Background: Lower extremity artery disease (LEAD) is greatly harmful to Type 2 Diabetes Mellitus patients. Traditional Chinese Medicine (TCM) is an alternative therapy to delay the development of macrovascular diseases, but the existing evidence of its efficacy, safety and mechanism of action is insufficient. We report a study protocol of a multi-center, randomized, double-blind, placebo-controlled trial that aims to use well-designed clinical trial to evaluate the efficacy and safety of Chinese herbal medicine (CHM) Shen-Qi Hua-Yu formula, and to explore efficacy mechanism of the TCM granules and the biomarkers of TCM syndrome. Methods: This is a multi-center, double-blind, randomized, and placebo-controlled study that randomized 120 participants into 2 groups. The treatment group will receive TCM granules and conventional medicine, while the control group will receive placebo in addition to conventional medicine. Two groups will receive 12-week treatment and 48-week follow-up, with a total of 13 visits. Primary efficacy outcomes included ankle brachial index. Secondary efficacy outcomes included fasting plasma glucose, blood lipid, hemorheology indexes, advanced glycation end products, the inner diameter, peak systolic velocity, end diastolic velocity and mean average velocity of the anterior tibial artery, posterior tibial artery and dorsalis pedis artery, and TCM syndrome score. The safety and endpoint outcomes will be evaluated in this trial. The study will explain the biological therapeutic mechanism of Shen-Qi Hua-Yu formula for diabetic LEAD, and try to use Isobaric tags for Relative and Absolute Quantitation (iTRAQ) and Western blot to screen biomarkers of characteristic diagnosis and clinical efficiency evaluation of the TCM syndrome. Discussion: This study is a multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of CHM in patients with diabetic LEAD, and to interpret the therapeutic mechanism of Shen-Qi Hua-Yu formula in treatment of diabetic LEAD through proteomics technology, and to screen biomarkers with characteristics of TCM diagnosis and clinical efficacy evaluation. On the other hand, to our knowledge, this study may be the first trial of CHM formulas to observe cardiovascular outcomes through long-term follow-up for the treatment of diabetic LEAD, which is of great value. Trial registration: This study is registered on the Chinese Clinical Trial Registry: ChiCTR1900026372.

Background: Type 2 diabetes mellitus (T2DM) is a clinical metabolic syndrome characterized by persistent hyperglycemia, which is caused by defective insulin secretion and decreased function in regulating glucose metabolism. Dachaihu Decoction (DCHD) is a traditional Chinese medicine formula that has been gradually used in T2DM treatment. A comprehensive analysis on the efficacy and safety of DCHD in T2DM treatment is necessary.Objective: This meta-analysis aimed to systematically assess the clinical efficacy and safety of DCHD in the T2DM treatment and provide a reference for subsequent research and clinical practice.Methods: Both Chinese and English databases were searched from their inceptions to November 2021. All retrieved studies were screened according to inclusion and exclusion criteria and randomized controlled trials about DCHD on T2DM were enrolled. The quality of the literature was assessed using the bias risk assessment tool in the Cochrane Handbook. Data extraction was performed on the selected studies. Review Manager 5.4 and Stata 16.0 were used for meta-analysis. Sources of heterogeneity were also explored by using meta-regression and subgroup analysis. Funnel plot and Egger’s test were used to assess publication bias and the evidence quality was assessed by GRADE.Results: 17 eligible studies, involving 1,525 patients, were included in this study. Compared with conventional treatment, combined treatment with DCHD was significantly better in improving HbA1c (MD = −0.90%, 95%CI: −1.20 to −0.60, p < 0.01), FBG (MD = −1.08 mmol/L, 95%CI: −1.28 to −0.87, p < 0.01), 2hPG (MD = −1.25 mmol/L, 95%CI: −1.42 to −1.09, p < 0.01), TC (MD = −0.50 mmol/L, 95%CI: −0.70 to −0.30, p < 0.01), TG (MD = −0.44 mmol/L, 95%CI: −0.61 to −0.26, p < 0.01), LDL-C (MD = −0.58 mmol/L, 95%CI: −0.85 to −0.31, p < 0.01), HOMA-IR (SMD = −2.04, 95%CI: −3.09 to −0.99, p < 0.01), HOMA-β (SMD = 2.48, 95%CI: 2.20 to 2.76, p < 0.01) and BMI (MD = −1.52 kg/m2, 95%CI: −2.55 to −0.49, p < 0.01). When DCHD used alone, it had a similar efficacy to conventional treatment in HbA1c (MD = −0.04%, 95%CI: −0.17 to 0.09, p = 0.57) and FBG (MD = 0.13 mmol/L, 95%CI: −0.09 to 0.36, p = 0.24). It can also reduce 2hPG, even if not as effective as conventional treatment (MD = 0.54 mmol/L, 95%CI: 0.19 to 0.89, p < 0.01). Due to the small number of included studies, it is unclear whether DCHD used alone has an improving effect on lipid metabolism, BMI, HOMA-IR and HOMA-β. Analysis of adverse events showed DCHD was relatively safe. No obvious publication bias was detected by Funnel plot and Egger’s test.Conclusion: Based on this meta-analysis, we found that the combination with DCHD in the T2DM treatment has more advantages than conventional treatment alone, which can further regulate the glucose and lipid metabolism, reduce insulin resistance, improve islet function and lower BMI. DCHD alone also plays a certain role in regulating glucose. Meanwhile, DCHD is relatively safe. However, limited by the quality and quantity of included studies, the efficacy and safety of DCHD remain uncertain. More high-quality studies are still needed to provide more reliable evidence for the clinical application of DCHD.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021296718, identifier CRD42021296718.