Piperazine ferulate–irbesartan combo better than monotherapy in diabetic kidney disease

Piperazine ferulate (PF) appears to improve the efficacy of irbesartan in the treatment of diabetic nephropathy (DN), with the combination affording blood glucose control and renal function protection without increasing the incidence of adverse events (AEs), according to a study.

“These findings indicate that PF combined with irbesartan therapy in DN may have a better effect than irbesartan alone,” the investigators said. “The combined action of several mechanisms may contribute to mediate these effects.”

The current study was based on a meta-analysis of 12 trials that involved 1,300 DN patients (age range, 30–70 years), of which 650 were in the combination group and 650 in the irbesartan monotherapy group. PF was orally administered at 50–200 mg/d. Treatment lasted 8 weeks in five trials, 10 weeks in one, and 12 weeks in five.

Pooled data showed that compared with irbesartan alone, the addition of PF largely increased the total efficacy rate (odds ratio [OR], 4.95, 95 percent confidence interval [CI], 3.11–7.58; p<0.0001). [Clin Ther 2020;42:2196-2212]

The investigators pointed out that the combination provided good blood glucose control as a result of reductions in the levels of fasting plasma glucose (FPG; mean difference [MD], −1.40; p=0.03) and 2-h plasma glucose (MD, −1.65; p<0.0001).

Meanwhile, renal function improved and was preserved owing to decreases in serum creatinine (Scr; MD, −10.24; p<0.0001), 24-hour urinary protein (MD, −0.07; p<0.0001), urinary albumin excretion rate (UAER; MD, −22.52; p<0.0001), urinary β₂-microglobulin (β₂-MG; MD, −0.15; p<0.0001), and blood urea nitrogen (BUN; MD, −1.54; p=0.0002) content.

“PF, a nonpeptide endothelin (ET) receptor antagonist, can reduce the secretion of ET-1 by inhibiting renal transforming growth factor β1 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,” the investigators noted. [Immunopharmacol Immunotoxicol 2016;38:39-49]

Indeed, PF plus irbesartan improved renal microcirculation by regulating the whole blood viscosity low shear (MD, −1.41; p<0.0001), whole blood viscosity high shear (MD, −0.54; p<0.0001), whole blood viscosity (MD, −1.31; p<0.0001), whole blood reduction viscosity (MD, −1.42; p<0.0001), platelet aggregation rate (MD, −0.42; p<0.0001), plasma viscosity (MD, −13.02; p<0.0001), and fibrinogen content (MD, −0.25; p=0.003).

Equally important is that PF–irbesartan combo caused no severe adverse effects. Common adverse effects were dizziness, chest tightness, nausea, vomiting, abdominal pain, transient hypotension, thirst, and irritability. 

However, the investigators advised caution when interpreting the findings of the meta-analysis, as “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, randomized controlled trials, and studies that used double-blind methods, should be performed for further investigation,” they said.