Emerging Therapies for Diabetic Nephropathy Patients: Beyond Blockade of the Renin-Angiotensin System

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

Free versus Fixed Combination Antihypertensive Therapy for Essential Arterial Hypertension: A Systematic Review and Meta-Analysis

<div><p>Background</p><p>In a free drug combination, each Blood pressure (BP)-lowering drug is administered as a separate pill, while in a fixed drug combination several BP-lowering agents are combined in a single pill. Using a single pill may enhance compliance and simplify treatment, which would translate into better clinical outcomes. The objective of this meta-analysis is to compare the effects of using a fixed combination versus free combination of BP-lowering agents in the management of patients with essential hypertension.</p><p>Methods</p><p>We searched Cochrane CENTRAL, MEDLINE, and EMBASE for randomized clinical trials (RCTs) addressing the objective of the review and assessing at least one of the following outcomes: BP-lowering efficacy, rapidity in achieving BP target, compliance, incidence of side effects, mortality, and morbidity. Two review authors independently selected eligible studies, abstracted data, and assessed risk of bias of included trials. The primary meta-analyses used a random-effects model.</p><p>Results</p><p>We identified seven RCTs with a total of 397 participants. Meta-analysis of efficacy in controlling BP showed a non-significant reduction of mean systolic BP of 0.81 mmHg (95% CI -3.25, 1.64) favoring the fixed combination group. As for adverse events, results showed a non-significant 13% risk reduction favoring the free combination (risk ratio 1.13, 95% CI 0.85, 1.5). Low quality of evidence was noted for both outcomes. Rapidity in achieving BP target was assessed in only one trial, and the results favored the fixed combination. Adherence to treatment was assessed in three trials, no pooled analysis was possible for this outcome. None of the included trials assessed mortality and morbidity.</p><p>Conclusion</p><p>The available low quality evidence does not confirm or rule out a substantive difference between fixed combination and free combination therapy in the management of HTN. Well designed RCTs with a long duration of follow-up and assessment of morbidity and mortality outcomes are needed.</p></div

Forest plot for the effect of fixed vs. free antihypertensive drug therapy on adverse Events.

<p>Forest plot for the effect of fixed vs. free antihypertensive drug therapy on adverse Events.</p

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

<p>(+): low risk of bias, (-): high risk of bias, (?): unclear risk of bias.</p

Forest plot for the effect of fixed vs free antihypertensive drug therapy on mean systolic blood pressure.

<p>Forest plot for the effect of fixed vs free antihypertensive drug therapy on mean systolic blood pressure.</p

Free vs. Fixed combination antihypertensive therapy for essential arterial hypertension: PRISMA Flow chart.

<p>Free vs. Fixed combination antihypertensive therapy for essential arterial hypertension: PRISMA Flow chart.</p

Characteristics of included studies.

<p>Characteristics of included studies.</p

Risk of bias in included studies.

<p>Risk of bias in included studies.</p

Forest plot for the effect of fixed versus free antihypertensive drug therapy on the control of blood pressure.

<p>Forest plot for the effect of fixed versus free antihypertensive drug therapy on the control of blood pressure.</p

Summary of findings table: Fixed antihypertensive drug therapy compared to free antihypertensive drug therapy for essential arterial hypertension.

<p>Summary of findings table: Fixed antihypertensive drug therapy compared to free antihypertensive drug therapy for essential arterial hypertension.</p