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      Sulodexide therapy for the treatment of diabetic nephropathy, a meta-analysis and literature review

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          Abstract

          Sulodexide is a heterogeneous group of sulfated glycosaminoglycans (GAGs) that is mainly composed of low-molecular-weight heparin. Clinical studies have demonstrated that sulodexide is capable of reducing urinary albumin excretion rates in patients with type 1 and type 2 diabetes, suggesting that sulodexide has renal protection. However, this efficacy remains inconclusive. In this article, we used meta-analysis to summarize the clinical results of all prospective clinical studies in order to determine the clinical efficacy and safety of sulodexide in diabetic patients with nephropathy. Overall, sulodexide therapy was associated with a significant reduction in urinary protein excretion. In the sulodexide group, 220 (17.7%) achieved at least a 50% decrease in albumin excretion rate compared with only 141 (11.5%) in the placebo. The odds ratio comparing proportions of patients with therapeutic success between the sulodexide and placebo groups was 3.28 (95% confidence interval, 1.34–8.06; P=0.01). These data suggest a renoprotective benefit of sulodexide in patients with diabetes and micro- and macroalbuminuria, which will provide important information for clinical use of this drug as a potential modality for diabetic nephropathy, specifically, the prevention of end-stage renal disease that is often caused by diabetes.

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          Most cited references 51

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          Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease.

          Reduction of proteinuria is associated with delayed progression of chronic kidney disease. Reports suggest that angiotensin-receptor blockers (ARBs) reduce proteinuria, but results are variable. The relative effect of ARBs and angiotensin-converting enzyme (ACE) inhibitors, and their combined administration, remains uncertain. To establish the effect of ARBs versus placebo and alternative treatments, and the effect of combined treatment with ARBs and ACE inhibitors, on proteinuria. English-language studies in MEDLINE and the Cochrane Library Central Register of Controlled Trials (January 1990 to September 2006), reference lists, and expert contacts. Randomized trials of ARBs versus placebo, ACE inhibitors, calcium-channel blockers, or the combination of ARBs and ACE inhibitors in patients with or without diabetes and with microalbuminuria or proteinuria for whom data were available on urinary protein excretion at baseline and at 1 to 12 months. Two investigators independently searched and abstracted studies. Forty-nine studies involving 6181 participants reported results of 72 comparisons with 1 to 4 months of follow-up and 38 comparisons with 5 to 12 months of follow-up. The ARBs reduced proteinuria compared with placebo or calcium-channel blockers over 1 to 4 months (ratio of means, 0.57 [95% CI, 0.47 to 0.68] and 0.69 [CI, 0.62 to 0.77], respectively) and 5 to 12 months (ratio of means, 0.66 [CI, 0.63 to 0.69] and 0.62 [CI, 0.55 to 0.70], respectively). The ARBs and ACE inhibitors reduced proteinuria to a similar degree. The combination of ARBs and ACE inhibitors further reduced proteinuria more than either agent alone: The ratio of means for combination therapy versus ARBs was 0.76 (CI, 0.68 to 0.85) over 1 to 4 months and 0.75 (CI, 0.61 to 0.92) over 5 to 12 months; for combination therapy versus ACE inhibitors, the ratio of means was 0.78 (CI, 0.72 to 0.84) over 1 to 4 months and 0.82 (CI, 0.67 to 1.01) over 5 to 12 months. The antiproteinuric effect was consistent across subgroups. Most studies were small, varied in quality, and did not provide reliable data on adverse drug reactions. Proteinuria reduction is only a surrogate for important progression of renal failure. The ARBs reduce proteinuria, independent of the degree of proteinuria and of underlying disease. The magnitude of effect is similar regardless of whether the comparator is placebo or calcium-channel blocker. Reduction in proteinuria from ARBs and ACE inhibitors is similar, but their combination is more effective than either drug alone. Uncertainty concerning adverse effects and outcomes that are important to patients limits applicability of findings to clinical practice.
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            Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data

            Background Meta-analysis handles randomized trials with no outcome events in both treatment and control arms inconsistently, including them when risk difference (RD) is the effect measure but excluding them when relative risk (RR) or odds ratio (OR) are used. This study examined the influence of such trials on pooled treatment effects. Methods Analysis with and without zero total event trials of three illustrative published meta-analyses with a range of proportions of zero total event trials, treatment effects, and heterogeneity using inverse variance weighting and random effects that incorporates between-study heterogeneity. Results Including zero total event trials in meta-analyses moves the pooled estimate of treatment effect closer to nil, decreases its confidence interval and decreases between-study heterogeneity. For RR and OR, inclusion of such trials causes small changes, even when they comprise the large majority of included trials. For RD, the changes are more substantial, and in extreme cases can eliminate a statistically significant effect estimate. Conclusion To include all relevant data regardless of effect measure chosen, reviewers should also include zero total event trials when calculating pooled estimates using OR and RR.
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              Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death.

              Surveys have documented the continued popularity of low-dose dopamine to influence renal dysfunction even though few data support it and editorials and reviews have discouraged its use. To evaluate the effects of low-dose dopamine (< or =5 microg/kg of body weight per minute) compared with placebo or no therapy in patients with or at risk for acute renal failure. MEDLINE (1966-January 2005), EMBASE (1980-week 5, 2005), CANCERLIT (1975-2002), CINAHL (1982-January 2005), and CENTRAL (The Cochrane Library, fourth quarter, 2004); bibliographies of retrieved publications; and additional information from 50 trials. Two reviewers independently selected parallel-group randomized and quasi-randomized controlled trials of low-dose dopamine versus control. Study methods, clinical and renal physiologic outcomes, and adverse events (arrhythmias and myocardial, limb, and cutaneous ischemia) were extracted. 61 trials that randomly assigned 3359 patients were identified. Meta-analyses using random-effects models showed no effect of low-dose dopamine on mortality (relative risk, 0.96 [95% CI, 0.78 to 1.19]), need for renal replacement therapy (relative risk, 0.93 [CI, 0.76 to 1.15]), or adverse events (relative risk, 1.13 [CI, 0.90 to 1.41]). Low-dose dopamine increased urine output by 24% (CI, 14% to 35%) on day 1. Improvements in serum creatinine level (4% relative decrease [CI, 1% to 7%]) and measured creatinine clearance (6% relative increase [CI, 1% to 11%]) on day 1 were clinically insignificant. There were no significant changes on days 2 and 3 of therapy. Statistically significant between-study heterogeneity in physiologic but not clinical outcomes was unexplained by prespecified hypotheses. Low-dose dopamine offers transient improvements in renal physiology, but no good evidence shows that it offers important clinical benefits to patients with or at risk for acute renal failure.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                03 December 2015
                : 9
                : 6275-6283
                Affiliations
                [1 ]Emergency Department, First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
                [2 ]Dalian Hospital of Traditional Chinese Medicine, Dalian, People’s Republic of China
                [3 ]Intensive Care Unit, Tianjin First Central Hospital, People’s Republic of China
                Author notes
                Correspondence: Yu Zhang Emergency, Department, First Affiliated Hospital of Dalian Medical University, Number 222, ZhongShan, Dalian 116011, People’s Republic of China, Tel +86 411 8363 5963, Email yuzhangmd@ 123456yeah.net
                Article
                dddt-9-6275
                10.2147/DDDT.S87973
                4671764
                26664049
                © 2015 Li et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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