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Individuals with type 2 diabetes, hypertension and obesity have poor outcomes from coronavirus-19 (COVID-19). The presence of microvascular disease (retinopathy, microalbuminuria or neuropathy) is an independent risk factor for early death in COVID-19. Microvascular dysfunction is a systemic condition which includes pulmonary manifestations. Impaired gas transfer, due to microangiopathy in type 2 diabetes, suggests that individuals will be vulnerable to the pro-inflammatory state and microthrombi characteristic of ‘endothelitis’ in COVID-19. Drugs that improve blood flow in the intrapulmonary peri-alveolar microcirculation – namely, nitric oxide or phosphodiesterase-5 inhibitors – are therefore promising candidates for clinical trials in COVID-19. A concerning feature of the coronavirus disease-19 (COVID19) pandemic has been the adverse outcomes observed in individuals with diabetes, obesity and hypertension.1–3 People with diabetes are more likely to experience severe outcomes of hospitalisation (odds ratio 2.67, 95% CI 1.91 to 3.74),1 with mortality rates near 10%.3 A publication comprising 7,336 patients showed the risk of fatal outcome from COVID-19 was up to 50% higher in patients with diabetes.4 In unadjusted analyses, higher glycated haemoglobin (HbA1c) was associated with worse hospital outcomes in type 2 diabetes.4 However, in multivariable analyses of a large series from France,5 glycaemic control (HbA1c) was not significant whereas the presence of macroand/or microvascular disease are independent risk factors for early death in people with diabetes hospitalised for COVID-19. HbA1c represents glycaemic exposure over the preceding 3 months whereas microvascular burden is a marker of metabolic dysfunction over an individual’s lifetime.6 Microvascular dysfunction, in particular, is also attracting attention as a pathogenetic mechanism in COVID-19. Viral entry into pneumocytes leads to immune activation and a pro-inflammatory state in the adjacent endothelial cells of the microcirculation.7 Microthrombi contribute further to the impediment of microvascular blood flow through the lung.8 COVID-19 has therefore been considered an ‘endothelitis’.7 The classic triad of microvascular complications of diabetes (retinopathy, neuropathy and nephropathy) are manifestations of much wider, systemic microvascular dysfunction which also affect vascular beds located in the brain, heart and lung.6,9 Reduced lung volumes in diabetes, determined by forced expiratory volume in 1 second (FEV1) and vital capacity, relate to the presence of diabetes microvascular complications and glycaemic exposure,10 even after adjustment for smoking and gender. Obesity and hypertension themselves contribute to microangiopathy, with inter-relationships between impaired microvascular function, hypertension and insulin resistance.6 The transfer capacity of the lung (TLco) is a measure of the capacity for diffusion of oxygen across the alveolus into the microvasculature. It has been shown that, in non-smokers with type 2 diabetes but no overt cardiopulmonary disease, TLco was lower than in agematched healthy controls – even after adjusting for cardiac output.11 Importantly, individuals with evidence of microvascular dysfunction (retinopathy, microalbuminuria or neuropathy) had worse TLco. Impairment of alveolar-capillary recruitment was evident regardless of obesity status, and suggested that parenchymal changes could impede opening or distention of alveolar capillaries. There is significant ‘redundancy’ of the pulmonary circulation, such that nearly 50% of gas transfer may be lost before measures of blood oxygenation diminish.12 Therefore, the lower TLco seen in diabetes11,13,14 would be unlikely to manifest clinically unless a huge stressor was applied to the system. COVID-19 infection is just such a stressor. Severe COVID19 pneumonia produces diffuse alveolar damage and widespread endothelial dysfunction and microthrombi result in matched and unmatched ventilation/perfusion (V/Q) defects, for which an individual with preceding pulmonary microangiopathy would be ill-prepared. Unlike sepsis syndromes, blood pressure and the macrocirculation appear relatively unaffected by COVID-19.15 To summarise: a drug that could improve peri-hilar microvascular recruitment may therefore improve oxygenation. 1 Consultant Diabetologist and Clinical Senior Lecturer in Metabolic Medicine, University of Surrey, King's College Hospital NHS Foundation Trust 2 Consultant Diabetologist, King's College Hospital NHS Foundation Trust 3 Consultant Physician, King's College Hospital NHS Foundation Trust 4 Professor of Cardiovascular Medicine, University of Surrey, UK 5 Honorary Professor of Diabetes, University of Oxford, Oxford, UK

Nitric oxide and phosphodiesterase-5 inhibitors: possible treatments for COVID-19 in diabetes