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Background: There are few contemporary data on outcomes, costs, and treatment following a hospitalization for heart failure (hHF) in epidemiologically representative cohorts., Objectives: This study sought to describe rehospitalizations, hospitalization costs, use of guideline-directed medical therapy (GDMT) (renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), and mortality after hHF., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational, longitudinal cohort study using data from electronic health records or claims data sources in Japan, Sweden, the United Kingdom, and the United States. Adults with a first hHF discharge between 2018 and 2022 were included. The 1-year event rates per 100 patient-years (ERs) for death and rehospitalizations (with a primary diagnosis of heart failure (HF), chronic kidney disease [CKD], myocardial infarction, stroke, or peripheral artery disease) were calculated. Hospital health care costs were cumulatively summarized. Cumulative GDMT use was assessed using Kaplan-Meier estimates., Results: Of 263,525 patients, 28% died within the first year post-hHF (ER: 28.4 [95% CI: 27.0-29.9]). Rehospitalizations were mainly driven by HF (ER: 13.6 [95% CI: 9.8-17.4]) and CKD (ER: 4.5 [95% CI: 3.6-5.3]), whereas the ERs for myocardial infarction, stroke, and peripheral artery disease were lower. Health care costs were predominantly driven by HF and CKD. Between 2020 and 2022, use of renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists changed little, whereas uptake of sodium-glucose cotransporter-2 inhibitors increased 2- to 7-fold., Conclusions: Incident post-hHF rehospitalization risks and costs were high, and GDMT use changed little in the year following discharge, highlighting the need to consider earlier and greater implementation of GDMT to manage risks and reduce costs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Cleland was supported by a British Heart Foundation Centre of Research Excellence (grant number RE/18/6/34217). Dr Bozkurt has received consulting, advisory or research support from Abbott Vascular, Amgen, AstraZeneca, Baxter Healthcare Corporation, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Liva Nova, Relypsa, Renovacor, Roche, Sanofi, scPharmaceuticals, and Vifor. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Edwards Lifesciences, Medtronic, Novartis, Pharmacosmos, Roche, Laboratoires Servier, and Vifor. Drs Adamsson Eryd, Bodegård, Khordoc, and Zhang are employees of AstraZeneca. Dr Cleland has received grants and/or personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Bristol Myer Squibb, Idorsia, Johnson & Johnson, Medtronic, MyoKardia, NI Medical, Novartis, Pharmacosmos, Pharma Nord, Respicardia, Laboratoires Servier, Torrent Pharmaceuticals, Vifor, and VisCardia. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Vardeny has received personal or institutional research support from AstraZeneca. Dr Lund has received grant support, lecture fees, and/or consulting fees from Abbott Laboratories, Alleviant, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Edwards Lifesciences, Lexicon Pharmaceuticals, Medscape, Merck Sharp & Dohme, MyoKardia, Novartis, OrionPharma, Pharmacosmos, Sanofi, and Vifor. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Guidelines recommend early initiation of multiple guideline-directed medical therapies (GDMTs) to reduce mortality/rehospitalization in patients with heart failure and reduced ejection fraction. Understanding GDMT use is critical to improving clinical practice., Objectives: This study sought to describe GDMT use in Japan, Sweden, and the United States in contemporary real-world settings., Methods: EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational cohort study using routine-care databases. Patients initiating any GDMT within 12 months of a hospitalization for heart failure (hHF) discharge were included. Dapagliflozin (the only sodium-glucose cotransporter-2 inhibitor approved at study onset), sacubitril/valsartan, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were considered separately. Doses and discontinuation were assessed in the 12 months following initiation. Target dose was defined as ≥100% of the guideline-recommended dose., Results: Overall, 266,589 patients were included. Mean times from hHF to GDMT initiation were longer for novel GDMTs (dapagliflozin or sacubitril/valsartan) than for other GDMTs: 39 and 44 vs 12 to 13 days (Japan), 44 and 33 vs 22 to 31 days (Sweden), and 33 and 19 vs 18 to 24 days (United States). Pooled across countries, proportions of patients who discontinued therapy (not including switches from ACE inhibitor or ARB to sacubitril/valsartan) within 12 months were 23.5% (dapagliflozin), 26.4% (sacubitril/valsartan), 38.4% (ACE inhibitors), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs). Corresponding target dose achievements were 75.7%, 28.2%, 20.1%, 6.7%, 7.2%, and 5.1%, respectively., Conclusions: Initiation of novel GDMTs is delayed compared with other GDMTs. Few patients received target doses of GDMTs requiring uptitration. Persistence was higher for dapagliflozin than other GDMTs., Competing Interests: Funding Support and Author Disclosures EVOLUTION HF is funded by AstraZeneca. Dr Savarese has received grants from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Merck, Novartis, Pharmacosmos, and Vifor; and personal fees from AstraZeneca, Cytokinetics, Medtronic, Pharmacosmos, Roche, Servier, and Vifor. Dr Vardeny has received personal or institutional research support from AstraZeneca. Drs Adamsson Eryd and Bodegård are employees of AstraZeneca. Dr Lund has received grant support, lecture fees, and consulting fees from AstraZeneca. Dr Thuresson is an employee of Statisticon, which has received funding from AstraZeneca. Dr Bozkurt has received consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, scPharmaceuticals, Baxter, Sanofi, Relypsa, Vifor, Roche, and Boehringer Ingelheim; has served on the steering committees of Relypsa and Renovacor; has served on a Clinical Event Committee for Abbott Pharmaceuticals; and has served on the Data Safety Monitoring Board for LivaNova Pharmaceuticals. Dr Kishi has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Randomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics., Methods: De-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects., Results: Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58-0.75; p < 0.001), ACD (HR: 0.52, 95%CI 0.45-0.60; p < 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53-0.68; p < 0.001), MI (HR: 0.85, 95%CI 0.78-0.92; p < 0.001), and stroke (HR: 0.78, 95%CI 0.72-0.85; p < 0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region., Conclusions: This CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically diverse population, and across multiple subgroups. Trial registration NCT02993614., (© 2021. The Author(s).)

This study of real-world data from the Maccabi database in Israel compared the risk of heart failure hospitalization (HHF) or death in patients with type 2 diabetes (T2D) initiating sodium-glucose cotransporter-2 (SGLT2) inhibitors versus other glucose-lowering drugs (OGLDs) according to baseline left ventricular (LV) ejection fraction (EF). After propensity-matching patients by baseline EF there were 10 614 episodes of treatment initiation; 57% had diabetes for >10 years, the mean glycated haemoglobin level was 66 mmol/mol (8.2%), ∼43% had cardiovascular disease, ∼7% had heart failure and ∼ 20% had chronic kidney disease. A total of 2876 patients (∼9%) had reduced EF (<50%). Over a mean follow-up of 1.5 years there were 371 HHFs or deaths, 88 (23.7%) in patients with reduced EF. Initiation of SGLT2 inhibitors versus OGLDs was associated with lower risk of HHF or death overall (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.46-0.70]; P < 0.001) and in patients with both reduced EF (HR 0.61, 95% CI 0.40-0.93) and preserved EF (HR 0.55, 95% CI 0.43-0.70), with no significant heterogeneity (P interaction = 0.72). Our findings from real-world clinical practice show that the lower risk of HHF and death associated with use of SGLT2 inhibitors versus OGLDs is consistent in T2D patients with both reduced and preserved EF., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To examine heart failure (HF) and chronic kidney disease (CKD) risks reduction associated with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared to other glucose-lowering drugs (oGLD) in the early stage of type 2 diabetes patients without established cardiovascular or renal diseases (CVRD-free T2D)., Materials and Methods: We performed an observational cohort study using a Japanese hospital claims registry, Medical Data Vision. CVRD-free T2D patients were identified between 1 April 2014 and 30 September 2018. SGLT-2i and oGLD new users (and dipeptidyl peptidase 4 inhibitors [DPP-4i] separately) were subjected to 1:1 propensity-score matching analysis. Hazard ratios (HRs) of cardiorenal disease (HF and/or CKD), HF, CKD, stroke, myocardial infarction (MI), and all-cause mortality, were estimated using unadjusted Cox regression., Results: A total of 108 362 CVRD-free patients including 54 181 SGLT-2i and 54 181 oGLD users were matched. Baseline characteristics were well balanced (mean age 59.1 years, 63% male, and follow-up 1.50 years [162 970 patient-years]). Compared to oGLD group, SGLT-2i group had lower risk of cardiorenal disease, HF, CKD, stroke, and all-cause mortality with HRs (95% confidence intervals) 0.55 (0.49-0.61), 0.73 (0.61-0.87), 0.45 (0.39-0.52), 0.69 (0.59-0.81), and 0.52 (0.46-0.58), respectively, while no difference in MI. These were consistent in 1:1 propensity-score matching analysis between SGLT-2i and DPP-4i users (n = 17 232 in each group)., Conclusions: In Japanese CVRD-free T2D patients, SGLT-2i initiation was associated with lower risk of cardiorenal diseases, stroke, and all-cause mortality compared to oGLD, suggesting preventive effect of SGLT-2i treatment in the early stage of T2D patients without CVRD manifestation., (© 2021 John Wiley & Sons Ltd.)

There are limited data on cardiovascular efficacy and safety of type 2 diabetes therapies in Japan, where treatments are characterized by lower metformin use and higher dipeptidyl peptidase-4 inhibitor (DPP4i) use versus other countries. We investigated the cardiovascular outcomes in Japanese patients with type 2 diabetes initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) matched 1:1 to patients initiating other glucose-lowering drugs (33,890 patients/group) or DPP4i (9,876 patients/group). SGLT2i initiation was associated with lower risks (hazard ratio of in-hospital death [death] 0.56, 95% confidence interval [CI] 0.47-0.67; hospitalization for heart failure 0.75, 95% CI 0.64-0.89; composite of hospitalization for heart failure or death 0.65, 95% CI 0.58-0.74 and stroke 0.66, 95% CI 0.52-0.84 versus other glucose-lowering drugs and lower risks of death 0.52, 95% CI 0.36-0.73) and composite of hospitalization for heart failure or death (0.65, 95% CI 0.51-0.83) versus DPP4i. In conclusion, SGLT2i initiators had lower risks of cardiovascular events versus other glucose-lowering drug initiators and, uniquely, versus DPP4i initiators in Japanese real-world practice., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims: We compared the new use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus dipeptidyl peptidase-4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic kidney disease (CKD), in patients with type 2 diabetes without a history of prevalent cardiovascular and renal disease, defined as cardiovascular and renal disease (CVRD) free, managed in routine clinical practice., Materials and Methods: In this observational cohort study, patients were identified from electronic health records from England, Germany, Japan, Norway, South Korea and Sweden, during 2012-2018. In total, 1 006 577 CVRD-free new users of SGLT2i or DPP4i were propensity score matched 1:1. Unadjusted Cox regression was used to estimate hazard ratios (HRs) for outcomes: cardiorenal disease, HF, CKD, stroke, myocardial infarction (MI), cardiovascular and all-cause mortality., Results: Baseline characteristics were well balanced between the treatment groups (n = 105 130 in each group) with total follow-up of 187 955 patient years. Patients had a mean age of 56 years, 43% were women and they were indexed between 2013 and 2018. The most commonly used agents were dapagliflozin (91.7% of exposure time) and sitagliptin/linagliptin (55.0%), in the SGLT2i and DPP4i, groups, respectively. SGLT2i was associated with lower risk of cardiorenal disease, HF, CKD, all-cause and cardiovascular mortality; HR (95% confidence interval), 0.56 (0.42-0.74), 0.71 (0.59-0.86), 0.44 (0.28-0.69), 0.67 (0.59-0.77), and 0.61 (0.44-0.85), respectively. No differences were observed for stroke [0.87 (0.69-1.09)] and MI [0.94 (0.80-1.11)]., Conclusion: In this multinational observational study, SGLT2i was associated with a lower risk of HF and CKD versus DPP4i in patients with type 2 diabetes otherwise free from both cardiovascular and renal disease., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: The economic burden of diabetes is driven by the management of vascular complications. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated reductions in cardiovascular and renal complications, including hospitalization for heart failure (HHF) and renal disease progression, in randomized clinical trials. The objective of this study was to evaluate the cost-effectiveness of the SGLT2i class versus standard of care in type 2 diabetes mellitus (T2DM), using evidence from both clinical trial and real-world studies., Methods: An established T2DM model was adapted to use contemporary outcomes evidence from real-world studies and randomized controlled trial evaluations of SGLT2i, and extrapolated over a lifetime for HHF, myocardial infarction, stroke, end-stage renal disease and all-cause mortality. The economic analysis considered adults with T2DM, with and without established cardiovascular disease, and was conducted over a lifetime from the perspective of the health care payer in the United Kingdom, United States and China, discounted at country-specific rates., Results: SGLT2i were consistently associated with increased treatment costs, reduced complication costs and gains in quality-adjusted life years driven by differences in projected life expectancy, cardiovascular and microvascular morbidity and weight loss. SGLT2i were estimated to be cost-saving or cost-effective at relevant thresholds for the overall population in the United Kingdom, United States and China, with cost-effectiveness being the greatest in higher risk subgroups., Conclusions: The findings highlight the need to take into account cost savings from reducing common, morbid and preventable T2DM complications when considering the cost of diabetes medications., (© 2020 John Wiley & Sons Ltd.)

Background: Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings., Methods: In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis., Findings: Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12·2), 170 335 (44·1%) of 386 248 were women, and 111 933 (30·1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0·69, 95% CI 0·61-0·77; p<0·0001), all-cause death (0·59, 0·52-0·67; p<0·0001), and the composite of hospitalisation for heart failure or all-cause death (0·64, 0·57-0·72; p<0·0001). Risks of myocardial infarction (HR 0·88, 0·80-0·98; p=0·020) and stroke (0·85 0·77-0·93; p=0·0004) were significantly but modestly lower with SGLT2 inhibitors versus DPP-4 inhibitors., Interpretation: In this large, international, observational study, initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with lower risks of heart failure, death, myocardial infarction, and stroke, providing further support for the cardiovascular benefits associated with use of SGLT2 inhibitors in patients with type 2 diabetes., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Cardiovascular and kidney outcome trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors slow progression of chronic kidney disease in patients with type 2 diabetes with or without chronic kidney disease. The aim of this study was to assess whether these benefits extend to patients with type 2 diabetes treated in routine clinical practice., Methods: CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records, and national registries in Israel, Italy, Japan, Taiwan, and the UK. Propensity scores for SGLT2 inhibitor initiation were developed in each country, with 1:1 matching with initiators of other glucose-lowering drugs. Propensity score included (in addition to other clinical and demographic variables) baseline eGFR and eGFR slope before SGLT2 inhibitor or other glucose-lowering drug initiation. The main outcome measure was rate of eGFR decline (slope) calculated with a linear mixed regression model. Differences in eGFR slope between SGLT2 inhibitors and other glucose-lowering drugs were calculated and pooled. We also assessed a composite outcome of 50% eGFR decline or end-stage kidney disease., Findings: After propensity matching, there were 35 561 episodes of treatment initiation in each group, from 65 231 individual patients. Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, tofogliflozin, and luseogliflozin accounted for 57·9%, 34·1%, 5·7%, 1·4%, 0·5%, and 0·4% of SGLT2 inhibitor initiation episodes, respectively. At baseline, 29 363 (41·3%) of 71 122 initiations were in women, mean age was 61·3 years, mean HbA 1c was 72 mmol/mol (8·71%), and mean eGFR was 90·7 mL/min per 1·73 m 2 . During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs other glucose-lowering drugs 1·53 mL/min per 1·73 m 2 per year, 95% CI 1·34-1·72, p<0·0001). During a mean follow-up of 14·9 months, 351 composite kidney outcomes occurred: 114 (3·0 events per 10 000 patient-years) among initiators of SGLT2 inhibitors and 237 (6·3 events per 10 000 patient-years) among initiators of other glucose-lowering drugs (hazard ratio 0·49, 95% CI 0·35-0·67; p<0·0001). These findings were consistent across countries (p heterogeneity 0·10) and prespecified subgroups., Interpretation: In this large, international, real-world study of patients with type 2 diabetes, initiation of SGLT2 inhibitor therapy was associated with a slower rate of kidney function decline and lower risk of major kidney events compared with initiation of other glucose-lowering drugs. These data suggest that the benefits of SGLT2 inhibitors on kidney function identified in clinical trials seem to be largely generalisable to clinical practice., Funding: AstraZeneca., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes in patients with type 2 diabetes through distinct mechanisms. However, evidence on clinical outcomes in patients treated with both GLP-1 RA and SGLT2i is lacking. We aim to provide insight into the effects of open-label SGLT2i use in parallel with or shortly after once-weekly GLP-1 RA exenatide (EQW) on cardiorenal outcomes., Methods: In the EXSCEL cardiovascular outcomes trial EQW arm, SGLT2i drop-in occurred in 8.7% of participants. These EQW+SGLT2i users were propensity-matched to: (1) placebo-arm participants not taking SGLT2i (n = 572 per group); and to (2) EQW-arm participants not taking SGLT2i (n = 575), based on their last measured characteristics before SGLT2i initiation, and equivalent study visit in comparator groups. Time-to-first major adverse cardiovascular event (MACE) and all-cause mortality (ACM) were compared using Cox regression analyses. eGFR slopes were quantified using mixed model repeated measurement analyses., Results: In adjusted analyses, the risk for MACE with combination EQW+SGLT2i use was numerically lower compared with both placebo (adjusted hazard ratio 0.68, 95% CI 0.39-1.17) and EQW alone (0.85, 0.48-1.49). Risk of ACM was nominally significantly reduced compared with placebo (0.38, 0.16-0.90) and compared with EQW (0.41, 0.17-0.95). Combination EQW+SGLT2i use also nominally significantly improved estimated eGFR slope compared with placebo (+ 1.94, 95% CI 0.94-2.94 mL/min/1.73 m 2 /year) and EQW alone (+ 2.38, 1.40-3.35 mL/min/1.73 m 2 /year)., Conclusions: This post hoc analysis supports the hypothesis that combinatorial EQW and SGLT2i therapy may provide benefit on cardiovascular outcomes and mortality. Trial registration Clinicaltrials.gov, Identifying number: NCT01144338, Date of registration: June 15, 2010.

Aims: Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium-glucose cotransporter-2 inhibitors (SGLT-2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT-2i CVOTs of a general T2D population., Methods: T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, VERTIS-CV) by the total T2D population., Results: In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV-preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE-TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2-, 3- and 4-fold higher compared to the CANVAS (34%), EMPA-REG OUTCOME (21%) and VERTIS-CV (17%) trials, respectively., Conclusions: In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE-TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: The sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole., Research Design and Methods: SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers ( n = 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2i at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis., Results: In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49-1.28]), as did dapagliflozin users (0.55 [0.26-1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27-0.95]; dapagliflozin: 0.66 [0.25-1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87-2.69] mL/min/1.73 m 2 per year) and for dapagliflozin users (+2.28 [1.01-3.54] mL/min/1.73 m 2 per year)., Conclusions: This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline., (© 2018 by the American Diabetes Association.)

The multinational, observational CVD-REAL study recently showed that initiation of sodium-glucose co-transporter-2 inhibitors (SGLT-2i) was associated with significantly lower rates of death and heart failure vs other glucose-lowering drugs (oGLDs). This sub-analysis of the CVD-REAL study sought to determine the association between initiation of SGLT-2i vs oGLDs and rates of myocardial infarction (MI) and stroke. Medical records, claims and national registers from the USA, Sweden, Norway and Denmark were used to identify patients with T2D who newly initiated treatment with SGLT-2i (canagliflozin, dapagliflozin or empagliflozin) or oGLDs. A non-parsimonious propensity score was developed within each country to predict initiation of SGLT-2i, and patients were matched 1:1 in the treatment groups. Pooled hazard ratios (HRs) and 95% CIs were generated using Cox regression models. Overall, 205 160 patients were included. In the intent-to-treat analysis, over 188 551 and 188 678 person-years of follow-up (MI and stroke, respectively), there were 1077 MI and 968 stroke events. Initiation of SGLT-2i vs oGLD was associated with a modestly lower risk of MI and stroke (MI: HR, 0.85; 95%CI, 0.72-1.00; P = .05; Stroke: HR, 0.83; 95% CI, 0.71-0.97; P = .02). These findings complement the results of the cardiovascular outcomes trials, and offer additional reassurance with regard to the cardiovascular effects of SGLT-2i, specifically as it relates to ischaemic events., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe., Objectives: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions., Methods: New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis., Results: After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease., Conclusions: In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown., Objectives: This study sought to determine the association between initiation of SGLT-2i therapy and HF or death in patients with and without CVD., Methods: The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes were identified. Patients prescribed an SGLT-2i or other glucose-lowering drugs (GLDs) were matched based on a propensity score for initiation of an SGLT-2i. Hazard ratios (HRs) for the risk of death, HF, and HF or death in patients with and without established CVD were estimated for each country and pooled., Results: After propensity score matching, 153,078 patients were included in each group. At baseline, 13% had established CVD. Compared with therapy using other GLDs, initiation of an SGLT-2i was associated with lower risk of death in patients with and without CVD (HR: 0.56; 95% confidence interval [CI]: 0.44 to 0.70; and HR: 0.56; 95% CI: 0.50 to 0.63, respectively). There were also associations between SGLT-2i and lower risk of HF (HR: 0.72; 95% CI: 0.63 to 0.82; and HR: 0.61; 95% CI: 0.48 to 0.78, respectively) and the composite of HF or death (HR: 0.63; 95% CI: 0.57 to 0.70; and HR: 0.56; 95% CI: 0.50 to 0.62, respectively) observed in patients with and without established CVD., Conclusions: In this large, multinational, observational study, initiation of SGLT-2i was associated with lower risk of death and HF regardless of pre-existing CVD. Ongoing clinical trials will provide further evidence regarding the benefit of SGLT-2i in patients without established CVD. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile., Methods: CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia., Findings: Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0·9 (SD 4·1) years (80 669 patient-years) and mean age of 61 (12·0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0·53 [95% CI 0·40-0·71]), major adverse cardiovascular events (0·78 [0·69-0·87]), and hospital events for heart failure (0·70 [0·61-0·81]; p<0·0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0·76 [0·65-0·90]; p=0·001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0·60 [0·42-0·85] vs 0·55 [0·34-0·90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0·70 (0·59-0·83) versus 0·90 (0·76-1·07) in the group without., Interpretation: In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk., Funding: AstraZeneca., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class., Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany., Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51-0.73; P <0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41-0.57; P <0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48-0.60; P <0.001) with no significant heterogeneity by country., Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614., (© 2017 The Authors.)