Effectiveness of Azvudine Compared to Nirmatrelvir/Ritonavir in COVID-19 Patients with Diabetes: A Real-World Retrospective Analysis

Effectiveness of Azvudine Compared to Nirmatrelvir/Ritonavir in COVID-19 Patients with Diabetes: A Real-World Retrospective Analysis | 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 Effectiveness of Azvudine Compared to Nirmatrelvir/Ritonavir in COVID-19 Patients with Diabetes: A Real-World Retrospective Analysis Zefeng Zhu, Zichen Wang, Qiqin Chen, Qijin Chen, Xialing Li, Yeying Liu, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7493337/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Backgrounds: Azvudine and Nirmatrelvir/ritonavir have been approved for the treatment of mild to moderate COVID-19 in adults at high risk for progression to severe disease. Diabetes is a high-risk complication of COVID-19. Currently, the effectiveness of Azvudine and Nirmatrelvir/ritonavir in patients with both diabetes and COVID-19 remains unclear. This study aims to compare the effectiveness of these two drugs in patients with diabetes and COVID-19. Methods: In this retrospective study. Our team enrolled 13763 hospitalized patients with COVID-19 infection presenting with comorbid diabetes mellitus between December 5, 2022, and January 31, 2023. These patients were from six different hospitals in the GuangXi Zhuang Autonomous Region, including 288 patients treated with Azvudine and 112 patients treated with Nirmatrelvir/Ritonavir. The primary outcome comprised a composite endpoint of disease progression, characterized by all-cause mortality, intensive care unit (ICU) admission, or need for invasive mechanical ventilation. Data for all participants were retrospectively collected through electronic medical record review supplemented by telephone follow-up. We used propensity-score matching (PSM) to allow for a more direct comparison of the effectiveness between the two antiviral treatment groups. Findings: Among 400 enrolled patients, 41 deaths occurred during hospitalization or post-discharge follow-up (Azvudine group: n = 29; Nirmatrelvir/ritonavir group: n = 12). After propensity score matching (PSM), 17 deaths were recorded across both cohorts. Statistical analysis demonstrated no significant between-group differences in composite outcomes (including invasive mechanical ventilation and ICU admission). However, Nirmatrelvir/ritonavir showed superior efficacy for all-cause mortality reduction versus Azvudine (Crude HR = 0.502; Adjusted HR [aHR] = 0.502, 95% CI: 0.133-1.180). Glucocorticoid use during therapy was associated with reduced mortality risk, while concomitant anticoagulant therapy increased composite outcome risk. Findings indicated a progressive elevation in mortality risk with advancing diabetes severity grade. Notably, Nirmatrelvir/ritonavir reduced mortality by 63% in severe diabetes patients (HR = 0.37, 95% CI: 0.11-1.00). Interpretation Regarding outcome measures, patients with diabetes and COVID-19 infection treated with Nirmatrelvir/ritonavir demonstrated superior outcomes compared to those treated with Azvudine. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research COVID-19 diabetes mellitus Real-world study Azvudine Nirmatrelvir/Ritonavir Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction In December 2019, China first reported the initial case of novel coronavirus pneumonia, which rapidly spread worldwide. The World Health Organization designated the virus as severe acute respiratory syndrome coronavirus 2 SARS-CoV-2. [ 17 ] Following shifts in pandemic containment strategies, the COVID-19 outbreak peaked in late December 2022. Studies indicate that diabetes has been established as an independent risk factor for SARS-COV-2 infection. [ 13 ] A meta-analysis have demonstrated that diabetes significantly increases the risk of ICU admission and mortality in patients with COVID-19. [ 19 ] The case of death rate among COVID-19 patients with diabetes is three times higher than in non-diabetic patients. Consequently, effective antiviral drugs are crucial for reducing patients' mortality and preventing disease progression. The preferred oral antiviral treatments for SARS-COV-2 patients in China include nirmatrelvir/ritonavir and Azvudine. Research demonstrates that these oral agents can shorten hospitalization duration, reduce viral load, decrease in-hospital mortality, and mitigate disease progression. [ 1 ][ 2 ][ 18 ] Nevertheless, the efficacy of these two oral antivirals remains incompletely understood for the special high-risk population of diabetic patients. Methods Study design and inclusion population This multicenter retrospective cohort study included all hospital patients diagnosed with SARS-CoV-2 infection from six hospitals in Guangxi Zhuang Autonomous Region. The participating hospitals were: The First Affiliated Hospital of Guilin Medical University, The Sixth People's Hospital of Nanning, Liuzhou People's Hospital, The First People's Hospital of Hechi,Wuzhou Red Cross Hospital, and Nantong University Xinglin College. The study period was from December 5 2022, to January 31, 2023. Inclusion criteria were as follows: (1) Hospitalized between December 5,2022, and January 31,2023, with a diagnosis of SARS-COV-2 infection, (2) Diagnosed with diabetes mellitus before medication use (Diagnostic criteria: presence of symptoms including dry mouth, polyuria, polydipsia, polyphagia, and weight loss, AND fasting plasma glucose ≥ 7.0 mmol/L OR 2-hour postprandial plasma glucose ≥ 11.1 mmol/L OR glycated hemoglobin (HbA1c) > 6.5 (3) being received antiviral treatment with Azvudine or Nirmatrelvir/Ritonavir. (Azvudine: 5mg once daily, swallowed whole on an empty stomach, for a course not exceeding 14 days. Nirmatrelvir 300 mg co-administered with Ritonavir 100 mg every 12 hours for 5 consecutive days, (4) Stable diabetic condition (fasting plasma glucose 4.4-7.0 mmol/L OR non-fasting plasma glucose < 10.0 mmol/L OR HbA1c < 7.0%). The exclusion criteria include: (1) individuals under 18 years of age, (2) incomplete medical records or those lost to follow-up, (3) patients who did not undergo antiviral treatment with Azvudine or Nirmatrelvir/Ritonavir, (4) Had used antiviral medications for COVID-19 within 14 days before the first dose of the study medication. Based on antiviral treatment received, eligible patients were stratified into Azvudine or Nirmatrelvir/Ritonavir cohorts. Ethics This investigation complies with STROBE reporting guidelines and secured ethical approval from six participating hospitals. As a retrospective cohort analysis utilizing anonymized data, informed consent was waived. Baseline variable Standardized extraction of medical records from six hospital systems captured enrolled patients' demographic and clinical data, including age, sex, height, weight, and related variables. Note the time when symptoms began and the date of hospital admission, along with records of prescriptions and drug dispensing, baseline medical history, and medication usage. simultaneous treatments for the present infection, including corticosteroid therapy, anticoagulant therapy, and intravenous immunoglobulin (IVIG) therapy. and traditional Chinese patent medicines etc.) patients' underlying comorbidities (such as diabetes melliitus, chronic liver disease, chronic kidney disease, cardiovascular and cerebrovascular disease, malignancies, and immunodeficiency—HIV infection or patients receiving long-term corticosteroid/immunosuppressant therapy, as well as heavy smokers.)clinical laboratory indicators at admission (white blood cell count(x109/L),neutorphil count(x109/L),lymphocyte count(x109/L). Follow-up and outcome During the observation period, patients with diabetes who were given either Azvudine or Nirmatrelvir/Ritonavir were considered to have received antiviral treatment.Concomitant therapies (e.g., antibiotics or corticosteroids) were permitted. The observation window spanned from symptom onset until the earliest occurrence of either recorded death or January 31, 2023. The primary outcome constituted a composite of disease progression events, comprising all-cause mortality, invasive mechanical ventilation necessity, and intensive care unit (ICU) admission. All-cause mortality alone constituted the secondary outcome. Furthermore, we recorded new multi-system complications that arose during the COVID-19 infection hospitalization, such as myocardial injury and heart failure (HF).The diagnosis of all complications was based on imaging or lab test results documented in the medical record system, including respiratory failure and the start of IMV. Heart failure or myocardial injury was characterized by the onset of new heart failure symptoms along with irregular B-type natriuretic peptide (BNP) levels.Arterial blood gas analysis results were the main basis for diagnosing respiratory failure. Surgical records were checked to determine if IMV was started and to note the date. Statistical analysis We assessed the efficacy of the antiviral medications Azvudine and Nirmatrelvir/Ritonavir in patients diagnosed with both diabetes and COVID-19 using observational data. The treating physician divided all patients receiving antiviral treatment into two groups based on the specific antiviral drug given. We implemented PSM with baseline covariates collected at admission, including age, gender, comorbidities, and clinical laboratory indicators. The reduction in sample size after matching is an inherent characteristic of the Propensity Score Matching (PSM) method, as PSM only retains individuals for whom a suitable match could be found. Unmatched individuals were typically excluded due to a lack of sufficiently similar counterparts with comparable baseline characteristics in the other group. To ensure matching quality, we set a caliper value of 0.2 times the standard deviation of the propensity score. This led to the exclusion of some individuals with extreme propensity scores, thereby enhancing internal validity at the cost of reducing the sample size. In both the unmatched and propensity score matched analysis cohorts, we evaluated baseline covariate characteristics, employing independent samples t-tests for continuous variables and chi-square tests for categorical variables. Our team compared concomitant therapies received throughout the infectious period across both groups. All statistical tests were two-tailed, adopting p-values below 0.05 as statistically significant. We defined January 31, 2023, as the follow-up endpoint. We use Poisson regression to compare the incidence probabilities between the two groups for invasive mechanical ventilation, respiratory failure, myocardial injury/heart failure, acute kidney injury, and acute exacerbations of chronic obstructive pulmonary disease. We also used the Kaplan-Meier method and log-rank test to compare survival curves between the two groups. A Cox proportional hazards models were used to analyze the association between antiviral intervention and outcomes. Two sequential models were constructed: Model 1 (unadjusted) and Model 2, which adjusted for potential confounders including age, sex, medical history, and time from symptom onset to hospitalization. As multiple outcome measures were compared, implemented Bonferroni correction to address increased type 1 error probability. The study contained two major bias types. The first type involved COVID-19 patients admitted primarily for other severe illnesses, making it difficult to determine the link between hospitalization and COVID-19 infection. The second type involved patients who chose to be hospitalized at local hospitals after outpatient or emergency department visits but lacked records in the electronic medical record system. Patients falling under the first type of bias were excluded from the study; however, bias factors related to the second type of patients were uncontrollable. A statistical power analysis was conducted to evaluate the capability for detecting clinical outcome differences between patients administered Azvudine versus Nirmatrelvir/Ritonavir. This analysis indicated 80% statistical power to identify a 24% difference in clinical outcomes. Results From December 5, 2022, to January 31, 2023, participating hospitals admitted 13763 SARS-CoV-2-infected patients. Among them, 206 pregnant women, 9871 without diabetes, 888 not receiving antiviral therapy, and 505 lost to follow-up were omitting. After excluding cases not meeting the study requirements, a total of 400 SARS-CoV-2-infected patients with diabetes were enrolled in this study. Inclusion criteria mandated patients over 18 years old possessing completely documented clinical data and medication records. The final cohort consisted of 112 patients receiving Nirmatrelvir/Ritonavir and 288 receiving Azvudine (Fig. 1). We conducted a 1:2 PSM between patients receiving Azvudine and those receiving Nirmatrelvir/Ritonavir. After PSM, 185 participants entered the final analysis. We compared baseline characteristics between the groups, including age, sex, length of hospitalization, duration of antiviral medication use, laboratory indicators (brain natriuretic peptide levels, lymphocyte counts, neutrophil counts, platelet counts, prothrombin time measurements, D-dimer concentrations, troponin levels, and C-reactive protein values), and medical history (Table 1). Although the PSM balanced a large portion of the data discrepancies, such as age and diabetes grading, some variables remained unable to be balanced after matching. Specifically, Respiratory disease prevalence proved significantly greater in Nirmatrelvir/Ritonavir versus Azvudine recipients(13[11.8%]vs 57[76.0%]; p < 0.001). At the termination of follow-up, there were 22 all-cause deaths that occurred in the overall cohort. After PSM,17 all-cause deaths were recorded in the matching groups during the follow-up period.We employed Poisson regression to compare the incidence rate ratios(IRRs) of the two groups.(Fig. 5) that we can adjust the different follow-up durations.Concurrently, Kaplan-Meier analysis with long-rank test and applied Bonferroni to adjusted multiple comparisons demonstrated that while the Nirmatrelvir/Ritonavir group showed no significant difference in the composite endpoint compared to the Azvudine group(Fig., 2), it exhibited a lower trend in all-cause death(aHR = 0.502)(Fig. 3). Critically, the nirmatrelvir/ritonavir group demonstrated a significant reduction in myocardial injury incidence(IRR = 0.16). Patients receiving azvudine had a higher intubation risk relative to those treated with nirmatrelvir/ritonavir, whereas the nirmatrelvir/ritonavir group showed a clinically relevant 52% reduction in mechanical ventilation risk(IRR = 0.48), though this did not reach statistical significance. The point estimate suggests clinical relevance. Longer duration of antiviral therapy was associated with reduced intubation risk, while the use of traditional Chinese medicines may increase intubation risk. In subgroup analyses, we found that nirmatrelvir/ritonavir reduced all-cause mortality by 63% in patients with severe diabetes (HR = 0.37, 95%CI:0.11-1.00). Concomitant anticoagulant use will diminish treatment effectiveness and increase composite endpoint risk. Critically, immunoglobulin administration substantially elevates composite endpoint risk, potentially negating therapeutic benefits. We suggest avoiding co-administration of immunoglobulin and considering temporarily ceasing anticoagulants or adjusting the dose when using them.We took the Azvudine group as the reference group for COX analysis. Through the COX analysis, we found thatNirmatrelvir/Ritonavir administration significantly reduced all-cause mortality incidence. (Table.2)(Crude HR 0.502 Adjusted HR 0.133–1.180). However, composite risk proved elevated in nirmatrelvir/ritonavir group than azvudine recipients. This might be due to the higher average age (73.1 vs 70.7 years), higher proportions of respiratory diseases (76.0% vs 11.8%), and greater tumor burden(20.0% vs 7.3%) in the nirmatrelvir/ritonavir group,Alternatively, this may reflect false positives attributable to multiple comparisons;in subsequent subgroup analyses, all participants were stratified by sex, antiviral medication use, corticosteroid administration, anticoagulant therapy, immunoglobulin treatment, and underlying conditions (including renal and hepatic diseases). The forest plot illustrates the risk magnitude of the composite endpoint across all strata.(Fig. 4) Within the sex subgroup, females exhibited a significantly lower risk magnitude compared to males. Participants without chronic liver or kidney diseases demonstrated reduced risk levels. Notably, although the nirmatrelvir/ritonavir group had a six-fold higher baseline prevalence of respiratory diseases (76% vs 12%), this subgroup showed a hazard ratio of 0.37 (p = 0.122). This suggests the antiviral regimen may potentially offset the additional riskattributable to respiratory comorbidities. Alternatively, this observation could represent a false-positive finding resulting from insufficient sample size. Discussion Since 2019, the number of global COVID-19 infections has reached 770 million. In late 2022, China experienced large-scale COVID-19 infections. [ 17 ] Currently, some patients continue to experience repeated infections. The Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (The 10th Trial Edition), released by the General Office of the National Health Commission on January 5, 2023, states that most patients infected with COVID-19 have a good prognosis. Critical illness frequently occurs in older adults [ 10 ] , individuals with chronic underlying health conditions, women during late pregnancy and the perinatal period, and obese persons. Individuals with diabetes mellitus constitute a high-risk population for severe to critical COVID-19. [ 5 ] In terms of certain risk factors, clinical manifestations, and clinical outcomes, COVID-19 resembles SARS and MERS. It has been reported that diabetes comorbidity is an independent predictor of morbidity and mortality in patients infected with SARS. [ 13 ][ 20 ] Recent studies indicate that diabetic patients with COVID-19 may face a more than 50% higher risk of fatal outcomes compared to those without diabetes. [ 16 ] A statistical analysis from Wuhan confirmed that COVID-19 patients with diabetes had a significantly higher mortality rate (14.5%) compared to non-diabetic patients. [ 4 ][ 11 ] Furthermore, a meta-analyses have established that diabetes is significantly associated with increased COVID-19 severity and mortality. [ 21 ] Therefore, the rational use of medications for treating COVID-19 infections in individuals with comorbid diabetes has become a critical focus in healthcare. Although Azvudine and Nirmatrelvir/Ritonavir constitute the primary antiviral agents endorsed by the National Health Commission, their evidence base for treating COVID-19 remains insufficient due to their relatively recent market introduction. Their effectiveness and safety profile have not yet been fully established. Particularly, as the demand for antiviral treatment with Azvudine in patients with concurrent diabetes and COVID-19 infection continues to rise, we cannot yet determine its therapeutic efficacy or safety for this specific patient group. Therefore, the collection and assessment of real-world data on clinical effectiveness and safety, along with the development of optimal clinical treatment strategies, are of critical importance. Previous studies have only confirmed that both Azvudine and Nirmatrelvir/Ritonavir are beneficial in reducing the risk of hospitalization or death. However, comparative analyses between the two drugs remain limited. [ 12 ][ 15 ] Furthermore, patients with diabetes often require long-term use of oral hypoglycemic agents or insulin injections. A hyperglycemic environment also exacerbates COVID-19 progression. Deposition of advanced glycation end products (AGEs) induces vascular endothelial injury. Furthermore, AGEs stimulate increased expression of the receptor for advanced glycation end products (RAGE), promoting a positive feedback loop that sustains the inflammatory state. AGE-mediated activation of RAGE is a major contributor to chronic endothelial dysfunction, thus heightening cardiovascular disease risk in diabetic patients. [ 8 ][ 3 ] The efficacy of antiviral treatments in individuals with coexisting diabetes and COVID-19 necessitate additional investigation to support clinical decision-making. This retrospective cohort study revealed that among patients with diabetes and COVID-19 infection, those administered Nirmatrelvir/Ritonavir or Azvudine exhibited no statistically significant difference in composite outcomes.This finding concurs with the conclusion of a previously published study. [ 7 ] However, the Nirmatrelvir/Ritonavir group demonstrated a significantly lower 60-day all-cause mortality rate (6.7% vs. 10.9%, aHR = 0.502, 95% CI: 0.133–1.180), and intubation was delayed by an average of two days in the Nirmatrelvir/Ritonavir group to the Azvudine group. The efficacy of Nirmatrelvir was attenuated when used concomitantly with anticoagulants. A study in Turkey revealed that among deceased patients, diabetic males exhibited a significantly higher mortality rate compared to females, with the difference being statistically significant. [ 6 ] This conclusion is consistent with our experimental findings(Fig. 4)(female 80(43.2)HR(95%C.I.):0.21(0.04 to 1) P: 0.046). [ 6 ] The results indicate that in patients with concurrent diabetes and COVID-19 infection, the efficacy and safety of Azvudine appear relatively inferior to Nirmatrelvir/Ritonavir. However, no statistically significant difference was observed between the two drugs in composite outcomes. We speculate that this may be attributed to a higher baseline comorbidity burden in the Nirmatrelvir/Ritonavir group compared to the Azvudine group. Furthermore, Prolonged antiviral therapy was associated with decreased risk of composite outcomes encompassing mechanical ventilation. potentially further diminishing the differences between the two groups. Furthermore, in the analyzed dataset,the Azvudine cohort possessed a significantly larger sample size than the Nirmatrelvir/Ritonavir group.Propensity score matching did not fully balance the differences between the groups. The smaller sample size in the Nirmatrelvir/Ritonavir group may have introduced inaccuracies, potentially masking the therapeutic benefits of Nirmatrelvir/Ritonavir. This source of bias cannot be overlooked. Other study have found that Azvudine is associated with a lower composite risk of disease progression compared to Nirmatrelvir/ritonavir, but this benefit is confined to patient populations under 65 years of age. In contrast, the mean age of participants in our study exceeded 65 years, which likely represents the primary reason for the discrepancy between our findings and those of previous research. [ 15 ] Studies have indicated that Nirmatrelvir/ritonavir treatment provides no significant benefit for COVID-19 patients with severe comorbidities. However, a meta-analysis demonstrates its association with significantly reduced mortality in COVID-19 patients. This discrepancy is potentially attributable to variations in comorbidity profiles and study populations, necessitating prudent analysis of the differences between these research conclusions. [ 9 ][ 14 ] Using real-world clinical data,we assessed the therapeutic efficacy and safety profiles of Azvudine versus Nirmatrelvir/Ritonavir among COVID-19 patients with diabetes. The results intend to provide evidence-based guidance for optimizing antiviral treatment selection in this patient population. However, our research has certain limitations. Although data were collected consecutively and we attempted to adjust for confounding factors, we cannot entirely eliminate potential biases inherent in retrospective studies. Furthermore, due to sample size constraints, propensity score matching (PSM) was performed at a 1:2 ratio. Compared to a 1:1 matching approach, this grouping may be less optimal. Additionally, the relatively small number of composite outcome events collected may result in a dataset potentially containing false positives. Declarations Contributors ZZF, CW and WZC proposed the idea and drafted the manuscript. LXL LYY LHQ and FJY performed quality control of the clinical data .CQQ ZZF and CQJ responsible for the data analysis and the collection of clinical data.XMH DXM CB HJQ ZX YY LXY and LBJ contributed to the collection of the clinical data. All authors read and approved the final version of the manuscript. All authors verified the underlying data for this study, have full access to all the data in the study, and take responsibility for the decision to submit for publication. Data sharing statement All data could be requested from the corresponding author.Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requiring the data. The use of data must also comply with the requirements of our institutes. A signed data access agreement with the sponsor is required before accessing shared data. Patient-level data will not be made available Ethical Approval This study was approved by six ethics committees, including the Ethics Committee of Guilin Medical University Affiliated Hospital (2024IITLL-04, HYLL20231218001, AF/SQ-06/2024, LL2024-49, LW-2025-04, 2025032601). Considering the retrospective study design and depersonalization of the data, the Ethics Committee agreed to waive the requirement for written informed consent. Declaration of interests All the authors declared no conflict of interest. Funding Declaration This study received no external funding. Acknowledgements Thank all the authors and participating institutions for their efforts and contributions to this article. References Zhang, J. L. et al. Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients. Signal. Transduct. 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Additional Declarations No competing interests reported. Supplementary Files floatimage2.png floatimage6.png Cite Share Download PDF Status: Published Journal Publication published 10 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 24 Nov, 2025 Reviews received at journal 20 Nov, 2025 Reviews received at journal 14 Nov, 2025 Reviewers agreed at journal 10 Nov, 2025 Reviewers agreed at journal 07 Nov, 2025 Reviewers agreed at journal 04 Nov, 2025 Reviewers invited by journal 24 Oct, 2025 Editor assigned by journal 24 Oct, 2025 Editor invited by journal 24 Oct, 2025 Submission checks completed at journal 18 Oct, 2025 First submitted to journal 18 Oct, 2025 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. 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4","display":"","copyAsset":false,"role":"figure","size":437181,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7493337/v1/d5c3d6ca568f091a359f0483.png"},{"id":95260609,"identity":"a0b92621-78c6-43bc-ab0c-370dc42f6358","added_by":"auto","created_at":"2025-11-06 04:20:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":126022,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7493337/v1/d09b359e109c015aa4bca6e5.png"},{"id":104739571,"identity":"ca8ab2aa-e6ec-4456-87e0-88288908a42a","added_by":"auto","created_at":"2026-03-16 16:09:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1386926,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7493337/v1/b42c654c-03aa-470a-993e-e31e68affbbc.pdf"},{"id":95260610,"identity":"cc891a4a-7e9d-4b0f-9cda-36ef2e88f63a","added_by":"auto","created_at":"2025-11-06 04:20:39","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":418636,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7493337/v1/819807b677cb4dd271386a04.png"},{"id":95260607,"identity":"735ab843-e6b7-40ca-87f2-107e5dc396ff","added_by":"auto","created_at":"2025-11-06 04:20:37","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":172949,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7493337/v1/e21c10aebed125675dc6860c.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effectiveness of Azvudine Compared to Nirmatrelvir/Ritonavir in COVID-19 Patients with Diabetes: A Real-World Retrospective Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn December 2019, China first reported the initial case of novel coronavirus pneumonia, which rapidly spread worldwide. The World Health Organization designated the virus as severe acute respiratory syndrome coronavirus 2 SARS-CoV-2. \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e Following shifts in pandemic containment strategies, the COVID-19 outbreak peaked in late December 2022. Studies indicate that diabetes has been established as an independent risk factor for SARS-COV-2 infection.\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e A meta-analysis have demonstrated that diabetes significantly increases the risk of ICU admission and mortality in patients with COVID-19.\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e The case of death rate among COVID-19 patients with diabetes is three times higher than in non-diabetic patients. Consequently, effective antiviral drugs are crucial for reducing patients' mortality and preventing disease progression. The preferred oral antiviral treatments for SARS-COV-2 patients in China include nirmatrelvir/ritonavir and Azvudine. Research demonstrates that these oral agents can shorten hospitalization duration, reduce viral load, decrease in-hospital mortality, and mitigate disease progression.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e Nevertheless, the efficacy of these two oral antivirals remains incompletely understood for the special high-risk population of diabetic patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and inclusion population\u003c/h2\u003e\u003cp\u003eThis multicenter retrospective cohort study included all hospital patients diagnosed with SARS-CoV-2 infection from six hospitals in Guangxi Zhuang Autonomous Region. The participating hospitals were: The First Affiliated Hospital of Guilin Medical University, The Sixth People's Hospital of Nanning, Liuzhou People's Hospital, The First People's Hospital of Hechi,Wuzhou Red Cross Hospital, and Nantong University Xinglin College. The study period was from December 5 2022, to January 31, 2023. Inclusion criteria were as follows: (1) Hospitalized between December 5,2022, and January 31,2023, with a diagnosis of SARS-COV-2 infection, (2) Diagnosed with diabetes mellitus before medication use (Diagnostic criteria: presence of symptoms including dry mouth, polyuria, polydipsia, polyphagia, and weight loss, AND fasting plasma glucose\u0026thinsp;\u0026ge;\u0026thinsp;7.0 mmol/L OR 2-hour postprandial plasma glucose\u0026thinsp;\u0026ge;\u0026thinsp;11.1 mmol/L OR glycated hemoglobin (HbA1c)\u0026thinsp;\u0026gt;\u0026thinsp;6.5 (3) being received antiviral treatment with Azvudine or Nirmatrelvir/Ritonavir. (Azvudine: 5mg once daily, swallowed whole on an empty stomach, for a course not exceeding 14 days. Nirmatrelvir 300 mg co-administered with Ritonavir 100 mg every 12 hours for 5 consecutive days, (4) Stable diabetic condition (fasting plasma glucose 4.4-7.0 mmol/L OR non-fasting plasma glucose\u0026thinsp;\u0026lt;\u0026thinsp;10.0 mmol/L OR HbA1c\u0026thinsp;\u0026lt;\u0026thinsp;7.0%). The exclusion criteria include: (1) individuals under 18 years of age, (2) incomplete medical records or those lost to follow-up, (3) patients who did not undergo antiviral treatment with Azvudine or Nirmatrelvir/Ritonavir, (4) Had used antiviral medications for COVID-19 within 14 days before the first dose of the study medication. Based on antiviral treatment received, eligible patients were stratified into Azvudine or Nirmatrelvir/Ritonavir cohorts.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e This investigation complies with STROBE reporting guidelines and secured ethical approval from six participating hospitals. As a retrospective cohort analysis utilizing anonymized data, informed consent was waived.\u003c/p\u003e\n\u003ch3\u003eBaseline variable\u003c/h3\u003e\n\u003cp\u003eStandardized extraction of medical records from six hospital systems captured enrolled patients' demographic and clinical data, including age, sex, height, weight, and related variables. Note the time when symptoms began and the date of hospital admission, along with records of prescriptions and drug dispensing, baseline medical history, and medication usage. simultaneous treatments for the present infection, including corticosteroid therapy, anticoagulant therapy, and intravenous immunoglobulin (IVIG) therapy. and traditional Chinese patent medicines etc.) patients' underlying comorbidities (such as diabetes melliitus, chronic liver disease, chronic kidney disease, cardiovascular and cerebrovascular disease, malignancies, and immunodeficiency\u0026mdash;HIV infection or patients receiving long-term corticosteroid/immunosuppressant therapy, as well as heavy smokers.)clinical laboratory indicators at admission (white blood cell count(x109/L),neutorphil count(x109/L),lymphocyte count(x109/L).\u003c/p\u003e\n\u003ch3\u003eFollow-up and outcome\u003c/h3\u003e\n\u003cp\u003eDuring the observation period, patients with diabetes who were given either Azvudine or Nirmatrelvir/Ritonavir were considered to have received antiviral treatment.Concomitant therapies (e.g., antibiotics or corticosteroids) were permitted. The observation window spanned from symptom onset until the earliest occurrence of either recorded death or January 31, 2023.\u003c/p\u003e\u003cp\u003eThe primary outcome constituted a composite of disease progression events, comprising all-cause mortality, invasive mechanical ventilation necessity, and intensive care unit (ICU) admission. All-cause mortality alone constituted the secondary outcome. Furthermore, we recorded new multi-system complications that arose during the COVID-19 infection hospitalization, such as myocardial injury and heart failure (HF).The diagnosis of all complications was based on imaging or lab test results documented in the medical record system, including respiratory failure and the start of IMV. Heart failure or myocardial injury was characterized by the onset of new heart failure symptoms along with irregular B-type natriuretic peptide (BNP) levels.Arterial blood gas analysis results were the main basis for diagnosing respiratory failure. Surgical records were checked to determine if IMV was started and to note the date.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eWe assessed the efficacy of the antiviral medications Azvudine and Nirmatrelvir/Ritonavir in patients diagnosed with both diabetes and COVID-19 using observational data. The treating physician divided all patients receiving antiviral treatment into two groups based on the specific antiviral drug given. We implemented PSM with baseline covariates collected at admission, including age, gender, comorbidities, and clinical laboratory indicators. The reduction in sample size after matching is an inherent characteristic of the Propensity Score Matching (PSM) method, as PSM only retains individuals for whom a suitable match could be found. Unmatched individuals were typically excluded due to a lack of sufficiently similar counterparts with comparable baseline characteristics in the other group. To ensure matching quality, we set a caliper value of 0.2 times the standard deviation of the propensity score. This led to the exclusion of some individuals with extreme propensity scores, thereby enhancing internal validity at the cost of reducing the sample size. In both the unmatched and propensity score matched analysis cohorts, we evaluated baseline covariate characteristics, employing independent samples t-tests for continuous variables and chi-square tests for categorical variables. Our team compared concomitant therapies received throughout the infectious period across both groups. All statistical tests were two-tailed, adopting p-values below 0.05 as statistically significant. We defined January 31, 2023, as the follow-up endpoint. We use Poisson regression to compare the incidence probabilities between the two groups for invasive mechanical ventilation, respiratory failure, myocardial injury/heart failure, acute kidney injury, and acute exacerbations of chronic obstructive pulmonary disease. We also used the Kaplan-Meier method and log-rank test to compare survival curves between the two groups. A Cox proportional hazards models were used to analyze the association between antiviral intervention and outcomes. Two sequential models were constructed: Model 1 (unadjusted) and Model 2, which adjusted for potential confounders including age, sex, medical history, and time from symptom onset to hospitalization. As multiple outcome measures were compared, implemented Bonferroni correction to address increased type 1 error probability. The study contained two major bias types. The first type involved COVID-19 patients admitted primarily for other severe illnesses, making it difficult to determine the link between hospitalization and COVID-19 infection. The second type involved patients who chose to be hospitalized at local hospitals after outpatient or emergency department visits but lacked records in the electronic medical record system. Patients falling under the first type of bias were excluded from the study; however, bias factors related to the second type of patients were uncontrollable. A statistical power analysis was conducted to evaluate the capability for detecting clinical outcome differences between patients administered Azvudine versus Nirmatrelvir/Ritonavir. This analysis indicated 80% statistical power to identify a 24% difference in clinical outcomes.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom December 5, 2022, to January 31, 2023, participating hospitals admitted 13763 SARS-CoV-2-infected patients. Among them, 206 pregnant women, 9871 without diabetes, 888 not receiving antiviral therapy, and 505 lost to follow-up were omitting. After excluding cases not meeting the study requirements, a total of 400 SARS-CoV-2-infected patients with diabetes were enrolled in this study. Inclusion criteria mandated patients over 18 years old possessing completely documented clinical data and medication records. The final cohort consisted of 112 patients receiving Nirmatrelvir/Ritonavir and 288 receiving Azvudine (Fig.\u0026nbsp;1). We conducted a 1:2 PSM between patients receiving Azvudine and those receiving Nirmatrelvir/Ritonavir. After PSM, 185 participants entered the final analysis. We compared baseline characteristics between the groups, including age, sex, length of hospitalization, duration of antiviral medication use, laboratory indicators (brain natriuretic peptide levels, lymphocyte counts, neutrophil counts, platelet counts, prothrombin time measurements, D-dimer concentrations, troponin levels, and C-reactive protein values), and medical history (Table\u0026nbsp;1). Although the PSM balanced a large portion of the data discrepancies, such as age and diabetes grading, some variables remained unable to be balanced after matching. Specifically, Respiratory disease prevalence proved significantly greater in Nirmatrelvir/Ritonavir versus Azvudine recipients(13[11.8%]vs 57[76.0%]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At the termination of follow-up, there were 22 all-cause deaths that occurred in the overall cohort. After PSM,17 all-cause deaths were recorded in the matching groups during the follow-up period.We employed Poisson regression to compare the incidence rate ratios(IRRs) of the two groups.(Fig.\u0026nbsp;5) that we can adjust the different follow-up durations.Concurrently, Kaplan-Meier analysis with long-rank test and applied Bonferroni to adjusted multiple comparisons demonstrated that while the Nirmatrelvir/Ritonavir group showed no significant difference in the composite endpoint compared to the Azvudine group(Fig., 2), it exhibited a lower trend in all-cause death(aHR\u0026thinsp;=\u0026thinsp;0.502)(Fig.\u0026nbsp;3). Critically, the nirmatrelvir/ritonavir group demonstrated a significant reduction in myocardial injury incidence(IRR\u0026thinsp;=\u0026thinsp;0.16). Patients receiving azvudine had a higher intubation risk relative to those treated with nirmatrelvir/ritonavir, whereas the nirmatrelvir/ritonavir group showed a clinically relevant 52% reduction in mechanical ventilation risk(IRR\u0026thinsp;=\u0026thinsp;0.48), though this did not reach statistical significance. The point estimate suggests clinical relevance. Longer duration of antiviral therapy was associated with reduced intubation risk, while the use of traditional Chinese medicines may increase intubation risk. In subgroup analyses, we found that nirmatrelvir/ritonavir reduced all-cause mortality by 63% in patients with severe diabetes (HR\u0026thinsp;=\u0026thinsp;0.37, 95%CI:0.11-1.00). Concomitant anticoagulant use will diminish treatment effectiveness and increase composite endpoint risk. Critically, immunoglobulin administration substantially elevates composite endpoint risk, potentially negating therapeutic benefits. We suggest avoiding co-administration of immunoglobulin and considering temporarily ceasing anticoagulants or adjusting the dose when using them.We took the Azvudine group as the reference group for COX analysis. Through the COX analysis, we found thatNirmatrelvir/Ritonavir administration significantly reduced all-cause mortality incidence. (Table.2)(Crude HR 0.502 Adjusted HR 0.133\u0026ndash;1.180). However, composite risk proved elevated in nirmatrelvir/ritonavir group than azvudine recipients. This might be due to the higher average age (73.1 vs 70.7 years), higher proportions of respiratory diseases (76.0% vs 11.8%), and greater tumor burden(20.0% vs 7.3%) in the nirmatrelvir/ritonavir group,Alternatively, this may reflect false positives attributable to multiple comparisons;in subsequent subgroup analyses, all participants were stratified by sex, antiviral medication use, corticosteroid administration, anticoagulant therapy, immunoglobulin treatment, and underlying conditions (including renal and hepatic diseases). The forest plot illustrates the risk magnitude of the composite endpoint across all strata.(Fig.\u0026nbsp;4) Within the sex subgroup, females exhibited a significantly lower risk magnitude compared to males. Participants without chronic liver or kidney diseases demonstrated reduced risk levels. Notably, although the nirmatrelvir/ritonavir group had a six-fold higher baseline prevalence of respiratory diseases (76% vs 12%), this subgroup showed a hazard ratio of 0.37 (p\u0026thinsp;=\u0026thinsp;0.122). This suggests the antiviral regimen may potentially offset the additional riskattributable to respiratory comorbidities. Alternatively, this observation could represent a false-positive finding resulting from insufficient sample size.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince 2019, the number of global COVID-19 infections has reached 770\u0026nbsp;million. In late 2022, China experienced large-scale COVID-19 infections.\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e Currently, some patients continue to experience repeated infections. The Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (The 10th Trial Edition), released by the General Office of the National Health Commission on January 5, 2023, states that most patients infected with COVID-19 have a good prognosis. Critical illness frequently occurs in older adults\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, individuals with chronic underlying health conditions, women during late pregnancy and the perinatal period, and obese persons. Individuals with diabetes mellitus constitute a high-risk population for severe to critical COVID-19.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e In terms of certain risk factors, clinical manifestations, and clinical outcomes, COVID-19 resembles SARS and MERS. It has been reported that diabetes comorbidity is an independent predictor of morbidity and mortality in patients infected with SARS.\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e][\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003eRecent studies indicate that diabetic patients with COVID-19 may face a more than 50% higher risk of fatal outcomes compared to those without diabetes.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003eA statistical analysis from Wuhan confirmed that COVID-19 patients with diabetes had a significantly higher mortality rate (14.5%) compared to non-diabetic patients.\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003eFurthermore, a meta-analyses have established that diabetes is significantly associated with increased COVID-19 severity and mortality.\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003eTherefore, the rational use of medications for treating COVID-19 infections in individuals with comorbid diabetes has become a critical focus in healthcare. Although Azvudine and Nirmatrelvir/Ritonavir constitute the primary antiviral agents endorsed by the National Health Commission, their evidence base for treating COVID-19 remains insufficient due to their relatively recent market introduction. Their effectiveness and safety profile have not yet been fully established. Particularly, as the demand for antiviral treatment with Azvudine in patients with concurrent diabetes and COVID-19 infection continues to rise, we cannot yet determine its therapeutic efficacy or safety for this specific patient group.\u003c/p\u003e\u003cp\u003eTherefore, the collection and assessment of real-world data on clinical effectiveness and safety, along with the development of optimal clinical treatment strategies, are of critical importance. Previous studies have only confirmed that both Azvudine and Nirmatrelvir/Ritonavir are beneficial in reducing the risk of hospitalization or death. However, comparative analyses between the two drugs remain limited.\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e Furthermore, patients with diabetes often require long-term use of oral hypoglycemic agents or insulin injections. A hyperglycemic environment also exacerbates COVID-19 progression. Deposition of advanced glycation end products (AGEs) induces vascular endothelial injury. Furthermore, AGEs stimulate increased expression of the receptor for advanced glycation end products (RAGE), promoting a positive feedback loop that sustains the inflammatory state. AGE-mediated activation of RAGE is a major contributor to chronic endothelial dysfunction, thus heightening cardiovascular disease risk in diabetic patients.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e The efficacy of antiviral treatments in individuals with coexisting diabetes and COVID-19 necessitate additional investigation to support clinical decision-making. This retrospective cohort study revealed that among patients with diabetes and COVID-19 infection, those administered Nirmatrelvir/Ritonavir or Azvudine exhibited no statistically significant difference in composite outcomes.This finding concurs with the conclusion of a previously published study.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e However, the Nirmatrelvir/Ritonavir group demonstrated a significantly lower 60-day all-cause mortality rate (6.7% vs. 10.9%, aHR\u0026thinsp;=\u0026thinsp;0.502, 95% CI: 0.133\u0026ndash;1.180), and intubation was delayed by an average of two days in the Nirmatrelvir/Ritonavir group to the Azvudine group. The efficacy of Nirmatrelvir was attenuated when used concomitantly with anticoagulants. A study in Turkey revealed that among deceased patients, diabetic males exhibited a significantly higher mortality rate compared to females, with the difference being statistically significant.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003eThis conclusion is consistent with our experimental findings(Fig.\u0026nbsp;4)(female 80(43.2)HR(95%C.I.):0.21(0.04 to 1) P: 0.046).\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003eThe results indicate that in patients with concurrent diabetes and COVID-19 infection, the efficacy and safety of Azvudine appear relatively inferior to Nirmatrelvir/Ritonavir. However, no statistically significant difference was observed between the two drugs in composite outcomes. We speculate that this may be attributed to a higher baseline comorbidity burden in the Nirmatrelvir/Ritonavir group compared to the Azvudine group. Furthermore, Prolonged antiviral therapy was associated with decreased risk of composite outcomes encompassing mechanical ventilation. potentially further diminishing the differences between the two groups. Furthermore, in the analyzed dataset,the Azvudine cohort possessed a significantly larger sample size than the Nirmatrelvir/Ritonavir group.Propensity score matching did not fully balance the differences between the groups. The smaller sample size in the Nirmatrelvir/Ritonavir group may have introduced inaccuracies, potentially masking the therapeutic benefits of Nirmatrelvir/Ritonavir. This source of bias cannot be overlooked. Other study have found that Azvudine is associated with a lower composite risk of disease progression compared to Nirmatrelvir/ritonavir, but this benefit is confined to patient populations under 65 years of age. In contrast, the mean age of participants in our study exceeded 65 years, which likely represents the primary reason for the discrepancy between our findings and those of previous research.\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003eStudies have indicated that Nirmatrelvir/ritonavir treatment provides no significant benefit for COVID-19 patients with severe comorbidities. However, a meta-analysis demonstrates its association with significantly reduced mortality in COVID-19 patients. This discrepancy is potentially attributable to variations in comorbidity profiles and study populations, necessitating prudent analysis of the differences between these research conclusions.\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e][\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003eUsing real-world clinical data,we assessed the therapeutic efficacy and safety profiles of Azvudine versus Nirmatrelvir/Ritonavir among COVID-19 patients with diabetes. The results intend to provide evidence-based guidance for optimizing antiviral treatment selection in this patient population.\u003c/p\u003e\u003cp\u003eHowever, our research has certain limitations. Although data were collected consecutively and we attempted to adjust for confounding factors, we cannot entirely eliminate potential biases inherent in retrospective studies. Furthermore, due to sample size constraints, propensity score matching (PSM) was performed at a 1:2 ratio. Compared to a 1:1 matching approach, this grouping may be less optimal. Additionally, the relatively small number of composite outcome events collected may result in a dataset potentially containing false positives.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZZF, CW and WZC proposed the idea and drafted the manuscript. LXL LYY LHQ and FJY performed quality control of the clinical data .CQQ ZZF and CQJ responsible for the data analysis and the collection of clinical data.XMH DXM CB HJQ ZX YY LXY and LBJ contributed to the collection of the clinical data. All authors read and approved the final version of the manuscript. All authors verified the underlying data for this study, have full access to all the data in the study, and take responsibility for the decision to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sharing statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data could be requested from the corresponding author.Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requiring the data. The use of data must also comply with the requirements of our institutes. A signed data access agreement with the sponsor is required before accessing shared data. Patient-level data will not be made available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by six ethics committees, including the Ethics Committee of Guilin Medical University Affiliated Hospital (2024IITLL-04, HYLL20231218001, AF/SQ-06/2024, LL2024-49, LW-2025-04, 2025032601). Considering the retrospective study design and depersonalization of the data, the Ethics Committee agreed to waive the requirement for written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declared no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThank all the authors and participating institutions for their efforts and contributions to this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhang, J. L. et al. Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients. \u003cem\u003eSignal. Transduct. Target. 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PMID: 32334395; PMCID: PMC7162793.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Footnotes","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e* Corresponding author.No.15,Lequn Road,Xiufeng District, Guilin,Guangxi Province,China\u003c/span\u003e\u003cdiv id=\"Par4\" class=\"Para\"\u003eE-mail addresses:[email protected](W.Chen),[email protected](Z.Zhu).\u003c/div\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e\n \n"}],"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":"COVID-19, diabetes mellitus, Real-world study, Azvudine, Nirmatrelvir/Ritonavir","lastPublishedDoi":"10.21203/rs.3.rs-7493337/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7493337/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackgrounds:\u003c/strong\u003eAzvudine and Nirmatrelvir/ritonavir have been approved for the treatment of mild to moderate COVID-19 in adults at high risk for progression to severe disease. Diabetes is a high-risk complication of COVID-19. Currently, the effectiveness of Azvudine and Nirmatrelvir/ritonavir in patients with both diabetes and COVID-19 remains unclear. This study aims to compare the effectiveness of these two drugs in patients with diabetes and COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this retrospective study. Our team enrolled 13763 hospitalized patients with COVID-19 infection presenting with comorbid diabetes mellitus between December 5, 2022, and January 31, 2023. These patients were from six different hospitals in the GuangXi Zhuang Autonomous Region, including 288 patients treated with Azvudine and 112 patients treated with Nirmatrelvir/Ritonavir. The primary outcome comprised a composite endpoint of disease progression, characterized by all-cause mortality, intensive care unit (ICU) admission, or need for invasive mechanical ventilation. Data for all participants were retrospectively collected through electronic medical record review supplemented by telephone follow-up. We used propensity-score matching (PSM) to allow for a more direct comparison of the effectiveness between the two antiviral treatment groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFindings:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 400 enrolled patients, 41 deaths occurred during hospitalization or post-discharge follow-up (Azvudine group: \u003cem\u003en\u003c/em\u003e= 29; Nirmatrelvir/ritonavir group: \u003cem\u003e\u0026nbsp;n\u003c/em\u003e= 12). After propensity score matching (PSM), 17 deaths were recorded across both cohorts. Statistical analysis demonstrated no significant between-group differences in composite outcomes (including invasive mechanical ventilation and ICU admission). However, Nirmatrelvir/ritonavir showed superior efficacy for all-cause mortality reduction versus Azvudine (Crude HR = 0.502; Adjusted HR [aHR] = 0.502, 95% CI: 0.133-1.180). Glucocorticoid use during therapy was associated with reduced mortality risk, while concomitant anticoagulant therapy increased composite outcome risk. Findings indicated a progressive elevation in mortality risk with advancing diabetes severity grade. Notably, Nirmatrelvir/ritonavir reduced mortality by 63% in severe diabetes patients (HR = 0.37, 95% CI: 0.11-1.00).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterpretation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding outcome measures, patients with diabetes and COVID-19 infection treated with Nirmatrelvir/ritonavir demonstrated superior outcomes compared to those treated with Azvudine.\u003c/p\u003e","manuscriptTitle":"Effectiveness of Azvudine Compared to Nirmatrelvir/Ritonavir in COVID-19 Patients with Diabetes: A Real-World Retrospective Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-06 04:20:22","doi":"10.21203/rs.3.rs-7493337/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-24T08:50:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-20T11:26:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-14T13:21:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"273993553819250863658383705971844036269","date":"2025-11-10T12:29:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"114525161680152910763754676190105295940","date":"2025-11-07T07:28:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204974626912587438055677237381703137005","date":"2025-11-04T10:12:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-24T20:56:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-24T20:50:55+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-24T13:37:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-18T16:24:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-18T16:21:15+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":"bfefa266-2d42-4abc-86b4-fc021f1f9b27","owner":[],"postedDate":"November 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":57426836,"name":"Health sciences/Diseases"},{"id":57426837,"name":"Health sciences/Health care"},{"id":57426838,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-03-16T16:05:13+00:00","versionOfRecord":{"articleIdentity":"rs-7493337","link":"https://doi.org/10.1038/s41598-026-42215-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-03-10 15:59:32","publishedOnDateReadable":"March 10th, 2026"},"versionCreatedAt":"2025-11-06 04:20:22","video":"","vorDoi":"10.1038/s41598-026-42215-6","vorDoiUrl":"https://doi.org/10.1038/s41598-026-42215-6","workflowStages":[]},"version":"v1","identity":"rs-7493337","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7493337","identity":"rs-7493337","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}