The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without ...albuminuria have not been well studied.
We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m
of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding.
Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval CI, 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo.
In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).
Background Previous studies have shown that patients with chronic kidney disease, including those with diabetic nephropathy, are more likely to die of cardiovascular disease than reach end-stage ...renal disease (ESRD). This analysis was conducted to determine whether ESRD is a more common outcome than cardiovascular death in patients with type 2 diabetic nephropathy, significant proteinuria, and decreased kidney function who were selected for participation in a clinical trial. Study Design Retrospective analysis of the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database derived from 2 prospective randomized controlled clinical trials (IDNT Irbesartan Diabetic Nephropathy Trial and RENAAL Reduction of Endpoints in Non–Insulin-dependent Diabetes With the Angiotensin II Antagonist Losartan). Setting & Participants 3,228 adult patients with type 2 diabetic nephropathy from IDNT and RENAAL were combined to establish the DIAMETRIC database. This is the largest global source of clinical information for patients with type 2 diabetic nephropathy who have decreased kidney function and significant proteinuria. Intervention Angiotensin receptor blocker versus non–angiotensin receptor blocker therapy to slow the progression of type 2 diabetic nephropathy (in the prospective trials). Outcomes & Measurements Incidence rates of ESRD, cardiovascular death, and all-cause mortality. Results Mean follow-up was 2.8 years; 19.5% of patients developed ESRD, approximately 2.5 times the incidence of cardiovascular death and 1.5 times the incidence of all-cause mortality. ESRD was more common than cardiovascular death in all subgroups analyzed with the exception of participants with low levels of albuminuria (albumin excretion <1.0 g/g) and well-preserved levels of kidney function (estimated glomerular filtration rate >45 mL/min/1.73 m2 ) at baseline. Limitations All participants were included in a prospective clinical trial. Conclusions Patients with type 2 diabetic nephropathy, characterized by decreased kidney function and significant proteinuria, are more likely to reach ESRD than die during 3 years' mean follow-up. Given the rapidly increasing number of cases of type 2 diabetes worldwide, this has implications for predicting future renal replacement therapy requirements.
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.
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).
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).
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.
Sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown beneficial effects on renal outcomes mainly in patients with established atherosclerotic cardiovascular disease. Here we report analyses ...of renal outcomes with the SGLT2 inhibitor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 diabetes both with and without established atherosclerotic cardiovascular disease and mostly with preserved renal function.
In DECLARE-TIMI 58, patients with type 2 diabetes, HbA
6·5-12·0% (47·5-113·1 mmol/mol), with either established atherosclerotic cardiovascular disease or multiple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or placebo once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular filtration rate eGFR to less than 60 mL/min per 1·73m
, end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR <15mL/min per 1·73 m
), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same but excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, subgroup analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, number NCT01730534.
The trial took place between April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m
, 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m
, and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m
at baseline (one participant had missing data for eGFR); 6974 (40·6%) had established atherosclerotic cardiovascular disease and 10 186 (59·4%) had multiple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus placebo (hazard ratio HR 0·76, 95% CI 0·67-0.87; p<0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p<0·0001). We identified a 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min per 1·73 m
(120 1·4% vs 221 2·6%; HR 0·54 95% CI 0·43-0·67; p<0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11 0·1% vs 27 0·3%; HR 0·41 95% CI 0·20-0·82; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus placebo across various prespecified subgroups, including those defined by baseline eGFR (cardiorenal outcome p
=0·97; renal-specific outcome p
=0·87) and the presence or absence of established atherosclerotic cardiovascular disease (cardiorenal outcome p
=0·67; renal-specific outcome p
=0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the placebo group. The mean change equalised by 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with placebo.
Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease, most of whom had preserved renal function.
AstraZeneca.
Current phosphate management strategies in end-stage renal disease (dietary phosphate restriction, dialysis, and phosphate binders) are inadequate to maintain target phosphate levels in most ...patients. Dietary phosphate restriction is challenging due to “hidden phosphates” in processed foods, and dialysis and phosphate binders are insufficient to match average dietary phosphate intake. As phosphate binders must be taken with each meal, patients need to ingest many, large pills several times a day, negatively impacting quality of life. Recent advances in our understanding of phosphate absorption pathways have led to the development of new nonbinder therapies that block phosphate absorption. This review describes the limitations of current phosphate management strategies and discusses new therapies in development that inhibit phosphate absorption pathways. These new therapies present an opportunity to rethink phosphate management, potentially by prescribing phosphate absorption inhibitors as a primary therapy and adding phosphate binders if needed.
Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized ...trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml mean±SD; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml mean±SD; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.
Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events.
Data for AKI resulting in or during hospitalization or emergency department visits were collected as part of the ...serious adverse events reporting process of the Systolic Blood Pressure Intervention Trial (SPRINT).
9,361 participants 50 years or older with 1 or more risk factors for cardiovascular disease.
Participants were randomly assigned to a systolic BP target of <120 (intensive arm) or <140mmHg (standard arm).
Primary outcome was the number of adjudicated AKI events. Secondary outcomes included severity of AKI and degree of recovery of kidney function after an AKI event. Baseline creatinine concentration was defined as the most recent SPRINT outpatient creatinine value before the date of the AKI event.
There were 179 participants with AKI events in the intensive arm and 109 in the standard arm (3.8% vs 2.3%; HR, 1.64; 95% CI, 1.30-2.10; P<0.001). Of 288 participants with an AKI event, 248 (86.1%) had a single AKI event during the trial. Based on modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria for severity of AKI, the number of AKI events in the intensive versus standard arm by KDIGO stage was 128 (58.5%) versus 81 (62.8%) for AKI stage 1, 42 (19.2%) versus 18 (14.0%) for AKI stage 2, and 42 (19.2%) versus 25 (19.4%) for AKI stage 3 (P=0.5). For participants with sufficient data, complete or partial resolution of AKI was seen for 169 (90.4%) and 9 (4.8%) of 187 AKI events in the intensive arm and 86 (86.9%) and 4 (4.0%) of 99 AKI events in the standard arm, respectively.
Trial results are not generalizable to patients with diabetes mellitus or without risk factors for cardiovascular disease.
More intensive BP lowering resulted in more frequent episodes of AKI. Most cases were mild and most participants had complete recovery of kidney function.
Registered at ClinicalTrials.gov with study number NCT01206062.
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