and Company, PHRI Population Health Research Institute, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim (Canada) Ltd., Merck &amp; Co., Inc. Other Relationship; Self; AstraZeneca, Bristol-Myers Squibb, Insulet Corporation. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. P. Welsh: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Roche Diagnostics. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. P. Rossing: Advisory Panel; Self; Sanofi. Consultant; Self; Astellas Pharma Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; Novo Nordisk A/S. J.R. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Advanced Clinical Intelligence, IQVIA. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Merck KGaA, Novo Nordisk A/S.

1098-P: Biomarkers of Tubular Injury and Effects of Canagliflozin in the CANVAS Trial

Introduction: Canagliflozin (CANA) slows progression of kidney disease, which may be at least partly mediated by improvements in tubular function. To test this hypothesis, we assessed effects of CANA on markers of tubular function and injury in the CANVAS trial. Methods: Urine biomarkers of tubule function (β2-microglobulin [B2M], cystatin C, and uromodulin), tubular injury (interleukin-18 [IL-18], kidney injury molecule-1 [KIM-1], neutrophil gelatinase associated lipocalin [NGAL], and osteopontin), and inflammation (monocyte chemotactic protein-1 [MCP-1]) were measured at baseline and after 12 months. Biomarker concentrations were standardized for urine creatinine concentration. Differences between CANA and placebo treatment were assessed using ANCOVA models. Results: We included 3723 CANVAS participants with available urine samples (eGFR 77.1 ml/min/1.73 m2 and median UACR 11.7 mg/g). Clinical characteristics and biomarker levels were well balanced between treatment groups at baseline. CANA compared to placebo significantly reduced urinary KIM-1, uromodulin, cystatin C, and osteopontin. It did not change NGAL or MCP-1 and increased IL-18 and B2M. Results were consistent in subgroups by baseline UACR except MCP-1, which decreased in patients with UACR ≥30 mg/g (Table). Conclusion: CANA had variable effects on markers of tubule cell injury and function, decreasing 4, while 2 remained stable and 2 increased. Disclosure T. Sen: None. J. Li: Employee; Self; George Institute. B. Neal: Research Support; Self; Janssen Research &amp; Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research &amp; Development, LLC. M.J. Jardine: Other Relationship; Self; See Other Relationship field. J. Ix: Research Support; Self; Baxter. M.G. Shlipak: Advisory Panel; Self; Cricket Health, Tai Diagnostics. V. Perkovic: Other Relationship; Self; See Other Relationshipfield. Y. Yavin: Employee; Self; Janssen Research &amp; Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research &amp; Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research &amp; Development, LLC

156-OR: Fear of Hypoglycemia in People with Type 1 Diabetes and Problematic Hypoglycaemia: A Mismatch between Worry and Behaviour?

Problematic hypoglycemia complicates insulin therapy in &amp;gt;25% of adults with type 1 diabetes (T1D). Previous work has identified relationships between cognitive barriers to hypoglycemia avoidance and impaired awareness of hypoglycemia (IAH) with recurrent severe episodes (SH). We investigated fear of hypoglycemia in people with IAH and SH enrolling in a trial of interventions to restore hypoglycemia awareness (“HARPdoc” ClinicalTrials.gov NCT02940873) and compared their data with T1D clinic attenders not enriched for problematic hypoglycemia. Method: Adults with T1D (HARPdoc cohort; n=98, age 54±13 yr, 56% female, T1D duration 40±15 yr) and problematic hypoglycemia (Clarke score 5.5±1.0) completed the Hypoglycemia Fear Survey II (HFS), Hyperglycemia Avoidance Scale (HAS) and anonymous 12 month SH recall forms. The T1D clinic comparator group was n=467, age 46±14 yr, 50% female, T1D duration 30±13 yr. Results: In preliminary analyses, the HARPdoc cohort (n=88) reported higher scores on total HFS (p=0.018) and its worry subscale (p&amp;lt;0.0001) than the comparator. Behavior subscale scores were lower (p&amp;lt;0.0001). In the HARPdoc cohort, 25% (n = 22) reported low worry about hypoglycemia despite high SH risk (vs. 8% in the comparator). People with high worry scored the HAS worry subscale higher (p&amp;lt;0.001). The HARPdoc cohort were grouped by frequency of SH (&amp;lt;2; 2 - 4; 5-12 and &amp;gt;12 SH per yr). Worry scores increased with higher SH rates (p=0.004). Behavior scores increased (p=0.041) but not above the comparator 75th centile. In the ’maintaining high glucose’ subset of HFS behavior items, scores increased between the high SH rate groups (p=0.042) but not the lower rate groups. Conclusion: The majority of people with significant hypoglycemia problems show appropriately increased worry but not corresponding increases in behavior scores. A subgroup show inappropriately low worry. Inability to change behaviors, and worry about hyperglycemia, may be barriers to avoiding SH. Disclosure R.H. Maclean: None. P. Jacob: None. S. Haywood: None. P. Choudhary: Advisory Panel; Self; Abbott, Eli Lilly and Company, Insulet Corporation, Medtronic. Research Support; Self; European Union, JDRF. Speaker’s Bureau; Self; Dexcom, Inc., Novartis AG, Novo Nordisk A/S, Sanofi-Aventis. S.R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S. Other Relationship; Self; MannKind Corporation. E. Toschi: None. D. Kariyawasam: None. T.C. Anderbro: None. S.A. Amiel: Advisory Panel; Self; Medtronic, Novo Nordisk A/S, Roche Pharma. Other Relationship; Self; Diabetes UK. Funding JDRF (4-SRA-2017-266-M-N)