Association of Chronic Hyperglycemia and Glycemic Variability with Mortality in COVID-19: Meta-Analysis of Cohort Studies

TL;DR

This study finds that both high blood sugar levels and unstable blood sugar are linked to worse outcomes and higher death rates in hospitalized COVID-19 patients.

Contribution

The study uniquely quantifies the separate impacts of chronic hyperglycemia and glycemic variability on mortality in hospitalized COVID-19 patients.

Findings

Poor glycemic control increases the risk of severe or critical illness, ICU admission, and mechanical ventilation.

Glycemic variability is strongly associated with higher mortality in hospitalized patients with low heterogeneity.

Glycemic variability remains a significant risk factor for mortality in multivariable models, suggesting it is an independent prognostic marker.

Abstract

Background and Objectives: Dysglycemia is a major determinant of adverse outcomes in COVID-19, yet the separate contributions of poor glycemic control and glycemic variability (GV) remain incompletely defined. We conducted a systematic review and meta-analysis of observational cohort studies (both prospective and retrospective) to quantify the impact of chronic hyperglycemia and glucose instability on disease severity, intensive care requirements, and mortality in patients with COVID-19. Materials and Methods: We searched PubMed, Scopus, and Web of Science from January 2020 to October 2024 for observational cohort studies reporting clinically relevant COVID-19 outcomes stratified by glycemic control or GV. Dysglycemia definitions varied across studies (HbA1c-based chronic hyperglycemia, fasting glucose, or admission/in-hospital hyperglycemia). GV was assessed using metrics including mean amplitude of glycemic excursions (MAGE), standard deviation (SD), coefficient of variation (CV), or maximum daily glucose difference. Twelve studies met inclusion criteria and were included in qualitative synthesis; five studies were eligible for quantitative synthesis of clinical outcomes. Random-effects DerSimonian–Laird models were applied due to anticipated clinical heterogeneity. Heterogeneity was evaluated using Cochran’s Q, τ2, and I2 statistics. Results: Overall, 12 observational studies (9 prospective and 3 retrospective cohorts; n = 1,008,310 patients) were included. In quantitative analyses of five eligible cohorts, poor glycemic control was associated with a significantly increased risk of severe or critical COVID-19 (pooled RR = 1.75, 95% CI: 1.45–2.11; I2 = 29%), ICU admission (RR = 1.54, 95% CI: 1.18–2.01), and mechanical ventilation (RR = 1.72, 95% CI: 1.31–2.26). Three studies evaluating GV demonstrated a strong association with adverse outcomes (pooled RR = 2.07, 95% CI: 1.71–2.50; I2 = 0%); this low heterogeneity should be interpreted cautiously given the limited number of studies. GV remained associated with mortality in multivariable models, indicating that glycemic variability is separately associated with mortality as a clinically relevant prognostic risk marker in hospitalized COVID-19 patients. Conclusions: Both chronic hyperglycemia and elevated glycemic variability are each associated with increased risk of severe COVID-19 outcomes. Glycemic variability appeared to be a consistent, low-heterogeneity prognostic marker of mortality, being separately associated with higher death risk in hospitalized COVID-19 patients, highlighting its potential utility as a dynamic metabolic biomarker. Early identification and targeted management of dysglycemia—especially glucose instability—may improve prognosis in hospitalized COVID-19 patients. PROSPERO: CRD420251250718.

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