Largest Study to Date Links Glucose Control to COVID-19 Outcomes

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The strong link between glucose control and COVID-19 outcomes has been re-affirmed in the largest study thus far of hospitalized patients with pre-existing type 2 diabetes.

The retrospective, multicenter study, from 7337 hospitalized patients with COVID-19, was published online in Cell Metabolism by Lihua Zhu, Renmin Hospital of Wuhan University, China, and colleagues.

The study finds that, while the presence of type 2 diabetes per se is a risk factor for worse COVID-19 outcomes, better glycemic control among those with pre-existing type 2 diabetes appears to be associated with significant reductions in adverse outcomes and death.

"We were surprised to see such favorable outcomes in the well-controlled blood glucose group among patients with COVID-19 and pre-existing type 2 diabetes," said senior author Hongliang Li, also of Renmin Hospital, in a statement.

"Considering that people with diabetes had much higher risk for death and various complications, and there are no specific drugs for COVID-19, our findings indicate that controlling blood glucose well may act as an effective auxiliary approach to improve the prognosis of patients with COVID-19 and pre-existing diabetes," Li added.

Asked to comment on the findings, David Klonoff MD, cautioned that the way in which the "well-controlled" diabetes group was distinguished from the "poorly controlled" one in this study used a "non-standard method for distinguishing these groups based on variability."

So "there was a great deal of overlap between the two groups," he observed.

Klonoff is medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center, San Mateo, California.

Diabetes Itself Was Associated With Worse COVID-19 Outcomes

Of the 7337 participants with confirmed COVID-19 in the Chinese study, 13% (952) had pre-existing type 2 diabetes while the other 6385 did not have diabetes.

Median ages were 62 years for those with and 53 years for those without diabetes. As has been reported several times since the pandemic began, the presence of diabetes was associated with a worse COVID-19 prognosis.

Those with pre-existing diabetes received significantly more antibiotics, antifungals, systemic corticosteroids, immunoglobulin, antihypertensive drugs, and vasoactive drugs than did those without diabetes. They were also more likely to receive oxygen inhalation (76.9% vs 61.2%), non-invasive ventilation (10.2% vs 3.9%), and invasive ventilation (3.6% vs 0.7%).

Over 28 days starting with the day of admission, the type 2 diabetes group was significantly more likely to die compared with those without diabetes (7.8% vs 2.7%; P < .001), with a crude hazard ratio of 2.90 (P < .001). After adjustments for age, gender, and COVID-19 severity, the diabetes group was still significantly more likely to die, with a hazard ratio of 1.49 (P = .005).

Those with diabetes were also significantly more likely to develop acute respiratory distress syndrome (adjusted hazard ratio, 1.44), acute kidney injury (3.01), and septic shock (1.95).

"The results were unequivocal to implicate diabetes mellitus in higher risk of death and other detrimental outcomes of COVID-19," the authors write, although they caution "there were notable differences in the covariate distributions between the two groups."

With T2D, Tighter Glycemic Control Predicted Better Outcome

Among the 952 with COVID-19 and type 2 diabetes, 282 individuals had "well-controlled" blood glucose, ranging from 3.9 to 10.0 mmol/L (~70 - 180 mg/dl) with median 6.4 mmol/L (115 mg/dL) and hemoglobin A1c of 7.3%.

The other 528 were "poorly controlled," defined as the lowest fasting glucose level 3.9 mmol/L or above and the highest 2-hour postprandial glucose exceeding 10.0 mmol/L, with median 10.9 mmol/L (196 mg/dL) and A1c of 8.1%.

Just as with the diabetes vs no diabetes comparison, those in the "well-controlled" blood glucose group had lower use of antivirals, antibiotics, antifungals, systemic corticosteroids, immunoglobulin, and vasoactive drugs.

They also were less likely to require oxygen inhalation (70.2% vs 83.5%), non-invasive ventilation (4.6% vs 11.9%), invasive ventilation (0% vs 4.2%), and extracorporeal membrane oxygenation (0% vs 0.8%).

In-hospital death was significantly lower in the "well-controlled" group (1.1% vs. 11.0%; crude hazard ratio, 0.09; P < .001). After adjustments for the previous factors plus site effect, the difference remained significant (0.13; P < .001). Adjusted hazard ratio for acute respiratory distress syndrome was 0.41 (P < .001) and for acute heart injury it was 0.21 (P = .003).

Stress Hyperglycemia in COVID-19 Associated With Greater Mortality

Klonoff was senior author on a previous study from the United States that showed that both diabetes and uncontrolled hyperglycemia among people without prior diabetes — the latter "presumably due to stress," he said — were strong predictors of mortality among hospitalized patients with COVID-19.

The new Chinese research only looks at individuals with previously diagnosed type 2 diabetes, Klonoff pointed out in an email to Medscape Medical News.

"The article by Zhu et al did not look at outcomes of hospitalized COVID-19 patients with uncontrolled hyperglycemia. Per [the US study], in COVID-19 stress hyperglycemia, compared to diabetes, was associated with greater mortality."

In addition, although international guidance now advises optimizing blood glucose levels in all patients with hyperglycemia and COVID-19, it's actually not yet totally clear which in-target range improves COVID-19 prognosis the best, Klonoff said.

He is now working on a study aimed at answering that question.

Zhu and colleagues have disclosed no relevant financial relationships. Klonoff is a consultant to Abbott, Ascensia, Dexcom, EOFlow, Fractyl, Lifecare, Novo, Roche, and Thirdwayv.

Cell Metab. Published online April 30, 2020. Full text

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