Pharma GmbH Research Articles

318-OR: Tirzepatide Reduces Albuminuria in Patients with T2D—Post Hoc Pooled Analysis of SURPASS 1–5

In SURPASS 4, the GIP/GLP-1 receptor agonist tirzepatide (TZP) showed a potential kidney protective effect in people with T2D and high CV risk by slowing the rate of eGFR decline and reducing urine albumin-creatinine ratio (UACR) vs insulin glargine over 2 years. In this post-hoc analysis, we explored effects of TZP on UACR changes in SURPASS 1-5 trials. UACR (% difference) for TZP (5, 10, 15 mg) vs comparators (COMPs) was analyzed. Analyses were conducted in the pooled entire SURPASS 1-5 population and populations pooled by COMP: placebo (SURPASS 1 & 5); active (SURPASS 2 [semaglutide 1 mg] & SURPASS 3-4 [insulins]); and insulins. In each pooled population, data were examined in all patients and in subgroups defined by baseline UACR ≥30 mg/g or eGFR <60 mL/min/1.73m2. Mixed model for repeated measures was used to analyze on-treatment data from baseline up to the end of treatment visit. UACR data was available in 6263 patients of whom 1846 had UACR ≥30 mg/g and 537 had eGFR <60 mL/min/1.73m2. UACR decreased more with TZP 5, 10, and 15 mg vs COMPs in pooled SURPASS 1-5 and consistently across pooled placebo, active, and insulin COMP studies (Table). UACR lowering appeared more pronounced in subgroups with baseline UACR ≥30 mg/g or eGFR <60 mL/min/1.73m2. In people with T2D, including those with reduced kidney function, TZP decreased UACR vs COMPs to a clinically relevant degree, supporting a potential kidney protective effect. Disclosure 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. K.R.Tuttle: Consultant; Lilly, AstraZeneca, Gilead Sciences, Inc., Research Support; Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Novo Nordisk, Goldfinch Bio, Inc., Traveere Pharmaceuticals. I.Pavo: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. Z.Yang: Employee; Eli Lilly and Company. R.Wiese: Employee; Eli Lilly and Company. A.Hemmingway: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. D.Cherney: Other Relationship; Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon and Novo-Nordisk, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring and Novo-Nordisk. N.Sattar: Advisory Panel; Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Novartis, Roche Diagnostics, Consultant; Afimmune Limited, Hanmi Pharm. Co., Ltd., Pfizer Inc., Other Relationship; Abbott, AstraZeneca, Boehringer Ingelheim Pharma GmbH&Co.KG, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; AstraZeneca, Boehringer Ingelheim Pharma GmbH&Co.KG, Novartis, Roche Diagnostics. Funding Eli Lilly and Company

1566-P: The TM6SF2 rs58542926 Polymorphism Dissociates Hepatocellular Lipids from Insulin Resistance in Recent-Onset Type 2 Diabetes

Increased hepatocellular lipid content (HCL) is generally linked to insulin resistance, which contributes to greater risk of type 2 diabetes and cardiovascular complications. Conversely, a single-nucleotide polymorphism (TM6SF2EK; rs58542926) in the transmembrane 6 superfamily member 2 gene has been associated with nonalcoholic fatty liver disease (NAFLD), but lower cardiovascular risk. Thus, this case-control study tested the role of this polymorphism for tissue-specific insulin sensitivity during the early course of diabetes. Males with recent-onset type 2 diabetes with (TM6SF2EK: n=16) or without (TM6SF2EE: n=16) the heterozygous TM6SF2 polymorphism of similar age and BMI, underwent Botnia-clamps with [6,6-2H2]glucose to measure whole-body, hepatic and adipose tissue insulin sensitivity. HCL and liver fibrosis were assessed with 1H-magnetic resonance spectroscopy and non-invasive tests (FIB4, APRI, AST/ALT), respectively. A subset of both groups (n=24) was re-evaluated after 5 years. Despite doubled HCL, TM6SF2EK had similar hepatic and adipose tissue insulin sensitivity and even 27% higher whole-body insulin sensitivity than TM6SF2EE. The novel diabetes endotypes were equally distributed among both groups. After 5 years, whole-body insulin sensitivity, HCL and liver fibrosis indices were similar, while adipose tissue insulin sensitivity decreased by 87% and 55% both in TM6SF2EK and TM6SF2EE and circulating triacylglycerol increased in TM6SF2EE only. The TM6SF2 gene polymorphism rs58542926 dissociates ectopic fat content from insulin resistance in recent-onset type 2 diabetes, which is however attenuated by disease duration. This suggests that diabetes-related metabolic alterations dominate over the effects of the TM6SF2 gene polymorphism during the early course of diabetes and NAFLD. Disclosure K.Bódis: None. R.Guthoff: Other Relationship; Alimera, Bayer Inc., Novartis, Allergan. V.Schrauwen-hinderling: None. H.Al-hasani: None. V.Burkart: None. J.Szendroedi: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. D.F.Markgraf: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. M.Bombrich: None. M.Schön: None. B.Knebel: None. O.P.Zaharia: None. G.J.Bönhof: None. Y.Karusheva: None. Y.Kupriyanova: None. J.Kotzka: None.

777-P: Early Weight Loss and Late Metabolic Outcomes in Tirzepatide-Treated Participants with Type 2 Diabetes

Tirzepatide (TZP), a novel, once-weekly GIP/GLP-1 receptor agonist, significantly improved glycemic control with robust weight loss vs comparators in the SURPASS 1-5 trials. The aim of this analysis was to assess whether the magnitude of early weight loss with TZP (<5% or ≥5% at Week 8) would be associated with different clinical response in terms of HbA1c and weight at Week 40/42 across the SURPASS 1-5 trials. These phase 3 trials included participants with type 2 diabetes receiving TZP as monotherapy or add-on to background antihyperglycemic medications. This post-hoc analysis used pooled data from all TZP arms (5, 10, and 15 mg) across trials. Participants achieving ≥5% early weight loss at Week 8 had lower HbA1c and weight at baseline, and experienced greater reductions in HbA1c and weight at Week 40/42 vs those achieving <5% early weight loss (Table). Among participants achieving ≥5% early weight loss, greater proportions met HbA1c <7% and ≤6.5%, ≥10% weight loss, and the composite endpoint of HbA1c <7% and ≥10% weight loss. Early weight loss with TZP predicts greater reductions of HbA1c and weight at Week 40/42. However, even the one third of participants achieving <5% weight loss early in the course of therapy are likely to meet the ADA/EASD dual treatment goals of HbA1c <7% and ≥10% weight loss. Disclosure 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. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. L.Van gaal: Advisory Panel; Merck Sharp & Dohme Corp., Speaker's Bureau; Boehringer Ingelheim Pharma GmbH&Co.KG, Eli Lilly and Company, Novo Nordisk. M.Liu: Consultant; Eli Lilly and Company. Á.Rodríguez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Torcello-gomez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.I.Kiljanski: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

797-P: Safety Profile of Once-Weekly Subcutaneous Semaglutide in a Real-World Adult Population with T2D

Real-world (RW) drug safety studies complement safety information from randomized clinical trials. This post hoc analysis of pooled data from nine global non-interventional studies (SURE program: 10 countries, ~30 weeks duration) investigated the safety and prescription patterns of once-weekly (OW) semaglutide in 3,505 adults with T2D in routine practice, overall and by patient subgroup and medical specialty stratification. All safety data reported by site physicians were collected and presented using descriptive statistics. Results: Tables 1 and 2. A two-fold increase in level-2 hypoglycemia was associated with insulin use and microvasculopathy. No new safety concerns were observed with OW semaglutide in this large, diverse, RW population with T2D; the safety profile was in line with that of phase 3 trials of semaglutide. Disclosure J.Yale: Advisory Panel; Sanofi, Novo Nordisk Canada Inc., Eli Lilly and Company, Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Abbott, Mylan, Research Support; Sanofi, Novo Nordisk Canada Inc., Bayer Inc., Speaker's Bureau; Sanofi, Novo Nordisk Canada Inc., Eli Lilly and Company, Bayer Inc., AstraZeneca, Merck & Co., Inc., Boehringer Ingelheim (Canada) Ltd., Janssen Pharmaceuticals, Inc., Abbott, Dexcom, Inc. A.Major-pedersen: Employee; Novo Nordisk A/S. A.Catarig: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. R.Jain: Employee; Novo Nordisk Global Business Services, Stock/Shareholder; Novo Nordisk Global Business Services. M.Menzen: Advisory Panel; Boehringer Ingelheim Pharma GmbH&Co.KG, Novo Nordisk A/S, Ascensia Diabetes Care, Eli Lilly and Company, Novartis, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Santis, Boehringer Ingelheim Pharma GmbH&Co.KG, Novo Nordisk A/S, Bayer Inc., Eli Lilly and Company, Novartis. P.Holmes: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Novo Nordisk, Roche Diagnostics, Speaker's Bureau; Novo Nordisk, AstraZeneca, Eli Lilly and Company, Bayer Inc. Funding Novo Nordisk A/S

76-LB: Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA)–Experienced Adults with Type 2 Diabetes (T2D) Switching to Once-Weekly (OW) Semaglutide in a Real-World Setting—SURE Program Post Hoc Analysis

Retrospective database studies have shown that switching between some GLP-1RAs may be associated with additional benefits on glycemic control and body weight (BW). This prospective post hoc analysis of pooled data from the SURE real-world program (9 ~30 week studies in 10 countries) investigated outcomes associated with switching to OW semaglutide from another GLP-1RA in adults with T2D. Endpoints included change in HbA1c and BW from baseline to end of study, percentage achieving HbA1c <7% (when baseline HbA1c ≥7%) or BW change ≥5%, and safety. For change in HbA1c and BW, a random coefficient-adjusted mixed analysis for repeated measures was used, regardless of semaglutide treatment status. In total 651 participants (mean age 60 years; 53% male) switched to OW semaglutide: 64% from liraglutide, 31% from dulaglutide. Significant changes were observed in HbA1c and BW (Figure); 33% of participants with baseline HbA1c ≥7% achieved HbA1c <7%, and 28% reduced BW by ≥5%. No new safety concerns were identified; 3% discontinued due to AEs, 2% reported ≥1 hypoglycemic episode (blood glucose <54 mg/dL) and 8/11 participants with ≥1 level 2 hypoglycemic episode were on insulin. In adults with T2D previously treated with GLP-1RAs, switching to OW semaglutide may provide additional benefits with convenient OW dosing. Disclosure G. Rudofsky: Consultant; AstraZeneca, Eli Lilly and Company, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. M. Menzen: Advisory Panel; Boehringer Ingelheim Pharma GmbH&Co. KG, Novo Nordisk A/S, Ascensia Diabetes Care, Eli Lilly and Company, Novartis, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Santis, Boehringer Ingelheim Pharma GmbH&Co. KG, Novo Nordisk A/S, Bayer Inc., Eli Lilly and Company, Novartis. L. Potier: Consultant; Lilly Diabetes, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim Inc. A. Catarig: Employee; Novo Nordisk, Stock/Shareholder; Novo Nordisk. A. Clark: Employee; Novo Nordisk A/S. P. Priyadarshini: None. C. Abreu: Speaker's Bureau; Lilly, Novo Nordisk. Funding Novo Nordisk

1237-P: Proteomic Indicators of Metabolic Health in Diabetes and Social Vulnerability

Introduction: Understanding the health impacts of socioeconomic deprivation (SED) and its interaction with type 2 diabetes is important for patient care and effective public health initiatives. Large-scale proteomic profiling using aptamer-based technology to measure 7,000 proteins has facilitated the development of blood-based proteomic signatures for 10 cardiometabolic SomaSignal Tests (SST), including a test that predicts the 4-year risk of a cardiovascular event (CV risk). Methods: The cross-sectional PsoBid study recruited participants from socioeconomically deprived and affluent areas of Glasgow, Scotland with similar age ranges and equal proportions of male and female, to identify relevant health disparities. We used regression analyses to estimate the association between SSTs and socioeconomic status (affluent (n = 257, 50.7%), deprived (n = 250, 49.3%)) and prevalent diabetes (n = 27 (5.3%), 7 (2.7%) affluent, 20 (8.0%) SV). Results: Diabetes was associated with SST predicted increased visceral fat, lean body mass, liver fat, body fat percentage, resting energy rate, and CV risk score, and worse proteomic predictors of cardiorespiratory fitness, glucose tolerance, alcohol impact, and kidney health (p<0.05). SED was associated with SST predicted increased visceral adiposity and CV risk score, and decreased cardiorespiratory fitness, glucose tolerance, and kidney health (p<0.05). The association between diabetes and CV risk score was highest among socioeconomically deprived participants (interaction p-value: 0.01). Conclusion: These results demonstrate that participants with diabetes and SED have proteomic phenotypes consistent with decreased cardiometabolic health compared to participants without diabetes or SV and SED is associated with worse predicted cardiovascular risk in patients with diabetes. Proteomics may be useful in identifying and monitoring the health effects of diabetes and SED or the impact of relevant interventions. Disclosure M.Simpson: Employee; SomaLogic Operating CO., Inc. R.Ostroff: Employee; SomaLogic. S.A.Williams: Employee; SomaLogic. N.Sattar: Advisory Panel; Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Novartis, Roche Diagnostics, Consultant; Afimmune Limited, Hanmi Pharm. Co., Ltd., Pfizer Inc., Other Relationship; Abbott, AstraZeneca, Boehringer Ingelheim Pharma GmbH&Co.KG, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; AstraZeneca, Boehringer Ingelheim Pharma GmbH&Co.KG, Novartis, Roche Diagnostics.

749-P: Selection of BI 456906 as a Dual GCGR/GLP-1R Agonist Based on In Vitro Potency and In Vivo Target Engagement Biomarkers

Glucagon (GCG) and glucagon-like peptide 1 (GLP-1) are peptide hormones that pharmacologically regulate bodyweight by increasing energy expenditure and reducing energy intake, respectively. Several dual (GCG receptor [GCGR]/GLP-1 receptor [GLP-1R]) agonistic peptides are in clinical development for obesity. We describe preclinical data leading to selection of BI 456906 as a dual agonist. Functional potencies of the compounds were determined in CHO-K1 cells stably expressing human GCGR and GLP-1R. EC50 for GCGR mediated cAMP increase were 0.52 nM for BI 456906, 0.92 nM for BI 456908 and 0.44 nM for BI 456987. EC50 for GLP-1R engagement were 0.33 nM, 0.61 nM and 1.43 nM, respectively. Upon acute, single dosing to lean mice, engagement of the GCGR and GLP-1R was determined by testing for improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma FGF-21 and liver nicotinamide N-methyltransferase mRNA expression (100 nmol/kg), respectively. Specificity of the biomarkers was confirmed using the selective GLP-1R agonist semaglutide and GLP-1R knockout mice. Bodyweight and glucose lowering (HbA1c) efficacies were investigated in subchronic dosing studies in diet-induced obese (DIO) and diabetic (db/db) mice, respectively. In DIO mice, BI 456906 (30 nmol/kg qd), BI 456908 (30 nmol/kg qd) and BI 456897 (10 nmol/kg qd) achieved bodyweight lowering from baseline of 25%, 27%, and 26%, respectively. In db/db mice, BI 456906 and BI 456908 (10 and 20 nmol/kg qd) substantially lowered HbA1c (0.4-0.6%); no clear effect was observed for BI 456897 (3 and 7 nmol/kg qd). As a balanced GCGR/GLP-1R agonist with robust in vivo efficacy BI 456906 (30 nmol/kg qd) was further characterized, and superior bodyweight lowering (32% vs 27%; p<0.05) was seen versus a maximally effective semaglutide dose (100 nmol/kg qd). This was attributed to an increase in energy expenditure. The selected candidate, BI 456906, is currently in clinical development in people with obesity and NASH. Disclosure R.Augustin: None. L.Thomas: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. T.Zimmermann: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. E.Simon: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. W.Rist: None. I.Uphues: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. W.Reindl: None. T.Klein: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. H.Neubauer: None. Funding Zealand Pharma A/S; Boehringer Ingelheim

164-LB: Durable Improvement in HbA1c in Youth-Onset T2D—A Post Hoc Analysis of the DINAMO Trial of Empagliflozin and Linagliptin vs. Placebo

The increasing prevalence of childhood overweight and obesity has led to a substantial increase in T2D in youth. The clinical course of youth-onset T2D is more aggressive than in adults, with a faster decline in beta‑cell function leading to worse glycemic control and an early onset of complications. The DINAMO trial compared the efficacy and safety of empagliflozin and linagliptin with placebo in 157 participants aged 10-17 years. Participants were randomized (1:1:1) to linagliptin 5 mg, empagliflozin 10 mg, or placebo. At Week 12, those in the empagliflozin group who did not attain HbA1c <7.0% were re‑randomized (1:1) to empagliflozin 10 or 25 mg. Responders were defined as having no rescue medication and a HbA1c change from baseline ≤-0.5% or attained HbA1c <7.0% at Week 26. Empagliflozin results were pooled. Significantly more participants responded to empagliflozin vs placebo (rate difference 23.6, 95% CI 4.3-41.4; p=0.01); this response was maintained to Week 52 by 40% of the group. Results for linagliptin vs placebo were not significant. Empagliflozin provided a clinically meaningful response even at higher HbA1c and FPG levels (Table). These results show that empagliflozin provides a clinically relevant, statistically significant, and durable improvement in glycemic control, suggesting SGLT2 inhibitors could be a new therapy for T2D in youth. Disclosure 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. T. Danne: Research Support; Abbott Diabetes, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Medtronic, Stock/Shareholder; DreaMed Diabetes, Ltd. W. V. Tamborlane: None. G. J. Klingensmith: Advisory Panel; Boehringer Ingelheim Inc., Consultant; AstraZeneca, Boehringer Ingelheim Inc., Novo Nordisk, Takeda Pharmaceutical Co., Ltd. D. Neubacher: Employee; Boehringer Ingelheim Pharma GmbH&Co. KG. I. Tartakovsky: Employee; Boehringer Ingelheim International GmbH. J. Marquard: Employee; Boehringer Ingelheim Inc. P. Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson & Johnson. S. M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

794-P: Effectiveness and Safety of iGlarLixi in People with Type 2 Diabetes (Pw2D), Not at Target on Basal Insulin (BI) and Oral Antidiabetic Therapy (BOT)—Results from the Observational, Prospective Study CHANCE

iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide, is a once-daily treatment advancement option for Pw2D not at target on BOT. CHANCE investigated effectiveness and safety of switching the BI to iGlarLixi in daily clinical practice. Primary objective was to assess absolute change in HbA1c 24 weeks (W24) after switching to iGlarLixi. Secondary objectives included changes in fasting plasma glucose (FPG), bodyweight (BW), use of oral antidiabetic drugs (OADs), dose of previous BI, and hypoglycemia incidence. Overall, data from 70 Pw2D were analyzed. Mean BI dose was 38.9 units per day and individual target HbA1c was 6.9%. iGlarLixi was started with 30 dose steps per day (DS/d); at W24, mean dose was 41.6 DS/d. HbA1c decreased by -0.7% (P < 0.001), while FPG trended down by ~20 mg/dL. This was accompanied by a -3.0 kg decrease in BW (P = 0.442). Numbers of OADs used decreased markedly 24 weeks after switching to iGlarLixi (P < 0.05). Hypoglycemia incidence was low before and did not change significantly after switching to iGlarLixi. In conclusion, advancing BOT by switching the BI to iGlarLixi, improved glycemic control of Pw2D in daily clinical practice without BW gain and with low hypoglycemia incidence; however, titration was not sufficient to reach glycemic targets after 24 weeks. Disclosure T.Wiesner: Advisory Panel; Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH, Lilly Diabetes, Boehringer Ingelheim Inc., Abbott Diabetes, Novo Nordisk, Dexcom, Inc., Novartis. M.Pfohl: Advisory Panel; Boehringer Ingelheim and Eli Lilly Alliance, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Sanofi-Aventis Deutschland GmbH. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Sanofi-Aventis Deutschland GmbH. J.Müller: Employee; Sanofi-Aventis Deutschland GmbH, Stock/Shareholder; Bayer Inc., Inmunebio Inc. J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Merck Sharp & Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk. Funding Sanofi-Aventis Deutschland GmbH

AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccines and booster vaccination in siponimod treated patients with secondary progressive multiple sclerosis (P12-3.004)

<h3>Objective:</h3> We are aiming to understand the cellular and humoral immune responses to SARS-CoV-2 mRNA booster vaccinations in siponimod treated patients. <h3>Background:</h3> SARS-CoV-2 mRNA vaccines are a key factor fighting the COVID-19 pandemic across the globe. However, data are lacking on the efficacy of vaccination in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs) both over time and after a booster vaccination. <h3>Design/Methods:</h3> AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, any first-line DMT or without treatment at all in clinical routine. Cohort 1 receives SARS-CoV-2 mRNA vaccination while continuing their current siponimod treatment, cohort 2 interrupts siponimod treatment for the purpose of a full vaccination cycle and cohort 3 receives vaccination during continuous treatment with first-line DMTs (glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. Primary endpoint is the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies one week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells is evaluated in all patients. Both parameters are analyzed in week one, month one and six month after initial vaccination cycle and one month after a booster vaccination. <h3>Results:</h3> After a positive first interim analysis showing both SARS-CoV-2 neutralizing antibodies and T-cell responses one week after complete vaccination in siponimod patients, final data of the study will be available in early 2023 including the effect of booster vaccination, which was received by 38 of 41 patients during study. <h3>Conclusions:</h3> This final analysis of the AMA-VACC trial will provide first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination and booster vaccination in siponimod treated SPMS patients and support physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment. <b>Disclosure:</b> Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS Celgene. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Novartis. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Ziemssen has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for BMS Celgene. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for TEVA. The institution of Dr. Ziemssen has received research support from Biogen. The institution of Dr. Ziemssen has received research support from Novartis. The institution of Dr. Ziemssen has received research support from Merck. The institution of Dr. Ziemssen has received research support from Sanofi. The institution of Dr. Ziemssen has received research support from Celgene. Dr. Groth has received personal compensation for serving as an employee of Novartis Pharma GmbH. Dr. Winkelmann has received personal compensation for serving as an employee of Novartis Pharma GmbH. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Prof. Bopp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Prof. Bopp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pathios Therapeutics. The institution of Prof. Bopp has received research support from DFG (German Research Foundation). The institution of Prof. Bopp has received research support from BMBF. Prof. Bopp has received intellectual property interests from a discovery or technology relating to health care.

Final results of the PANGAEA 2.0 study: Treatment benefits of fingolimod for active RRMS patients switching from other DMTs (P6-3.009)

<h3>Objective:</h3> The aim of the PANGAEA 2.0 study was to investigate the efficacy and long-term benefits (3 years) of fingolimod in relapsing-remitting multiple sclerosis (RRMS) patients with disease activity switching from other disease-modifying therapies (DMTs). <h3>Background:</h3> In the treatment of RRMS, individualized sequential therapies can be used to optimize the outcome. It is, however, necessary to understand the efficacy and overall impact of sequential switching. <h3>Design/Methods:</h3> The non-interventional, real-world evidence study included 2,579 disease-active RRMS-patients treated with fingolimod at 240 neurological practices and clinics in Germany out of which 966 completed the study. The patients, who were either untreated or treated with an approved DMT other than fingolimod before study start, were observed for 3 years. To obtain insight into the effectiveness of changing to fingolimod, subgroup analyses were based on the patients’ last therapy before switching: oral DMT (oDMT; dimethyl fumarate, teriflunomide), injectable DMT (iDMT; interferons, glatiramer acetate), natalizumab, other DMTs and treatment-naive. <h3>Results:</h3> At baseline, the patient population was mostly female (71.1%) and patients were on average 39.2 (±10.8) years old. The majority of patients had received only 1 treatment prior to study start. In total, 1,138 patients had received an iDMT as last therapy before receiving fingolimod. On average, patients presented with an EDSS of 2.4±1.5 at study start. Over 3 years, the mean EDSS total score remained on a relatively stable level in the subgroups iDMT (EDSS: 2.4±1.6) and oDMT (EDSS: 2.6±1.5). The EDSS increased slightly in the group who was previously on natalizumab treatment (EDSS: 3.3±1.6) along with a slight increase in FSMC. The mean SDMT remained on a stable level in all subgroups. <h3>Conclusions:</h3> PANGAEA 2.0 brings us real-world insights into the effectiveness of fingolimod in disease-active RRMS-patients. The results show that the disease burden remained relatively stable during 3 years on fingolimod, regardless of the previous therapy. <b>Disclosure:</b> Dr. Weiss has received personal compensation for serving as an employee of Novartis Pharma GmbH. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for BMS Celgene. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Roche. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Novartis. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Ziemssen has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for BMS Celgene. Dr. Ziemssen has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Ziemssen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for TEVA. The institution of Dr. Ziemssen has received research support from Biogen. The institution of Dr. Ziemssen has received research support from Novartis. The institution of Dr. Ziemssen has received research support from Merck. The institution of Dr. Ziemssen has received research support from Sanofi. The institution of Dr. Ziemssen has received research support from Celgene.

Duration of bite force reduction following a single injection of botulinum toxin in the masseter muscle bilaterally: A one-year non-randomized trial.

Previous studies concerning the effect of botulinum toxin in masseter muscle have mainly reported effects observed through inspection of facial features or differences in pain levels. One systematic review of studies utilizing objective measurements reported that long-term muscular effect of botulinum neurotoxin injections into masseter muscle was inconclusive. To evaluate the duration of reduced maximal voluntary bite force (MVBF) after botulinum toxin intervention. The intervention group was comprised of individuals seeking aesthetic treatment for masseter reduction (n= 20), the reference group (n= 12) comprised of individuals with no intervention. Intervention through 25 units of Xeomin® (Merz Pharma GmbH & Co KGaA, Frankfurt am Main, Germany) botulinum neurotoxin type A injected into the masseter muscles bilaterally (totalling 50 units). A reference group did not receive any intervention. MVBF was measured in Newtons using a strain gauge meter at the incisors and first molars. MVBF was measured at baseline, at 4 weeks, 3 months, 6 months, and after 1 year. Both groups were similar in terms of bite force, sex and age at baseline. MVBF remained similar compared to baseline in the reference group. At 3 months, a significant reduction at all measurement points was observed in the intervention group; at 6 months, this reduction was no longer significant. A single intervention of 50 units of botulinum neurotoxin results in a reversible MVBF reduction of at least 3months, although a visually discernable reduction may be more long-lasting.

Abstract P2-01-01: Interim analysis (n=200) from ELEANOR: a multi-national, prospective, non-interventional study among patients with HER2+ and HR+ early breast cancer treated with extended adjuvant neratinib in the clinical routine

Abstract Background Recent advances in the treatment of human epidermal growth factor receptor positive (HER2+) early breast cancer (eBC) have led to a reduction in recurrence risk; still a relevant percentage of patients relapses over time, predominantly presenting with distant recurrence. Neratinib is registered in Europe as extended adjuvant treatment for adult patients with HER2+, hormone receptor positive (HR+) eBC, who completed adjuvant trastuzumab-based therapy within one year prior to start of neratinib. In the ExteNET study, neratinib improved the absolute 5-year invasive disease-free survival (iDFS) rate by 5.1% versus placebo in this population (90.8% vs. 85.7%; HR 0.58 [95% CI 0.41-0.82]), mainly by reducing the rate of distant metastases. According to explorative analyses from ExteNET, the effect may be even more pronounced in patients with non-pCR after neoadjuvant trastuzumab treatment and/or in patients completing the full duration of neratinib therapy (i.e. ≥11 months of neratinib treatment). Diarrhea, the most common grade 3 adverse event (neratinib: 39% without primary diarrhea prophylaxis, median cumulative duration 5 days; placebo: 1%; no grade 4 events) can generally be managed through adequate prophylaxis and treatment management. ELEANOR is the first non-interventional study (NIS) of real-world use of neratinib and its management in eBC patients in Germany, Austria and Switzerland. Methods Enrollment of 300 adult female patients with HER2+/HR+ eBC is planned in accordance with the SmPC specifications. Primary endpoint is the rate of patients adherent to neratinib treatment (i.e. neratinib use for ≥75% of treatment days). Secondary objectives include characterization of patients scheduled to receive neratinib, details on neratinib treatment, recurrences, safety/tolerability, and health-related quality of life (HRQoL). CANKADO, an eHealth application developed to support patient/physician communication, is an integral part of the NIS. Here, we report results of the preplanned interim analysis based on 200 enrolled patients. Results At data cut-off (May 2022), 202 patients had been observed for 3 months; patient enrollment is ongoing. Median age was 53.0 years and 66.3% of patients were at increased risk of disease recurrence (defined as non-pCR or AJCC stage &amp;gt; I). Most patients had received prior neoadjuvant treatment (79.7%). Post-neoadjuvant treatment included dual HER2 blockade with trastuzumab and pertuzumab (38.8%/23.9% of pCR/non-pCR patients) and trastuzumab-emtansine (T-DM1, 53.5% of non-pCR patients). Neratinib treatment had been documented for 187 patients, treatment was ongoing for 46.0% of patients. Diarrhea was the most common adverse event (78.6% any grade, 19.3% grade 3, 2 patients grade 4), but was markedly lower when indirectly compared to ExteNET (39% grade 3). The neratinib dose escalation schedule was chosen for 36.4% of patients and led to a decreased incidence of severe diarrhea (16.2% grade 3, no grade 4 events). 93.9% (95% CI: 87.9-97.5%) of 115 evaluable patients adhered to neratinib treatment. Conclusion The results of this preplanned interim analysis reflect the current treatment landscape in Germany, Austria and Switzerland. These results confirm, in line with the observed adherence data, that extended adjuvant neratinib use is feasible in typical clinical practice settings. Furthermore, treatment management strategies such as diarrhea prophylaxis or neratinib dose escalation are routinely used and can increase treatment tolerability markedly. The study is funded by Pierre Fabre Pharma GmbH (Freiburg, Germany), Pierre Fabre Pharma Austria (Wels, Austria) and Pierre Fabre Pharma AG (Allschwil, Switzerland). Citation Format: Rupert Bartsch, Nadia Harbeck, Denise Wrobel, Matthias Zaiss, Jürgen Terhaag, Dagmar Guth, Andrea Distelrath, Rachel Wuerstlein, Mark-Oliver Zahn, Diana Lüftner, Michael Schwitter, Marija Balic, Christian Jackisch, Volkmar Müller, Gabriel Rinnerthaler, Marcus Schmidt, Khalil Zaman, Timo Schinköthe, Anna Resch, Urs Breitenstein. Interim analysis (n=200) from ELEANOR: a multi-national, prospective, non-interventional study among patients with HER2+ and HR+ early breast cancer treated with extended adjuvant neratinib in the clinical routine [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-01-01.

Pharmacokinetic and bioequivalence study of Telzap® Plus fixed-dose combination compared with MikardisPlus® in healthy volunteers after single administration

Introduction. A fixed dose combination of telmisartan and hydrochlorothiazide is indicated for treatment of in the treatment of arterial hypertension. The combination of these substances causes an additive effect that helps to reduce blood pressure. A bioequivalence study of Telzap® Plus compared with MikardisPlus® was conducted with 63 volunteers.Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of the fixed dose combination drug product Telzap® Plus (tablets 80 mg + 12,5 mg, Zentiva KS company, Czech Republic) compared with drug products MikardisPlus® (telmisartan+hydrochlorothiazide, tablets 80 mg + 12,5 mg, Boehringer Ingelheim Pharma GmbH &amp; Co. KG, Germany) in healthy volunteers after a single administration under fasting.Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover fourperiod replicate single-center clinical trial was conducted. The concentrations of hydrochlorothiazide and telmisartan in plasma samples were determined with a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals for the pharmacokinetic parameters Cmax and AUC0-72 were calculated.Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of hydrochlorothiazide and telmisartan. All 90 % confidence intervals for the estimated pharmacokinetic parameters of hydrochlorothiazide were in the range of 80–125 %, 90 % confidence intervals for telmisartan were within the bioequivalence range of 80–125 % for AUC0-72, and 79,30–126,11 % for Cmax.Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent.

Physicochemical stability of carmustine-containing medicinal products after reconstitution and after dilution to ready-to-administer infusion solutions stored refrigerated or at room temperature

IntroductionThe aim of this study was to determine and compare the physicochemical stability of two carmustine-containing medicinal products licensed and marketed in Europe as Carmustin Obvius (Medac GmbH) and Carmubris...

Upregulation of SGLT1 and 2 promotes oxidative stress in right atrial appendages of patients with low-grade inflammatory responses: potential role in atrial fibrillation

Abstract Introduction Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with increased morbidity and mortality. Inflammatory infiltrates have been observed in atrial tissues from AF patients suggesting that low-grade inflammation contributes to the pro-fibrotic, pro-remodeling and pro-senescence responses of the atrial tissue favoring AF. Although sodium glucose co-transporter2 inhibitors (SGLT2i) have shown beneficial effects in heart failure, the expression and role of SGLT2 in cardiac tissues remain unclear. Purpose This study examined the expression of SGLT1 and 2 in right atrial appendages (RAA) of cardiac patients, and, if so, to determine the underling mechanism and their functional role. Methods RAA were harvested from patients undergoing coronary artery bypass surgery or aortic valve replacement at the University Hospital of Strasbourg. Patients with comorbidities such as malignancies and chronic inflammatory diseases were excluded. The expression level of markers was assessed using RT-qPCR, Western blot analysis, and immunofluorescence staining, and the level of reactive oxygen species using dihydroethidium staining. Results Analysis of RAA samples evidenced up-to a 4-fold difference in the NOS3 mRNA level. Those with low levels of NOS3 mRNA showed high levels of ICAM1, F3, MMP9, TGF-β1, TP53, CDKN1A, CDKN2A, SLCA1, SLCA2, IL1B, IL6, TNF-a and CD68 whereas the contrary was observed in those with high levels of NOS3 mRNA. SGLT1/2 mRNA levels were negatively correlated with that of eNOS and positively with those of IL-1, IL-6, TNF- α, CD68, and the senescence marker p53. Western blot analysis of RAA indicated that those expressing low levels of eNOS protein showed high levels of ICAM-1, VCAM-1, TF, MMP-2, TGF-b, SGLT1, SGLT2, p-p65, p53, p21 and p16 proteins whereas the contrary was observed in those with high levels of eNOS protein. Immunofluorescence staining indicated that SGLT1/SGLT2 signals were colocalized with those of CD31, an endothelial cell marker, in RAA, and associated with those of CD68 and TNF-α. Samples with high levels of SGLT1 and 2 displayed higher levels of oxidative stress that were inhibited by the antioxidant NAC (N-acetylcysteine), VAS-2870 (NADPH oxidase inhibitor), perindoprilat (ACE inhibitor), losartan (AT1R antagonist), empagliflozin (selective SGLT2 inhibitor), sotagliflozin (dual SGLT1/2 inhibitor) and by infliximab (TNF-α receptor neutralizing antibody). Conclusion The findings indicate that high expression levels of SGLT1 and 2 are observed in RAA showing low eNOS levels associated with pro-inflammatory, pro-senescent, pro-remodeling and pro-fibrotic responses. They were further associated with increased levels of oxidative stress sensitive to inhibitors of either the local angiotensin system, TNF-alpha or SGLT2. Thus, inhibition of SGLT2 appears to be an interesting approach to reduce the stimulatory pro-oxidant signal in atrium related to low-grade inflammation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH &amp; Co. KG

Communication disconnect concerning erectile dysfunction in male heart failure patients: cardiologists and GPs need to talk about sex

Abstract Background Heart failure (HF) and erectile dysfunction (ED) share risk and pathogenetic factors manifesting in a higher prevalence of ED in male HF patients. Despite being a recognized comorbidity, scientific research in this field is limited. Purpose This research aims to better understand the patient journey from a patients' as well as health care professionals' (HCP) perspective in terms of communication, education and ED treatment as recognized concomitant disease in HF patients. Methods Data was collected using two independent online surveys between Nov 21 and Jan 22 from diagnosed male HF patients (N=927) and HCPs including general practitioners (GP), cardiologists and internists (N=78) on quality of life (QoL) with focus on sexual life. As part of the patient survey, male HF patients with ED (N=176) were asked to provide further information about their experiences and ED-related communication with HCPs. Results Male HF patients reported their sexual life as being important (56%*) and their sexual health impacting QoL, with 43% of all men asked (N=927) being unsatisfied with their sexual life. Focusing on HF patients with ED (N=176), half was not aware of the link between HF and ED. Only 33% of male HF patients stated that they were informed about a potential link by their HCP, equally distributed to GPs, cardiologists and urologists. HCPs in turn reported that only 20% of their patients proactively consult them, but the majority of male HF patients with ED (69%) stated that they feel left alone and wish for more personal exchange regarding the topic of ED with a doctor (74%). HCPs reported awareness of strong ED burden in 70% of their male HF patients. In contrast to the patients' perspective, 56% of HCPs report that they do address the topic of ED to their HF patients. Top ranked reason for not addressing the topic of ED from HCP side were the assumption and/or knowledge that patients feel uncomfortable talking about ED. Interestingly, only 7% of male HF patients with ED indeed indicated feeling uncomfortable. Despite their pronounced sexual dissatisfaction only 40% of male HF patients with ED indicated that they talk to a doctor about ED treatment options. In consequence, only 22% of them take prescription drugs. More frequently, HCPs reported that about one third of their patients are non-compliant with HF medication due to ED highlighting the high importance of sexual health for patients' QoL. Conclusions We identified a communication disconnect between HCPs and HF patients regarding ED. As patients' QoL is strongly affected by sexual health, they wish for more personal exchange and information. There is a strong need to proactively address the topic of ED by cardiologists and GPs as the first point of contact for HF patients. New ideas for tools generating a better understanding and more confident conversations about HF and ED are warranted. *On a scale from 1 = “not important” to 10 = “very important” rated ≥7. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma GmbH

Living with heart failure: quality of life, particularly sexual life, is impaired by emotional burden as reported by patients

Abstract Background Symptoms of heart failure (HF) include shortness of breath and limited exercise capacity as a result of fluid retention and circulatory disorders. Life expectancy of HF patients has improved, mainly driven by current treatment modalities. The burden of HF in terms of quality of life (QoL) and emotional well-being is frequently neglected and is less well described than typical HF symptoms. Purpose The aim of this study is to better understand the impact of HF on patients' QoL and emotional well-being from the patients' perspective. Methods Data on disease perception and physical as well as emotional burden was collected using an online survey from Nov to Dec 21 from patients with HF diagnosis (Nfemale=830; Nmale=927). Results Overall, the majority of HF patients considered being capable of fulfilling everyday routines as highly important. In detail, 87% of HF patients rated taking care of themselves, 82% running the household independently, 83% mobility outside the house and 74% social life with highest importance*. Impairments in the same QoL determining aspects from above showed a bimodal distribution of HF patients meaning that they were either highly affected or not affected at all. Male and female HF patients rated QoL aspects in terms of importance and impairment equally, except sexual life importance and sexual impairments, which were ranked higher by men (56% vs. 42%*, 39% vs. 32%§, respectively). Being asked about their biggest concern regarding HF via an open-ended question, death was the most commonly reported term. However, 20% indicated social and emotional worries as their first concern. Indeed, HF patients were frequently emotionally affected and almost every second HF patient stated considerable restrictions of their daily obligations and every third of their social life due to emotional problems. Patient-reported emotions were being worried (53%#), listless/without energy (47%#), fatigue (45%#) and/or afraid (42%#). Interestingly, the fraction of HF patients being unsatisfied with their sexual life was larger when patients indicated feeling emotionally affected (worried, listless, fatigue, afraid). On the other hand, HF patients indicating no negative emotions were more satisfied with their sexual life highlighting the importance of sexual health contributing to QoL. Conclusion(s) The emotional burden experienced by HF patients is as high as their physical impairments culminating in considerable restrictions of their daily routines due to emotional problems. Additionally, emotional well-being is strongly linked with sexual satisfaction. *On a scale from 1 = “not important” to 10 = “very important” rated ≥7. §On a scale from 1 = “not affected” to 10 = “no activity possible” rated ≥7. #On a scale of 1 = “never” to 10 = “very often” rated ≥7. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma GmbH

Single pill treatment in daily practice is associated with improved clinical outcomes and all-cause mortality in cardiovascular diseases: results from the START project

Abstract Objective Current guidelines for the management of arterial hypertension, dyslipidemia, or secondary cardiovascular (CV) prevention recommend combination drug treatments with single pill combinations (SPC). This concept is expected to improve adherence to treatment and, as a consequence, to reduce the risk of adverse CV outcomes associated with these clinical conditions. Aim of our study was to assess whether SPC are clinically superior to multi pill combination (MPC) with identical drugs in reducing CV events and al-cause mortality in a huge population under real world conditions in daily practice. Methods We analyzed an anonymized claims dataset (AOK PLUS, a statutory German sickness fund) including patients with hypertension and other CV diseases in the years 2012–2017; minimum follow-up was 1 year or until date of death, After 1:1-Propensity Score Matching (PSM), selected CV outcomes (myocardial infarction, stroke, transitory ischemic attack, coronary artery disease, heart failure, acute renal failure, cardiovascular hospitalization, all cause hospitalization) as well as all-cause mortality were compared using Incidence Rate Ratios (IRRs) and non-parametric tests. Results 50,622 patients (25,311 patients in SPC versus MPC group) aged ≥18 years treated with SPC or identical MPC were followed up for at least 1 year or until death. No significant differences in baseline characteristics were observed after PSM. Nine different clinical outcomes were compared for each group. In all comparisons, significantly lower incidence rate ratios (IRR) were identified for SPC, confirmed by comparison of Kaplan-Meier estimates: stroke (IRR=0.77; 95% CI 0.67–0.88; p&amp;lt;0.001), transitory ischemic attack (IRR=0.61; 95% CI 0.48–0.78; p&amp;lt;0.001), myocardial infarction (IRR=0.76; 95% CI 0.63–0.90; p=0.0016), coronary artery disease (IRR=0.66; 95% CI 0.57–0.77; p&amp;lt;0.001), heart failure (IRR=0.59; 95% CI 0.54–0.64; p&amp;lt;0.001), acute renal failure (IRR=0.54; 95% CI 0.56–0.64; p&amp;lt;0.001) all cause hospitalization (IRR=0.72; 95% CI 0.71–0.74; p&amp;lt;0.001), cardiovascular hospitalization (IRR=0.63; 95% CI 0.57–0.69; p&amp;lt;0.001), and all-cause mortality (IRR=0.62; 95% CI 0.57–0.68; p&amp;lt;0.001). The mean time to first events and time to death were also in favor to SPC (any event: SPC 966.052 days/median 873; MPC 846.936 days/median 647; death: SPC 1,719.424 days; MPC 1,657.248 days; log rank for both comparisons: p&amp;lt;0.001). Conclusion In clinical practice, the SPC regimen is associated with a lower incidence of CV events and lower all-cause mortality. Time to the event is also significantly longer in the SPC group compared to MPC. These results strongly support the concept of SPC and the implementation into daily practice to improve patient's prognosis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): APONTIS PHARMA GmbH &amp; Co. KG

Empagliflozin treatment differentially modifies visceral and subcutaneous adipose tissue lipidomes and pro-inflammatory cytokines in zucker fatty diabetic rats

Abstract EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial) trial highlighted the relevance of pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus (T2DM) and/or cardiovascular disease. Although the pathways through which SGLT2 inhibitors exert a beneficial effect on the cardiovascular system are still unknown, it has been suggested that energy metabolism regulation and a reduction of systemic inflammation could be some of the mechanisms implicated. Available data also suggests that empagliflozin treatment could be able to exert regulatory effects on adipose tissue (AT) depots. The aim of our study was to evaluate the impact of empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) depots in a rat model of obesity and T2DM. Diabetic obese Zucker Fatty (ZDF) rats were treated with 30 mg/kg/day of empagliflozin p.o for 6 weeks. The lipidomes of VAT and SAT depots were analyzed using ultra-high performance liquid chromatography coupled to mass spectrometry. Empagliflozin's effect on pro-inflammatory markers in AT was analyzed by RT-PCR. In VAT, 18 metabolites were significantly altered in empagliflozin-treated rats vs. controls. Nearly all diglycerides tested (13 of 14) were significantly increased in treated rats, as the most notable altered chemical class. Furthermore, 3 oxidized fatty acids (FA) and FA like gadoleic acid and linoleic acid were also significantly increased. In SAT, a total of 14 metabolites were significantly altered. Most of them (13 of 14) were glycerophospholipids. Significantly lower levels of 4 lysophosphatidylethanolamines, 4 lysophosphatidylcholines, and 3 lysophosphatidylinositols and higher levels of 2 phosphatidylcholines were shown. In contrast to VAT, a significant decrease in most of these metabolites was observed in empagliflozin-treated samples. Several ratios of metabolites were also calculated to infer the potential enzyme activities related to lipid metabolism in both VAT and SAT. However, the ratios studied were only statistically significant in VAT of empagliflozin-treated rats vs. control, where the main potential enzyme activities altered were desaturases and elongases. Empagliflozin treatment also reduces the expression of the pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα) and monocyte-chemotactic protein-1 (MCP-1) in VAT, with no changes in SAT, except for interleukin-13 (IL-13), which also decreases compared to untreated diabetic ZDF rats. In conclusion, empagliflozin increased oxidized FA and diglycerides in VAT and decreased glycerophospholipid levels in SAT. The anti-inflammatory effect of empagliflozin in VAT is not observed in SAT. The effect of empagliflozin on the regulation of the adipose tissue lipidome and inflammatory profile is different depending on the localization of the depots. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH and Co