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Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

ABSTRACT: Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m2 per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m2 per year (95% CI, 0.4 to 1.4), respectively (P<0.01 for each canagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ?30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; P<0.001) than with glimepiride. Patients receiving glimepiride, canagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects.

SUBMITTER: Heerspink HJ

PROVIDER: S-EPMC5198289 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

Heerspink Hiddo J L HJ Desai Mehul M Jardine Meg M Balis Dainius D Meininger Gary G Perkovic Vlado V

Journal of the American Society of Nephrology : JASN 20160818 1

Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride u ...[more]

PMID: 27539604

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Project description:BACKGROUND:Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. METHODS:The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR <60 and ?60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45 to <60, 60 to <90, and ?90 mL/min/1.73 m2). RESULTS:At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55-0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79-1.07; P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke ( P heterogeneity = 0.01), as were results for almost all safety outcomes. CONCLUSIONS:The effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629, NCT01989754.

Project description:Data on risk factors predicting rapid progression to end-stage renal disease (ESRD) or short-term kidney function decline (i.e., within 1 year) in chronic kidney disease (CKD) are rare but urgently needed to plan treatment. This study describes the association and predictive value of urinary uromodulin (uUMOD) for rapid progression of CKD.We assessed uUMOD, demographic/treatment parameters, estimated glomerular filtration rate (eGFR), and proteinuria in 230 CKD patients stage I-V. ESRD and 25% decline of eGFR was documented at the end of follow-up period and used as a composite endpoint. Association between logarithmic uUMOD and eGFR/proteinuria was calculated using linear regression analysis, adjusting for age, gender, and body mass index. We performed multivariable Cox proportional hazard regression analysis to evaluate the association of uUMOD with the composite endpoint. Therefore, patients were categorized into quartiles. The predictive value of uUMOD for the above outcomes was assessed using receiver-operating characteristic (ROC) curve analysis.Follow-up was 57.3?±?18.7 weeks, baseline age was 60 (18;92) years, and eGFR was 38 (6;156) mL/min/1.73?m. Forty-seven (20.4%) patients reached the composite endpoint. uUMOD concentrations were directly associated with eGFR and inversely associated with proteinuria (??=?0.554 and ??=?-0.429, P?<?.001). In multivariable Cox regression analysis, the first 2 quartiles of uUMOD concentrations had a hazard ratio (HR) of 3.589 [95% confidence interval (95% CI) 1.002-12.992] and 5.409 (95% CI 1.444-20.269), respectively, in comparison to patients of the highest quartile (?11.45??g/mL) for the composite endpoint. In ROC-analysis, uUMOD predicted the composite endpoint with good sensitivity (74.6%) and specificity (76.6%) at an optimal cut-off at 3.5??g/mL and area under the curve of 0.786 (95% CI 0.712-0.860, P?<?.001).uUMOD was independently associated with ESRD/rapid loss of eGFR. It might serve as a robust predictor of rapid kidney function decline and help to better schedule arrangements for future treatment.

Project description:Introduction:Diabetic nephropathy remains a highly prevalent microvascular complication in individuals with type 2 diabetes mellitus (T2DM). Hispanic individuals are at increased risk of metabolic and cardiovascular complications compared with non-Hispanic white individuals. We described the long-term kidney outcomes using a culturally based approach to diabetes management in Hispanic patients implemented by the Joslin Diabetes Center's Latino Diabetes Initiative. Methods:Our retrospective study included 594 Hispanic patients evaluated at the Joslin Diabetes Center from July 2002 to July 2015. Demographic and clinical data were collected from the outpatient visits. Results:Uncontrolled high blood pressure (hazard ratio [HR]: 1.72; 95% confidence interval [CI]:1.18-2.51; P = 0.005), overweight (HR: 2.68; 95% CI: 1.13-6.38; P = 0.026), and longstanding T2DM duration (HR: 1.11; 95% CI: 1.08-1.14; P < 0.0001) at baseline were significantly associated with increased risk of chronic kidney disease (CKD). Although poor glycemic control (HR: 1.18; 95% CI: 1.099-1.258; P < 0.0001), systolic blood pressure (SBP) >140 (HR: 1.01; 95% CI: 1.006-1.02; P = 0.0002), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (HR: 1.53; 95% CI: 1.03-2.29; P = 0.04) were significantly associated with increased CKD incidence during follow-up. Interestingly, statin use was associated with lower CKD incidence during the follow-up (HR: 0.52; 95% CI: 0.42-0.65; P < 0.0001). The annual rate of renal function decline in our cohort was estimated to be -1.39 ml/min per 1.73 m2. Conclusion:Renal function decline in Latinos is associated with expected but modifiable variables, such as uncontrolled diabetes, uncontrolled hypertension, and being overweight. However, the annual rate of renal function decline in our cohort was estimated to be comparatively higher than previous reports in Hispanic individuals without T2DM, and the general US population with T2DM, but lower than expected for this high-risk group. We highlight the importance of a culturally based patient-centered therapeutic approach to improve long-term outcomes in Hispanic patients at high risk of CKD.

Project description:BACKGROUND:Statins have shown multiple effects on different renal risk factors such as lowering of total cholesterol (TC) and lowering of urine protein:creatinine ratio (UPCR). We assessed whether these effects of statins vary between individuals, the extent of discordance of treatment effects on both TC and UPCR within an individual, and the association of responses in TC and UPCR with estimated glomerular filtration rate (eGFR) decline. METHODS:The PLANET I and II (Renal effects of Rosuvastatin and Atorvastatin in Patients Who Have Progressive Renal Disease) trials examined effects of atorvastatin and rosuvastatin on proteinuria and renal function in patients with proteinuria. We post hoc analysed 471 therapy-adherent proteinuric patients from the two trials and assessed the individual variability in UPCR and TC response from 0 to 14?weeks and whether these responses were predictive of eGFR decline during the subsequent 9?months of follow-up. RESULTS:UPCR and TC response varied between individuals: mean UPCR response was -1.3% (5th-95th percentile -59.9 to 141.8) and mean TC response was -93.9?mg/dL (-169.1 to -26.9). Out of 471 patients, 123 (26.1%) showed a response in UPCR but not in TC, and 96 (20.4%) showed a response in TC but not in UPCR. eGFR (mL/min/1.73 m2) did not decrease significantly from baseline in both UPCR responders [0.4; 95% confidence interval (CI) -1.6 to 0.9; P?=?0.54] and TC responders (0.3; 95% CI -1.8 to 1.1; P?=?0.64), whereas UPCR and TC non-responders showed a significant decline in eGFR from baseline (1.8; 95% CI 0.6-3.0; P?=?0.004 and 1.7; 95% CI 0.5-2.9; P?=?0.007, respectively). A lack of response in both parameters resulted in the fastest rate of eGFR decline (2.1; 95% CI 0.5-3.7; P?=?0.01). These findings were not different for rosuvastatin or atorvastatin. CONCLUSIONS:Statin-induced changes in cholesterol and proteinuria vary between individuals and do not run in parallel within an individual. The initial fall in cholesterol and proteinuria is independently associated with a reduction in eGFR decline. This highlights the importance of monitoring both cholesterol and proteinuria after initiating statin therapy.

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Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

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Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

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