Clinical Trials on Diabetic Nephropathy: A Cross-Sectional Analysis.
ABSTRACT: INTRODUCTION:Treatment options and decisions are often based on the results of clinical trials. We have evaluated the public availability of results from completed, registered phase III clinical trials on diabetic nephropathy and current treatment options. METHODS:This was a cross-sectional analysis in which STrengthening the Reporting of OBservational studies in Epidemiology criteria were applied for design and analysis. In June 2017, 34 completed phase III clinical trials on diabetic nephropathy in the ClinicalTrials. gov registry were identified and matched to publications in the ClinicalTrials.gov registry and to those in the PubMed and Google Scholar databases. If no publication was identified, the principal investigator was contacted. The ratio of published and non-published studies was calculated. Various parameters, including study design, drugs, and comparators provided, were analyzed. RESULTS:Drugs/supplements belonged to 26 different categories of medications, with the main ones being angiotensin-converting enzyme inhibitors, angiotensin-II receptors blockers, and dipeptidyl-peptidase-4-inhibitors. Among the trials completed before 2016 (n?=?32), 22 (69%) were published, and ten (31%) remained unpublished. Thus, data on 11 different interventions and more than 1000 patients remained undisclosed. Mean time to publication was 26.5 months, which is longer than the time constrictions imposed by the U.S. Food and Drug Administration Amendments Act. Most trials only showed weak effects on micro- and macroalbuminuria, with an absolute risk reduction of 1.0 and 0.3%, respectively, and the number needed to treat varied between 91 and 333, without any relevant effect on end-stage-renal disease by intensive glucose-lowering treatment. Comparison of the results, however, was difficult since study design, interventions, and the renal outcome parameters vary greatly between the studies. CONCLUSION:Despite the financial and human resources involved and the relevance for therapeutic guidelines and clinical decisions, about one-third of phase III clinical trials on diabetic nephropathy remain unpublished. Interventions used in published trials showed a low efficacy on renal outcome. FUNDING:Deutsche Forschungsgemeinschaft (DFG): SFB 1118.
Project description:Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been glycemic control and blood pressure lowering using agents blocking the renin-angiotensin system. Clinical trials are currently under way using novel agents for the treatment of patients with diabetic nephropathy. Promising agents emerging from some of the completed trials include pirfenidone and bardoxolone methyl, which have been shown in two recent randomized controlled trials in patients with diabetic nephropathy to result in an improved estimated glomerular filtration rate compared to placebo. Also, paricalcitol has been shown to decrease the urinary albumin-to-creatinine ratio, whereas sulodexide failed to do so in a large randomized double-blind placebo-controlled trial. Of note, pyridoxamine has also shown promise in the treatment of diabetic nephropathy if started early in the disease course. These preliminary trials have shown significant promise for managing patients with diabetic nephropathy, sparking active research in this field and providing the rationale for further clinical testing in long-term, hard-outcomes trials.
Project description:OBJECTIVE: To evaluate the effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (AIIRAs) on renal outcomes and all cause mortality in patients with diabetic nephropathy. DATA SOURCES: Medline, Embase, the Cochrane controlled trials register, conference proceedings, and contact with investigators. STUDY SELECTION: Trials comparing ACE inhibitors or AIIRAs with placebo or with each other in patients with diabetic nephropathy. DATA EXTRACTION: Mortality, renal outcomes (end stage renal disease, doubling of serum creatinine concentration, prevention of progression of microalbuminuria to macroalbuminuria, remission of microalbuminuria), and quality of trials. DATA SYNTHESIS: 36 of 43 identified trials compared ACE inhibitors with placebo (4008 patients), four compared AIIRAs with placebo (3331 patients), and three compared ACE inhibitors with AIIRAs (206 patients). We obtained unpublished data for 11 trials. ACE inhibitors significantly reduced all cause mortality (relative risk 0.79, 95% confidence interval 0.63 to 0.99) compared with placebo but AIIRAs did not (0.99, 0.85 to 1.17), although baseline mortality was similar in the trials. Both agents had similar effects on renal outcomes. Reliable estimates of the unconfounded relative effects of ACE inhibitors compared with AIIRAs could not be obtained owing to small sample sizes. CONCLUSION: Although the survival benefits of ACE inhibitors for patients with diabetic nephropathy are known, the relative effects of ACE inhibitors and AIIRAs on survival are unknown owing to the lack of adequate head to head trials.
Project description:OBJECTIVE:Appendicitis is considered the most frequent surgical emergency in children. While the management of paediatric appendicitis is evolving, the precise amount of unpublished completed trials, potentially introducing bias into meta-analyses, is unknown. Controversial issues include the appropriate choice of surgical procedures, criteria for diagnosis of appendicitis, the role of antibiotic treatment and pain management. Selective reporting may introduce bias into evidence-based clinical decision-making, and the current, precise extent of unpublished results in paediatric appendicitis is unknown. We therefore assessed the publication status of completed clinical studies involving children registered on ClinicalTrials.gov. DESIGN:Cross sectional analysis. STrengthening the Reporting of OBservational studies in Epidemiology criteria were applied for design and analysis. SETTING AND PARTICIPANTS:ClinicalTrials.gov was queried for completed studies which were matched to publications on ClinicalTrials.gov, PubMed or Google Scholar. If no publication could be identified, principal investigators were contacted. INTERVENTIONS/EXPOSURE:Observational analysis. PRIMARY AND SECONDARY OUTCOME MEASURES:The proportion of published and unpublished studies was calculated. Subgroup analysis included studies on surgical procedures, diagnosis, antibiotic treatment and pain management. RESULTS:Out of n=52 completed clinical studies involving children with appendicitis, n=33 (63%) were published and n=19 (37%) were unpublished. Eighty-three per cent (n=43/52) of clinical trials assessed the above-listed controversial issues. Diagnostic studies were most rigorously published (91% of trials reported), data on surgical procedures, antibiotic and pain management were less transparent. Sixty-six per cent of interventional studies and 60% of randomised studies were published. Median time-to-publication, for example, the delay between completion of the trial until public availability of the results was 24 (IQR 12-36), range 2-92 months. CONCLUSION:Despite the importance of appendicitis in clinical practice for the paediatric surgeon, there remains scientific uncertainty due to unpublished clinical trial results with room for improvement in the future. These data are helpful in framing the shifting paradigms in paediatric appendicitis because it adds transparency to the debate.
Project description:Diabetic nephropathy is rapidly becoming the major cause of end-stage renal disease and cardiovascular mortality worldwide. Standard of care therapies include strict glycemic control and blockade of the renin-angiotensin-aldosterone axis. While these treatments slow progression of diabetic nephropathy, they do not arrest or reverse it. Newer therapies targeting multiple molecular pathways involved in renal inflammation, fibrosis, and oxidative stress have shown promise in animal models. Subsequently, many of these agents have been investigated in clinical human trials with mixed results. In this review, we will discuss recent findings of novel agents used in the treatment of diabetic nephropathy.
Project description:Hypertension is highly prevalent in patients with diabetic nephropathy. Diabetic nephropathy is the leading cause of CKD and end-stage kidney disease in the United States. The etiology of hypertension in diabetic nephropathy involves mechanisms with multiple inter-related mediators that result in renal sodium reabsorption and peripheral vasoconstriction. The management of hypertension in these patients is focused on treatments that target these mediators. Clinical trials have established that drugs that inhibit the renin-angiotensin-aldosterone system should be used as first-line agents on the basis of their ability to slow down progression of kidney disease and lower albuminuria. There is further interest into how the combination of drugs that inhibit this pathway at multiple steps will contribute further to the management of hypertension and diabetic nephropathy. This article presents an updated review of the mechanisms involved in hypertension in patients with diabetic nephropathy. It also reviews the past clinical trials using single agents as therapeutics and the more recent trials involving novel drugs or drug combinations used to treat these patients. Retrospective analyses of multiple studies are included to better examine the significance of the currently proposed blood pressure targets for patients with diabetic nephropathy.
Project description:Despite improvements in glycemic and blood pressure control in patients with type 1 diabetes, diabetic nephropathy remains the most common cause of chronic kidney disease worldwide. A major challenge in preventing diabetic nephropathy is the inability to identify high-risk patients at an early stage, emphasizing the importance of discovering new therapeutic targets and implementation of clinical trials to reduce diabetic nephropathy risk.Limitations of managing patients with diabetic nephropathy with renin-angiotensin-aldosterone system blockade have been identified in recent clinical trials, including the failure of primary prevention studies in T1D and the demonstration of harm with dual renin-angiotensin-aldosterone system blockade. Fortunately, several new targets, including serum uric acid, insulin sensitivity, vasopressin, and sodium-glucose cotransporter-2 inhibition, are promising in the prevention and treatment of diabetic nephropathy.Diabetic nephropathy is characterized by a long clinically silent period without signs or symptoms of disease. There is an urgent need for improved methods of detecting early mediators of renal injury, to ultimately prevent the initiation and progression of diabetic nephropathy. In this review, we will focus on early diabetic nephropathy and summarize potential new therapeutic targets.
Project description:OBJECTIVES:Emergence delirium (ED) is a frequent and potentially serious complication of general anaesthesia in children. Although there are various treatment strategies, no general management recommendations can be made. Selective reporting of study results may impair clinical decision-making. We, therefore, analysed whether the results of completed registered clinical studies in patients with paediatric ED are publicly available or remain unpublished. DESIGN:Cross-sectional analysis. SETTING:ClinicalTrials.gov and ClinicalTrialsRegister.eu. PARTICIPANTS AND OUTCOME MEASURES:We determined the proportion of published and unpublished studies registered at ClinicalTrials.gov and ClinicalTrialsRegister.eu that were marked as completed by 1st September 2018. The major trial and literature databases were used to search for publications. In addition, the study investigators were contacted directly. For published trials, time to publication was calculated as the difference in months between study completion date and publication date. RESULTS:Of the 44 registered studies on paediatric ED, only 24 (54%) were published by September 2019. Published trials contained data from n=2556 patients, whereas n=1644 patients were enrolled in unpublished trials. Median time to publication was 19 months. Studies completed in recent years were published faster, but still only 9 of 24 trials were published within 12 months of completion. CONCLUSION:There is a distinct publication gap in clinical research in paediatric ED that may have an impact on meta-analyses and clinical practice.
Project description:Purpose of the review:Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are recommended for eligible patients with type 2 diabetes for the secondary prevention of adverse cardiovascular and kidney disease outcomes. Patients with type 2 diabetes and albuminuric chronic kidney disease, a history of atherosclerotic cardiovascular disease, and/or heart failure with reduced ejection fraction should be assessed for the use of these therapies. Sources of information:The sources include published clinical trials with SGLT2is, with a focus on cardiovascular safety studies and kidney protection trials. Methods:Information was gathered via a review of relevant literature and clinical practice guidelines, incorporated with real-life clinical experience. Key findings:Clinicians prescribing these agents must be familiar with the benefits of SGLT2is on cardiovascular and renal endpoints, and with adverse effects of SGLT2is, including mycotic genital infections and diabetic ketoacidosis. Primary care physicians and specialists should know how to adjust antihypertensive, antiglycemic, and diuretic agents. With the results of completed cardiovascular outcome trials and the Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy trial, nephrologists specifically have a unique opportunity to impact the safe, effective, and equitable implementation of SGLT2is into clinical practice. Limitations:Further work is needed in specific patient subgroups, including patients with chronic kidney disease stages IV and V, patients with kidney disease but lower levels of albuminuria, and in patients without diabetes.
Project description:Diabetic nephropathy is a long-standing complication of diabetes mellitus and is responsible for more than 40% of end-stage renal disease cases in developed countries. Unfortunately, conventional renin-angiotensin-aldosterone system (RAAS) inhibitor medications only partially protect against the development and progression of diabetic nephropathy. Moreover, RAAS inhibitors have failed as primary prevention therapy in type 1 diabetes. Thus, agents targeting alternative pathogenic mechanisms leading to diabetic nephropathy have been intensively investigated, which is the topic of this review.Promising emerging agents have targeted neurohormonal activation (alternative components of the RAAS and neprilysin inhibition), tubuloglomerular feedback mechanisms (sodium glucose cotransporter 2 inhibition and incretin-based therapy) and renal inflammation/fibrosis.Evidence demonstrating the potential of these agents to protect and prevent progression of diabetic nephropathy is summarized in this review. There are dedicated clinical trials ongoing with these therapies, which have the potential to change the clinical practice.
Project description:Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, renin angiotensin-aldosterone system blockade and multifactorial intervention. However, the renal protection provided by these therapeutic modalities is incomplete. There is a scarcity of studies analysing the nephroprotective effect of antihyperglycaemic drugs beyond their glucose lowering effect and improved glycaemic control on the prevention and progression of diabetic nephropathy. This article analyzes the exisiting data about older and newer drugs as well as the mechanisms associated with hypoglycemic drugs, apart from their well known blood glucose lowering effect, in the prevention and progression of diabetic nephropathy. Most of them have been tested in humans, but with varying degrees of success. Although experimental data about most of antihyperglycemic drugs has shown a beneficial effect in kidney parameters, there is a lack of clinical trials that clearly prove these beneficial effects. The key question, however, is whether antihyperglycemic drugs are able to improve renal end-points beyond their antihyperglycemic effect. Existing experimental data are post hoc studies from clinical trials, and supportive of the potential renal-protective role of some of them, especially in the cases of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Dedicated and adequately powered renal trials with renal outcomes are neccessary to assess the nephrotection of antihyperglycaemic drugs beyond the control of hyperglycaemia.