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      Differential glycaemic control with basal insulin glargine 300 U/mL versus degludec 100 U/mL according to kidney function in type 2 diabetes: A subanalysis from the BRIGHT trial

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          Abstract

          Aims

          Chronic kidney disease (CKD) challenges diabetes management and is associated with increased cardiovascular morbidity and mortality. We examined whether clinical outcomes with insulin glargine 300 U/mL (Gla‐300) and insulin degludec 100 U/mL (IDeg‐100) are affected by renal function in a prespecified subgroup analysis from the BRIGHT trial.

          Materials and methods

          BRIGHT (NCT02738151) was a multicentre, open‐label, randomized, active‐controlled, two‐arm, parallel‐group, 24‐week study in insulin‐naïve uncontrolled type 2 diabetes (T2D). Participants were randomized 1:1 to evening Gla‐300 (n = 466) or IDeg‐100 (n = 463) and stratified based on baseline estimated glomerular filtration rate (eGFR) for this analysis.

          Results

          Heterogeneity of treatment effect across renal function subgroups was observed ( P = .02), reflecting a greater mean glycated haemoglobin (HbA1c) reduction from baseline to week 24 with Gla‐300 versus IDeg‐100 in the eGFR <60 mL/min/1.73 m 2 subgroup (least squares mean difference: −0.43% [95% confidence interval: −0.74% to −0.12%]), while there were no differences in hypoglycaemia incidence or rates over 24 weeks in that subgroup. HbA1c reductions were similar between treatments in the other eGFR subgroups. However, heterogeneity was observed for annualized rates of anytime (24 hours) or nocturnal (00:00‐05:59 hours) confirmed hypoglycaemia (≤70 mg/dL [≤3.9 mmol/L]) over 24 weeks showing less hypoglycaemia with Gla‐300 versus IDeg‐100 in the ≥90 mL/min/1.73 m 2.

          Conclusions

          Kidney function seems to affect the glucose‐lowering effects of Gla‐300 versus IDeg‐100 in insulin‐naïve T2D. Greater HbA1c reductions with Gla‐300 without increase in hypoglycaemia risk, were observed in patients with eGFR <60 mL/min/1.73 m 2.

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          Most cited references9

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          Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 12‐month trial including 6‐month extension

          Aims To compare the efficacy and safety of new insulin glargine 300 U/ml (Gla‐300) with insulin glargine 100 U/ml (Gla‐100) over 12 months of treatment in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs (OADs). Methods EDITION 2 (NCT01499095) was a randomized, 6‐month, multicentre, open‐label, two‐arm, phase IIIa study investigating once‐daily Gla‐300 versus Gla‐100, plus OADs (excluding sulphonylureas), with a 6‐month safety extension. Results Similar numbers of participants in each group completed 12 months of treatment [Gla‐300, 315 participants (78%); Gla‐100, 314 participants (77%)]. The reduction in glycated haemoglobin was maintained for 12 months with both treatments: least squares (LS) mean (standard error) change from baseline −0.55 (0.06)% for Gla‐300 and −0.50 (0.06)% for Gla‐100; LS mean difference −0.06 [95% confidence interval (CI) −0.22 to 0.10)%]. A significant relative reduction of 37% in the annualized rate of nocturnal confirmed [≤3.9 mmol/l (≤70 mg/dl)] or severe hypoglycaemia was observed with Gla‐300 compared with Gla‐100: rate ratio 0.63 [(95% CI 0.42–0.96); p = 0.031], and fewer participants experienced ≥1 event [relative risk 0.84 (95% CI 0.71–0.99)]. Severe hypoglycaemia was infrequent. Weight gain was significantly lower with Gla‐300 than Gla‐100 [LS mean difference −0.7 (95% CI −1.3 to −0.2) kg; p = 0.009]. Both treatments were well tolerated with a similar pattern of adverse events (incidence of 69 and 60% in the Gla‐300 and Gla‐100 groups). Conclusions In people with type 2 diabetes treated with Gla‐300 or Gla‐100, and non‐sulphonylurea OADs, glycaemic control was sustained over 12 months, with less nocturnal hypoglycaemia in the Gla‐300 group.
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            Hypoglycemia, chronic kidney disease, and diabetes mellitus.

            Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency.
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              Effects of glycaemic management on diabetic kidney disease

              Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin’s reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents.
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                Author and article information

                Contributors
                mhalu@lf1.cuni.cz
                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
                28 April 2020
                August 2020
                : 22
                : 8 ( doiID: 10.1111/dom.v22.8 )
                : 1369-1377
                Affiliations
                [ 1 ] Diabetes Centre Institute for Clinical and Experimental Medicine Prague Czech Republic
                [ 2 ] Department of Medicine University of Toronto Toronto Ontario Canada
                [ 3 ] Department of Cardiology University Hospital RWTH Aachen Aachen Germany
                [ 4 ] Sanofi Paris France
                [ 5 ] Ividata Levallois‐Perret France
                [ 6 ] Department of Diabetes and Endocrinology Guy’s and St Thomas’ NHS Trust London UK
                [ 7 ] Dallas Diabetes Research Center at Medical City Dallas Texas
                [ 8 ] Section of Endocrinology and Metabolism, Department of Medicine Perugia University Medical School Perugia Italy
                Author notes
                [*] [* ] Correspondence

                Martin Haluzík, Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.

                Email: mhalu@ 123456lf1.cuni.cz

                Author information
                https://orcid.org/0000-0002-0201-6888
                https://orcid.org/0000-0002-8807-6442
                https://orcid.org/0000-0002-2617-8320
                https://orcid.org/0000-0001-8324-3275
                https://orcid.org/0000-0003-4966-4003
                Article
                DOM14043
                10.1111/dom.14043
                7383874
                32243043
                d868b5ed-81f9-4943-af5d-4fc7a3ad8c13
                © 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 18 December 2019
                : 20 March 2020
                : 25 March 2020
                Page count
                Figures: 4, Tables: 1, Pages: 2, Words: 5075
                Funding
                Funded by: Sanofi , open-funder-registry 10.13039/100004339;
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                August 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:27.07.2020

                Endocrinology & Diabetes
                basal insulin,diabetes complications,insulin analogues,randomized trial,type 2 diabetes

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