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Background: Reduction of proteinuria is associated with delayed progression of chronic kidney disease. Reports suggest that angiotensin-receptor blockers (ARBs) reduce proteinuria, but results are variable. The relative effect of ARBs and angiotensin-converting enzyme (ACE) inhibitors, and their combined administration, remains uncertain.Purpose: To establish the effect of ARBs versus placebo and alternative treatments, and the effect of combined treatment with ARBs and ACE inhibitors, on proteinuria.Data Sources: English-language studies in MEDLINE and the Cochrane Library Central Register of Controlled Trials (January 1990 to September 2006), reference lists, and expert contacts.Study Selection: Randomized trials of ARBs versus placebo, ACE inhibitors, calcium-channel blockers, or the combination of ARBs and ACE inhibitors in patients with or without diabetes and with microalbuminuria or proteinuria for whom data were available on urinary protein excretion at baseline and at 1 to 12 months.Data Extraction: Two investigators independently searched and abstracted studies.Data Synthesis: Forty-nine studies involving 6181 participants reported results of 72 comparisons with 1 to 4 months of follow-up and 38 comparisons with 5 to 12 months of follow-up. The ARBs reduced proteinuria compared with placebo or calcium-channel blockers over 1 to 4 months (ratio of means, 0.57 [95% CI, 0.47 to 0.68] and 0.69 [CI, 0.62 to 0.77], respectively) and 5 to 12 months (ratio of means, 0.66 [CI, 0.63 to 0.69] and 0.62 [CI, 0.55 to 0.70], respectively). The ARBs and ACE inhibitors reduced proteinuria to a similar degree. The combination of ARBs and ACE inhibitors further reduced proteinuria more than either agent alone: The ratio of means for combination therapy versus ARBs was 0.76 (CI, 0.68 to 0.85) over 1 to 4 months and 0.75 (CI, 0.61 to 0.92) over 5 to 12 months; for combination therapy versus ACE inhibitors, the ratio of means was 0.78 (CI, 0.72 to 0.84) over 1 to 4 months and 0.82 (CI, 0.67 to 1.01) over 5 to 12 months. The antiproteinuric effect was consistent across subgroups.Limitations: Most studies were small, varied in quality, and did not provide reliable data on adverse drug reactions. Proteinuria reduction is only a surrogate for important progression of renal failure.Conclusion: The ARBs reduce proteinuria, independent of the degree of proteinuria and of underlying disease. The magnitude of effect is similar regardless of whether the comparator is placebo or calcium-channel blocker. Reduction in proteinuria from ARBs and ACE inhibitors is similar, but their combination is more effective than either drug alone. Uncertainty concerning adverse effects and outcomes that are important to patients limits applicability of findings to clinical practice. [ABSTRACT FROM AUTHOR]

There is a clear relationship between anaemia and cardiovascular risk in chronic renal failure (CRF) patients. Left ventricular hypertrophy (LVH) is present in about three-quarters of patients starting dialysis, and is a strong predictor of mortality. Anaemia contributes to The development of LVH, mainly Via increased cardiac output. In some patients, anaemia results in an increase in LV mass, while in others it also results in LV end-diastolic volume dilatation. These changes increase The risk of arrhythmias, myocardial infarction and myocardial fibrosis. The lower The haemoglobin, The more likely it is that LVH and heart failure will develop. Furthermore, a haemoglobin of <11 g/dl is associated with increased morbidity and mortality. Partial correction of anaemia with epoetin leads to a partial, but not complete, reversal of LVH. One large retrospective study (Lombardy Registry) found that epoetin use was accompanied by a 30% reduction in crude relative risk of mortality. A progressive reduction in The relative risk of general and cardiovascular mortality was found with increasing haematocrit, with and without adjustment for co-morbid conditions. Mean hospitalizations also decreased with increasing haematocrit. The long-term effects of normalized haematocrit/haemoglobin values in uraemic patients have not yet been evaluated exhaustively in prospective, randomized, multicentre studies. Epoetin treatment has been shown to induce lasting improvements in patients' sense of well-being, reduce fatigue, increase appetite and work capacity, and improve exercise tolerance, libido and work performance. Further studies are needed to demonstrate whether greater haemoglobin concentrations are associated with greater improvements in quality of life during epoetin treatment. [ABSTRACT FROM PUBLISHER]

Background: GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACE) and can also have kidney benefits. However, whether GLP-1 receptor agonists improve clinically important kidney outcomes remains uncertain. We aimed to comprehensively assess the effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes by performing a meta-analysis of randomised controlled trials., Methods: For this meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials that included at least 500 participants with type 2 diabetes, compared a GLP-1 receptor agonist with placebo with at least 12 months of follow-up, and reported a primary clinical kidney or cardiovascular outcome, from database inception to March 26, 2024. Post hoc, we included the SELECT trial (NCT03574597), which enrolled participants with cardiovascular disease and a BMI of 27 kg/m 2 or more without diabetes. Study-level summary data were extracted independently by two authors for inclusion in this random-effects analysis. The main kidney outcome was a composite outcome, consisting of kidney failure (kidney replacement therapy or a persistent estimated glomerular filtration rate [eGFR] <15 mL/min per 1·73 m 2 ), a sustained reduction in eGFR by at least 50% or the nearest equivalent, or death from kidney failure. The main cardiovascular outcome was MACE, consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. This study is registered with PROSPERO, CRD42024528864., Findings: Of the 5140 records identified through the literature search, 11 trials, involving 85 373 participants (29 386 female, 55 987 male), were included in the meta-analysis. In participants with type 2 diabetes (67 769), GLP-1 receptor agonists reduced the composite kidney outcome by 18% compared with placebo (hazard ratio [HR] 0·82, 95% CI 0·73-0·93; I 2 =26·41%), kidney failure by 16% (HR 0·84, 0·72-0·99; I 2 =0%), MACE by 13% (HR 0·87, 0·81-0·93; I 2 =49·75%), and all-cause death by 12% (HR 0·88, 0·83-0·93; I 2 =0%). The effect on the composite kidney outcome (HR 0·81, 95% CI 0·72-0·92; I 2 =23·11%), kidney failure (HR 0·84, 0·72-0·98; I 2 =0%), MACE (HR 0·86, 0·80-0·92; I 2 =48·9%), and all-cause death (HR 0·87, 0·82-0·91; I 2 =0%) was similar when the SELECT trial was included, with no evidence of heterogeneity between this trial and those including participants with type 2 diabetes (p heterogeneity >0·05). There was no difference in the risk of serious adverse events, including acute pancreatitis and severe hypoglycaemia, between the GLP-1 receptor agonist and placebo groups (risk ratio [RR] 0·95, 95% CI 0·90-1·01; I 2 =88·5%). However, treatment discontinuation due to adverse events occurred more frequently in the GLP-1 receptor agonist groups (RR 1·51, 95% CI 1·18-1·94; I 2 =96·3%)., Interpretation: We found evidence that GLP-1 receptor agonists significantly reduce clinically important kidney events, kidney failure, and cardiovascular events., Funding: None., Competing Interests: Declaration of interests SVB reports consulting fees from Bayer, AstraZeneca, GSK, and Vifor Pharma; speaking fees from Bayer, AstraZeneca, Pfizer, and Vifor Pharma (all honoraria paid to his institution); and non-financial research support from Bayer. MMYL reports receiving grants through his employer, the University of Glasgow, from AstraZeneca, Boehringer Ingelheim, and Roche Diagnostics; MMYL is a member of a trial steering committee for Cytokinetics and a clinical endpoints committee for Bayer. NS reports consulting and speaking fees from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and ZP Therapeutics; and grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics, paid to the University of Glasgow. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reports research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing education grants from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig, Sanofi, Carbon Brand, and Jiangsu Hanson; and consulting fees from Abbott, Bayer, Eli Lilly, Novo Nordisk, Pfizer, Sanofi, Kowa, and Hanmi. CTR reports research grants through Brigham and Women's Hospital from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis; and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. JJVM reports payments to his employer, the University of Glasgow, for work on clinical trials, consulting, lecturing, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; personal lecture fees from Abbott, Hikma, Sun Pharmaceuticals, Servier, and Theracos; and personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, and Servier. PR has received grants to his institution from Novo Nordisk, AstraZeneca, and Bayer; and has received honoraria for scientific advisory boards and steering groups from AstraZeneca, Abbott, Bayer, Boehringer Ingelheim, Gilead, Novo Nordisk, Sanofi, Eli Lilly, and Novartis. GB has received honoraria from Bayer, KBP Biosciences, Alnylam, AstraZeneca, Novo Nordisk, and InREGEN. KWM has received grants from AHA, Apple, Bayer, California Institute Regenerative Medicine (CIRM), CSL Behring, Eidos, Ferring, Gilead, Google (Verify), Idorsia, Johnson & Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; and consulting fees from Applied Therapeutics, Bayer, BMS, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson & Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, and Theravance; and has equity in Human, Medeloop, Precordior, and Regencor. JFEM reports grants from Novo Nordisk, the EU, and McMaster University (Hamilton, Canada); consulting fees from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim; honoraria from Novo Nordisk, AstraZeneca, Bayer, and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi, and Boehringer Ingelheim, and has had a leadership role in the Kidney Disease Improving Global Outcomes group. HMC reports serving on advisory panels for Novo Nordisk and Bayer; receiving research funding from Sanofi, Roche, and IQVIA; receiving grants from the Chief Scientist Office, Diabetes UK, the European Commission, JDRF (Breakthrough T1D), and the Medical Research Council; serving on a speaker's bureau for Novo Nordisk; and holding stock in Roche and Bayer. KRT is supported by National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, OT2OD032581 and Centers for Disease Control and Prevention project numbers 75D301–21-P-12254 and 75D301–23-C-18264. She has also received investigator-initiated grant support from Travere Therapeutics, Bayer, and the Doris Duke Charitable Foundation, outside of the submitted work. She reports consultancy fees from AstraZeneca, Boehringer Ingelheim, Bayer, Eli Lilly, Novo Nordisk, Travere Therapeutics, and Pfizer; and speaker fees from Novo Nordisk. REP reports speaker fees from Eli Lilly and Novo Nordisk; consulting fees from Bayer, Bayer HealthCare Pharmaceuticals, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Intas Pharmaceuticals, Eli Lilly, Novo Nordisk, Pfizer, and Sun Pharmaceutical Industries; and grants from Biomea Fusion, Carmot Therapeutics, Dompé, Endogenex, Fractyl, Eli Lilly, Novo Nordisk, and Sanofi. VP has received honoraria for roles on steering committees, data monitoring committees, or advisory boards or for scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, GSK, Janssen, Novo Nordisk, Novartis, Otsuka, Travere, Tricida, and UpToDate; and is Board Director for George Clinical, St Vincents Health Australia and several independent medical research institutes. AB declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Cardiovascular disease is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), each prevent cardiovascular disease. However, trial results may not be generalizable, and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored the generalizability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD dataset from January 1, 2001, to July 31, 2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB with ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure) and secondary outcomes. Because the prespecified criteria were met, confirming trial emulation, we then explored treatment heterogeneity among 3 trial-underrepresented subgroups: females, persons aged ≥75 years, and those with chronic kidney disease. In the trial-eligible population (n = 137 155), results for the primary outcome demonstrated similar effects of ARB and ACEi (hazard ratio = 0.97; 95% CI, 0.93-1.01), meeting the prespecified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age, and chronic kidney disease. This suggests that ONTARGET trial findings are generalizable to trial-underrepresented subgroups. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: People with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m 2 , kidney replacement therapy, and kidney or CV death) by 24%., Objectives: This prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population., Methods: Participants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee., Results: A total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment., Conclusions: Semaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153)., Competing Interests: Funding Support and Author Disclosures The FLOW trial was funded by Novo Nordisk A/S. Dr Pratley has received speaker fees paid to his employer, AdventHealth (through December 31, 2023) from Eli Lilly, Lilly USA LLC, and Novo Nordisk; has received consulting fees directed to his institution from AbbVie, AstraZeneca, Bayer AG, Bayer HealthCare Pharmaceuticals, Corcept Therapeutics, Dexcom, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Hanmi Pharmaceutical, Hengrui (USA) Ltd, Intas Pharmaceuticals, Eli Lilly, Lilly USA LLC, Merck, Novo Nordisk, Pfizer, Rivus Pharmaceuticals, Scholar Rock, and Sun Pharmaceutical Industries; has received grants directed to his institution from Biomea Fusion, Carmot Therapeutics, Dompe, Endogenex, Fractyl, Eli Lilly, Novo Nordisk, and Sanofi; and has received personal fees (from January 1, 2024) from AdventHealth, a nonprofit entity. Dr Tuttle has received support from National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, and OT2OD032581, and from Centers for Disease Control and Prevention project numbers 75D301-21-P-12254 and 75D301-23-C-18264; has received investigator-initiated grant support from Travere, Bayer, and the Doris Duke Foundation outside of the submitted work; has received consulting fees from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and has received speaker fees from Novo Nordisk. Dr Rossing has received grants from Bayer, AstraZeneca, and Novo Nordisk; has received honoraria paid to the Steno Diabetes Centre Copenhagen from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer; and has received consulting fees from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer. Dr Perkovic has received honoraria for steering committee, data monitoring committee, or advisory board roles or for scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, GSK, Janssen, Novo Nordisk, Novartis, Otsuka, Travere, Tricida, and UptoDate; and is Board Director for George Clinical, St Vincent’s Health Australia and several independent medical research institutes. Dr Mann has received grants from Novo Nordisk, the European Union, and McMaster University, Hamilton, Canada; has received consulting fees from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim; has received honoraria from Novo Nordisk, AstraZeneca, Bayer, and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi, and Boehringer Ingelheim, as well as a leadership role in the Kidney Disease: Improving Global Outcomes group. Dr MacIsaac was a FLOW trial investigator and member of the FLOW global expert panel; has received research grants from Novo Nordisk, Servier, Medtronic, The Rebecca Cooper Medical Research Foundation, St Vincent’s Research Foundation, The Juvenile Diabetes Research Foundation, Grey Innovations, The Diabetes Australia Research Trust/Program, and The National Health and Medical Research Council of Australia; has received honoraria for lectures from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, MSD, Novartis, and Boehringer Ingelheim; has been on the advisory boards for Novo Nordisk, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, AstraZeneca, and MSD; has received travel support from Novo Nordisk, Sanofi, Boehringer Ingelheim, and AstraZeneca; and has been a principal investigator for industry-sponsored clinical trials run by Novo Nordisk, Sanofi, Bayer, Johnson-Cilag, and AbbVie. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Kamenov has received speaker fees from Actavis, AstraZeneca, Bayer-Schering, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, KRKA, Merck, MLD, MSD (Merck), Mundipharma, Mylan, Novartis, Novo Nordisk, Pfizer, Sandoz, Sanofi, Servier, TEVA Pharmaceuticals, Valentis, Vedra, and Viatris. Dr Hadjadj has received grants from Asdia, Asten, AstraZeneca, Homeperf, LVL, Nestle Home Care, Pierre Fabre, and VitalAire; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Servier, and Valbiotis; has received speaker fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bayer, Dino Santé, Eli Lilly, Novartis, Novo Nordisk, Pierre Fabre, Sanofi, Servier, and Valbiotis; and has received meeting invitations from AstraZeneca, Abbott, Dino Santé, Eli Lilly, and Novo Nordisk. Dr Bakris has received consulting fees from Bayer, KBP Biosciences, Ionis, Alnylam, AstraZeneca, Quantum Genomics, Novo Nordisk, and Dia Medica Therapeutics. Dr Mahaffey has received grants from the American Heart Association, Apple, Bayer, California Institute Regenerative Medicine, CSL Behring, Eidos, Ferring, Gilead, Google (Verify), Idorsia, Johnson and Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; and has received consulting fees from Applied Therapeutics, Bayer, Bristol Myers Squibb, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson and Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, PhaseBio, Portola, Quidel, and Theravance; and holds equity in Human, Medeloop, Precordior and Regencor. Drs Rasmussen, Nielsen, Idorn, Hansen, and Baeres are employees of and shareholders in Novo Nordisk., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

People with type 2 diabetes and chronic kidney disease have a high risk for kidney failure and cardiovascular (CV) complications. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2i) independently reduce CV and kidney events. The effect of combining both is unclear. FLOW trial participants with type 2 diabetes and chronic kidney disease were stratified by baseline SGLT2i use (N = 550) or no use (N = 2,983) and randomized to semaglutide/placebo. The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death or CV death. The risk of the primary outcome was 24% lower in all participants treated with semaglutide versus placebo (95% confidence interval: 34%, 12%). The primary outcome occurred in 41/277 (semaglutide) versus 38/273 (placebo) participants on SGLT2i at baseline (hazard ratio 1.07; 95% confidence interval: 0.69, 1.67; P = 0.755) and in 290/1,490 versus 372/1,493 participants not taking SGLT2i at baseline (hazard ratio 0.73; 0.63, 0.85; P < 0.001; P interaction 0.109). Three confirmatory secondary outcomes were predefined. Treatment differences favoring semaglutide for total estimated glomerular filtration rate slope (ml min -1 /1.73 m 2 /year) were 0.75 (-0.01, 1.5) in the SGLT2i subgroup and 1.25 (0.91, 1.58) in the non-SGLT2i subgroup, P interaction 0.237. Semaglutide benefits on major CV events and all-cause death were similar regardless of SGLT2i use (P interaction 0.741 and 0.901, respectively). The benefits of semaglutide in reducing kidney outcomes were consistent in participants with/without baseline SGLT2i use; power was limited to detect smaller but clinically relevant effects. ClinicalTrials.gov identifier: NCT03819153 ., (© 2024. The Author(s).)

Background: Guidelines by the National Institute for Health and Care Excellence recommend an angiotensin receptor blocker (ARB) rather than an angiotensin-converting enzyme inhibitor (ACEi) for the treatment of hypertension for people of African and Caribbean descent, due to an increased risk of angioedema associated with ACEi use observed in US trials. However, the effectiveness and risk of these drugs in Black populations in UK routine care is unknown., Methods and Findings: We applied a reference trial emulation approach to UK Clinical Practice Research Datalink Aurum data (linked with data from Hospital Episode Statistics and Office for National Statistics) to study the comparative effectiveness of ARB and ACEi in ethnic minority groups in England, after benchmarking results against the ONTARGET trial. Approximately 17,593 Black, 30,805 South Asian, and 524,623 White patients receiving a prescription for ARB/ACEi between 1 January 2001 and 31 July 2019 were included with a median follow-up of 5.2 years. The primary composite outcome was cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure with individual components studied as secondary outcomes. Angioedema was a safety endpoint. We assessed outcomes using an inverse-probability-weighted Cox proportional hazards model for ARB versus ACEi with heterogeneity by ethnicity assessed on the relative and absolute scale. For the primary outcome, 27,327 (18.0%) events were recorded in the ARB group (event rate: 25% per 5.5 person-years) and 80,624 (19.1%) events (event rate: 26% per 5.5 person-years) in the ACEi group. We benchmarked results against ONTARGET and observed hazard ratio (HR) 0.96 (95% CI: 0.95, 0.98) for the primary outcome, with an absolute incidence rate difference (IRD)% of -1.01 (95% CI: -1.42, -0.60) per 5.5 person-years. We found no evidence of treatment effect heterogeneity by ethnicity for the primary outcome on the multiplicative (Pint = 0.422) or additive scale (Pint = 0.287). Results were consistent for most secondary outcomes. However, for cardiovascular-related death, which occurred in 37,554 (6.6%) people, there was strong evidence of heterogeneity on the multiplicative (Pint = 0.002) and additive scale (Pint < 0.001). Compared to ACEi, ARB were associated with more events in Black individuals (HR 1.20 (95% CI: 1.02, 1.40); IRD% 1.07 (95% CI: 0.10, 2.04); number-needed-to-harm (NNH): 93) and associated with fewer events in White individuals (HR 0.91 (95% CI: 0.88, 0.93); IRD% -0.87 (95% CI: -1.10, -0.63); number-needed-to-treat (NNT): 115), and no differences in South Asian individuals (HR 0.97 (95% CI: 0.86, 1.09); IRD% -0.17 (95% CI: -0.87, 0.53)). For angioedema, HR 0.56 (95% CI: 0.46, 0.67) with no heterogeneity for ARB versus ACEi on the multiplicative scale (Pint = 0.306). However, there was heterogeneity on the additive scale (Pint = 0.023). Absolute risks were higher in Black individuals (IRD% -0.49 (95% CI: -0.79, -0.18); NNT: 204) compared with White individuals (IRD% -0.06 (95% CI: -0.09, -0.03); NNT: 1667) and no difference among South Asian individuals (IRD% -0.05 (95% CI: -0.15, 0.05) for ARB versus ACEi., Conclusions: These results demonstrate variation in drug effects of ACEi and ARB for some outcomes by ethnicity and suggest the potential for adverse consequences from current UK guideline recommendations for ARB in preference to ACEi for Black individuals., Competing Interests: PB was funded by a GSK PhD studentship at the time of analysis. AS is employed by LSHTM on a fellowship sponsored by GSK. EP was an employee of Compass Pathways at the time of the review. CC has received consultation, advisory board membership or research funding from the Ontario Ministry of Health, Sanofi, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim and Baxter. In 2018 CC co-chaired a KDIGO potassium controversies conference sponsored at arm’s length by Fresenius Medical Care, AstraZeneca, Vifor Fresenius Medical Care, Relypsa, Bayer HealthCare and Boehringer Ingelheim. JFEM reports honoraria from AstraZeneca, Bayer, Boehringer, Novo Nordisk, UpToDate Inc., Idorisia, Labchem, Parexel, Roche, Sanofi. MC was an employee of GSK at the time of the study. All other authors have no conflicts., (Copyright: © 2024 Baptiste et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: In the FLOW trial, semaglutide reduced the risks of kidney and cardiovascular (CV) outcomes and death in participants with type 2 diabetes mellitus (T2D) and chronic kidney disease (CKD). These prespecified analyses assessed the effects of semaglutide on CV outcomes and death by CKD severity., Methods: Participants were randomised to subcutaneous semaglutide 1 mg or placebo weekly. The main outcome was a composite of CV death, non-fatal myocardial infarction (MI) ornon-fatal stroke (CV death/MI/stroke) as well as death due to any cause by baseline CKD severity. CKD was categorised by eGFR < or ≥60 mL/min/1.73 m2, UACR < or ≥300 mg/g or KDIGO risk classification., Results: 3533 participants were randomised with a median follow-up of 3.4 years. Low/moderate KDIGO risk was present in 242 (6.9%), while 878 (24.9%) had high and 2412 (68.3%) had very high KDIGO risk. Semaglutide reduced CV death/MI/stroke by 18% (HR 0.82 [95% CI 0.68-0.98]; P = .03), with consistency across eGFR categories, UACR levels and KDIGO risk classification (all P-interaction >.13). Death due to any cause was reduced by 20% (HR 0.80 [0.67-0.95]; P = .01), with consistency across eGFR categories and KDIGO risk class (P-interaction .21 and .23, respectively). The P-interaction treatment effect for death due to any cause by UACR was .01 (<300 mg/g HR 1.17 [0.83-1.65]; ≥300 mg/g HR 0.70 [0.57-0.85])., Conclusions: Semaglutide significantly reduced the risk of CV death/MI/stroke regardless of baseline CKD severity in participants with T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown., Methods: We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute per 1.73 m 2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m 2 and a urinary albumin-to-creatinine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m 2 ), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically., Results: Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m 2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%)., Conclusions: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.)., (Copyright © 2024 Massachusetts Medical Society.)

Background and Hypothesis: This post-hoc analysis explored the semaglutide effects on eGFR slope by baseline glycemic control, blood pressure (BP), body mass index (BMI), and albuminuria status in people with type 2 diabetes and high cardiovascular risk., Methods: Pooled SUSTAIN 6 and PIONEER 6 data were analyzed for change in estimated glomerular filtration (eGFR) slope by baseline HbA1c (<8%/≥8%; <64 mmol/mol/≥64 mmol/mol), systolic BP (<140/90 mmHg/≥140/90 mmHg), and BMI (<30 kg/m2/≥30 kg/m2). SUSTAIN 6 data were analyzed by baseline urinary albumin: creatinine ratio (UACR; <30/30 - 300/>300 mg/g)., Results: The estimated absolute treatment differences (ETD) overall in eGFR slope [95% confidence intervals] favored semaglutide versus placebo in the pooled analysis (0.59 [0.29;0.89] mL/min/1.73m2/year) and in SUSTAIN 6 (0.60 [0.24;0.96] mL/min/1.73m2/year); the absolute benefit was consistent across all HbA1c, BP, BMI, and UACR subgroups (all p-interaction > 0.5)., Conclusion: A clinically meaningful reduction in risk of chronic kidney disease progression was observed with semaglutide versus placebo regardless of HbA1c, BP, BMI, and UACR levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The SELECT trial previously reported a 20% reduction in major adverse cardiovascular events with semaglutide (n = 8,803) versus placebo (n = 8,801) in patients with overweight/obesity and established cardiovascular disease, without diabetes. In the present study, we examined the effect of once-weekly semaglutide 2.4 mg on kidney outcomes in the SELECT trial. The incidence of the pre-specified main composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15 ml min -1  1.73 m - 2 , persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) was lower with semaglutide (1.8%) versus placebo (2.2%): hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.63, 0.96; P = 0.02. The treatment benefit at 104 weeks for eGFR was 0.75 ml min -1  1.73 m - 2 (95% CI 0.43, 1.06; P < 0.001) overall and 2.19 ml min -1  1.73 m - 2 (95% CI 1.00, 3.38; P < 0.001) in patients with baseline eGFR <60 ml min -1  1.73 m - 2 . These results suggest a benefit of semaglutide on kidney outcomes in individuals with overweight/obesity, without diabetes.ClinicalTrials.gov identifier: NCT03574597 ., (© 2024. The Author(s).)

Aims: The triglyceride-glucose index (TyG) has been proposed as an alternative to insulin resistance and as a predictor of cardiovascular outcomes. Little is known on its role in chronic stable cardiovascular disease and its predictive power at controlled low density lipoprotein (LDL) levels., Methods and Results: Our study population consisted of 29 960 participants in the ONTARGET and TRANSCEND trials that enrolled patients with known atherosclerotic disease. Triglycerides and glucose were measured at baseline. TyG was calculated as the logarithmized product of fasting triglycerides and glucose divided by 2. The primary endpoint of both trials was a composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The secondary endpoint was all-cause death and the components of the primary endpoint. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) with extensive covariate adjustment for demographic, medical history, and lifestyle factors. During a mean follow-up of 4.3 years, 4895 primary endpoints and 3571 all-cause deaths occurred. In fully adjusted models, individuals in the highest compared to the lowest quartile of the TyG index were at higher risk for the primary endpoint (HR 1.14; 95% CI 1.05-1.25) and for myocardial infarction (HR 1.30; 95% CI 1.11-1.53). A higher TyG index did not associate with the primary endpoint in individuals with LDL levels < 100 mg/dL., Conclusion: A higher TyG index is associated with a modestly increased cardiovascular risk in chronic stable cardiovascular disease. This association is largely attenuated when LDL levels are controlled., Registration: www.clinicaltrials.gov: NCT00153101., Competing Interests: Conflict of interest: M.B. is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939) and reports personal fees from Abbott, Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. B.H. reports no conflicts. F.M. reports grants and personal fees from Medtronic and personal fees from Recor, Boehringer Ingelheim, and Berlin Chemie. He is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219, project number 322900939), and Deutsche Herzstiftung, has received scientific support and/or speaker honoraria from Ablative Solutions, Medtronic, and ReCor Medical, and speaker honoraria/consulting fees from Ablative Solutions, Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. G.M. reports no conflicts. J.F.E.M. reports no conflicts. R.S. reports no conflicts. H.S. reports personal fees from Boehringer Ingelheim. K.K.T. reports no conflicts. E.M.L. reports no conflicts. S.Y. reports institutional grants for the ONTARGET and TRANSCEND trials but not related to the current analysis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Fixed-dose combination treatments reduce cardiovascular disease in primary prevention. We aim to explore whether those benefits differ in the presence of CKD., Methods: We conducted an individual participant data meta-analysis in 18,162 participants on the efficacy and safety of treatment for the primary prevention of cardiovascular disease. Combination therapies consisted of at least two BP-lowering drugs and a statin, with or without aspirin versus placebo or minimal care. Here, we examine the differential effect of fixed-dose combination treatment on the risk of developing cardiovascular disease in participants with a low eGFR (<60 ml/min per 1.73 m 2 ; Chronic Kidney Disease Epidemiology Collaboration formula) compared with a normal eGFR (≥60 ml/min per 1.73 m 2 ). The primary composite outcome was time to first occurrence of a combination of cardiovascular death, myocardial infarction, stroke, or arterial revascularization., Results: At baseline, the mean level of eGFR was 76 ml/min per 1.73 m 2 (SD 17). In total, 3315 (18%) participants had low eGFR at baseline. During a median follow-up of 5 years, among participants with normal eGFR, the primary outcome occurred in 232 (3%) participants in the treatment group compared with 339 (5%) in the control group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P < 0.001). In participants with low eGFR, the primary outcome occurred in 64 (4%) participants in the treatment group compared with 130 (8%) in the control group (hazard ratio, 0.49; 95% confidence interval, 0.36 to 0.66; P < 0.001; P for interaction 0.047). The relative risk reduction among participants with low eGFR was larger for combination strategies, including aspirin compared with treatments without aspirin. Apart from dizziness, other side effects did not differ between treatment and control groups, regardless of the stage of their kidney function., Conclusions: A fixed-dose combination treatment strategy is effective and safe at preventing cardiovascular disease, irrespective of eGFR, but relative and absolute risk reductions are larger in individuals with low eGFR., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;11&#95;08&#95;CJN0000000000000251.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Aims: Evaluate changes in haemodynamic markers as mediators of cardiovascular (CV) and kidney benefits with empagliflozin., Methods: Post-hoc analysis of EMPA-REG OUTCOME in patients with type 2 diabetes (T2D) and established CV disease receiving empagliflozin (10 and 25 mg) or placebo. Outcomes were CV death, hospitalisation for heart failure [HF], HF death, incident/worsening nephropathy, new onset macroalbuminuria, and the composite of sustained estimated glomerular filtration rate decline ≥40 % from baseline, renal replacement therapy or renal death. To be considered a mediator, changes in variable (pulse pressure, mean arterial pressure and cardiac workload) over time had to be (1) affected by active treatment, (2) associated with the outcome, and (3) adjustment for changes over time must reduce treatment effect versus an unadjusted analysis. Variables were evaluated in Cox regression analyses., Results: Pulse pressure, mean arterial pressure and cardiac workload were significantly reduced by empagliflozin vs placebo. Using change from baseline to Week 12 or sensitivity analyses (time-dependent updated mean and current change from baseline) of these CV parameters, only small impacts on empagliflozin effect on CV and kidney outcomes were shown., Conclusions: Improvements in haemodynamic parameters did not substantially mediate empagliflozin benefits on CV and kidney outcomes in patients with T2DM and established CV disease., Competing Interests: Declaration of competing interest B.K.K. reports lecture fees and/or advisory board memberships and/or study participation from Astellas, Bayer, Boehringer Ingelheim, Chiesi, Riepharm, Pfizer, Sanofi, Servier, and Vifor Pharma. He is the past president of the German Hypertension Society DHL. J.F.E.M. reports honoraria from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, Sanofi, and Vifor. S.J.H., and M.M. are employees of Boehringer Ingelheim, the manufacturer of empagliflozin. R.C. has received consulting fees from Boehringer Ingelheim and Eli Lilly. L.G. has participated in advisory boards for RES MED, Boehringer Ingelheim, and Sanofi Aventis, S.P. has received research grant from Daiichi Sankyo, honoraria from Daiichi Sankyo, Pfizer, Hanmi, Daewoong, Takeda, Donga and Boryung and Servier. D.F. has received honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck & Co., and Sanofi., C.W. reports honoraria from Boehringer Ingelheim, Eli Lilly and Company, Mitsubishi, and Merck Sharp & Dohme., (Copyright © 2023. Published by Elsevier Inc.)

Background: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D., Methods: FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes., Results: Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression., Conclusion: FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants., Materials and Methods: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m 2 ). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed., Results: Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m 2 , glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants., Conclusion: SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Despite available interventions, people with type 2 diabetes (T2D) remain at risk of chronic kidney disease (CKD). Finerenone, a potent and selective nonsteroidal mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitors (SGLT2is) can reduce both kidney and cardiovascular risks in people with CKD and T2D. Here we outline the design of a study to investigate whether dual therapy with finerenone and an SGLT2i is superior to either agent alone., Methods: CONFIDENCE (NCT05254002) is a randomized, controlled, double-blind, double-dummy, international, multicenter, three-armed, parallel-group, 7.5 - to 8.5-month, Phase 2 study in 807 adults with T2D, stage 2-3 CKD and a urine albumin:creatinine ratio (UACR) ≥300-<5000 mg/g. The primary objective is to demonstrate that 6 months of dual therapy comprising finerenone and the SGLT2i empagliflozin is superior for reducing albuminuria versus either agent alone. Interventions will be once-daily finerenone 10 mg or 20 mg (target dose) plus empagliflozin 10 mg, or empagliflozin 10 mg alone, or finerenone 10 mg or 20 mg (target dose) alone., Results: The primary outcome is a relative change from baseline in UACR among the three groups. Secondary outcomes will further characterize efficacy and safety, including changes in estimated glomerular filtration rate and incident hyperkalemia., Conclusions: CONFIDENCE is evaluating the safety, tolerability and efficacy of dual use of finerenone and an SGLT2i in adults with CKD and T2D. Should an additive effect be shown, early and efficient intervention with dual finerenone and SGLT2i therapy could slow disease progression and provide long-term benefits for people with CKD and T2D., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Patients with chronic kidney disease (CKD) carry a high cardiovascular (CV) risk. Since whether this risk is reduced by aspirin is unclear, we examined if the effect of aspirin on cardiovascular outcomes varied by baseline kidney function in a primary cardiovascular disease prevention trial. The International Polycap Study-3 (TIPS-3) trial had randomized people without previous cardiovascular disease to aspirin (75 mg daily) or placebo. We now examined aspirin versus placebo on cardiovascular events in participants grouped by estimated glomerular filtration rate (eGFR), using a threshold of 60 ml/min/1.73 m 2 , and by using tertiles of eGFR. The primary outcome was a composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. A total of 5712 participants were randomized with a mean follow-up of 4.6 years. Of these, 983 (17.2%) had an eGFR under 60 ml/min/1.73 m 2 (mean eGFR 49 ml/min/1.73 m 2 ) and 4,729 over 60 ml/min/1.73 m 2 (mean 84 ml/min/1.73 m 2 ). In participants with an eGFR under 60 ml/min/1.73 m 2 there were 26 primary outcomes in 502 participants on aspirin and 39/481 on placebo (hazard ratio 0.57; 95% confidence interval 0.34-0.94). In participants with an eGFR over 60 ml/min/1.73 m 2 there were 90 primary outcomes in 2357 participants on aspirin and 95/2372 on placebo (0.95; 0.71-1.27). With tertiles of eGFR under 70, 70-90, and over 90 ml/min/1.73 m 2 , risk reductions with aspirin for the primary outcome were larger at lower eGFR levels (0.62; 0.43-0.91) for the lowest tertile, (0.96; 0.62-1.49) for the middle, and (1.30; 0.77-2.18) for the highest tertile. Thus, our findings support aspirin may reduce cardiovascular events in people with moderate to advanced stage CKD., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin reduced the risks of progressive kidney disease, hospitalised heart failure or cardiovascular death, and death from all causes in patients with chronic kidney disease (CKD) with or without type 2 diabetes. Patients with more severe CKD are at higher risk of kidney failure, cardiovascular events and all-cause mortality. In this post hoc analysis, we assessed the efficacy and safety of dapagliflozin according to baseline Kidney Disease Improving Global Outcomes (KDIGO) risk categories., Methods: DAPA-CKD was a double-blind, placebo-controlled trial that randomised patients with an eGFR of 25-75 ml min -1 [1.73 m] -2 and urinary albumin/creatinine ratio (UACR) of ≥22.6 and <565.0 mg/mmol (200-5000 mg/g) to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of ≥50% reduction in eGFR, end-stage kidney disease (ESKD), and death from a kidney or cardiovascular cause. Secondary endpoints included a kidney composite (≥50% reduction in eGFR, ESKD and death from a kidney cause), a cardiovascular composite (heart failure hospitalisation or cardiovascular death), and death from all causes. We used Cox proportional hazards regression analyses to assess relative and absolute effects of dapagliflozin across KDIGO risk categories., Results: Of the 4304 participants in the DAPA-CKD study, 619 (14.4%) were moderately high risk, 1349 (31.3%) were high risk and 2336 (54.3%) were very high risk when categorised by KDIGO risk categories at baseline. Dapagliflozin reduced the hazard of the primary composite (HR 0.61; 95% CI 0.51, 0.72) and secondary endpoints consistently across KDIGO risk categories (all p for interaction >0.09). Absolute risk reductions for the primary outcome were also consistent irrespective of KDIGO risk category (p for interaction 0.26). Analysing patients with and without type 2 diabetes separately, the relative risk reduction with dapagliflozin in terms of the primary outcome was consistent across subgroups of KDIGO risk categories. The relative frequencies of adverse events and serious adverse events were also similar across KDIGO risk categories., Conclusion/interpretations: The consistent benefits of dapagliflozin on kidney and cardiovascular outcomes across KDIGO risk categories indicate that dapagliflozin is efficacious and safe across a wide spectrum of kidney disease severity., Trial Registration: ClinicalTrials.gov NCT03036150., Funding: The study was funded by AstraZeneca., (© 2022. The Author(s).)

Aims: The LEADER trial demonstrated that the glucagon-like peptide-1 receptor agonist (GLP1-RA) liraglutide reduces kidney and cardiovascular (CV) risk in patients with type 2 diabetes. We previously developed a Parameter Response Efficacy (PRE) score that translates multiple short-term risk marker changes, from baseline to first available follow-up measurement, into a predicted long-term drug effect on clinical outcomes. The objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of liraglutide in reducing the risk of kidney and CV outcomes. Methods: Short-term changes in glycated hemoglobin (HbA1c), systolic blood pressure (BP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, and potassium were monitored in the LEADER trial. Associations between risk markers and kidney or CV outcomes were established using a multivariable Cox proportional hazards model in a separate pooled database of 6,355 patients with type 2 diabetes. The regression coefficients were then applied to the short-term risk markers in the LEADER trial to predict the effects of liraglutide on kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) and CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, and CV death) outcomes. Results: Liraglutide compared to placebo reduced HbA1c (1.4%), systolic BP (3.0 mmHg), UACR (13.2%), body weight (2.3 kg), hemoglobin (2.6 g/L), and increased HDL-cholesterol (0.01 mmol/L) (all p -values <0.01). Integrating multiple risk marker changes in the PRE score resulted in a predicted relative risk reduction (RRR) of 16.2% (95% CI 13.7-18.6) on kidney outcomes which was close to the observed RRR of 15.5% (95% CI -9.0-34.6). For the CV outcome, the PRE score predicted a 7.6% (95% CI 6.8-8.3) RRR, which was less than the observed 13.2% (95% CI 3.2-22.2) RRR. Conclusion: Integrating multiple short-term risk markers using the PRE score adequately predicted the effect of liraglutide on the composite kidney outcome. However, the PRE score underestimated the effect of liraglutide for the composite CV outcome, suggesting that the risk markers included in the PRE score do not fully capture the CV benefit of liraglutide., Competing Interests: JFEM has received consulting fees from Novo Nordisk, AstraZeneca, Amgen, Braun, ACI, Fresenius, Celgene, Gambro, Abbvie, Roche, Sandoz, Lanthio, Sanifit, Relypsam, and ZS Pharma; and grants from the European Union, McMaster University Canada. OM declares advisory board membership from AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp and Dohme, Boehringer Ingelheim, BOL Pharma; Speakers bureau honorarium from AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp and Dohme and Boehringer Ingelheim; and research grants from Novo Nordisk and AstraZeneca. HJLH is a consultant for AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, Mitsubishi Tanabe and MundiPharma and has a policy that all honoraria are paid to his employer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tye, de Vries, Mann, Schechter, Mosenzon, Denig and Heerspink.)

Introduction: Cardiovascular disease is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based on evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those aged ≥75 years, from ethnic minority backgrounds or with low kidney function may be limited.Using individual anonymised data from the Ongoing Telmisartan Alone and the Ramipril Global Endpoint Trial (ONTARGET) trial, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within a real-world setting in the area of cardiovascular disease. If the original trial results are replicable, we will estimate treatment effects and risk in groups underrepresented and excluded from the original clinical trial., Methods and Analysis: We will develop a cohort analogous to the ONTARGET trial within the Clinical Practice Research Datalink between 1 January 2001 and 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for congestive heart failure. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include under represented and excluded groups., Ethics and Dissemination: Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 22658). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 20&#95;012). Access to the individual patient data from the ONTARGET trial was obtained by the trial investigators. Findings will be submitted to peer-reviewed journals and presented at conferences., Competing Interests: Competing interests: PJB is funded by a GSK PhD studentship. CC has received consultation, advisory board membership or research funding from the Ontario Ministry of Health, Sanofi, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim and Baxter. In 2018 she co-chaired a KDIGO potassium controversies conference sponsored at arm’s length by Fresenius Medical Care, AstraZeneca, Vifor Fresenius Medical Care, relypsa, Bayer HealthCare and Boehringer Ingelheim. She co-chairs the cloth mask knowledge exchange, a stakeholder group that includes cloth mask manufacturers and fabric distributors. MC is an employee of, and own shares in, GSK., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes., Methods: Pooled (n=12 637) and by-trial data from SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; n=3297) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; n=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline., Results: The median follow-up durations were 2.1 years for SUSTAIN 6 and 3.8 years for LEADER. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years after randomization by 24% versus placebo (95% CI, 20%-27%; P <0.001). Significant reductions were also observed in by-trial data analyses ( P <0.001 for all), the largest being with semaglutide 1.0 mg (33% [95% CI, 24%-40%]; P <0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m 2 /y ( P <0.0001 and P <0.001), respectively, versus placebo. Effects appeared larger in patients with baseline eGFR <60 versus ≥60 mL/min/1.73 m 2 ( P interaction =0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR], 0.86 [95% CI, 0.75-0.99]; P =0.039 and HR, 0.80 [95% CI, 0.66-0.97]; P =0.023, respectively). Similar, nonsignificant, directional results were observed for 30% and 57% eGFR reductions (HR, 0.92 [95% CI, 0.84-1.02]; P =0.10 and HR, 0.89 [95% CI, 0.69-1.13]; P =0.34). In patients with baseline eGFR 30 to <60 mL/min/1.73 m 2 , the likelihood of persistent reduction for all thresholds was increased, ranging from HR 0.71 for 30% reduction (95% CI, 0.59-0.85; P =0.0003, P interaction =0.017) to 0.54 for 57% reduction (95% CI, 0.36-0.81; P =0.003, P interaction =0.035)., Conclusions: In patients with type 2 diabetes, semaglutide/liraglutide offered kidney-protective effects, which appeared more pronounced in patients with preexisting chronic kidney disease.

Background: Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program., Methods: Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ 2 -test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed., Results: Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097-0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05)., Conclusions: Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity., Clinical Trial Registration: http://clinicaltrials.gov.uniqueidentifier :NCT00153101., (© 2021. The Author(s).)

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline., Methods: The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020., Recommendations: The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines.

Aims: To investigate whether effects on chronic kidney disease risk factors could explain the apparent reduction in kidney outcomes (composite of macroalbuminuria, doubling of serum creatinine, renal replacement therapy, or renal death), primarily driven by changes in albuminuria, after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide in patients with type 2 diabetes in the LEADER and SUSTAIN 6 trials., Materials and Methods: We evaluated the mediation effect of glycated haemoglobin (HbA1c), systolic blood pressure (BP), and body weight on the kidney effects of GLP-1RAs. Diastolic BP, haemoglobin, heart rate, low-density lipoprotein and total cholesterol, and white blood cell count were also investigated. The mediation effect was estimated by the novel Vansteelandt statistical method. Subgroups with estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m 2 were examined in LEADER., Results: We observed that HbA1c mediated 25% (95% confidence interval [CI] -7.1; 67.3) and 26% (95% CI noncalculable), and systolic BP 9% (95% CI 2.8; 22.7) and 22% (95% CI noncalculable) of kidney effects of GLP-1RAs in LEADER and SUSTAIN 6, respectively. Small or no mediation was observed for the other parameters; for example, body weight mediated 9% (95% CI -7.9; 35.5) in the former and did not mediate effects in the latter study. Mediation by HbA1c was greater in patients with eGFR ≥60 mL/min/1.73 m 2 (57%) versus those with eGFR <60 mL/min/1.73 m 2 (no mediation)., Conclusions: Our results suggest that HbA1c and systolic BP may moderately mediate kidney benefits of liraglutide and semaglutide, with all other variables having a small to no effect. Potential kidney benefits may be driven by other mediators or potentially by direct mechanisms., (© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose of Review: To summarize and explain the new guideline on blood pressure (BP) management in chronic kidney disease (CKD) published by Kidney Disease: Improving Global Outcomes (KDIGO), an independent global nonprofit organization which develops and implements evidence-based clinical practice guidelines in kidney disease. KDIGO issued its first clinical practice guideline for the Management of Blood Pressure (BP) in Chronic Kidney Disease (CKD) for patients not receiving dialysis in 2012 and now updated the guideline in 2021., Recent Findings: Recommendations in this update were developed based on systematic literature reviews and appraisal of the quality of the evidence and strength of recommendation following the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The updated guideline includes five chapters covering BP measurement techniques, lifestyle interventions for lowering BP, and management of BP in three target populations, namely adults (with and without diabetes), kidney transplant recipients, and children. A dedicated chapter on BP measurement emphasizing standardized preparation and measurement protocols for office BP measurement is a new addition, following protocols used in large randomized trials of BP targets with pivotal clinical outcomes. Based on the available evidence, and in particular in the CKD subgroup of the SPRINT trial, the 2021 guideline suggests a systolic BP target of <120 mm Hg, based on standardized measurements, for most individuals with CKD not receiving dialysis, with the exception of kidney transplant recipients and children. This recommendation is strictly contingent on the measurement of BP using standardized office readings and not routine office readings., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Guidelines recommend to start blood pressure (BP)-lowering drugs also according to cardiovascular risk including history of cardiovascular events. We hypothesized that in patients with a history of myocardial infarction (MI), stroke, both or none of those, the index events predict the next event and have different SBP risk associations to different cardiovascular outcomes., Design and Measurements: In this pooled posthoc, nonprespecified analysis, we assessed outcome data from high-risk patients aged 55 years or older with a history of cardiovascular events or proven cardiovascular disease, randomized to the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and to Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease Trial investigating telmisartan, ramipril and their combination with a median follow-up of 56 months. Standardized office BP was measured every 6 months. Associations of mean achieved BP on treatment were investigated on MI, stroke and cardiovascular death. We identified patients with previous MI (N = 13 487), stroke (N = 4985), both (N = 1509) or none (N = 10 956) of these index events. Analyses were done by Cox regression, analysis of variance and Chi2-test. 30 937 patients with complete data were enrolled between 1 December 2001 and 31 July 2003, and followed until 31 July 2008. Data of both trials were pooled as the outcomes were similar., Results: Patients with MI as index event had a higher risk to experience a second MI [hazard ratio 1.42 (confidence interval (CI) 1.20-1.69), P < 0.0001] compared with patients with no events but no increased risk for a stroke as a next event [hazard ratio 0.95 (CI 0.73-1.23), n.s.]. The risk was roughly doubled when they had both, MI and stroke before [hazard ratio 2.07 (CI 1.58-2.71), P < 0.0001]. Patients with a stroke history had a roughly three-fold higher likelihood to experience a second stroke [hazard ratio 2.89 (CI 2.37-3.53) P < 0.0001] but not MI [hazard ratio 1.07 (CI 0.88-1.32), n.s.]. Both types of index events increased roughly three-fold the risk of a second stroke compared with no previous events. The SBP-risk relationship was not meaningfully altered by the event history. After MI and stroke the risk for subsequent events and cardiovascular death was increased over the whole SBP spectrum. A J-shape relationship between BP and outcome was only observed for cardiovascular death., Conclusion: Previous MI and previous stroke are associated with increased risk for the same event in the future, independent of achieved SBP. Thus, secondary prevention may also be chosen according to the event history of patients., Clinical Trial Registration: http://clinicaltrials.gov. Unique identifier: NCT00153101., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A recently published nomenclature by a "Kidney Disease Improving Global Outcomes" (KDIGO) Consensus Conference suggested that the word "kidney" should be used in medical writings instead of "renal" or "nephro" when referring to kidney disease and kidney health. Whereas the decade-old move to use "kidney" more frequently should be supported when communicating with the public-at-large, such as the World Kidney Day, or in English speaking countries in communications with patients, care-partners, and non-medical persons, our point of view is that "renal" or "nephro" should not be removed from scientific and technical writings. Instead, the terms can coexist and be used in their relevant contexts. Cardiologists use "heart" and "cardio" as appropriate such as "heart failure" and "cardiac care units" and have not replaced "cardiovascular" with "heartvessel", for instance. Likewise, in nephrology, we consider that "chronic kidney disease" and "continuous renal replacement therapy" should coexist. We suggest that in scientific writings and technical communications, the words "renal" and "nephro" and their derivatives are more appropriate and should be freely used without any pressure by medical journals to compel patients, care-partners, healthcare providers, researchers and other stakeholders to change their selected words and terminologies. We call to embrace the terms "kidney", "renal" and "nephro" as they are used in different contexts and ask that scientific and medical journals not impose terminology restrictions for kidney disease and kidney health. The choice should be at the discretion of the authors, in the different contexts including in scientific journals.

Objective: A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events., Research Design and Methods: LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5-5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with >30% reduction ( n = 2,928), 30-0% reduction ( n = 1,218), or any increase in UACR ( n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [<30 mg/g, 30-300 mg/g, or ≥300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes., Results: For MACE, hazard ratios (HRs) for those with >30% and 30-0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in >30% reduction subgroups with baseline micro- or macroalbuminuria., Conclusions: A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential., (© 2021 by the American Diabetes Association.)

Background: Diabetes and hypertension are risk factors for renal and cardiovascular outcomes. Data on the association of achieved blood pressure (BP) with renal outcomes in patients with and without diabetes are sparse. We investigated the association of achieved SBP, DBP with renal outcomes and urinary albumin excretion (UAE) in people with vascular disease., Methods: In this pooled analysis, we assessed renal outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, randomized to The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and to Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease trials investigating telmisartan, ramipril and their combination with a median follow-up of 56 months. Standardized office BP was measured every 6 months, estimated glomerular filtration rate (eGFR) and UAE at baseline, 2 years and study end. Associations of mean achieved BP on treatment were investigated on major renal outcomes including end-stage renal disease (ESRD), decline of eGFR by at least 40%, doubling of creatinine and the composites thereof and on UAE. Analyses were by Cox regression analysis, analysis of variance and Chi2-test. Of 30 937 patients with complete data, 19 450 patients without and 11 487 with diabetes were enrolled between 1 December 2001 and 31 July 2003 and followed until 31 July 2008. Data were pooled as the outcomes for telmisartan 80 mg/day (n = 2903) or placebo (n = 2907) for Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease and ramipril 10 mg/day (n = 8407), telmisartan 80 mg/day (n = 8386) or the combination of both (n = 8334) were similar., Results: For both those with and without diabetes, the hazard ratios for the composites ESRD or doubling of serum creatinine (707 events overall) and ESRD or 40% eGFR loss (2371 events overall) reached a nadir at achieved SBP of 120 to less than 140 mmHg, and increased with higher and lower SBP with similar relative risk with or without diabetes. For example, risk for the former composite reached a hazard ratios 3.06 (confidence interval 1.90-4.92) with a mean achieved SBP more than 160 mmHg compared with 120 to less than 130 mmHg with diabetes and hazard ratios 2.14 (1.09-4.26) without diabetes. In contrast, the development of new microalbuminuria and macroalbuminuria (3002 and 846 events overall) associated linearly over the whole range of achieved SBP (apart from a slight increase in risk at SBP less than 120 mmHg only in those without diabetes). Absolute risks for the composite and albuminuria outcomes were consistently greater in those with diabetes as compared with without diabetes with high event rates over the whole SBP spectrum. The increased renal risk at low SBP was not related to a meaningful reduction of mandated study drugs or open label renin-angiotensin-aldosterone system inhibition., Conclusion: In patients at high cardiovascular risk, SBP levels more than 140 mmHg and less than 120 are associated with increased risk for renal outcomes. Renal risk was greater in diabetes across the whole range of achieved SBP and DBP. These data suggest similar target BP range in patients with and without diabetes to prevent renal outcomes, a frequent complication in high-risk vascular patients., Clinical Trial Registration: Clinical Trial registration: http://clinicaltrials.gov.Unique identifier: NCT00153101., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)