**4.1 Medications used in diabetes**

As it was not feasible to conduct RCTs initially, expert opinion and observational studies regarding treatment with medication for T2D suggest the following [15]:

Regular monitoring blood glucose of patients on insulin should be encouraged [15]. A retrospective study in patients in China found that patients with T2D required more medical interventions and had a significantly higher mortality and multiple organ injury than the non-diabetic individuals [3]. Within PWD they found that well controlled BG (CBG 3.9–10 mmol/L) was associated with reduction in adverse outcomes including lower mortality as compared with poorly controlled BG while in hospital. Hence correlation of improved glycaemic control with better outcomes was made and aggressive blood glucose lowering treatment with tablets and insulin was advocated.

#### *4.1.1 Insulin*

Insulin therapy is the mainstay in acute unwell PWD admitted to hospital where oral tablets have been stopped or not enough to control the hyperglycaemia. However, there is some evidence that insulin treatment is associated with adverse clinical outcomes in patients with T2D and COVID-19, including increased mortality. Use of insulin was associated with enhanced inflammation (increased IL-1β-dependent CRP and IL-6) and injury of vital organs (acute cardiac injury and acute kidney injury) during the progression of COVID-19 in patients with T2D [16]. Hypoglycaemia was higher in patients on insulin and may have contributed to the increased mortality although a sub-group without hypoglycaemia still had increased mortality. Insulin has been the mainstay in ill PWD and if hyperglycaemia and insulin result in adverse outcomes, there is a difficult dilemma for clinicians [17]. A UK study of 2.85 million PWD, a higher risk of COVID-19 related mortality was seen in patients on insulin, but the higher risk was thought to be due to residual confounding factors rather than direct drug effects [18]. Currently guidelines continue to endorse insulin in unwell PWD. Caution and close monitoring is to be exerted while using insulin treatment in PWD and COVID-19.

#### *4.1.2 Metformin*

Metformin, a lipophilic biguanide, has been associated with reduced mortality in women with obesity or T2D admitted to hospital with COVID-19 infection [19]. Several explanations have been provided including decreased inflammatory factors. Retrospective studies evaluating use of Metformin in T2D and COVID-19 infection have mainly suggested some benefit or no harm or benefit whereas a single study has suggested some harm, but overall use of Metformin is considered to be safe [20]. The CORONADO study which was a prospective study noted that Metformin was associated with a lower risk of death in PWD hospitalized with COVID-19 infection [21]. Dehydration with Covid-19 may increase the risk of lactic acidosis in patients taking metformin, hence temporary cessation of the drug along with usual sick day rules should be followed. Renal function should be monitored closely [15]. As metformin may reduce progression to severe COVID-19 infection, after initial cessation and review of clinical parameters including hypoxic state, lactate and renal parameters, metformin may be re-introduced if appropriate [13]. The MET-Covid Trial is an RCT designed to evaluate use of Metformin versus placebo for outpatient treatment and post exposure prophylaxis of COVID-19 infection [22].

#### *4.1.3 Sodium glucose co-transporter 2 inhibitors*

Sodium glucose co-transporter 2 inhibitors (SGLT2i) primarily act on the proximal tubule to block sodium and glucose absorption. Given that the mechanisms that are attributed to the protective effects of SGLT2i overlap with the mechanisms that are activated in COVID-19 infection, SGLT2i seem to have the potential to protect against end organ damage through cardio-renal protection [23]. Initiation of this medication should not be done during any likely infection, and for patients with T2D with COVID-19 infection, on SGLT2I, risk of dehydration and euglycemic DKA remains and should temporarily stop this medication and follow sick day rules. Renal function should be monitored closely [15]. A retrospective study to evaluate SGLT2i and COVID19 infection in a large UK based primary care dataset concluded that as compared to DPP4i, SGLT2i did not confer an increased risk of COVID-19 infection [24]. They deemed that clinicians can safely use SGLT2i the everyday care of PWD during COVID-19. DARE-19, is the first randomized controlled multi-centre trial

investigating the use of Dapagliflozin, and the goals are to prevent COVID-19 related organ dysfunction or mortality and to improve clinical recovery [23].
