Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria

Abstract

Background and objectives Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria.Design, setting, participants, & measurements This was a randomized, multicenter, placebo-controlled, doubleblind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing.Results Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), 216% (imarikiren 5 mg), 227% (imarikiren 20 mg), 238% (imarikiren 40 mg), 239% (imarikiren 80 mg), and 231% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P,0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P,0.001). Remission rates (urine albumin-to-creatinine ratio ,30 mg/g creatinine and decreased $30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated.Conclusions Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.

Efficacy of Direct Renin Inhibitors in Slowing Down the Progression of Diabetic Kidney Disease: A Meta-Analysis

“…Table 1 shows the characteristics of the included studies and participants. Of all the included studies, two compared the monotherapy of direct renin inhibitors with angiotensin receptor blocker (ARB) [11,13], while two studies compared the combination of direct renin inhibitors with monotherapy of ARB or angiotensin-converting enzyme inhibitor (ACEI) [9,12]. The dose for ARB, ACEI and direct renin inhibitors varied in the included study.…”

“…Major adverse events that were significantly higher in the direct renin inhibitor group were hyperkalemia and hypotension. However, studies conducted by Ito et al [ 11 ] and Parving et al [ 9 ] did not show any significant difference between the two groups in terms of adverse events. Considering the benefits of direct renin inhibitors in terms of reducing UACR and albuminuria levels, further studies need to be continued in people with diabetic kidney disease.…”

Novel pharmacological interventions for diabetic kidney disease

“…Aliskiren, when used alone or in combination with valsartan, was comparable to standard ACEi or ARB in preventing aldosterone breakthrough [92]. Another renin inhibitor, imarikiren (TAK-272), which is a potent and selective DRI, was found to reduce uACR by up to 39% in a phase 2 study, with a dose-dependent improvement in albuminuria [93]. Unfortunately, the remission rates of albuminuria were not superior to the ARB candesartan.…”