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OBJECTIVE To compare medical resource use, costs, and health utilities for 14,752 patients with type 2 diabetes who were randomized to once-weekly exenatide (EQW) or placebo in addition to usual diabetes care in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Medical resource use data and responses to the EuroQol 5-Dimension (EQ-5D) instrument were collected at baseline and throughout the trial. Medical resources and medications were assigned values by using U.S. Medicare payments and wholesale acquisition costs, respectively. Secondary analyses used English costs. RESULTS Patients were followed for an average of 3.3 years, during which time those randomized to EQW experienced 0.41 fewer inpatient days (7.05 vs. 7.46 days; relative rate ratio 0.91; P = 0.05). Rates of outpatient medical visits were similar, as were total inpatient and outpatient costs. Mean costs for nonstudy diabetes medications over the study period were ∼$1,600 lower with EQW than with placebo (P = 0.01). Total within-study costs, excluding study medication, were lower in the EQW arm than in the placebo arm ($28,907 vs. $30,914; P ≤ 0.01). When including the estimated cost of EQW, total mean costs were significantly higher in the EQW group than in the placebo group ($42,697 vs. $30,914; P < 0.01). With English costs applied, mean total costs, including exenatide costs, were £1,670 higher in the EQW group than the placebo group (£10,874 vs. £9,204; P < 0.01). There were no significant differences in EQ-5D health utilities between arms over time. CONCLUSIONS Medical costs were lower in the EQW arm than the placebo arm, but total costs were significantly higher once the cost of branded exenatide was incorporated.

In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced risk of cardiovascular (CV) death by 38% and hospitalization for heart failure (HHF) by 35% in patients with type 2 diabetes (T2D) and CV disease. We aimed to identify phenotypes of patients with different risk of outcomes and to explore treatment effects across these groups. Overall, 7020 patients were treated with EMPA 25, 10 mg or placebo (PBO). For this post-hoc analysis, patients were randomly separated into training (2/3) and validation sets (1/3 of patients). Latent class analysis identified 3 clusters using 6639 patients with complete data. The association of clusters to CV death and CV death/HHF, and treatment effect of EMPA vs. PBO across clusters was explored by Cox regression. Cluster 1 included younger patients with shorter T2D duration. Cluster 2 included more women with non-coronary atherosclerotic disease (CAD), and Cluster 3 older patients with advanced CAD. In the training set, risk of CV death varied across clusters (Cluster 2 vs. 1 HR 1.83 [95% CI 1.23, 2.71], Cluster 3 vs. 1 HR 1.86 [1.30, 2.67]) with similar pattern for CV death/HHF. Treatment effect of EMPA was consistent across clusters (Figure). Results were replicated in the validation set. We identified 3 phenotypes of patients with varying risk of outcomes. The consistent treatment effect across clusters reaffirms the robustness of CV death/HHF reduction with EMPA. Disclosure A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. T. Ahmad: None. 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. I. Zwiener: Employee; Self; Boehringer Ingelheim International GmbH. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. S. Hantel: Employee; Self; Boehringer Ingelheim Pharma GmbH & Co. KG. N. Desai: None. R.J. Mentz: Consultant; Self; Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Sanofi. Research Support; Self; GlaxoSmithKline plc. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

GLP-1 RA effects on major kidney outcome in unselected T2D patients at high cardiovascular (CV) risk are modest or neutral. However, GLP-1 RA may provide renal benefit in those at high risk of worsening kidney disease. We examined once-weekly exenatide (EQW) effects on eGFR slope and UACR change, as a function of baseline UACR, in a subset of EXSCEL participants. Of 14752 EXSCEL participants, eGFR slope was assessed in those with baseline UACR and ≥1 post-baseline eGFR (n=3503 [23.7%]) via mixed model repeated measures (MMRM) analysis (median follow-up 3.3 years). UACR percent change from baseline to first post-baseline measurement (median time 8.9 months) was assessed in those with baseline and ≥1 follow-up UACR (n=2828 [19.2%]) via ANCOVA of log-transformed UACR, with baseline UACR as a covariate. Participants with baseline UACR measurements were generally similar to the overall EXSCEL population, and balanced across treatment arms. EQW improved eGFR slope in those with baseline UACR>100mg/g and UACR>200mg/g, but not at lower UACR thresholds. No difference in EQW effect on eGFR was observed as a function of baseline eGFR, CV disease history, RAAS inhibitor use, or SBP. UACR improvement was similar across UACR categories. This EXSCEL post-hoc analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR. Disclosure L.E. Clegg: Employee; Self; AstraZeneca. A. van der Aart: None. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca, Bristol-Myers Squibb. C. Sjöström: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. R.J. Mentz: Consultant; Self; Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Sanofi. Research Support; Self; GlaxoSmithKline plc. R.R. Holman: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding AstraZeneca

OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI −0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70–1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74–0.98]). Retinopathy rates did not differ by treatment group or in the HbA1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR CONCLUSIONS EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m2 in analyses unadjusted for multiplicity.

SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) improve cardiovascular (CV) and renal outcomes through distinct mechanisms. However, evidence is lacking on clinical outcomes in patients treated with both classes. EXSCEL, the cardiovascular outcomes trial for the GLP-1 RA exenatide, provides an opportunity to explore CV and renal outcomes with dual GLP-1RA and SGLT2i treatment, as ∼10% of participants had an SGLT2i added to their glycemic management during follow-up. Cohorts of SGLT2i users in the exenatide arm were propensity-matched to: 1) users of exenatide but not SGLT2i; 2) placebo arm participants that did not take SGLT2i, based on last measured characteristics before SGLT2i initiation. Subsequent time-to-first adjudicated major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR decline was quantified in the matched cohorts using a mixed model repeated measurement (MMRM) analysis. Exenatide plus SGLT2i use numerically decreased the MACE hazard ratio and significantly reduced ACM risk, compared with exenatide alone and with placebo. The combination also significantly improved eGFR slope in both comparisons. This post hoc analysis offers support for the hypothesis that combinatorial exenatide and SGLT2i use may provide benefit on renal function and all-cause mortality. Disclosure L.E. Clegg: Employee; Self; AstraZeneca. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca, Novartis AG. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca, Bristol-Myers Squibb Company. S. Bachina: Employee; Self; AstraZeneca. M. Thuresson: Consultant; Self; AstraZeneca. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. S. Gustavson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; AstraZeneca. C. Sjöström: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J.A. Ruggles: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Apple, AstraZeneca. A.F. Hernandez: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation. Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation. J.B. Buse: Consultant; Self; Neurimmune AG. Research Support; Self; AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg, Novo Nordisk A/S, Senseonics, vTv Therapeutics, Zafgen, Inc. R.J. Mentz: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; GlaxoSmithKline plc. Other Relationship; Self; Amgen Inc., AstraZeneca, Bayer AG, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation. R.R. Holman: Advisory Panel; Self; Bayer AG, Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp. Other Relationship; Self; AstraZeneca, Bayer AG, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.

Background: EXSCEL was a multinational, randomized, blinded, placebo-controlled, pragmatic CV outcome trial of once-weekly exenatide on the background of usual care. We report exenatide’s impact on estimated glomerular filtration rate (eGFR), new macroalbuminuria and 2 renal composites from a prespecified analysis plan. Methods: Opportunistic local laboratory data were collected. Overall least squares mean difference (LSMD) eGFR (95% confidence interval [95% CI]) was calculated for 13844 patients with baseline and ≥1 follow-up value. Effect on new macroalbuminuria was estimated with a Cox regression model. Effects on renal composites were estimated with interval censored time to event models, with and without covariate adjustment (demographics and disease characteristics). Results: Intention-to-treat analyses showed no significant difference in eGFR levels with exenatide (LSMD +0.21 [-0.27, 0.70] mL/min.1.73m2, p=0.39). New macroalbuminuria occurred in 2.2% and 2.5% of the exenatide and placebo groups (p=0.19). There was a 15% lower renal composite 2 adjusted risk with exenatide (p=0.027) (Table). Conclusions: A composite of 40% eGFR decline, renal replacement, renal death or new macroalbuminuria was significantly reduced in an adjusted analysis by the addition of exenatide in a broad range of people with type 2 diabetes. Other renal outcomes were numerically but not statistically improved with exenatide. Disclosure M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. R.J. Mentz: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. P. Merrill: None. J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck & Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company. S.G. Goodman: Research Support; Self; Amgen Inc.. Consultant; Self; Amgen Inc.. Research Support; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; Bayer AG. Consultant; Self; Bayer AG. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Bristol-Myers Squibb Company. Consultant; Self; Bristol-Myers Squibb Company. Research Support; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation. Research Support; Self; Pfizer Inc.. Consultant; Self; Pfizer Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Consultant; Self; Regeneron Pharmaceuticals, Inc.. Research Support; Self; CSL Behring. N. Iqbal: Employee; Self; AstraZeneca. N. Jakuboniene: None. B.G. Katona: Employee; Self; AstraZeneca. Y. Lokhnygina: None. R.D. Lopes: Consultant; Self; Bayer AG, Boehringer Ingelheim GmbH. Other Relationship; Self; Bristol-Myers Squibb Company. Consultant; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; GlaxoSmithKline plc., Medtronic. Consultant; Self; Merck & Co., Inc.. Other Relationship; Self; Pfizer Inc.. A.P. Maggioni: None. P.K. Ohman: Employee; Self; AstraZeneca. 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. A. Ramachandran: None. T. Tankova: None. 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. A.F. Hernandez: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. Consultant; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. R.R. Holman: Research Support; Self; AstraZeneca, Merck & Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck & Co., Inc.. Other Relationship; Self; AstraZeneca.

SGLT2i, empagliflozin and canagliflozin, have been shown to reduce the incidence of major adverse CV events (MACE), all-cause mortality (ACM) and renal events in CV outcomes trials (CVOTs), with robust real-world evidence (RWE) suggesting class effect benefits. In the exenatide CVOT EXSCEL, ∼10% of patients took an SGLT2i with ∼5% use of dapagliflozin (DAPA). Effects of all SGLT2i, and DAPA alone, on MACE, ACM, and eGFR were analyzed in EXSCEL participants randomized to placebo. Propensity-matched cohorts (including by study visit) of SGLT2i users and non-users (n=709 per group) were generated, based on their last measured characteristics before SGLT2i initiation. Subsequent time-to-first adjudicated MACE and ACM were compared using a Cox regression. Decline in eGFR over time (slope) was quantified in the matched cohorts using a mixed model repeated measurement (MMRM) analysis. SGLT2i overall, and DAPA alone, numerically decreased the MACE hazard ratio, and SGLT2i significantly reduced the ACM risk (Table). The eGFR slope was improved significantly for SGLT2i overall and DAPA alone (Table). This post-hoc EXSCEL analysis supports a beneficial class effect for SGLT2i on MACE, ACM, and renal function, consistent with published CVOTs, Real-World data, and for DAPA alone. DECLARE, the ongoing DAPA CVOT, will complete in 2018.Time-to-First Adjudicated EventPropensity-matched cohortnEventsSubject-years of follow-upCrude rate (events/100 subject-years)Unadjusted hazard ratio (95% CI)Adjusted hazard ratio (95% CI)MACEaNo SGLT2i709449904.45SGLT2i709288223.410.78 (0.48–1.27)0.79 (0.49–1.28)No DAPA354224844.54DAPA354114082.690.59 (0.28–1.24)0.55 (0.26–1.15)All-cause mortalityNo SGLT2i7093711083.34SGLT2i709148711.610.48 (0.26–0.89)0.50 (0.27–0.95)No DAPA354135382.42DAPA35474321.620.66 (0.25–1.69)0.66 (0.25–1.72)MMRM analysisPropensity matched cohorteGFR slope (standard error)Treatment effect (95% CI)p-valueeGFR slope (mL/min/1.73m2/year) No SGLT2i−0.91 (0.26)SGLT2i+0.87 (0.37)+1.78 (0.87–2.69)0.00013No DAPA−1.04 (0.37)DAPA+1.24 (0.54)+2.28 (1.01–3.54)0.0004aMACE: a composite endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke Disclosure L. Clegg: Employee; Self; AstraZeneca. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Consultant; Self; Janssen Research & Development, Fresenius SE & Co. KGaA. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. W. Tang: Employee; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. S. Bachina: Employee; Self; AstraZeneca. R.D. Fox: None. P. Fenici: Employee; Self; AstraZeneca. M. Thuresson: Consultant; Self; AstraZeneca. R.J. Mentz: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc. A.F. Hernandez: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. Consultant; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. R.R. Holman: Research Support; Self; AstraZeneca, Merck & Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck & Co., Inc.. Other Relationship; Self; AstraZeneca.