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Letter to the Editor| Volume 14, ISSUE 5, P564-565, October 2020

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SGLT-2 inhibitors for COVID-19 — A miracle waiting to happen or just another beat around the bush?

Published:May 27, 2020DOI:https://doi.org/10.1016/j.pcd.2020.05.013
SGLT-2 inhibitors for COVID-19 — A miracle waiting to happen or just another beat around the bush?
Previous ArticleCOVID-19 and diabetes: What does the clinician need to know?
Next ArticleObesity and risk of COVID-19: analysis of UK biobank
      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 (COVID-19). Hydroxychloroquine, anti-retrovirals, type-1 angiotesin receptor blockers, statin, vitamin D, melatonin etc are being tried with questionable benefits [
      • Phadke M.
      • Saunik S.
      COVID-19 treatment by repurposing drugs until the vaccine is in sight.
      Drug Dev. Res. 2020; (Epub ahead of print. PMID: 32227357; PMCID: PMC7228332)https://doi.org/10.1002/ddr.21666
      ]. While there are intensive debates regarding safety of different classes of antidiabetics at the advent of COVID-19 [
      • Pal R.
      • Bhadada S.K.
      Should anti-diabetic medications be reconsidered amid COVID-19 pandemic?.
      Diabetes Res. Clin. Pract. 2020; 163108146https://doi.org/10.1016/j.diabres.2020.108146
      ,
      • Ceriello A.
      • Stoian A.P.
      • Rizzo M.
      COVID-19 and diabetes management: what should be considered?.
      Diabetes Res. Clin. Pract. 2020; 163108151https://doi.org/10.1016/j.diabres.2020.108151
      ], multiple ongoing studies are evaluating the adjuvant role of various antidiaetics like dipeptidyl peptidase-4 (DPP-4) inhibitors [
      • Iacobellis G.
      COVID-19 and diabetes: can DPP4 inhibition play a role?.
      Diabetes Res. Clin. Pract. 2020; 162108125https://doi.org/10.1016/j.diabres.2020.108125
      ,
      • ClinicalTrials.gov
      Effects of DPP4 Inhibition on COVID-19.
      2020
      https://clinicaltrials.gov/ct2/show/NCT04341935
      ], pioglitazone [
      • Carboni E.
      • Carta A.R.
      • Carboni E.
      Can pioglitazone be potentially useful therapeutically in treating patients with COVID-19?.
      Med. Hypotheses. 2020; 140109776https://doi.org/10.1016/j.mehy.2020.109776
      ], glucagon-like peptide-1 (GLP-1) agonists [
      • Bornstein S.R.
      • Dalan R.
      • Hopkins D.
      • Mingrone G.
      • Boehm B.O.
      Endocrine and metabolic link to coronavirus infection.
      Nat. Rev. Endocrinol. 2020; 16 (April): 297-298https://doi.org/10.1038/s41574-020-0353-9
      ] in reducing the severity of COVID-19. Dapagliflozin, an inhibitor of sodium-glucose transporter-2 (SGLT-2) has been recent addition to the trend [
      • ClinicalTrials.gov
      Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19).
      2020
      ].
      Higher lactate dehydrogenase (LDH) and lactic acidosis have been found to statistically significantly associated with COVID-19 (p = 0.0001) [
      • Mardani R.
      • Ahmadi Vasmehjani A.
      • Zali F.
      • Gholami A.
      • Mousavi Nasab S.D.
      • Kaghazian H.
      • et al.
      Laboratory parameters in detection of COVID-19 patients with positive RT-PCR; a diagnostic accuracy study.
      Arch. Acad. Emerg. Med. 2020; 8: e43
      ]. Cure and Cure [
      • Cure E.
      • Cure M.C.
      Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis.
      Diabetes Metab. Syndr. 2020; 14: 405-406
      ] 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+/Ca2+ exchange system to protrude Na+ resulting in intracellular Ca2+. The resulting cellular swelling and excitotoxicity lead to apoptosis [
      • Matsumoto Y.
      • Yamamoto S.
      • Suzuki Y.
      • Tsuboi T.
      • Terakawa S.
      • Ohashi N.
      • et al.
      Na+/H+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons.
      Stroke. 2004; 35: 185-190
      ]. SGLT-2 inhibitors inhibit this very NHE, thus protects from cellular lysis [
      • Cure E.
      • Cure M.C.
      Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis.
      Diabetes Metab. Syndr. 2020; 14: 405-406
      ,
      • Uthman L.
      • Baartscheer A.
      • Bleijlevens B.
      • Schumacher C.A.
      • Fiolet J.W.T.
      • Koeman A.
      • et al.
      Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.
      Diabetologia. 2018; 61: 722-726
      ]. SGLT-2 inhibitors, irrespective of glycemic status decreases pro-inflammatory cytokines including those directly involved in “cytokine storm” of COVID-19 [
      • Bonnet F.
      • Scheen A.J.
      Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: the potential contribution to diabetes complications and cardiovascular disease.
      Diabetes Metab. 2018; 44: 457-464
      ]. Moreover, SGLT-2 inhibitors promote the activation of alternative renin-angiotesin-aldosterone pathway through greater expression of angiotesin converting enzyme type-2 (ACE2) [
      • Kawanami D.
      • Matoba K.
      • Takeda Y.
      • Nagai Y.
      • Akamine T.
      • Yokota T.
      • et al.
      SGLT2 inhibitors as a therapeutic option for diabetic nephropathy.
      Int. J. Mol. Sci. 2017; 18: 1083
      ], a pathway that is grossly perturbed by SARS-CoV2 [
      • Cheng H.
      • Wang Y.
      • Wang G.Q.
      Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19.
      J. Med. Virol. 2020; (Epub ahead of print. PMID: 32221983)https://doi.org/10.1002/jmv.25785
      ].
      Table 1Rationality of using dapagliflozin in COVID-19.
      A. Reduced serum lactate level
      1. Reduces oxygen consumption in tissues and channelizes glucose towards the aerobic pathway, thus diminishing lactate production
      2. Reduces lactate release from adipose tissue
      3. Increased renal excretion of lactate
      B. Inhibition of NHE
      C. Organ protective effective (heart, vasculature, kidney)
      D. Activation of alternative RAAS pathway by activating ACE2
      E. Decreased proinflammatory cytokines
      F. Glycemic control
      SGLT-2 inhibitors possess organ-protective effects beyond its glycemic benefits [
      • Minze M.G.
      • Will K.J.
      • Terrell B.T.
      • Black R.L.
      • Irons B.K.
      Benefits of SGLT2 inhibitors beyond glycemic control - a focus on metabolic, cardiovascular and renal outcomes.
      Curr. Diabetes Rev. 2018; 14: 509-517
      ]. As large-scale analysis has revealed that patients with cardiometabolic and renal impairments are particularly vulnerable for worst COVID-19 outcome [
      • Guan W.J.
      • Liang W.H.
      • Zhao Y.
      • Liang H.R.
      • Chen Z.S.
      • Li Y.M.
      • et al.
      Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.
      Eur. Respir. J. 2020; 2000547https://doi.org/10.1183/13993003.00547-2020
      ], 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) [
      • ClinicalTrials.gov
      Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19).
      2020
      ], 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 3-4 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 [
      • Bornstein S.R.
      • Rubino F.
      • Khunti K.
      • Mingrone G.
      • Hopkins D.
      • Birkenfeld A.L.
      • Boehm B.
      • Amiel S.
      • Holt R.I.
      • Skyler J.S.
      • DeVries J.H.
      • Renard E.
      • Eckel R.H.
      • Zimmet P.
      • Alberti K.G.
      • Vidal J.
      • Geloneze B.
      • Chan J.C.
      • Ji L.
      • Ludwig B.
      Practical recommendations for the management of diabetes in patients with COVID-19.
      Lancet Diabetes Endocrinol. 2020; 8 (April) . doi:10.1016/S2213-8587(20)30152-2 Epub 2020 Apr 23. PMID: 32334646; PMCID: PMC7180013: 546-550
      ]. Although association between SGLT-2 inhibitors and peripheral arterial disease (PAD) is still unclear [
      • Chatterjee S.
      • Bandyopadhyay D.
      • Ghosh R.K.
      • Majumdar U.
      • Aneja A.
      • Lavie C.J.
      • et al.
      SGLT-2 inhibitors and peripheral artery disease: a statistical hoax or reality?.
      Curr. Probl. Cardiol. 2019; 44: 207-222
      ], there are instances of severe PAD complicating the course of COVID-19 [
      • Zhou B.
      • She J.
      • Wang Y.
      • Ma X.
      Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report.
      J. Thromb. Thrombolysis. 2020; : 1-4https://doi.org/10.1007/s11239-020-02084-w
      ]. In this view the DARE-19 trial seems to be an extremely risky proposition. Moreover, therapeutic armamentarium targeted against the 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.

      Conflict of interest

      Nil.

      Funding

      Nil.

      References

        • Phadke M.
        • Saunik S.
        COVID-19 treatment by repurposing drugs until the vaccine is in sight.
        Drug Dev. Res. 2020; (Epub ahead of print. PMID: 32227357; PMCID: PMC7228332)https://doi.org/10.1002/ddr.21666
        View in Article
        • Pal R.
        • Bhadada S.K.
        Should anti-diabetic medications be reconsidered amid COVID-19 pandemic?.
        Diabetes Res. Clin. Pract. 2020; 163108146https://doi.org/10.1016/j.diabres.2020.108146
        View in Article
        • Ceriello A.
        • Stoian A.P.
        • Rizzo M.
        COVID-19 and diabetes management: what should be considered?.
        Diabetes Res. Clin. Pract. 2020; 163108151https://doi.org/10.1016/j.diabres.2020.108151
        View in Article
        • Iacobellis G.
        COVID-19 and diabetes: can DPP4 inhibition play a role?.
        Diabetes Res. Clin. Pract. 2020; 162108125https://doi.org/10.1016/j.diabres.2020.108125
        View in Article
        • ClinicalTrials.gov
        Effects of DPP4 Inhibition on COVID-19.
        2020
        https://clinicaltrials.gov/ct2/show/NCT04341935
        View in Article
        • Carboni E.
        • Carta A.R.
        • Carboni E.
        Can pioglitazone be potentially useful therapeutically in treating patients with COVID-19?.
        Med. Hypotheses. 2020; 140109776https://doi.org/10.1016/j.mehy.2020.109776
        View in Article
        • Bornstein S.R.
        • Dalan R.
        • Hopkins D.
        • Mingrone G.
        • Boehm B.O.
        Endocrine and metabolic link to coronavirus infection.
        Nat. Rev. Endocrinol. 2020; 16 (April): 297-298https://doi.org/10.1038/s41574-020-0353-9
        View in Article
        • ClinicalTrials.gov
        Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19).
        2020 (Available from: https://www.clinicaltrials.gov/ct2/show/NCT04350593 (Last accessed 1 May 2020))
        View in Article
        • Mardani R.
        • Ahmadi Vasmehjani A.
        • Zali F.
        • Gholami A.
        • Mousavi Nasab S.D.
        • Kaghazian H.
        • et al.
        Laboratory parameters in detection of COVID-19 patients with positive RT-PCR; a diagnostic accuracy study.
        Arch. Acad. Emerg. Med. 2020; 8: e43
        View in Article
        • Cure E.
        • Cure M.C.
        Can dapagliflozin have a protective effect against COVID-19 infection? A hypothesis.
        Diabetes Metab. Syndr. 2020; 14: 405-406
        View in Article
        • Matsumoto Y.
        • Yamamoto S.
        • Suzuki Y.
        • Tsuboi T.
        • Terakawa S.
        • Ohashi N.
        • et al.
        Na+/H+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons.
        Stroke. 2004; 35: 185-190
        View in Article
        • Uthman L.
        • Baartscheer A.
        • Bleijlevens B.
        • Schumacher C.A.
        • Fiolet J.W.T.
        • Koeman A.
        • et al.
        Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation.
        Diabetologia. 2018; 61: 722-726
        View in Article
        • Bonnet F.
        • Scheen A.J.
        Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: the potential contribution to diabetes complications and cardiovascular disease.
        Diabetes Metab. 2018; 44: 457-464
        View in Article
        • Kawanami D.
        • Matoba K.
        • Takeda Y.
        • Nagai Y.
        • Akamine T.
        • Yokota T.
        • et al.
        SGLT2 inhibitors as a therapeutic option for diabetic nephropathy.
        Int. J. Mol. Sci. 2017; 18: 1083
        View in Article
        • Cheng H.
        • Wang Y.
        • Wang G.Q.
        Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19.
        J. Med. Virol. 2020; (Epub ahead of print. PMID: 32221983)https://doi.org/10.1002/jmv.25785
        View in Article
        • Minze M.G.
        • Will K.J.
        • Terrell B.T.
        • Black R.L.
        • Irons B.K.
        Benefits of SGLT2 inhibitors beyond glycemic control - a focus on metabolic, cardiovascular and renal outcomes.
        Curr. Diabetes Rev. 2018; 14: 509-517
        View in Article
        • Guan W.J.
        • Liang W.H.
        • Zhao Y.
        • Liang H.R.
        • Chen Z.S.
        • Li Y.M.
        • et al.
        Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.
        Eur. Respir. J. 2020; 2000547https://doi.org/10.1183/13993003.00547-2020
        View in Article
        • Bornstein S.R.
        • Rubino F.
        • Khunti K.
        • Mingrone G.
        • Hopkins D.
        • Birkenfeld A.L.
        • Boehm B.
        • Amiel S.
        • Holt R.I.
        • Skyler J.S.
        • DeVries J.H.
        • Renard E.
        • Eckel R.H.
        • Zimmet P.
        • Alberti K.G.
        • Vidal J.
        • Geloneze B.
        • Chan J.C.
        • Ji L.
        • Ludwig B.
        Practical recommendations for the management of diabetes in patients with COVID-19.
        Lancet Diabetes Endocrinol. 2020; 8 (April) . doi:10.1016/S2213-8587(20)30152-2 Epub 2020 Apr 23. PMID: 32334646; PMCID: PMC7180013: 546-550
        View in Article
        • Chatterjee S.
        • Bandyopadhyay D.
        • Ghosh R.K.
        • Majumdar U.
        • Aneja A.
        • Lavie C.J.
        • et al.
        SGLT-2 inhibitors and peripheral artery disease: a statistical hoax or reality?.
        Curr. Probl. Cardiol. 2019; 44: 207-222
        View in Article
        • Zhou B.
        • She J.
        • Wang Y.
        • Ma X.
        Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report.
        J. Thromb. Thrombolysis. 2020; : 1-4https://doi.org/10.1007/s11239-020-02084-w
        View in Article

      Article info

      Publication history

      Published online: May 27, 2020
      Received: May 13, 2020

      Identification

      DOI: https://doi.org/10.1016/j.pcd.2020.05.013

      Copyright

      © 2020 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

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