bluuebunny/crossref_metadata_2025_split huggingface dataset:
272-OR: Weight Loss with Time-Restricted Feeding or Treatment with Obeticholic Acid/Semaglutide Combination Have a Different Impact on Nonalcoholic Steatohepatitis in Diet-Induced Obese Mice
Authors: BRIAND FRANCOIS , GRASSET ESTELLE , BREYNER NATALIA , SULPICE THIERRY 
Published: May 2022

Introduction: Combination of therapies is a promising strategy for the treatment of NASH and liver fibrosis. Here we evaluated whether the Farnesoid X Receptor agonist obeticholic acid (OCA) combined with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (SEMA) would show superior effects than weight loss induction with time-restricted feeding (TRF) in mice.
Methods: Mice were fed a 60% high fat/2% cholesterol diet with 10% fructose supplemented drinking water (HFCF diet) for 25 weeks to induce obesity and NASH/liver fibrosis. After the diet-induction period, mice were kept on HFCF diet and treated with vehicle (control) or OCA 30mg/kg p.o. QD + SEMA 0.06mg/kg s.c. QD, or placed on TRF from the last 3 hours of the dark cycle till the end of the light cycle, without access to food, but free access to normal drinking water (i.e. without fructose) every day, for 6 weeks.
Results: OCA+SEMA induced a 20% lower caloric intake, which led to a 27% lower body weight (p&lt;0.0vs. control) . TRF had a weaker effect on caloric intake (-9%) but also reduced body weight (-11%, p&lt;0.vs. control) . Both OCA+SEMA and TRF reduced the HOMA-IR index of insulin resistance and significantly reduced plasma ALT and AST levels, but these effects were more pronounced with OCA+SEMA. TRF, and to a greater extent OCA+SEMA, significantly reduced liver weight, hepatic fatty acids, triglycerides, and total cholesterol levels. Both OCA+SEMA and TRF led to significantly lower NAFLD activity score. However, OCA+SEMA did not alter liver fibrosis, while TRF showed a clear anti-fibrotic effect in the liver, with lower % Sirius Red labelling (p&lt;0.vs. control) .
Conclusion: OCA+SEMA combination reduced body weight and NAFLD activity score but did not improve hepatic fibrosis, while TRF improved both NASH and liver fibrosis. These TRF benefits should be further investigated in obese NASH patients.

Disclosure
F.Briand: None. E.Grasset: None. N.Breyner: None. T.Sulpice: None.
28-OR: Effects of Time-Restricted Eating vs. Low-Carbohydrate Diet on Mean Glucose in Type 2 Diabetes Patients
Authors: CARBONEL ALEXANDER , VELIS ESTEPHANY , CALINAWAN TESS L. , KIWAN RASHA , SMITH CAITLIN , SVID CHANNEL , SHUBROOK JAY H. 
Published: May 2022

Background: Time restricted eating (TRE) and Low Carbohydrate Diets (LCD) have become popular dietary patterns with potential metabolic benefits for T2DM patients. The objective of this study is to evaluate TRE on glucose control compared to LCD for individuals with T2DM after completing a 72 hour medically supervised induction fast.
Methods: Participants completed a 72 hour medically supervised induction fast and were randomized to TRE (n=14, 8-hour daily feeding period) or LCD (n=10, &lt;45 grams total per day) for 4 weeks. Blood glucose was captured by FreeStyle Libre pro continuous glucose monitors (CGM) . GMI at 1 month post fast was compared to A1C values measured within 6 months prior to treatment.
Results: A total of 24 participants completed the protocol (mean age = 53.9, range 35-72) . GMI was reduced from 8.99% to 7.30% (p=0.002) in TRE and 7.99% to 6.77% in LCD (p=0.001) . Reductions in GMI range were greater in the first 2 weeks compared to last 2 weeks. The TRE group spent less time within the target range (67.7% vs. 74.8%, p=0.32) , more time hyperglycemic (29.4% vs. 21.0% p=0.25) , and less time hypoglycemic (2.8% vs. 4.2%, p=0.42) . Hypoglycemia was numerically less common in the TRE group (3/14 participants) compared to the LCD (6/participants) in CGM data beyond the induction fast. Glucose variability was similar in TRE (28.6%) and LCD (28.2%) . There were no SAEs experienced in either group. When surveyed, participants believed TRE and LCD were realistic nutritional therapies.
Conclusion: These results suggest that both TRE and LCD supplemented by a medically supervised induction fast are efficacious and safe nutritional therapies to improve blood glucose in patients with T2DM. The participants will be followed for 12 months to analyze long-term effects.

Disclosure
A.Carbonel: None. E.Velis: None. T.L.Calinawan: None. R.Kiwan: None. C.Smith: None. C.Svid: None. J.H.Shubrook: Consultant; Abbott, AstraZeneca, Bayer AG, Eli Lilly and Company, Novo Nordisk.
297-OR: TXNIP DNA Methylation (DNAme) and Long-Term HbA1c in Type 1 Diabetes (T1D)
Authors: MILLER RACHEL G. , MYCHALECKYJ JOSYF , ONENGUT-GUMUSCU SUNA , ORCHARD TREVOR J. , COSTACOU TINA 
Published: May 2022

DNAme is associated with past HbA1c in DCCT/EDIC but these associations were examined when there was separation in HbA1c distribution by trial intervention arm. Thus, we performed an epigenome-wide association study (EWAS) of DNAme and HbA1c in a T1D cohort without intervention or risk factor exclusion to identify loci with DNAme associated with concurrent and future HbA1c over 28 years. Whole blood DNAme was assayed via Illumina EPIC beadchip in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood onset (&lt;17 years) T1D (n=411; mean age 29, T1D duration 21 yrs) . After quality control DNAme at 683,597 CpGs were analyzed. We performed cross-sectional EWAS with baseline HbA1c in linear models adjusted for T1D duration, sex, smoking pack-years, estimated blood cell composition, and batch covariates and longitudinal repeated measures analyses of HbA1c (2, 4, 6, 8, 16, 23, and 28 yrs post-baseline) . DNAme was significantly inversely associated with current HbA1c at two CpGs: cg19693031 (Chr 1, TXNIP locus, p=9.5x10-11) and cg21534330 (Chr 17, CSNK1D locus, p=3.3x10-10) . In GWAS, we further identified 34 methylation quantitative trait loci (meQTLs) in the SLC2A1 - SLC2A1-AS1 linkage-disequilibrium block (Chr 1: 43408279-43438299) associated with cg19693031 DNAme. All cg19693031 meQTLs identified were also reported as whole blood expression QTLs (eQTLs) in GTEx. For cg21534330, none of 15 trans meQTLs were eQTLs in GTEx. In repeated measures analysis, cg19693031 DNAme was consistently associated with lower average HbA1c over 28 years (-0.26 per 5% DNAme, p&lt;0.0001, no time interaction) . DNAme at cg21534330 was not associated with HbA1c after baseline. Our results replicate prior findings that DNAme at cg19693031 in TXNIP relates to glycemic control in T1D and extend this association prospectively over 28 years. These findings strengthen the potential for interventions targeting TXNIP to improve glycemic control in T1D through its role in SLC2A1/GLUT1-mediated glucose regulation.

Disclosure
R.G.Miller: Stock/Shareholder; Becton, Dickinson and Company. J.Mychaleckyj: None. S.Onengut-gumuscu: None. T.J.Orchard: None. T.Costacou: None.

Funding
American Diabetes Association (1-19-JDF-109) ; NIH/NIDDK (R01-DK034818) , Rossi Memorial Fund
309-OR: Lipocalin 2 Deficiency Impairs Mitochondrial Dynamics and Phospholipid Metabolism in Brown Adipocytes
Authors: SU HONGMING , GUO HONG , QIU XIAOXUE , LIN TE-YUEH , CHEN XIAOLI 
Published: May 2022

Impaired mitochondrial bioenergetics in brown adipocytes links to the disrupted energy metabolism and thermogenesis in obesity. Phospholipids, particularly cardiolipin and phosphatidic acid (PA) are critical regulators of mitochondrial membrane architecture and dynamics. Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as the platform for phospholipid biosynthesis. MAM dysfunction disturbs phospholipid metabolism, thereby disrupting mitochondrial function. However, little is known about the participating factors that regulate MAM phospholipid metabolism. We have previously characterized the role of lipocalin 2 (Lcn2) in thermogenesis and mitochondrial function in adipocytes. Herein, we found that Lcn2 was located at MAMs and had a specific PA binding capability. The mitochondrial fusion-fission process induced by the fasting-refeeding cycle was impaired in Lcn2 knockout (KO) brown adipocytes. We also observed that the levels of phosphorylated Drp1 (Ser616) and Opa1 were decreased in brown adipose tissue (BAT) of Lcn2 KO mice compared to WT controls upon acute cold stimulation, whereas Lcn2 overexpression in BAT led to an increase in Drp1 phosphorylation and Opa1 level. Moreover, Lcn2 deficiency significantly enhanced the cold-stimulated accumulation of Opa1 as well as MAM markers SigmaR1, Ip3R1, and Facl4 at MAMs in BAT, suggesting impaired MAM function. CL316,243, a β3-adrenergic receptor agonist has a cold mimic effect on mitochondrial bioenergetics. In brown adipocytes, Lcn2 deficiency significantly attenuated the CL316,243 induction of Drp1 phosphorylation. Intriguingly, lipidomic analysis of BAT mitochondria isolated from mice treated with CL316,243 for 14 days showed that Lcn2 deficiency blunted CL316,243-induced cardiolipin biosynthesis and altered phospholipid metabolism. Together, we discovered a role of Lcn2 as a novel PA transfer protein in mitochondrial bioenergetics via regulating phospholipid metabolism.

Disclosure
H.Su: None. H.Guo: None. X.Qiu: None. T.Lin: None. X.Chen: None.

Funding
This work was supported by NIDDK Grant (RDK123042) awarded to Xiaoli Chen.
340-OR: LY3437943 (LY) , a Novel Triple GIP/GLP-1/Glucagon Receptor Agonist, Provides Glucose Lowering and Weight Loss in Patients with T2DM after 12 Weeks of Treatment
Authors: URVA SHWETA , LOH MEI TENG , COSKUN TAMER , DU YU , BENSON CHARLES , LOGHIN CORINA , HAUPT AXEL , MILICEVIC ZVONKO 
Published: May 2022

Multi-receptor incretin agonists are being developed for several metabolic disorders. LY is an investigational triple agonist with potent activity on glucose-dependent insulinotropic polypeptide (GIP) , glucagon-like polypeptide-1 (GLP-1) , and glucagon receptors. LY was safely studied in a prior first-in-human study and pharmacokinetics properties supported once weekly dosing. The primary objective of this randomized, double-blind, placebo-controlled, Phase 1 proof-of-concept study was to assess the safety and tolerability of multiple ascending doses of LY in patients with type 2 diabetes (T2D) . Seventy-two patients were randomized (9:3:1) to 5 rising dose cohorts of subcutaneous LY, placebo, and dulaglutide 1.5mg, respectively. Within cohort, dose-escalation was implemented at highest 2 cohorts. Vital signs, laboratory data and adverse events (AEs) were monitored to assess safety and tolerability. Efficacy was assessed by monitoring change in glycated hemoglobin (HbA1c) and body weight at week 12. The most common treatment-emergent AEs were gastrointestinal (nausea and diarrhea) , which were mostly mild in severity. By week 12, mean systolic and diastolic blood pressure decreased from baseline in LY compared to placebo group, while pulse and heart rate increased from baseline within most LY cohorts and dulaglutide, but not with placebo. By week 12, mean HbA1c decreased from baseline in all groups, with higher doses of LY showing statistically significant placebo-adjusted decreases of up to 1.56%. Except at the initial cohort, dose-dependent decreases in mean placebo-adjusted body weight of up to 8.96 kg were observed with LY. LY3437943 exhibits safety and tolerability profile similar to other incretins. Promising glycemic and body weight loss efficacy within this study highlights the potential for LY to provide additional benefit versus existing therapies in treatment of T2D and obesity.

Disclosure
S. Urva: Employee; Eli Lilly and Company. M. Loh: Employee; Eli Lilly and Company. T. Coskun: Employee; Eli Lilly and Company. Y. Du: None. C. Loghin: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly. Stock/Shareholder; Lilly. Z. Milicevic: Employee; Eli Lilly and Company.

Funding
Eli Lilly and Company
350-OR: The Oral Disposition Index (ODI) Predicts Type 1 Diabetes (T1D) in Autoantibody-Positive (Ab+) Individuals
Authors: ISMAIL HEBA M. , CUTHBERTSON DAVID D. , REDONDO MARIA J. , JACOBSEN LAURA M. , ATKINSON MARK A. , SOSENKO JAY ,   DIABETES PREVENTION TRIAL TYPE 1, TYPE 1 DIABETES TRIALNET
Published: May 2022

The ODI is a measure of β-cell function accounting for insulin sensitivity. ODI has primarily been studied in adults and shown to be inversely predictive of type 2 diabetes (T2D) ; however, little is known about ODI’s prediction of T1D. We thus used data from Ab+ Trialnet Pathway to Prevention (PTP) and Diabetes Prevention Trial Type 1 (DPT-1) cohorts (relatives of T1D patients) to study this. Data were analyzed from 33PTP participants: age (mean±SD) 15.8±12.1 yrs; BMI 21.1±13.1 kg/m2; 50.1% female, and 2from DPT-1: age 14.8±10.0 yrs; BMI 21.8±6.1 kg/m2; 51.2% female. Insulin measures at baseline included insulin sensitivity [ (1/Fasting Insulin) ; 1/FI) ], β-cell function [C-peptide index: (30 min C-pep-0 min C-pep) / (30 min glucose-0 min glucose) ], and ODI [ (1/FI) x (C-peptide Index) ]. Spearman correlations of C-peptide Index vs. 1/FI were r=-0.47 (p&lt;0.001) in PTP, and r=-0.22 (p=0.001) in DPT-1. The figure shows cumulative incidence curves according to ODI quartiles (Q) for progression to T1D in both PTP and DPT-1. The diagnosis of T1D was inversely related to ODI, with Q4 vs. Q1 hazard ratios and 95% CIs of [0.13 (0.10, 0.16) , p=0.006] for PTP and of [0.13 (0.06, 0.29) , p=0.002] for DPT-1.
In conclusion, ODI is inversely predictive of T1D among Ab+ individuals. Thus, as with predicting T2D, insulin sensitivity should be taken into account when β-cell function is used to predict T1D in Ab+ populations.

Disclosure
H.M.Ismail: n/a. D.D.Cuthbertson: None. M.J.Redondo: Advisory Panel; Provention Bio, Inc. L.M.Jacobsen: None. M.A.Atkinson: None. J.Sosenko: None. Diabetes prevention trial type 1: n/a. Type 1 diabetes trialnet: n/a.

Funding
NIH
37-LB: Feasibility of a Remote Clinical Trial in People with Type 2 Diabetes—Findings from the MOTIVATE T2D Trial
Authors: DAVIES ANDREW P. , HESKETH KATIE , LOW JONATHAN , SPRUNG VICTORIA S. , JONES HELEN , MCMANUS ALI M. , COCKS MATTHEW ,   MOTIVATE TEAM
Published: May 2022

The execution of clinical trials can be expensive and present logistical challenges regarding recruitment and retention of participants. Innovative research design fostering convenience by eliminating research facility visits may enhance recruitment and retention. We examined the feasibility of a remote clinical trial in people living with type 2 diabetes (T2D) . People with recently diagnosed T2D were recruited across the UK and Canada to the MOTIVATE T2D trial (NCT04653532) ; a feasibility randomised controlled trial investigating two exercise and physical activity interventions. Participants received a self-testing kit, via mail, at baseline and post-intervention (6 months) . Measures included, HbA1c, lipid profile, anthropometrics and blood pressure and 14-day flash glucose and physical activity monitoring. Between Jan 2021 and Jan 2022 286 patients were eligible, of whom 110 (UK n=63, Can n=47, male n=58, white n=95) consented. Mean journey time from research facilities was ≤1h in 18%, 1-2h in 50% and &gt;2h in 33% of participants. Availability of outcome data is presented in Table 1. Remote testing resulted in benefits to recruitment and good participant retention and protocol adherence. As such, remote clinical trials are feasible in people with T2D and future clinical trials should consider a remote clinical trial based approach as an alternative to conventional designs.

Disclosure
A. P. Davies: None. K. Hesketh: None. J. Low: None. V. S. Sprung: None. H. Jones: None. A. M. Mcmanus: None. M. Cocks: None. Motivate team: n/a.

Funding
UK Medical Research Council (MR/T032189/1) , Canadian Institute for Health Research (UCD-170587)
372-P: Predicting Real-World Severe Hypoglycemia in Americans with Diabetes (iNPHORM)
Authors: RATZKI-LEEWING ALEXANDRIA , HARRIS STEWART B. , BLACK JASON E. , ZOU GUANGYONG , WEBSTER-BOGAERT SUSAN , RYAN BRIDGET L. 
Published: May 2022

Most prediction models for diabetes-related iatrogenic severe hypoglycemia (SH) have derived from trial/administrative records subject to poor generalizability, ascertainment bias, and incomplete data capture. Redressing this gap, iNPHORM leveraged the clinical and methodological advantages of prospective self-report to develop and internally validate a 1-year SH prediction model for use in real-world clinical contexts.
Adults (18-90 years old) with insulin- and/or secretagogue-treated type 1 or 2 diabetes (T1D, T2D) were recruited from a US-wide probability-based internet panel and followed for one year. Monthly emailed questionnaires assessed SH incidence and related factors. To model recurrent 1-year SH (daytime + nocturnal) , Andersen-Gill Cox proportional hazards regression was performed on participants completing ≥1 follow-up. Missing data were multiply imputed with chained equations. Machine learning penalized regression with lasso was used to select clinically plausible predictors.
A total of 986 (T1D: 17%) participants were analyzed (retention rate: 86.2%) . The mean age was 51 (SD: 14.3) years, 49.6% were male, and the median duration of T1D/T2D was 12 (IQR: 14) years. Among T2D participants, 38% were on insulin (without secretagogues) , 38% on secretagogues (without insulin) , and 24% on insulin plus secretagogues. Across follow-up, 35.1% (95% CI: 32.2-38.1%) reported ≥1 SH, and the annual rate was 4.97 (95% CI: 4.13-5.99) . Combination insulin-secretagogue therapy; use of an insulin pump and continuous glucose monitoring; decreased age; increased previous SH requiring healthcare utilization; chronic kidney disease; and food insecurity predicted 1-year SH risk. The optimism adjusted c-statistic was 0.75.
iNPHORM is the first long-term, prospective study on SH prediction in the general US population with T1D and T2D. Our 7-variable model can be used to identify patients at high-risk of SH, leading to more valid, cost-effective prevention strategies in the real world.

Disclosure
A.Ratzki-leewing: Consultant; Eli Lilly and Company, Other Relationship; Sanofi. S.B.Harris: Consultant; Abbott, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi, Other Relationship; Abbott, AstraZeneca, Bayer Inc., Dexcom, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; Applied Therapeutics Inc., AstraZeneca, Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF) , Novo Nordisk, Sanofi, The Lawson Foundation. J.E.Black: None. G.Zou: None. S.Webster-bogaert: None. B.L.Ryan: None.

Funding
Sanofi Global
397-P: eGFR Changes from Adolescence into Young Adulthood in Type 1 Diabetes: Evaluation of Novel eGFR Formulae
Authors: BABALOLA FUNMBI , SOCHETT ETIENNE B. , CURTIS JACQUELINE , MOINEDDIN RAHIM , ELIA YESMINO T. , SCHOLEY JAMES W. , CHERNEY DAVID , WHITE CHRISTINE A. , MAHMUD FARID H. 
Published: May 2022

Background: Diabetic kidney disease (DKD) is one of the leading causes of CKD and ESRD. Decline in eGFR represents an early marker of DKD that may precede microalbuminuria. The optimal eGFR formula during transition from adolescence into adulthood remains unclear.
Objective: To assess longitudinal change in eGFR in youth with T1D transitioning to young adulthood using CKiDU25 creatinine-sex-adjusted (CKiDU25-1) , CKiDU25 combined-creatinine-cystatin (CKiDU25-2) , and CKDEPI40 eGFR formulas.
Methods: eGFR was calculated at four time points. Subsequently, linear mixed effect model was used to calculate subject specific eGFR slopes. The percentage of decliners, defined as eGFR slope &lt;/= -3ml/min/1.73m2/year, corresponding to larger eGFR decline was determined. Relationships between eGFR slope and average A1C, ACR, sex, and diabetes duration was assessed using linear regression.
Results: There were 99 participants, of which 45% were male, assessed over an average of 7.4 ± 1 years, beginning at 14 ±1.7 to 21.3 ± 2.1 years. Mean eGFR for CKiDU25-1 was 108.1 ± 13.1, slope of -2.9 ± 2.9, and 44% decliners. Mean eGFR for CKiDU25-2 was 104.8 ± 11.9, slope of -2.7 ± 2.2 and 42% decliners. Mean eGFR for CKDEPI40 was 114.8 ± 6.9, slope of 0.8 ± 0.9 and no eGFR decliners. Comparison of all three eGFRs and slopes showed no significant difference between CKiD-1 and CKiD-2, however there was significant differences between CKDEPI40 and both CKiDU25 eGFR and slopes. There was a significant relationship between sex and eGFR slope with males having greater decline in eGFR with all formulae. No significant relationship was found between eGFR slope and ACR, A1C and diabetes duration.
Conclusion: CKiDU25-1 and CKiDU25-2 formulae provide similar eGFRs and eGFR slopes while the CKDEPI40 had a higher mean eGFR and no change in eGFR over time. If cystatin-C is not available, CKiDU25-1 provides a suitable alternative for assessment of eGFR changes in youth with type 1 diabetes transitioning into early adulthood.

Disclosure
F.Babalola: None. E.B.Sochett: None. J.Curtis: None. R.Moineddin: None. Y.T.Elia: None. J.W.Scholey: n/a. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. C.A.White: None. F.H.Mahmud: None.
416-P: Mortality, Major Adverse Cardiovascular Events (MACE) and Diabetic Complications in Men with Hypogonadism and Type 2 Diabetes on Long-Term Testosterone Treatment: An Update from a Urological Registry Study
Authors: HAIDER KARIM S. , HAIDER AHMAD , SAAD FARID 
Published: May 2022

Background: Men with hypogonadism are at increased risk of MACE and mortality. Studies in men with T2DM show that testosterone therapy reduces both MACE and mortality.
Methods: In a registry of 883 men with hypogonadism, 370 men (41.9%) have T2DM. 190 received TU 1000 mg/12 weeks (T-group) , 180 opted against treatment (CTRL) . All patients received standard diabetes treatment including lifestyle courses at a diabetes center. MACE, mortality, and diabetic complications were recorded and compared between groups.
Results: Mean baseline age in the T-group and CTRL was 61.0±5.3 and 63.0±4.9 years. Mean follow-up in T-group and CTRL was 9.0 and 9.7 years. 71 patients (37.4%) in the T-group and 74 (41.1%) in CTRL had a history of cardiovascular disease (myocardial infarction MI, stroke, or coronary artery disease diagnosis) (p&lt;0.05) . Baseline smoking prevalence was 41.6% (79 men) in the T-group and 37.4% (67 men) in CTRL (p=0.415) . The T-group had a worse baseline risk factor profile than CTRL: BMI (36.5±4.4 vs. 32.8±4.7 kg/m²) , systolic blood pressure (163.0±13.3 vs. 145.5±14.5 mmHg) , LDL (4.7±0.8 vs. 4.1±1.4 mmol/L) , HbA1c 9.5±1.4 vs. 7.8±0.7% (p&lt;0.00for all) . Mortality: during the entire observation period, 21 patients (11.1%) died in the T-group vs. 62 (34.4%) in CTRL (p&lt;0.0001) . Major adverse cardiovascular events (MACE) : in the T-group, there were no cases of MI or stroke. In CTRL, there were 62 cases of MI (34.4%) and 51 cases of stroke (28.3%) . Diabetic complications: in the T-group and CTRL, the incidence of retinopathy was 4 (2.1%) vs. 30 (16.7%) (p&lt;0.0001) , nephropathy 1 (0.01%) vs. 7 (0.4%) (p=0.05) , polyneuropathy (5.3%) vs. 97 (53.9%) (p&lt;0.0001) , diabetic foot syndrome 0 (0%) vs. 17 (9.4%) (p&lt;0.0001) .
Conclusions: Long-term treatment with TU in men with hypogonadism and T2DM reduces mortality, MACE, and diabetic complications, compared to untreated controls.

Disclosure
K.S.Haider: Other Relationship; Bayer AG. A.Haider: Other Relationship; Bayer AG. F.Saad: Consultant; Bayer AG, Stock/Shareholder; AbbVie Inc., Bayer AG, GlaxoSmithKline plc.

Funding
Bayer AG