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Analysis of All-Cause Hospitalization and Death Among Nonhospitalized Patients With Type 2 Diabetes and SARS-CoV-2 Infection Treated With Molnupiravir or Nirmatrelvir-Ritonavir During the Omicron Wave in Hong Kong
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JAMA Netw Open
The findings of this cohort study suggest that oral antiviral use was associated with a 29% lower risk of all-cause mortality and/or hospitalization for both molnupiravir users and nirmatrelvir-ritonavir users with type 2 diabetes and SARS-CoV-2 infection during the Omicron wave in Hong Kong. These findings support the effectiveness of either oral antiviral drug in the outpatient setting. Further studies in specific populations, such as individuals in residential care homes and individuals with chronic kidney disease, are suggested.
Nirmatrelvir-ritonavir was preferred over molnupiravir unless patients were taking concomitant medications contraindicated for nirmatrelvir-ritonavir.
To our knowledge, our study is the first to specifically evaluate a group of molnupiravir-treated patients with type 2 diabetes, and we observed that molnupiravir use was associated with a lower risk of all-cause mortality and hospitalization and further benefit in in-hospital disease progression. Furthermore, a beneficial effect was observed across a broad spectrum of patients with type 2 diabetes, stratified by age, sex, vaccination status, and baseline insulin use-factors commonly identified as prognostic factors of COVID-19 outcomes.26 In considering prescribing of oral antiviral medications, patients with type 2 diabetes often have cardiovascular comorbidities with potential drug-drug interactions between nirmatrelvir-ritonavir and essential cardiovascular medications.27 Our findings suggest that in scenarios in which patients with type 2 diabetes are not eligible to receive nirmatrelvir-ritonavir, molnupiravir may be a reasonable option.
Of note, for both oral antiviral medications studied here, results for the subgroup with chronic kidney disease did not reach statistical significance, as the sample size was relatively small (3.7% in the molnupiravir cohort and 0.3% in the nirmatrelvir-ritonavir cohort). This could be explained by concern regarding kidney function owing to nirmatrelvir-ritonavir use. Similarly, for both oral antiviral agents, HRs in the subgroup with diabetic complications did not reach statistical significance. In fact, the presence of diabetic complications, especially microvascular complications, has been established as a risk factor for severe COVID-19.29 It has been postulated that underlying systemic endothelial and microvascular dysfunction may lead to excessive pulmonary endothelial and microvascular injury upon SARS-CoV-2 infection and thus to worse COVID-19 outcomes.29 Whether this may explain the attenuation of effectiveness of oral antiviral medications warrants further evaluation. The sample size of this subgroup was also relatively small. Hence, our results encourage future studies with larger sample sizes to clarify the effectiveness of oral antiviral agents among patients with type 2 diabetes and concomitant chronic kidney disease or diabetic complications.
The primary outcome was a composite outcome of all-cause mortality and/or hospitalization. Secondary outcomes included (1) all-cause mortality, (2) all-cause hospitalization, and (3) a composite outcome of in-hospital disease progression (in-hospital mortality, invasive mechanical ventilation, or intensive care unit admission). For all-cause hospitalization, only the first hospital admission after diagnosis of SARS-CoV-2 infection was used if a patient had multiple hospital admissions.
Most patients were older than 65 years.
The most common comorbidity was hypertension. Regarding diabetes-specific characteristics, 420 (26.5%) to 689 (37.4%) of all individuals were insulin users and 256 (16.1%) to 541 (29.4%) of all individuals had diabetic complications. In this study cohort, none of the included patients had previous SARS-CoV-2 infection.
Compared with nirmatrelvir-ritonavir users, molnupiravir users were older with more preexisting comorbidities, were less likely to be fully vaccinated or boosted, and were more likely to be insulin users and have more diabetic complications. There was no difference in age and CCI score of patients who received molnupiravir before and after nirmatrelvir-ritonavir approval.
Key Points
Question Are oral antiviral medications such as molnupiravir and nirmatrelvir-ritonavir associated with improved outcomes among patients with type 2 diabetes and COVID-19?
Findings In this cohort study of 22 098 patients in Hong Kong with type 2 diabetes and confirmed SARS-CoV-2 infection, oral antiviral use was associated with a 29% lower risk of all-cause mortality and/or hospitalization for both molnupiravir users and nirmatrelvir-ritonavir users compared with respective control participants.
Meaning These findings suggest that treatment with molnupiravir or nirmatrelvir-ritonavir was associated with a lower risk of all-cause mortality and hospitalization among patients with COVID-19 and type 2 diabetes.

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