162-OR: Interrelationship between Hypoglycemia (HYPO) and Cardiovascular (CV) and Mortality Outcomes in the CAROLINA Trial

Older people with T2D have a high prevalence of comorbidities, frailty and polypharmacy. We investigated the effects of linagliptin (LINA) 5 mg versus glimepiride (GLIM) 1-4 mg once daily across age groups in the CARdiovascular Outcome Study of LINAgliptin Versus Glimepiride in T2D (CAROLINA®). CAROLINA® recruited adults with relatively early T2D, HbA1c 6.5-8.5%, and elevated CV risk and its primary outcome was CV death, non-fatal myocardial infarction, or non-fatal stroke (3P-MACE), with secondary outcomes including mortality as well as change from baseline in HbA1c, weight and hypoglycemia. Of 6033 patients (median age 64 [range 36-85]), 846 (14.0%) were ≥75 years. During median follow-up of 6.3 years, CV and mortality outcomes rates did not differ between treatment groups overall and across age categories (interaction p-values >0.05). Over time, following some initial dynamics, changes in HbA1c levels were comparable between treatment-groups and across age, but hypoglycemia risk (Fig) and weight were significantly lower with LINA vs. GLIM overall and consistently across age groups. These data demonstrate that results for CV and mortality outcomes were consistent across age subgroups, but LINA has a modest benefit in weight and a significantly lower hypoglycemia burden than GLIM, which are important safety considerations when selecting therapy for the elderly. Disclosure M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. R.E. Pratley: Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Janssen Scientific Affairs, LLC., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals Incorporated, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. T. Kadowaki: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; Abbott, Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Cosmic Corporation, Daiichi Sankyo, Eli Lilly Japan K.K., FUJIFILM, Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Medscape Education, Medtronic, Mitsubishi Tanabe Pharma Corporation, MSD Corporation, NIPRO Medical Corporation, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Asahi Mutual Life Insurance. Y. Seino: Research Support; Self; ARKRAY, Bayer Yakuhin, Ltd., Boehringer Ingelheim International GmbH, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Speaker’s Bureau; Self; Becton, Dickinson and Company, Eli Lilly Japan K.K., Kao Corporation, Merck Sharp & Dohme Corp., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. K.R. Andersen: None. M. Mattheus: None. A. Keller: Employee; Self; Boehringer Ingelheim International GmbH. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

CAROLINA® (CARdiovascular Outcome Study of LINAgliptin Versus Glimepiride in Type 2 Diabetes) was a randomized controlled clinical trial designed to compare the effects of linagliptin (LINA) with glimepiride (GLIM) on CV events and other outcomes in patients with relatively early type 2 diabetes (T2D) with elevated CV risk. To characterize the effects on net CV disease and hospitalization burden of this population, we assessed effects of LINA vs. GLIM on all first plus recurrent CV events and any-cause hospitalizations using a negative binomial model. A total of 6033 participants were enrolled (mean age 64.0 years, HbA1c 7.2%, BMI 30.1 kg/m2, eGFR 77 ml/min/1.73m2, median T2D duration 6.3 years, UACR 9 mg/g, 42% with CV disease, 4.5% with heart failure [HF]). Adding recurrent events increased the number of events for analysis from first event by 10 to 77% across CV/HF outcomes and by 119% for hospitalizations with corresponding increase in rates per 100-patient years in both treatment groups (e.g., 3P-MACE from 2.1 to 2.8 [LINA] and 2.1 to 2.9 [GLIM]), over median 6.3 years. Analyses of first-event and first plus recurrent events are presented (Fig). In conclusion, no significant differences were observed between LINA or GLIM for either first or recurrent CV or hospitalization events. These data underscore the significant CV disease burden experienced even in relatively early T2D and reinforce the safety of LINA. Disclosure N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. E. Pfarr: None. M. Mattheus: None. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

Severe hypoglycemia is associated with high CV and mortality risk. CARMELINA (CArdiovascular and Renal Microvascular outcomE study with LINAgliptin) evaluated the CV safety and kidney outcomes of LINA in 6979 subjects with type 2 diabetes and cardio-renal disease (mean age 65.9 years, HbA1c 8.0%, eGFR 54.6 ml/min/1.73m2) and demonstrated CV safety of LINA with respect to the primary composite outcome of CV death/MI/stroke (3P-MACE) and no effect on all-cause mortality. We assessed interrelationships between time to first severe hypoglycemia or plasma glucose < 54 mg/dL, which occurred in 557 (15.9%) and 572 (16.4%) in the LINA and placebo (PBO) groups, and 3P-MACE or all-cause mortality, using adjusted Cox models. Hypoglycemia preceded 3P-MACE in 146 participants (at median 58 days in n=74 LINA; at 55 days in n=72 PBO), and was associated with a 43% higher risk (HR 1.43 [95% CI 1.23, 1.66]), when adjusted for region and hypoglycemia. Higher adjusted risk of all-cause mortality was also associated with preceding hypoglycemia (HR 1.31 [1.11, 1.53]) in 129 participants who died (at median 65 days in n=65 LINA; at 49 days in n=64 PBO). More frequent hypoglycemia was associated with a greater magnitude of incremental risk (Figure A) that attenuated with further adjustment. (Figure B). In conclusion, preceding hypoglycemia was independently associated with increased risk for 3P-MACE and mortality. Disclosure J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck & Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Lilly Diabetes. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Servier. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Bayer AG, Merck Sharp & Dohme Corp., Novartis AG. N. Marx: Advisory Panel; Self; Amgen Inc., AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.H. Alexander: Advisory Panel; Self; CSL Behring, Novo Nordisk A/S. Consultant; Self; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Quantum Genomics, Zafgen, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CSL Behring, National Institutes of Health. Research Support; Spouse/Partner; Sanofi. Research Support; Self; U.S. Food and Drug Administration. R.D. Toto: Advisory Panel; Self; Relypsa, Inc. Board Member; Self; Akebia Therapeutics. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Quest Diagnostics, Vifor Pharma, WebMD. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. C. Wanner: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. Board Member; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Mitsubishi Tanabe Pharma Corporation. E. Pfarr: None. S. Schnaidt: Employee; Self; Boehringer Ingelheim Pharma GmbH & Co. KG. J. George: Employee; Self; Boehringer Ingelheim International GmbH. M. von Eynatten: Employee; Self; Boehringer Ingelheim International GmbH. D.K. McGuire: Consultant; Self; Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. V. Perkovic: Advisory Panel; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Baxter, Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Durect Corporation, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Research & Development, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Pharmalink, Relypsa, Inc., Roche Pharma, Sanofi, Servier, Vitae. Research Support; Self; Australian National Health and Medical Research Council. Other Relationship; Self; AbbVie Inc., Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Janssen Research & Development, Pfizer Inc. B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. Funding Boehringer Ingelheim; Eli Lilly and Company

SGLT2 inhibitors may lead to short term decrease in eGFR, with later stabilization and long-term reduction in the risk for end stage kidney disease. Fast decline (FD) in eGFR can be defined as a reduction of ≥3 ml/min/1.73m2/year and is associated with poor long-term renal prognosis. In this post-hoc analysis we studied the effect of dapagliflozin (dapa) on the risk for FD in the DECLARE-TIMI 58 trial. In DECLARE-TIMI 58, 17,160 patients with T2D and established or increased risk for CVD, with mean baseline eGFR of 85.2 ml/min/1.73m2, were randomized to dapa vs. placebo and followed for a median of 4.2 years. The risk for FD was compared between treatment arms. In the time frame of 0.5 years (after stabilization) to 4 years, the proportion of patients with FD was reduced with dapa vs. placebo (26.8% vs. 37.1% respectively, p<0.0001). This observation was persistent in all subgroups assessed (Table). The mean (SD) reduction in eGFR per year was 6.3 (3.7) vs. 0.0 (2.5) ml/min/1.73m2/year in the FD (N=4,788) vs. non-FD (N=10,224) patients. The proportion of patients with FD during the entire study period (i.e., 0-4 years) was reduced with dapa vs. placebo as well (33.6% vs. 37.0% respectively, p<0.0001). Dapagliflozin reduced the risk for FD in eGFR in a broad population of patients with T2D and either established or increased risk for CVD, but relatively preserved renal function, irrespective of patients’ baseline characteristics.

Treatment guideline recommendations for individuals with cardiovascular (CV) disease and type 2 diabetes (T2D) focus on medications with proven CV benefits. However, considerations relating to avoidance of hypoglycemia (HYPO) remain important. We report in the CARdiovascular Outcome Study of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) the effects of treatment on a range of HYPO outcomes. CAROLINA recruited adults with relatively early T2D, HbA1c 6.5-8.5%, and elevated CV risk who were randomized to linagliptin 5 mg (LINA) or glimepiride 1-4 mg (GLIM) once daily added to usual care. Time to first or sum of first plus recurrent HYPO was assessed across categories: any, symptomatic with BG ≤70 mg/dL or severe, BG &amp;lt;54 mg/dL or severe, severe, or, leading to hospitalization, using Cox proportional hazards models or negative binomial regression. 6033 participants (mean age 64.0 years, HbA1c 7.2%, median T2D duration 6.3 years, 42% with CV disease) were followed for median 6.3 years. HbA1c over time did not differ between groups, but a significantly lower frequency of HYPO events was observed with LINA (Fig), regardless of definition, a difference further accentuated when including recurrent HYPO. In conclusion, these data demonstrate that LINA, compared with GLIM, has a significantly lower HYPO burden. Given the potentially harmful clinical impact of HYPO, these data may help inform therapy selection. Disclosure B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. M. Hoeiberg: Employee; Self; Boehringer Ingelheim International GmbH. E. Pfarr: None. M. Mattheus: None. T. Meinicke: None. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. M. Espeland: Other Relationship; Self; Boehringer Ingelheim International GmbH, Ironwood Pharmaceuticals. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp &amp; Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. N. Marx: Other Relationship; Self; Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Research Institute, Inc., Medtronic, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

CARMELINA was a randomized placebo-controlled clinical trial designed to demonstrate the cardiovascular (CV) safety of linagliptin in patients with T2D and concomitant cardiorenal disease. To characterize the effects of linagliptin on net CV disease and hospitalization burden of this population, we assessed the effects of linagliptin versus placebo on all first plus recurrent CV events and any-cause hospitalizations using a negative binomial model. A total of 6979 participants were enrolled (mean age 66 y, eGFR 54.6 ml/min/1.73m2, median UACR 162 mg/g, 58.5% with history of ischemic heart disease, 26.8% with heart failure). Adding recurrent events increased the number of events for analysis from 5.3-57.5% across CV/HF outcomes and 112.4% for hospitalizations. Results of analyses of first plus recurrent events for linagliptin vs. placebo are presented along with first-event analyses results for comparison (Figure). Linagliptin showed similar risk of either first or recurrent CV or hospitalization events compared with placebo in patients with T2D and cardiorenal disease. These data support the overall and CV safety of linagliptin and, considering the number of recurrent events, underscores the significant CV disease burden experienced by T2D patients and cardiorenal disease. Disclosure N. Marx: Advisory Panel; Self; Amgen Inc., AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. D.K. McGuire: Consultant; Self; Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck &amp; Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Lilly Diabetes. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Servier. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Bayer AG, Merck Sharp &amp; Dohme Corp., Novartis AG. R.D. Toto: Advisory Panel; Self; Relypsa, Inc. Board Member; Self; Akebia Therapeutics. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Quest Diagnostics, Vifor Pharma, WebMD. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. C. Wanner: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. Board Member; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Mitsubishi Tanabe Pharma Corporation. E. Pfarr: None. S. Schnaidt: Employee; Self; Boehringer Ingelheim Pharma GmbH &amp; Co. KG. J. George: Employee; Self; Boehringer Ingelheim International GmbH. M. von Eynatten: Employee; Self; Boehringer Ingelheim International GmbH. V. Perkovic: Advisory Panel; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Baxter, Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Durect Corporation, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Research &amp; Development, Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Pharmalink, Relypsa, Inc., Roche Pharma, Sanofi, Servier, Vitae. Research Support; Self; Australian National Health and Medical Research Council. Other Relationship; Self; AbbVie Inc., Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Janssen Research &amp; Development, Pfizer Inc. B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc. J.H. Alexander: Advisory Panel; Self; CSL Behring, Novo Nordisk A/S. Consultant; Self; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Quantum Genomics, Zafgen, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CSL Behring, National Institutes of Health. Research Support; Spouse/Partner; Sanofi. Research Support; Self; U.S. Food and Drug Administration. Funding Boehringer Ingelheim; Eli Lilly and Company

In the EMPA-REG OUTCOME trial of 7020 patients with T2DM and CV disease, empagliflozin (EMPA) significantly reduced risk for 3P-MACE, CV death, hospitalization for heart failure (HHF) and the composite of HHF or CV death, compared to placebo (PBO). We explored these outcomes in subgroups based on achievement of 7 CV risk factor goals at baseline, defined as: HbA1c &amp;lt;7.5%; LDL-C &amp;lt;100 mg/dL or statin use; systolic BP &amp;lt;140 or diastolic BP &amp;lt;90 mmHg; ACE inhibitor/ARB use; normoalbuminuria; aspirin use; and non-smoking status. Within the PBO group alone, the hazard ratio (HR) for 3P-MACE was 2.21 (95% CI 1.53, 3.19) and 1.42 (1.06, 1.89) for patients achieving 0-3 or 4-5 risk factor goals at baseline, respectively, compared to those reaching 6-7. Similarly, patients achieving only 0-3 or 4-5 goals had increased risk for CV death (HR 4.00 [2.26, 7.11] and 2.48 [1.52, 4.06], respectively), HHF or CV death (HR 2.89 [1.82, 4.57] and 1.90 [1.31, 2.78]) and an increased point estimate for HHF (HR 1.91 [0.96, 3.79] and 1.67 [1.00, 2.80]) versus those achieving 6-7 goals at baseline. EMPA consistently reduced the risk for these CV events versus PBO across all subgroups (p for interaction=NS for all; Figure). In conclusion, CV risk increases with fewer CV risk factors controlled, but the cardioprotective effect of EMPA was consistent regardless of the number of risk factors controlled. Disclosure S.E. Inzucchi: Consultant; Self; vTv Therapeutics, Zafgen, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. K. Khunti: Advisory Panel; Self; Amgen Inc., AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. Speaker’s Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Menarini Group, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Servier, Takeda Pharmaceutical Company Limited. D.H. Fitchett: Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Lilly Diabetes. Other Relationship; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C. Wanner: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp. Board Member; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Mitsubishi Tanabe Pharma Corporation. M. Mattheus: Employee; Self; Boehringer Ingelheim Pharma GmbH&amp;Co.KG. J. George: Employee; Self; Boehringer Ingelheim International GmbH. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc. Funding Boehringer Ingelheim; Eli Lilly and Company

In the THEMIS trial of 19,220 patients with stable CAD and T2DM without prior MI or stroke followed for a median of 39.9 months, ticagrelor plus aspirin (ASA) lowered ischemic CV events but increased major bleeding events compared with placebo plus ASA, with a more favorable net clinical benefit in those with prior PCI. We now report the efficacy and safety by diabetes-related factors and background antihyperglycemic therapy. While the incidence of the primary efficacy outcome (CV death, MI, stroke; MACE) event rates (overall 8.1%) was higher with increasing diabetes duration (11.1% &amp;gt;20 years vs. 6.7% ≤5 years) and A1c (11.8% &amp;gt;10% vs. 6.4% ≤6%), the relative benefits of ticagrelor on MACE reduction (overall HR 0.90; p=0.04) did not differ across these various subgroups (p-values for interaction=0.83 and 0.16, respectively). In contrast, the primary safety outcome (TIMI major bleeding) event rate (overall 1.6%) did not vary by diabetes duration or A1c and was similarly increased by ticagrelor in all of these subgroups (overall HR=2.32 [1.82,2.94]; p&amp;lt;0.01). The impact of diabetes duration and A1c were similar in the prior PCI subgroup. Regardless of treatment assignment, patients treated with insulin vs. not had a higher risk for MACE (HR=1.65 [1.49, 1.83]; p&amp;lt;0.01) with no difference in major bleeding (HR=0.92 [0.71, 1.19]; p=0.52), while those treated with sulfonylurea vs. not had no difference in risk for MACE (HR=1.00 [0.91,1.11]; p=0.93) or major bleeding (HR=1.12 [0.89,1.41]; p=0.34) endpoints. The efficacy and safety of ticagrelor did not differ based on background antihyperglycemic therapy. These data suggest that, in general, the relative benefits and risks of ticagrelor added to aspirin are consistent regardless of T2DM duration, A1c, or background antihyperglycemic therapy. NCT01991795. Disclosure L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp &amp; Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. K. Fox: Other Relationship; Self; AstraZeneca, Servier. T. Simon: Advisory Panel; Self; Novartis Pharmaceuticals Corporation, Servier. Board Member; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc. Consultant; Self; Air Liquide, Sanofi. S. Mehta: Research Support; Self; AstraZeneca. E. Lev: None. R.G. Kiss: Speaker’s Bureau; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Pfizer Inc. A.J. Dalby: None. H. Bueno: Advisory Panel; Self; AstraZeneca, Bayer AG, Novartis AG. Consultant; Self; Amgen, Bristol-Myers Squibb, Pfizer Inc. Research Support; Self; AstraZeneca, Novartis AG. W. Ridderstråle: Employee; Self; AstraZeneca. A. Himmelmann: Employee; Self; AstraZeneca. J. Prats: Other Relationship; Self; AstraZeneca. Y. Liu: None. J.J. Lee: None. J. Amerena: None. M.N. Kosiborod: Consultant; Self; Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. P.G. Steg: Consultant; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Idorsia, Mylan, Novartis AG, Pfizer Inc., Sanofi, Servier. Research Support; Self; Amarin Corporation. Speaker’s Bureau; Self; Novo Nordisk A/S.

Insulin in T2D is associated with hypoglycemia and weight gain, requires training, can be expensive, and is generally not preferred by patients. Reducing insulin needs is attractive to both patients and practitioners. In EMPA-REG OUTCOME, 7020 patients were treated with empagliflozin (EMPA) 10, 25 mg, or placebo (PBO). Median follow-up was 3.1 yrs. After the first 12 weeks, changes in background glucose-lowering therapy were permitted. We assessed treatment effects of pooled EMPA vs. PBO on time to new initiation of insulin among insulin-naïve patients and time to total daily insulin dose increase by &amp;gt;20% among insulin-treated patients. In 3633 (52%) insulin-naïve patients, EMPA reduced need for insulin use vs. PBO by 54% (11.1% vs. 22.3%; HR 0.46 [0.39-0.54]), adjusted for key covariates (Figure). In 3387 (48%) patients using insulin at baseline, EMPA reduced need for a &amp;gt;20% increase in insulin dose by 57% (19.1% vs. 36.8%; HR 0.43 [0.37-0.49]). Reductions in incident insulin use was most pronounced in patients within 5 yrs of T2D diagnosis (HR 0.31 [0.21-0.45]) compared with T2D duration of &amp;gt;5-10 yrs (0.42 [0.31-0.59]) or &amp;gt;10 yrs (0.56 [0.44-0.71); P&amp;lt;sub&amp;gt;interaction =0.03. In patients with T2D and CVD, EMPA markedly and durably delays the need for insulin initiation, more so in those recently diagnosed, and reduces need for large dose increases in those already using insulin. Disclosure M. Vaduganathan: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Relypsa, Inc. Consultant; Self; Amgen, AstraZeneca, Baxter. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. M. Brueckmann: Employee; Self; Boehringer Ingelheim International GmbH. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. S. Verma: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Other Relationship; Self; AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Eli Lilly and Company, EOCI Pharmacomm, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi, Sanofi, Sun Pharmaceuticals, Toronto Knowledge Translation Working Group. M. Mattheus: None. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck &amp; Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck &amp; Co., Inc., vTv Therapeutics. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. J. Butler: Consultant; Self; Amgen, Array BioPharma, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, CVRx, G3 Pharmaceuticals, Innolife Co., Ltd., Janssen Pharmaceuticals, Inc., Luitpold Pharmaceuticals, Inc., Medtronic, Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Relypsa, Inc., VIfor. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

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 &amp; 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 &amp; 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 &amp; Co., Inc., Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Polfa Tarchomin S.A., Sanofi, Servier. Speaker&amp;#x2019;s Bureau; Self; Astra, Bioton, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Merck Sharp &amp; 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 &amp; 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 &amp; 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 &amp; 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 &amp; 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

In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes (T2D) with established atherosclerotic cardiovascular disease (ASCVD), empagliflozin reduced the risk of hospitalization for HF (HHF) by 35% (HR [95%CI] 0.65 [0.50-0.85]), CV death/HHF by 34% (0.66 [0.55-0.79]), and CV death by 38% (0.62 [0.49-0.77]) with an early separation of the cumulative incidence curves. We aimed to explore at what time point after randomization the benefits became apparent. Overall, 7020 patients were treated with empagliflozin 10, 25 mg or placebo. We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF and CV death based on Hazard Ratios (HRs) (95% CI), and calculated the HR on the day the effect reached significance using Cox proportional hazards models. The reduction in risk with empagliflozin vs. placebo reached significance at day 17 for HHF [0.10 [0.01, 0.87), p=0.0372], and day 27 for CV death/HHF [HR 0.28 (0.08, 0.97), p=0.0445], and sustained significant throughout follow-up (Figure). The benefit on CV death reached significance for the first time at day 59 [HR 0.28 (0.08, 0.96)]. HRs stabilized as the number of patients with events increased over time. The benefit of empagliflozin in reducing the risk of HHF, CV death/HHF and CV death emerged within weeks after treatment initiation in EMPA-REG OUTCOME. The earliest effect appears to be on HHF. Disclosure S. Verma: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Other Relationship; Self; AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Eli Lilly and Company, EOCI Pharmacomm, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi, Sanofi, Sun Pharmaceuticals, Toronto Knowledge Translation Working Group. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck &amp; Co., Inc. Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. M. Mattheus: None. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck &amp; Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck &amp; Co., Inc., vTv Therapeutics. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

CONCLUDE was a randomized, open-label, treat-to-target trial in participants with T2D, who received basal insulin ± oral antihyperglycemic drugs (OADs) and had ≥1 baseline hypoglycemia risk factors, including moderate renal impairment. Participants were randomized to degludec U200 or glargine U300 (± OADs). CONCLUDE demonstrated no significant difference in the overall symptomatic hypoglycemia rate with degludec U200 vs. glargine U300 in the maintenance period (primary endpoint, tested for superiority). However, lower rates of nocturnal symptomatic and severe hypoglycemia in the maintenance period (exploratory secondary endpoints) were observed with degludec U200 vs. glargine U300. The current post-hoc analysis investigated these hypoglycemia endpoints and HbA1c stratified by baseline estimated glomerular filtration rate (eGFR) subgroups (&amp;lt;60, 60-&amp;lt;90, ≥90 mL/min/1.73 m2). Change in HbA1c from baseline to end of treatment and rates and rate ratios for all hypoglycemia endpoints were comparable across eGFR subgroups and to the primary analyses. No statistically significant interactions were found between the subgroups for the endpoints assessed (Table). Irrespective of renal function, degludec U200 and glargine U300 resulted in similar HbA1c, and hypoglycemia rates were consistent with the primary analyses. Disclosure T.R. 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. H.S. Bajaj: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Kowa Pharmaceuticals America, Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., mdBriefCase, Medscape, Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc. S.R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S. Other Relationship; Self; MannKind Corporation. T. Jia: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. K. Khunti: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Board Member; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier. Speaker’s Bureau; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. D.C. Klonoff: Consultant; Self; Abbott, Ascensia Diabetes Care, Dexcom, Inc., EOFlow, Fractyl Laboratories, Inc., Know Labs, LifeCare, Inc., Novo Nordisk Inc., Roche Diabetes Care. S. Ladelund: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi, Servier. M.V. Hansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. A. Philis-Tsimikas: Advisory Panel; Self; Lilly Diabetes, Medtronic, Novo Nordisk A/S, Sanofi. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Lilly Diabetes, Medtronic, Novo Nordisk A/S, Sanofi. Funding Novo Nordisk A/S

In DAPA-HF, the SGLT2 inhibitor (i) dapagliflozin (dapa) reduced worsening heart failure (HF) and cardiovascular death in 4744 patients (pts) with HF and reduced ejection fraction (HFrEF.) Only 45% had type 2 diabetes (T2D) at baseline. We evaluated whether dapa reduced the incidence of diabetes in the 55% of pts without T2D. Pts were randomized to dapa 10 mg or placebo and followed for a median of 18.2 months. New-onset T2D was defined as A1c ≥6.5% measured at 2 consecutive study visits post-randomization or investigator-reported new T2D (with the initiation of a glucose-lowering agent.) The effect of dapa on incident T2D was assessed using a Cox proportional hazards model and confirmed with a Fine and Gray competing risk model to account for mortality. Of the 2605 non-T2D pts at baseline, 157 developed T2D on trial, 150 (95.5%) of whom had prediabetes (A1c 5.7-6.4%) (136 [86.6%] using the more restrictive 6.0-6.4% criterion.) Those with incident T2D had a higher mean baseline A1c (6.2 ±0.3 vs. 5.7 ±0.4%; p&amp;lt;0.001), greater BMI (28.5 ±5.9 vs. 27.1 ±5.7 kg/m2; p=0.003), and lower eGFR (61.5 ±17.4 vs. 68.2 ±19.3 ml/min/1.73 m2; p&amp;lt;0.001) than those who remained nondiabetic. Dapa reduced new-onset diabetes by 32%: placebo 93/1307 (7.1%) vs. dapa 64/1298 (4.9%); HR 0.68 (95% CI, 0.50-0.94; p=0.019) (Cox.) Results were virtually identical using the Fine and Gray model. Diabetes prevention may be another benefit of dapagliflozin. Disclosure S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck &amp; Co., Inc., vTv Therapeutics. K. Docherty: Speaker’s Bureau; Self; Eli Lilly and Company. Other Relationship; Self; AstraZeneca. L. Kober: Speaker’s Bureau; Self; AstraZeneca, Novartis AG. Other Relationship; Self; AstraZeneca. M.N. Kosiborod: Consultant; Self; Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. F. Martinez: Board Member; Self; AstraZeneca, Novartis Pharmaceuticals Corporation. P. Ponikowski: None. M.S. Sabatine: Consultant; Self; Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix Inc., Esperion Therapeutics, Inc., IFM Therapeutics, Intarcia Therapeutics, Ionis Pharmaceuticals, Inc., Medicines Company, MedImmune, Merck &amp; Co., Inc. Research Support; Self; Amgen, AstraZeneca, Bayer U.S., Daiichi Sankyo, Eisai Inc., Intarcia Therapeutics, Janssen Research and Development, Medicines Company, MedImmune, Merck &amp; Co., Inc., Novartis AG, Pfizer Inc., Quark Pharmaceuticals. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. J. Belohlavek: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH. M. Böhm: Speaker’s Bureau; Self; Abbott, Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Medtronic, Novartis Pharmaceuticals Corporation, Servier, Vifor Pharma Group. C. Chiang: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Merck Sharp &amp; Dohme Corp., Novartis AG, Pfizer Inc., Sanofi. R.A. de Boer: Speaker’s Bureau; Self; Abbott, AstraZeneca, Novartis AG, Roche Diagnostics France. M. Diez: Other Relationship; Self; AstraZeneca. A. Dukat: None. C.E.A. Ljungman: Advisory Panel; Self; AstraZeneca, Novartis AG, Pfizer Foundation. Stock/Shareholder; Self; AstraZeneca. Other Relationship; Self; AstraZeneca, Novartis AG. S. Verma: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Other Relationship; Self; AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Eli Lilly and Company, EOCI Pharmacomm, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi, Sanofi, Sun Pharmaceuticals, Toronto Knowledge Translation Working Group. D.L. DeMets: Consultant; Self; Actelion Pharmaceuticals US, Inc., AstraZeneca, Boston Scientific, Bristol-Myers Squibb, DalCor Pharmaceuticals, Intercept Pharmaceuticals, Inc., Medtronic. O. Bengtsson: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M. Sjöstrand: Employee; Self; AstraZeneca. P. Jhund: Advisory Panel; Self; Cytokinetics Inc. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Novartis AG. Other Relationship; Self; AstraZeneca. J.J. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc. Funding AstraZeneca

Titration following initiation of BI tends to occur in the first 8-12 weeks. At this time, patients may be at risk of experiencing hypoglycemia, which itself may present a barrier to optimal glycemic control. BRIGHT was the first randomized controlled trial comparing efficacy and safety of two second-generation BI analogs in insulin-naïve patients with T2DM, and showed less hypoglycemia with insulin glargine 300 U/mL (Gla-300) vs. insulin degludec 100 U/mL (IDeg) in the initial 12-week titration period. We investigated patient characteristics and clinical outcomes (including HbA1c change, and hypoglycemia incidence during weeks 13-24) by the occurrence of early confirmed (≤70 mg/dL) hypoglycemia (in the titration period) using descriptive statistics. Participants experiencing hypoglycemia within the first 12 weeks tended to be older, had lower BMI, more impaired renal function, longer duration of diabetes, and were more likely to be using SUs at baseline (Table). Overall, hypoglycemia incidence during weeks 13-24 was lower in the group that did not experience hypoglycemia within the first 12 weeks. HbA1c reductions at week 12 were greater in those with hypoglycemia in the titration period. These findings suggest that patients experiencing early hypoglycemia with second-generation BI analogs have increased hypoglycemia risk in later stages of therapy. Disclosure S.B. Harris: Advisory Panel; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck &amp; Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; Canadian Diabetes Association, Canadian Institutes of Health Research, The Lawson Foundation. L. Berard: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Abbott, Ascensia Diabetes Care, AstraZeneca, Bayer AG, Becton, Dickinson and Company, Janssen Pharmaceuticals, Inc., LifeScan Canada, Mylan, Novo Nordisk Inc., Sanofi. Research Support; Self; Montmed Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc. J. Westerbacka: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. Z. Bosnyak: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. L. Melas-Melt: Consultant; Self; Sanofi. F. Lauand: Employee; Self; Sanofi. T.S. Bailey: Advisory Panel; Self; Abbott. Consultant; Self; Capillary Biomedical, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Sanofi. Research Support; Self; Abbott, Ascensia Diabetes Care, Becton, Dickinson and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Calibra Medical, Capillary Biomedical, Inc., Companion Medical, Dance Biopharm Holdings Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, GlySens Incorporated, Kowa Pharmaceutical Europe Co. Ltd., Lexicon Pharmaceuticals, Inc., Medtronic, Novo Nordisk Inc., POPS! Diabetes Care, POPS! Diabetes Care, Sanofi, Senseonics, vTv Therapeutics, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker's Bureau; Self; Abbott, MannKind Corporation, Medtronic, Novo Nordisk Inc., Sanofi US, Senseonics. K. Khunti: Advisory Panel; Self; Amgen Inc., AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Menarini Group, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Funding Sanofi (NCT02738151)

In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced the risk of CV death by 38% in T2D patients (pts) with CV disease. EMPA induces an initial, reversible dip in estimated glomerular filtration rate (eGFR). We investigated whether this transient initial renal hemodynamic effect was influenced by baseline characteristics or had an impact on the EMPA-induced risk reduction in CV death. In a post-hoc analysis, among the 6,668 pts randomized to EMPA 10 mg, 25 mg or placebo [PBO] with eGFR available, 28.3% of EMPA pts vs. 13.4% PBO experienced an initial eGFR decline &amp;gt;10% from baseline to Week 4 (odds ratio [OR; 95% CI]: 2.7 [2.3-3.0]). Multivariate logistic regression was used to identify baseline characteristics predictive of eGFR dip &amp;gt;10%. The impact of an eGFR dip &amp;gt;10% on the risk reduction in CV death was assessed using Cox regression. Diuretic use and higher KDIGO (Kidney Disease: Improving Global Outcomes) risk category at baseline were predictive of an eGFR dip &amp;gt;10% with EMPA vs. PBO. Serious adverse events were generally lower or similar in EMPA vs. PBO, regardless of predictive baseline factors. EMPA-induced CV death risk reduction was consistent across subgroups below vs. above average eGFR dipping OR (Panel A) and not affected by eGFR dip &amp;gt;10% (Panel B). T2D pts with more advanced kidney disease and/or on diuretic therapy were more likely to experience an eGFR dip &amp;gt;10% with EMPA. EMPA reduced CV death, regardless of an initial eGFR dip &amp;gt;10%. Disclosure S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck &amp; Co., Inc., vTv Therapeutics. B.J. Kraus: Research Support; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. M.R. Weir: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc. G. Bakris: Consultant; Self; Alnylam, Merck &amp; Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. M. Mattheus: None. D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. I. Ritter: Employee; Self; Boehringer Ingelheim International GmbH. M. von Eynatten: Other Relationship; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck &amp; Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Koitka-Weber: Employee; Self; Boehringer Ingelheim International GmbH.