Potential Safety Issues with Use of Sodium-Glucose Cotransporter 2 Inhibitors, Particularly in People with Type 2 Diabetes and Chronic Kidney Disease

Milder, Tamara Y.; Stocker, Sophie L.; Day, Richard O.; Greenfield, Jerry R.

doi:10.1007/s40264-020-01010-6

Cited by 29 publications

(29 citation statements)

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“…We have noticed that all patients but one (a patient with gestational diabetes) who had developed EDKA received SGLT-2i treatment; however, a negative association with AKI was noted, thus implying a prophylactic effect on renal function. Treatment with SGLT-2i has been reported to trigger EDKA in T2D patients with or without COVID-19 infection, usually during other infections, sepsis or surgery [43][44][45]. These regimens might be prescribed even for T1D; interestingly, a single case report of a patient with T1D who received empagliflozin 25 mg q24h and developed EDKA during COVID-19 pneumonia has been recently published [46].…”

Section: Discussionmentioning

confidence: 99%

Diabetes-related acute metabolic emergencies in COVID-19 patients: a systematic review and meta-analysis

Papadopoulos

Koutroulos²,

Zikoudi³

et al. 2021

Diabetol Int

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Aims COVID-19 is associated with diabetic ketoacidosis (DKA), hyperglycaemic hyperosmolar state (HHS) and euglycaemic DKA (EDKA); however, evidence regarding parameters affecting outcome and mortality rates is scarce. Methods A systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January 2020 to 7 January 2021 to identify all studies describing clinical profile, outcome and mortality rates regarding DKA, HHS, DKA/HHS and EDKA cases in COVID-19 patients. The appropriate Joanna Briggs Institute tools were used for quality assessment; quality of evidence was approached using GRADE. Univariate and multivariate analyses were used to assess correlations between clinical characteristics and outcome based on case reports. Combined mortality rates (CMR) were estimated from data reported in case report series, cross-sectional studies, and meta-analyses. The protocol was submitted to PROSPERO (ID: 229356/230737). Results From 312 identified publications, 44 were qualitatively and quantitatively analyzed. Critical COVID-19 necessitating ICU (P = 3 × 10-8), DKA/HHS presence (P = 0.021), and AKI (P = 0.037) were independently correlated with death. Increased COVID-19 severity (P = 0.003), elevated lactates (P < 0.001), augmented anion gap (P < 0.001), and AKI (P = 0.002) were associated with DKA/HHS. SGLT-2i were linked with EDKA (P = 0.004) and negatively associated with AKI (P = 0.023). CMR was 27.1% (95% CI 11.2-46.9%) with considerable heterogeneity (I 2 = 67%). Conclusion Acute diabetes-related metabolic emergencies in COVID-19 patients lead to increased mortality; key determinants are critical COVID-19 illness, coexistence of DKA/HHS and AKI. Previous SGLT-2i treatment, though associated with EDKA, might preserve renal function in COVID-19 patients.

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Section: Discussionmentioning

confidence: 99%

Diabetes-related acute metabolic emergencies in COVID-19 patients: a systematic review and meta-analysis

Papadopoulos

Koutroulos²,

Zikoudi³

et al. 2021

Diabetol Int

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“…Glycaemic stability can mislead the clinician, since hyperglycosuria induced by SGLT-2i may blunt hyperglycaemia during infection and contribute to a lack of insulin, finally promoting ketogenesis [77]. Therefore, it is strongly advised that the use of SGLT-2i should be discontinued at once in both T2D and T1D patients as soon as COVID-19 is diagnosed; in these cases, exclusive administration of insulin is considered to be the safest choice [79][80][81].…”

Section: Discussionmentioning

confidence: 99%

Acute Metabolic Emergencies in Diabetes and COVID-19: a systematic review and meta-analysis of case reports

Papadopoulos¹,

Koutroulos²,

Zikoudi³

et al. 2021

Preprint

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BackgroundCOVID-19 is associated with DKA (Diabetic Ketoacidosis), HHS (Hyperglycaemic Hyperosmolar State) and EDKA (Euglycaemic DKA). High mortality has been observed in COVID-19-related diabetic ketoacidosis; however, evidence is scarce.MethodsA systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January to December 2020 to identify all case reports describing DKA, HHS, and EDKA, in COVID-19 patients. The Joanna Briggs Institute critical appraisal checklist for case reports was used for quality assessment. Univariate and multivariate analysis assessed correlations of study origin, combined DKA/HHS, age, BMI, HbA1c, administered antidiabetics, comorbidities, symptoms onset, disease status (DS), CRP, ferritin, d-dimers, glucose, osmolarity, pH, bicarbonates, ketones, lactates, β-hydroxybutyric acid, anion gap, and acute kidney injury (AKI) with outcome. The relevant protocol was submitted to PROSPERO database (ID: 229356).ResultsFrom 312 identified publications, 41 including 71 cases analyzed qualitatively and quantitatively. The types of acute metabolic emergencies observed were DKA (45/71, 63.4%), EDKA (6/71, 8.5%), combined DKA/HHS (19/71, 26.8%), and HHS (1/71, 1.4%). Overall mortality was 32.4% (22/68 patients; 3 missing). Multivariate analysis by classical regression demonstrated that COVID-19 DS4 (P=3•10−8), presence of DKA/HHS (P=0.021), and development of AKI (P=0.037) were all independently correlated with death. Increased DS (P=0.003), elevated lactates (P<0.001), augmented anion gap (P<0.001), and presence of AKI (P=0.002) were associated with DKA/HHS. SGLT-2i administration was linked with EDKA (P=0.004); however, a negative association with AKI was noted (P=0.023).ConclusionCOVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality. Key determinants are critical COVID-19 illness, coexistence of DKA/HHS and AKI. Awareness of clinicians to timely assess them might enable early detection and immediate treatment commencing. As previous treatment with was negatively associated with AKI, thus implying a prophylactic effect on renal function, the issue of discontinuation of SGLT-2i in COVID-19 patients remains to be further evaluated.Key messagesWhat is already known on this subject▸Diabetes mellitus (DM) is a risk factor for poor outcomes in COVID-19 patients.▸Diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) are not rare in COVID-19 diabetic and non-diabetic patients; key determinants of outcome remain unknown.What this study adds▸COVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality; key determinants are critical COVID-19 illness, coexistence of DKA and HHS as well as development of acute kidney injury.▸SGLT2-i administration is linked with euglycaemic DKA in patients with COVID-19, though preserving renal function.

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“…and so cannot be recommended [25] ( Table 4 [ [25][26][27][28][29]). People with diabetes should be encouraged to continue medication prescribed for hypertension, diabetes or dyslipidemia.…”

Section: Sulfonylureamentioning

confidence: 99%

“…Furthermore, patients with diabetes and COVID-19 should follow their usual antidiabetic treatment with the exception of SGLT2 inhibitors [26]. Avoidance of diabetic ketoacidosis associated with SGLT2 inhibitors is of particular medical importance during the COVID-19 pandemic [27].…”

Section: Sulfonylureamentioning

confidence: 99%

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The Optimal Medical Therapy for Glycemic Control in COVID-19

Yanai

2021

J Endocrinol Metab

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Diabetes is highly linked to the severity of coronavirus disease 2019 (COVID-19). My recent meta-analysis also suggested a higher prevalence of diabetes in severe COVID-19 as compared with non-severe COVID-19. Recent observational studies have shown that hyperglycemia was significantly associated with severity of COVID-19 in both diabetic and non-diabetic patients. To prevent worse outcome of COVID-19, more tight glucose control is required. I studied the association between hyperglycemia and worse outcome of COVID-19, the putative beneficial and harmful effects, and clinical outcomes of oral hypoglycemic drugs and insulin use in glycemic control among COVID-19 patients, by searching literatures. Although there were some negative studies, the meta-analysis reported that the treatment using metformin was associated with reduction in mortality due to COVID-19. One study showed that treatment with sitagliptin, one of dipeptidyl peptidase-4 (DPP4) inhibitors, during hospitalization was associated with reduction of mortality, with a clinical improvement as compared with patients on the standard care. There were no clinical studies showed effects of glucagon-like peptide-1 receptor agonists, pioglitazone and sulfonylurea on COVID-19 outcomes. Regarding sodium-glucose cotransporter 2 (SGLT2) inhibitors, a case of euglycemic diabetic ketoacidosis (DKA) associated with COVID-19 and a case of DKA that was difficult to distinguish from COVID-19 were reported. COVID-19 patients who need hospital care may deteriorate rapidly, an early and appropriate initiation of insulin therapy in hyperglycemic COVID-19 patients may be to be encouraged.

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Potential Safety Issues with Use of Sodium-Glucose Cotransporter 2 Inhibitors, Particularly in People with Type 2 Diabetes and Chronic Kidney Disease

Cited by 29 publications

References 84 publications

Diabetes-related acute metabolic emergencies in COVID-19 patients: a systematic review and meta-analysis

Diabetes-related acute metabolic emergencies in COVID-19 patients: a systematic review and meta-analysis

Acute Metabolic Emergencies in Diabetes and COVID-19: a systematic review and meta-analysis of case reports

The Optimal Medical Therapy for Glycemic Control in COVID-19

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