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Aim: To assess the association between urinary albumin-to-creatinine ratio (UACR) categories within the normal range with mortality and adverse cardiovascular outcomes., Materials and Methods: PubMed and Embase were systematically searched for real-world evidence studies. Studies were manually evaluated according to predefined eligibility criteria. We included prospective and retrospective cohort studies of the association between UACR categories <30 mg/g and cardiovascular outcomes or mortality. Published information regarding study design, participants, UACR categorization, statistical methods, and results was manually collected. Two UACR categorization approaches were defined: a two-category (UACR <10 mg/g vs. 10-30 mg/g) and a three-category division (UACR <5 mg/g vs. 5-10 and 10-30 mg/g). A random effects meta-analysis was performed on studies eligible for the meta-analysis., Results: In total, 22 manuscripts were identified for the systematic review, 15 of which were eligible for the meta-analysis. The results suggest an association between elevated UACR within the normal to mildly increased range and higher risks of all-cause mortality, cardiovascular death, and coronary heart disease, particularly in the range of 10-30 mg/g. Compared with UACR <10 mg/g, the hazard ratio [HR (95% confidence interval, CI)] for UACR between 10 and 30 mg/g was 1.41 (1.15, 1.74) for all-cause mortality and 1.56 (1.23, 1.98) for coronary heart disease. Compared with UACR <5 mg/g, the risk of cardiovascular mortality for UACR between 10 and 30 mg/g was more than twofold [HR (95% CI): 2.12 (1.61, 2.80)]. Intermediate UACR (5-10 mg/g) was also associated with a higher risk of all-cause mortality [HR (95% CI): 1.14 (1.05, 1.24)] and cardiovascular mortality [HR (95% CI): 1.50 (1.14, 1.99)]., Conclusions: We propose considering higher UACR within the normoalbuminuric range as a prognostic factor for cardiovascular morbidity and mortality. Our findings underscore the clinical significance of even mild increases in albuminuria., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Contemporary guidelines recommend the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) independently of glycemic control in patients with type 2 diabetes and those with kidney disease, with heart failure, or at high risk of cardiovascular disease. Using a large Israeli database, we assessed whether long-term use of SGLT2is versus dipeptidyl peptidase 4 inhibitors (DPP4is) is associated with kidney benefits in patients with type 2 diabetes overall and in those without evidence of cardiovascular or kidney disease., Methods: Patients with type 2 diabetes who initiated SGLT2is or DPP4is between 2015 and 2021 were propensity score-matched (1:1) according to 90 parameters. The kidney-specific composite outcome included confirmed ≥40% decline in eGFR or kidney failure. The kidney-or-death outcome included also all-cause mortality. Risks of outcomes were assessed using Cox proportional hazard regression models. The between-group difference in eGFR slope was also assessed. Analyses were repeated in patients' subgroup lacking evidence of cardiovascular or kidney disease., Results: Overall, 19,648 propensity score-matched patients were included; 10,467 (53%) did not have evidence of cardiovascular or kidney disease. Median follow-up was 38 months (interquartile range, 22-55). The composite kidney-specific outcome occurred at an event rate of 6.9 versus 9.5 events per 1000 patient-years with SGLT2i versus DPP4i. The respective event rates of the kidney-or-death outcome were 17.7 versus 22.1. Compared with DPP4is, initiation of SGLT2is was associated with a lower risk for the kidney-specific (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.61 to 0.86; P < 0.001) and kidney-or-death (HR, 0.80; 95% CI, 0.71 to 0.89; P < 0.001) outcomes. The respective HRs (95% CI) in those lacking evidence of cardiovascular or kidney disease were 0.67 (0.44 to 1.02) and 0.77 (0.61 to 0.97). Initiation of SGLT2is versus DPP4is was associated with mitigation of the eGFR slope overall and in those lacking evidence of cardiovascular or kidney disease (mean between-group differences 0.49 [95% CI, 0.35 to 0.62] and 0.48 [95% CI, 0.32 to 0.64] ml/min per 1.73 m 2 per year, respectively)., Conclusions: Long-term use of SGLT2is versus DPP4is in a real-world setting was associated with mitigation of eGFR loss in patients with type 2 diabetes, even in those lacking evidence of cardiovascular or kidney disease at baseline., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of American Society of Nephrology.)

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: Cardiometabolic disorders contribute to morbidity and mortality in people with severe mental illnesses (SMI), yet lifestyle-intervention efficacy in patients with SMI is unclear. Israel's unique mental-health rehabilitation hostels (MHRHs) provide housing to subjects with SMI. We tested how multi-component lifestyle intervention affects cardiometabolic risk-factors in at-risk SMI populations residing in MHRHs., Methods: In a prospective, cluster-randomized, controlled study, six MHRHs, paired by residents' functioning level, were randomized to lifestyle intervention (nutrition education, physical education), or usual care. Subjects recruited included those with ≥1 of: BMI > 25 kg/m 2 ; plasma triglycerides ≥150 mg/dL; HbA1c ≥ 5.7%; fasting plasma glucose ≥ 100 mg/dL and plasma HDL < 40 (men) / 50 (women) mg/dL. Primary outcome was BMI change after 15 months; other outcomes were plasma lipids levels and glycemic control. Low cooperation in one MHRH pair led to their exclusion, the others were assigned to intervention or control., Results: Eighty residents were enrolled to intervention groups and 74 to control. Compared to baseline, intervention-arm participants experienced improvements in BMI (-0.83 kg/m 2 [-1.36, -0.29] 95%CI ), triglycerides (-30.60 mg/dL [-49.39, -11.82] 95%CI ) and LDL (-15.51 mg/dL [-24.53, -6.50] 95%CI ) (all P ≤ 0.003). BMI improvement correlated with number of dietitian consultations (r = -0.30; P = 0.001). No significant differences were found between treatment arms in BMI (-0.46 kg/m 2 [-1.11, 0.18] 95%CI ;P = 0.189), triglycerides (-24.70 mg/dL [-57.66, 8.25] 95%CI ), LDL (-9.24 mg/dL [-20.50, 2.03] 95%CI ), HDL and glycemic control., Conclusions: Lifestyle intervention significantly improved BMI, LDL and triglycerides compared to baseline in at-risk MHRHs residents with SMI, yet compared to usual care the differences did not reach statistical significance. The association between the number of dietitian's consultations and BMI improvement suggests that programs should highlight participants' adherence., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Current guidelines recommend prescribing SGLT2 inhibitors to patients with type 2 diabetes and established or at high risk for atherosclerotic cardiovascular disease (ASCVD), irrespective of HbA1c levels. We studied the association of HbA1c with cardiovascular and renal outcomes and whether the benefit of dapagliflozin varies by baseline HbA1c., Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomly assigned to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular and renal outcomes by baseline HbA1c in the overall population and with dapagliflozin versus placebo in HbA1c subgroups were studied by Cox regression models., Results: In the overall population, higher baseline HbA1c was associated with a higher risk of cardiovascular death or hospitalization for heart failure (HHF); major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and ischemic stroke; and cardiorenal outcomes (adjusted hazard ratios 1.12 [95% CI 1.06-1.19], 1.08 [1.04-1.13], and 1.17 [1.11-1.24] per 1% higher level, respectively). Elevated HbA1c was associated with a greater increased risk for MACE and cardiorenal outcomes in patients with multiple risk factors (MRF) than in established ASCVD (P-interaction = 0.0064 and 0.0093, respectively). Compared with placebo, dapagliflozin decreased the risk of cardiovascular death/HHF, HHF, and cardiorenal outcomes, with no heterogeneity by baseline HbA1c (P-interaction > 0.05)., Conclusions: Higher HbA1c levels were associated with greater cardiovascular and renal risk, particularly in the MRF population, yet the benefits of dapagliflozin were observed in all subgroups irrespective of baseline HbA1c, including patients with HbA1c <7%., (© 2022 by the American Diabetes Association.)

Background: Randomized controlled trials showed that sodium/glucose cotransporter-2 inhibitors (SGLT2i) protect the heart and kidney in an array of populations with type 2 diabetes (T2D) and increased cardiorenal risk. However, the extent of these benefits also in lower kidney-risk T2D populations needs further investigation., Methods: Members of Maccabi Healthcare Systems listed in their T2D registry who initiated new glucose lowering agents (GLA), were divided into SGLT2i initiators and other GLAs (oGLAs). Groups were propensity score-matched by baseline demographic and medical characteristics. Two composite cardiovascular outcomes were defined: all-cause mortality (ACM) or hospitalization for heart failure (hHF); and ACM, myocardial infraction (MI) or stroke. The cardiorenal outcome was: ACM, new end-stage kidney disease (ESKD) or  ≥  40% reduction from baseline estimated glomerular filtration rate (eGFR). Renal-specific outcome was new ESKD or  ≥  40% eGFR reduction. Single components of cardiovascular and kidney outcomes were also assessed. Three subgroup definitions of low baseline kidney-risk were used: eGFR  >  90 ml/min/1.73 m 2 ; urinary albumin below detectable levels; and low risk according to Kidney Disease: Improving Global Outcomes (KDIGO) classification. Analyses were performed utilizing an unadjusted model, and a model adjusted to baseline eGFR and urinary albumin-to-creatinine ratio., Results: Between April 1, 2015 and June 30, 2018; 68,187 patients initiated new GLAs - 11,321 SGLT2i initiators and 42,077 oGLAs initiators were eligible. Propensity score-matching yielded two comparable cohorts; each included 9219 participants. Median follow-up was 1.7 years. Compared to oGLAs, SGLT2i initiators had lower incidence of ACM or hHF [HR 95%CI   =  0.62 (0.51-0.75) ]; ACM, MI or stroke [0.67 (0.57-0.80) ]; the cardiorenal outcome [0.65 (0.56-0.76) ]; and the renal-specific outcome [0.70 (0.57-0.85) ]. SGLT2i initiators also had lower risk for ACM, hHF and  ≥  30%,  ≥  40%,  ≥  50%,  ≥  57% eGFR reduction. No difference between groups was observed for MI or stroke. In the low baseline kidney-risk subgroups, SGLT2i initiation was generally associated with lower risk of the cardiovascular and cardiorenal outcomes, driven mainly by lower ACM incidence., Conclusions: Our findings in the general population of patients with T2D demonstrates lower risk of cardiorenal outcomes associated with initiation of SGLT2i compared with oGLAs, including specifically in patients with low baseline kidney-risk., (© 2021. The Author(s).)

Objective: International guidelines propose prescribing sodium-glucose cotransporter 2 (SGLT2) inhibitors to patients with type 2 diabetes (T2D) as secondary prevention in patients with established atherosclerotic cardiovascular disease (ASCVD) or for primary prevention of cardiovascular events in high-risk patients with multiple risk factors (MRF) for ASCVD. The current analyses expand on the cardiovascular renal and metabolic effects of SGLT2 inhibitors in MRF patients., Research Design and Methods: In DECLARE-TIMI 58, 17,160 patients with T2D and MRF (59.4%) or established ASCVD (40.6%) were randomized to dapagliflozin versus placebo; patients were followed for a median of 4.2 years. The cardiovascular and renal outcomes in the MRF cohort were studied across clinically relevant subgroups for treatment effect and subgroup-based treatment interaction., Results: Among patients with MRF, the reduction with dapagliflozin in risk of cardiovascular death or hospitalization for heart failure (CVD/HHF) (hazard ratio [HR] 0.84, 95% CI 0.67-1.04) and the renal-specific outcome (HR 0.51, 95% CI 0.37-0.69) did not differ from that for patients with ASCVD ( P interaction 0.99 and 0.72, respectively). The effect on CVD/HHF was entirely driven by a reduction in HHF (HR 0.64, 95% CI 0.46-0.88). The benefits of dapagliflozin on HHF and on the renal-specific outcome, among the subset with MRF, were directionally consistent across clinically relevant subgroups. At 48 months, HbA 1c , weight, systolic blood pressure, and urinary albumin-to-creatinine ratio were lower with dapagliflozin versus placebo and estimated glomerular filtration rate was higher ( P < 0.001)., Conclusions: In patients with T2D and MRF, dapagliflozin reduced the risk of HHF and adverse renal outcomes regardless of baseline characteristics. These analyses support the benefit of dapagliflozin for important outcomes in a broad primary prevention population., (© 2021 by the American Diabetes Association.)

Aim: To assess the associations between baseline glucose-lowering agents (GLAs) and cardiorenal outcomes with dapagliflozin versus placebo in the DECLARE-TIMI 58 study., Materials and Methods: DECLARE-TIMI 58 assessed the cardiorenal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. This post hoc analysis elaborates the efficacy and safety outcomes by baseline GLA for treatment effect and GLA-based treatment interaction., Results: At baseline, 14 068 patients (82.0%) used metformin, 7322 (42.7%) sulphonylureas, 2888 (16.8%) dipeptidyl peptidase-4 inhibitors, 750 (4.4%) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and 7013 (40.9%) insulin. Dapagliflozin reduced the composite of cardiovascular death (CVD) and hospitalization for heart failure (HHF) versus placebo regardless of baseline GLA, with greater benefit in the small group of patients with baseline use of GLP-1 RAs (HR [95% CI] 0.37 [0.18, 0.78] vs. 0.86 [0.75, 0.98] in GLP-1 RA users vs. non-users, P interaction = .03). The overall HR for major adverse cardiovascular events (CVD, myocardial infarction or ischaemic stroke) was 0.93 (95% CI 0.84, 1.03) with dapagliflozin versus placebo, with no interaction by baseline GLA (P interaction > .05). The renal-specific outcome was reduced with dapagliflozin versus placebo in the overall cohort (HR [95%CI] 0.53[0.43-0.66]), with no interaction by baseline GLA (P interaction > .05). All of these outcomes were similar in those with versus those without baseline metformin use., Conclusions: The effects of dapagliflozin on cardiorenal outcomes were generally consistent regardless of baseline GLA, with consistent benefits regardless of baseline metformin use. The potential clinical benefit of combining sodium-glucose co-transporter-2 inhibitors with GLP-1 RAs, given some evidence of cardiovascular risk reduction with both classes, should be explored further., (© 2020 John Wiley & Sons Ltd.)

Aim: To investigate whether the cardiovascular and renal benefits observed with dapagliflozin in the DECLARE‐TIMI 58 trial are also observed in patients with short and long‐standing diabetes. Materials and Methods: This post hoc analysis studied the dual primary efficacy endpoints, a composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) and major adverse cardiovascular events (MACE; CVD, myocardial infarction [MI], ischaemic stroke) by diabetes duration. Results: Of the 17 160 patients, 3836 had diabetes duration of ≤5 years, 4731 >5‐10 years, 3952 >10‐15 years, 2433 >15‐20 years and 2206 >20 years. Dapagliflozin reduced the risk of CVD/HHF by a similar amount across diabetes duration subgroups, ranging from HR 0.79 (0.58‐1.06) in patients with diabetes duration of ≤5 years to 0.75 (0.55‐1.03) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.76). Hazard ratios (HRs) for MACE ranged from 1.08 (0.87‐1.35) in patients with diabetes duration of ≤5 years to 0.67 (0.52‐0.86) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.004). This was driven by greater reductions in the risk of MI and ischaemic stroke with dapagliflozin in patients with long‐standing diabetes (interaction trend P‐values 0.019 and 0.015, respectively). The duration‐based MACE heterogeneity was apparent in those with or without a history of prior MI and in those with multiple risk factors. The renal‐specific outcome was reduced with dapagliflozin with HRs ranging from 0.79 (0.47‐1.34) in patients with diabetes duration of ≤5 years to 0.42 (0.25‐0.72) in those patients with diabetes duration of >20 years (interaction trend P‐value 0.084). Conclusions: Dapagliflozin reduced the risk of CVD/HHF consistently, regardless of diabetes duration, whereas the treatment effect for MACE differed by duration subgroups, with significant reductions with dapagliflozin in patients with long‐standing diabetes. [ABSTRACT FROM AUTHOR]