key: cord-0806839-b15xw6cy authors: Chatterjee, Subhankar title: SGLT-2 inhibitors for COVID-19 — A miracle waiting to happen or just another beat around the bush? date: 2020-05-28 journal: Prim Care Diabetes DOI: 10.1016/j.pcd.2020.05.013 sha: 0fd265b3726b8842f503de60a4c94743f1fc4f0c doc_id: 806839 cord_uid: b15xw6cy nan To the Editor: In the absence of an effective drug or vaccine against novel severe acute respiratory syndrome corona virus (SARS-Cov-2) till date, "repurposing approach" of old pharmaceuticals has been applied to combat against 2019-coronavirus disease . Hydroxychloroquine, anti-retrovirals, type-1 angiotesin receptor blockers, statin, vitamin D, melatonin etc are being tried with questionable benefits [1] . While there are intensive debates regarding safety of different classes of antidiabetics at the advent of COVID-19 [2, 3] , multiple ongoing studies are evaluating the adjuvant role of various antidiaetics like dipeptidyl peptidase-4 (DPP-4) inhibitors [4, 5] , pioglitazone [6] , glucagon-like peptide-1 (GLP-1) agonists [7] in reducing the severity of COVID-19. Dapagliflozin, an inhibitor of sodium-glucose transporter-2 (SGLT-2) has been recent addition to the trend [8] . Higher lactate dehydrogenase (LDH) and lactic acidosis have been found to statistically significantly associated with COVID-19 (p=0.0001) [9] . Cure et al [10] have hypothesized that dapagliflozin might be beneficial in this context as it decreases lactatemia through different mechanisms (table-1). With hyperlactatemia the Lactate-H + symporter gets activated to carry lactate and H + into the cell leading to decreased intracellular pH. At the same time, Na + -H + exchanger (NHE), an antiporter which works to throws out H + in lieu of Na + , also gets activated leading to cellular swelling. This, in turn, reverses the Na + /Ca 2+ exchange system to protrude Na + resulting in intracellular Ca 2+ . The resulting cellular swelling and excitotoxicity lead to apoptosis [11] . SGLT-2 inhibitors inhibit this very NHE, thus protects from cellular lysis [10, 12] . SGLT-2 inhibitors, irrespective of glycemic status decreases pro-inflammatory cytokines including those directly involved in "cytokine storm" of COVID-19 [13] . Moreover, SGLT-2 inhibitors promote the activation of alternative renin-angiotesin-aldosterone pathway through greater expression of J o u r n a l P r e -p r o o f angiotesin converting enzyme type-2 (ACE2) [14] , a pathway that is grossly perturbed by SARS-CoV2 [15] . SGLT-2 inhibitors possess organ-protective effects beyond its glycemic benefits [16] . As largescale analysis has revealed that patients with cardiometabolic and renal impairments are particularly vulnerable for worst COVID-19 outcome [17] , SGLT-2 inhibitors might afford additional vital organ protection in the settings of COVID-19. With these hopes "Dapagliflozin in Respiratory Failure in Patients With COVID-19" (DARE-19, clinical trial number NCT04350593) [8] , a phase-3 multi-national double-blind placebo-controlled randomized trial has been started. The study population includes hospitalized patients >18 years of age with mild-moderate COVID-19 infection having at least one of the following: type-2 diabetes, hypertension, diabetes, atherosclerotic cardiovascular disease, heart failure, stage 3 to 4 chronic kidney disease. Patients with severe disease, type-1 diabetes, history of diabetic ketoacidosis (DKA) within last 6 months or on treatment with any SGLT-2 inhibitors were excluded. Patients will be treated with either dapagliflozin 10 mg once daily or placebo on top of standard of care. The primary efficacy endpoint of the study is time to first occurrence of all-cause death or comorbid disease complications through the follow-up period of 1month. Although the proposed mechanistic benefits of SGLT-2 inhibitors in COVID-19 settings seem to be lucrative, the decision to take-up this trial is not beyond criticism. Expert panel has recommended against the use of SGLT-2 inhibitors among COVID-19 patients due to risk of dehydration and euglycemic DKA [18] . Although association between SGLT-2 inhibitors and peripheral arterial disease (PAD) is still unclear [19] , there are instances of severe PAD complicating the course of COVID-19 [20] . In this view the DARE-19 trial seems to be an extremely risky proposition. Moreover, therapeutic armamentarium targeted against the J o u r n a l P r e -p r o o f associated metabolic perturbations must be instituted judiciously but extrapolation of the same drugs to combat against SARS-CoV2 will probably be proved to be a futile approach with every possibility of missing the actual target, the virion. This ultimately results in beating the bush for treatment of comorbidities at the cost of losing the track to treat a viral infection. J o u r n a l P r e -p r o o f COVID-19 treatment by repurposing drugs until the vaccine is in sight Should anti-diabetic medications be reconsidered amid COVID-19 pandemic? COVID-19 and diabetes management: What should be considered? COVID-19 and diabetes: Can DPP4 inhibition play a role? Effects of DPP4 Inhibition on COVID-19 Can pioglitazone be potentially useful therapeutically in treating patients with covid-19? Med Hypotheses Endocrine and metabolic link to coronavirus infection Dapagliflozin in Respiratory Failure in Patients With COVID-19 (DARE-19) Laboratory Parameters in Detection of COVID-19 Patients with Positive RT-PCR; a Diagnostic Accuracy Study Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis Na+/H+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of lowering of cytosolic Na + and vasodilation Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease Inhibitors as a Therapeutic Option for Diabetic Nephropathy Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19 Benefits of SGLT2 Inhibitors Beyond Glycemic Control -A Focus on Metabolic, Cardiovascular and Renal Outcomes Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis Practical recommendations for the management of diabetes in patients with COVID-19 SGLT-2 Inhibitors and Peripheral Artery Disease: A Statistical Hoax or Reality? Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report Organ protective effective (heart, vasculature, kidney) Activation of alternative RAAS pathway by activating ACE2