Effects of mulberry twig alkaloids and canagliflozin in inadequately controlled type 2 diabetes: a randomized controlled study based on flash glucose monitoring

Effects of mulberry twig alkaloids and canagliflozin in inadequately controlled type 2 diabetes: a randomized controlled study based on flash glucose monitoring | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Effects of mulberry twig alkaloids and canagliflozin in inadequately controlled type 2 diabetes: a randomized controlled study based on flash glucose monitoring Huiqin Li, ShanShan Tao, Xiao Zhou, Rengna Yan, Baowen Yu, Yong Luo, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8391022/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Background Herbal medicines hold therapeutic potential for diabetes management. This study compared the efficacy and safety of mulberry twig alkaloids (SZ-A) versus canagliflozin administration in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus (T2DM) by using the flash glucose monitoring (FGM) system. Methods Sixty patients were randomly assigned to two groups: SZ-A group (n = 30) and canagliflozin group (n = 30). All patients received add-on therapy either SZ-A or canagliflozin treatment for 12 weeks. FGM was applied for 7 days-period before and after treatment. General clinical data were collected and analyzed. Results After 12 weeks of treatment, both SZ-A and canagliflozin significantly reduced HbA 1c , fasting and postprandial glucose, 24h mean blood glucose, and time above rang (TAR). Time in range (TIR) was comparable between SZ-A (72.08%) and canagliflozin (73.85%), with no increase in time below range (TBR). In contrast to canagliflozin, SZ-A significantly reduced postprandial glucose excursion (PPGE) after breakfast and dinner. Both SZ-A and canagliflozin also improved insulin resistance and enhanced insulin sensitivity in patients. Additionally, both treatments significantly improved metabolism parameters, including weight, waist circumference, and triglyceride. Conclusion SZ-A showed hypoglycemic and metabolic effects comparable to canagliflozin, with superior control of postprandial glucose excursion after breakfast and dinner. Clinical trial registration : www.clinicaltrials.gov identifier is NCT05856578 (Registered 15 March 2022). Health sciences/Diseases Biological sciences/Drug discovery Health sciences/Endocrinology Health sciences/Health care Health sciences/Medical research Mulberry twig alkaloids Canagliflozin the flash glucose monitoring system type 2 diabetes mellitus Figures Figure 1 Figure 2 Figure 3 Introduction With the aging population and worsened lifestyle factors, the global prevalence of diabetes has been increasing steadily and has reached the endemic levels [ 1 ]. The estimated prevalence of diabetes in China significant increased from 10.9% in 2013 to 12.4% in 2018[ 2 ]. Most of these individuals (90%) have type 2 diabetes mellitus (T2DM). Although there are various hypoglycemic drugs for T2DM at present, only 36.7% of diabetic patients received treatment, and 50.1% of these treated patients had adequate glycemic control [ 2 , 3 ]. Poor glycemic control can lead to worse outcomes, including more complications and higher hospitalization rates and mortality in diabetic patients. The health burden of diabetes and its complications is increasing in China. The use of traditional herbal medicines has a long history, and long-term use is safe and more easily accepted by the Chinese people. Currently herbal medicines have development potential for the treatment of metabolic diseases such as diabetes [ 4 , 5 ]. Polyhydroxy alkaloids contained in mulberry plants have the activity of inhibiting glucosidases, indicating that the hypoglycemic active components in mulberry branches may be related to polyhydroxy alkaloids [ 6 ]. Mulberry twig alkaloids (Sangzhi alkaloids, SZ-A) tablets are the active components of alkaloids extracted from the mulberry plants[ 7 ], which were approved by the China National Medical Products Administration for T2DM treatment in 2020. SZ-A can reduce glucose levels through multiple targets, including inhibiting α-glycosidase activity, improving insulin resistance, enhancing insulin secretion, weight loss, and ameliorating intestinal flora imbalance [ 8 – 10 ]. Moreover, this drug can also regulate dyslipidemia and anti-inflammatory effects [ 9 , 11 , 12 ]. Previous studies reported that SZ-A and acarbose exhibited similar hypoglycemic effects, while SZ-A had better safety and fewer related adverse reactions [ 13 , 14 ]. However, there are few clinical studies comparing SZ-A tablets with other oral hypoglycemic drugs, except for acarbose. Sodium dependent glucose transporters 2 (SGLT2) inhibitors, as a class of widely used hypoglycemic drugs, can reduce glucose reabsorption by the proximal tubules, increase urinary glucose excretion, and thus lower blood glucose levels [ 15 , 16 ]. Thus, SGLT2 inhibitors have an insulin-independent hypoglycemic mechanism through reduced renal glucose reabsorption. Canagliflozin is an SGLT2 inhibitor developed for the treatment of T2DM. In patients with T2DM inadequately controlled with metformin, canagliflozin could significantly decrease glycosylated hemoglobin A 1c (HbA 1c ), fasting blood glucose (FBG), and body weight at 12 weeks with a low frequency of hypoglycemia [ 17 ]. However, canagliflozin increases the risk of genital mycotic infections and urinary tract infections, partially limiting its clinical use[ 18 ]. Patients with diabetes use professional mode fast glucose monitoring (FGM) system to provide personalized treatment basis for health-care professionals through retrospective analysis of the glycemic profiles [ 19 ]. Therefore, the aim of the current study was to assess the efficacy and safety of oral SZ-A compared with canagliflozin as add-on therapy in inadequately controlled patients with T2DM by using professional mode FGM system. Subjects, Materials and Methods Study population This randomized, controlled, single-center study was conducted at the Endocrinology Department of Nanjing First Hospital, Nanjing Medical University, China. It was approved by the Ethics Committee of Nanjing First Hospital (KY20220124-03). All procedures followed were in accordance with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for inclusion in this study. It was registered at ClinicalTrial.gov with registration number NCT05856578 (date of registration: 15 March 2022). The patient inclusion criteria were as follows: (1) Aged 18–75 years with a body mass index (BMI) ≥ 18 kg/m 2 and diagnosis of T2DM (meeting the WHO1999 diagnostic criteria) for at least 6 months; (2) Insufficient glycemic control (HbA 1c 7.0–9.0%) for no more than 2 oral hypoglycemic drugs, and all drug doses were stable for more than 2 months (If the combined medication were used, the dose of sulphonylureas should be less than the half of maximum dose); (3) not receiving treatment with α-glycosidase inhibitors and SGLT2 inhibitors; (4) subjects were able and willing to monitor peripheral blood sugar and regularity of diet and exercise; (5) volunteered to participate and provided signed informed consent prior to the trial. The exclusion criteria were as follows: (1) T1DM; (2) hepatic and renal dysfunctions: alanine transferase (ALT) higher than the 2.5 times the upper limit of normal or serum creatinine (SCr) higher than the 1.3 times the upper limit of normal; (3) poor compliance in diet or drug adherence; (4) recurrent or urinary tract infection; (5) repeated hypoglycemia; (6) history of alcohol dependence or drug abuse in the past 5 years; (7) treatment with systemic corticosteroids or other medications impacting the levels of cholesterol in the past 3 months; (8) acute infections or acute complications in the past 4 weeks; (9) pregnancy, lactation or preparation for pregnancy; (10) Severe diseases decided by doctors including: severe cardiopulmonary disease, endocrine disease, cancers, and mental illness. Study design In this prospective, open-label, randomized controlled study, 60 eligible patients with T2DM were enrolled between March and December 2022. They were randomly assigned in a 1:1 ratio to receive either oral SZ-A (50 mg three times daily) or oral canagliflozin (100 mg once daily) for 12 weeks. The random allocation sequence was generated by an independent statistician using a computer-generated random number list, with allocation conducted using a block randomization procedure (block size of [X]). Three patients withdrew consent, one patient experienced stomachache, and one patient experienced the symptomatic hypoglycemia; finally, 55 patients completed the study. The study design and flowchart of patients in this trial were shown in Supplementary Fig. 1 . The sample size was calculated based on the primary outcome of change in HbA 1c at 12 weeks, with an expected mean difference of 0% and a common standard deviation of 1.0%, using a two-sided α of 0.05 and 80% power. The calculated minimum sample size was 27 per group, which was inflated to 30 per group (total 60) to account for an anticipated dropout rate of 10%. The study lasted for 13 weeks. All patients received a standardized diet and were also required to refrain from both structured and recreational physical activities. There was no change in the type or dosage of medication taken by the patients before enrollment and during this study. All subjects received oral standard meal tolerance test (MTT) and FGM at baseline and week 11 of the treatment. The subjects were required to visit the local study center every four weeks. Clinical and laboratory examination Patient data, including demographic characteristics, lifestyle habits, medical history and medication use, were obtained using a standard questionnaire. Height and body weight were measured using a digital scale, and BMI was calculated as weight divided by height squared (kg/m 2 ). Blood samples were collected after the patients fasted overnight (≥ 8 hours). Biochemical parameters, including blood glucose (BG), ALT, aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), SCr and uric acid were measured using routine laboratory methods using a HITACHI 7600 device (HITACHI, Tokyo, Japan). Levels of insulin were measured with a radioimmunoassay kit. C-peptide (C-p) were assessed with chemiluminescent microparticle immunoassay (Architect system, USA). The homeostasis model assessment for insulin resistance (HOMA-IR), insulin secrete (HOMA-IS), and β cell function (HOMA-β) were assessed through previously published procedures [ 20 ]. The FGM system The FreeStyle Libre professional-mode FGM system (Abbott Diabetes Care, UK) has a disposable sensor, a handheld reader, and associated software. The sensor was applied at the clinic to the upper arm of the participants for 7 days and recorded interstitial glucose concentrations every 15 min. The glucose data were not available to the patients. After completion of the FGM intervention, the glucose data were downloaded. We analyzed the FGM data from day 2 to day 6. The following glycemic variability indices obtained from the FGM were calculated: 24-h mean blood glucose (24h MBG) (defined as the average glucose of 96 measurements equally spaced in time), mean amplitude of glycemic excursion (MAGE), standard deviation of mean glucose (SDBG), and coefficient of variation (CV %). Time in rang (TIR, glucose level 3.9–10.0 mmol/L), time above rang (TAR, glucose level > 10.0 mmol/L), and time below rang (TBR, glucose level 10.0 mmol/L and area over the curve (AOC) of a glucose level < 3.9 mmol/L were calculated using the trapezoid rule. Postprandial glucose excursion (PPGE) was calculated as the peak glucose value after meals minus the glucose level at the beginning of each meal [ 21 ]. Statistical analysis All statistical analyses were performed using SPSS 22.0 (SPSS Inc., USA) and GraphPad Prism 6.0 (GraphPad Inc., USA). Data are described as mean ± standard deviation (SD) for normally distributed continuous variables and median with interquartile range for non-normally distributed continuous variables. Categorical data are presented as frequency. Student’s t test and Wilcoxon test were used to compare the baseline characteristics between two groups. Comparisons between the pre- and post-treatment levels of parameters were made using paired t‑test for normally distributed continuous variables and Wilcoxon matched-pairs test for non-normally distributed continuous parameters. The post-treatment levels of parameters between two groups were analyzed by covariance. A P -value of less than 0.05 was considered statistically significant. Results Baseline Characteristics A total of 60 patients were recruited, and 55 patients (30 men and 25 women, with a mean age of 60.29 ± 8.40 years) with T2DM successfully completed this study. The dropout rates of the SZ-A and canagliflozin groups were 10% and 6.67%, respectively. There was no significant difference between two groups in age, sex, BMI, BP, diabetic duration, application of hypoglycemic drugs, HbA 1c , FBG, and PBG at baseline. The baseline clinical and laboratory characteristics of subjects are described in Table 1 and Table 2 . Basic metabolism profiles After 12 weeks of treatment, the body weight significantly decreased in both SZ-A (66.24 ± 10.14 vs. 64.61 ± 10.23 kg, P <0.001) and canagliflozin (66.78 ± 10.95 vs. 65.11 ± 10.74 kg, P <0.001) groups. BMI and WC at 12 week were significant lower than baseline levels in both groups ( P <0.01). There was no significant difference between two groups. Changes in Waist-hip ratio, SBP, DBP, heart rate, and uric acid from baseline showed no significant differences in both groups ( Table 2 ). SZ-A could significantly decrease TC, TG and HDL, while canagliflozin could significantly decrease TG and increase HDL after 12 weeks treatment. Changes in HDL showed significant between-group difference ( P 0.05). Blood glucose levels and islet function As shown in Figure 1 , both SZ-A and canagliflozin could significantly improve the glycemic control in T2DM. All of FBG, 1h and 2h-PBG decreased significantly in both groups (Figure 1A). Meanwhile, the between-group difference was not statistically significant ( P >0.05). In terms of insulin levels (Figure 1B), both SZ-A and canagliflozin had effects on lowering fasting insulin level (FINS). Compared with canagliflozin, SZ-A could also significantly reduce 1h postprandial insulin level (1h-PINS). Neither SZ-A nor canagliflozin had this effect on 2h-PINS. Furthermore, both SZ-A and canagliflozin could reduce fasting C-p (FC-p) level (Figure 1C). However, SZ-A had more significant effects on lowering 1h-postprandial C-p (1h-PC-p) level as compared with canagliflozin. Similar to 2h-PINS, neither of SZ-A or canagliflozin could reduce 2h-PC-p. As presented in Figure 2 , the HbA 1c at 12 weeks was significantly lower than baseline in both the SZ-A and canagliflozin groups (8.13 ± 0.59 vs. 7.20 ± 0.50%, P <0.001 and 8.11 ± 0.50 vs. 7.17 ± 0.54 mmol/L, P <0.001; respectively). There was no significant between-group difference with respect to HbA 1c at 12-week ( P =0.582). There was no significant between-group difference in HOMA-IR, HOMA-IS or HOMA-b level at baseline (Figure 2B, 2C, 2D). At the 12-week evaluation, HOMA-IR level was significantly lower than baseline ( P <0.01) in both the SZ-A and canagliflozin groups. Meanwhile, HOMA-IS level was significantly higher than baseline ( P 0.05). HOMA-b seemed no change either in the SZ-A group or the Canagliflozin group at 12-week ( P >0.05). Variables of FGM Table 3 showed the glucose fluctuation variables measured using an FGM for oral administration with SZ-A and canagliflozin. As shown in Figure 2E, a difference was seen in the 24h MBG. TIR 3.9-10mmol/L at 12 weeks in SZ-A and canagliflozin was significantly higher than baseline (Figure 2F, 63.59 ± 19.29 vs. 73.85 ± 20.96 mmol/L, P =0.026 and 57.35 ± 23.36 vs. 72.08 ± 16.61%, P =0.003; respectively). Similar differences were also seen in the AUC 3.9-10mmol/L ( P 10mmol/L at 12 weeks was significantly lower in the SZ-A and canagliflozin group than baseline (34.93 ± 19.64 vs. 23.85 ± 20.69 mmol/L, P =0.011 and 39.91 ± 25.69 vs. 26.23 ± 17.45%, P =0.008; respectively). The AUC > 10mmol/L was significantly decreased in both groups ( P <0.05). It is particularly important that both SZ-A and canagliflozin did not increase TBR<3.9mmol/L and AOC<3.9mmol/L. The SDBG at 12 weeks was lower than baseline in the SZ-A group ( P =0.001). There was no significant difference in glycemic variability parameters (MAGE, SDBG, CV%) in the canagliflozin group ( P >0.05). Covariance analysis revealed no significant between-group at 12 weeks in glycemic variability parameters ( P >0.05). As a a-glycosidase inhibitor, SZ-A can effectively reduce postprandial blood glucose. We further compared the effects of SZ-A and canagliflozin on postprandial blood glucose peaks using FGM measurements. Both SZ-A and canagliflozin significantly reduced postprandial blood glucose (PPBG) peak-breakfast, pre-lunch BG, PPBG peak-lunch, and pre-dinner BG ( P <0.05). SZ-A also decreased PPGE of breakfast and PPBG peak-dinner, while canagliflozin increased PPGE of dinner ( P <0.05). In contrast to canagliflozin, SZ-A could significantly lower PPGE of breakfast and dinner ( P 0.05). FGM glucose profile The average blood glucose concentration per hour measured using the FGM in patients before and after oral administration of SZ-A or canagliflozin was shown in Figure 3. We observed that patients taking SZ-A had significantly lower mean glucose levels after three meals. Patients who took canagliflozin had significantly decreased mean glucose levels after three meals, and their early morning mean glucose levels were also decreased. There was no significant difference at baseline and 12 weeks between two groups. But SZ-A seemed to lower mean glucose levels after dinner than canagliflozin. Adverse Events There were no serious adverse reactions occurred during this study. In the SZ-A group, one patient experienced stomachache. After discontinuing the SZ-A table, the patient's stomachache relieved. One patient experienced the symptomatic hypoglycemia in the canagliflozin group. Symptoms of hypoglycemia relieved after eating. These two patients launched this study. Discussion In this randomized controlled study, we evaluated the therapeutic efficacy of SZ-A and canagliflozin in glucose profiles by FGM and other metabolism parameters in patients with T2DM. We found that HbA 1c decreased by 0.93% after treatment SZ-A for 12 weeks, which was similar to that in the canagliflozin group (0.94%). This result of our study was consistent with previous reports [ 13 ]. Same as canagliflozin, SZ-A also showed to significantly reduce FBG, PBG, 24h-MBG, and TAR and increase TIR. In addition to inhibiting α-glucosidase activity, our study suggested that SZ-A also improved insulin resistance and enhanced insulin sensitivity in patients with diabetes. The above results indicated that SZ-A had a good hypoglycemic effect which is equivalent to canagliflozin. Furthermore, SZ-A treatment could significantly improve other metabolism parameters, such as weight, BMI, WC, TC, and TG. Use of FGM continues to expand in clinical practice. The FGM system can provide valuable data on Time-in-Ranges metrics, the Ambulatory Glucose Profile, overlay reports, and daily views for persons with diabetes and their healthcare providers [ 22 ]. There was an association of lower TIR with an increased risk of diabetes-related microvascular complications, all-cause and CVD mortality in patients with T2DM [ 23 , 24 ]. Recent analyses showed an inverse relationship between TIR and HbA 1c . An increase of 10% in TIR corresponds to a decrease of approximately 0.5% in HbA 1c [ 25 ]. HbA 1c is an average value and does not reflect glucose variability. Therefore, TIR could be used as a surrogate marker for long-term adverse clinical outcomes [ 26 ]. After treatment for 12 weeks, the TIR (3.9-10mmol/L) in the SZ-A group increased by 14.73%, which seems to be greater increase tendency in the canagliflozin group (9.9%), but there was no statistical difference between two groups. According to recommendations from the international consensus on TIR [ 26 ], the target of TIR is > 70% in T2DM. In this study, we observed that the TIR was above 70% in both SZ-A (72.08%) and canagliflozin (73.85%) groups. Similar to the TIR, AUC of glucose 3.9–10.0 mmol/L was significantly higher after treatment with SZ-A and canagliflozin. There was no difference in time of reaching target of glucose between two groups. In addition, we also found that the TAR was significantly lower in both groups. A multicenter, randomized, double-blind, parallel-controlled clinical study conducted in 600 patients with T2DM showed that no hypoglycemia events occurred in either SZ-A group or acarbose group [ 13 ]. Hypoglycemia is an important consideration during the evaluation of hypoglycemic treatment [ 27 ]. During our entire study, the patients in SZ-A group did not experience hypoglycemia. Meanwhile, the results of FGM showed that SZ-A did not increase the risk of hypoglycemia while reducing hyperglycemia. One patient in the canagliflozin group withdrew from this study due to symptomatic hypoglycemia. Compare with SZ-A, canagliflozin decreased the early morning mean glucose levels, which might mean that canagliflozin could increase the risk of hypoglycemia. Previous animal experiments had revealed that SZ-A had other pharmacological effects such as improving basal insulin levels, alleviating insulin resistance, and glucose stimulated insulin secretion [ 8 ]. In this study, we found that SZ-A treatment improved the insulin resistance and enhanced insulin sensitivity in patients with diabetes. We also found that SZ-A could reduce the insulin level both fasting and 1h-postprandial, and the latter effect was even better than canagliflozin. One reason was that SZ-A improved insulin resistance and corrected hyperinsulinemia at the same time. Another reason might be related to SZ-A delaying glucose digestion and absorption, leading to a slow increase in glucose stimulated insulin secretion. However, the functions of islet β cells seem not be improved either in SZ-A or canagliflozin. This is mainly related to the hypoglycemic mechanism of drugs. SZ-A may primarily exert hypoglycemic effect by inhibiting α-glycosidase, while canagliflozin reduces blood glucose by promoting urinary glucose excretion. Effective weight management is essential for patients with T2DM [ 28 ]. Animal studies had confirmed that SZ-A alleviated high-fat diet-induced obesity and reduced serum levels of lipid metabolism parameters in mice [ 29 , 30 ]. Further study showed that SZ-A alleviated obesity and metabolic syndrome by improving the gut microbiota and its metabolism profiles of high-fat diet-induced obese mice [ 31 ]. Our findings suggested that SZ-A treatment 12 weeks could significantly improve body weight, BMI, and WC, which was similar to canagliflozin. Meanwhile, SZ-A treatment also decreased lipid metabolism parameters, such as TC and TG. Unlike the increase of HDL in the treatment of canagliflozin, the SZ-A treatment reduced HDL in the patients. Therefore, the potential pharmacological characteristics and the underlying mechanism of SZ-A remain to be investigated. Some limitations of this study must be addressed. First, the observation period was relatively short. Because the treatment of diabetes is a long-term process. A longer duration of observation is required to further evaluate the efficacy and safety of SZ-A and the durability of response. Second, this was not a double-blind study. We could not exclude possible bias induced by the recognition of the drugs. Third, the patient population included a range of HbA 1c from 7.0% to 9.0%. Thus, no conclusions can be made about the comparison of SZ-A in patients with more severe hyperglycemia. Finally, while key glycemic metrics (HbA 1c , TIR) appeared similar and SZ-A showed better control of specific postprandial glucose excursions, the small sample size and short duration necessitate confirmation by larger, mullonger-term studies before definitive conclusions on equivalence or superiority can be drawn. In summary, our study demonstrated that the hypoglycemic effect of SZ-A was comparable to that of canagliflozin in patients with T2DM. SZ-A treatment could also significantly improve metabolism parameters and TIR which is similar to canagliflozin. In addition, SZ-A significantly lowered the postprandial glucose excursions after breakfast and dinner compared to canagliflozin. This study provides evidence to support the application of SZ-A in Chinese patients with inadequately controlled T2DM. Abbreviations ALT alanine transferase AOC area over the curve AST aspartate aminotransferase AUC area under the curve BMI body mass index CV%: the coefficient of variation DBP diastolic blood pressure DPP-VI dipeptidyl peptidase-IV FC-p fasting C-peptide FGM the flash glucose monitoring FINS fasting insulin HbA 1c glycosylated hemoglobin A 1c HC hip circumference HOMA-IR the homeostasis model assessment for insulin resistance HOMA-IS the homeostasis model assessment for insulin secrete HOMA-β the homeostasis model assessment for β cell function HDL high density lipoprotein LDL low density lipoprotein MAGE: mean amplitude of glycemic excursions MaxBG: maximum blood glucose MBG mean blood glucose MinBG: minimum blood glucose PC-p postprandial C-peptide PINS postprandial insulin PPBG postprandial blood glucose PPGE postprandial glucose excursion SBP systolic blood pressure SCr serum creatinine SDMG standard deviation SGLT2 sodium dependent glucose transporters 2 SZ-A Sangzhi alkaloids T2DM type 2 diabetes mellitus TAR time above range TBR time below range TC total cholesterol TG triglyceride WC waist circumference. Declarations Declaration of competing interest There are no conflicts of interest. Funding This work was supported by the National Key R&D Program of China (No.2018YFC1314100) and Nanjing Medical Science and Technology Development Foundation (No. ZKX22038) Author Contribution M.J., K.X. and L.H. designed the study. L.H., K.X., T.S., Z.X. Z.P. and Y.R. contributed in contributing the study and data collection. K.X., T.S., Y.B. and L.Y. analysed the data. K.X. contributed to write the first draft. All authors reviewed the manuscript. M.J. and L.H. gave final approval of the manuscript. The guarantor of this manuscript is M.J.. Acknowledgement We thank all of the participants for their cooperation, and members of Endocrinology department of Nanjing First hospital for their support. 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Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Care in Diabetes-2024. Diabetes Care . 47 (Suppl 1), S145–s157 (2024). Sun, Q. W. et al. Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice. Nutrients 14 (23), (2022). Wang, F., Xu, S. J., Ye, F., Zhang, B. & Sun, X. B. Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet/Streptozotocin-Induced Diabetic Mice. Nutrients 15 (18), (2023). Liu, D. et al. Ramulus mori (Sangzhi) alkaloids regulates gut microbiota disorder and its metabolism profiles in obese mice induced by a high-fat diet. Front. Pharmacol. 14 , 1166635 (2023). Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table13.docx SupplementaryFigure1.docx Cite Share Download PDF Status: Published Journal Publication published 21 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 11 Mar, 2026 Reviews received at journal 10 Mar, 2026 Reviews received at journal 02 Mar, 2026 Reviewers agreed at journal 27 Feb, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviewers invited by journal 18 Jan, 2026 Editor assigned by journal 17 Jan, 2026 Editor invited by journal 17 Jan, 2026 Submission checks completed at journal 13 Jan, 2026 First submitted to journal 13 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8391022","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":577155201,"identity":"16172cb2-8bb3-4158-be6f-aa69fd422821","order_by":0,"name":"Huiqin Li","email":"","orcid":"","institution":"Nanjing First Hospital, Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Huiqin","middleName":"","lastName":"Li","suffix":""},{"id":577155202,"identity":"b6418eea-31ce-41c1-bdbd-af1aca3a711f","order_by":1,"name":"ShanShan Tao","email":"","orcid":"","institution":"Nanjing First Hospital, Nanjing Medical 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06:56:35","extension":"xml","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":111358,"visible":true,"origin":"","legend":"","description":"","filename":"7ba497b396474b2a932e3d8df677880f1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/0b1cf6f73d391066e574a43c.xml"},{"id":100855719,"identity":"ccd447f3-b99d-4d1b-a4cb-2a00bf495ca7","added_by":"auto","created_at":"2026-01-22 06:56:52","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123589,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/5c664698f6bed5a53d32ea60.html"},{"id":100855649,"identity":"36a12ead-52d0-4cf5-9961-7c875a2b0cd0","added_by":"auto","created_at":"2026-01-22 06:56:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1930173,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of glycemic control parameters from baseline to week 12. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01, \u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001\u003c/p\u003e\n\u003cp\u003eAbbreviations: TIR: time in range; 24h MBG: 24 hr mean glucose; FBG, fasting blood glucose; PBG, postprandial blood glucose;\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/b34e9d0b50a023b65d2fad4d.png"},{"id":100855540,"identity":"f4a787f1-7132-4bc2-a45b-607d27e0a613","added_by":"auto","created_at":"2026-01-22 06:56:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1776801,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of index for insulin secretion and resistance from baseline to week 12. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01, \u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001\u003c/p\u003e\n\u003cp\u003eAbbreviations: FINS, fasting insulin; PINS, postprandial insulin; FC-p, fasting C-peptide; PC-p, postprandial C-peptide; HOMA-IR, the homeostasis model assessment for insulin resistance; HOMA-IS, the homeostasis model assessment for insulin secrete; HOMA-β, the homeostasis model assessment for β cell function.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/a3ec9cefcfc3472f8d76b2a6.png"},{"id":100855769,"identity":"3d9a56eb-1601-4aad-9ddf-4e27c04feb43","added_by":"auto","created_at":"2026-01-22 06:57:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2281173,"visible":true,"origin":"","legend":"\u003cp\u003eThe 24hr FGM glucose fluctuation profile before and after mulberry twig alkaloids or canagliflozin treatment. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05, \u003csup\u003e#\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/27218ad7bd43970cf210e27f.png"},{"id":107928024,"identity":"2ede62aa-5a74-4034-9031-bfe0f6a1f2a5","added_by":"auto","created_at":"2026-04-27 16:06:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6273116,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/a39feda5-62d4-4746-b285-acef108e3f12.pdf"},{"id":100855625,"identity":"cc54a669-4521-4af5-aa02-6a333f473d10","added_by":"auto","created_at":"2026-01-22 06:56:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":23533,"visible":true,"origin":"","legend":"","description":"","filename":"Table13.docx","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/2e77082f78a81d869b2fbf4c.docx"},{"id":100855671,"identity":"a2fbcd11-bbfc-4f06-9079-41f41aa0b33a","added_by":"auto","created_at":"2026-01-22 06:56:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":214641,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8391022/v1/f090436d305a705eafccfdcd.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of mulberry twig alkaloids and canagliflozin in inadequately controlled type 2 diabetes: a randomized controlled study based on flash glucose monitoring","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWith the aging population and worsened lifestyle factors, the global prevalence of diabetes has been increasing steadily and has reached the endemic levels [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The estimated prevalence of diabetes in China significant increased from 10.9% in 2013 to 12.4% in 2018[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Most of these individuals (90%) have type 2 diabetes mellitus (T2DM). Although there are various hypoglycemic drugs for T2DM at present, only 36.7% of diabetic patients received treatment, and 50.1% of these treated patients had adequate glycemic control [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Poor glycemic control can lead to worse outcomes, including more complications and higher hospitalization rates and mortality in diabetic patients. The health burden of diabetes and its complications is increasing in China.\u003c/p\u003e \u003cp\u003eThe use of traditional herbal medicines has a long history, and long-term use is safe and more easily accepted by the Chinese people. Currently herbal medicines have development potential for the treatment of metabolic diseases such as diabetes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Polyhydroxy alkaloids contained in mulberry plants have the activity of inhibiting glucosidases, indicating that the hypoglycemic active components in mulberry branches may be related to polyhydroxy alkaloids [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Mulberry twig alkaloids (Sangzhi alkaloids, SZ-A) tablets are the active components of alkaloids extracted from the mulberry plants[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], which were approved by the China National Medical Products Administration for T2DM treatment in 2020. SZ-A can reduce glucose levels through multiple targets, including inhibiting α-glycosidase activity, improving insulin resistance, enhancing insulin secretion, weight loss, and ameliorating intestinal flora imbalance [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Moreover, this drug can also regulate dyslipidemia and anti-inflammatory effects [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Previous studies reported that SZ-A and acarbose exhibited similar hypoglycemic effects, while SZ-A had better safety and fewer related adverse reactions [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, there are few clinical studies comparing SZ-A tablets with other oral hypoglycemic drugs, except for acarbose.\u003c/p\u003e \u003cp\u003eSodium dependent glucose transporters 2 (SGLT2) inhibitors, as a class of widely used hypoglycemic drugs, can reduce glucose reabsorption by the proximal tubules, increase urinary glucose excretion, and thus lower blood glucose levels [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Thus, SGLT2 inhibitors have an insulin-independent hypoglycemic mechanism through reduced renal glucose reabsorption. Canagliflozin is an SGLT2 inhibitor developed for the treatment of T2DM. In patients with T2DM inadequately controlled with metformin, canagliflozin could significantly decrease glycosylated hemoglobin A\u003csub\u003e1c\u003c/sub\u003e (HbA\u003csub\u003e1c\u003c/sub\u003e), fasting blood glucose (FBG), and body weight at 12 weeks with a low frequency of hypoglycemia [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, canagliflozin increases the risk of genital mycotic infections and urinary tract infections, partially limiting its clinical use[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with diabetes use professional mode fast glucose monitoring (FGM) system to provide personalized treatment basis for health-care professionals through retrospective analysis of the glycemic profiles [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Therefore, the aim of the current study was to assess the efficacy and safety of oral SZ-A compared with canagliflozin as add-on therapy in inadequately controlled patients with T2DM by using professional mode FGM system.\u003c/p\u003e"},{"header":"Subjects, Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis randomized, controlled, single-center study was conducted at the Endocrinology Department of Nanjing First Hospital, Nanjing Medical University, China. It was approved by the Ethics Committee of Nanjing First Hospital (KY20220124-03). All procedures followed were in accordance with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for inclusion in this study. It was registered at ClinicalTrial.gov with registration number NCT05856578 (date of registration: 15 March 2022).\u003c/p\u003e \u003cp\u003eThe patient inclusion criteria were as follows: (1) Aged 18\u0026ndash;75 years with a body mass index (BMI)\u0026thinsp;\u0026ge;\u0026thinsp;18 kg/m\u003csup\u003e2\u003c/sup\u003e and diagnosis of T2DM (meeting the WHO1999 diagnostic criteria) for at least 6 months; (2) Insufficient glycemic control (HbA\u003csub\u003e1c\u003c/sub\u003e 7.0\u0026ndash;9.0%) for no more than 2 oral hypoglycemic drugs, and all drug doses were stable for more than 2 months (If the combined medication were used, the dose of sulphonylureas should be less than the half of maximum dose); (3) not receiving treatment with α-glycosidase inhibitors and SGLT2 inhibitors; (4) subjects were able and willing to monitor peripheral blood sugar and regularity of diet and exercise; (5) volunteered to participate and provided signed informed consent prior to the trial. The exclusion criteria were as follows: (1) T1DM; (2) hepatic and renal dysfunctions: alanine transferase (ALT) higher than the 2.5 times the upper limit of normal or serum creatinine (SCr) higher than the 1.3 times the upper limit of normal; (3) poor compliance in diet or drug adherence; (4) recurrent or urinary tract infection; (5) repeated hypoglycemia; (6) history of alcohol dependence or drug abuse in the past 5 years; (7) treatment with systemic corticosteroids or other medications impacting the levels of cholesterol in the past 3 months; (8) acute infections or acute complications in the past 4 weeks; (9) pregnancy, lactation or preparation for pregnancy; (10) Severe diseases decided by doctors including: severe cardiopulmonary disease, endocrine disease, cancers, and mental illness.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eIn this prospective, open-label, randomized controlled study, 60 eligible patients with T2DM were enrolled between March and December 2022. They were randomly assigned in a 1:1 ratio to receive either oral SZ-A (50 mg three times daily) or oral canagliflozin (100 mg once daily) for 12 weeks. The random allocation sequence was generated by an independent statistician using a computer-generated random number list, with allocation conducted using a block randomization procedure (block size of [X]). Three patients withdrew consent, one patient experienced stomachache, and one patient experienced the symptomatic hypoglycemia; finally, 55 patients completed the study. The study design and flowchart of patients in this trial were shown in \u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e. The sample size was calculated based on the primary outcome of change in HbA\u003csub\u003e1c\u003c/sub\u003e at 12 weeks, with an expected mean difference of 0% and a common standard deviation of 1.0%, using a two-sided α of 0.05 and 80% power. The calculated minimum sample size was 27 per group, which was inflated to 30 per group (total 60) to account for an anticipated dropout rate of 10%.\u003c/p\u003e \u003cp\u003eThe study lasted for 13 weeks. All patients received a standardized diet and were also required to refrain from both structured and recreational physical activities. There was no change in the type or dosage of medication taken by the patients before enrollment and during this study. All subjects received oral standard meal tolerance test (MTT) and FGM at baseline and week 11 of the treatment. The subjects were required to visit the local study center every four weeks.\u003c/p\u003e\n\u003ch3\u003eClinical and laboratory examination\u003c/h3\u003e\n\u003cp\u003ePatient data, including demographic characteristics, lifestyle habits, medical history and medication use, were obtained using a standard questionnaire. Height and body weight were measured using a digital scale, and BMI was calculated as weight divided by height squared (kg/m\u003csup\u003e2\u003c/sup\u003e). Blood samples were collected after the patients fasted overnight (\u0026ge;\u0026thinsp;8 hours). Biochemical parameters, including blood glucose (BG), ALT, aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), SCr and uric acid were measured using routine laboratory methods using a HITACHI 7600 device (HITACHI, Tokyo, Japan). Levels of insulin were measured with a radioimmunoassay kit. C-peptide (C-p) were assessed with chemiluminescent microparticle immunoassay (Architect system, USA). The homeostasis model assessment for insulin resistance (HOMA-IR), insulin secrete (HOMA-IS), and β cell function (HOMA-β) were assessed through previously published procedures [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eThe FGM system\u003c/h3\u003e\n\u003cp\u003eThe FreeStyle Libre professional-mode FGM system (Abbott Diabetes Care, UK) has a disposable sensor, a handheld reader, and associated software. The sensor was applied at the clinic to the upper arm of the participants for 7 days and recorded interstitial glucose concentrations every 15 min. The glucose data were not available to the patients. After completion of the FGM intervention, the glucose data were downloaded. We analyzed the FGM data from day 2 to day 6. The following glycemic variability indices obtained from the FGM were calculated: 24-h mean blood glucose (24h MBG) (defined as the average glucose of 96 measurements equally spaced in time), mean amplitude of glycemic excursion (MAGE), standard deviation of mean glucose (SDBG), and coefficient of variation (CV %). Time in rang (TIR, glucose level 3.9\u0026ndash;10.0 mmol/L), time above rang (TAR, glucose level\u0026thinsp;\u0026gt;\u0026thinsp;10.0 mmol/L), and time below rang (TBR, glucose level\u0026thinsp;\u0026lt;\u0026thinsp;3.9mmol/L) were also calculated. The incremental area under the curve (AUC) of the glucose level\u0026thinsp;\u0026gt;\u0026thinsp;10.0 mmol/L and area over the curve (AOC) of a glucose level\u0026thinsp;\u0026lt;\u0026thinsp;3.9 mmol/L were calculated using the trapezoid rule. Postprandial glucose excursion (PPGE) was calculated as the peak glucose value after meals minus the glucose level at the beginning of each meal [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using SPSS 22.0 (SPSS Inc., USA) and GraphPad Prism 6.0 (GraphPad Inc., USA). Data are described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) for normally distributed continuous variables and median with interquartile range for non-normally distributed continuous variables. Categorical data are presented as frequency. Student\u0026rsquo;s t test and Wilcoxon test were used to compare the baseline characteristics between two groups. Comparisons between the pre- and post-treatment levels of parameters were made using paired t‑test for normally distributed continuous variables and Wilcoxon matched-pairs test for non-normally distributed continuous parameters. The post-treatment levels of parameters between two groups were analyzed by covariance. A \u003cem\u003eP\u003c/em\u003e-value of less than 0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eBaseline Characteristics\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eA total of 60 patients were recruited, and 55 patients (30 men and 25 women, with a mean age of 60.29 ± 8.40 years) with T2DM successfully completed this study. The dropout rates of the SZ-A and canagliflozin groups were 10% and 6.67%, respectively. There was no significant difference between two groups in age, sex, BMI, BP,\u0026nbsp;diabetic duration, application of hypoglycemic drugs, HbA\u003csub\u003e1c\u003c/sub\u003e, FBG, and PBG at baseline. The baseline clinical and laboratory characteristics of subjects are described in \u003cstrong\u003eTable 1\u003c/strong\u003e and \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBasic metabolism profiles\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAfter 12 weeks of treatment, the body weight significantly decreased in both SZ-A (66.24 ± 10.14 vs. 64.61 ± 10.23 kg, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) and canagliflozin (66.78 ± 10.95 vs. 65.11 ± 10.74 kg, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) groups. BMI and WC at 12 week were significant lower than baseline levels in both groups (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01). There was no significant difference between two groups. Changes in Waist-hip ratio, SBP, DBP, heart rate, and uric acid from baseline showed no significant differences in both groups (\u003cstrong\u003eTable 2\u003c/strong\u003e). SZ-A could significantly decrease TC, TG and HDL, while canagliflozin could significantly decrease TG and increase HDL after 12 weeks treatment. Changes in HDL showed significant between-group difference (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). There was no significant between-group difference in TC, TG, or LDL (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBlood glucose levels and islet function\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in \u003cstrong\u003eFigure 1\u003c/strong\u003e,\u0026nbsp;both SZ-A and canagliflozin could significantly improve the glycemic control in T2DM. All of FBG, 1h and 2h-PBG decreased significantly in both groups (Figure 1A). Meanwhile, the between-group difference was not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). In terms of insulin levels (Figure 1B), both SZ-A and canagliflozin had effects on lowering fasting insulin level (FINS). Compared with canagliflozin, SZ-A could also significantly reduce 1h postprandial insulin level (1h-PINS). Neither SZ-A nor canagliflozin had this effect on 2h-PINS. Furthermore, both SZ-A and canagliflozin could reduce fasting C-p (FC-p) level (Figure 1C). However, SZ-A had more significant effects on lowering 1h-postprandial C-p (1h-PC-p) level as compared with canagliflozin. Similar to 2h-PINS, neither of SZ-A or canagliflozin could reduce 2h-PC-p.\u003c/p\u003e\n\u003cp\u003eAs presented in \u003cstrong\u003eFigure 2\u003c/strong\u003e, the HbA\u003csub\u003e1c\u003c/sub\u003e at 12 weeks was significantly lower than baseline in both the SZ-A and canagliflozin groups (8.13 ± 0.59 vs. 7.20 ± 0.50%, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001 and 8.11 ± 0.50 vs. 7.17 ± 0.54 mmol/L, \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001; respectively). There was no significant between-group difference with respect to HbA\u003csub\u003e1c\u003c/sub\u003e at 12-week (\u003cem\u003eP\u003c/em\u003e=0.582). There was no significant between-group difference in HOMA-IR, HOMA-IS or HOMA-b\u0026nbsp;level at baseline (Figure 2B, 2C, 2D). At the 12-week evaluation, HOMA-IR level was significantly lower than baseline (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01) in both the SZ-A and\u0026nbsp;canagliflozin\u0026nbsp;groups. Meanwhile, HOMA-IS level was significantly higher than baseline (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.01) in both groups. However, there was no significant between-group difference (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). HOMA-b\u0026nbsp;seemed no change either in the SZ-A group or the Canagliflozin group at 12-week (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVariables of FGM\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e showed the glucose fluctuation variables measured using an FGM for oral administration with SZ-A and\u0026nbsp;canagliflozin. As shown in Figure 2E, a difference was seen in the 24h MBG. TIR 3.9-10mmol/L at 12 weeks in SZ-A and\u0026nbsp;canagliflozin\u0026nbsp;was significantly higher than baseline (Figure 2F, 63.59 ± 19.29 vs. 73.85 ± 20.96 mmol/L, \u003cem\u003eP\u003c/em\u003e=0.026 and 57.35 ± 23.36 vs. 72.08 ± 16.61%, \u003cem\u003eP\u003c/em\u003e=0.003; respectively). Similar differences were also seen in the AUC 3.9-10mmol/L (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.001). The TAR\u0026gt;10mmol/L at 12 weeks was significantly lower in the SZ-A and\u0026nbsp;canagliflozin group than baseline\u0026nbsp;(34.93 ± 19.64 vs. 23.85 ± 20.69 mmol/L, \u003cem\u003eP\u003c/em\u003e=0.011 and 39.91 ± 25.69 vs. 26.23 ± 17.45%, \u003cem\u003eP\u003c/em\u003e=0.008; respectively). The AUC \u0026gt; 10mmol/L was significantly decreased in both groups (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). It is particularly important that both SZ-A and\u0026nbsp;canagliflozin\u0026nbsp;did not increase TBR\u0026lt;3.9mmol/L and AOC\u0026lt;3.9mmol/L. The SDBG at 12 weeks\u0026nbsp;was lower than baseline\u0026nbsp;in the SZ-A\u0026nbsp;group (\u003cem\u003eP\u003c/em\u003e=0.001).\u0026nbsp;There was no significant difference in glycemic variability parameters (MAGE, SDBG, CV%) in the\u0026nbsp;canagliflozin\u0026nbsp;group (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). Covariance analysis revealed no significant between-group at 12 weeks in glycemic variability parameters (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003eAs a\u0026nbsp;a-glycosidase inhibitor, SZ-A can effectively reduce postprandial blood glucose. We further compared the effects of SZ-A and\u0026nbsp;canagliflozin\u0026nbsp;on postprandial blood glucose peaks using FGM measurements. Both SZ-A and\u0026nbsp;canagliflozin\u0026nbsp;significantly reduced\u0026nbsp;postprandial blood glucose (PPBG) peak-breakfast, pre-lunch BG, PPBG peak-lunch, and pre-dinner BG (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05).\u0026nbsp;SZ-A\u0026nbsp;also decreased PPGE of breakfast and PPBG peak-dinner, while\u0026nbsp;canagliflozin increased\u0026nbsp;PPGE of dinner (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). In contrast to canagliflozin, SZ-A could significantly lower\u0026nbsp;PPGE of breakfast and dinner (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05).\u0026nbsp;There was no significant between-group difference in\u0026nbsp;PPGE of\u0026nbsp;lunch (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFGM glucose profile\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe average blood glucose concentration per hour measured using the FGM in patients before and after oral administration of SZ-A or\u0026nbsp;canagliflozin was shown in Figure 3. We observed that patients taking\u0026nbsp;SZ-A\u0026nbsp;had significantly lower mean glucose levels after three meals. Patients who took\u0026nbsp;canagliflozin had significantly\u0026nbsp;decreased\u0026nbsp;mean glucose levels after three meals, and their\u0026nbsp;early morning\u0026nbsp;mean glucose levels were\u0026nbsp;also decreased. There was no significant difference at baseline and 12 weeks between two groups. But SZ-A seemed to lower\u0026nbsp;mean glucose levels\u0026nbsp;after dinner than\u0026nbsp;canagliflozin.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAdverse Events\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere were no serious adverse reactions occurred during this study. In the SZ-A group, one patient experienced stomachache. After discontinuing the SZ-A table, the patient's stomachache relieved. One patient experienced the symptomatic hypoglycemia in the canagliflozin group. Symptoms of hypoglycemia relieved after eating. These two patients launched this study.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this randomized controlled study, we evaluated the therapeutic efficacy of SZ-A and canagliflozin in glucose profiles by FGM and other metabolism parameters in patients with T2DM. We found that HbA\u003csub\u003e1c\u003c/sub\u003e decreased by 0.93% after treatment SZ-A for 12 weeks, which was similar to that in the canagliflozin group (0.94%). This result of our study was consistent with previous reports [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Same as canagliflozin, SZ-A also showed to significantly reduce FBG, PBG, 24h-MBG, and TAR and increase TIR. In addition to inhibiting α-glucosidase activity, our study suggested that SZ-A also improved insulin resistance and enhanced insulin sensitivity in patients with diabetes. The above results indicated that SZ-A had a good hypoglycemic effect which is equivalent to canagliflozin. Furthermore, SZ-A treatment could significantly improve other metabolism parameters, such as weight, BMI, WC, TC, and TG.\u003c/p\u003e \u003cp\u003eUse of FGM continues to expand in clinical practice. The FGM system can provide valuable data on Time-in-Ranges metrics, the Ambulatory Glucose Profile, overlay reports, and daily views for persons with diabetes and their healthcare providers [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. There was an association of lower TIR with an increased risk of diabetes-related microvascular complications, all-cause and CVD mortality in patients with T2DM [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Recent analyses showed an inverse relationship between TIR and HbA\u003csub\u003e1c\u003c/sub\u003e. An increase of 10% in TIR corresponds to a decrease of approximately 0.5% in HbA\u003csub\u003e1c\u003c/sub\u003e [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. HbA\u003csub\u003e1c\u003c/sub\u003e is an average value and does not reflect glucose variability. Therefore, TIR could be used as a surrogate marker for long-term adverse clinical outcomes [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. After treatment for 12 weeks, the TIR (3.9-10mmol/L) in the SZ-A group increased by 14.73%, which seems to be greater increase tendency in the canagliflozin group (9.9%), but there was no statistical difference between two groups. According to recommendations from the international consensus on TIR [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], the target of TIR is \u0026gt;\u0026thinsp;70% in T2DM. In this study, we observed that the TIR was above 70% in both SZ-A (72.08%) and canagliflozin (73.85%) groups. Similar to the TIR, AUC of glucose 3.9\u0026ndash;10.0 mmol/L was significantly higher after treatment with SZ-A and canagliflozin. There was no difference in time of reaching target of glucose between two groups. In addition, we also found that the TAR was significantly lower in both groups.\u003c/p\u003e \u003cp\u003eA multicenter, randomized, double-blind, parallel-controlled clinical study conducted in 600 patients with T2DM showed that no hypoglycemia events occurred in either SZ-A group or acarbose group [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Hypoglycemia is an important consideration during the evaluation of hypoglycemic treatment [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. During our entire study, the patients in SZ-A group did not experience hypoglycemia. Meanwhile, the results of FGM showed that SZ-A did not increase the risk of hypoglycemia while reducing hyperglycemia. One patient in the canagliflozin group withdrew from this study due to symptomatic hypoglycemia. Compare with SZ-A, canagliflozin decreased the early morning mean glucose levels, which might mean that canagliflozin could increase the risk of hypoglycemia.\u003c/p\u003e \u003cp\u003ePrevious animal experiments had revealed that SZ-A had other pharmacological effects such as improving basal insulin levels, alleviating insulin resistance, and glucose stimulated insulin secretion [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In this study, we found that SZ-A treatment improved the insulin resistance and enhanced insulin sensitivity in patients with diabetes. We also found that SZ-A could reduce the insulin level both fasting and 1h-postprandial, and the latter effect was even better than canagliflozin. One reason was that SZ-A improved insulin resistance and corrected hyperinsulinemia at the same time. Another reason might be related to SZ-A delaying glucose digestion and absorption, leading to a slow increase in glucose stimulated insulin secretion. However, the functions of islet β cells seem not be improved either in SZ-A or canagliflozin. This is mainly related to the hypoglycemic mechanism of drugs. SZ-A may primarily exert hypoglycemic effect by inhibiting α-glycosidase, while canagliflozin reduces blood glucose by promoting urinary glucose excretion.\u003c/p\u003e \u003cp\u003eEffective weight management is essential for patients with T2DM [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Animal studies had confirmed that SZ-A alleviated high-fat diet-induced obesity and reduced serum levels of lipid metabolism parameters in mice [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Further study showed that SZ-A alleviated obesity and metabolic syndrome by improving the gut microbiota and its metabolism profiles of high-fat diet-induced obese mice [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Our findings suggested that SZ-A treatment 12 weeks could significantly improve body weight, BMI, and WC, which was similar to canagliflozin. Meanwhile, SZ-A treatment also decreased lipid metabolism parameters, such as TC and TG. Unlike the increase of HDL in the treatment of canagliflozin, the SZ-A treatment reduced HDL in the patients. Therefore, the potential pharmacological characteristics and the underlying mechanism of SZ-A remain to be investigated.\u003c/p\u003e \u003cp\u003eSome limitations of this study must be addressed. First, the observation period was relatively short. Because the treatment of diabetes is a long-term process. A longer duration of observation is required to further evaluate the efficacy and safety of SZ-A and the durability of response. Second, this was not a double-blind study. We could not exclude possible bias induced by the recognition of the drugs. Third, the patient population included a range of HbA\u003csub\u003e1c\u003c/sub\u003e from 7.0% to 9.0%. Thus, no conclusions can be made about the comparison of SZ-A in patients with more severe hyperglycemia. Finally, while key glycemic metrics (HbA\u003csub\u003e1c\u003c/sub\u003e, TIR) appeared similar and SZ-A showed better control of specific postprandial glucose excursions, the small sample size and short duration necessitate confirmation by larger, mullonger-term studies before definitive conclusions on equivalence or superiority can be drawn.\u003c/p\u003e \u003cp\u003eIn summary, our study demonstrated that the hypoglycemic effect of SZ-A was comparable to that of canagliflozin in patients with T2DM. SZ-A treatment could also significantly improve metabolism parameters and TIR which is similar to canagliflozin. In addition, SZ-A significantly lowered the postprandial glucose excursions after breakfast and dinner compared to canagliflozin. This study provides evidence to support the application of SZ-A in Chinese patients with inadequately controlled T2DM.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealanine transferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAOC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earea over the curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003easpartate aminotransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earea under the curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCV%: the coefficient of variation\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ediastolic blood pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDPP-VI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edipeptidyl peptidase-IV\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFC-p\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efasting C-peptide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFGM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe flash glucose monitoring\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFINS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efasting insulin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHbA\u003csub\u003e1c\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eglycosylated hemoglobin A\u003csub\u003e1c\u003c/sub\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehip circumference\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHOMA-IR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe homeostasis model assessment for insulin resistance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHOMA-IS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe homeostasis model assessment for insulin secrete\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHOMA-β\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe homeostasis model assessment for β cell function\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHDL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh density lipoprotein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLDL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elow density lipoprotein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMAGE: mean amplitude of glycemic excursions\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMaxBG: maximum blood glucose\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMBG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emean blood glucose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMinBG: minimum blood glucose\u003c/div\u003e \u003cdiv class=\"Description\"\u003e\u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePC-p\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epostprandial C-peptide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePINS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epostprandial insulin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPBG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epostprandial blood glucose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPGE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epostprandial glucose excursion\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esystolic blood pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSCr\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserum creatinine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSDMG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSGLT2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esodium dependent glucose transporters 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSZ-A\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSangzhi alkaloids\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eT2DM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etype 2 diabetes mellitus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etime above range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTBR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etime below range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etotal cholesterol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etriglyceride\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ewaist circumference.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDeclaration of competing interest\u003c/h2\u003e \u003cp\u003eThere are no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Key R\u0026amp;D Program of China (No.2018YFC1314100) and Nanjing Medical Science and Technology Development Foundation (No. ZKX22038)\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.J., K.X. and L.H. designed the study. L.H., K.X., T.S., Z.X. Z.P. and Y.R. contributed in contributing the study and data collection. K.X., T.S., Y.B. and L.Y. analysed the data. K.X. contributed to write the first draft. All authors reviewed the manuscript. M.J. and L.H. gave final approval of the manuscript. The guarantor of this manuscript is M.J..\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003e We thank all of the participants for their cooperation, and members of Endocrinology department of Nanjing First hospital for their support.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and confidentiality considerations but are available from the corresponding author upon reasonable request and subject to the approval of the Institutional Ethics Committee.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAschner, P. et al. The International Diabetes Federation's guide for diabetes epidemiological studies. \u003cem\u003eDiabetes Res. Clin. Pract.\u003c/em\u003e \u003cb\u003e172\u003c/b\u003e, 108630 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, L. et al. 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(Oxf)\u003c/em\u003e. \u003cb\u003e76\u003c/b\u003e (6), 810\u0026ndash;815 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartens, T. W. et al. Making sense of glucose metrics in diabetes: linkage between postprandial glucose (PPG), time in range (TIR) \u0026amp; hemoglobin A1c (A1C). \u003cem\u003ePostgrad. Med.\u003c/em\u003e \u003cb\u003e133\u003c/b\u003e (3), 253\u0026ndash;264 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu, J. et al. Time in Range in Relation to All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes: A Prospective Cohort Study. \u003cem\u003eDiabetes Care\u003c/em\u003e. \u003cb\u003e44\u003c/b\u003e (2), 549\u0026ndash;555 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu, J. et al. Association of Time in Range, as Assessed by Continuous Glucose Monitoring, With Diabetic Retinopathy in Type 2 Diabetes. \u003cem\u003eDiabetes Care\u003c/em\u003e. \u003cb\u003e41\u003c/b\u003e (11), 2370\u0026ndash;2376 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeck, R. W. et al. The Relationships Between Time in Range, Hyperglycemia Metrics, and HbA1c. \u003cem\u003eJ. Diabetes Sci. Technol.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e (4), 614\u0026ndash;626 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBattelino, T. et al. rd,,,,,,, and Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes care. 42(8), 1593\u0026ndash;1603.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRana, J. S., Moffet, H. H., Liu, J. Y. \u0026amp; Karter, A. J. Severe Hypoglycemia and Risk of Atherosclerotic Cardiovascular Disease in Patients With Diabetes. \u003cem\u003eDiabetes Care\u003c/em\u003e. \u003cb\u003e44\u003c/b\u003e (3), e40\u0026ndash;e41 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCommittee, A. D. A. P. P. 8. Obesity and Weight Management for the Prevention and Treatment of Type 2 Diabetes: Standards of Care in Diabetes-2024. \u003cem\u003eDiabetes Care\u003c/em\u003e. \u003cb\u003e47\u003c/b\u003e (Suppl 1), S145\u0026ndash;s157 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun, Q. W. et al. Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice. \u003cem\u003eNutrients\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e(23), (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, F., Xu, S. J., Ye, F., Zhang, B. \u0026amp; Sun, X. B. Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet/Streptozotocin-Induced Diabetic Mice. \u003cem\u003eNutrients\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e(18), (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu, D. et al. Ramulus mori (Sangzhi) alkaloids regulates gut microbiota disorder and its metabolism profiles in obese mice induced by a high-fat diet. \u003cem\u003eFront. Pharmacol.\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e, 1166635 (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mulberry twig alkaloids, Canagliflozin, the flash glucose monitoring system, type 2 diabetes mellitus","lastPublishedDoi":"10.21203/rs.3.rs-8391022/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8391022/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHerbal medicines hold therapeutic potential for diabetes management. This study compared the efficacy and safety of mulberry twig alkaloids (SZ-A) versus canagliflozin administration in poorly oral-antidiabetic controlled patients with type 2 diabetes mellitus (T2DM) by using the flash glucose monitoring (FGM) system.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSixty patients were randomly assigned to two groups: SZ-A group (n = 30) and canagliflozin group (n = 30). All patients received add-on therapy either SZ-A or canagliflozin treatment for 12 weeks. FGM was applied for 7 days-period before and after treatment. General clinical data were collected and analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter 12 weeks of treatment, both SZ-A and canagliflozin significantly reduced HbA\u003csub\u003e1c\u003c/sub\u003e, fasting and postprandial glucose, 24h mean blood glucose, and time above rang (TAR). Time in range (TIR) was comparable between SZ-A (72.08%) and canagliflozin (73.85%), with no increase in time below range (TBR). In contrast to canagliflozin, SZ-A significantly reduced postprandial glucose excursion (PPGE) after breakfast and dinner. Both SZ-A and canagliflozin also improved insulin resistance and enhanced insulin sensitivity in patients. Additionally, both treatments significantly improved metabolism parameters, including weight, waist circumference, and triglyceride.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSZ-A showed hypoglycemic and metabolic effects comparable to canagliflozin, with superior control of postprandial glucose excursion after breakfast and dinner.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical trial registration\u003c/em\u003e: www.clinicaltrials.gov identifier is NCT05856578 (Registered 15 March 2022).\u003c/p\u003e","manuscriptTitle":"Effects of mulberry twig alkaloids and canagliflozin in inadequately controlled type 2 diabetes: a randomized controlled study based on flash glucose monitoring","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-22 06:53:20","doi":"10.21203/rs.3.rs-8391022/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-11T04:04:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-10T18:13:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-02T09:50:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164098024336113391747220921330927576319","date":"2026-02-27T05:31:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"95799861254347015385142440353746714312","date":"2026-02-25T12:23:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-19T02:11:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-17T23:20:03+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-17T18:05:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-13T08:14:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-01-13T07:59:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"89f8d9d4-67d9-4d92-93b5-022d8d71b0b4","owner":[],"postedDate":"January 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":61403158,"name":"Health sciences/Diseases"},{"id":61403162,"name":"Biological sciences/Drug discovery"},{"id":61403163,"name":"Health sciences/Endocrinology"},{"id":61403164,"name":"Health sciences/Health care"},{"id":61403165,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-04-27T16:04:00+00:00","versionOfRecord":{"articleIdentity":"rs-8391022","link":"https://doi.org/10.1038/s41598-026-48843-2","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-04-21 15:59:28","publishedOnDateReadable":"April 21st, 2026"},"versionCreatedAt":"2026-01-22 06:53:20","video":"","vorDoi":"10.1038/s41598-026-48843-2","vorDoiUrl":"https://doi.org/10.1038/s41598-026-48843-2","workflowStages":[]},"version":"v1","identity":"rs-8391022","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8391022","identity":"rs-8391022","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}