It is now well established that hyperglycaemia is an independent risk factor for adverse COVID-19 outcomes, including mortality. During the earlier stages of the pandemic, it was suggested that certain classes of glucose-lowering medication (e.g. SGLT2 inhibitors and DPP-4 inhibitors) were possibly associated with an increased risk of severe COVID-19 complications, whereas other classes (e.g. metformin) had perhaps beneficial effects in COVID-19 infection. However, these hypotheses have not been robustly demonstrated in any subsequent studies and expert opinion varies considerably regarding what to do with these glucose-lowering therapies before and during COVID-19 infection.
This large, well-conducted and unique observational study sought to explore any association between a range of glucose-lowering medications and COVID-19-related mortality in people living with type 2 diabetes. It was conducted with data from the National Diabetes Audit for nearly 3 million people living with type 2 diabetes and registered with a general practice in England since 2003.
13,479 (0.5% of those included in the analyses) COVID-19-related deaths occurred during the study period (February 16 to August 31, 2020). Metformin, SGLT2 inhibitors and sulfonylureas were associated with reduced risks of COVID-19-related mortality, whereas insulin and DPP-4 inhibitors were associated with an increased risk compared with those who were not prescribed these drugs. GLP-1 receptor agonists and thiazolidinediones (pioglitazone) were found to have a neutral effect on mortality. Notably, it was not possible to estimate the impact of combinations of glucose-lowering therapies on COVID-19 related mortality.
The authors discuss that these findings are likely to be related in part to confounding by indication, as these different drug classes are used at different stages of type 2 diabetes disease progression. For example, SGLT2 inhibitors and sulfonylureas are less likely to be used in older frail individuals due to adverse effects of volume depletion and hypoglycaemia, respectively. Conversely, DPP-4 inhibitors are more likely to be used in older frail individuals, and also in the context of renal impairment, because of their favourable safety profile. The National Diabetes Audit does not include frailty as a parameter, so it was not possible to adjust for this variable. However, we do know that renal impairment with an eGFR <60 mL/min carries a high risk of adverse COVID-19 outcomes.
Moreover, the absolute increases and reductions in risk of mortality observed in this study were very small between the different classes of glucose-lowering medications and, additionally, there was no measure of medication adherence in this study.
On the basis of their findings, the authors concluded that there is no current requirement during the COVID-19 pandemic to change or stop specific glucose-lowering medications to reduce the risk of COVID-19 mortality in people living with type 2 diabetes.
This is a reassuring message for both healthcare professionals and people living with diabetes, and, hopefully, will help re-focus efforts to optimise glycaemic control and cardiovascular risk factors to mitigate the future risk of adverse COVID-19 outcomes.
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