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      Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin‐angiotensin blockers

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          Abstract

          Aims

          To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate ( eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin ( HbA1c), systolic blood pressure ( SBP), body weight or eGFR.

          Methods

          We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes ( T2DM) on stable angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline.

          Results

          Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12‐week reductions in albuminuria compared with placebo: −33.2% [95% confidence interval ( CI) −45.4, −18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: −23.5% (95% CI −37.6, −6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal‐related adverse events were observed in any group.

          Conclusions

          Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin‐angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin‐induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long‐term renal and cardiovascular risk.

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          Most cited references24

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          Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin.

          Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment.
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            Aliskiren combined with losartan in type 2 diabetes and nephropathy.

            Diabetic nephropathy is the leading cause of end-stage renal disease in developed countries. We evaluated the renoprotective effects of dual blockade of the renin-angiotensin-aldosterone system by adding treatment with aliskiren, an oral direct renin inhibitor, to treatment with the maximal recommended dose of losartan (100 mg daily) and optimal antihypertensive therapy in patients who had hypertension and type 2 diabetes with nephropathy. We enrolled 599 patients in this multinational, randomized, double-blind study. After a 3-month, open-label, run-in period during which patients received 100 mg of losartan daily, patients were randomly assigned to receive 6 months of treatment with aliskiren (150 mg daily for 3 months, followed by an increase in dosage to 300 mg daily for another 3 months) or placebo, in addition to losartan. The primary outcome was a reduction in the ratio of albumin to creatinine, as measured in an early-morning urine sample, at 6 months. The baseline characteristics of the two groups were similar. Treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). A small difference in blood pressure was seen between the treatment groups by the end of the study period (systolic, 2 mm Hg lower [P=0.07] and diastolic, 1 mm Hg lower [P=0.08] in the aliskiren group). The total numbers of adverse and serious adverse events were similar in the groups. Aliskiren may have renoprotective effects that are independent of its blood-pressure-lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. (ClinicalTrials.gov number, NCT00097955 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.
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              Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease

              Aims Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m2]. Methods In this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated. Results Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (–0.33, –0.44 and –0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin. Conclusion Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.
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                Author and article information

                Journal
                Diabetes Obes Metab
                Diabetes Obes Metab
                10.1111/(ISSN)1463-1326
                DOM
                Diabetes, Obesity & Metabolism
                Blackwell Publishing Ltd (Oxford, UK )
                1462-8902
                1463-1326
                26 April 2016
                26 April 2016
                : 18
                : 6 ( doiID: 10.1111/dom.2016.18.issue-6 )
                : 590-597
                Affiliations
                [ 1 ] University of GroningenUniversity Medical Center GroningenThe Netherlands
                [ 2 ]AstraZeneca, Gothenburg MölndalSweden
                [ 3 ]AstraZeneca Wilmington DEUSA
                Author notes
                [*] [* ] Correspondence to: Hiddo J. L. Heerspink, Hanzeplein 1, PO Box 30 001, 9700 RB, Groningen, The Netherlands.

                E‐mail: h.j.lambers.heerspink@ 123456umcg.nl

                Article
                DOM12654
                10.1111/dom.12654
                4850750
                26936519
                2a4e0fae-1446-4d3d-ba8f-4d326ad7cd1d
                © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 31 December 2015
                : 23 January 2016
                : 27 February 2016
                Page count
                Pages: 8
                Funding
                Funded by: AstraZeneca
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                dom12654
                June 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.8 mode:remove_FC converted:29.04.2016

                Endocrinology & Diabetes
                albuminuria,dapagliflozin,diabetes,hypertension,sodium glucose cotransporter‐2

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