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Diabetes Distilled: COVID-19 and diabetes – the chicken or the egg?

Kevin Fernando
This review explores the bidirectional relationship between COVID-19 and hyperglycaemia and new-onset diabetes. Pre-existing diabetes is a well-known risk factor for more severe COVID-19 infection; however, COVID-19 has also been associated with increased risk of new-onset diabetes (both type 1 and type 2). Proposed mechanisms include direct beta-cell destruction, corticosteroid use and physiological stress hyperglycaemia. However, it remains uncertain whether new-onset diabetes post-COVID is permanent, as many with stress hyperglycaemia revert to normoglycaemia with time and no longer require glucose-lowering medication. It is important to continue the long-term surveillance of people with new-onset diabetes to ensure good management of glycaemic control as well as other cardiometabolic risk factors. Stress hyperglycaemia without a subsequent diagnosis of diabetes may also identify those at high risk of diabetes, in whom early diagnosis, interventions and monitoring of complications are pivotal. Individuals with previous severe COVID-19 infection are already at risk of future cardiovascular and renal events and should have regular monitoring of their cardiorenal risk factors, as well as screening for microvascular and macrovascular complications. They may also benefit from treatment with newer diabetes therapies such as SGLT2 inhibitors and GLP-1 receptor agonists, which have been shown to reduce these complications.

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Diabetes has been well established as a risk factor for severe COVID-19 infection and subsequent mortality. Conversely, COVID-19 infection itself has been associated with significant new-onset hyperglycaemia and diabetes, as well as worsening of glycaemic control in those with established diabetes. These glucose excursions have been associated with worse outcomes even in those without diabetes. Moreover, the risk of mortality appears to be higher in those with new-onset diabetes than in those with established diabetes complicated by COVID-19 infection.

This recently published review authored by Kamlesh Khunti and colleagues explored this bidirectional relationship between COVID-19, hyperglycaemia and new-onset diabetes. Severe hyperglycaemia has been commonly reported in acutely unwell individuals, and this phenomenon has also been observed in those with COVID-19 infection, both with and without diabetes.

Several studies have observed an increase in new-onset type 1 and type 2 diabetes with COVID-19 infection, although findings elsewhere are conflicting. However, a consistent finding was an increased severity of diabetic ketoacidosis (DKA) with a new presentation of type 1 diabetes in younger individuals.

Other studies have also noted an increased frequency of DKA and hyperosmolar hyperglycaemic state (HHS) in those with known diabetes and COVID-19 infection. One small, UK-based study found a high prevalence of DKA in people living with type 2 diabetes, suggesting insulinopenia in those with COVID-19 infection. These episodes of DKA were also observed to be more prolonged, and individuals had higher insulin requirements compared to non-COVID-related DKA. A larger, US-based study investigated the characteristics and mortality associated with DKA among patients hospitalised with or without COVID-19. The authors observed that individuals had higher BMI, higher insulin requirements, more protracted DKA and higher mortality compared to those without COVID-19.

The mechanism underlying new-onset diabetes in those with COVID-19 infection has yet to be elucidated. However, it is likely to be multifactorial, with contributions from direct beta-cell destruction and corticosteroid use (dexamethasone has become the mainstay of management of severe COVID-19 infection since publication of the RECOVERY trial), as well as physiological stress hyperglycaemia. The authors remind us that stress hyperglycaemia is a sign of relative insulin deficiency and may be more severe in the presence of a “cytokine storm”, which is known to be a feature of severe COVID-19 infection.

It is also likely that many individuals had pre-existing but undiagnosed diabetes, and these untreated individuals would be expected to have a more profound hyperglycaemia and other adverse metabolic risk factors compared to those with established diabetes, leading to worse COVID-related outcomes as discussed earlier. Furthermore, social distancing and lockdown measures have resulted in more sedentary lifestyles and changes in eating habits for many, contributing to weight gain and an increased risk of developing type 2 diabetes.

Finally, the authors discussed management of people with new-onset diabetes following COVID-19 infection. They acknowledged, given the mechanistic uncertainties underlying the new diagnosis of diabetes, that clear management guidance is challenging. They also suggest that it is unclear whether new-onset diabetes post-COVID is permanent, as many with stress hyperglycaemia revert to normoglycaemia with time and no longer require glucose-lowering medication.

There is little follow-up data of new-onset diabetes related to COVID-19. However, interestingly, a recent case series from India described three individuals who had COVID-19 and developed new-onset diabetes and DKA, which was initially managed with intravenous fluids and insulin. These individuals were switched to multiple daily subcutaneous injections of insulin and, at 6-week follow-up, all had their insulin stopped and were subsequently initiated on oral glucose-lowering drugs. Two individuals had GAD antibodies checked, which returned negative. The authors suggested that the new-onset diabetes and DKA observed in this case series was due to transient insulinopenia.

Given that risk factors for adverse COVID-19 outcomes include hyperglycaemia, obesity and cardiorenal disease, Khunti and colleagues suggest that newer antidiabetes agents such as SGLT2 inhibitors and GLP-1 receptor agonists may be preferable due to their potent glucose-lowering effects as well as secondary benefits of weight and blood pressure reduction. Moreover, these newer therapeutic agents have also been associated with a reduction in atherosclerotic events (both SGLT2 inhibitors and GLP-1 receptor agonists) as well as major adverse renal and heart failure events (SGLT2 inhibitors).

Notably, the recently published DARE-19 study explored the efficacy and safety of dapagliflozin in people admitted to hospital with COVID-19 infection (see my previous Diabetes Distilled). Dapagliflozin did not prevent organ dysfunction or mortality in people with and without diabetes; however, the safety profile of dapagliflozin was reassuring and supported the continuation of the agent in hospitalised individuals under conditions of close monitoring.

Khunti et al conclude it is important to continue the long-term surveillance of people with new-onset diabetes to ensure good management of glycaemic control as well as other cardiometabolic risk factors. Stress hyperglycaemia without a subsequent diagnosis of diabetes may also identify those at high risk of diabetes, in whom early diagnosis, interventions and monitoring of complications are pivotal.

It is currently being debated whether all individuals should be screened for diabetes following a diagnosis of COVID-19 infection; this has significant workload implications, and it remains to be seen whether it would be a cost-effective approach. Many international guidelines (including NICE PH38) already recommend screening high-risk individuals for type 2 diabetes and intervening appropriately with lifestyle interventions and, occasionally and somewhat controversially, metformin. Additionally, individuals with previous severe COVID-19 infection are already at risk of future cardiovascular and renal events and should have regular monitoring of their cardiorenal risk factors, as well as screening for microvascular and macrovascular complications.

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