AIMS:In VERTIS CV, ertugliflozin was associated with a 30% risk reduction for adjudication-confirmed, first and total hospitalizations for heart failure (HHF) in participants with type 2 diabetes and atherosclerotic cardiovascular disease. We evaluated the impact of ertugliflozin on the broader spectrum of all reported heart failure (HF) events independent of adjudication confirmation. METHODS AND RESULTS:Data from participants who received ertugliflozin (5 or 15 mg) were pooled and compared versus placebo. HF events included all investigator-reported HF adverse events (AEs) and serious AEs (SAEs) based on the narrow standardized Medical Dictionary for Regulatory Activities (MedDRA) query 'cardiac failure'. Terms for orthopnoea, dyspnoea, and peripheral oedema were evaluated separately. The effect of ertugliflozin on the first HF event was assessed by Cox proportional hazard models. Total HF events were assessed by Andersen-Gill models to account for first and recurrent events. A total of 8238 participants received ≥1 dose of ertugliflozin or placebo (mean follow-up 3.5 years). Investigator-reported HF events and AE capture yielded 420 first and 627 total HF events (vs. 238 and 345 adjudication-confirmed HHF events, respectively, in the primary analyses). Ertugliflozin reduced the risk for first (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.57-0.84; p < 0.001) and total HF AEs (HR 0.66; 95% CI 0.57-0.78; p < 0.001), with similar results for first and total HF SAEs. Additionally, ertugliflozin reduced oedema risk, but not orthopnoea/dyspnoea. CONCLUSION:The effect of ertugliflozin was consistent across the spectrum of total investigator-reported HF AEs and was similar in magnitude to adjudicated HHF events.

Introduction: VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the sodium-glucose cotransporter 2 inhibitor ertugliflozin in patients with type 2 diabetes and established atherosclerotic CV disease. The aim of the current analyses was to evaluate VERTIS CV cardiorenal outcomes according to baseline use of renin-angiotensin-aldosterone system (RAAS) inhibitors or diuretics, including mineralocorticoid receptor antagonists (MRAs). Methods: Participants received ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo once daily and were followed for a mean of 3.5 years. Prespecified CV and kidney outcomes were analyzed by Cox proportional hazard modeling in participant subgroups defined by baseline use of RAAS inhibitors (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) or diuretics (loop diuretics, non-loop diuretics, MRAs), with interaction testing to assess for treatment effect modification. Results: A total of 8,246 patients were randomized in VERTIS CV. At baseline, 6,686 (81%) participants were being treated with RAAS inhibitors, 3,542 (43%) with diuretics, 1,252 (15%) with loop diuretics, and 674 (8%) with MRAs. No significant interactions were observed for cardiorenal outcomes by baseline use of RAAS inhibitors or MRAs (pinteraction > 0.05 for all). Statistically significant interactions for a first event of hospitalization for heart failure (HHF) or CV death, and of HHF (alone), were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin treatment versus placebo. Conclusion: In VERTIS CV, baseline use of diuretics, particularly loop diuretics, identified a subgroup that demonstrated greater benefit with ertugliflozin on first HHF/CV death and HHF outcomes, with no modification of treatment effect observed with baseline use of RAAS inhibitors or MRAs. There was no evidence of treatment effect on the kidney composite outcomes by baseline use of RAAS inhibitors, diuretics, loop diuretics, or MRAs.

AIM:To conduct post hoc analyses of the VERTIS CV (NCT01986881) trial to explore the effects of ertugliflozin on serum uric acid (UA) and gout-related outcomes. MATERIALS AND METHODS:Participants with type 2 diabetes and atherosclerotic cardiovascular disease were randomised (1:1:1) to placebo, ertugliflozin 5 mg or ertugliflozin 15 mg. Mean UA over time (260 weeks) was evaluated for pooled ertugliflozin versus placebo overall, and by baseline quintile of UA (≤4.3 mg/dL [≤255.8 µmol/L], >4.3-5.1 mg/dL [>255.8-303.4 µmol/L], >5.1-5.8 mg/dL [>303.4-345.0 µmol/L], >5.8-6.9 mg/dL [>345.0-410.4 µmol/L] and >6.9 mg/dL [>410.4 µmol/L]), glycated haemoglobin level, albuminuria status, estimated glomerular filtration rate and KDIGO (Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease) risk category. The effect of ertugliflozin on a composite of gout onset or initiation of anti-gout medication was assessed. RESULTS:The mean UA levels at baseline were 5.67 and 5.62 mg/dL in the placebo and ertugliflozin groups, respectively. Ertugliflozin reduced UA over Weeks 6-260 compared with placebo, with least squares mean (LSM) changes (95% confidence interval [CI]) from baseline at Week 260 of 0.07 mg/dL (-0.02, 0.15) and -0.19 mg/dL (-0.25, -0.13) in the placebo and pooled ertugliflozin groups, respectively. At Week 260, placebo-adjusted LSM change (95% CI) from baseline in UA was -0.26 mg/dL (-0.36, -0.16) with ertugliflozin. Ertugliflozin was associated with reductions in UA across baseline UA quintiles compared with placebo. The incidence of the composite of gout-related outcomes was 84/2539 (3.3%) for placebo and 133/5091 (2.6%) for ertugliflozin (hazard ratio for the composite 0.76 [95% CI 0.580, 1.002]). CONCLUSIONS:Ertugliflozin was generally associated with lowering UA overall and across subgroups compared with placebo, and numerically reduced rates of gout-related outcome events.

Cardiovascular (CV) disease is the most common cause of death in Europe. Despite proven benefits, use of lipid-lowering therapy remains suboptimal. Treatment goals are often not achieved, even in patients at high risk with atherosclerotic CV disease (ASCVD).The occurrence of CV events in patients on lipid-lowering drugs is defined as “residual risk”, and can result from inadequate control of plasma lipids or blood pressure, inflammation, diabetes, and environmental hazards. Assessment of CV risk factors and vascular imaging can aid in the evaluation and management decisions for individual patients.Lifestyle measures remain the primary intervention for lowering CV risk. Where drug therapies are required to reach lipid treatment targets, their effectiveness increases when they are combined with lifestyle measures delivered through formal programs. However, lipid drug dosage and poor adherence to treatment remain major obstacles to event-free survival.This article discusses guideline-supported treatment algorithms beyond statin therapy that can help reduce residual risk in specific patient profiles while also likely resulting in substantial healthcare savings through better patient management and treatment adherence.

AIM:To assess weight loss and cardiorenal outcomes by baseline body mass index (BMI) in VERTIS CV. METHODS:Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. These post hoc analyses evaluated cardiometabolic and cardiorenal outcomes (a composite of death from CV causes or hospitalization for heart failure [HHF], CV death, HHF and an exploratory composite kidney outcome including ≥40% estimated glomerular filtration rate [eGFR] decrease) by baseline BMI, using conventional clinical categories and Cox proportional hazards models. RESULTS:In total, 8246 adults were randomized (mean age 64.4 years, diabetes duration 13.0 years, BMI 32.0 kg/m2, 61% with BMI >30 kg/m2). Absolute body weight reduction was greater with ertugliflozin versus placebo at 3 and 5 years in the overall population (p < 0.001) and across BMI subgroups. Ertugliflozin increased the proportion of participants achieving ≥5% and ≥10% body weight reduction (ertugliflozin 34.9% and 13.6%, placebo 19.4% and 4.1%; odds ratio [95% confident interval, CI], 2.21 [1.76-2.77] and 3.65 [2.39-5.57], respectively) at 5 years. No significant difference was observed in the effect of ertugliflozin on HHF across BMI subgroups (Pinteraction = 0.61). Similarly, no significant difference was observed in the effect of ertugliflozin on the kidney composite outcome across BMI subgroups (Pinteraction = 0.39). Results were similar for other CV outcomes, and safety was consistent with the known ertugliflozin profile. CONCLUSION:Weight loss was observed across baseline BMI and was sustained over 5 years of follow-up. The effects of ertugliflozin on HHF and kidney composite were consistent across baseline BMI.

11141 Background: Cancer cachexia is defined by weight loss that nutritional support cannot fully reverse, leading to worse pt outcomes. Cachexia prevalence across cancer types relies on outdated studies. This study assesses the frequency of cachexia diagnosis using ICD9/10 codes or observed weight loss consistent with real-world cachexia diagnosis and its impact on survival. Methods: Retrospective, observational, real-world analysis using deidentified adult pt data from Clinformatics Data Mart database (Aug 1, 2016-Jul 31, 2021). Pts with at least 1 of 23 cancer types were identified using diagnostic and procedure codes and classified in 1 of 3 cachexia categories: (1) diagnosed (diagnostic code identified); (2) observed (BMI decrease: >10% within 12 mo, >5% within 6 mo, or >2% with a BMI <20 kg/m2), (3) none (with no cachexia diagnostic code/observed). For observed, pts required ≥10 BMI records. Summary statistics presented as mean, median, or n (%). Survival rates compared using Cox proportional hazards model. Results: 672,665 pts were identified; 278,923 met inclusion criteria. Diagnosed + observed (subgroup) cachexia rates are shown for the 5 most prevalent cancer types (Table). Over 5 y, diagnosed cachexia rates ranged from 0.9-6.3%; observed from 60-83% (in subgroup with ≥10 BMI records). After cancer diagnosis, observed cachexia was identified on average 0-11 mo, while formal diagnosis occurred on average 11-24 mo. At least 16% of diagnosed and 31% observed pts received diagnosis or met observed criteria at or before cancer diagnosis. Average percent BMI decrease over 5 y was 22.0% ± 12.1, 17.8% ± 9.5, and 6.8% ± 5.5 for diagnosed, observed, and none, respectively. Compared with no cachexia, diagnosed and observed showed worse survival (HR 10.72 [95% CI 10.56-10.88]; HR 2.35 [95% CI 2.32-2.38]), respectively. Conclusions: Across all cancer subtypes, prevalence of observed cachexia cases documented by weight loss far exceeded cachexia prevalence based on diagnostic coding. After cancer diagnosis, pts met diagnostic criteria of cachexia within 1 y, but formal diagnosis took up to 2 y. The presence of cancer cachexia (diagnosed or observed), with or without metastatic disease, was associated with lower survival.[Table: see text]

Cardiovascular (CV) disease is the leading cause of morbidity and mortality for people with type 2 diabetes (T2D).1, 2 Accordingly, CV risk reduction is a key component of the standard of care for T2D, with professional society treatment recommendations endorsing a multifactorial approach that simultaneously targets individual atherosclerotic CV disease (ASCVD) risk factors.1, 3 These risk factors include obesity, physical inactivity, smoking, hypertension, hyperglycaemia, insulin resistance/hyperinsulinaemia and dyslipidaemia.1, 3, 4 With regards to lipids, statins are the mainstay for ASCVD risk reduction for people with T2D, but even when low-density lipoprotein cholesterol (LDL-C) levels are controlled, residual ASCVD risk remains.5, 6 Results from the REDUCE-IT trial demonstrated that icosapent ethyl (IPE) decreased the risk of ischaemic events, including CV death, in a population with established ASCVD or with diabetes plus other ASCVD risk factors, whose LDL-C levels on statin treatment were 41-100 mg/dl with elevated fasting triglyceride (TG) levels (135-499 mg/dl).7 The prevalence of these criteria in populations with T2D and ASCVD is not well documented. We conducted post hoc analyses to explore eligibility for IPE therapy, according to the REDUCE-IT criteria, in a clinical trial population with T2D and ASCVD. The present post hoc analyses were based on data from the VERTIS CV trial (NCT01986881). During VERTIS CV, participants with T2D and established ASCVD were enrolled across 34 countries.8 Full eligibility criteria for VERTIS CV were reported previously, including a requirement for the dose of any lipid-modifying medication to be stable for at least 4 weeks, and the exclusion of participants with fasting TG >600 mg/dl at screening.8 Eligibility for IPE therapy in the VERTIS CV population at baseline was assessed according to the REDUCE-IT trial inclusion criteria (receiving statin therapy, fasting TG 135-499 mg/dl and LDL-C 41-100 mg/dl).7 The characteristics of four subgroups were evaluated based on fasting lipid levels at baseline: (a) TG <135 mg/dl and LDL-C <70 mg/dl; (b) TG <135 mg/dl and LDL-C ≥70 mg/dl; (c) TG ≥135 mg/dl and LDL-C <70 mg/dl; and (d) TG ≥135 mg/dl and LDL-C ≥70 mg/dl, the LDL-C threshold being in widespread clinical use.1 These analyses were irrespective of treatment allocation (ertugliflozin or placebo) in VERTIS CV. The VERTIS CV trial population (n = 8246) had a mean age of 64.4 years, duration of T2D 13.0 years, and glycated haemoglobin 8.2%.8 Among 8208 participants (99.5%) with a fasting baseline TG measurement, median TG was 153.0 mg/dl (Q1-Q3: 111-216 mg/dl) and 4960 (60.4%) had TG ≥135 mg/dl. Among 8105 participants (98.3%) with a fasting baseline LDL-C measurement, median LDL-C was 82.0 mg/dl (Q1-Q3: 61-110 mg/dl) and 5294 (65.3%) had LDL-C ≥70 mg/dl (see Table S1 for further data). Across the four subgroups based on baseline TG and LDL-C thresholds there were few notable differences in demographic and clinical characteristics (Table 1). Most participants were receiving antihypertensive medication and/or antiplatelet or anticoagulant therapies (Table S1). Lipid-modifying medication was used by 84.5% of participants, which was a statin in most cases (81.8%), with small numbers of participants taking ezetimibe (3.6%), fibrate (8.1%), niacin (1.0%), or omega 3 fish oil (4.7%); eight participants (0.1%) were receiving IPE (Table S1). The REDUCE-IT trial inclusion criteria were met by 29.6% of the overall VERTIS CV population at baseline, with a further 30.3% not meeting the full REDUCE-IT criteria but having baseline TG >135 mg/dl (Figure 1). Results from these post hoc analyses of baseline data from the VERTIS CV trial found considerable potential for residual CV risk reduction in this clinical trial population with T2D and ASCVD who were already receiving standard of care. These data show that 29.6% of participants in VERTIS CV would be eligible for IPE therapy based on the REDUCE-IT trial inclusion criteria. At the time of randomization, which spanned December 2013 to April 2017,8 0.1% of participants in the VERTIS CV population were receiving IPE at baseline. The REDUCE-IT trial,7 with primary results published in 2019, found a reduction in CV events when IPE was added to statins in those with or without diabetes at baseline. The prespecified REDUCE-IT DIABETES analyses found a large absolute risk reduction in the first CV events and a large reduction in total CV events with IPE in the subgroup with diabetes.9 Consequently, treatment guidelines were updated to include the addition of IPE where indicated.1, 3 In the present analyses, an additional 30.3% of participants in VERTIS CV had TG >135 mg/dl without meeting the REDUCE-IT trial's criteria with respect to statin use and/or LDL-C level, suggesting further potential for lipid management in this population. In addition, we found that 18.2% of participants in VERTIS CV were not receiving statin therapy at baseline. Suboptimal use of statins has been reported elsewhere.10 Furthermore, 65.3% of participants had LDL-C ≥70 mg/dl when measured at baseline in VERTIS CV, suggesting that in the majority of the population, LDL-C management could be improved. While the addition of non-statin agents (such as ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitor) to statins may be considered to further reduce LDL-C,1, 3 the baseline data from VERTIS CV suggest that only a minority of participants were prescribed combination lipid-modifying therapy. While the REDUCE-IT trial eligibility criteria included elevated TG,7 informing the cut off for the current post hoc analyses, it should be noted that this is a means to identify risk and the benefit of IPE may not directly relate to the amount of TG lowering. With regards to other TG-lowering agents, the effect of fibrates on CV events is unclear1, 3 and research is ongoing for other promising agents (such as angiopoietin-like protein 3 inhibitors). In conclusion, based on baseline lipid profiles and treatment observed in the contemporary VERTIS CV trial, and in the context of guideline recommendations based on the REDUCE-IT trial results, these data highlight the need to scrutinize, and potentially intensify, lipid therapies in more than half of people with T2D and ASCVD. All authors contributed to the acquisition, analysis, or interpretation of data, and had full access to all of the data. All authors contributed to drafting the manuscript and revising it critically for important intellectual content. All authors approved the final version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Editorial support was provided by Kim Russell, PhD, of Engage Scientific Solutions (Horsham, UK) and was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Pfizer Inc., New York, NY, USA. Some of these data were presented at the American Diabetes Association (ADA), 82nd Scientific Sessions, June 3-7 March 2022, New Orleans, LA, USA. This analysis was sponsored by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Pfizer Inc., New York, NY, USA. JMK reports non-financial compensation: Pfizer. DLB discloses the following relationships - Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences and Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol-Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care and TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis and Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees) and Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte and Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. SD-J has led clinical trials for AstraZeneca, Boehringer Ingelheim and Novo Nordisk, Inc.; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co. Inc. and Sanofi; and has equity interests in Jana Care, Inc. and Aerami Therapeutics. DZIC has received consulting fees and/or speaking honorarium from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, Bayer, Prometic, BMS, Maze, Gilead, CSL Behring, Otsuka, Novartis, Youngene, Lexicon, and Novo Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring and Novo Nordisk. FC has received research grants from Swedish Research Council, Swedish Heart & Lung Foundation, and King Gustav V and Queen Victoria Foundation; as well as fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, Novo Nordisk, Boehringer Ingelheim, and Pfizer. DKM has received consulting fees from Afimmune, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Behring, Esperion, Lexicon, Lilly USA, Merck Sharp & Dohme, Metavant, Novo Nordisk, Pfizer Inc., GlaxoSmithKline and Sanofi US; and has received payment for expert testimony from Kirkland & Ellis on behalf of Boehringer Ingelheim. REP has received fees (directed to his institution) from AstraZeneca, Glytec, LLC, Hanmi Pharmaceutical Co., Ltd, Janssen, Lexicon Pharmaceuticals, Inc., Merck & Co. Inc., Mundipharma, Novo Nordisk, Pfizer, Poxel SA, Sanofi, Sanofi US Services, Inc., Scohia Pharma Inc. and Sun Pharmaceutical Industries. C-CL is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. NBC, RF, and JPM are employees and shareholders of Pfizer Inc. CPC has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk and Pfizer; fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan and Sanofi; as well as serving on Data and Safety Monitoring Boards for the Veteran's Administration, Applied Therapeutics and Novo Nordisk. Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. TABLE S1. CV medication use and fasting lipids at baseline. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Aim: To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study. Materials and Methods: Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. Liver steatosis and fibrosis were assessed post hoc using the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index to explore associations with cardiorenal outcomes (ertugliflozin and placebo data pooled, intention-to-treat analysis set). Cardiorenal outcomes (major adverse CV events [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and a composite kidney outcome) were stratified by baseline HSI and FIB-4 quartiles (Q1-Q4). Change in liver indices and enzymes over time were assessed (for ertugliflozin vs. placebo). Results: Amongst 8246 participants, the mean age was 64.4 years, body mass index 32.0 kg/m(2), HSI 44.0 and FIB-4 score 1.34. The hazard ratios (HRs) for MACE, HHF/CV death, CV death, and HHF by FIB-4 score quartile (Q4 vs. Q1) were 1.48 (95% confidence interval [CI] 1.25, 1.76), 2.0 (95% CI 1.63, 2.51), 1.85 (95% CI 1.45, 2.36), and 2.94 (95% CI 1.98, 4.37), respectively (P < 0.0001 for all). With HSI, the incidence of HHF was higher in Q4 versus Q1 (HR 1.52 [95% CI 1.07, 2.17]; P < 0.05). The kidney composite outcome did not differ across FIB-4 or HSI quartiles. Liver enzymes and HSI decreased over time with ertugliflozin. Conclusion: In VERTIS CV, higher FIB-4 score was associated with CV events. HSI correlated with HHF. Neither measure was associated with the composite kidney outcome. Ertugliflozin was associated with a reduction in liver enzymes and HSI.

The efficacy and safety of ertugliflozin have not been well characterized in Asian populations with type 2 diabetes (T2D) and overweight or obesity as defined by the Chinese Diabetes Society [body mass index (BMI) ≥ 24 kg/m2]. These post hoc analyses of pooled data from two randomized, double-blind, 26-week studies assessed the efficacy and safety of ertugliflozin (5 mg or 15 mg) compared with placebo in participants from Asia with T2D and baseline BMI ≥ 24 kg/m2, with inadequate glycemic control on metformin. Longitudinal analyses were used to calculate least squares (LS) mean [95

Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown. Materials and methods Among participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time-dependent approaches were used to evaluate associations between early (change from baseline to the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes. Results For the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome. Conclusions In these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods. ClinicalTrials.gov identifier NCT01986881

Purpose The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA. Methods In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term “sleep apnea syndrome.” A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA. Results Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m 2 ; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28–0.96; P = 0.04). Conclusions In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA. Trial registration. ClinicalTrials.gov identifier: NCT01986881.

Abstract Introduction We analysed data from the VERTIS CV trial that investigated the CV and kidney safety and efficacy of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin (ERTU) vs placebo (PBO) to assess the impact of metformin (MET) use at baseline (BL). These analyses are timely because the recent ESC guidelines recommendation to use SGLT2 inhibitor or GLP-1 RAs as initial glucose-lowering therapy in patients with type 2 diabetes (T2D) with or at high risk for atherosclerotic cardiovascular disease (ASCVD) has been questioned because outcome trials of these drug classes included a large proportion of patients with MET as background therapy, yet MET was not used at BL in approximately 25% of patients in each trial. Purpose These analyses determined cardiorenal endpoints of VERTIS CV according to use of BL MET to assess for evidence of treatment effect modification for ERTU by BL MET use, adjusting for the probability (propensity) of BL MET use. Methods VERTIS CV was an international, double-blind, PBO-controlled trial of 2 doses of ERTU (5 mg; 15 mg) vs PBO in patients with T2DM and ASCVD. As prospectively planned, the 2 ERTU dose groups were combined for all analyses vs PBO. Differences in risk of CV and kidney outcomes between ERTU and PBO across subgroups by BL MET use were conducted using Cox proportional hazards model along with propensity adjustment using inverse probability for treatment weighting to account for differences in patient mix between those with and without BL MET influenced by individual BL characteristics and risk factors. Treatment (categorical), BL MET use (categorical) and the interaction term between treatment and BL MET use subgroup (no or yes) were used in each model to assess effect modification by BL MET use. Hazard ratio and 95% CI are presented along with Pinteraction for evaluation of treatment effect modification by BL MET use. Results In VERTIS CV, 8246 patients were randomised to ERTU 5 mg, 15 mg or PBO. Of these, 6286 (76%) patients used MET (alone or with other glucose-lowering agents [GLA]) at BL. Differences in BL characteristics by BL MET use subgroup (no or yes) included a higher mean UACR (204.4 vs 129.8 mg/g), more patients with eGFR <60 mL/min/1.73 m2 (34.8% vs 17.9%), more patients on a single GLA (76.9% vs 18.3%), higher insulin use (67.6% vs 40.9%), lower sulphonylurea use (32.2% vs 43.8%) and a slightly longer disease duration (14.4 vs 12.5 years) in the subgroup without vs with BL MET, respectively. No significant differences in the relative risk for cardiorenal outcomes were observed with or without BL MET use (Figure; all Pinteraction values >0.05). Conclusions In VERTIS CV, there was no evidence for effect modification by BL MET use on the effects of ERTU on cardiorenal outcomes in patients with T2D and ASCVD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Among patients with type 2 diabetes (T2D) treated with statins, residual cardiovascular (CV) risk remains. Because icosapent ethyl (IPE) has been shown to decrease CV risk in patients on statin therapy, we explored potential eligibility for IPE therapy in VERTIS CV (NCT01986881) , the CV outcomes trial of ertugliflozin in which all patients had T2D and atherosclerotic CV disease (ASCVD) . We analyzed eligibility for IPE based on REDUCE-IT trial inclusion criteria (on statin, fasting triglyceride of 135 to 499 mg/dL and low-density lipoprotein cholesterol of 41 to 100 mg/dL) . Among 8246 patients randomized, the mean age was 64 years and 30% were female. At baseline, 6747 (81.8%) patients used statins, while 293 (3.6%) used ezetimibe, 389 (4.7%) used fish oil, and 8 (0.1%) used IPE. The REDUCE-IT trial inclusion criteria were met by 2444 (29.6%) patients at baseline and an additional 2500 (30.3%) did not fully meet the criteria but had baseline triglyceride level >135 mg/dL (Figure) . In conclusion, this analysis of the VERTIS CV trial population identified important opportunities to reduce residual CV risk: consideration of adding statin therapy in 18% of patients and of adding IPE based on the REDUCE-IT trial inclusion criteria or triglyceride level threshold in 60% of patients. These findings highlight the need to optimize lipid therapies in patients with T2D and ASCVD. Disclosure J.M.Kim: Other Relationship; Pfizer Inc. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc. D.L.Bhatt: Research Support; Afimmune Limited, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi USA, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Novartis AG, Sanofi. S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Sanofi. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp & Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp & Dohme Corp., Novo Nordisk. D.K.Mcguire: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, ESPERION Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. C.Liu: Employee; Merck & Co., Inc., Stock/Shareholder; Merck & Co., Inc. N.B.Cater: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding Merck Sharp & Dohme Corp.

Introduction: Given the potential link between non-alcoholic fatty liver disease and increased cardiovascular (CV) risk, the associations between markers of hepatic steatosis/fibrosis with CV and kidney outcomes were explored. Methods: These post hoc analyses were conducted on data from the VERTIS CV trial that randomized patients with type 2 diabetes (T2D) and atherosclerotic CV disease (ASCVD) to ertugliflozin 5 or 15 mg or placebo, with all randomized groups pooled for the present analyses. The presence of hepatic steatosis was estimated by hepatic steatosis index (HSI; 8 х ALT/AST + BMI + 2 if T2D + 2 if female); and for hepatic fibrosis, fibrosis-4 score (FIB-4; [age х AST]/[platelets count х √ALT]). Patients were divided into quartiles (Q1 to Q4) according to baseline for each score. CV and kidney outcomes (CV death/myocardial infarction/stroke [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and sustained ≥40% decrease in eGFR from baseline/dialysis or transplantation/kidney death) were stratified by baseline HSI and FIB-4 quartiles. Results: Among 8246 patients, the mean age was 64.4 years, mean BMI 32.0 kg/m 2 , mean HSI 44.0, and mean FIB-4 score 1.34. Event rates of MACE, HHF/CV death, CV death, and HHF increased with FIB-4 quartile ( Fig A ). The hazard ratios (HR, 95% CI) of events by FIB-4 quartile (Q4 vs Q1) were 1.48 (1.25, 1.76), 2.0 (1.63, 2.51), 1.85 (1.45, 2.36), and 2.94 (1.98, 4.37) for MACE, HHF/CV death, CV death, and HHF, respectively. The kidney composite did not differ across FIB-4 quartiles. CV and kidney outcomes did not differ across HSI quartiles, except for higher incidence of HHF in the upper HSI quartile (HR [95% CI], Q4 vs Q1: 1.52 [1.07, 2.17]) ( Fig B ). Conclusion: In VERTIS CV, baseline fibrosis scores were associated with incident CV events in patients with T2D and ASCVD, despite the upper cutoff excluding advanced fibrosis. Steatosis only correlated with HHF, and neither measure was associated with the composite kidney outcome.

Background: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes. Methods: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events. Results: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75–1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54–0.90]; P =0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44–0.90]; no HF: HR, 0.79 [95% CI, 0.54–1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30–0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58–1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min –1 ·1.73 m –2 , albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56–0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72–0.96]). Conclusions: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01986881.