Effectiveness of nirmatrelvir/ritonavir and molnupiravir on post-COVID diabetes risk among an older adult cohort: a target trial emulation study
et al., BMC Medicine, doi:10.1186/s12916-026-04791-2, Mar 2026
Retrospective analysis finding lower risk of post-COVID diabetes with nirmatrelvir/ritonavir but not molnupiravir. The effect may be entirely due to confounding.
Authors excluded only 8% of non-diabetic patients for nirmatrelvir/ritonavir contraindications, compared to the ~20% prevalence expected based on external data1, a gap that may be attributed to limited data and an unusually narrow drug interaction list covering roughly half the FDA-contraindicated medications. Notably the prevalence of renal disease (in the molnupiravir arm where there is no contraindication) is remarkably low, suggesting under-ascertainment from the EHR data. The undetected contraindicated patients (e.g., severe CKD, liver cirrhosis) carry substantially elevated diabetes risk (estimated 1.5-3x baseline) and, critically, would accumulate asymmetrically in the nirmatrelvir/ritonavir control arm through the clone-censor-weight mechanism: clinicians who knew the real-world contraindication would not prescribe nirmatrelvir/ritonavir, causing these patients to be censored from the treatment arm while remaining in the control arm, inflating its event rate. Quantitative modeling shows that if 10% of the trial population had undetected contraindications with 2x the diabetes risk, the observed hazard ratio of 0.75 corrects to approximately 1.0, i.e., the entire effect disappears. This bias is structurally absent from the molnupiravir trial (which has no renal or hepatic contraindication exclusions), providing a parsimonious explanation for why nirmatrelvir/ritonavir appears protective while molnupiravir shows no benefit. Authors do not acknowledge this issue, do not test broader contraindication criteria in sensitivity analyses, and did not recognize that their chosen negative control outcome (injury/trauma) is insensitive to this confounding.
Table S1 shows an exclusion for drug contraindications to nirmatrelvir/ritonavir in the molnupiravir arm, however this conflicts with Figure 1.
Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity2-16. Multiple analyses have identified variants potentially created by molnupiravir17-21. Studies show significantly increased risk of acute kidney injury22, cardiovascular toxocity23, and neurological symptoms22. Treatment may increase viral rebound24,25.
Study covers molnupiravir and paxlovid.
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Lim et al., Prevalence of Medical Contraindications to Nirmatrelvir/Ritonavir in a Cohort of Hospitalized and Nonhospitalized Patients With COVID-19, Open Forum Infectious Diseases, doi:10.1093/ofid/ofac389.
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Guo et al., 17 Mar 2026, retrospective, China, peer-reviewed, mean age 73.0, 17 authors, study period 11 March, 2022 - 10 October, 2023.
Contact: marc@cuhk.edu.hk, yeoh_ek@cuhk.edu.hk.
Abstract: BMC Medicine
https://doi.org/10.1186/s12916-026-04791-2
Article in Press
Effectiveness of nirmatrelvir/ritonavir and
molnupiravir on post-COVID diabetes risk among an
older adult cohort: a target trial emulation study
Zihao Guo, Yuchen Wei, Aimin Yang, Carlos Wong, Xi Xiong, Kailu Wang, Guozhang Lin,
Huwen Wang, Chi Hung, Conglu Li, Carrie Yam, Tsz Chow, Shi Zhao, Chris Mok, David
Hui, Eng Yeoh & Ka Chong
Received: 19 Nov 2025
Accepted: 09 Mar 2026
Cite this article as: Guo, Z., Wei,
Y., Yang, A. et al. Effectiveness
of nirmatrelvir/ritonavir and
molnupiravir on post-COVID diabetes
risk among an older adult cohort: a
target trial emulation study. BMC
Med (2026).
https://doi.org/10.1186/s1291
6-026-04791-2
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MANUSCRIPT
PRESS
Effectiveness of nirmatrelvir/ritonavir and molnupiravir on post-COVID diabetes risk
among an older adult cohort: A target trial emulation study
Zihao Guo, PhD1#; Yuchen Wei, PhD1#; Aimin Yang, PhD2; Carlos King Ho Wong, PhD3,4,5;
Xi Xiong, PhD3,6; Kailu Wang, PhD1; Guozhang Lin, MSc1; Huwen Wang, PhD7; Chi Tim
Hung, MBBS1; Conglu Li, MSc1; Carrie Ho Kwan Yam, PhD1; Tsz Yu Chow, BSc1; Shi
Zhao, PhD1,8; Chris Ka Pun Mok, PhD9; David SC Hui, MBBS10; Eng Kiong Yeoh, MBBS1*;
Ka Chun Chong, PhD1*
1
School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong
Kong Special Administrative Region, China
2
Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of
Hong Kong, Hong Kong
3
Laboratory of Data Discovery for Health, Hong Kong Science Park, Hong Kong Special
Administrative Region, China
4
Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka
Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special
Administrative Region, China
5
Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical
Medicine, London, United Kingdom
6
Research Department of Practice and Policy, School of Pharmacy, University College
London, London, United Kingdom
7
Duke-NUS Medical School, Singapore
8
School of Public Health, Tianjin Medical University, China
9
Li Ka Shing Institute of Health Sciences, Chinese University of..
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats: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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats: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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats: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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats: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.</jats:p>\n </jats:sec>",
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Late treatment
is less effective
is less effective
