eGFR Subgroups Research Articles

Effects of canagliflozin on total heart failure events across the kidney function spectrum: Participant-level pooled analysis from the CANVAS Program and CREDENCE trial.

People with type 2 diabetes (T2D) face high risks of heart failure (HF) hospitalizations that are often recurrent, especially as kidney function declines. We examined the effects of canagliflozin on total HF events by baseline kidney function in patients with T2D at high cardiovascular risk and/or with chronic kidney disease. Leveraging pooled participant-level data from the CANVAS programme (n = 10 142) and CREDENCE trial (n = 4401), first and total HF hospitalizations were examined. Cox proportional hazards models were built for the time to first HF hospitalization, and proportional means models based on cumulative mean functions were used for recurrent HF hospitalizations. Treatment effects were evaluated overall as well as within baseline estimated glomerular filtration rate (eGFR) strata (<45, 45-60, and >60 ml/min/1.73 m2). HF hospitalizations were independently and blindly adjudicated. Among 14 540 participants with available baseline eGFR values, 672 HF hospitalizations occurred over a median follow-up of 2.5 years. Among participants who experienced a HF hospitalization, 357 had a single event (201 in placebo-treated patients and 156 in canagliflozin-treated patients), 77 had 2 events, and 39 had >2 events. Canagliflozin reduced risk of first HF hospitalization (hazard ratio 0.58, 95% confidence interval [CI] 0.48-0.70) consistently across baseline eGFR strata (pinteraction = 0.84). Canagliflozin reduced total HF hospitalizations overall (mean event ratio 0.63, 95% CI 0.54-0.73) and across eGFR subgroups (pinteraction = 0.51). Canagliflozin also reduced cardiovascular death and total HF hospitalizations (mean event ratio 0.72, 95% CI 0.65-0.80) and across eGFR subgroups (pinteraction = 0.82). The absolute risk reductions were numerically larger, and numbers needed to treat were smaller when evaluating total events versus first events alone. These observed HF benefits were highly consistent across the range of eGFR, with larger absolute benefits in participants who had worse kidney function at baseline. In individuals with T2D at high cardiovascular risk and/or with chronic kidney disease, canagliflozin reduced the total burden of HF hospitalizations, with consistent benefits observed across the kidney function spectrum. ClinicalTrials.gov Identifier: CANVAS (NCT01032629), CANVAS-R (NCT01989754), CREDENCE (NCT02065791).

#362 Dosing low, winning high: unlocking the promise of endothelin antagonism for the treatment of CKD in the zibotentan/dapagliflozin ZENITH trials

Abstract Background and Aims The Phase 2b ZENITH-CKD trial demonstrated that combined treatment with the endothelin A receptor (ETAR) antagonist zibotentan and the sodium-glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin yields a robust and significant reduction in albuminuria in individuals with chronic kidney disease (CKD), compared to dapagliflozin treatment alone [1]. This is hypothesized to translate into a significant reduction of kidney function decline and may further confer cardiometabolic benefits including reducing blood pressure, LDL cholesterol and (in type 2 diabetes) HbA1c in the ongoing Phase 3 ZENITH High Proteinuria trial. The usage of ETAR antagonists has until now been limited by the class effect of fluid retention, which is associated with an increased risk of heart failure in the at-risk CKD population. Zibotentan has previously been investigated at 10 mg per day in Phase 3 for the treatment of prostate cancer. Method Model-Informed Drug Development (MIDD) was integrated with clinical pharmacology data to develop the dose strategy for both ZENITH trials. A low-dose strategy was selected considering the increased plasma exposure of zibotentan in kidney impairment. The Phase 2b dose steps were selected based on an exposure response model for the efficacy marker urinary albumin to creatinine ratio (uACR) and were supported using clinical trial simulations. The dose strategy for Phase 3 was defined based on a combined analysis of ZENITH-CKD results for both efficacy and tolerability: efficacy (uACR reduction on top of dapagliflozin) was analysed with a Dose-Response Mixed Model for Repeated Measures, and tolerability (fluid retention events, defined as a combination of specified body weight and BNP increase) was evaluated with Kaplan Meier analyses. Results Zibotentan doses of 0.25 mg and 1.5 mg (in a first, discontinued study part also 5 mg), in combination with dapagliflozin 10 mg, were selected for ZENITH-CKD. Clinical trial simulations indicated that inclusion of the low dose of 0.25 mg was crucial to characterise the dose-response relationship. Dose-uACR response modelling of ZENITH-CKD data predicted a zibotentan dose of 0.75 mg to result in a mean uACR reduction of around 25% in addition to the reduction with dapagliflozin. A post-hoc regression analysis of uACR mean changes from baseline, stratified by dose, showed a trend towards lower uACR reduction with higher eGFR levels. Kaplan-Meier analyses of the fluid retention risk in different eGFR subgroups indicated that the fluid retention risk increased with increasing zibotentan dose for eGFR levels &amp;lt;45 mL/min/1.73 m2, while for higher eGFR levels, no differences were observed between treatments with dapagliflozin alone and added zibotentan 0.25 mg or 1.5 mg. Therefore, a kidney-function based zibotentan dose strategy was selected for the ZENITH High Proteinuria trial: Combined zibotentan/dapagliflozin is being compared against dapagliflozin alone; within the combination treatment arm, 0.25 mg zibotentan is selected for participants with baseline eGFR levels &amp;lt;45 mL/min/1.73 m2, and 0.75 mg is selected for higher eGFR level, with a tolerance eGFR window for participants whose eGFR declines below this cut-off, and with the possibility to reduce the dose to 0.25 mg in case of tolerability findings. Conclusion The favourable benefit/risk profile that was demonstrated for combined zibotentan/dapagliflozin in ZENITH-CKD was enabled by the zibotentan low-dose strategy. The wide dose ranging and MIDD further enabled selection of a kidney-function based zibotentan dosing strategy for ZENITH High Proteinuria which is designed to further balance benefit/risk. The low-dose zibotentan strategy and the combination with dapagliflozin opened for the first time a therapeutic window for ETAR antagonists, with the potential to redefine their value for the treatment of CKD. This work was sponsored by AstraZeneca.

Prognostic importance of prognostic nutritional index and modified Glasgow prognostic score in advanced lung cancer with targetable mutation

BackgroundInflammation and nutrition are important parameters that significantly affect survival in various malignancies. Prognostic nutritional index (PNI) and modified Glasgow prognostic score (mGPS) can reflect both inflammatory and nutritional conditions. Therefore, we aimed to evaluate the prognostic value of PNI and mGPS in patients who had the targetable mutation and also received targeted therapy.Materials and MethodsAdvanced lung cancer patients with EGFR mutation (mut) and ALK rearrangement were enrolled to study, retrospectively. PNI has with the following formula: 10 × serum albumin (g/dl) + 0.005 × peripheral lymphocyte count (per mm3) and threshold value was accepted as 50. Modified GPS was also calculated using albumin and CRP level and patients were scored as range 0 to 2.ResultsA total of 182 patients enrolled in the study. 132 and 50 of 182 patients had EGFR mut and ALK rearrangement, respectively. PFS was significantly longer in high PNI group in both the EGFR and ALK rearrangement-positive subgroups (P = 0.004 for EGFR mut-positive group; P = 0.017 for ALK rearrangement-positive group). Additionally, PFS was significantly shortened from mGPS 0 to 2 (P = < 0.001 for EGFR mut-positive group; P = 0.016 for ALK rearrangement-positive group).ConclusionBoth PNI and mGPS can be used as a reliable, inexpensive, and easily applicable prognostic index in the advanced lung cancer patients who had the targetable mutation and also received targeted therapy.

Vaccine Effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA.2 in CKD.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has posed increased risks of hospitalization and mortality in patients with underlying CKD. Current data on vaccine effectiveness of COVID-19 vaccines are limited to patients with CKD on dialysis and seroconversion in the non-dialysis population. A case-control study was conducted of adults with CKD using data extracted from the electronic health record database in Hong Kong. Adults with CKD and COVID-19 confirmed by PCR were included in the study. Each case was matched with up to ten controls attending Hospital Authority services without a diagnosis of COVID-19 on the basis of age, sex, and index date (within three calendar days). The vaccine effectiveness of BNT162b2 and CoronaVac in preventing COVID-19 infection, hospitalizations, and all-cause mortality was estimated using conditional logistic regression adjusted by patients' comorbidities and medication history during the outbreak from January to March 2022. A total of 20,570 COVID-19 cases, 6604 COVID-19-related hospitalizations, and 2267 all-cause mortality were matched to 81,092, 62,803, and 21,348 controls, respectively. Compared with the unvaccinated group, three doses of BNT162b2 or CoronaVac were associated with a reduced risk of infection (BNT162b2: 64% [95% confidence interval (CI), 60 to 67], CoronaVac: 42% [95% CI, 38 to 47]), hospitalization (BNT162b2: 82% [95% CI, 77 to 85], CoronaVac: 80% [95% CI, 76 to 84]), and mortality (BNT162b2: 94% [95% CI, 88 to 97], CoronaVac: 93% [95% CI, 88 to 96]). Vaccines were less effective in preventing infection and hospitalization in the eGFR <15 and 15-29 ml/min per 1.73 m 2 subgroups as compared with higher GFR subgroups. However, receipt of vaccine, even for one dose, was effective in preventing all-cause mortality, with estimates similar to the higher eGFR subgroups, as compared with unvaccinated. A dose-response relationship was observed between the number of BNT162b2 or CoronaVac doses and the effectiveness against COVID-19 infection and related comorbidity in the CKD population.

Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis

BackgroundSemaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects. This post hoc analysis investigated the association between major adverse cardiovascular events (MACE) and baseline kidney parameters and whether the effect of semaglutide on MACE risk was impacted by baseline kidney parameters in people with T2D at high cardiovascular risk.MethodsParticipants from the SUSTAIN 6 and PIONEER 6 trials, receiving semaglutide or placebo, were categorised according to baseline kidney function (estimated glomerular filtration rate [eGFR] < 45 and ≥ 45–<60 versus ≥ 60 mL/min/1.73 m2) or damage (urine albumin:creatinine ratio [UACR] ≥ 30–≤300 and > 300 versus < 30 mg/g). Relative risk of first MACE by baseline kidney parameters was evaluated using a Cox proportional hazards model. The same model, adjusted with inverse probability weighting, and a quadratic spline regression were applied to evaluate the effect of semaglutide on risk and event rate of first MACE across subgroups. The semaglutide effects on glycated haemoglobin (HbA1c), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated.ResultsIndependently of treatment, participants with reduced kidney function (eGFR ≥ 45–<60 and < 45 mL/min/1.73 m2: hazard ratio [95% confidence interval]; 1.36 [1.04;1.76] and 1.52 [1.15;1.99]) and increased albuminuria (UACR ≥ 30–≤300 and > 300 mg/g: 1.53 [1.14;2.04] and 2.52 [1.84;3.42]) had an increased MACE risk versus those without. Semaglutide consistently reduced MACE risk versus placebo across all eGFR and UACR subgroups (interaction p value [pINT] > 0.05). Semaglutide reduced HbA1c regardless of baseline eGFR and UACR (pINT>0.05); reductions in BW were affected by baseline eGFR (pINT<0.001) but not UACR (pINT>0.05). More participants in the lower eGFR or higher UACR subgroups experienced SAEs versus participants in reference groups; the number of SAEs was similar between semaglutide and placebo arms in each subgroup.ConclusionsMACE risk was greater for participants with kidney impairment or damage than for those without. Semaglutide consistently reduced MACE risk across eGFR and UACR subgroups, indicating that semaglutide provides cardiovascular benefits in people with T2D and at high cardiovascular risk across a broad spectrum of kidney function and damage.Trial registrationsNCT01720446; NCT02692716.

Polar vasculosis is associated with better kidney outcome in type 2 diabetes with biopsy-proven diabetic kidney disease: A multicenter cohort study.

This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes. We enrolled 811 patients with type 2 diabetes, biopsy-proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline. Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow-up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person-years) and 79 of 134 (11.4 events/100 person-years) cases with and without polar vasculosis, respectively. Kaplan-Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all-cause mortality before DKD progression as a competing event. This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria.

#3015 EFFECT OF DAPAGLIFLOZIN ON ALBUMINURIA IN PATIENTS WITH TYPE 2 DIABETES AND CKD

Abstract Background and Aims Albuminuria in patients with diabetes presents a higher risk for adverse renal and cardiovascular (CV) outcomes. Sodium-glucose co-transporter 2 (SGLT2) inhibitors demonstrate improved albuminuria and reduces the risk of end-stage renal disease in patients with chronic kidney disease. The study aim was the impact of the SGLT2 inhibitor dapagliflozin on urine albumin-to-creatinine ratio (UACR) and GFR decline. Method In the single center trial, total 132 participants with CKD and type 2 diabetes (T2D) were randomly assigned to dapagliflozin (n = 78) 10 mg once daily or placebo (n = 54). Kidney inclusion criteria were eGFR 30-60ml/min/1.73 m2 and any UACR. The primary end point was a composite of sustained decline in eGFR ≥50%, end-stage renal disease, or kidney or cardiovascular death. Percentage treatment difference was estimated by geometric mean ratio for the overall cohort and by eGFR and UACR subgroups. Progression/regression of UACR were assessed. Hazard ratios, 95% confidence intervals (CI), and p-values were estimated by Cox proportional hazards model. Results Median baseline eGFR was 42.3ml/min/1.73 m2, with 5% at &amp;lt;30ml/min/1.73 m2. At baseline, median UACR was 103 mg/g, and 1/4 of patients had normoalbuminuria, 2/4 had micro, and 1/4 had macroalbuminuria. Median follow up was 18 months. The UACR difference for dapagliflozin vs placebo was -25.1% (95% CI -27.5, -23.2; p&amp;lt;0.001). Reductions were similar across eGFRs. In UACR 30-299mg/g and ≥300mg/g, reductions were significant in dapagliflozin (p&amp;lt;0.001). Progression risk was lower and regression risk higher in dapagliflozin vs placebo (p&amp;lt;0.001). Conclusion Dapagliflozin significantly slowed long-term eGFR decline in patients with CKD with T2D compared with placebo, and significantly reduced UACR and had favorable effects on UACR progression and regression.

Trends of clinical parameters and incidences of diabetes mellitus complications among patients with type 2 diabetes mellitus in Hong Kong, 2010-2019: a retrospective cohort study.

Diabetes mellitus-related characteristics, including available medications, onset ages, and newly-introduced management program, have been changing recently in Hong Kong, especially after the introduction of the Risk Assessment and Management Program-Diabetes Mellitus in all outpatient clinics in 2009. To understand the plural change and improve the management of patients with Type 2 Diabetes Mellitus (T2DM) based on the latest data, we examined the trends of clinical parameters, T2DM complications and mortality in patients with T2DM in Hong Kong from 2010 to2019. In this retrospective cohort study, we acquired data from the Clinical Management System of the Hospital Authority in Hong Kong. Among adults with T2DM diagnosed on or before Sept 30, 2010, and with at least one attendance in general outpatient clinics between Aug 1, 2009, to Sept 30, 2010, we investigated the age-standardised trends of clinical parameters including haemoglobin A1c, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol (LDL-C), body mass index and estimated glomerular filtration rate (eGFR), complications including cardiovascular disease (CVD), peripheral vascular disease (PVD), sight-threatening diabetic retinopathy (STDR), neuropathy, eGFR<45mL/min/1.73m2 and end-stage renal disease (ESRD), and all-cause mortality from 2010 to 2019 and tested the statistical significance of the trends using generalised estimating equation by sex, level of clinical parameters and age groups. In total, 82,650 males and 97,734 females with T2DM were identified. LDL-C decreased from 3 to 2mmol/L in both males and females, while other clinical parameters changed within 5% over the full decade from 2010 to 2019. CVD, PVD, STDR, and neuropathy had declining incidences, while ESRD and all-cause mortality had increasing incidences from 2010 to 2019. The incidence of eGFR<45mL/min/1.73m2 increased in males but decreased in females. The odds ratio (OR) of ESRD (1.13, 95% CI [1.12, 1.15]) was highest in both males and females while the ORs of STDR (0.94, 95% CI [0.92, 0.96]) and neuropathy (0.90, 95% CI [0.88, 0.92]) were lowest in males and females, respectively. Complications and all-cause mortality trends varied among baseline HbA1c, eGFR, and age subgroups. In contrast to the findings in other age groups, the incidence of any outcomes did not decrease in younger patients (<45 years) from 2010 to2019. Improvements were observed in LDL-C and incidences of most complications from 2010 to 2019. Worse performance in the younger age group and increasing incidence of renal complications and mortality need more attention in managing patients with T2DM. The Health and Medical Research Fund, the Health Bureau, and Government of the Hong Kong Special Administrative Region.

Baseline eGFR, albuminuria and renal outcomes in patients with SGLT2 inhibitor treatment: an updated meta-analysis.

To elucidate the association between baseline renal characteristics and the disparities in renal outcomes among patients with SGLT2i treatment. Pubmed, Medline, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov were searched from inception to November 2022. Event-driven randomized controlled trials of SGLT2i with reports of renal outcomes were included. Sensitivity analyses of prespecified eGFR and UACR subgroups were conducted. Generally, compared with placebo, the use of SGLT2i was associated with improved renal prognosis (HR = 0.64, 95%CI 0.59-0.70). The magnitude of risk reductions in composite renal outcomes between SGLT2i versus placebo was comparable among different eGFR stratifications (normal renal function: HR = 0.49, 95%CI 0.31-0.79; mild renal impairment: HR = 0.57, 95%CI 0.48-0.68; moderate renal impairment: HR = 0.70, 95%CI 0.63-0.78; severe renal impairment: HR = 0.72, 95%CI 0.62-0.84; P for subgroup difference = 0.09). However, renal benefits seemd to be more prominent in normal to mildly increased albuminuria stratum (HR = 0.51, 95%CI 0.39-0.66) and severely increased albuminuria stratum (HR = 0.57, 95%CI 0.47-0.68), when compared with moderately increased albuminuria stratum (HR = 0.79, 95%CI 0.65-0.96; P for subgroup difference = 0.01). Generally, the use of SGLT2i was consistently associated with decreased risk of renal events in all prespecified eGFR and albuminuria spectrums, even in patients with substantial renal impairment. The renal benefits of SGLT2i seemed to be independent of baseline eGFR, while the risk reduction in renal events was more profound among patients with mildly increased albuminuria or severely increased albuminuria.

261 IMPACT OF BASELINE KIDNEY FUNCTION ON SGLT2 INHIBITOR EFFECTS ON RENAL AND HEART FAILURE OUTCOMES: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce renal and heart failure (HF) events in people with and without diabetes. Although their glycemic efficacy is dependent on kidney function, it remains unclear to what extent baseline kidney function influences the magnitude of SGLT2i cardiorenal effects. Methods We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials testing the effects of SGLT2i on renal and CV outcomes (PROSPERO registration number CRD42022325976). Efficacy outcomes, stratified by five estimated glomerular filtration rate (eGFR) categories, included progression of renal disease (as defined in each trial), a composite HF outcome (defined as CV death or hospitalization/urgent visit for HF), and all-cause mortality. Results Eleven trials testing five SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) in 77,541 participants were included. The majority of participants (39.8%) had eGFR values between 60 and 90 ml/min/1.73m2, with only 1.3% having advanced kidney disease (eGFR between 20 and 30 ml/min/1.73m2). Overall, SGLT2i reduced the risk of renal disease progression by 41% (HR 0.59, 95%CI 0.54–0.65, p&amp;lt;0.001) and the risk of HF outcomes by 22% (HR 0.78, 95%CI 0.73–0.83, p&amp;lt;0.001). Meta-regression analyses showed a significant direct relationship between baseline eGFR and the magnitude of SGLT2i renal protection (p=0.040). The greatest relative risk reduction was in participants with eGFR values ≥90 ml/min/1.73m2 (HR 0.43, 95%CI 0.32–0.58) and the smallest was in those with an eGFR between 30 and 45 ml/min/1.73m2 (HR 0.64, 95%CI 0.55–0.76). Conversely, the HF outcome showed a non-significant trend to greater benefit in participants with lower eGFR categories (p=0.086). The greatest relative risk reduction was in those with an eGFR between 20 and 30 ml/min/1.73m2 (HR 0.68, 95%CI 0.48–0.96, p=0.026) and the smallest was in those with an eGFR ≥90ml/min/1.73m2 (HR 0.87, 95%CI 0.56–1.35, p=0.52). Conclusions SGLT2i reduce risk of renal disease progression and HF outcomes for all eGFR subgroups. However, the opposite trends for the influence of baseline kidney function between renal and HF outcomes suggest different SGLT2i mechanisms for renal and cardiac protection.

Insight on Efficacy of Renal Artery Denervation for Refractory Hypertension with Chronic Kidney Diseases: A Long-Term Follow-Up of 24-Hour Ambulatory Blood Pressure.

Aims To explore the long-term efficacy and safety of renal denervation in patients with RHT and CKD, a post hoc analysis of eGFR subgroups was completed. Methods Fifty-four patients with refractory hypertension with chronic kidney disease were treated with RDN and enrolled in the study. Patients were divided into three groups according to eGFR: eGFR 46–90 ml/min group, eGFR 15–45 ml/min group, and eGFR <15 ml/min group. The planned follow-up period was 48 months to assess 24 h ambulatory blood pressure, renal function, type of antihypertensive medication, and RDN complications. Results The ablation sites of the GFR 46–90 ml/min group and GFR 15–45 ml/min group were 32.57 ± 2.99 and 29.53 ± 5.47, respectively. No complications occurred in the GFR 46–90 ml/min group. The GFR<15 ml/min group was treated with 27.07 ± 5.59 ablation. Renal artery dissection occurred in each group of GFR 15–45 ml/min and GFR <15 ml/min. And renal stent implantation artery was performed on these two patients. No severe renal artery stenosis occurred. There were no significant differences in Scr and eGFR between the three groups at each follow-up point. Compared with baseline, SBP was significantly of each group decreased to varying degrees at each follow-up time point. SBP decreased most in the GFR 46–90 ml/min group. Compared with baseline, the type of antihypertensive drugs used in the GFR46-90 ml/min group decreased significantly except for 36 and 48 months. At 48 months' postadmission, there was a significant decrease in the type of antihypertensive medication used in the GFR15-45 ml/min group, and there was no significant decrease in the type of antihypertensive medication used in the GFR<15 ml/min group. Conclusions RDN can safely reduce SBP in CKD patients combined with RHT for 48 months, with the most pronounced reduction in the GFR15-45 ml/min group. The variety of antihypertensive drugs was significantly reduced after RDN. This was particularly evident in patients with GFR 15–45 ml/min.

Hemoglobin A1c Reduction With the GLP-1 Receptor Agonist Semaglutide Is Independent of Baseline eGFR: post hoc Analysis of the SUSTAIN and PIONEER Programs

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for reducing hemoglobin A1c (HbA1c) in people with type 2 diabetes (T2D), including those with reduced kidney function. This post hoc analysis assessed the HbA1c-lowering efficacy of semaglutide, a GLP-1RA, in participants with a range of kidney functions in the SUSTAIN 4-6 and 10 (subcutaneous semaglutide) and PIONEER 5 and 6 (oral semaglutide) clinical trials. Trial-level changes from baseline to end of treatment (EOT) in HbA1c and body weight (BW) were assessed in participants with estimated glomerular filtration rate (eGFR) >15 ml/min per 1.73 m2 by subgroups categorized according to baseline eGFR. Adverse events were also evaluated. The analysis included 8859 participants. The mean comparator-adjusted reduction in HbA1c from baseline to EOT with semaglutide ranged from 0.6% to 1.6% points across trials, with similar reductions across the eGFR subgroups (interaction P-value≥ 0.33 for difference between eGFR subgroups within each trial). Greater weight loss from baseline to EOT with semaglutide versus comparator was observed across almost all baseline eGFR subgroups, with nominally greater weight loss with lower versus higher eGFR in SUSTAIN 6 and 10 and PIONEER 5 and 6 (interaction P< 0.05). No new safety concerns with semaglutide were identified. The HbA1c-lowering effect of semaglutide in participants with T2D was comparable irrespective of eGFR, which ranged upwards from eGFR >15 ml/min per 1.73 m2.

FC 124: Real-World Use of Once-Weekly Semaglutide by Baseline Estimated Glomerular Filtration Rate—A Post-Hoc Analysis of Pooled Data From the Sure Studies (Canada, Denmark/Sweden, Switzerland and UK)

Abstract BACKGROUND AND AIMS The SURE programme of observational real-world studies is investigating once-weekly (OW) subcutaneous semaglutide in routine clinical practice across a diverse type 2 diabetes (T2D) patient population, including those with chronic kidney disease. This pooled post-hoc analysis of SURE Canada, Denmark/Sweden, Switzerland and UK evaluated OW semaglutide use and outcomes according to kidney function at semaglutide initiation. METHOD The SURE studies (all ∼30 weeks’ duration) enrolled adults (≥18 years) with T2D who received OW semaglutide and other anti-hyperglycaemic drugs prescribed at physician discretion; pooled data were analysed to determine change from baseline to end of study (EOS) in HbA1c and body weight (BW) by estimated glomerular function rate (eGFR) subgroups (&amp;lt;30, 30 to &amp;lt;45, 45 to &amp;lt;60, 60 to &amp;lt;90, and ≥90 mL/min/1.73 m2). Safety outcomes were assessed; only serious adverse drug reactions (SADRs) were systematically recorded. RESULTS Data from 913 patients with median (interquartile range) age of 61 (54–68) years and T2D duration of 11.0 (6.2–17.2) years were included. Patients with eGFR &amp;lt;45 mL/min/1.73 m2 were more likely to be older with longer T2D duration than those with eGFR ≥45 mL/min/1.73 m2. Patients with low eGFR were more likely to be receiving insulin at baseline than those in higher eGFR subgroups. At EOS, there were significant reductions in HbA1c and BW in all subgroups with eGFR ≥30 mL/min/1.73 m2 (P &amp;lt;0.0001; Figure 1). The rates of SADRs and adverse events leading to treatment discontinuation were low across all eGFR subgroups (≤0.3% and ≤1.8%, respectively). Overall, 50/72 patients who experienced more than or equal to severe or documented hypoglycaemic episode were receiving insulin at baseline. CONCLUSION OW semaglutide provided clinically relevant glycaemic control and BW improvements, and was well tolerated, in patients with varying degrees of kidney impairment at treatment initiation in a real-world setting. These findings support semaglutide use in routine clinical practice regardless of patients’ kidney function.

Efficacy and safety of dronedarone versus placebo in patients with atrial fibrillation stratified according to renal function: Post hoc analyses of the EURIDIS‐ADONIS trials

BackgroundThe use of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is complex because impaired renal clearance can cause increased drug levels, and risk of intolerance or adverse events. Due to the propensity for CKD to occur alongside atrial fibrillation/atrial flutter (AF/AFL), it is essential that AAD safety and efficacy are assessed for patients with CKD.HypothesisDronedarone, an approved AAD, may present a suitable therapeutic option for patients with AF/AFL and concomitant CKD.MethodsEURIDIS‐ADONIS (EURIDIS, NCT00259428; ADONIS, NCT00259376) were identically designed, multicenter, double‐blind, parallel‐group trials investigating AF/AFL control with dronedarone 400 mg twice daily versus placebo (randomized 2:1). In this post hoc analysis, the primary endpoint was time to first AF/AFL. Patients were stratified according to renal function using the CKD‐Epidemiology Collaboration equation and divided into estimated glomerular filtration rate (eGFR) subgroups of 30–44, 45–59, 60–89, and ≥90 ml/min. Time‐to‐events between treatment groups were compared using log‐rank testing and Cox regression.ResultsAt baseline, most (86%) patients demonstrated a mild or mild‐to‐moderate eGFR decrease. Median time to first AF/AFL recurrence was significantly longer with dronedarone versus placebo for all eGFR subgroups except the 30 to 44 ml/min group, where the trend was similar but statistical power may have been limited by the small population. eGFR stratification had no significant effect on serious adverse events, deaths, or treatment discontinuations.ConclusionsThis analysis suggests that dronedarone could be an effective therapeutic option for AF with an acceptable safety profile in patients with impaired renal function.

Impact of Renal Function on Effectiveness and Safety Associated With Low Dose Dabigatran in Non-valve Atrial Fibrillation Patients After Catheter Ablation.

Aim: The purpose of this study is to compare the effectiveness and safety of 110 mg dabigatran in non-valve atrial fibrillation (NVAF) patients with different eGFRs.Methods: We conducted a single-center retrospective cohort study to investigate the effectiveness and safety of 110 mg dabigatran for NVAF patients between January 2017 and December 2018 based on the eGFR category.Results: A total of 560 NVAF patients who treated with 110 mg dabigatran were included for analysis. In 12 months, the Kaplan-Meier survival curves indicated that the lower eGFR subgroups were more likely to experience thrombosis, bleeding, and cumulative events earlier (P = 0.021 for thrombosis; P = 0.026 for bleeding; P = 0.001 for cumulative events). Gastrointestinal bleeding occurred more frequently in the moderate group than in other groups (6.94% in the moderate group vs. 1.54% in the mild group vs. 1.22% in the normal group, P = 0.028). By multivariate analysis, chronic kidney disease (P = 0.043; OR = 4.273, 95% CI 1.043–17.543) and diabetes mellitus (P = 0.023; OR = 2.194, 95% CI 1.114–4.323) were independent predictors of the composite endpoints. A positive linear relationship was observed between eGFR levels and occurrence rate of thrombosis and bleeding under anticoagulation patients with 110 mg dabigatran (R2 = 0.432 and R2 = 0.784, respectively).Conclusions: Impaired renal function was associated with decreased safety and increased thrombosis risks in NVAF patients taking low dose dabigatran.

Effects of canagliflozin on major adverse cardiovascular events by baseline estimated glomerular filtration rate: Pooled Hispanic subgroup analyses from the CANVAS Program and CREDENCE trial.

To assess the risk of major adverse cardiovascular events (MACE) of canagliflozin in Hispanic patients with type 2 diabetes (T2D) and high cardiovascular risk or nephropathy with varying levels of kidney function. This post hoc analysis included integrated, pooled data from the CANVAS Program and CREDENCE trial. The effects of canagliflozin versus placebo on major adverse cardiovascular events (MACE; i.e. cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) were assessed in subgroups by baseline estimated glomerular filtration rate (eGFR; <45, 45-60, and >60 mL/min/1.73 m2 ) overall and in the Hispanic cohort. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models, with subgroup by treatment interaction terms added to test for heterogeneity. A total of 14 543 participants were included; 3029 (20.8%) self-identified as Hispanic. In the overall population, canagliflozin reduced the risk of MACE compared with placebo (HR, 0.83; 95% CI, 0.75, 0.92), with no heterogeneity observed across eGFR subgroups (interaction P=.22). In the Hispanic cohort, canagliflozin also reduced the risk of MACE (HR, 0.71; 95% CI, 0.55, 0.92), with no heterogeneity by baseline eGFR (interaction P=.25), including among the Hispanic participants at highest risk with a baseline eGFR of less than 45 mL/min/1.73m2 . Canagliflozin reduced the risk of MACE overall, and among Hispanic participants with T2D and high cardiovascular risk or nephropathy in the CANVAS Program and CREDENCE trial, without heterogeneity by baseline eGFR.

Safety and effectiveness of ipragliflozin in Japanese patients with type 2 diabetes mellitus and impaired renal function: subgroup analysis of a 3-year post-marketing surveillance study (STELLA-LONG TERM)

STELLA-LONG TERM, a 3-year post-marketing surveillance study, evaluated the safety and effectiveness of the sodiumglucose cotransporter 2 inhibitor ipragliflozin in Japanese type 2 diabetes mellitus (T2DM) patients. Final results in the safety (n = 6697) and effectiveness populations (n = 5625) were analyzed by stratifying patients by baseline estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) into four subgroups (≥90, 60 to &lt;90, 45 to &lt;60, and &lt;45) and two subgroups (≥60 and &lt;60). Adverse drug reaction (ADR) incidence, and changes from baseline in glycosylated hemoglobin (HbA1c), bodyweight, and eGFR were assessed. The percentage of patients experiencing ADRs and serious ADRs was similar across most eGFR subgroups. Polyuria/pollakiuria was the most common ADR. Renal disorders and volume depletion ADRs were more frequent in the subgroups with more severe renal impairment at baseline than in those with an eGFR of 60 to &lt;90 or ≥90 mL/min/1.73 m2. Bodyweight and HbA1c decreased in all subgroups, the latter by − 0.91% to − 0.40% (P &lt;0.05 vs. baseline). eGFR increased in the 45 to &lt;60 mL/min/1.73 m2 subgroup (+ 1.42 ± 8.77 mL/min/1.73 m2; P = 0.006). It decreased in the ≥90 and 60 to &lt;90 mL/min/1.73 m2 subgroups (− 8.27 ± 13.73 and − 1.22 ± 10.34 mL/min/1.73 m2; P &lt;0.001), but not to &lt;60 mL/min/1.73 m2. In conclusion, there were no new or unexpected safety findings in Japanese patients treated with ipragliflozin for T2DM, and long-term sustained improvements in HbA1c and bodyweight were observed regardless of the presence of renal impairment.

SGLT2 Inhibitors and Kidney and Cardiac Outcomes According to Estimated GFR and Albuminuria Levels: A Meta-analysis of Randomized Controlled Trials

Rationale & ObjectiveThere are few data on the absolute effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors, despite their importance in treatment decision making. We investigated absolute treatment effects according to baseline kidney disease status.Study DesignMeta-analysis.Study PopulationsAdults with type 2 diabetes, chronic kidney disease, or heart failure.Selection Criteria for StudiesRandomized controlled trials of SGLT2 inhibitors (10 trials to November 20, 2020) for clinical outcomes of kidney disease progression, heart failure events, and major cardiovascular events.Data ExtractionPublications of 10 trials to November 20, 2020.Analytical ApproachThe incidence rate difference (IRD) between SGLT2 inhibitor and placebo was compared across estimated glomerular filtration rate (eGFR) or urinary albumin-creatinine ratio (UACR) subgroups.ResultsSubgroup analyses included data from seven trials (61,821 participants with diabetes or chronic kidney disease). SGLT2 inhibitor treatment, in eGFR subgroups of <45, 45 to <60, and ≥60 mL/min/1.73 m2, reduced 16.0, 9.5, and 1.9 heart failure events per 1,000 patient-year, respectively (P < 0.001 for heterogeneity). In urine UACR subgroups of >300, 30 to 300, and <30 mg/g, SGLT2 inhibitors reduced 17.3, 1.4, and 2.2 kidney disease events per 1,000 patient-year, respectively (P < 0.001 for heterogeneity), and 14.8, 8.7, and 2.1 heart failure events per 1,000 patient-year, respectively (P = 0.006 for heterogeneity). The pooled IRDs for major cardiovascular events were also greater in lower eGFR or overt albuminuria subgroups. In secondary analyses, risk differences calculated using pooled baseline and relative risks were comparable to the pooled IRDs, while the relative risk reductions for kidney and heart failure outcomes were consistent across the subgroups. For treatment-related harms, IRDs were similar between eGFR subgroups.LimitationsStudy-level data rather than individual patient data were used.ConclusionsSGLT2 inhibitor treatment resulted in greater reductions of cardiovascular events in patients with lower eGFR and higher albuminuria and had substantially greater absolute benefits of renoprotection in patients with overt albuminuria than in their counterparts.

775-P: Effects of Canagliflozin (CANA) on Major Adverse Cardiovascular Events (MACE) by Baseline EGFR: Pooled Hispanic Subgroup Analysis from the CANVAS Program and CREDENCE

Introduction: CANA reduced the risk of MACE (cardiovascular [CV] death, nonfatal myocardial infarction, and nonfatal stroke) in the CANVAS Program and CREDENCE trials of patients with type 2 diabetes with high CV risk or nephropathy, respectively, regardless of baseline eGFR. The risk of MACE by renal status had not been examined in Hispanic participants, who have a higher MACE burden. Methods: This analysis used integrated data from the CANVAS Program (N = 10,142) and CREDENCE (N = 4401). The effects of CANA versus placebo on MACE were assessed in subgroups defined by baseline eGFR ( 60 mL/min/1.73 m2) overall and in the Hispanic subgroup. Results: Of the 14,540 participants with baseline eGFR values, 3028 (21%) self-identified as Hispanic. In the overall population, CANA reduced the risk of MACE (HR, 0.83; 95% CI, 0.75, 0.92), with consistent effects across eGFR subgroups (interaction P value = 0.22; Figure). In the Hispanic subgroup, CANA also reduced the risk of MACE (HR, 0.71; 95% CI, 0.55, 0.92) regardless of eGFR (interaction P value = 0.25). Even the highest risk Hispanic participants with baseline eGFR Conclusion: CANA reduced the risk of MACE overall and among Hispanic participants from the CANVAS Program and CREDENCE, regardless of baseline eGFR. Disclosure M. R. Weir: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Vifor Pharma Management Ltd. J. Gogate: Employee; Self; Janssen Research & Development, LLC. C. Damaraju: Employee; Self; Janssen Research & Development, LLC. R. Correa-rotter: Consultant; Self; GlaxoSmithKline plc., Other Relationship; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc., Speaker’s Bureau; Self; AbbVie Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceutical Co. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. Funding Janssen Scientific Affairs, LLC

321-OR: Effects of Canagliflozin (CANA) on Hospitalization for Heart Failure (HHF) by Baseline EGFR: Pooled Analysis from the CANVAS Program and CREDENCE

People with type 2 diabetes (T2D) are at high risk for CV events, including HHF, especially as kidney function declines. We examined the effects of CANA on risk of HHF by baseline eGFR in patients with T2D and high CV risk and/or chronic kidney disease from the CANVAS Program and CREDENCE. Patient-level data from the CANVAS Program (N = 10,142) and CREDENCE (N = 4401) were pooled. Cox proportional hazards model for the time to first/second HHF events and proportional means model based on cumulative mean function for recurrent HHF events were used to assess effects overall as well as within baseline eGFR strata ( 60 mL/min/1.73 m2). HHF events were independently and blindly adjudicated. In 14,540 participants with baseline eGFR values over a median follow-up of 130 weeks, 672 HHF events occurred; 357 (53%) were single events. CANA decreased the time to first HHF event (HR 0.58, 95% CI 0.48, 0.70; Figure), consistently regardless of baseline eGFR (interaction P = 0.84), and time to second HHF event (HR 0.67, 95% CI 0.46, 0.96; too few events to stratify by eGFR). CANA also decreased total HHF events overall (mean event ratio 0.63, 95% CI 0.54, 0.73) and across eGFR subgroups (interaction P = 0.51). In individuals with T2D in the CANVAS Program and CREDENCE, CANA decreased the risk of first and recurrent HHF events, with consistent benefits independent of baseline eGFR. Disclosure M. N. Kosiborod: Consultant; Self; Amgen Inc., Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk, Sanofi, Vifor Pharma Management Ltd., Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. J. Gogate: Employee; Self; Janssen Research & Development, LLC. J. Seufert: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi, Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. Funding Janssen Scientific Affairs, LLC