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Background: In people with type 2 diabetes at high risk of cardiovascular or kidney disease, sodium-glucose co-transporter 2 (SGLT2) inhibitors consistently reduce the risk of hospitalisations for heart failure. Less is known about their effects on hospitalisation from any cause, especially in people with type 2 diabetes without atherosclerotic cardiovascular disease, which includes most of the global population of people with type 2 diabetes. We aimed to assess the effect of the SGLT2 inhibitor, dapagliflozin, on the risks of hospitalisations for any cause and for specific causes in people with type 2 diabetes with and without atherosclerotic cardiovascular disease., Methods: The DECLARE-TIMI 58 trial was a double-blind, multicentre, randomised, placebo-controlled study. People with type 2 diabetes and either risk factors for or established atherosclerotic cardiovascular disease were randomly assigned (1:1) to receive oral dapagliflozin 10 mg or placebo once daily. In these post-hoc analyses, the effects of dapagliflozin on risks of first non-elective any-cause and cause-specific hospitalisation were assessed with Cox proportional hazards regression models overall and in the subset of participants without prevalent atherosclerotic cardiovascular disease. The risk of total (first plus subsequent) non-elective hospitalisations was assessed with Lin-Wei-Ying-Yang model. Investigator-reported System Organ Class terms were used to classify cause-specific hospitalisations. The trial is registered with ClinicalTrials.gov, NCT01730534., Findings: Between April 25, 2013, and Sept 18, 2018, 17 160 people (6422 [37·4%] women, 10 738 [62·6%] men; mean age 63·9 years [SD 6·8]) were enrolled in the original trial, of whom 10186 (59·4%) had multiple risk factors for but did not have established atherosclerotic cardiovascular disease, and 6835 (39·8%) had both no evidence of atherosclerotic cardiovascular disease and low KDIGO risk. Over a median follow-up of 4·2 years (IQR 3·9-4·4), dapagliflozin was associated with a lower risk of first non-elective hospitalisation for any cause (2779 [32·4%] of 8582 people in the dapagliflozin group vs 3036 [35·4%] of 8578 people in the placebo group; hazard ratio [HR] 0·89 [95% CI 0·85-0·94]) and total (first plus subsequent) non-elective hospitalisations for any cause (risk ratio 0·92 [95% CI 0·86-0·97]). The association between dapagliflozin use and the risk of first non-elective hospitalisation for any cause was consistent in subgroups of participants with (HR 0·92 [95% CI 0·85-0·99] and without (0·87 [0·81-0·94]) atherosclerotic cardiovascular disease at baseline (p interaction=0·31). Compared with the placebo group, the dapagliflozin group had lower risk of first hospitalisations due to cardiac disorders (HR 0·91 [95% CI 0·84-1·00]), metabolism and nutrition disorders (0·73 [0·60-0·89]), renal and urinary disorders (0·61 [0·49-0·77]), and due to any other cause excluding these three causes (0·90 [0·85-0·96]). Treatment with dapagliflozin was also associated with a lower risk of hospitalisations due to musculoskeletal and connective tissue disorders (HR 0·81 [0·67-0·99]) and infections and infastations (HR 0·86 [0·78-0·96])., Interpretation: Dapagliflozin reduced the risk of first and total non-elective hospitalisations for any cause in people with type 2 diabetes, regardless of the presence of atherosclerotic cardiovascular disease, including hospitalisations not directly attributed to cardiac, kidney, or metabolic causes. These findings might have implications on health-related quality of life for people with type 2 diabetes and on health-care costs attributable this condition., Funding: AstraZeneca., Competing Interests: Declaration of interests MS reports travel support from AstraZeneca and Novo Nordisk paid to Hadassah Medical Center, Jerusalem, Israel. SDW reports grants from AstraZeneca, Bristol-Myers Squibb, Sanofi, and Amgen; grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen; grants and consulting fees from Merck; and personal fees from Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, St Jude Medical, Xoma, Servier, AstraZeneca, and Bristol-Myers Squibb. SDW's spouse is employed by Merck. IR reports being a member of an advisory board for AstraZeneca, Eli Lilly, Novo Nordisk. Consultancy fees AstraZeneca, Insuline Medical, Concenter BioPharma, and Pluristem; and Speaker's Bureau from AstraZeneca, Eli Lilly and Company, Novo Nordisk, and Sanofi. ELG and SAM are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical, The Medicines Company, and Zora Biosciences. AR and IY report hourly payments from AstraZeneca paid to Hadassah Medical Center and hourly payments from Novo Nordisk. TAZ reports research grants from the Austrian Science Funds and the German Research Foundation, honoraria for serving on advisory boards from Boehringer Ingelheim; personal fees from AstraZeneca, Boehringer Ingelheim, and Sun Pharmaceutical Industries; and educational grants from Eli Lilly. MF, PAJ, IAMG-N, and AML are employees at BioPharmaceuticals Research & Development, AstraZeneca, Gothenburg, Sweden. LAL reports research funding from Astra Zeneca and Lexicon; has provided continuing medical education on behalf of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, and Servier; and has acted as an advisor to AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, Pfizer, and Sanofi. DLB reports being a member of an advisory board for from 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; is a member of the Board of Directors for AngioWave (with stock options), Boston VA Research Institute, Bristol-Myers Squibb (holds stock), DRS.LINQ (with stock options), High Enroll (holds stock), Society of Cardiovascular Patient Care, and TobeSoft; is the Inaugural Chair of the American Heart Association Quality Oversight Committee; consultantcy fees from Broadview Ventures; is a member of Data Monitoring Committees for 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, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute; Rutgers University; Honoraria from the American College of Cardiology, Arnold and Porter law firm, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute), Belvoir Publications, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD, Wiley; is the Deputy Editor of Clinical Cardiology; is the Chair of the NCDR-ACTION Registry Steering Committee; is the Chair of the VA CART Research and Publications Committee; is named on the patent for sotagliflozin, which is assigned to Brigham and Women's Hospital who assigned to Lexicon (neither DLB nor Brigham and Women's Hospital receive any income from this patent); research funding from 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 from Elsevier; is a site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; is a trustee of the American College of Cardiology; and has done unfunded research for FlowCo and Takeda. DKM reports research support for Clinical Trials Leadership from Boehringer Ingelheim, Sanofi, Merck, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, and CSL Behring; and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck, Novo Nordisk, Applied Therapeutics, Metavant, Sanofi, Altimmune and Intercept Pharma, CSL Behring, Bayer, and GlaxoSmithKline. JPHW reports consultancy and speaking engagements contracted via the University of Liverpool, Liverpool, UK (no personal payment) from Alnylam, AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Eli Lilly, Napp, Novo Nordisk, Mundipharma, Pfizer, Rhythm Pharmaceuticals, Saniona, and Ysopia; grants paid to the University of Liverpool from AstraZeneca and Novo Nordisk; and honoraria and lecture fees (personal) from AstraZeneca, Boehringer Ingelheim, Merck, Napp, Novo Nordisk, Mundipharma, Sanofi, and Takeda. AC reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Boehringer Ingelheim, Eli Lilly, Sanofi, Pfizer, and Medial Early-Sign. MSS reports grants and consulting fees from Amgen, AstraZeneca, Intarcia, Janssen Research & Development, Medicines Company, MedImmune, Merck, and Novartis; consulting fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis; and grants from Bayer, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; MSS is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Roche, and Zora Biosciences. OM reports being a member of an advisory board for Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, AstraZeneca; research grant support paid to Hadassah Hebrew University Hospital from Novo Nordisk, AstraZeneca; and Speaker's Bureau from AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, and Boehringer Ingelheim., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk., Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes., Results: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001)., Conclusions: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease., (© 2022 by the American Diabetes Association.)

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk., Research Design and Methods: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m 2 , end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death., Results: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g ( P < 0.0125, P interaction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups ( P < 0.05, P interaction = 0.480)., Conclusions: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease., (© 2021 by the American Diabetes Association.)

Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown., Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR)., Design, Setting, and Participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018., Interventions: Dapagliflozin vs placebo., Main Outcomes and Measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF., Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher., Conclusions and Relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria., Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.

Aims: Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels., Methods and Results: This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026)., Conclusion: Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels., (© 2020 European Society of Cardiology.)

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function., Methods: In DECLARE-TIMI 58, patients with type 2 diabetes, HbA 1c 6·5-12·0% (47·5-113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate [eGFR] to less than 60 mL/min per 1·73m 2 , end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min per 1·73 m 2 ), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, subgroup analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, number NCT01730534., Findings: The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m 2 , 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m 2 , and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m 2 at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio [HR] 0·76, 95% CI 0·67-0.87; p<0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p<0·0001). We identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73 m 2 (120 [1·4% vs 221 [2·6%]; HR 0·54 [95% CI 0·43-0·67]; p<0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11 [0·1%] vs 27 [0·3%]; HR 0·41 [95% CI 0·20-0·82]; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus placebo across various prespecified subgroups, including those defined by baseline eGFR (cardiorenal outcome p interaction =0·97; renal-specific outcome p interaction =0·87) and the presence or absence of established atherosclerotic cardiovascular disease (cardiorenal outcome p interaction =0·67; renal-specific outcome p interaction =0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the placebo group. The mean change equalised by 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with placebo., Interpretation: Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function., Funding: AstraZeneca., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy., Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest., Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72-0.99; P=0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88-1.13; P=0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81-1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65-1.00; P=0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72-1.00; P=0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010)., Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown., Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality., Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016)., Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Background: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined., Methods: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease., Results: In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001)., Conclusions: In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.

Background: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined., Methods: We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m 2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause., Results: We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001)., Conclusions: In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

Background: The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined., Methods: We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function., Findings: We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83-0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80-0·93]) and not in those without (1·00 [0·87-1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71-0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48-0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline., Interpretation: SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Patients with type 2 diabetes mellitus have an increased risk for the development of cardiac and other vascular events, heart failure (HF), and decline in renal function. After several large cardiovascular outcome trials with mostly neutral results, 2 studies of the sodium-glucose co-transporter 2 inhibitors (SGLT2is), empagliflozin and canagliflozin, reported favorable effects on the primary endpoint, a composite of myocardial infarction, stroke, and cardiovascular death. In addition, reductions of hospitalizations for HF were observed; in the case of empagliflozin, reductions in both cardiovascular mortality and total mortality occurred. These findings prompted several analyses to elucidate the mechanisms of action of SGLT2is and have initiated several large clinical trials in patients with HF without type 2 diabetes mellitus. This review summarizes known and possible mechanisms that contribute to these salutary effects of SGLT2is. Also discussed is the interplay between cardiac and renal function, as well as safety issues associated with this class of drugs., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)