A Comparison of Sodium-Glucose Co-Transporter 2 Inhibitor Kidney Outcome Trial Participants with a Real-World Chronic Kidney Disease Primary Care Population.

BACKGROUND/HYPOTHESIS: Observational studies suggest sodium-glucose co-transporter-2 (SGLT2) inhibitor kidney outcome trials are not representative of the broader population of people with chronic kidney disease (CKD). However, there are limited data on the generalisability to those without co-existing type 2 diabetes (T2D), and the representativeness of the EMPA-KIDNEY trial has not been adequately explored. We hypothesised that SGLT2 inhibitor kidney outcome trials are more representative of people with co-existing T2D than those without, and that EMPA-KIDNEY is more representative than previous trials. METHODS: A cross-sectional analysis of adults with CKD in English primary care was conducted using the Oxford-Royal College of General Practitioners Clinical Information Digital Hub. The proportions that met the eligibility criteria of SGLT2 inhibitor kidney outcome trials were determined, and their characteristics described. Logistic regression analyses were performed to identify factors associated with trial eligibility. RESULTS: Of 6,670,829 adults, 516,491 (7.7%) with CKD were identified. In the real-world CKD population, 0.9%, 2.2%, and 8.0% met the CREDENCE, DAPA-CKD, and EMPA-KIDNEY eligibility criteria, respectively. All trials were more representative of people with co-existing T2D than those without T2D. Trial participants were 9-14 years younger than the real-world CKD population, and had more advanced CKD, including higher levels of albuminuria. A higher proportion of the CREDENCE (100%), DAPA-CKD (67.6%) and EMPA-KIDNEY (44.5%) trial participants had T2D compared to the real-world CKD population (32.8%). Renin-angiotensin system inhibitors were prescribed in almost all trial participants, compared to less than half of the real-world CKD population. Females were under-represented and less likely to be eligible for the trials. CONCLUSION: SGLT2 inhibitor kidney outcome trials represent a sub-group of people with CKD at high risk of adverse kidney events. Out study highlights the importance of complementing trials with real-world studies, exploring the effectiveness of SGLT2 inhibitors in the broader population of people with CKD.

Implementation of chronic kidney disease guidelines for sodium-glucose co-transporter-2 inhibitor use in primary care in the UK: a cross-sectional study.

Background: The cardiovascular and kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with chronic kidney disease (CKD) are well established. The implementation of updated SGLT2 inhibitor guidelines and prescribing in the real-world CKD population remains largely unknown. Methods: A cross-sectional study of adults with CKD registered with UK primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022 was undertaken. Pseudonymised data from electronic health records held securely within the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) were extracted. An update to a previously described ontological approach was used to identify the study population, using a combination of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) indicating a diagnosis of CKD and laboratory confirmed CKD based on Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. A logistic regression model was used to identify factors associated with SGLT2 inhibitor prescribing, reported as odds ratios (ORs) with 95% confidence intervals (CI). The four guidelines under investigation were the United Kingdom Kidney Association (UKKA) Clinical Practice Guideline SGLT2 Inhibition in Adults with Kidney Disease (October 2021), American Diabetes Association (ADA) and KDIGO Consensus Report on Diabetes Management in CKD (October 2022), National Institute for Health and Care Excellence (NICE) Guideline Type 2 Diabetes in Adults: Management (June 2022), and NICE Technology Appraisal Dapagliflozin for Treating CKD (March 2022). Findings: Of 6,670,829 adults, we identified 516,491 (7.7%) with CKD, including 32.8% (n = 169,443) who had co-existing type 2 diabetes (T2D). 26.8% (n = 138,183) of the overall CKD population had a guideline directed indication for SGLT2 inhibitor treatment. A higher proportion of people with CKD and co-existing T2D were indicated for treatment, compared to those without T2D (62.8% [n = 106,468] vs. 9.1% [n = 31,715]). SGLT2 inhibitors were prescribed to 17.0% (n = 23,466) of those with an indication for treatment, and prescriptions were predominantly in those with co-existing T2D; 22.0% (n = 23,464) in those with T2D, and <0.1% (n = 2) in those without T2D. In adjusted multivariable analysis of people with CKD and T2D, females (OR 0.69, 95% CI 0.67-0.72, p <0.0001), individuals of Black ethnicity (OR 0.84, 95% CI 0.77-0.91, p <0.0001) and those of lower socio-economic status (OR 0.72, 95% CI 0.68-0.76, p <0.0001) were less likely to be prescribed an SGLT2 inhibitor. Those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m2 (eGFR 45-60 mL/min/1.73 m2 OR 0.65, 95% CI 0.62-0.68, p <0.0001, eGFR 30-45 mL/min/1.73 m2 OR 0.73, 95% CI 0.69-0.78, p <0.0001, eGFR 15-30 mL/min/1.73 m2 OR 0.52, 95% CI 0.46-0.60, p <0.0001, eGFR <15 mL/min/1.73 m2 OR 0.03, 95% CI 0.00-0.23, p = 0.0037, respectively). Those with albuminuria (urine albumin-to-creatinine ratio 3-30 mg/mmol) were less likely to be prescribed an SGLT2 inhibitor, compared to those without albuminuria (OR 0.78, 95% CI 0.75-0.82, p <0.0001). Interpretation: SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. Individuals at higher risk of adverse outcomes are paradoxically less likely to receive SGLT2 inhibitor treatment. The timeframe between the publication of guidelines and data extraction may have been too short to observe changes in clinical practice. Enhanced efforts to embed SGLT2 inhibitors equitably into routine care for people with CKD are urgently needed, particularly in those at highest risk of adverse outcomes and in the absence of T2D. Funding: None.

Sodium-glucose cotransporter-2 inhibitors and kidney outcomes in real-world type 2 diabetes populations: A systematic review and meta-analysis of observational studies.

AIM: To conduct a systematic review of observational studies to explore the real-world kidney benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in a large and diverse population of adults with type 2 diabetes (T2D). MATERIALS AND METHODS: We searched MEDLINE, EMBASE and Web of Science for observational studies that investigated kidney disease progression in adults with T2D treated with SGLT2 inhibitors compared to other glucose-lowering therapies. Studies published from database inception to July 2022 were independently reviewed by two authors and evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. A random-effects meta-analysis was performed on studies with comparable outcome data, reported as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: We identified 34 studies performed across 15 countries with a total population of 1 494 373 for inclusion. In the meta-analysis of 20 studies, SGLT2 inhibitors were associated with a 46% lower risk of kidney failure events compared with other glucose-lowering drugs (HR 0.54, 95% CI 0.47-0.63). This finding was consistent across multiple sensitivity analyses and was independent of baseline estimated glomerular filtration rate (eGFR) or albuminuria status. SGLT2 inhibitors were associated with a lower risk of kidney failure when compared with dipeptidyl peptidase-4 inhibitors and a combination of other glucose-lowering drug classes (HR 0.50, 95% CI 0.38-0.67 and HR 0.51, 95% CI 0.44-0.59, respectively). However, when compared to glucagon-like peptide 1 receptor agonists there was no statistically significant difference in the risk of kidney failure (HR 0.93, 95% CI 0.80-1.09). CONCLUSIONS: The reno-protective benefits of SGLT2 inhibitors apply to a broad population of adults with T2D treated in routine clinical practice, including those at lower risk of kidney events with normal eGFR and without albuminuria. These findings support the early use of SGLT2 inhibitors in T2D for preservation of kidney health.

Serum sodium concentration and the progression of established chronic kidney disease.

BACKGROUND: Higher serum sodium concentration has been reported to be a risk factor for the development of incident chronic kidney disease (CKD), but its relationship with the progression of established CKD has not been investigated. We hypothesised that increased serum sodium concentration is a risk factor for estimated glomerular filtration rate (eGFR) decline in CKD. METHODS: This was a retrospective cohort study using data collected over a 6-year period, with baseline data obtained during the first 2 years. We included patients known to our renal service who had had a minimum of three blood tests every 2 years and an eGFR of < 60 mL/min/1.73 m2 at baseline. Exclusion criteria were renal replacement therapy, diabetes mellitus, heart failure and decompensated liver disease. A multiple linear regression model investigated the relationship between baseline serum sodium and eGFR decline after adjustment for confounding factors. RESULTS: 7418 blood results from 326 patients were included. There was no relationship between serum sodium concentration and estimated glomerular filtration rate at baseline. After multivariable adjustment, a 1 mmol/L increase in baseline serum sodium was associated with a 1.5 mL/min/1.73 m2 decline in eGFR during the study period (95% CI 0.9, 2.0). A reduction in eGFR was not associated with significant changes in serum sodium concentration over 6 years. CONCLUSION: Higher serum sodium concentration is associated with the progression of CKD, independently of other established risk factors. Conversely, significant alterations in serum sodium concentration do not occur with declining kidney function.

The association between serum sodium concentration, hypertension and primary cardiovascular events: a retrospective cohort study.

The mechanisms underlying the adverse cardiovascular effects of increased salt intake are incompletely understood, but parallel increases in serum sodium concentration may be of importance. The aim of this retrospective cohort study was to investigate the relationship between serum sodium, hypertension and incident cardiovascular disease (CVD). Routinely collected primary care data from the Royal College of General Practitioners Research and Surveillance Centre were analysed. A total of 231,545 individuals with a measurement of serum sodium concentration at baseline were included. Exclusion criteria were: age < 40 years; abnormal serum sodium; diabetes mellitus; prior CVD event; stage 5 chronic kidney disease; and liver cirrhosis. The primary outcome was incident CVD (myocardial infarction, acute coronary syndrome, coronary revascularisation, stroke, transient ischaemic attack or new heart failure diagnosis) over 5 years. There was a 'J-shaped' relationship between serum sodium concentration and primary cardiovascular events that was independent of established risk factors, medications and other serum electrolytes. The lowest cardiovascular risk was found with a serum sodium between 141 and 143 mmol/l. Higher serum sodium was associated with increased risk in hypertensive individuals, whereas lower concentrations were associated with increased risk in all individuals. Therefore, alterations in serum sodium concentration may be a useful indicator of CVD risk. Higher serum sodium could have a direct effect on the vasculature, particularly in hypertensive individuals. Lower serum sodium may be a reflection of complex volume and neuroendocrine changes.

The effect of dietary salt on blood pressure in individuals receiving chronic dialysis: a systematic review and meta-analysis of randomised controlled trials.

Dietary salt reduction in the general population lowers blood pressure and cardiovascular risk. Despite being widely recommended, there is limited evidence as to whether this is applicable to individuals with end-stage renal disease (ESRD) receiving dialysis. Therefore, we carried out a systematic review and meta-analysis of randomised controlled trials (RCTs) investigating dietary salt reduction in individuals receiving dialysis. Studies were identified through search strategies for CENTRAL, MEDLINE, and EMBASE. Two authors independently assessed studies for eligibility with the inclusion criteria as follows: participants aged 18 years and over; a reduction in salt intake of at least 1 g/day over one week; no concomitant interventions during the study. The primary outcome was change in systolic and diastolic blood pressure. 848 reports were screened, from which 12 studies were selected for the systematic review. Four were RCTs (91 participants) that met the study inclusion criteria: three were conducted in haemodialysis patients and one in peritoneal dialysis patients; three were crossover trials and one was a parallel study. Dietary salt reduction was associated with an 8.4 mmHg reduction in systolic blood pressure (95% CI 4.8-12.0, Ι2 = 0%), and a 4.4 mmHg reduction in diastolic blood pressure (95% CI 2.2-6.6, Ι2 = 0%). In conclusion, few studies have investigated the role of dietary salt reduction in individuals with ESRD receiving dialysis, but these results suggest the importance of this intervention for lowering blood pressure in this group.

An ontological approach to identifying cases of chronic kidney disease from routine primary care data: a cross-sectional study.

BACKGROUND: Accurately identifying cases of chronic kidney disease (CKD) from primary care data facilitates the management of patients, and is vital for surveillance and research purposes. Ontologies provide a systematic and transparent basis for clinical case definition and can be used to identify clinical codes relevant to all aspects of CKD care and its diagnosis. METHODS: We used routinely collected primary care data from the Royal College of General Practitioners Research and Surveillance Centre. A domain ontology was created and presented in Ontology Web Language (OWL). The identification and staging of CKD was then carried out using two parallel approaches: (1) clinical coding consistent with a diagnosis of CKD; (2) laboratory-confirmed CKD, based on estimated glomerular filtration rate (eGFR) or the presence of proteinuria. RESULTS: The study cohort comprised of 1.2 million individuals aged 18 years and over. 78,153 (6.4%) of the population had CKD on the basis of an eGFR of < 60 mL/min/1.73m2, and a further 7366 (0.6%) individuals were identified as having CKD due to proteinuria. 19,504 (1.6%) individuals without laboratory-confirmed CKD had a clinical code consistent with the diagnosis. In addition, a subset of codes allowed for 1348 (0.1%) individuals receiving renal replacement therapy to be identified. CONCLUSIONS: Finding cases of CKD from primary care data using an ontological approach may have greater sensitivity than less comprehensive methods, particularly for identifying those receiving renal replacement therapy or with CKD stages 1 or 2. However, the possibility of inaccurate coding may limit the specificity of this method.

Modest Salt Reduction Lowers Blood Pressure and Albumin Excretion in Impaired Glucose Tolerance and Type 2 Diabetes Mellitus: A Randomized Double-Blind Trial.

The role of salt restriction in patients with impaired glucose tolerance and diabetes mellitus is controversial, with a lack of well controlled, longer term, modest salt reduction trials in this group of patients, in spite of the marked increase in cardiovascular risk. We carried out a 12-week randomized double-blind, crossover trial of salt restriction with salt or placebo tablets, each for 6 weeks, in 46 individuals with diet-controlled type 2 diabetes mellitus or impaired glucose tolerance and untreated normal or high normal blood pressure (BP). From salt to placebo, 24-hour urinary sodium was reduced by 49±9 mmol (2.9 g salt). This reduction in salt intake led to fall in clinic BP from 136/81±2/1 mm Hg to 131/80±2/1 mm Hg, (systolic BP; P<0.01). Mean ambulatory 24-hour BP was reduced by 3/2±1/1 mm Hg (systolic BP, P<0.01 and diastolic BP, P<0.05), and albumin/creatinine ratio was reduced from 0.73 mg/mmol (0.5-1.5) to 0.64 mg/mmol (0.3-1.1; P<0.05). There was no significant change in fasting glucose, hemoglobin A1c, or insulin sensitivity. These results demonstrate that a modest reduction in salt intake, to approximately the amount recommended in public health guidelines, leads to significant and clinically relevant falls in BP in individuals who are early on in the progression of diabetes mellitus with normal or mildly raised BP. The reduction in urinary albumin excretion may carry additional benefits in reducing cardiovascular disease above the effects on BP.

The health impacts of dietary sodium and a low-salt diet.

High salt intake is now endemic worldwide. It contributes to the generation and maintenance of high blood pressure, which is now the biggest risk factor for global disease. There is now compelling evidence to support salt reduction in hypertensives and a substantial body of evidence to support salt reduction in the general population to reduce risk of death from cardiovascular disease. In specific diseases such as heart failure and chronic kidney disease, guidelines support the World Health Organization target for reduced salt intake at 5 g daily. Achieving a diet that is lower in salt has challenges, but is more likely to be achieved through salt reduction strategies particularly focused on processed food and through educational programs. To be effective, these interventions require collaboration between industry, health agencies and governments.

Altering plasma sodium concentration rapidly changes blood pressure during haemodialysis.

BACKGROUND: Plasma sodium is increased following each meal containing salt. There is an increasing interest in the effects of plasma sodium concentration, and it has been suggested that it may have direct effects on blood pressure (BP) and possibly influences endothelial function. Experimental increases of plasma sodium concentration rapidly raise BP even when extracellular volume falls. METHODS: Ten patients with end-stage renal failure established on haemodialysis were studied during the first 2 h of dialysis without fluid removal during this period. They were randomized to receive haemodialysis with (i) dialysate sodium concentration prescribed to 135 mmol/L and (ii) 145 mmol/L in random order in a prospective, single-blinded crossover study. BP measurements and blood samples were taken every 30 min. RESULTS: Pre-dialysis sitting BP was 137/76 ± 7/3 mmHg. Lower dialysate sodium concentration (135 mmol/L) reduced plasma sodium concentration [139.49 ± 0.67 to 135.94 ± 0.52 mmol/L (P < 0.001)], whereas plasma sodium concentration was not altered by higher dialysate sodium (145 mmol/L) (140.17 ± 0.66 mmol/L at baseline to 140.72 ± 0.43 mmol/L at 120 min). Systolic BP was lower with dialysate sodium concentration 135 mmol/L [area under the curve (AUC) 15823.50 ± 777.15 (mmHg)min] compared with 145 mmol/L [AUC 17018.20 ± 1102.17 (mmHg)min], mean difference 1194.70 ± 488.41 (mmHg)min, P < 0.05. There was a significant positive relationship between change in plasma sodium concentration and change in systolic BP. This direct relationship suggests that a fall of 1 mmol/L in plasma sodium concentration would be associated with a 1.7 mmHg reduction in systolic BP (P < 0.05). CONCLUSIONS: The potential mechanism for the increase in BP seen with salt intake may be through small but significant changes in plasma sodium concentration.

Dietary salt influences postprandial plasma sodium concentration and systolic blood pressure.

The plasma sodium concentration has a direct effect on blood pressure in addition to its effects on extracellular volume regulated through changes in the endothelium. The mechanism for elevated blood pressure seen with habitually increased salt intake is unclear, especially the effect of salt in a single meal on plasma sodium concentration and blood pressure. To resolve this we compared the effect of soup with or without 6 g of salt (an amount similar to that in a single meal) on the plasma sodium concentration and blood pressure in 10 normotensive volunteers using a randomized, crossover design. The plasma sodium concentration was significantly increased by 3.13±0.75 mmol/l with salted compared with unsalted soup. Blood pressure increased in volunteers ingesting soup with added salt, and there was a significant positive correlation between plasma sodium concentration and systolic blood pressure. A 1-mmol/l increase in plasma sodium was associated with a 1.91-mm Hg increase in systolic blood pressure by linear regression. Thus, changes in plasma sodium concentration occur each time a meal containing salt is consumed. A potential mechanism for the changes in blood pressure seen with salt intake may be through its effects on plasma sodium concentration.

Altered dietary salt intake for preventing and treating diabetic kidney disease.

BACKGROUND: There is strong evidence that our current consumption of salt is a major factor for increased blood pressure (BP) and a modest reduction in salt intake lowers BP whether BP levels are normal or raised. Tight control of BP in diabetics lowers the risk of strokes, heart attacks and heart failure and slows the progression of diabetic kidney disease (DKD). Currently there is no consensus in restricting salt intake in diabetic patients. OBJECTIVES: To evaluate the effect of altered salt intake on BP and markers of cardiovascular disease and DKD. SEARCH STRATEGY: In January 2010, we searched the Cochrane Renal Group's Specialised Register, CENTRAL (in The Cochrane Library), MEDLINE (from 1966) and EMBASE (from 1980) to identify appropriate articles. SELECTION CRITERIA: We included all randomised controlled trials of salt reduction in individuals with type 1 and type 2 diabetes. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies and resolved differences by discussion with a third independent author. We calculated mean effect sizes using both the fixed-effect and random-effects models. MAIN RESULTS: Thirteen studies (254 individuals) met our inclusion criteria. These included 75 individuals with type 1 diabetes and 158 individuals with type 2 diabetes. The median reduction in urinary sodium was 203 mmol/24 h (11.9 g/day) in type 1 diabetes and 125 mmol/24 h (7.3 g/day) in type 2 diabetes. The median duration of salt restriction was one week in both type 1 and type 2 diabetes. BP was reduced in both type 1 and type 2 diabetes. In type 1 diabetes (56 individuals), salt restriction reduced BP by -7.11/-3.13 mm Hg (systolic/diastolic); 95% CI: systolic BP (SBP) -9.13 to -5.10; diastolic BP (DBP) -4.28 to -1.98). In type 2 diabetes (56 individuals), salt restriction reduced BP by -6.90/-2.87 mm Hg (95% CI: SBP -9.84 to -3.95; DBP -4.39 to -1.35). There was a greater reduction in BP in normotensive patients, possibly due to a larger decrease in salt intake in this group. AUTHORS' CONCLUSIONS: Although the studies are not extensive, this meta-analysis shows a large fall in BP with salt restriction, similar to that of single drug therapy. All diabetics should consider reducing salt intake at least to less than 5-6 g/day in keeping with current recommendations for the general population and may consider lowering salt intake to lower levels, although further studies are needed.