Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: The CREDENCE trial

Aims Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium-glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. Methods and results The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. Conclusion Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia

Dapagliflozin and Anemia in Patients with Chronic Kidney Disease

BACKGROUND: In the DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease) trial, dapagliflozin improved kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) with or without type 2 diabetes (T2D). In this post hoc analysis of DAPA-CKD, we assessed the effects of dapagliflozin on the correction and prevention of anemia. METHODS: The DAPA-CKD trial randomized patients (1:1) with an estimated glomerular filtration rate of 25 to 75 ml/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 200 to 5000 mg/g to receive dapagliflozin 10 mg or placebo daily. Hematocrit was measured at baseline, 2 weeks, 2 and 4 months, and every 4 months thereafter. Anemia was defined as hematocrit less than 39% in men and less than 36% in women. Correction and incidence of anemia were defined as two consecutive measurements above or below these thresholds relative to baseline, respectively, during follow-up. We classified anemia-related adverse events using data from site investigator reports. RESULTS: Mean age of the 4304 participants was 61.8 years, and 67.5% had T2D. Among the 4292 (99.7%) participants with baseline hematocrit data, 1716 (40.0%) had anemia. Over the 2.4-year median follow-up, patients assigned to dapagliflozin had an increase in hematocrit of 2.3 percentage points (95% confidence interval [CI], 2.1 to 2.5) greater than those assigned to placebo. Among patients with anemia at baseline, anemia was corrected in 443 (53.3%) patients randomized to receive dapagliflozin and 247 (29.4%) patients randomized to receive placebo (hazard ratio, 2.29; 95% CI, 1.96 to 2.68). Among patients without anemia at baseline, 10.4% of patients assigned to dapagliflozin developed incident anemia compared with 23.7% in the placebo group (hazard ratio, 0.39; 95% CI, 0.31 to 0.48). Anemia-related adverse events occurred in 2.2% of patients assigned to dapagliflozin compared with 3.8% assigned to placebo. Effects of dapagliflozin on the correction and prevention of anemia were consistent in patients with and without T2D. The adverse event profile was similar to that known for dapagliflozin. CONCLUSIONS: This exploratory analysis suggests that dapagliflozin is associated with the prevention or correction of anemia in patients with CKD with and without T2D. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03036150.

Blood pressure effects of canagliflozin and clinical outcomes in type 2 diabetes and chronic kidney disease: Insights from the CREDENCE trial

Background: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) experience a high burden of hypertension but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population is uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP lowering therapy is also unknown. Methods: The CREDENCE trial randomized people with T2DM and CKD to canagliflozin or placebo. Post-hoc, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mmHg while receiving ≥3 classes of BP lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4,401 participants of whom 3,361 (76.4%) had baseline systolic BP ≥130 mmHg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50mmHg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP lowering therapy subgroups (all P-interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP lowering agents during the trial (HR 0.68, 95% CI 0.61-0.75). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease (HR 0.70, 95% CI 0.59-0.82) was consistent across BP and BP lowering therapy subgroups (all P-interaction ≥0.35), as were effects on other key kidney, cardiovascular and safety outcomes. Conclusions: In people with T2DM and CKD, canagliflozin lowers systolic BP across all BP defined subgroups and reduces the need for additional BP lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP lowering therapy in people with CKD. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique Identifier: NCT02065791

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

Background: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. Methods: In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol). Results: Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR). Conclusions: Participants with a wide range of underlying kidney diseases receiving renin–angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2–4 and increased albuminuria, with and without T2D

Cost-effectiveness analysis of timely dialysis referral after renal transplant failure in Spain

<p>Abstract</p> <p>Background</p> <p>A cost-effectiveness analysis of timely dialysis referral after renal transplant failure was undertaken from the perspective of the Public Administration. The current Spanish situation, where all the patients undergoing graft function loss are referred back to dialysis in a late manner, was compared to an ideal scenario where all the patients are timely referred.</p> <p>Methods</p> <p>A Markov model was developed in which six health states were defined: hemodialysis, peritoneal dialysis, kidney transplantation, late referral hemodialysis, late referral peritoneal dialysis and death. The model carried out a simulation of the progression of renal disease for a hypothetical cohort of 1,000 patients aged 40, who were observed in a lifetime temporal horizon of 45 years. In depth sensitivity analyses were performed in order to ensure the robustness of the results obtained.</p> <p>Results</p> <p>Considering a discount rate of 3 %, timely referral showed an incremental cost of 211 €, compared to late referral. This cost increase was however a consequence of the incremental survival observed. The incremental effectiveness was 0.0087 quality-adjusted life years (QALY). When comparing both scenarios, an incremental cost-effectiveness ratio of 24,390 €/QALY was obtained, meaning that timely dialysis referral might be an efficient alternative if a willingness-to-pay threshold of 45,000 €/QALY is considered. This result proved to be independent of the proportion of late referral patients observed. The acceptance probability of timely referral was 61.90 %, while late referral was acceptable in 38.10 % of the simulations. If we however restrict the analysis to those situations not involving any loss of effectiveness, the acceptance probability of timely referral was 70.10 %, increasing twofold that of late referral (29.90 %).</p> <p>Conclusions</p> <p>Timely dialysis referral after graft function loss might be an efficient alternative in Spain, improving both patients’ survival rates and health-related quality of life at an affordable cost. Spanish Public Health authorities might therefore promote the inclusion of specific recommendations for this group of patients within the existing clinical guidelines.</p

Infecção pelo vírus da hepatite c em pacientes em hemodiálise: prevalência e fatores de risco

CONTEXTO: Doentes com doença renal crônica em tratamento hemodialítico apresentam risco aumentado de aquisição do vírus da hepatite C (VHC). Elevadas taxas de prevalência têm sido detectadas em unidades de diálise do mundo inteiro. Estudos recentes têm demonstrado que a infecção pelo VHC interfere de forma negativa na sobrevida dos pacientes em hemodiálise e naqueles submetidos ao transplante renal. OBJETIVOS: Determinar a prevalência e os fatores de risco da infecção pelo VHC em pacientes submetidos a hemodiálise. MÉTODOS: Realizou-se estudo transversal entre janeiro e dezembro de 2007. Neste período, 236 pacientes em hemodiálise foram testados pelo ELISA de terceira geração. Os casos positivos foram submetidos a pesquisa qualitativa do HCV-RNA pelo método de PCR. Consideraram-se como portadores de infecção pelo VHC aqueles pacientes com anti-VHC e HCV-RNA positivos. Dosagens mensais de ALT e a média do valor de 12 meses foram obtidas em 195 pacientes. Do total de pacientes, 208 (88,1%) responderam ao questionário padronizado visando a identificação de fatores de risco associados à infecção pelo VHC. RESULTADOS: A prevalência de pacientes anti-VHC positivos encontrada entre os 236 testados foi de 14,8% (35/236); destes, a pesquisa do HCV-RNA foi positiva em 71,6% (25/35). Portanto, a prevalência da infecção crônica pelo VHC foi de 10,6% (25/236) dos pacientes. Pela análise bivariada, os principais fatores de risco associados à infecção pelo VHC foram o tempo de hemodiálise, o número de transfusões de sangue, a realização prévia de diálise peritonial e história de doença sexualmente transmissível. Contudo, após análise multivariada, somente o tempo de hemodiálise e história de doença sexualmente transmissível foram significativamente associados à infecção pelo VHC. Pacientes com mais de 10 anos de hemodiálise apresentaram risco de aquisição do VHC 73,9 (IC de 17,5 a 311,8) vezes maior quando comparados a pacientes com até 5 anos de tratamento. Indivíduos com doença sexualmente transmissível prévia apresentaram risco 4,8 (IC de 1,1 a 19,9) vezes superior de contaminação pelo VHC quando comparados àqueles sem doença sexualmente transmissível. O valor médio da ALT foi significantemente maior nos pacientes infectados pelo VHC (44,0 ± 13,5 U/L versus 33,5 ± 8,0 U/L, PCONTEXT: Chronic renal disease patients on hemodialysis are at increased risk of infection by hepatitis C virus (HCV). High prevalence rates have been reported from dialysis units worldwide. Recent studies have shown an inverse relation between HCV infection and life expectancy of patients on hemodialysis and those undergoing renal transplant. OBJECTIVES: Assess the prevalence of and risk factors for HCV infection in patients undergoing hemodialysis. METHODS: A cross-sectional study was undertaken from January to December, 2007. During this period, 236 patients were tested for anti-HCV antibodies with third generation ELISA. Those who tested positive further underwent qualitative PCR testing for HCV-RNA. A subject was considered HCV-infected if both tests (anti-HCV and HCV-RNA) were positive. Monthly serum ALT and the mean for the 12-month period were obtained from 195 patients. Two hundred eight (88.1%) patients answered a standardized questionnaire aiming to identify risk factors for HCV infection. RESULTS: Of the 236 subjects studied, 14.8% (35/236) tested positive for anti-HCV antibodies. Of these, 71.6% (25/35) tested positive for HCV-RNA. Chronic HCV infection was thus prevalent in 10.6% (25/236). Bivariate analysis showed time on hemodialysis, number of blood transfusions, previous peritoneal dialysis and previous sexually transmitted diseases to be the main risk factors for HCV infection. Yet multivariate analysis showed that just time on hemodialysis and previous sexually transmitted diseases were significantly associated with HCV infection. Patients on hemodialysis for over 10 years were 73.9 (CI 17.5-311.8) times as likely to have acquired HCV, compared with those on hemodialysis for up to 5 years. Patients with previous sexually transmitted diseases had a 4.8 times higher risk of HCV infection compared with those without previous sexually transmitted diseases. Mean serum ALT was significantly higher in HCV-infected patients (44.0 ±13.5 U/L versus 33.5 ± 8.0 U/L, P<0,001). CONCLUSION: HCV infection was highly prevalent in the dialysis unit studied. Time on dyalitic treatment and previous sexually transmitted diseases were the main risk factors for HCV infection. HCV-infected patients on hemodialysis had higher serum ALT levels than those without chronic HCV infection