Add-on Rehmannia-6-Based Chinese Medicine in Type 2 Diabetes and CKD: A Multicenter Randomized Controlled Trial

Abstract

Background: Diabetes is the leading cause of CKD and kidney failure. We assessed the real-world effectiveness of Rehmannia-6-based Chinese medicine treatment, the most used Chinese medicine formulation, on the change in eGFR and albuminuria in patients with diabetes and CKD with severely increased albuminuria.

Methods: In this randomized, assessor-blind, standard care-controlled, parallel, multicenter trial, 148 adult patients from outpatient clinics with type 2 diabetes, an eGFR of 30-90 ml/min per 1.73 m 2 , and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g were randomized 1:1 to a 48-week add-on protocolized Chinese medicine treatment program (using Rehmannia-6-based formulations in the granule form taken orally) or standard care alone. Primary outcomes were the slope of change in eGFR and UACR between baseline and end point (48 weeks after randomization) in the intention-to-treat population. Secondary outcomes included safety and the change in biochemistry, biomarkers, and concomitant drug use.

Results: The mean age, eGFR, and UACR were 65 years, 56.7 ml/min per 1.73 m 2 , and 753 mg/g, respectively. Ninety-five percent ( n =141) of end point primary outcome measures were retrievable. For eGFR, the estimated slope of change was -2.0 (95% confidence interval [CI], -0.1 to -3.9) and -4.7 (95% CI, -2.9 to -6.5) ml/min per 1.73 m 2 in participants treated with add-on Chinese medicine or standard care alone, resulting in a 2.7 ml/min per 1.73 m 2 per year (95% CI, 0.1 to 5.3; P = 0.04) less decline with Chinese medicine. For UACR, the estimated proportion in the slope of change was 0.88 (95% CI, 0.75 to 1.02) and 0.99 (95% CI, 0.85 to 1.14) in participants treated with add-on Chinese medicine or standard care alone, respectively. The intergroup proportional difference (0.89, 11% slower increment in add-on Chinese medicine, 95% CI, 0.72 to 1.10; P = 0.28) did not reach statistical significance. Eighty-five adverse events were recorded from 50 participants (add-on Chinese medicine versus control: 22 [31%] versus 28 [36%]).

Conclusions: Rehmannia-6-based Chinese medicine treatment stabilized eGFR on top of standard care alone after 48 weeks in patients with type 2 diabetes, stage 2-3 CKD, and severely increased albuminuria.

Clinical trial registry: Semi-individualized Chinese Medicine Treatment as an Adjuvant Management for Diabetic Nephropathy (SCHEMATIC), NCT02488252 .

Graphical abstract

Figure 1

Flow diagram of study. A total of 148 patients were randomized from territory registry prescreening of eGFR and UACR and in-person full screening. The reason for exclusion is listed in Supplemental Material 9. The main reason for exclusion was ineligibility (n=153 of 276, 55%). Of all patient refusals, the main reason was the lack of time for extra study visits (n=38 of 118, 32%). Randomization was stratified by phenotype subgroups according to Chinese medicine practice. Add-on Chinese medicine versus control: phenotype subgroup 1 (29 versus 36); subgroup 2 (15 versus nine); subgroup 3 (18 versus 19); subgroup 4 (four versus five); and subgroup 5 (five versus eight). Primary analysis was based on the intention-to-treat population with 95% participants' end point primary outcome measures available. Per-protocol population for the intervention group was defined as the participants completed at least 60% designated doses of drug (49 and 63 from add-on Chinese medicine and standard care, respectively). A sensitivity analysis using 80% completion as per-protocol population was performed. UACR, urine albumin-to-creatinine ratio.

Figure 2

Primary and secondary outcomes. The primary outcomes were the change of eGFR and UACR. Same data with enlarged y-axis are shown by inset. (A) The estimated difference in the slope of eGFR decline was 2.7 ml/min per 1.73 m² per year (95% CI, 0.1 to 5.3; P = 0.04) less after receiving add-on Chinese medicine. Participants who received add-on Chinese medicine had 3.1 ml/min per 1.73 m² (95% CI, 1.0 to 5.3; P = 0.004) higher end point least-squares mean eGFR (±SEM) when compared with standard care control (54.8±0.8 versus 51.7±0.8 ml/min per 1.73 m²). (B) For UACR, the estimated proportional difference at end point (0.88, 12% lower in add-on Chinese medicine, 95% CI, 0.73 to 1.06; P = 0.18) between participants who received add-on Chinese medicine and standard care control (geometric mean [±SEM]: 659±9 versus 748±9 mg/g) did not reach statistical significance. The estimated proportional difference in the slope of change (0.89, 11% slower increment in add-on Chinese medicine, 95% CI, 0.72 to 1.10; P = 0.28) was also statistically insignificant. CI, confidence interval.

Figure 3

Primary outcomes stratified by subgroups at baseline. Forest plots of the estimated difference in the slope of change of primary outcomes between groups according to baseline subgroups. There was no significant interaction between treatment effect and different subgroups. (A) Forest plot of the estimated difference in the slope of eGFR change between groups according to baseline subgroups. (B) Forest plot of the estimated proportional difference in the slope of UACR change between groups according to baseline subgroups. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ChinMed, Chinese medicine; DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium-glucose cotransporter-2 inhibitor.