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Background <p>Accumulating evidence indicates that SARS-CoV-2 infection is associated with a broad spectrum of post-acute COVID sequelae, including diabetes. While nirmatrelvir/ritonavir and molnupiravir have demonstrated efficacy in reducing acute COVID-19 severity, their protective effects against post-COVID diabetes remain uncertain. In this study, we aimed to evaluate the effectiveness of these antiviral agents in reducing post-COVID diabetes risks, including new-onset diabetes in non-diabetic individuals and exacerbated diabetes in those with pre-existing diabetes.</p> Methods <p>We emulate target randomized controlled trials of COVID-19 antivirals in hospitalized patients who tested positive for SARS-CoV-2 between March 11, 2022, and October 10, 2023, in Hong Kong. Two analytic patient cohorts for assessing incident diabetes and exacerbation of diabetes for rehospitalization, including those with or without diabetes confirmed before the index date, were identified. Cloning, censoring, and weighting were used to emulate the target trials of nirmatrelvir/ritonavir and molnupiravir, involving treatment arm and control arm within each trial. Cause-specific Cox proportional hazard model and an extended form of Cox model for modeling recurrent hospitalizations were used to estimate the hazard ratio (HR) between arms in each trial, adjusting for baseline covariates.</p> Results <p>Among 88,643 hospitalized patients first time infected by SARS-CoV-2 identified, 35,997 and 18,865 eligible patients were included in the two analytic cohorts for the analysis on newly onset diabetes and exacerbated diabetes for rehospitalization, respectively. The median follow-up period ranged from 344 to 365 days across treatment and control arms of target trials. Compared with the no treatment arm, non-diabetic patients who received nirmatrelvir/ritonavir showed a significantly lower risk of post-COVID incident diabetes (HR: 0.75, 95% CI: 0.61 to 0.92). A reduced risk of diabetes rehospitalizations (HR: 0.70, 95% CI: 0.60 to 0.81) was observed among the diabetic patients. No significant associations were found for the use of molnupiravir and post-COVID diabetes outcomes.</p> Conclusions <p>Our study demonstrates the effectiveness of nirmatrelvir/ritonavir in reducing the risks of post-acute COVID sequelae of diabetes in the hospitalized population, regardless of their diabetic status, whereas molnupiravir showed no significant benefit. Our findings offer valuable clinical insights for managing diabetes during the post-acute phase of SARS-CoV-2 infection.</p>

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Effectiveness of nirmatrelvir/ritonavir and molnupiravir on post-COVID diabetes risk among an older adult cohort: a target trial emulation study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Zihao Guo,
  • Yuchen Wei,
  • Aimin Yang,
  • Carlos King Ho Wong,
  • Xi Xiong,
  • Kailu Wang,
  • Guozhang Lin,
  • Huwen Wang,
  • Chi Tim Hung,
  • Conglu Li,
  • Carrie Ho Kwan Yam,
  • Tsz Yu Chow,
  • Shi Zhao,
  • Chris Ka Pun Mok,
  • David S. C. Hui,
  • Eng Kiong Yeoh,
  • Ka Chun Chong

摘要

Background

Accumulating evidence indicates that SARS-CoV-2 infection is associated with a broad spectrum of post-acute COVID sequelae, including diabetes. While nirmatrelvir/ritonavir and molnupiravir have demonstrated efficacy in reducing acute COVID-19 severity, their protective effects against post-COVID diabetes remain uncertain. In this study, we aimed to evaluate the effectiveness of these antiviral agents in reducing post-COVID diabetes risks, including new-onset diabetes in non-diabetic individuals and exacerbated diabetes in those with pre-existing diabetes.

Methods

We emulate target randomized controlled trials of COVID-19 antivirals in hospitalized patients who tested positive for SARS-CoV-2 between March 11, 2022, and October 10, 2023, in Hong Kong. Two analytic patient cohorts for assessing incident diabetes and exacerbation of diabetes for rehospitalization, including those with or without diabetes confirmed before the index date, were identified. Cloning, censoring, and weighting were used to emulate the target trials of nirmatrelvir/ritonavir and molnupiravir, involving treatment arm and control arm within each trial. Cause-specific Cox proportional hazard model and an extended form of Cox model for modeling recurrent hospitalizations were used to estimate the hazard ratio (HR) between arms in each trial, adjusting for baseline covariates.

Results

Among 88,643 hospitalized patients first time infected by SARS-CoV-2 identified, 35,997 and 18,865 eligible patients were included in the two analytic cohorts for the analysis on newly onset diabetes and exacerbated diabetes for rehospitalization, respectively. The median follow-up period ranged from 344 to 365 days across treatment and control arms of target trials. Compared with the no treatment arm, non-diabetic patients who received nirmatrelvir/ritonavir showed a significantly lower risk of post-COVID incident diabetes (HR: 0.75, 95% CI: 0.61 to 0.92). A reduced risk of diabetes rehospitalizations (HR: 0.70, 95% CI: 0.60 to 0.81) was observed among the diabetic patients. No significant associations were found for the use of molnupiravir and post-COVID diabetes outcomes.

Conclusions

Our study demonstrates the effectiveness of nirmatrelvir/ritonavir in reducing the risks of post-acute COVID sequelae of diabetes in the hospitalized population, regardless of their diabetic status, whereas molnupiravir showed no significant benefit. Our findings offer valuable clinical insights for managing diabetes during the post-acute phase of SARS-CoV-2 infection.