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OBJECTIVE The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.

Achieving HbA1c targets, weight loss (WL) and systolic blood pressure (SBP) reductions lowers micro- and macrovascular risk in type 2 diabetes (T2D). In SUSTAIN clinical trials, once-weekly (OW) semaglutide, a glucagon-like peptide-1 analog, significantly reduced HbA1c and body weight (BW) and reduced SBP (except in SUSTAIN 8) vs. comparators. This post hoc analysis evaluated composites of these endpoints with semaglutide vs. comparators in SUSTAIN 1-5 and 7-10. Trials were analyzed individually to determine the proportion of subjects achieving composite endpoints A (HbA1c Across the trials, mean baseline HbA1c, BW and SBP ranges were 8.0-8.4%, 89.5-96.9 kg and 127.9-136.4 mmHg, respectively. Greater proportions of subjects achieved the composite endpoints with semaglutide vs. comparator (A: 12.4-19.1% [0.5 mg]; 18.9-36.7% [1.0 mg] vs. 0.8-15.7% [comparator]; B: 2.5-8.0% [0.5 mg]; 5.0-14.8% [1.0 mg] vs. 0.2-3.0% [comparator]; p Significantly greater proportions of subjects achieved clinically relevant composite endpoints with OW semaglutide vs. comparators, including more stringent endpoint of HbA1c ≤6.5% and WL ≥10%. These data may assist clinicians in their decision-making in T2D care. Disclosure P. Gaede: None. A. Catarig: Employee; Self; Novo Nordisk. K. M. Dungan: Advisory Panel; Self; Eli Lilly and Company, Tolerion, Inc., Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Elsevier, Novo Nordisk, Other Relationship; Self; UpToDate, Research Support; Self; Abbott, Sanofi-Aventis, Viacyte, Inc. C. Hindsberger: Consultant; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. J. Ollgaard: Employee; Self; Novo Nordisk A/S. S. C. Bain: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Napp Pharmaceuticals, Novo Nordisk A/S, Sanofi, Consultant; Self; ADOCIA, Speaker’s Bureau; Self; Bayer AG, Medscape, WebMD LLC. Funding Novo Nordisk A/S

As the first oral GLP-1 receptor agonist (GLP-1RA), oral semaglutide (sema) may facilitate increased access to the benefits of GLP-1RA therapy in broader care settings. Understanding the management of GLP-1RA therapy when intolerability occurs, including gastrointestinal (GI) adverse events (AEs), is important to overcome potential barriers to treatment persistence. The PIONEER 6 trial (NCT02692716; N=3183) examined the efficacy and safety of oral sema in patients (pts) with T2D either ≥50 years with established cardiovascular (CV) or kidney disease, or ≥60 years with CV risk factors. In total, 27% of pts stopped taking oral sema at least once during the trial due to an AE, but only 12% permanently discontinued due to an AE. We thus evaluated medication management strategies within PIONEER 6 to assess their role in supporting treatment continuation. Pts on oral sema underwent dose escalation starting at 3 mg, increasing to 7 mg after 4 weeks, and 14 mg after 8 weeks. Investigators were permitted to reduce the dose if AEs developed and to re-escalate the dose once symptoms had resolved or diminished. Pts were educated as needed to address GI tolerability issues throughout the trial. Pts who discontinued treatment because of an AE were encouraged to resume treatment once willing or once the AE had ceased. The time off oral sema was considered a treatment pause. If treatment pauses were >21 days, re-escalation from a lower dose was recommended to mitigate GI AEs. Discontinuation of oral sema (temporary and permanent) mostly occurred during the initial dose escalation period. In total, 23% of pts receiving oral sema had ≥1 treatment pause, the majority of whom (72%) had just one pause. The median duration of treatment pause was 21 (IQR 7-51) days. Importantly, 75% of pts restarted oral sema after the first AE-related treatment discontinuation. These data highlight the role of treatment pauses, flexibility, and education in mitigating potential AEs to support treatment persistence on GLP-1RAs. Disclosure V. R. Aroda: Consultant; Self; Applied Therapeutics, Duke, Novo Nordisk, Pfizer Inc., Sanofi, Employee; Spouse/Partner; Janssen, Merck, Research Support; Self; Applied Therapeutics, Eli Lilly and Company, Fractyl, Medpace, Medpace, Novo Nordisk, Premier, Sanofi, Stock/Shareholder; Spouse/Partner; Janssen, Merck. R. Bauer: Employee; Self; Novo Nordisk A/S. A. L. Davies: Employee; Self; Novo Nordisk. E. B. Kreiner: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. P. J. Lin: Advisory Panel; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. S. C. Bain: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Napp Pharmaceuticals, Novo Nordisk A/S, Sanofi, Consultant; Self; ADOCIA, Speaker’s Bureau; Self; Bayer AG, Medscape, WebMD LLC. Funding Novo Nordisk A/S

OBJECTIVE A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. RESEARCH DESIGN AND METHODS LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5–5 years, in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (N=2,928), 30–0% reduction N=1,218) or any increase in UACR (N=4,124) irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [ RESULTS For MACE, hazard ratios (HRs) for those with >30% and 30%–0% UACR reduction were 0.82 (95% CI 0.71–0.94; P=0.006) and 0.99 (0.82–1.19; P=0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs (95% CI) were 0.67 (0.49–0.93; P=0.02) and 0.97 (0.66–1.43; P=0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria. CONCLUSIONS A reduction in albuminuria during the first year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential.

OBJECTIVE A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. RESEARCH DESIGN AND METHODS LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5–5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction (n = 2,928), 30–0% reduction (n = 1,218), or any increase in UACR (n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [ RESULTS For MACE, hazard ratios (HRs) for those with >30% and 30–0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria. CONCLUSIONS A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential.

Objective: To evaluate the effect of anti-IL-21 and liraglutide, alone and in combination, compared to placebo, on preservation of β-cell function after 54 weeks of treatment in adults with recently diagnosed type 1 diabetes. Methods: This was a multicenter, double-dummy, double-blind, efficacy, safety and pharmacokinetic randomized control trial (NCT02443155) in adults recently diagnosed with type 1 diabetes and non-fasting C-peptide peak ≥0.2 nmol/L, comprising a 54-week treatment period followed by a 26-week observation period. Primary endpoint: area under the curve (AUC)0-4h for meal-stimulated C-peptide at week 54 relative to baseline. Results: At week 54, combination treatment was associated with a significant improvement of 48% in meal-stimulated C-peptide secretion versus placebo (Table). The insulin requirement was significantly lowered by 0.13 U/kg. Trends for better glycemic control and lower risk of hypoglycemic episodes at 54 weeks compared to placebo were also observed. No safety concerns were identified. Treatment benefits were not sustained at 26 weeks after end of treatment. Conclusion: Treatment with anti-IL-21 and liraglutide for 54 weeks was safe and resulted in sustained insulin secretion and lower insulin dose. Trends for improved glucose control and fewer hypoglycemic episodes compared to placebo were observed. Disclosure M.G. von Herrath: Employee; Self; Novo Nordisk A/S. S.C. Bain: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; AstraZeneca. B.W. Bode: Advisory Panel; Self; InPen, Medtronic. Consultant; Self; ADOCIA, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Pfizer Inc. Research Support; Self; Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Medtronic, Novo Nordisk A/S, Provention Bio, Inc., Senseonics, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., InPen, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Sanofi, Senseonics, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Glytec. J. Clausen: Other Relationship; Self; Novo Nordisk A/S. K. Coppieters: Other Relationship; Self; Novo Nordisk A/S. L. Gaysina: None. J. Gumprecht: Consultant; Self; Astra, Bioton, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Polfa Tarchomin S.A., Sanofi, Servier. Speaker’s Bureau; Self; Astra, Bioton, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Polfa Tarchomin S.A., Sanofi, Servier. T.K. Hansen: None. C. Mathieu: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intrexon, MannKind Corporation, Medtronic, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk Inc., Pfizer Inc., Roche Diagnostic USA, Sanofi. Research Support; Self; Intrexon, Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk Inc., Sanofi. C. Morales Portillo: Board Member; Self; Novo Nordisk, Lilly, MSD, Astra, Sanofi, Abbot. Research Support; Self; Novo Nordisk, Sanofi, AstraZeneca, Pzifer, Lilly, Merck, Lexicon, FPS, Hanmi, Janssen, Boehringer, Takeda, Roche, Theracos. Speaker’s Bureau; Self; Sanofi, Novo Nordisk, AstraZeneca, Roche, Lilly, Boehringer, MSD, Ferrer, Janssen, Abbot. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Teva Pharmaceutical Industries Ltd. S. Segel: Employee; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. G.M. Tsoukas: Advisory Panel; Self; Amgen, Novo Nordisk Inc. Speaker’s Bureau; Self; Amgen Canada. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diagnostics K.K. Funding Novo Nordisk A/S

Objective The LEADER trial (NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide-1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial.Research Design and Methods We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE: composite of CV death, non-fatal myocardial infarction or non-fatal stroke) from the following candidates: HbA1c, body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure and LDL-cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model, and the new Vansteelandt method designed to utilize all available information from the mediator and to control for confounding factors.Results Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates.Conclusions These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.

Aim: To determine the sensor performance of the Abbott Freestyle® Libre iCGMS during glycemic challenges and acute exercise during multiple 23-hours inpatient phases. Methods: 17 people with T1D (4 women, age 34.9 ± 15.5 years, BMI 25.9 ± 3.0 kg/m2, HbA1c 7.3 ± 1.4% (56 ± 15 mmol/mol)) on multiple daily injections were included in the study, consisting of four 23-hours inpatient phases with meal-induced glycemic disturbances and 45-minutes moderate-intensity cycle ergometer exercises. iCGMS was compared to reference blood glucose by median absolute relative difference (MARD), Clarke Error Grid (CEG) and Bland-Altman (intention-to-treat). Results: The overall MARD (IQR) during the inpatient phases (excluding exercise) was 12.9% (6.1-21.5%), during hypoglycemia 31.6% (14.0-46.8%), euglycemia 14.5% (7.0-22.5%) and hyperglycemia 8.7% (4.6-14.6%). The overall Bland-Altman analysis showed a bias (95% LoA) of 19.8 mg/dL (-78.37-118 mg/dL) and CEG is illustrated in the Figure. The overall MARD during exercise was 29.8% (17.5-39.8%), during hypoglycemia 45.1% (35.2-51.1%), euglycemia 30.7% (18.7-39.2%) and hyperglycemia 16.3% (10.0-22.8%). Conclusion: iCGMS interstitial glucose readings should be used cautiously during hypoglycemia and exercise and need confirmatory blood glucose measurements. Disclosure O. Moser: Research Support; Self; Abbott, Dexcom, Inc., Novo Nordisk A/S. M.L. Eckstein: Research Support; Self; Novo Nordisk A/S. O. McCarthy: None. R. Deere: None. J. Pitt: None. D.M. Williams: None. J. Hayes: None. S.C. Bain: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Mylan, NAPP Pharmaceuticals Limited, Novo Nordisk A/S, Sanofi. R.M. Bracken: None. Funding Novo Nordisk A/S

The DEPICT-2 trial (NCT02460978) evaluated the efficacy and safety of dapagliflozin (DAPA) as add-on to adjustable insulin (INS) in patients (pts) with inadequately controlled T1D (A1c 7.5-10.5%) over 24 weeks. This phase 3 study randomized pts 1:1:1 to DAPA 5 mg (n=271), 10 mg (n=270) or placebo (PBO; n=272) plus INS. INS dose could be adjusted by the investigator according to self-monitored blood glucose readings, local guidance and individual circumstances. At Week 24, DAPA 5 and 10 mg significantly decreased A1c (0.37% and 0.42% reductions in the DAPA 5 mg and 10 mg groups respectively), total daily insulin dose (TDD), and body weight (Table). As measured by masked continuous glucose monitoring (CGM), mean interstitial glucose, mean amplitude of glucose excursion (MAGE) and mean percent of readings within target glycemic range (>70-≤180 mg/dL) vs. PBO were improved. There was an increase in pts who reduced their A1c by ≥0.5% without severe hypoglycemia (odds ratios [95% CI]: 2.71 [1.81, 4.06] and 3.07 [2.05, 4.60] for DAPA 5 and 10 mg respectively). Hypoglycemic events, including severe hypoglycemia were balanced between treatment groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events on DAPA. In conclusion, DAPA vs. PBO as add-on to INS in pts with T1D was well tolerated, improved glycemic control and decreased variability without increasing hypoglycemia but with more DKA events. Week 24 outcomesDAPA 5 mg + INS (n=271)DAPA 10 mg + INS (n=270)Placebo + INS (n=272)HbA1c, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 8.45 (0.69) −0.34 (0.05) −0.37 (−0.49, −0.26) 70-≤180 mg/dL, % Mean (SD) at baseline Wk 24 adjusted mean change from baseline (SE) Difference vs PBO (95% CI) p value. 43.50 (12.43) 5.92 (0.82) 9.02 (6.97, 11.06) Disclosure C. Mathieu: Research Support; Self; Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Advisory Panel; Self; Sanofi. Research Support; Self; Merck Sharp & Dohme Corp.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novartis AG. Advisory Panel; Self; Novartis AG, Bristol-Myers Squibb Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca, Pfizer Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Hanmi Pharmaceutical. Research Support; Self; Roche Diagnostics Corporation. Advisory Panel; Self; Roche Diagnostics Corporation. Research Support; Self; Medtronic. Advisory Panel; Self; Medtronic, MannKind Corporation. Research Support; Self; Intrexon. Advisory Panel; Self; Intrexon, Dianax, UCB, Inc.. Research Support; Self; Abbott. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. P. Gillard: None. P.A. Senior: Consultant; Self; Abbott, AstraZeneca. Research Support; Self; AstraZeneca, Prometic Life Sciences Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc., Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Abbott. Research Support; Self; Viacyte, Inc.. C. Hasslacher: None. E. Araki: Speaker's Bureau; Self; Astellas Pharma US, Inc., MSD K.K., Kowa Pharmaceuticals America, Inc., Sanofi, Novo Nordisk Inc.. Research Support; Self; Astellas Pharma US, Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceuticals U.S.A., Inc., Daiichi Sankyo Company, Limited, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Sanofi, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama?Pharmaceutical Co. M. Lind: Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eli Lilly and Company. Advisory Panel; Self; MSD K.K.. Research Support; Self; Pfizer Inc.. Consultant; Self; Medtronic. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca. S. Jabbour: None. N. Arya: Employee; Self; AstraZeneca. F.A. Thoren: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.

Despite a variety of treatment options for type 2 diabetes (T2D), more than half of patients do not achieve glycemic control. In a post-hoc analysis of the DUAL I (oral antidiabetic drugs [OADs]), II, V and VII (basal insulin + OADs) trials, we evaluated patients with an A1C >9% at baseline to determine the impact of IDegLira on their glycemic control. Within each DUAL trial, baseline characteristics for patients with A1C >9% were similar for all treatment groups. In DUAL I, II and V, treatment with IDegLira resulted in greater reductions in A1C from baseline, vs. comparators of basal insulin or liraglutide, leading to lower A1C at end of trial (EOT). In DUAL VII, reduction in A1C from baseline and A1C at EOT were comparable for IDegLira and insulin glargine U100 (100 U/mL) + insulin aspart (≤4 times/day). At EOT, the composite endpoint of A1C In conclusion, even in patients with T2D with A1C >9%, IDegLira treatment achieved glycemic control with a high proportion of patients achieving A1C Disclosure D. Sugimoto: Research Support; Self; Novo Nordisk A/S. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. D. Gouet: Research Support; Self; Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH, Medtronic, Johnson & Johnson Diabetes Institute, LLC., Sanofi. R. Takács: None. T. Jia: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. P. örsy: Employee; Self; Novo Nordisk A/S. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca.

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

In clinical trials insulin degludec (Tresiba) was associated with less hypoglycaemia and less day to day glucose variability than older basal insulins. This study assessed the use of insulin degludec in type 1 diabetes in real clinical practice in the UK. Data were extracted from General Practice records in 2 areas of England for people with type 1 diabetes, prescribed insulin degludec, who had weight and HbA1c measurements at baseline and at least 3 months into treatment. 77 eligible people were identified (43M, 44F). Mean age was 53.3 years (SD 19.9). In this unselected group, there was a significant reduction in HbA1c from 9.5% to 8.9% (p These data were considered alongside data from the ABCD Nationwide Degludec Audit. In this audit, there were 144 people with type 1 diabetes who had weight and HbA1c measurements at baseline and at least 3 months into treatment at the time of the analysis (65M, 79F). Mean age was 44.1 years (SD 15.7). There was no significant reduction in HbA1c with degludec treatment (8.9% to 8.7%), and no significant increase in weight (77.2 to 77.7 kg). We have previously shown in the ABCD Nationwide Degludec Audit that there is no significant change in HbA1c or weight in those switched to insulin degludec for reasons of hypoglycaemia (n=88), although hypoglycaemia is significantly improved. A significant reduction in HbA1c and significant increase in weight is seen in those switched to insulin degludec for reasons other than hypoglycaemia (n=56). If the majority of those in the General Practice database were switched to degludec for reasons other than hypoglycaemia, such as to reduce day to day glucose variability, this may explain the observed results. Disclosure A.N. Lumb: Other Relationship; Self; Novo Nordisk A/S, Abbott. Consultant; Self; Johnson & Johnson Services, Inc.. I.W. Gallen: None. A. Bickerton: Other Relationship; Self; Novo Nordisk A/S. Advisory Panel; Self; Amgen Inc. R.R. Abraham: Advisory Panel; Self; Novo Nordisk Inc. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca. R. Harper: None. R.E. Ryder: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; Bioquest, Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S.

Achieving glycemic targets is challenging, and responsiveness to therapy may diminish over time in T2D. Semaglutide, a new once-weekly GLP-1 analog for T2D treatment, showed superior reductions in HbA1c and body weight (BW) in SUSTAIN 1-5 and 7 clinical trials vs. placebo or active comparators. This meta-analysis assessed the efficacy and safety of semaglutide 0.5 mg and 1.0 mg according to diabetes duration. Pooled efficacy data in 3,066 subjects were analyzed by T2D duration (≤5 [1,174], >5 to ≤10 [988] and >10 years [904]). Semaglutide consistently reduced HbA1c (1.4-1.8%) and BW (3.8-5.8 kg) from baseline comparably across subgroups (Figure). The proportion of subjects on semaglutide (both doses) vs. comparators reporting AEs was 69.6% (≤5 years), 69.9% (>5 to ≤10 years) and 73.5% (>10 years) vs. 65.9, 70.8 and 69.0%. Serious AEs were reported by 6.2, 7.2 and 8.3% vs. 6.6, 6.0 and 6.3% respectively. Nausea was reported by 20.5, 20.7 and 20.1% vs. 9.3, 9.1 and 9.5%; vomiting by 9.4, 7.2 and 8.7% vs. 4.5, 4.2 and 4.3% subjects receiving semaglutide vs. comparators, respectively. Premature treatment discontinuation due to AEs was reported by 7.7, 7.9 and 8.5% vs. 3.6, 3.6 and 4.6% with semaglutide vs. comparators. In conclusion, semaglutide consistently reduced HbA1c and BW, regardless of diabetes duration. AE reporting with semaglutide was unaffected by diabetes duration. Disclosure J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. L.B. Chaykin: Advisory Panel; Self; Intarcia Therapeutics, Inc. J. Luedemann: Other Relationship; Self; Novo Nordisk Inc., Eli Lilly and Company. S. Madsbad: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Eli Lilly and Company, Eli Lilly and Company. Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi-Aventis, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. J.F. Larsen: Employee; Self; Novo Nordisk A/S. E. Yildirim: Employee; Self; Novo Nordisk A/S. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca.

The major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes ( IDDM1 ). Common allelic variants at the class II HLA-DRB1 , -DQA1 , and -DQB1 loci account for the major part of IDDM1 . Previous studies suggested that other MHC loci are likely to contribute to IDDM1 , but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen–presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1 , DQA1 , and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1 .

Mutations in the hepatocyte nuclear factor–1α (HNF-1α) gene have recently been shown to cause maturityonset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-1α gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (

One form of maturity-onset diabetes of the young (MODY) results from mutations in a gene, designated MODY3, located on chromosome 12 in band q24. The present study was undertaken to define the interactions between glucose and insulin secretion rate (ISR) in subjects with mutations in MODY3. Of the 13 MODY3 subjects, six subjects with normal fasting glucose and glycosylated hemoglobin and seven overtly diabetic subjects were studied as were six nondiabetic control subjects. Each subject received graded intravenous glucose infusions on two occasions separated by a 42-h continuous intravenous glucose infusion designed to prime the β-cell to secrete more insulin in response to glucose. ISRs were derived by deconvolution of peripheral C-peptide levels. Basal glucose levels were higher and insulin levels were lower in MODY3 subjects with diabetes compared with nondiabetic subjects or with normal healthy control subjects. In response to the graded glucose infusion, ISRs were significantly lower in the diabetic subjects over a broad range of glucose concentrations. ISRs in the nondiabetic MODY3 subjects were not significantly different from those of the control subjects at plasma glucose levels

Of all the common diseases that have a genetic component, IDDM is probably the most tractable to the experimentalist. Large numbers of nuclear multiplex families are available, which can be stored as permanent cell lines; diagnosis is relatively unambiguous; and a mouse strain, the NOD, spontaneously develops autoimmune IDDM similar to the human disorder. In addition, the resolution and accessibility of the human genome map has been revolutionized by the discovery and widespread application of the PCR, particularly the amplification of short, tandemly repeated segments of DNA called microsatellites, which display high levels of allelic polymorphism. With these reagents, the stage is set for dissection of the genetic factors that control the pathophysiology of IDDM.

To assess the effectiveness of structured blood glucose testing in poorly controlled, noninsulin-treated type 2 diabetes.This 12-month, prospective, cluster-randomized, multicenter study recruited 483 poorly controlled (A1C ≥ 7.5%), insulin-naïve type 2 diabetic subjects from 34 primary care practices in the U.S. Practices were randomized to an active control group (ACG) with enhanced usual care or a structured testing group (STG) with enhanced usual care and at least quarterly use of structured self-monitoring of blood glucose (SMBG). STG patients and physicians were trained to use a paper tool to collect/interpret 7-point glucose profiles over 3 consecutive days. The primary end point was A1C level measured at 12 months.The 12-month intent-to-treat analysis (ACG, n = 227; STG, n = 256) showed significantly greater reductions in mean (SE) A1C in the STG compared with the ACG: -1.2% (0.09) vs. -0.9% (0.10); Δ = -0.3%; P = 0.04. Per protocol analysis (ACG, n = 161; STG, n = 130) showed even greater mean (SE) A1C reductions in the STG compared with the ACG: -1.3% (0.11) vs. -0.8% (0.11); Δ = -0.5%; P0.003. Significantly more STG patients received a treatment change recommendation at the month 1 visit compared with ACG patients, regardless of the patient's initial baseline A1C level: 179 (75.5%) vs. 61 (28.0%);0.0001. Both STG and ACG patients displayed significant (P0.0001) improvements in general well-being (GWB).Appropriate use of structured SMBG significantly improves glycemic control and facilitates more timely/aggressive treatment changes in noninsulin-treated type 2 diabetes without decreasing GWB.

Both in patients with IDDM (1) and in healthy control subjects (2,3), increased urinary albumin excretion rate (AER) is associated with high relative morbidity and mortality. In IDDM patients, genetic susceptibility factors are most likely contributing to an increased AER (4,5) resulting in a cumulative incidence of nephropathy (AER >300 mg/24 h) of -30% (6). So far, candidate genes, proposed as susceptibility markers linked to abnormal albuminuria, have been identified because of the knowledge of pathophysiological events related to diabetic nephropathy. Heparan sulfate proteoglycan (HSPG, i.e., Perlecan) constitutes an integrated part of the glomerular basement membrane. It consists of a central core protein to which anionie sulfated polysaccharide chains (heparan sulfate [HS]) are linked (7), thus contributing to the negative charge of the glomerular filtration barrier and thereby indirectly to the composition of the glomerular filtration product (8,9). In IDDM patients, it has been demonstrated that increased AER is reduced by the administration of heparin (10) most likely because of a stimulating effect on the HS synthesis (11).