key: cord-0937130-t8j7kqbo
authors: Schernthaner, Guntram
title: Can glucose-lowering drugs affect the prognosis of COVID-19 in patients with type 2 diabetes?
date: 2021-03-30
journal: Lancet Diabetes Endocrinol
DOI: 10.1016/s2213-8587(21)00059-0
sha: 39007ceb4c73b077fbf0077e14a779cfa244e158
doc_id: 937130
cord_uid: t8j7kqbo

nan

The emergence of a novel coronavirus, SARS-CoV-2, in December, 2019, has had devastating consequences on health, social, and economic systems around the world. Of the estimated 115 million people (about 10% with diabetes) who have been infected with SARS-CoV-2, more than 2·5 million patients had died due to COVID-19 at the time of writing (data from the Johns Hopkins Coronavirus Research Center). People with diabetes and related comorbidities are at increased risk of severe COVID-19 complications, and COVID-19-related mortality in this population is two to three times higher than that in people without diabetes. 1 Various mechanisms might explain why patients with diabetes are over-represented among those admitted to hospital with severe COVID-19 and have an increased risk for death. Metabolic inflammation is common in patients with diabetes and predisposes them to an enhanced release of cytokines. 2 For COVID-19, a cytokine storm has been implicated in the multiorgan failure reported in patients with severe disease. Inflammatory-driven processes are probably primary drivers of coagulopathy in COVID-19. Venous thromboembolism, arterial thrombosis, and thrombotic microangiopathy substantially contribute to increased morbidity and mortality in patients with COVID-19. 3 The chronic inflammation and hypercoagulable state common in diabetes could contribute to the high mortality risk associated with COVID-19 and diabetes.

Glucose-lowering drugs used in the treatment of patients with diabetes might have significant effects on COVID-19 pathophysiology, potentially affecting the risk of progression to severe disease and mortality. In The Lancet Diabetes & Endocrinology, Kamlesh Khunti and colleagues 4 report COVID-19 mortality rates for patients with type 2 diabetes on different glucoselowering therapies, in an observational nationwide study in England. The pre-infection prescription of glucoselowering therapies and risk of COVID-19 mortality was analysed in 2·85 million people with type 2 diabetes, covering almost the whole population of people with type 2 diabetes who were registered with a general practice in England (irrespective of whether or not patients had been admitted to hospital). Overall, a COVID-19-related death occurred in 13 479 (0·5%) of the 2 851 465 patients during the study period (Feb 16 to Aug 31, 2020). Metformin, SGLT2 inhibitors, and sulfonylureas were associated with reduced risks of the COVID-19-related mortality, whereas insulin and DPP-4 inhibitors were associated with increases in risk; neutral results were found for GLP-1 receptor agonists and thiazolidinediones. Unfortunately, data were not available to allow the researchers to identify when the drugs were stopped during the progression of COVID-19, and it was not possible to establish whether the combination therapies that are widely used to control diabetes in England had any effect on mortality.

Khunti and colleagues' findings 4 are in line with a recent update from the nationwide CORONADO study in France, 5 which also showed that, in patients admitted to hospital with COVID-19 and diabetes, metformin use was associated with a decrease and insulin was associated with an increase in mortality risk. A significantly reduced mortality rate associated with the use of metformin (odds ratio 0·62 [95% CI 0·43-0·89]) was also reported in a recent meta-analysis of five studies 6 including 8121 patients with diabetes who were admitted to hospital for COVID-19. The findings of these studies, including the study by Khunti and colleagues, [4] [5] [6] are probably related at least in part to confounding by indication, as metformin is used early in the disease course of type 2 diabetes, whereas insulin is initiated later. The use of SGLT2 inhibitors compared with DPP-4 inhibitors was associated with significantly lower mortality risk associated with COVID-19 in both Khunti and colleagues' study in England 4 and another recent study in Denmark. 7 However, in Khunti and colleagues' study, 4 47% of the patients receiving a DPP-4 inhibitor were aged 70 years or older, compared with only 18% taking an SGLT2 inhibitor. Patients with an eGFR between 15 mL/min per 1·73 m² and less than 60 mL/min per 1·73 m² had a very high mortality risk in univariate analyses (hazard ratio 3·7 [95% CI 3·5-3·9] for 45 to <60 mL/min per 1·73 m² to 9·1 [8·4-9·9] for 15 to <30 mL/min per 1·73 m²). Notably, almost 25% of patients on a DPP-4 inhibitor had eGFR of less than 60 mL/min per 1·73 m², compared with only 4·1% of patients on an SGLT2 inhibitor.

How might these findings inform clinical practice? On the basis of evidence from smaller studies, Lim and colleagues 8 recommended that DPP-4 inhibitors be used across a broad spectrum of COVID-19 severity, but that SGLT2 inhibitors should only be used with caution, and metformin should be stopped in severe cases. Because positive results with respect to all-cause mortality have previously been reported for metformin and SGLT2 inhibitors, 9 withdrawal or non-use of these drugs could have a negative effect on the prognosis of patients with type 2 diabetes and COVID-19. Given the large cohort in Khunti and colleagues' study 4 and the absence of evidence for risk with these drugs, recommendations on the use of glucose-lowering drugs by people with type 2 diabetes during the COVID-19 pandemic might now become more liberal, allowing use of all glucose-lowering drugs in stable situations. However, because of the limitations of such real-world studies, prospective randomised clinical trials are necessary to more meaningfully explore which glucose-lowering agents, if any, induce benefit or harm in patients with COVID-19. Irrespective of therapy choice, strict management of cardiovascular risk factors and tight glycaemic control are crucial for patients with diabetes and COVID-19. Antithrombotic therapy for the prevention and treatment of COVID-19-associated thrombosis 3 as well as anti-inflammatory therapy 10 will hopefully translate into improved outcomes. 3 Finally, vaccination prioritisation of patients with type 2 diabetes who are at very high risk of severe COVID-19 could help protect this vulnerable population.

Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study

Endocrine and metabolic link to coronavirus infection

The emerging threat of (micro) thrombosis in COVID-19 and its therapeutic implications

Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study

Mortality risk with preadmission metformin use in patients with COVID-19 and diabetes: a meta-analysis

Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2

COVID-19 and diabetes mellitus: from pathophysiology to clinical management

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs

RA) in high-risk patients with type 2 diabetes

Dexamethasone in hospitalized patients with COVID-19