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1.
The nephrological perspective on SGLT-2 inhibitors in type 1 diabetes.
Gillard, P, Schnell, O, Groop, PH
Diabetes research and clinical practice. 2020;:108462
Abstract
Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index ≥27 kg/m2. Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM.
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Efficacy and safety of Shenkang injection as adjuvant therapy in patients with diabetic nephropathy: A protocol for systematic review and meta-analysis.
Wang, Y, Li, M, Li, C, Xu, S, Wu, J, Zhang, G, Cai, Y
Medicine. 2020;(52):e23821
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Abstract
BACKGROUND Diabetic nephropathy is a frequent microvascular complication of diabetes mellitus that causes end-stage renal disease most of the time. In China, Shenkang injection is one of widely used traditional Chinese medicine for treating chronic kidney disease, but its efficacy and safety have not yet been clarified. We will systematically review the current randomized controlled trial (RCT) evidence to summarize the efficacy and safety of Shenkang injection in treating diabetic nephropathy. METHODS We will search 7 literature databases including PubMed, EMBASE, Cochrane Library, Sinomed, Chinese National Knowledge Infrastructure, Wanfang, and VIP. Two trial registry platforms will also be searched. The time frame of the search will be from the inceptions of the databases to December 31, 2020. RCTs assessing Shenkang injection combined with basic treatments versus basic treatments alone for treating diabetic nephropathy will be included. The risk of bias within the individual RCTs will be evaluated using criteria proposed by the Cochrane Handbook 5.1.0. The primary outcomes to be investigated are glomerular filtration rate and serum creatinine; the secondary outcome will include 24-hour urine albumin excretion rate, blood urea nitrogen, fasting blood glucose, postprandial blood glucose, hemoglobin A1c, total cholesterol, triglyceride, response to treatment, and incidence of adverse events. The effect data of individual RCTs by performing random-effects model meta-analysis. Statistical heterogeneity will be measured by the Cochran Q test and I-squared statistics. Three subgroup analyses, set based on clinical experience, will be performed to explore the sources of heterogeneity. Sensitivity analyses excluding RCTs with high risk of bias and using fixed effect model will be done to test the robustness of the meta-analytic results. Publication bias across included RCTs will be evaluated by funnel plots and Egger test. RESULTS This study will provide systematic review on the efficacy and safety of Shenkang Injection as adjuvant therapy in patients with diabetic nephropathy by rigorous quality assessment and reasonable data synthesis. The results will be submitted to a peer-reviewed journal for publication. CONCLUSION This systematic review will provide the best evidence currently on Shenkang Injection as adjuvant therapy in patients with diabetic nephropathy. INPLASY REGISTRATION NUMBER INPLASY2020110014.
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Fenofibrate decreased microalbuminuria in the type 2 diabetes patients with hypertriglyceridemia.
Sun, X, Liu, J, Wang, G
Lipids in health and disease. 2020;(1):103
Abstract
BACKGROUND This study was to research the efficacy of fenofibrate in the treatment of microalbuminuria in the patients with type 2 diabetes mellitus (T2DM) and hypertriglyceridemia. METHODS Type 2 diabetic patients (56) with microalbuminuria and hypertriglyceridemia aged 30 to 75 were randomly divided into the fenofibrate treatment group(n = 28) and the control group (n = 28) for 180 days. Urinary microalbumin /creatinine ratio (UACR) and other metabolic parameters were compared at baseline, during treatment and after treatment. RESULTS After 180 days, the reduction of level of fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) between two groups showed no difference. In the treatment group, uric acid (UA) (296.42 ± 56.41 vs 372.46 ± 72.78), triglyceride (TG) [1.51(1.17, 2.06) vs 3.04(2.21, 3.29)], and UACR [36.45 (15.78,102.41) vs 129.00 (53.00, 226.25)] were significantly decreased compared with the baseline. The high-density lipoprotein cholesterol (HDL-C) levels were significantly increased (1.22 ± 0.26 vs 1.09 ± 0.24) compared with the baseline. The decrease in UACR [- 44.05(- 179.47, - 12.16) vs - 8.15(- 59.69, 41.94)]in treatment group was significantly higher compared with the control group. The decrease in UACR was positively associated with the decreases in TG (r = 0.447, P = 0.042) and UA (r = 0.478, P = 0.024) after fenofibrate treatment. CONCLUSION In the patients with hypertriglyceridemia and type 2 diabetes mellitus, fenofibrate can improve microalbuminuria and do not increase the deterioration of glomerular filtration rate. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02314533, 2014.12.9.
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Evaluation of the efficacy and safety of TWHF in diabetic nephropathy patients with overt proteinuria and normal eGFR.
Xiong, C, Li, L, Bo, W, Chen, H, XiaoWei, L, Hongbao, L, Peng, Z
Journal of the Formosan Medical Association = Taiwan yi zhi. 2020;(3):685-692
Abstract
BACKGROUND/PURPOSE The aim of this study was to evaluate the efficacy and safety of Tripterygium Wilfordii Hook F (TWHF) in DN patients with overt proteinuria and normal eGFR. METHODS 124 eligible DN patients were randomly assigned into two groups to receive either valsartan 160 mg/d treatment (control group) or TWHF 60 mg/d plus valsartan 160 mg/d treatments (TWHF group) for 24 weeks. The changes of clinical, biochemical data and adverse events during observation period were all analyzed. The primary endpoint was a reduction in 24-h urine protein excretion between baseline and the end of study, the secondary endpoint was to observe the change in estimated glomerular filtration rate (eGFR) between two groups. RESULTS After treatment, there was a more significant decrease in proteinuria in patients who received TWHF treatment (from 4.95 ± 1.27 g/24 h to 3.36 ± 0.83 g/24 h) compared to valsartan monotherapy (from 5.21 ± 1.59 g/24 h to 4.52 ± 1.06 g/24 h). The percentage change in urine protein excretion was -32.12% in TWHF group and -13.24% in valsartan group. Patients' plasma albumin in TWHF group (from 32.53 ± 5.24 g/L to 36.91 ± 4.42 g/L) was higher than that in control group (from 33.18 ± 4.87 g/L to 34.67 ± 4.75 g/L). No significant change in blood pressure, blood glucose, eGFR, and serum potassium was observed. But the adverse events in TWHF group were higher than those in control group. CONCLUSION TWHF is more effective than valsartan monotherapy in reduction of proteinuria in DN patients with overt proteinuria and normal eGFR, but with more adverse effects.
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[SGLT2 inhibitors, beyond glucose-lowering effect: impact on nephrology clinical practice].
Costanza, G, Pesce, F, Forcella, M, Leonardi, G, Seminara, G, Di Natale, E, Granata, A
Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. 2020;(4)
Abstract
Epidemiological data show an increasing diffusion of diabetes mellitus worldwide. In the diabetic subject, the risk of onset of chronic kidney disease (CKD) and its progression to the terminal stage remain high, despite current prevention and treatment measures. Although SGLT2 inhibitors have been approved as blood glucose lowering drugs, they have shown unexpected and surprising cardioprotective and nephroprotective efficacy. The multiple underlying mechanisms of action are independent and go beyond glycemic lowering. Hence, it has been speculated to extend the use of these drugs also to subjects with advanced stages of CKD, who were initially excluded because of the expected limited glucose-lowering effect. Non-diabetic patients could also benefit from the favorable effects of SGLT2 inhibitors: subjects with renal diseases with different etiologies, heart failure, high risk or full-blown cardiovascular disease. In addition, these drugs have a good safety profile, but several post-marketing adverse event have been reported. The ongoing clinical trials will provide clearer information on efficacy, strength and safety of these molecules. The purpose of this review is to analyze the available evidence and future prospects of SGLT2 inhibitors, which could be widely used in nephrology clinical practice.
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Subtypes of Type 2 Diabetes Determined From Clinical Parameters.
Ahlqvist, E, Prasad, RB, Groop, L
Diabetes. 2020;(10):2086-2093
Abstract
Type 2 diabetes (T2D) is defined by a single metabolite, glucose, but is increasingly recognized as a highly heterogeneous disease, including individuals with varying clinical characteristics, disease progression, drug response, and risk of complications. Identification of subtypes with differing risk profiles and disease etiologies at diagnosis could open up avenues for personalized medicine and allow clinical resources to be focused to the patients who would be most likely to develop diabetic complications, thereby both improving patient health and reducing costs for the health sector. More homogeneous populations also offer increased power in experimental, genetic, and clinical studies. Clinical parameters are easily available and reflect relevant disease pathways, including the effects of both genetic and environmental exposures. We used six clinical parameters (GAD autoantibodies, age at diabetes onset, HbA1c, BMI, and measures of insulin resistance and insulin secretion) to cluster adult-onset diabetes patients into five subtypes. These subtypes have been robustly reproduced in several populations and associated with different risks of complications, comorbidities, genetics, and response to treatment. Importantly, the group with severe insulin-deficient diabetes (SIDD) had increased risk of retinopathy and neuropathy, whereas the severe insulin-resistant diabetes (SIRD) group had the highest risk for diabetic kidney disease (DKD) and fatty liver, emphasizing the importance of insulin resistance for DKD and hepatosteatosis in T2D. In conclusion, we believe that subclassification using these highly relevant parameters could provide a framework for personalized medicine in diabetes.
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Association of urinary non-albumin protein with the different urinary marker for glomerular and tubular damage in patients with type 2 diabetes.
Siddiqui, K, Joy, SS, Nawaz, SS, Alnaqeb, D, Mujammami, M, Al-Rubeaan, K
BMC nephrology. 2020;(1):255
Abstract
BACKGROUND/AIM: In recent years, the diagnostic utility of urinary protein levels has been demonstrated for the early detection and progression of kidney disease. This study aimed to evaluate the associations of the non-albumin protein (NAP) with different urinary marker for tubular and glomerular damage in patients with type 2 diabetes (T2D). METHODS In this observational cross-sectional study, 424 patients with T2D duration > 10 years were classified into two groups according to estimated glomerular filtration rate (eGFR). The ratios of different urinary markers (albumin, NAP, total protein, transferrin, retinol-binding protein (RBP), and neutrophil gelatinase-associated lipocalin (NGAL) to creatinine were analyzed. RESULTS The levels of urinary biomarkers increased significantly with decrease in eGFR levels. In the group with moderately decreased eGFR, the albumin to-creatinine ratio (ACR), non-albumin protein-to-creatinine ratio (NAPCR), and total protein-to-creatinine ratio (PCR) were independently associated with all urinary markers after being adjusted for risk factors. The area under the receiver operating characteristics (ROC) curve for ACR and PCR had a better diagnostic value than other urinary biomarkers. Comparing ROC curve of NAPCR with other urinary biomarkers, it was significantly better than NGAL/Cr (p = 0.033). CONCLUSIONS The findings of the present study confirm that ACR and PCR are diagnostic biomarkers in T2D patients with decreased eGFR. NAPCR in these patients diagnostically only outperformed NGAL/Cr.
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Primary versus secondary cardiorenal prevention in type 2 diabetes: Which newer anti-hyperglycaemic drug matters?
Giugliano, D, Ceriello, A, De Nicola, L, Perrone-Filardi, P, Cosentino, F, Esposito, K
Diabetes, obesity & metabolism. 2020;(2):149-157
Abstract
We are observing a resurgence of major diabetic vascular complications after a period of dramatic decrease during the period 1990 to 2010. The classical division of cardiovascular prevention into primary (with an event) and secondary (without an event) is largely used to describe cardiovascular risk in type 2 diabetes (T2D); however, there is evidence that the cardiovascular risk in diabetes may range from highest in patients who experienced a previous cardiovascular event to mild in patients with the main risk factors at target. Herein, we present details of the 14 cardiovascular outcome trials (CVOTs) published to date, including the total population investigated, and their separation into primary (T2D + multiple risk factors) and secondary prevention (T2D + established cardiovascular disease [CVD]) populations as detailed within the trials. We also summarize evidence for the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium glucose co-transporter-2 inhibitors (SGLT-2i) versus placebo on the risk of major cardiovascular events (MACE), heart failure (HF) and diabetic kidney disease (DKD). In primary prevention, SGLT-2i reduce both the risk of hospitalization for HF and progression of DKD; in secondary prevention, SGLT-2i are effective on the three endpoints, DPP-4i are neutral, while GLP1-RA show mixed results.
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Efficacy and safety of Ginkgo biloba for patients with early diabetic nephropathy: A protocol for systematic review and meta-analysis.
Wang, H, Yuan, M, Zou, X
Medicine. 2020;(35):e21959
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Abstract
BACKGROUND Diabetic nephropathy (DN) is not only an important microvascular complication of diabetes but also the main cause of end-stage renal disease. Ginkgo biloba has a variety of biological activities and has been widely used in China to treat kidney diseases such as DN. This article aimed to evaluate the efficacy and safety of G biloba in patients affected with DN in the early stage. METHODS This protocol follows the preferred reporting items for systematic review and meta-analysis protocols and the recommendations of the Cochrane Collaboration Handbook. Seven electronic databases will be searched from inception to July 31, 2020. Two investigators will independently identify relevant randomized controlled trials, fetch data, and assess the risk of bias with tools provided by Cochrane. A comprehensive meta-analysis will be conducted with the Cochrane Collaboration software (Review Manager 5.3) for eligible and appropriate studies. Further, the evidence will be assessed with the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS The results will be published in academic peer-reviewed journals, and the evidence gathered by this project will be dedicated to assessing the efficacy and safety of G biloba for DN patients in the early stage. CONCLUSION This systematic review and meta-analysis will synthesize the available evidence to demonstrate the efficacy of G biloba in delaying the progression of patients with early DN. TRIAL REGISTRATION NUMBER PROSPERO CRD42020166805.
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Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease.
Scheen, AJ
Expert opinion on drug safety. 2020;(3):243-256
Abstract
Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a complex relationship with the kidney so that their use in patients with type 2 diabetes (T2DM) and diabetic kidney disease (DKD) has long been challenged.Areas covered: SGLT2is in patients with DKD are discussed: renal mechanisms of action, PK/PD characteristics, clinical use in patients with stage 3 DKD, effects on estimated glomerular filtration rate (eGFR) and albuminuria, cardiovascular, and renal outcomes according to renal function, overall and renal safety, SGLT2is new place in updated guidelines.Expert opinion: Whereas initial concerns (reduced glucose-lowering efficacy, early reduction in eGFR) led to restrictions in the use of SGLT2is in patients with DKD, recent positive observations have completely reversed the scene. Indeed, albuminuria is reduced and eGFR is preserved in the long term by SGLT2is. A significant reduction in cardiovascular events and hard renal outcomes was reported even in patients with eGFR 30-60 mL/min/1.73 m2. The overall safety profile of SGLT2is is not altered in patients with mild to moderate DKD, with a reduced (rather than increased) risk of acute renal injury. This positive benefit/risk balance led recent guidelines to recommend SGLT2is in patients with T2DM and mild to moderate DKD, especially if albuminuria.