Efficacy and safety of Abelmoschus manihot in the treatment of patients with type 2 diabetes and microalbuminuria: A multicenter randomized, open-label, parallel-controlled clinical trial

To the Editor: Diabetic kidney disease (DKD) is a serious and increasingly prevalent complication of diabetes. Early clinical intervention can effectively mitigate kidney damage and promote disease reversal, particularly in patients with microalbuminuria whose kidney function remains largely preserved.[1] Recent clinical studies have demonstrated that Abelmoschus manihot (A. manihot) flowers (Huangkui capsules) show promising potential in the treatment of primary glomerular diseases, IgA nephropathy, and DKD.[2] Previous studies have also indicated that A. manihot exerts effects comparable to irbesartan in reducing urinary protein in patients with DKD and macroalbuminuria.[2] However, no evidence is available regarding whether A. manihot influences urinary protein levels in patients with microalbuminuria, despite its widespread clinical use in China for the treatment of proteinuria in chronic kidney disease.[3] Therefore, we conducted a multicenter randomized clinical trial with losartan as the positive control to assess whether A. manihot is as effective as losartan in treating type 2 diabetes with microalbuminuria. The trial was registered on August 20, 2019, under registration number ChiCTR1900025273. It was conducted in six hospitals located in Shanghai and Jiangsu, China. The study strictly adhered to the Declaration of Helsinki and received approval from the ethics committees of all participating centers, including the Ethics Committee of Shanghai Sixth People’s Hospital (main research center, approval No. 2019-066). The first patient was enrolled on December 16, 2019, and the final patient completed the study on February 8, 2022. Written informed consent was obtained from all participants. The number of patients enrolled at each participating center is provided in Supplementary Table 1, https://links.lww.com/CM9/C781. Eligible participants were between 18 and 75 years of age, diagnosed with diabetes and microalbuminuria according to the Expert Consensus on the Prevention and Treatment of Diabetic Kidney Disease (2014 Edition).[4] Inclusion criteria included an albumin-to-creatinine ratio (ACR) between 30 and 300 mg/g, controlled blood pressure of ≤140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥60 mL·min−1·1.73 m−2, and glycated hemoglobin ≤9%. Patients were randomly assigned in a 1:1 ratio to the control group, which received losartan potassium tablets (Cozaar, MSD Hangzhou Pharmaceutical Co., Ltd., Hangzhou, Zhejiang Province, China) at a dose of 100 mg once daily, or to the experimental group, which received A. manihot (Huangkui capsules, Suzhong Pharmaceutical Group Co., Ltd., Taizhou, Jiangsu Province, China) at a dose of 2.15 g three times daily. The treatment duration was 24 weeks. The primary and secondary efficacy endpoints were the changes in ACR and eGFR from baseline, respectively. Sample size estimation and other detailed methods are provided in the Supplementary Materials, https://links.lww.com/CM9/C781. Statistical analyses were conducted using R software version 4.2.0 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Values are presented as mean with 95% confidence intervals. Among the 302 patients screened, 239 met the inclusion criteria and were randomly assigned to the two study groups: 120 patients in the losartan group and 119 in the A. manihot group. A total of 185 patients (77.4%) completed the trial protocol [Supplementary Figure 1, https://links.lww.com/CM9/C781]. All participants were of Han Chinese ethnicity. Baseline characteristics of the participants are presented in Supplementary Table 2, https://links.lww.com/CM9/C781. The losartan group had a baseline ACR value of 119.5 (95% confidence interval [CI], 105.3–133.6) mg/g, which decreased by 30.5 (6.2–54.7) mg/g at the endpoint (P = 0.049). Similarly, the A. manihot group had a baseline ACR value of 123.8 (108.2–139.4) mg/g, which decreased by 33.9 (17.1–50.8) mg/g at the endpoint (P = 0.001). Losartan produced a rapid reduction in ACR followed by a rebound due to “aldosterone escape,” whereas A. manihot achieved a gradual and sustained reduction in proteinuria without rebound effects [Figure 1A]. No significant difference was observed between the two groups in treatment efficacy (P = 0.825) [Figure 1A and B]. A. manihot demonstrated noninferiority to losartan but did not show superiority.Figure 1: Losartan and A. manihot showed comparable effects on ACR reduction and eGFR change. (A) Mean ACR during the 24-week treatment period. (B) Total and subgroup analysis of the change in ACR from baseline. (C) Change in eGFR from baseline during the 24-week treatment period. Data are expressed as mean with 95% confidence intervals; † P <0.01 vs. losartan group; * P <0.05, ‡ P <0.01, § P <0.001 vs. baseline. ACR: Albumin-to-creatinine ratio; A. manihot: Abelmoschus manihot; eGFR: Estimated glomerular filtration rate.Subgroup analysis was conducted in participants with a baseline ACR <100 mg/g. The decreases in ACR were 6.92 (−7.80 to 21.64) mg/g in the losartan group and –4.28 (−13.13 to 4.57) mg/g in the A. manihot group. Among participants with ACR ≥100 mg/g, the decreases in ACR were 56.83 (8.30–105.36) mg/g in the losartan group (P = 0.044) and 82.29 (49.74–114.84) mg/g in the A. manihot group (P <0.001), with no significant difference between the groups (P = 0.415) [Figure 1B]. These results suggest that current clinical evidence supports the use of proteinuria-lowering treatments only in patients with ACR ≥100 mg/g, with no evidence supporting effective reduction of urinary protein in patients with ACR <100 mg/g using currently available drugs. The baseline eGFR values in the losartan and A. manihot groups were 95.47 (91.78–99.16) and 97.84 (94.32–101.36) mL·min−1·1.73 m−2, respectively. After 24 weeks of treatment, eGFR decreased by 3.58 (1.70–5.46) and 3.57 (1.17–5.97) mL·min−1·1.73 m−2 in the respective groups, with no significant difference between them [Figure 1C]. The incidence of adverse events did not differ significantly between the two groups (P = 0.973) [Supplementary Table 3, https://links.lww.com/CM9/C781]. After 24 weeks of treatment, there were no significant differences in blood pressure, glycosylated hemoglobin A1c (HbA1c), or plasma potassium between the groups [Supplementary Figure 2, https://links.lww.com/CM9/C781]. It is known that both glucose-lowering and antihypertensive therapies can reduce urinary protein in patients with diabetes. However, Supplementary Figure 2, https://links.lww.com/CM9/C781 shows that both drugs in this study had minimal effects on blood glucose and blood pressure, suggesting that the proteinuria-lowering effects of A. manihot and losartan are not dependent on changes in these parameters. The primary strength of this study is its evaluation of the therapeutic effect of A. manihot on microalbuminuria in early-stage DKD. By including an active control group, we demonstrated that A. manihot is noninferior to losartan, the current first-line clinical therapy, in reducing ACR levels, thereby providing an alternative treatment option for this condition. This study has several limitations. First, the treatment duration was only 24 weeks, and longer-term clinical trials are needed to confirm the sustained efficacy of A. manihot in the management of microalbuminuria in diabetic patients. Second, although the primary endpoint was urinary protein reduction, large-scale clinical trials with hard renal outcomes, such as progression to end stage renal disease and other composite kidney endpoints, are necessary to validate the renal protective effects of A. manihot. In conclusion, A. manihot significantly reduced ACR in patients with type 2 diabetes and microalbuminuria, with efficacy noninferior to losartan. Subgroup analysis demonstrated that both treatments reduced ACR only in patients with a baseline ACR ≥100 mg/g. Acknowledgments The authors thank Danfeng Peng, Yun Shen, Lianxi Li, Yinfang Tu, Dandan Yan, Mingliang Zhang, Yangxue Li, and others for their contributions in patient enrollment. The authors also thank Jinbo Liu and Ling Chen from Nanjing Sigma Medical Technology Co., Ltd. for their contributions to data management. The authors acknowledge Suzhong Pharmaceutical Group Co., Ltd. for supplying the study medications. Funding This work was supported by grants from the Three-year Project of Shanghai TCM Development (No. ZT[2018–2020]-FWTX-2003), National Key Clinical Specialty (No. Z155080000004), Shanghai Municipal Health Commission Clinical Research Fund (No. 202540071), and Shanghai Municipal Key Clinical Specialty. Conflicts of interest None.