Boehringer Ingelheim International GmbH Research Articles

53-OR: Efficacy and Safety of Coadministered s.c. Semaglutide and s.c. Cagrilintide in Type 2 Diabetes

Combining sema (semaglutide 2.4 mg) and amylin analog cagri (cagrilintide 2.4 mg) has weight loss benefits, but the impact on HbA1c is unknown. This study is the first to assess the efficacy and safety of CagriSema (co-administered) vs sema or cagri alone in participants (pts) with T2D. In this phase 2 (NCT04982575), multicenter, double-blind trial, adults with T2D (HbA1c 7.5-10.0%) and BMI ≥27 kg/m2 on metformin ± SGLT2i, were randomized to once-weekly s.c. CagriSema, sema, or cagri for 32 weeks (all escalated over 16 weeks to 2.4 mg). The primary endpoint was change from baseline in HbA1c; key secondary endpoints were body weight and safety. Of the 92 pts randomized (64% male; mean age 58 years and T2D duration 8.7 years), those receiving CagriSema had significantly greater reductions in HbA1c (vs cagri) and body weight (vs sema and cagri) at week 32 (Figure). The proportion of pts achieving HbA1c <7.0% and ≤6.5%, were 89% and 75% for CagriSema, 69% and 48% for sema, and 33% and 17% for cagri at week 32. GI AEs were most common (58% for CagriSema, 32% for sema, and 33% for cagri), were mainly mild/moderate, occurred during dose escalation, and lead to treatment discontinuation in 0%, 3%, and 0% of pts with CagriSema, sema, and cagri, respectively; no level 2 or 3 hypoglycemia was reported. CagriSema improved glycemic control and led to significant weight loss vs both sema or cagri, and was well tolerated with no new safety signals. Disclosure J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. S.Deenadayalan: Employee; Novo Nordisk A/S. L.Erichsen: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. S.Macura: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. S.D.Pedersen: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, HLS Therapeutics Inc., Bayer Inc., Viatris Inc., Bausch + Lomb, Research Support; Eli Lilly and Company, Novo Nordisk, AstraZeneca, Applied Therapeutics Inc., Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, Medtronic, Pfizer Inc., HLS Therapeutics Inc., Bayer Inc., Bausch + Lomb. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. Funding Novo Nordisk A/S

54-OR: Effect of Coadministered s.c. Semaglutide and s.c. Cagrilintide on Glycemic Levels Measured by CGM

Continuous glucose monitoring (CGM) offers insight into glycemic levels beyond the conventional measurement of HbA1c. This phase 2, multicenter, 32-week, double-blind trial (NCT04982575) compared the effects of CagriSema (co-administered semaglutide [sema] 2.4 mg and cagrilintide [cagri] 2.4 mg) vs sema (2.4 mg) or cagri (2.4 mg) alone, all as once-weekly subcutaneous injection, on CGM parameters (secondary endpoints). In total, 92 adult participants with T2D (HbA1c 7.5-10.0%), on metformin ± SGLT2i, and BMI ≥27 kg/m2 were randomized. Time in range (70-180 mg/dL) increased in all groups, reaching 88.9% with CagriSema at week 32 (Figure). Time in tight range (70-140 mg/dL; post-hoc analysis) increased from 16.0%, 8.8%, and 26.2% at baseline to 66.4%, 50.0%, and 36.7% at week 32 for CagriSema, sema, and cagri, respectively, with 0.8% or less in time below range for all groups. Mean glucose (measured by CGM) decreased from baseline to week 32 (CagriSema, -63.9; sema, -43.6; cagri, -23.4 mg/dL; estimated treatment difference [95% CI]: CagriSema vs sema, -20.2 [-39.8, -0.7; p=0.04], and CagriSema vs cagri, -40.5 [-59.4, -21.6; p<0.0001] mg/dL). Time in range with CagriSema reached nearly 90% at week 32, with little time below range in the first trial of CagriSema in people with T2D. Furthermore, CagriSema led to a greater reduction in mean glucose vs both sema or cagri alone. Disclosure C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. S.Deenadayalan: Employee; Novo Nordisk A/S. L.Erichsen: None. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. E.W.Lehmann: Employee; Novo Nordisk A/S. S.D.Pedersen: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, HLS Therapeutics Inc., Bayer Inc., Viatris Inc., Bausch + Lomb, Research Support; Eli Lilly and Company, Novo Nordisk, AstraZeneca, Applied Therapeutics Inc., Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, Medtronic, Pfizer Inc., HLS Therapeutics Inc., Bayer Inc., Bausch + Lomb. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. Funding Novo Nordisk A/S

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

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

52-OR: Effect of Oral Nonpeptide GLP-1 Receptor Agonist Orforglipron (LY3502970) in Participants with Obesity or Overweight—A Phase 2 Study

Orforglipron (OFG) is a novel once daily oral non-peptide GLP-1 receptor agonist (RA) which can be taken with or without food, in development for chronic weight management. The objective of this Phase 2 study was to assess the efficacy, safety, and tolerability of OFG in patients with obesity or overweight with ≥1 weight-related comorbidity. Participants (N=272) were randomized to placebo or OFG (12, 24, 36, or 45 mg) treatment. OFG doses were increased to target using different dose escalation schemes in each arm. The primary endpoint was to compare percent body weight (BW) change from baseline in OFG vs placebo at Week 26, while the study continued to 36 weeks. Secondary endpoints included change from baseline in waist circumference (WC) and BMI, and the percentage of participants achieving ≥5 or ≥10% weight loss. At baseline, mean BW was 108.7 kg, BMI was 37.9 kg/m2, and 94% of participants had a BMI ≥30 kg/m2. Mean percentage BW loss, mean change in BMI and WC, and the percentage of participants achieving ≥5% or ≥10% weight loss were significantly greater with all OFG doses vs placebo (Figure). The AE profile was similar to other GLP-1 RAs; most were GI-related and mild to moderate in severity. The novel non-peptide GLP-1 RA OFG led to greater reductions in BW, BMI, and WC compared with placebo. These promising data support continued development of OFG as an oral treatment for obesity. Disclosure S.Wharton: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim International GmbH, Bausch Health, Canada, Research Support; Novo Nordisk, Eli Lilly and Company, Speaker's Bureau; Novo Nordisk, Eli Lilly and Company, Bausch Health, Canada. C.M.Kazda: Employee; Eli Lilly and Company. M.Konig: None. T.Blevins: Other Relationship; Medtronic, Research Support; Lilly Diabetes, Novo Nordisk, Dexcom, Inc., Abbott Diabetes, Tandem Diabetes Care, Inc., Medtronic, Speaker's Bureau; Lilly Diabetes, Novo Nordisk A/S. L.B.Connery: None. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. S.Raha: Employee; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. D.A.Robins: None. E.J.Pratt: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

1802-PUB: Liraglutide as a Potential Drug Repurposing Candidate for Alzheimer’s Disease and Related Dementia—Real-World Evidence

Previous studies suggested GLP-1 receptor agonists (GLP1RA) may improve cognitive function and liraglutide’s effect on Alzheimer’s disease is being evaluated by the ELAD (Evaluating Liraglutide in Alzheimer's Disease) clinical trial. To examine whether liraglutide decrease Alzheimer’s disease and related dementia (ADRD) risk compared with other antidiabetics, we implemented an active comparator, new user cohort design identifying initiators of liraglutide, DPP-4 inhibitors (DPP4i), respectively, using a US nationwide 20% random sample of fee-for-service Medicare beneficiaries aged 70+ with parts A, B, and D coverage from 2007-2019. We required patients to have 2nd prescription of the same drug class and be free of ADRD in the 3-year window (during which requiring 3-year continuous enrollment of parts A, B) prior to drug initiation. The ADRD outcome was defined as 1) ≥1 ADRD claims in 1 year AND 2) ≥1 ADRD claims in another year or nursing home stay ≥ 6 months in the 3-year follow-up period. We estimated propensity scores (PS) to balance confounders across cohorts and estimated adjusted risk difference (RD) and 95% CI using inverse probability treatment and censoring weight. The initiators of liraglutide (n=1260) and DPP4i (n=15952) were followed for a median (IQR) duration of 3.0 (2.0 to 3.0) and 3.0 (1.7 to 3.0) years, respectively. During follow-up, incident cases of ADRD was 196 and 3215 in liraglutide and DPP4i, respectively; and incident rate was 63 and 85 per 1000 person-years, respectively. Adjusted RD (%) was -4.4 (95%CI -6.6 to -2.39) comparing liraglutide to DPP4i. Results were consistent across sensitivity analyses with varying exclusion criteria, baseline period, and outcome definitions. Our active comparator, new user cohort study of older patients showed liraglutide is associated with a decreased ADRD risk compared with alternatives. This study is limited by the relatively short duration of treatments. Disclosure T.Wang: None. J.B.Buse: Consultant; Alkahest, Anji Pharmaceuticals, AstraZeneca, Bayer Inc., Biomea Fusion, Inc., Boehringer Ingelheim International GmbH, CeQur SA, Cirius Therapeutics, Inc., Corcept Therapeutics, Eli Lilly and Company, GentiBio, Glycadia, Glyscend Inc., Janssen Pharmaceuticals, Inc., Mellitus Health, Pendulum Therapeutics, Praetego, LLC, Stability Health, Terns, Inc, Valo, Other Relationship; Novo Nordisk, Research Support; Dexcom, Inc., Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend Inc., Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. V.Pate: None. T.Stürmer: Stock/Shareholder; Novartis, Novo Nordisk, Roche Pharmaceuticals. Funding American Diabetes Association (4-22-PDFPM-06 to T.W.)

285-LB: LEAP2 Reduces Preprandial and Postprandial Glucose Levels and Ad Libitum Food Intake in Obese Men

The naturally occurring peptide liver-enriched antimicrobial peptide 2 (LEAP2) has gained interest as a ghrelin receptor antagonist. Recently, we reported food intake and plasma glucose-lowering effects of exogenous LEAP2 in lean healthy males. Here, we investigated the effects of LEAP2 infusion on ad libitum food intake and postprandial glucose tolerance in obese men. Twenty obese men (mean (SEM) age 44.2 (2.2) years; BMI 36.3 (0.8) kg/m2; body fat percentage 37.4 (0.9)%) were enrolled in this randomized, double-blind, placebo-controlled, crossover study comprising two experimental days. Experimental days involved a ~5-hour intravenous (iv) infusion of LEAP2 or placebo during which a liquid mixed meal test (MMT) and a subsequent ad libitum meal test were performed. Plasma glucose measures included fasted (preprandial), Cmax and Tmax values as well as area under the curve (AUC) during MMT. Ad libitum food intake was measured in kilojoule (kJ) and kJ/kg body weight. Compared to placebo, LEAP2 infusion lowered preprandial plasma glucose (mean (SEM): 5.03 (0.08) vs. 5.19 (0.06) mmol/L, P=0.0095) as well as Cmax (6.58 (0.18) vs. 6.98 mmol/L (0.18), P=0.0001) and AUC for plasma glucose during MMT (1,506 (33.4) vs. 1564 (30.4) min×mmol/L, P=0.0005), but not Tmax. Ad libitum food intake was reduced by ~13% during LEAP2 infusion compared to placebo (2,939 (266) vs. 3,378 (258) kJ, P=0.0118; 25.0 (2.4) vs. 28.4 (2.0) kJ/kg body weight, P=0.0140). We conclude that a continuous iv LEAP2 infusion reduces pre- and postprandial plasma glucose concentrations as well as ad libitum food intake in obese men. Disclosure A. Englund: None. C. A. Hagemann: Employee; Gubra ApS. L. S. Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. F. K. Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.

801-P: Short-Acting Exenatide Added Three Times Daily to Insulin Therapy Improves Fatty Liver Index in Type 1 Diabetes

Fatty liver index (FLI), a marker of hepatic fat content, has been reported as an independent risk factor for all-cause mortality and major cardiovascular events in type 1 diabetes. How short-acting glucagon-like peptide 1 receptor agonists (GLP-1RA) influence FLI in type 1 diabetes remains unknown. We analyzed FLI post-hoc in a phase 2, double-blind, randomized (1:1), clinical trial (NCT03017352) that assessed the efficacy of short-acting GLP-1RA exenatide 10 μg added three times daily to insulin therapy as compared with placebo over 26 weeks of treatment in 108 individuals with type 1 diabetes (76/32 men/women, age 50 (14) years (mean (standard deviation)), diabetes duration 21 (12) years, BMI 28 (4) kg/m2, glycated hemoglobin A1c 8.2 (0.7) % / 66 (7) mmol/mol). Exenatide significantly reduced FLI by 23 % (95 % confidence interval -44; -10, P = 0.001) (Table 1) as compared with placebo after 26 weeks’ treatment. In conclusion, short-acting exenatide reduced FLI-assessed hepatic fat content in patients with long-standing type 1 diabetes and inadequate glycemic control, alluding to potential beneficial effects of this GLP-1RA on both morbidity and mortality in type 1 diabetes. Disclosure N.Johansen: Other Relationship; AstraZeneca, Novo Nordisk, Research Support; JDRF. T.F.Dejgaard: Advisory Panel; Novo Nordisk, Research Support; Novo Nordisk, Speaker's Bureau; Boehringer-Ingelheim, Novo Nordisk, AstraZeneca. A.Lund: Speaker's Bureau; Novo Nordisk. C.K.Nielsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. Funding AstraZeneca

1658-P: Rectal Hyposensitivity, a Potential Marker of Enteric Autonomic Nerve Dysfunction, Is Significantly Associated with Gastrointestinally Mediated Glucose Disposal in Persons with Type 2 Diabetes

The incretin effect in type 2 diabetes is reduced, but the mechanisms behind are uncertain. We hypothesized that the incretin effect associates with degree of enteric autonomic nerve dysfunction and evaluated gastrointestinally mediated glucose disposal (GIGD), as a proxy for the incretin effect, and rectal sensitivity to mechanical distension representing afferent gut signalling. Sixty-six participants with either 1) longstanding type 2 diabetes, 2) newly onset (<1 year), medically untreated diabetes, or 3) healthy controls, underwent a 75 g oral glucose tolerance test (OGTT) and an intravenous isoglycemic glucose infusion to determine GIGD. Earliest sensation to rectal rapid balloon distention was determined as a proxy for autonomic neuropathy. Compared to controls (59.3±14.4%), GIGD was reduced in both early (36.4±14.7%) and longstanding diabetes (17.4±22.3%), with significant difference between all three groups (P<0.01). Both groups of diabetes needed higher pressure during rapid rectal balloon distention (3.7±1.1 kPa for longstanding diabetes, 4.0±1.3 for early diabetes), compared to controls (3.0±0.9 kPa, P<0.01), with no significant difference between the two diabetes groups. GIGD was inversely correlated with pressure at earliest sensation (rho 0.341, P<0.01). For those needing a pressure between 1 and 3 kPa and between 4 and 7 kPa, respectively, GIGD was 46.2%±24.9 and 34.4±23.9% (P=0.05). GIGD was inversely and significantly correlated with glucose values during OGTT, with strongest correlation to the 90-minute value (rho 0.873, P<0.01), and HbA1c (rho 0.653, P<0.01). We show that the degree of rectal hyposensitivity correlates with reduced GIGD and confirm that GIGD correlates with the degree of dysglycemia. These results warrant further studies on the potential role of gut autonomic dysfunction in the reduced incretin effect characterizing type 2 diabetes. Disclosure S.Meling: Consultant; Novo Nordisk, Lilly, AstraZeneca, Boehringer-Ingelheim, Sanofi. E.Tjora: None. N.Ejskjaer: None. S.Carlsen: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. P.Njølstad: None. C.Brock: Research Support; Abbott, ElectroCore. R.B.Nedergaard: Other Relationship; Grünenthal Group. E.Søfteland: None. Funding Helse Vest, Norway (F-11637/4800002072); Johan Selmer Kvanes Legat (Legacy)

1651-P: Elevated FGF21 Levels after Total Pancreatectomy and in Response to Single-Dose Glucagon Receptor Antagonism in Humans

Fibroblast growth factor 21 (FGF21) is a liver-secreted peptide hormone reportedly improving metabolic homeostasis, partly via reduced hunger for sugar, fat, protein and alcohol. Exogenous glucagon has been shown to increase circulating FGF21 levels, but the role of endogenous glucagon for the control of FGF21 secretion remains unknown. To elucidate the relationship between endogenous glucagon and FGF21 in humans, we investigated the effect of chronic pancreatic glucagon depletion and acute glucagon receptor antagonism, respectively, on FGF21 levels. Nine totally pancreatectomized subjects (7 men, 2 women, age 61.3 ± 10.3 years, BMI 22.6 ± 4.8 kg/m2) and 9 matched control subjects (6 men, 3 women, age 65.9 ± 8.8 years, BMI 23.9 ± 2.7 kg/m2) underwent two randomized, double-blinded test days 24 hours after single-dose oral administration of either the glucagon receptor antagonist LY2409021 (300 mg) or placebo. FGF21 levels were measured both in the fasting state and in response to an oral glucose tolerance test (OGTT). The pancreatectomized patients exhibited significantly increased mean fasting FGF21 levels compared to the control subjects (493 ± 429 vs 108 ± 58 pg/mL, P=0.02). In the control subjects, administration of LY2409021 significantly increased mean fasting levels of FGF21 (216 ± 117 vs 108 ± 58 pg/mL, P=0.004) whereas fasting FGF21 levels in the pancreatectomized patients were unaffected by LY2409021. In both groups, FGF21 levels increased in response to the OGTT, with no significant treatment effect of LY2409021. Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion. Disclosure M.F.G.Grøndahl: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. C.T.Juel: None. A.Lund: Speaker's Bureau; Novo Nordisk. S.Haedersdal: Consultant; Novo Nordisk. M.M.Andersen: None. J.S.Svenningsen: None. M.Gillum: None. B.Hartmann: Stock/Shareholder; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. Funding Aase and Ejnar Danielsen's Foundation; Novo Nordisk Foundation (LY2409021); Eli Lilly and Company

143-OR: Prevailing Glucose Levels Alter Left Ventricular Contractions Pattern, Myocardial Performance, and Myocardial Energy Efficiency

Mechanical dispersion (MD) describes heterogeneity in ventricular contraction patterns, and myocardial work (MW) indices quantify ventricular performance. Investigating the myocardial and functional response to acute hypoglycemia and hyperglycemia may aid in identifying putative mechanisms linking glycemia and cardiovascular disease (CVD). From echocardiography performed during euglycemic, hyperglycemic and hypoglycemic clamps, we explored the relationship between glycemia and MD and MW indices in individuals with type 1 diabetes, type 2 diabetes and without diabetes. MD was measured by speckle-tracking echocardiography, and MW measures were derived from pressure-strain loop analyses. We analyzed data (mean±SD) from 84 individuals: 20 young individuals with type 1 diabetes (age: 30±8 years); 24 middle-aged individuals with type 1 diabetes (age: 53±12 years); 21 older individuals with type 2 diabetes (63±7 years), and 21 controls (62±8 years). Results for MD and MW indices are illustrated in Figure 1. In conclusion, acute hyperglycemia leads to an energy-effective myocardium with homogeneous left ventricular contractions. Hypoglycemia increases constructive myocardial work, followed by a less energy-efficient myocardium and more heterogeneous left ventricular contractions, perhaps alluding to a possible link between hypoglycemia and CVD. Disclosure C.R.Andreasen: None. A.Andersen: None. P.G.Hagelqvist: None. K.Maytham: None. M.Sengeløv: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. F.J.Olsen: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. Funding Danish Diabetes Academy (17SA0031406); Novo Nordisk Foundation (16230)

244-OR: Signs of Glucagon Resistance after a Two-Week Hypercaloric Diet Intervention

Hyperglucagonemia is observed in individuals with obesity and contributes to the hyperglycemia of persons with diabetes. Hyperglucagonemia may arise due to reduced hepatic amino acid turnover and ensuing elevations in glucagonotropic amino acids. We recently observed reduced glucagon sensitivity and hyperglucagonemia in individuals with obesity and hypothesized it to be a consequence of steatosis. Here, we evaluated whether reduced glucagon sensitivity could be induced by a short-term hypercaloric diet intervention designed to increase hepatic fat content in healthy individuals. We recruited 20 healthy, lean individuals (BMI: 23 ± 0.3 (mean ± SD) kg/m2) to follow a hypercaloric diet (~5,000 kcal/day) and a sedentary lifestyle for 2 weeks. Amino acid turnover in response to infusion of glucagon was assessed during a pancreatic clamp with somatostatin and basal insulin. Participants were examined before and after the lifestyle-intervention and again after 8 weeks to assess the reversibility of any metabolic changes. Hepatic steatosis was assessed by magnetic resonance spectroscopy. The intervention led to increases in body weight (3.5 [2.8;4.2] (mean [95% confidence interval]) kg, P < 0.0001) and hepatic fat content (382 [206;705]%, P < 0.001). Insulin resistance was evident with unchanged fasting blood glucose levels and a 56% increase in fasting insulin (P < 0.001). Glucagon infusion led to a decrease in the concentration of total amino acids, but the percentage change in total amino acids was reduced (−2.5 ± 0.5 vs. −0.2 ± 0.7%, P = 0.015) and the average slope of the total amino acid curve was less steep (−2.0 ± 1.2 vs. −1.2 ± 0.3 μM/min, P = 0.016) after the intervention compared to baseline. All metabolic changes were normalized at follow-up. Our results indicate that short-term unhealthy behavior increasing hepatic fat content causes a reversible resistance to the effect of glucagon on amino acid turnover in healthy individuals, which may explain hyperglucagonemia associated with obesity and diabetes. Disclosure M.P.Suppli: None. J.I.Bagger: Speaker's Bureau; Novo Nordisk A/S. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck.

56-OR: A Long-Acting Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist Shows Weight Loss without Nausea or Vomiting

The contributions of glucose-dependent insulinotropic polypeptide (GIP) to overall metabolic and weight effects of incretin therapies are unclear. Weight loss efficacy has been observed with glucagon-like peptide 1 (GLP-1) and GIP receptor agonist tirzepatide, but weight loss efficacy has also been observed with GLP-1 agonism mixed with GIP antagonism. LY3537021 (LY), a selective, long-acting GIP receptor agonist, was tested in single [SAD, LY vs placebo (PBO)] and multiple ascending doses (MAD, LY vs PBO once weekly for 4 weeks) to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics. In SAD, healthy participants (N=39) had a mean age of 43.5 yrs and mean weight of 74.4 kg. People with T2D (N=6) had a mean age of 58.5 yrs and mean weight of 75.1 kg. Median Tmax was 12 to 84 hrs post dose and mean terminal T½ was approximately 11 to 14 days. PK in people with T2D appeared comparable to healthy participants. In MAD, healthy participants (N=18) had a mean age of 38.3 yrs and mean weight of 75.4 kg. People with T2D (N=18) had a mean age of 57.1 yrs and mean weight of 74.3 kg. In healthy MAD participants at day 57, numerically greater mean weight loss was reported in those who received LY (-1.1 to -2.2 kg) versus PBO (-0.4 kg). In people with T2D, numerically greater mean weight loss was reported for those receiving LY (-1.9 to -3.1 kg) versus PBO (-0.4 kg). LY did not result in gastric emptying delay. No serious adverse events or hypoglycemia occurred. Study participants had few mild gastrointestinal (GI) adverse events. Study findings included decreased appetite (LY: n=4, PBO: n=1), abdominal pain (LY: n=1, PBO: n=0) and diarrhea (LY: n=1, PBO: n=2). No nausea or vomiting was observed. Repeated dosing of a long-acting GIP receptor agonist, once weekly for 4 weeks, induced weight loss without gastric emptying delay or nausea and vomiting. The results suggest that GIP agonism can contribute to weight loss effects seen with multi-agonist incretins such as tirzepatide. Disclosure F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. S.Urva: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Rettiganti: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. E.J.Pratt: Employee; Eli Lilly and Company.

389-P: Glycemia and Cardiac Arrhythmias in People with Type 1 Diabetes

The impact of hypoglycemia, hyperglycemia and glycemic variability on cardiac arrhythmia susceptibility in people with type 1 diabetes is uncertain. We performed a 12-month prospective observational study employing continuous glucose monitoring and implantable loop recorders to investigate potential associations between glycemia and cardiac arrhythmias. Thirty adults with type 1 diabetes ([mean ± SD] age 63 ± 8 years, BMI 26 ± 5 kg/m2, HbA1c 7.3 ± 1.1% [56.9 ± 11.9 mmol/mol]) and without any history of cardiac arrhythmias were included. Daytime and nighttime incidence rate ratios (IRR) of arrhythmias were determined for hypoglycemia (interstitial glucose (IG) < 3.9 mmol/L), hyperglycemia (IG > 10.0 mmol/L), and glycemic variability (standard deviation and coefficient of variation). Hypoglycemia was not associated with an increased risk of cardiac arrhythmias in comparison with euglycemia (IG 3.9 - 10.0 mmol/L) and hyperglycemia. However, during daytime, a trend of increased risk of arrhythmias was observed when comparing hypoglycemia with euglycemia (IRR 1.08 [95% CI 0.99 - 1.18]). Furthermore, during daytime both the occurrence of hyperglycemia and time spent in hyperglycemia within the same hour of an arrhythmia were associated with an increased risk of arrhythmias compared to euglycemia (IRR 2.03 [95% CI 1.21 - 3.40] and IRR 1.07 [95% CI 1.02 - 1.13], respectively). Nighttime hypoglycemia and hyperglycemia were not associated with increased risk of arrhythmias. Increased glycemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during nighttime. In conclusion, daytime hypoglycemia and hyperglycemia may contribute to an increased risk of cardiac arrhythmias compared to euglycemia, in people with type 1 diabetes. No associations were found between glycemic levels and cardiac arrhythmias during nighttime, indicating diurnal differences in arrhythmogenic susceptibility. Disclosure P.G.Hagelqvist: None. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. A.Andersen: None. K.Maytham: None. C.R.Andreasen: None. S.Engberg: Employee; Novo Nordisk A/S. T.B.Lindhardt: None. J.Forman: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. Funding Novo Nordisk Foundation (28300)

270-OR: Health Care Utilization and Cost Associated with Empagliflozin in Older Adults with Type 2 Diabetes—Results from the EMPRISE study

Within the EMPRISE study program, we compared the cost and healthcare utilization of empagliflozin (EMPA) vs. dipeptidyl peptidase-4 inhibitors (DPP-4i) using Medicare data (2014-18). We identified 23,335 pairs of 1:1 propensity score-matched patients aged ≥65 years with type 2 diabetes (T2D) initiating EMPA or a DPP-4i, overall and stratified by baseline cardiovascular disease (CVD). We estimated ratios and differences in rates of healthcare utilization per 1,000 person-years, and costs per member per year (PMPY) for EMPA vs. DPP-4i using zero-inflated negative binomial or gamma models. Compared to DPP-4i, EMPA was associated with lower rates of hospital days [rate ratio (RR) (95% CI) 0.89 (0.82, 0.97); rate difference (RD) -557 (-587, -528)], number of hospitalizations [RR 0.86 (0.79, 0.93); RD -73 (-84, -61)], and number of emergency visits [RR 0.86 (0.82, 0.91); RD -128 (-145, -111)]. Estimates were similar when stratified by baseline CVD. Relative to DPP-4i, EMPA was associated with lower total costs in USD [RR 0.94 (0.92, 0.96); PMPY -1109 (-1478, -739)], and inpatient costs [RR 0.84 (0.81, 0.87); PMPY -713 (-847, -579)], and nearly-similar pharmacy costs [RR 1.04 (1.02, 1.06); PMPY 355 (177, 532)]. RRs in baseline CVD subgroups were similar, but absolute RDs were larger in those with CVD. Relative to DPP-4i, EMPA reduced healthcare utilization and costs in routine care. Disclosure P.T.Htoo: Employee; Johnson & Johnson. E.Patorno: Research Support; Boehringer Ingelheim Inc., National Institutes of Health, Patient-Centered Outcomes Research Institute, US Food and Drug Administration. H.Tesfaye: None. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; UCB, Inc., Boehringer Ingelheim International GmbH, Stock/Shareholder; Aetion, Inc. D.J.Wexler: Other Relationship; Novo Nordisk A/S. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis, Pfizer Inc. N.Schmedt: Employee; Boehringer Ingelheim International GmbH. A.Deruaz-luyet: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Paik: None. Funding Boehringer Ingelheim (116283)

1096-P: Plasma Metabolites Predict Loss of Glycemic Control in Youth with Type 2 Diabetes (T2D)

We aimed to identify metabolites that predict the loss of glycemic control in youth-onset T2D (Y-T2D), a disease characterized by more rapid decline in β-cell function than adults-onset T2D. The increasing incidence of Y-T2D highlights the need to understand its pathophysiology and develop appropriate interventions. We measured 40 plasma metabolites in 374 baseline and 10-year follow-up samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, using mass spectrometry with a targeted ZipChip based assay. Loss of glycemic control was defined as HbA1c ≥8% for 6 months or inability to wean from temporary insulin after acute metabolic decompensation. We evaluated associations with time to loss of glycemic control in Cox proportional hazards models adjusted for HbA1c, triglycerides, systolic blood pressure, and estimated insulin sensitivity. Participants were 14±2 years of age, 63% female; 72% experienced loss of glycemic control. Five baseline plasma metabolites (threonine, asparagine, glycine, glutamine, L-alpha-aminobutyrate) associated with lower risk of loss of glycemic control, and one baseline plasma metabolite (citrate) associated with higher risk of loss of glycemic control. After multivariable adjustments, only plasma citrate remained statistically significant (HR: 1.16 per 1 SD [95% CI 1.04, 1.30]). At 10-year follow-up, of these plasma metabolites only threonine (logFC: -0.28, p=3.8×10-11) and glycine (logFC: -0.17, p=5.7×10-5) were significantly lower. Plasma metabolites, such as citrate that might originate from an excess of fatty acids, predicted loss of glycemic control in youth with T2D. Future work should validate these findings and investigate their response to promising therapies. Disclosure P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. R.Gubitosi-klug: None. K.Drews: None. K.L.Tommerdahl: None. J.B.Tryggestad: None. E.M.Isganaitis: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. L.Pyle: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. T.B.Vigers: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. L.El ghormli: None. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. J.R.Ryder: None. A.S.Shah: None. J.L.Lynch: Research Support; Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases

424-P: Diabetic Kidney Disease (DKD) Worsens CV Outcomes after First-Ever Major Cardiovascular Event in Type 2 Diabetes (T2D)

Aim: CV prognosis worsens in T2D after a first CV event. We assessed impact of DKD on mortality and subsequent CV events after a first CV event. Methods: Death rate was recorded over a median 14.1 (IQR 13.8-14.5) years follow-up in 961 T2D subjects. Vital status (Italian Health Card Database) was censored on December 31, 2017 (major CV events available for 947 participants). Effect of DKD (ACR <30/≥30 mg/g) and/or CKD-EPI eGFR ≥60/<60 ml/min/1.73 m2) was determined by Kaplan-Meier (K-M) curves and hazard ratios (HR, 95% CI) by unadjusted and adjusted Cox regression models (age, diabetes duration (DD), sex, smoking, retinopathy, hypertension, dyslipidemia, prior CVD; no-DKD as reference). Results: At census, 229 subjects were dead (23.8%) and 298 participants out of 947 (31.5%) had a first CV event during a median 13.8 year pre-event follow-up. Compared with free-CV event subjects, those with CVD were older, more often men, with longer diabetes duration, worse CV risk profile, more microvascular complications and CVD before recruitment. During a median 6 yr post-first CV event follow-up 99 subjects died: 57 (27.4%) no DKD, 42 (46.7%) DKD (K-M, p=0.005). Compared to no DKD the latter had an unadjusted HR of 1.76 (1.18-2.63, p=0.005; adjusted 1.69, 1.13-2.52, p=0.011). Death rate increased with DKD worsening with statistically significant HR (unadjusted 3.31, 1.73-6.31, p<0.0001; adjusted 3.32, 1.65-6.64, p=0.001) for ACR≥30/eGFR<60. During a median 3.1 post-first CV event follow-up, a new CV event occurred in 124 subjects: 82 (39.4%) no DKD and 42 (46.7%) DKD (K-M, p=0.019) with unadjusted HR for a new CV event in DKD of 1.40 (0.96-2.03, p=0.077). Rate of a secondary CV event increased across DKD phenotypes with unadjusted (HR 3.42, 95% CI 1.76-6.65, p<0.0001) and adjusted HR of 3.18 (1.57-6.44; p=0.001) for ACR≥30/eGFR<60, respectively. Conclusions: In T2D subjects, DKD still worsens the risk of mortality and secondary CV events after the occurrence of a first CV event. Disclosure M.Garofolo: Consultant; Novo Nordisk, Employee; Eli Lilly and Company. D.Lucchesi: None. M.Giambalvo: None. M.Capobianco: None. P.Francesconi: None. G.Penno: Advisory Panel; Eli Lilly and Company, Bayer Inc., Consultant; Novo Nordisk, AstraZeneca, Boehringer Ingelheim Inc. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi.

450-P: N-Terminal Pro-B Type Natriuretic Peptide Concentrations in Diabetic Cardiomyopathy—Baseline Data from the ARISE-HF Trial

Background: Diabetic Cardiomyopathy (DbCM) is a form of Stage B heart failure (HF). Concentrations of N-terminal pro-B type natriuretic peptide (NT-proBNP) may predict risk for HF progression in persons with DbCM. The ARISE-HF study (NCT04083339) is evaluating efficacy of AT-001, a highly selective aldose reductase inhibitor (AT-001) to improve exercise tolerance in affected patients. The aim of this analysis was to assess association between baseline NT-proBNP and cardiac status in type 2 diabetes participants with DbCM. Methods: Impaired exercise tolerance and baseline characteristics were evaluated in 679 patients with DbCM as a function of NT-proBNP at enrollment. Results: Median NT-proBNP in the overall study population was 71 ng/L (IQR 35-133). Baseline characteristics were similar across NT-proBNP concentrations, however, participants with higher NT-proBNP had higher left atrial volume (p<0.001) and higher right ventricular systolic pressure (p=0.04) on baseline echocardiogram. Higher NT-proBNP concentrations were associated with reduced physical activity reflected in lower PASE Score and a worse functional capacity reflected in lower peak VO2 (p<0.001) (Table 1). Conclusion: Among patients with DbCM, elevated NT-proBNP is associated with echocardiographic abnormalities and worse cardiac functional capacity and inversely associated with activity. Disclosure J.Butler: Consultant; Abbott,, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer,, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma,, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sequana Medical, Vifor, Speaker's Bureau; Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Janssen. F.Zannad: Advisory Panel; BMS, Novo Nordisk, Pfizer Inc., Servier Laboratories, Other Relationship; Applied Therapeutics Inc., Bayer Inc., Boehringer Ingelheim and Eli Lilly Alliance, Merck & Co., Inc., Novartis. J.L.Januzzi: Consultant; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., AstraZeneca, Research Support; Applied Therapeutics Inc., Abbott, Roche Diagnostics, Novartis, Innolife Co., Ltd. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. J.Ezekowitz: Advisory Panel; Applied Therapeutics Inc. N.E.Ibrahim: None. C.S.Lam: Other Relationship; Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai. R.Perfetti: None. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. W.Tang: Consultant; Sequana Medical NV, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics LLC, Renovacor, Boston Scientific Corporation, Kiniksa Pharmaceuticals Inc, WhiteSwell Inc, CardiaTec Biosciences Inc, Other Relationship; American Board of Internal Medicine, Springer Nature, Research Support; National Heart, Lung, and Blood Institute. A.Urbinati: None.

317-OR: Metabolomic Analyses Identify Novel Predictors of Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes

Background: Diabetic kidney disease (DKD) develops by young adulthood in up to 50% of people with youth-onset type 2 diabetes (Y-T2D), increasing risk of dialysis and premature death. Understanding mechanisms responsible for early DKD is key to management and prevention; accordingly, we sought to identify metabolite signatures of DKD in Y-T2D. Methods: We measured 57 metabolites in 374 baseline plasma and urine samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, using mass spectrometry with a targeted ZipChip based assay. Urine albumin-to-creatinine ratio (UACR) was assessed annually for up to 15 years. Incident moderate and severe albuminuria were defined as UACR ≥30 and ≥300 mg/g, respectively, on ≥2 of 3 measures. We evaluated prediction of moderate and severe albuminuria in separate Cox proportional hazards models adjusted for HbA1c, triglycerides, systolic blood pressure, and estimated insulin sensitivity. Urine metabolites were normalized by urine creatinine. Results: Participants were 14±2 years of age, 37% male; 43% developed either moderate or severe albuminuria. Four urine metabolites predicted time to moderate albuminuria, while 8 urine metabolites predicted time to severe albuminuria, with 3 metabolites in common: 2-hydroxybutyric acid (moderate: HR: 0.82 per 1 SD [95% CI 0.70, 0.96]; severe: 0.70 [0.55, 0.88]), glycine (moderate: 0.81 [0.69, 0.94]; severe: 0.62 [0.45, 0.85]), citric acid (moderate: 0.78 [0.67, 0.91]; severe: 0.76 [0.58, 0.99]). Four plasma metabolites predicted time to moderate albuminuria and severe albuminuria, such as glutamic acid for moderate albuminuria (1.23 [1.03, 1.47]) and citric acid for severe albuminuria (1.39 [1.09, 1.77]). Conclusion: Higher urine metabolites involved in mitigating oxidative stress (glycine), glomerular epithelial cell injury (2-hydroxybutyric acid) and preserving mitochondrial function (citrate) predicted lower risk of albuminuria in Y-T2D. Disclosure L.Pyle: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. A.S.Shah: None. K.Drews: None. J.R.Ryder: None. R.Gubitosi-klug: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. T.B.Vigers: None. L.El ghormli: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. R.G.Nelson: None. S.Waikar: None. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. N.White: None. K.L.Tommerdahl: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK61242)

257-OR: Diabetic Kidney Disease (DKD) and Nonalcoholic Fatty Liver Disease (NAFLD) Confer Worsening All-Cause Mortality and Cardiovascular Disease (CVD) Risk in Type 2 Diabetes (T2D)

Aim: In T2D, the prevalence of NAFLD is 56-60% and approximately 40% have DKD; thus, a sizable proportion of subjects may have both conditions. We explored to which extent the coexistence of the two could further worsen mortality and CVD risk in T2D. Methods: We recorded vital status and data for major CVD (the latter available for 98.5% subjects) were retrieved on December 31st, 2017. DKD (eGFR <60 ml/min/1.73 m2 and/or ACR ≥30 mg/g) and NAFLD (fatty liver index ≥60) effects assessed by Kaplan-Meier curves and hazard ratios (HR, 95% CI) by adjusted Cox regressions. Results: Distributions of NAFLD and DKD are reported in Table. HbA1c was similar in subgroups; NAFLD had worse metabolic and inflammatory profile, DKD higher hypertension rate. Over a follow-up of 13.1±2.8 years, we recorded 229 deaths (23.8%) and 273 major CV (28.8%). Rates of other outcomes are reported in Table. Death rate was 16.3, 21.8, 25.6 and 43.8% (p<0.0001) across groups with full adjusted HR (Model 2), of 1.50 (1.07-2.10, p=0.020) in NAFLD only, 1.15 (0.58-2.27, p=0.697) in DKD only, and 2.73 (1.90-3.93, p<0.0001) in DKD/NAFLD. Table reports effects of DKD-NAFLD combinations on CV outcomes. Conclusions: DKD and NAFLD concur increasing mortality and CVD risk in T2D patients. Monitoring and managing DKD and NAFLD is required to prevent CVD and reduce mortality. Disclosure M.Garofolo: Consultant; Novo Nordisk, Employee; Eli Lilly and Company. D.Lucchesi: None. M.Giambalvo: None. M.Capobianco: None. P.Francesconi: None. G.Penno: Advisory Panel; Eli Lilly and Company, Bayer Inc., Consultant; Novo Nordisk, AstraZeneca, Boehringer Ingelheim Inc. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi.

1238-P: The Face of Diabetic Cardiomyopathy—Baseline Characteristics from the ARISE-HF Trial

Background: Diabetic Cardiomyopathy (DbCM) is a severe complication of diabetes and a cause of heart failure (HF) occurring in the absence of other causes of cardiac dysfunction. Methods and Results: ARISE-HF (NCT04083339) is a global Phase 3 randomized study evaluating the safety and efficacy of a novel highly selective aldose reductase inhibitor (AT-001) versus placebo to improve exercise capacity in individuals with DbCM (defined by elevated cardiac biomarkers or structural/functional cardiac abnormalities along with impaired exercise capacity). Table 1 details the 684 study participants with DbCM in the study: 50% female, with a mean age 67.5 years. Glycemic control at enrollment was excellent (HbA1c of 6.99%). At baseline, the median NT-proBNP was 71 ng/L and hs-cTnT was 9 ng/L. Among echocardiographic abnormalities evaluated at enrollment, the most common were abnormal global longitudinal strain and impaired diastolic relaxation. Daily physical activity was low (mean PASE score of 154.3 + 89.6). Significant impairment in cardiac functional capacity was present at enrollment with a peak VO2 of 15.7 + 3.8 ml/kg/min. Conclusion: The ARISE-HF trial is an ongoing phase 3 clinical trial evaluating the safety and efficacy of aldose reductase inhibition on exercise capacity in patients with DbCM. The baseline analysis of the study cohort provides a unique characterization of individuals with DbCM. Disclosure J.Butler: Consultant; Abbott,, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer,, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma,, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sequana Medical, Vifor, Speaker's Bureau; Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Janssen. F.Zannad: Advisory Panel; BMS, Novo Nordisk, Pfizer Inc., Servier Laboratories, Other Relationship; Applied Therapeutics Inc., Bayer Inc., Boehringer Ingelheim and Eli Lilly Alliance, Merck & Co., Inc., Novartis. J.L.Januzzi: Consultant; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., AstraZeneca, Research Support; Applied Therapeutics Inc., Abbott, Roche Diagnostics, Novartis, Innolife Co., Ltd. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. J.Ezekowitz: Advisory Panel; Applied Therapeutics Inc. N.E.Ibrahim: None. C.S.Lam: Other Relationship; Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai. R.Perfetti: None. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. W.Tang: Consultant; Sequana Medical NV, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics LLC, Renovacor, Boston Scientific Corporation, Kiniksa Pharmaceuticals Inc, WhiteSwell Inc, CardiaTec Biosciences Inc, Other Relationship; American Board of Internal Medicine, Springer Nature, Research Support; National Heart, Lung, and Blood Institute. A.Urbinati: None.