Therapeutic Efficacy of Piperazine Ferulate Combined With Irbesartan in Diabetic Nephropathy: A Systematic Review and Meta-analysis
Irbesartan is widely used clinically in the treatment of diabetic nephropathy (DN). It is believed that piperazine ferulate (PF) combined with irbesartan could result in an improved efficacy in the treatment of DN. We present the latest meta-analysis that details the combination of PF and irbesartan therapy.
Before January 31, 2020, we searched various electronic databases for appropriate articles. Our search was not restricted by keyword or language. We then filtered all articles using certain criteria and assessed the quality of the qualified studies.
The meta-analysis included 12 trials that involved 1300 patients (650 in the experimental group and 650 in the control group). The ages of the patients ranged from 30 to 79 years. Compared with irbesartan alone, the total effective rate of PF combined with irbesartan was significantly higher (odds ratio [OR] = 4.95; 95% CI, 3.11–7.58; P < 0.0001). The blood glucose level was controlled by significantly decreasing the fasting plasma glucose level (mean difference [MD] = −1.40; 95% CI, −2.70 to −0.11; P = 0.03) and 2-h plasma glucose level (MD = −1.65; 95% CI, −2.49 to −0.82; P < 0.0001). The combination therapy significantly decreased the levels of serum creatinine (MD = −10.24; 95% CI, −15.25 to −5.23; P < 0.0001), 24-h urinary protein (MD = −0.07; 95% CI, −0.09 to −0.05; P < 0.0001), urinary albumin excretion rate (MD = −22.52; 95% CI, −30.20 to −14.84; P < 0.0001), urinary β2-microglobulin (MD = −0.15; 95% CI, −0.17 to −0.13; P < 0.0001), and blood urea nitrogen (MD = −1.54; 95% CI, −2.36 to −0.72; P = 0.0002), which was beneficial for improving and protecting renal function. The renal microcirculation was improved by significantly decreasing the whole blood viscosity low shear (MD = −1.41; 95% CI, −1.84 to −0.99; P < 0.0001), whole blood viscosity high shear (MD = −0.54; 95% CI, −0.63 to −0.45; P < 0.0001), whole blood viscosity (MD = −1.31; 95% CI, −1.79 to −0.83; P < 0.0001), whole blood reduction viscosity (MD = −1.42; 95% CI, −1.79 to −1.06; P < 0.0001), platelet aggregation rate (MD = −0.42; 95% CI, −0.50 to −0.35; P < 0.0001), plasma viscosity (MD = −13.02; 95% CI, −15.47 to −10.56; P < 0.0001), and fibrinogen content (MD = −0.25; 95% CI, −0.42 to −0.09; P = 0.003).
PF combined with irbesartan could improve the efficiency in the treatment of DN. However, these results should be handled carefully. These findings should be verified by several rigorous randomized controlled trials.
published in 2017 by the International Diabetes Federation, approximately 463 million adults worldwide had diabetes at this time. A high percentage of patients with diabetes mellitus (up to 30%) develop DN.
Early DN has no obvious clinical symptoms. In the absence of timely treatment, it will lead to proteinuria and persistent hypertension and eventually progress to renal failure.
Studies have proven that DN is a major cause of end-stage renal disease (ESRD).
The blood of patients with diabetes is characterized by high viscosity, high aggregation, and hypercoagulability, which negatively affect blood flow in the microvessels, reduce oxygen supply in microcirculation, hinder blood material exchange in microvascular tissues, and result in a large amount of oxygen free radicals produced by glycation end products. At the same time, increasing leukocyte adhesion and fibrinogen can cause lesion of vascular endothelial cells, lesion of the vascular wall, and formation of peripheral microcirculation network microthromboses, which can take shape of various microvascular complications.
Therefore, improving the microcirculation in patients with DN has become an important treatment strategy.
Irbesartan, as a powerful Ang II receptor antagonist that specifically binds to Ang II receptor subtype 1, can block the receptor-mediated activity of Ang II
and improve the high-pressure and high-perfusion states of glomerular hyperfiltration.
In addition, it can improve renal hemodynamics and delay the progress of DN.
Several clinical studies have compared the efficacy of PF combined with irbesartan with that of irbesartan only, but few meta-analyses have been performed. Thus, we collected the published clinical randomized controlled trials (RCTs) on DN to provide a meta-analysis with detailed information for the combination of PF and irbesartan.
In patients with DN, it is common to find the changes in blood glucose levels,
renal functional impairment,
and hemodynamic changes.
Its main manifestation is that it begins with early glomerular hyperfiltration, then leads to massive albuminuria and decrease of glomerular filtration rate. Typical changes associated with DN are microcirculation disturbance and microvascular basement membrane thickening. The pathogenesis of DN is complex, and recent studies have found that it is closely related to a variety of vasoactive substances.
ET and Ang II, 2 powerful vasoconstrictive factors, play an important role in the pathogenesis of DN.
As a nonpeptide ET receptor antagonist, PF can inhibit the release of ET and plays a strong role in dilating blood vessels and improving the microcirculation.
In addition, it can inhibit the release of inflammatory factors, resist the damage of oxidative free radicals to tissues, accelerate the removal caused by oxidative free radicals,
inhibit the aggregation of platelets, reduce the hypercoagulable state of blood vessels, reduce the burden of kidneys, reduce kidney damage, and improve renal functions. A study
indicated that treatment with ferulic acid and its derivatives (PF tablets) on the basis of conventional hypoglycemic and reasonable dietary treatment for patients with diabetes can significantly reduce the UAER, which not only delays the progression of DN but also improves the quality of life of patients with DN. Sodium ferulate, a derivative of ferulic acid, has certain effects and fewer adverse events in treating patients with DN, which was conformed in a meta-analysis.
If the blood glucose is not well controlled, the risk of long-term microalbuminuria and hypertension in patients with diabetes will be increased by 40%, and it may cause renal dysfunction.
It is reported that an improvement of glycemic control, especially if associated with lower blood pressures, would reduce the renal function decline in patients with diabetes.
On the basis of common treatment, including irbesartan, PF was added to treat DN. FPG and 2 h PG levels in the treatment group were significantly lower than those before treatment. PF can increase the biological effect of blood glucose metabolism disorder by antagonizing ET-1, improve blood glucose metabolism, and help control blood glucose.
We reported that the combination of PF and irbesartan could effectively control the level of blood glucose by decreasing the levels of FPG and 2 h PG (P
In most patients, the first sign of DN is moderately increased urinary albumin excretion,
which is associated with higher risks of kidney failure
(ie, 30–300 mg/g of creatinine in a spot urine sample) (also termed microalbuminuria).
reported that PF combined with benazepril can significantly improve the clinical symptoms and renal function and reduce UAER of DN. In this study, the levels of Scr, 24-h urinary protein, UAER, β2-MG, and BUN (P
Thus, it can significantly decrease the levels of kidney damage markers in patients with DN. Concerning the indexes of renal function, there were individual differences in the absorption and use of drugs among the participants with different sx composition and mean age, so they were the main sources of heterogeneity.
to dilate blood vessels and improve renal microcirculation. It is believed that the action of PF against platelet aggregation can reduce the hypercoagulable state of renal microvessels to alleviate the burden of the kidney and the damage of kidney tissue. Further observation in this article revealed that whole blood viscosity low shear, whole blood viscosity high shear, whole blood viscosity, whole blood reduction viscosity, platelet aggregation rate, plasma viscosity, and fibrinogen content (P
In this study, we observed a related result that, compared with irbesartan therapy alone, irbesartan combined with PF causes significant improvements in TER of DN (P < 0.0001). PF combined with irbesartan caused no severe adverse effects in the treatment of DN; however, common adverse effects were dizziness, chest tightness, nausea, vomiting, abdominal pain, transient hypotension, thirst, and irritability. Therefore, PF combined with irbesartan has a better efficacy in the treatment of DN, and the combination would not increase the incidence of adverse effects with the increase of drug types, which may have high tolerability and clinical promotion value. Nevertheless, this meta-analysis has some limitations. For example, there was a high risk of detection bias because of the lack of blinding, inadequate outcome indicators of some studies, and poor quality of selected studies. It is recommended that the quality of articles be improved and the risk of bias reduced in future studies.
These findings indicate that PF combined with irbesartan therapy in DN may have a better effect than irbesartan alone. Moreover, the difference in the incidence of adverse effects between the 2 groups was not statistically significant, indicating that PF combined with irbesartan did not increase the risk of treatment. The combined action of several mechanisms may contribute to mediate these effects. In this study, the combination could control the levels of blood glucose by reducing the levels of FPG, 2 h PG, and HbA1c. PF combined with irbesartan plays a protective role for the renal function by decreasing Scr, 24-h urinary protein, UAER, β2-MG, and BUN content. Thus, PF combined with irbesartan may regulate the whole blood viscosity low shear, whole blood viscosity high shear, whole blood viscosity, whole blood reduction viscosity, platelet aggregation rate, plasma viscosity, and fibrinogen content, thus affecting the hemorheologic findings. Nevertheless, the reasons why our findings must be handled strictly are that there were inadequate outcome indicators of some studies and the quality of selected studies was poor. Thus, more high-quality studies, which include multicenter studies, studies with large samples, RCTs, and studies that used double-blind methods, should be performed for further investigation.