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Background: GLP1s are ineffective for a subset of patients. Differentiating between responders and non-responders based on baseline variables would allow for an individualized approach to managing diabetes. Methods: A retrospective analysis of 324 veterans at the Omaha VA with type 2 diabetes on a GLP1 agonist to evaluate effectiveness quantified by reductions in HbA1c (>/= 0.5%) body weight (>/= 3%) and insulin doses (>/= 10% decrease or off insulin) relative to baseline was done with the outcome being a complete response in all three. Associations between categorical variables of interest and the dichotomous outcome were assessed using Chi-Square and t-tests. A logistic regression was run for the dichotomous outcome and included variables with bivariate p-values less than 0.20. Results: In terms of, response to one, two or all outcome variables, Dulaglutide had, 22 (38.6%) , 21 (36.8%) and 9 (15.8%) ; Liraglutide had 45 (34.6%) , 44 (33%) and 33 (25.3%) ; Semaglutide had 24 (17.5%) , 64 (46.7%) and 43 (31.4%) . Patients on Semaglutide trended towards having higher odds of a complete response (odds 2.45 95% CI 0.93, 6.48) compared to Dulaglutide. Older patients had a higher odds of a complete response (odds 1.95% CI 1.01, 1.p=0.02 Table 1) . Variables including baseline A1c, insulin dose, BMI, Metformin, and eGFR were not significantly associated with a complete response to GLP1. Conclusion: Age and the type of GLP1 are variables that determine effectiveness. Disclosure S.Kunwar: None. K.Samson: None. C.Davis: None. V.Shivaswamy: Research Support; Eli Lilly and Company, Kowa Company, Ltd., Novo Nordisk. C.Desouza: Advisory Panel; AstraZeneca, Bayer AG, Novo Nordisk A/S, Consultant; Asahi Kasei Corporation.

Animal models of obesity have shown that the expression of Thromboxane A2 Receptor (tbxa2r) and thromboxane synthase (Tbxas1) are increased in adipose tissue (AT) and are associated with insulin resistance and inflammation. Objective: To compare Tbxa2r gene expression in the AT of human subjects with different degrees of obesity and to determine the association between AT Tbxa2r with BMI and markers of AT inflammation. Methods: Subcutaneous AT samples were collected from lean (BMI 40) subjects. Gene expression of Tbxa2r was analyzed in AT and compared among different groups. Correlation analysis to determine the association between AT Tbxa2r and obesity and obesity-related inflammation. Results: The mRNA levels of Tbxa2r were significantly higher in obese compared to normal subjects (P Conclusion: Signaling of TxA2 is higher in AT in obesity and is associated with BMI as well as inflammatory genes. Tbxa2r may be a potential therapeutic target for obesity-linked diseases including type 2 DM and CV disease. Disclosure D. Alcaraz alvarez: None. S. Viswanathan: None. T. Gopal: None. N. Kumar: None. K. Kelley: None. C. Desouza: Advisory Panel; Self; Bayer AG, Novo Nordisk, Consultant; Self; AstraZeneca.

Purpose: To delineate which factors help predict whether a patient is likely to respond or not respond to treatment with a glucagon-like peptide-1 (GLP-1) agonist. Methods: The medical records for veterans with type 2 diabetes mellitus who began treatment with any GLP-1 agonist at the Veterans Affairs Nebraska-Western Iowa Health Care system from January 1, 2015, to December 31, 2019, were retrospectively reviewed. Patient demographics and baseline objective data were collected at treatment onset. Defined decreases in hemoglobin A1C (HbA1c), body weight, and insulin dose over a minimum 6-month period were used to identify responders and nonresponders. Associations between categorical variables and response status were assessed using Chi-Square tests or Fisher’s exact tests, and Wilcoxon Rank Sum tests were used to examine differences in distributions of variables of interest between response status groups. Results: Of the 55 veterans evaluated during the study period, forty-two subjects (78%) responded to treatment with a GLP-1 agonist whereas twelve subjects (22%) did not respond. The median baseline HbA1c of those who responded was 8.7 (IQR: 8.3, 10.0) compared to 8.1 (IQR: 7.6, 8.8) for those who did not respond (p = 0.03). Among patients with peripheral neuropathy, 88.5% responded while only 65.5% of those without peripheral neuropathy responded (p = 0.046). Conclusion: We demonstrate that a response to GLP-1 agonist treatment was associated with a higher baseline HbA1C and the presence of peripheral neuropathy. These findings warrant future multivariate analyses of a larger cohort to determine the ideal candidates for GLP-1 agonist therapy. Disclosure B. A. Begley: None. C. Desouza: Advisory Panel; Self; Bayer AG, Novo Nordisk, Consultant; Self; AstraZeneca. V. Shivaswamy: Research Support; Self; Eli Lilly and Company, Kowa Pharmaceuticals, Novo Nordisk. K. Samson: None. E. Silverman: None.

The global PIONEER program investigated the efficacy and safety of oral semaglutide, a glucagon-like peptide-1 receptor agonist. Patients with type 2 diabetes were randomized to once-daily oral semaglutide (3, 7 or 14 mg, or flexibly dosed [flex]), placebo, or active comparator (empagliflozin 25 mg, sitagliptin 100 mg or liraglutide 1.8 mg). This exploratory subgroup analysis evaluated the effect of race on glycated hemoglobin (HbA1c) and body weight (BW) reductions at the end of treatment (week 26, 52 or 78). Data were analyzed from PIONEER 1-5, 7 and 8 by race (White, Asian, Black/African American). Baseline characteristics were generally similar across subgroups except for BW, which was lower in Asian patients. Generally, greater HbA1c reductions were observed with oral semaglutide 14 mg/flex vs. comparators across subgroups (Table). In PIONEER 1, 4 and 8, there was a significant interaction between treatment and race, with greater HbA1c reductions and estimated treatment differences in Asian patients than in other subgroups (Table). Overall, BW reductions were greater for oral semaglutide vs. comparators, regardless of subgroup and without significant interactions between treatment and race. Our findings in this exploratory subgroup analysis suggest that, in some PIONEER trials, Asian patients achieve greater HbA1c reductions than other race groups when treated with oral semaglutide. Disclosure C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. A. Amod: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Sanofi-Aventis, Servier. Consultant; Self; Servier. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk A/S, Sanofi-Aventis, Servier. K. Kallenbach: None. P.J. Lin: Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch + Lomb, Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Mead Johnson Nutrition, Merck & Co., Inc., Novo Nordisk Inc., Sun Pharmaceutical Industries Ltd. Other Relationship; Self; Elsevier. M. Abildlund Nielsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. R. Sørrig: Employee; Self; Novo Nordisk A/S. E. Montanya: Advisory Panel; Self; Sanofi. Consultant; Self; Novartis Pharmaceuticals Corporation. Employee; Spouse/Partner; Almirall. Speaker’s Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Funding Novo Nordisk A/S

Background: Thromboxane A2 (TxA2), a lipid mediator plays a critical role in cardiovascular disease and chronic inflammatory disorders. TxA2 signaling is regulated by TxA2 synthase (Tbxas1), an enzyme that produces TxA2, and TxA2 receptor (Tbxa2r). Objective: To determine if Tbxa2r gene expression in adipose tissue (AT) is higher in obese insulin resistant (IR) subjects compared to overweight non-IR subjects. Methods: Insulin resistance was measured via a homeostatic model assessment of insulin resistance (HOMA-IR). Subcutaneous AT biopsies were obtained from overweight (BMI between ≥25 to 2.5) subjects. Gene expression of Tbxa2r and Tbxas1 were analyzed in tissue samples and compared between groups. Results: The mRNA levels of Tbxa2r and Tbxas1 were significantly higher in obese IR subjects compared to overweight subjects (P Conclusion: Our data suggest that TxA2 signaling is activated in AT in obesity and is associated with the development of insulin resistance in obesity. Tbxas1 and/or Tbxa2r may be a potential therapeutic target for obesity-linked metabolic diseases. Disclosure D. Alcaraz Alvarez: None. S. Viswanathan: None. T. Thangavelu: None. N. Kumar: None. K. Kelley: None. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S.

We hypothesized that islet autoimmunity, hitherto considered the pathophysiologic basis of type 1 diabetes (T1D) and latent autoimmune diabetes of adults (LADA), could contribute to ß cell dysfunction in patients with type 2 diabetes (T2D). To evaluate this question, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study - Beta Cell Ancillary Study Network measured humoral islet autoimmunity (autoantibodies against 65 kDa glutamic acid decarboxylase (GAD65-Ab), islet autoantigen-2 (IA2-Ab) and zinc transporter-8 (ZnT8-Ab)) in 392 participants (age 57.2 ± 10.1 y; BMI 33.5 ± 6.2 kg/m2; diabetes duration 4.0 ± 3.0 y; HbA1c 7.5 ± 0.5 %; on metformin as the sole glucose-lowering medication), and cellular islet autoimmunity (T cell autoreactivity against a broad range of islet antigens) in 322 of the same participants. 41.4% had evidence of cellular islet autoimmunity and 13.5% had evidence of humoral islet autoimmunity, but only 5.4% had both. T cell autoreactivity to islet antigens, but not autoantibody-positivity, was associated with diminished ß cell function, as assessed by the ratio of incremental area under the curve (iAUC) of C-peptide to iAUC of glucose during 0-120 min of an OGTT (ß = -0.1403; se = 0.0612; p = 0.0219) or ∆C-peptide/∆glucose during 0-30 min of an OGTT (ß = -0.2113; se = 0.0728; p = 0.0037), adjusted for insulin sensitivity. T cell positive participants also had higher fasting plasma glucose (p = 0.045) and HbA1c (p = 0.001) than T cell negative participants. These findings indicate that islet autoimmunity in T2D patients is far more prevalent than previously recognized; T cell mediated islet autoimmunity is associated with diminished ß cell function. Disclosure B. Brooks-Worrell: None. C.S. Hampe: None. E.V. Gonzalez: None. B.M. Palomino: None. S.Z. Zangeneh: None. K. Utzschneider: Other Relationship; Self; Medtronic. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. M.E. Larkin: None. M.L. Johnson: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Abbott, Dexcom, Inc., Insulet Corporation, JDRF, Lilly Diabetes, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. N. Younes: None. N. Rasouli: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., Novo Nordisk Inc. C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb. J.Y. Park: None. H. Florez: None. W. Valencia: None. A. Shojaie: None. J.P. Palmer: None. A. Balasubramanyam: None. Funding National Institutes of Health (R01DK104832, U01DK098246)

Background: Thromboxane-Prostanoid Receptor (TP-R) is implicated in several chronic inflammatory disorders. Our preclinical animal studies showed that TP-R plays a critical role in obesity linked Insulin Resistance (IR). Aim: To determine the link between TP-R and obesity and/or obesity-associated inflammation/IR in human subjects. Methods: We collected PBMCs from lean normal and obese IR subjects and analyzed the expression of various inflammatory genes including TP-R, Thromboxane A2 Synthase (TXA2S), TNFα, and MCP-1. We obtained subcutaneous adipose tissue biopsies from obese subjects and analyzed the TP-R mRNA expression and its correlation with inflammatory cytokines mediating IR. Results: TP-R mRNA expression is significantly increased in PBMCs of obese IR subjects compared to lean normal subjects (P Conclusion: Our data demonstrate that TP-R expression is positively correlated with markers of obesity and/or IR and support our hypothesis that TP-R can be used as a biomarker or a therapeutic target for obesity related IR. Disclosure T. Thangavelu: None. S. Viswanathan: None. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US. Funding National Institute of General Medical Sciences; Great Plains Institutional Developmental Award for Clinical and Translational Research

Type 1 diabetes affects the structure and function of the brain, with psychomotor speed as the most commonly reported deficit. The current study sought to uncover the dynamics underlying motor processing in the brain of adults with type 1 diabetes using an arrow-based Flanker task. Adults (ages 19-35, N = 39) with type 1 diabetes and no major complications and a matched control group (N = 40) underwent magnetoencephalography (MEG) while performing the task. During the task, participants were presented with a row of five arrows facing right or left, and participants were instructed to respond by button press to the direction of the middle arrow. Analyses focused on the time period around movement execution to examine motor-related dynamics. Time series analyses were performed on the peak beta and gamma responses from the motor cortices. An ANOVA model and follow-up regression analyses were used to delineate the predictive value of each neural response in driving behavioral outcomes. Subsequent t-tests between frequent (3+ episodes per week) and infrequent (0-1 episodes per week) hypoglycemic groups were performed to examine response differences within the adults with type 1 diabetes. Responses driving behavior differed between adults with and without type 1 diabetes. In adults with type 1 diabetes, beta frequency responses were significant predictors of reaction time, where greater ipsilateral recruitment led to faster reaction times (b = .58, t = 3.64, p = .001). In contrast, gamma drove behavioral outcomes in the control group (b = -.43, t = -2.96, p = .005). Further, within group analyses revealed that more frequent episodes of hypoglycemia were associated with alterations specific to beta responses during the pre-movement baseline period (p < .05). These results show frequency specific alterations in motor dynamics in adults with type 1 diabetes, with an added effect of increased hypoglycemia. These findings strongly indicate that diabetes directly impacts motor control components in the brain, regulating behavioral outcomes. Disclosure C.M. Embury: None. V.A. Were: None. G.H. Lord: None. A. Drincic: Board Member; Self; Corcept Therapeutics. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US. T.W. Wilson: None. Funding National Institutes of Health (R01MH103220, R01MH116782)

Patients (pts) with T2D and renal impairment have limited glucose-lowering treatment options. Oral semaglutide (sema) 14 mg once daily (N=163) was compared with placebo (pbo, N=161) in a 26-week, randomized, phase 3a trial (NCT02827708) in pts with T2D and moderate renal impairment (eGFR 30-59 mL/min/1.73 m2), receiving 1-2 glucose-lowering agents (could include basal insulin). Endpoints: change in HbA1c (primary) and body weight (BW, secondary) to week 26. Two estimands were defined: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized pts. Oral sema was superior to (treatment policy) and significantly better than (trial product) pbo in reducing HbA1c and BW (Table). More pts reached HbA1c, BW loss, and composite targets with oral sema. At follow-up, eGFR was unchanged. Fewer pts on oral sema required rescue medication (4 vs. 10%). Adverse events were more frequent with oral sema (74 vs. 65%), most often mild/moderate nausea (19 vs. 7%). More patients on oral sema prematurely discontinued trial product (15 vs. 5%), mainly due to nausea and vomiting. In conclusion, in pts with T2D and moderate renal impairment, oral sema provided superior glycemic control and BW loss compared to pbo at 26 weeks, did not appear to affect renal function, and was well tolerated in line with the population and GLP-1RA class. Disclosure O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. S. Rosenlund: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J.W. Eriksson: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. S.R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Zealand Pharma A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. T. Sathyapalan: Speaker's Bureau; Self; Novo Nordisk Foundation. Other Relationship; Self; Bristol-Myers Squibb Company, Eli Lilly and Company, Sanofi-Aventis. T.M. Blicher: Employee; Self; Novo Nordisk A/S. O.H. Hels: Employee; Self; Novo Nordisk A/S. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi US. Funding Novo Nordisk A/S

Combining GLP-1 analogs and insulin has complementary benefits, but long-term data are sparse. In the LEADER cardiovascular (CV) outcomes trial (N=9340; median follow-up 3.8 years; NCT01179048), rates of major CV events and hypoglycemia were lower when liraglutide vs. placebo was added to standard care (frequently including insulin) in patients with type 2 diabetes (T2D) at high risk for CV disease, and there were improvements in control of glycemia, body weight, systolic blood pressure (SBP) and lipids. This post-hoc subgroup analysis assessed these outcomes by baseline insulin use: no insulin vs. basal-only vs. other. At baseline, 5171 (55%) patients were not on insulin treatment, 3159 (34%) were on basal-only insulin and 1010 (11%) were treated with other insulin regimens (9.7% premix). Insulin use at baseline was balanced overall between randomized treatment groups, but fewer patients randomized to liraglutide (29%) vs. placebo (43%) initiated in-trial insulin. In the basal-only subgroup, liraglutide reduced A1C vs. placebo (estimated treatment difference [ETD]: −0.48%, 95% CI: −0.57; −0.38), with a significant reduction in severe hypoglycemia rate (estimated rate ratio: 0.42, 95% CI: 0.26; 0.68). Liraglutide also reduced weight (ETD: −2.5 kg, 95% CI: −3.0; −2.1) and there were trends for reductions in SBP (ETD: −1.1 mmHg, 95% CI: −2.4; 0.1) and LDL cholesterol (ETD: -1.3 mg/dL, 95% CI: -3.6; 1.0). The CV risk reduction observed with liraglutide in the full trial population was similar in the basal-only subgroup (estimated hazard ratio: 0.84, 95% CI: 0.70; 1.00). Results were similar in the no-insulin subgroup. There was heterogeneity in the results for the smaller, other insulin subgroup with reductions in A1C and weight, but no significant differences in other endpoints. In conclusion, in basal insulin-treated patients with T2D and high CV risk, treatment with liraglutide improved glycemic control, reduced body weight and halved the severe hypoglycemia risk, with a similar CV risk reduction to patients not on insulin. Disclosure C. Tack: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Novo Nordisk A/S. S. Jacob: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, AstraZeneca, Eli Lilly and Company. Board Member; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk Foundation. Advisory Panel; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K., Menarini Group, Roche Diabetes Care Health and Digital Solutions. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Fractyl Laboratories, Inc., GlaxoSmithKline plc., Berlin-Chemie AG, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Berlin-Chemie AG, Merck Sharp & Dohme Corp., Medscape, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, GlaxoSmithKline plc., Novo Nordisk A/S. Consultant; Self; Nordic Bioscience, Empros. J. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Pfizer Inc.. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Merck KGaA, Itamar Medical Ltd., Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Diabetes UK, Applied Clinical Intelligence Ltd, Bayer AG, QuintilesIMS. N.R. Poulter: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc.. Research Support; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc., Servier. Other Relationship; Self; International Society of Hypertension. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc. H. Stegmann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. H. Bosch-Traberg: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. E. Startseva: Employee; Self; Novo Nordisk A/S. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott.

Microvascular and macrovascular complications drive morbidity, mortality, and health care costs in type 2 diabetes (T2D). The GRADE trial enrolled 5047 participants with T2D 2), 5.1% for myocardial infarction (self-report); and 2.0% for stroke (self-report). The Table describes age- and sex-adjusted associations between individual risk factors and complications as odds ratios comparing the presence vs. absence of the complication. Notable features include associations of HbA1c, obesity and blood pressure with micro- but not macrovascular disease; association of triglycerides with microvascular disease only; and associations of smoking and HDL with both micro- and macrovascular disease. These data reveal unexpected patterns in the clustering of risk factors with complications in GRADE patients with short T2D duration. ACR≥30eGFR2MIStrokeORpORpORpORpORpORpHBA1C at screening (%)1.0380.30660.6580.00300.8370.28541.0940.00170.9960.95910.9370.5605BMI (kg/m2)1.040 Disclosure K.J. Mather: Research Support; Self; Merck & Co., Inc., Sanofi-Aventis, Novo Nordisk A/S, Abbott. Advisory Panel; Self; Merck & Co., Inc. R. Pop-Busui: Research Support; Self; AstraZeneca. I. Bebu: None. C. Baker: None. R.M. Cohen: Stock/Shareholder; Self; Bristol-Myers Squibb Company. J.P. Crandall: None. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. J.B. Green: Consultant; Self; Merck Sharp & Dohme Corp.. Research Support; Self; AstraZeneca. Consultant; Self; Daiichi Sankyo Company, Limited. Research Support; Self; GlaxoSmithKline plc., Intarcia Therapeutics, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. M. Kirkman: Research Support; Self; Bayer AG, Theracos, Inc.. Consultant; Self; National Institutes of Health. Research Support; Self; National Institutes of Health, Centers for Disease Control and Prevention. H. Krause-Steinrauf: None. M.E. Larkin: None. J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc.. E.Z. Soliman: None. E.B. Schroeder: None. D.J. Wexler: None. G. Research Group: Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute. Other Relationship; Self; Bristol-Myers Squibb Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi-Aventis, Roche Diagnostics Corporation, Becton, Dickinson and Company, Centers for Disease Control and Prevention, National Diabetes Education Program.

To evaluate the clinical utility of Glycated Albumin (GA) as an intermediate-term marker of glycemic control (preceding 2-3 weeks), we compared the correlation and concordance of GA and fructosamine (FRA) with A1C and mean blood glucose (MBG) measurements. One hundred fifty subjects with type 1 (n=73) and type 2 diabetes (n=77) were assigned to Group 1 (n=98, A1C ≥7.5%, prescribed a change in diabetes therapy) and Group 2 (n=52, A1C In conclusion, GA may be a more useful diagnostic test than FRA in clinical situations requiring measurement of intermediate-term glycemic control. Disclosure C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. S. Hsia: Research Support; Self; Tobira Therapeutics, AstraZeneca, Bayer AG, Cirius Therapeutics, Eli Lilly and Company, Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck & Co., Inc., National Institute of General Medical Sciences, PhaseBio Pharmaceuticals, Inc., Sanofi-Aventis, TaiwanJ Pharmaceuticals Co., Ltd., Theracos, Inc., VTV Therapeutics, Bristol-Myers Squibb Company. L.C. Myers: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. E.J. Klein: None. R. Zhou: None. T. Kohzuma: Employee; Self; Asahi Kasei Corporation. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis.

This study assessed the relationship between FPG, PPG and glycated hemoglobin (A1C) target attainment using ADA glycemic targets in patients (pts) with T2D. A post-hoc analysis of the phase 3 LixiLan-O (NCT02058147) trial assessed the efficacy and safety of iGlarLixi (n=468) vs. insulin glargine U100 (iGlar) (n=466) and lixisenatide (Lixi) (n=233) in pts uncontrolled on metformin ± a second OAD, continuing only on metformin, over a 30-week period. The proportion of pts reaching both FPG and PPG target was highest for iGlarLixi, while the proportions of those reaching FPG or PPG targets only were highest for iGlar (targeting FPG) and Lixi (targeting PPG), respectively (Figure 1A). There was a stepwise trend in A1C change, end-of-study A1C, and proportion of pts reaching A1C goals in favor of iGlarLixi, followed by iGlar and Lixi (Figure 1B-D). Pts reaching both FPG and PPG targets had the greatest A1C drop and lowest A1C values, and represented the largest proportion of pts acheiving A1C target. No differences were observed in hypoglycemia rates in all treatment arms, and a greater proportion of pts experienced weight loss with iGlarLixi vs. iGlar (55.3% vs. 39.9%). By simultaneously targeting fasting and postprandial hyperglycemia, iGlarLixi treatment results in greater A1C reduction and better A1C target attainment than iGlar or Lixi alone. Disclosure C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. V. Fonseca: Consultant; Self; Abbott. Board Member; Self; American Association of Clinical Endocrinologists. Consultant; Self; Eli Lilly and Company. Stock/Shareholder; Self; Amgen Inc.. Consultant; Self; Asahi Kasei Corporation, AstraZeneca, Novo Nordisk Inc., ADOCIA, Intarcia Therapeutics, Inc., Sanofi-Aventis. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. L. Van Gaal: Advisory Panel; Self; Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen J & J, Merck MSD, Novo Nordisk, Sanofi and Servier/Intarcia. Speaker's Bureau; Self; Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen J & J, Merck MSD, Novo Nordisk, Sanofi and Servier/Intarcia. Research Support; Self; EU (Hepadip & Resolve consortium) and National Research Funds. F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson & Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd.. J. Chao: None. T.A. Dex: Employee; Self; Sanofi US. Stock/Shareholder; Self; Pfizer Inc., Merck Sharp & Dohme Corp., Teva Pharmaceutical Industries Ltd.. M. Roberts: None. A. Saremi: Employee; Self; Sanofi US. L.A. Leiter: Advisory Panel; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; GlaxoSmithKline plc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Servier. Speaker's Bureau; Self; Servier. Research Support; Self; Servier. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc.. Research Support; Self; Amgen Inc., Esperion Therapeutics, Kowa Pharmaceuticals America, Inc., The Medicines Company. Advisory Panel; Self; Akcea Therapeutics, Novartis Pharmaceuticals Corporation.

Semaglutide is a new GLP-1 analog for the once-weekly treatment of T2D. In the SUSTAIN 6 CV outcomes trial, subcutaneous semaglutide (0.5 mg and 1.0 mg) added to standard of care significantly reduced major adverse CV events (MACE: non-fatal MI, non-fatal stroke or CV death) vs. placebo over 2 years in subjects with T2D at high CV risk. This post-hoc analysis assessed whether this CV risk reduction was consistent in male and female subjects. Overall, 2,002 male and 1,295 female subjects were randomized. MACE was reported by fewer subjects with semaglutide vs. placebo in both sexes (p=0.45 for interaction); HR estimates were 0.68 (95% CI 0.50;0.92) in males, 0.84 (95% CI 0.54;1.31) in females and 0.74 (95% CI 0.58;0.95) in the overall study population. Overall, the pattern was similar across the individual MACE components (Table 1). AEs were reported by similar proportions of males and females across treatments. The most frequent AEs reported were gastrointestinal, with higher rates in females than in males. The proportions of subjects prematurely discontinuing treatment due to AEs were comparable for males and females (Table 1). MACE and its components was reported in consistent proportions of males and females, and generally lower with semaglutide vs. placebo regardless of sex. The HR estimates for MACE with semaglutide vs. placebo for males and females were consistent with that of the overall study population. Disclosure I. Hramiak: Advisory Panel; Self; AstraZeneca. Research Support; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Eli Lilly and Company. Advisory Panel; Self; GlaxoSmithKline plc.. Research Support; Self; GlaxoSmithKline plc.. Advisory Panel; Self; Roche Pharma, Insulet Corporation, Janssen Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Medtronic. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Merck & Co., Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Research Support; Self; Sanofi. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. J. Seufert: Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Boehringer Ingelheim GmbH, GI Dynamics Inc.. Research Support; Self; GI Dynamics Inc., GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Ipsen Biopharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation. Research Support; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Sanofi-Aventis Deutschland GmbH. Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH. Research Support; Self; Sanofi-Aventis Deutschland GmbH. Advisory Panel; Self; Sanofi. Research Support; Self; Ypsomed AG. T. Hansen: None. D. Thielke: Employee; Self; Novo Nordisk A/S. I. Lingvay: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company, AstraZeneca, Intarcia Therapeutics, Inc., Sanofi-Aventis. Research Support; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp., Pfizer Inc., GI Dynamics Inc., Novartis AG. Other Relationship; Self; Sanofi, AstraZeneca, Boehringer Ingelheim GmbH, Novo Nordisk A/S.

OBJECTIVE Endothelial progenitor cells (EPCs) are decreased in number and function in type 2 diabetes. Mechanisms by which this dysfunction occurs are largely unknown. We tested the hypothesis that a chronic inflammatory environment leads to insulin signaling defects in EPCs and thereby reduces their survival. Modifying EPCs by a knockdown of nuclear factor-κB (NF-κB) can reverse the insulin signaling defects, improve EPC survival, and decrease neointimal hyperplasia in Zucker fatty rats postangioplasty. RESEARCH DESIGN AND METHODS EPCs from Zucker fatty insulin-resistant rats were cultured and exposed to tumor necrosis factor-α (TNF-α). Insulin signaling defects and apoptosis were measured in the presence and absence of an NF-κB inhibitor, BAY11. Then, EPCs were modified by a knockdown of NF-κB (RelA) and exposed to TNF-α. For in vivo experiments, Zucker fatty rats were given modified EPCs post–carotid angioplasty. Tracking of EPCs was done at various time points, and neointimal hyperplasia was measured 3 weeks later. RESULTS Insulin signaling as measured by the phosphorylated–to–total AKT ratio was reduced by 56% in EPCs exposed to TNF-α. Apoptosis was increased by 71%. These defects were reversed by pretreatment with an NF-κB inhibitor, BAY11. Modified EPCs exposed to TNF-α showed a lesser reduction (RelA 20%) in insulin-stimulated AKT phosphorylation versus a 55% reduction in unmodified EPCs. Apoptosis was 41% decreased for RelA knockdown EPCs. Noeintimal hyperplasia postangioplasty was significantly less in rats receiving modified EPCs than in controls (intima-to-media ratio 0.58 vs. 1.62). CONCLUSIONS In conclusion, we have shown that insulin signaling and EPC survival is impaired in Zucker fatty insulin resistant rats. For the first time, we have shown that this defect can be significantly ameliorated by a knockdown of NF-κB and that these EPCs given to Zucker fatty rats decrease neointimal hyperplasia post–carotid angioplasty.

OBJECTIVE Approximately 25% of children and adolescents with type 1 diabetes will develop diastolic dysfunction. This defect, which is characterized by an increase in time to cardiac relaxation, results in part from a reduction in the activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), the ATP-driven pump that translocates Ca2+ from the cytoplasm to the lumen of the sarcoplasmic reticulum. To date, mechanisms responsible for SERCA2a activity loss remain incompletely characterized. RESEARCH DESIGN AND METHODS The streptozotocin (STZ)-induced murine model of type 1 diabetes, in combination with echocardiography, high-speed video detection, confocal microscopy, ATPase and Ca2+ uptake assays, Western blots, mass spectrometry, and site-directed mutagenesis, were used to assess whether modification by reactive carbonyl species (RCS) contributes to SERCA2a activity loss. RESULTS After 6–7 weeks of diabetes, cardiac and myocyte relaxation times were prolonged. Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca2+ was significantly reduced. Western blots and mass spectroscopic analyses revealed carbonyl adducts on select basic residues of SERCA2a. Mutating affected residues to mimic physio-chemical changes induced on them by RCS reduced SERCA2a activity. Preincubating with the RCS, methylglyoxal (MGO) likewise reduced SERCA2a activity. Mutating an impacted residue to chemically inert glutamine did not alter SERCA2a activity, but it blunted MGO's effect. Treating STZ-induced diabetic animals with the RCS scavenger, pyridoxamine, blunted SERCA2a activity loss and minimized diastolic dysfunction. CONCLUSIONS These data identify carbonylation as a novel mechanism that contributes to SERCA2a activity loss and diastolic dysfunction during type 1 diabetes.

OBJECTIVE Salsalate is a dimeric form of salicylic acid that has been shown to have anti-inflammatory activity and to reduce glucose levels, insulin resistance, and cytokine expression. However, the effect of salsalate on vascular injury has not been determined. The objective of this study is to investigate the effect of salsalate on vascular injury and repair in a rat model of carotid artery balloon catheter injury. RESEARCH DESIGN AND METHODS Salsalate treatment was started in female Zucker fatty rats (insulin resistant) 1 week before carotid artery balloon catheter injury and continued for 21 days, at which time the animals were killed and studied. RESULTS Treatment with salsalate significantly decreased the intima-to-media ratio and upregulated the expression of aortic endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) (ser 1177), and manganese superoxide dismutase (MnSOD) and reduced serum interleukin (IL)-6 with concomitant downregulation of nuclear factor (NF) κB subunit p65 and vascular endothelial growth factor (VEGF) expression in the balloon-injured carotid artery of female Zucker fatty rats. CONCLUSIONS The present study shows that salsalate treatment decreases vascular damage caused by balloon catheter injury in female Zucker fatty rats. The beneficial effect of salsalate on vascular injury was associated with upregulation of eNOS, p-eNOS, and MnSOD, which reduce oxidative stress and have anti-inflammatory properties, as evidenced by reduction in serum IL-6 and the downregulation of VEGF and NFκB, which promote inflammation without changing glucose levels. These results suggest that salsalate may be useful in reducing vascular injury and restenosis following interventional revascularization procedures.