CME INDIA Presentation by Dr N K Singh, Admin.

We are seeing too many uncontrolled hyperglycaemias in COVID! How it happens? Any reference to mechanism of hyperglycaemia in COVID apart from stress and steroids! Also, they drop sugars very rampantly post discharge…. Dr Manohar K N, Bengaluru ponders on such findings.

CME INDIA Discussion:

Dr Anu Jain from Ambala Cant., tells the same scenario, about a non-diabetic, thin built, post COVID patient with no family history of diabetes. Now his blood sugar levels shot up to 350 – 400mg/dl when he was hospitalized and Medrol 40mg i/v was given. Post discharge his insulin requirement reduced dramatically within 2 days & controlled on OHA. & now with tapering steroids, Metformin 500mg bd is required.

Dr Kapil Sud, Internist, Aligarh says, Corona virus has been shown to affect virtually every part of the body, then why not pancreas. Maybe we should include pancreatic markers in our workup and we might be seeing lots of pancreatic diseases later on.

Dr Prasun Dev, DM, Endo., KIMS, Hyderabad says, any illness, stress or hospitalization causes sugars to go up. Even normally, we routinely reduce insulin dosage at the time of discharge. This would also be true for COVID admissions. There are reports of type 1 diabetes like insulitis with COVID. This has been reported with other viruses too, like EBV and Coxsackie B. This is unlikely to be the cause for regular type 2 patients having high sugars. Steroids remain the most likely cause for that.

Dr A K Singh, DM, Endo., Kolkata has reviewed this bidirectional insult. https://www.researchgate.net/publication/340547240

1. High prevalence of diabetes is seen in patients with SARS-CoV-2 (COVID-19) and the presence of diabetes is a determinant of severity and mortality.
2. Diabetes might facilitate infection by COVID-19 due to increased viral entry into cell and impaired immune response.
3. Blood glucose control is important for all patients who have diabetes and COVID-19 infection.

Dr N K Singh: I would like to review 2 cases:

Case 1: 54 yr female with history of 12 year diabetes, on Sitagliptin 100mg, metformin 1gm, Dapagliflozin 10 mg od and Insulin glargine 16 U od, came to me with sore throat, diarrhea, fever and progressive dyspnea. BMI-35, rtPCR was positive. Spo2 79%. Renal, hepatic functions-normal. Glucose 161 mg/dL, bicarbonate 19 mmol/L, lactic acid 1.3 mmol/L, pH 7.51, Ferritin 450 ug/L, ESR 83 mm/h, CRP 110, D Dimer, IL-6 also raised. Her most recent HbA1c of 7.5%. She deteriorated in the next 24 hours she developed a metabolic acidosis with elevated anion gap, glucose 207 mg/dL, bicarbonate 14 mmol/L, venous blood pH 7.24 and lactic acid 1.6 mmol/L. The β-hydroxybutyrate was elevated at 7.2 mmol/L. She was started on IV insulin with dextrose support for treatment of DKA. She was treated as per DKA protocol until resolution of acidosis (pH normalized, bicarbonate stabilized and anion gap closed).

Diagnosis – euDKA, dextrose support was required at the start of insulin. Over the subsequent 6 days she clinically improved and transitioned to a weight-based insulin regimen. Later, discharged home with recommendation to hold Dapagliflozin.

Case 2: 34 Year male, no past history of diabetes, both parents’ diabetic, with 2-days fever, rtPCR positive, Spo2 80%, HRCT CORAD 5, at admission random sugar 609 mg/dL, Bicarbonate 14 mmol/L, eGFR 32mL/min, elevated anion gap. Urine 3+ ketones beta-hydroxybutyrate was >9.0 mmol/L., Venous pH was 7.2, serum osmolality 311 mOsm/kg, lactic acid 2.3 mmol/L, HbA1c 11%. Diagnosis: New onset diabetes with DKA and acute kidney injury.

Several specific factors responsible for increased risk and severity

• Impaired neutrophil chemotaxis and phagocytosis.
• Increased ACE-2 Expression: ACE-2 receptors are expressed in pancreatic islets and infection with SARS CoV has been seen to cause hyperglycaemia in people without pre-existing diabetes.
• Increased Furin: Diabetes is associated with an increase in furin, which is a type‐1 membrane‐bound protease, belonging to the proprotein convertase subtilisin/kexin family (PCSK). It is involved in the entry of coronaviruses into the cell and increased Furin has been reported in diabetes, which might facilitate viral replication
• Impaired T-Cell function: Alterations in CD4 lymphocytes have been reported in animal models with MERS. Lymphocytopenia has been observed in patients with COVID-19 and correlated with prognosis
• Increased Interleukin-6 (IL-6): Several cytokines are increased in COVID-19 infection. Amongst these, IL-6 is increased in diabetes and may play a more deleterious role in COVID-19 infection

Selection of OHA /GLP-1Ra and Insulin in COVID 19: Status Update

Metformin

• Antiproliferative and immunomodulatory effects by virtue of inhibition of AMP activated protein kinase and has shown protective role in pneumonia in mouse models.
• No anticipated harm with metformin and perhaps a possible benefit, although that needs to be confirmed in further studies
• Not to be used if fear of lactic acidosis feared in serious cases.

 Pioglitazone

• It has more potential for benefit than harm, and can be continued in people with T2DM and mild/moderate COVID-19, unless there are specific contraindications for its use. In the current context of COVID-19 and its relation to anti-diabetic drugs is not yet fully clear. Drug interaction with Favipiravir has been found.

DPP4 Inhibitors

• The relationship of coronavirus to this cellular type-II transmembrane protein DPP4 (CD26) has generated a great interest recently.
• DPP4 serves as the receptor for MERS-CoV, in the same way as ACE-2 is the receptor for SARS CoV and SARS CoV2.
• Though ACE-2 is recognized as the main receptor for SARS CoV-2, a recent modeling study did not rule out its interaction with CD26 or DPP4.
• Moreover, a possible interaction of DPP4 and renin-angiotensin system (RAS) pathways seems to be plausible, although not completely studied.
• Although there was an initial report of increase in nasopharyngitis with the DPP-4Is during the phase 3 clinical development program, however, the later larger trials with their meta-analysis and CVOTs with these class did not show any such signals.
• UK-based Clinical Practice Research Datalink (CPRD) that compared the respiratory tract infection with DPP-4Is to SUs, metformin, TZD and insulin, found no significant increase in risk.
• Few studies conducted in immunocompromised patients with human immunodeficiency virus (HIV), showing no increase in infection with the DPP-4Is.
• In a very recent multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. (Diabetes Care. Emerging Therapies: Drugs and Regimens.https://doi.org/10.2337/dc20-1521).

Why SGLT2 inhibitors to be avoided?

• COVID-19 may increase insulin demand and induce fever, nausea and anorexia with consequent hyperketonaemia, which accentuates the gastrointestinal symptoms of infection in a vicious cycle.
• Metabolic decompensation toward DKA, either hyperglycaemic or “euglycemic,” in susceptible diabetic patients on SGLT2 inhibitors can be further exacerbated by volume depletion from persistent glycosuria.
• As it is not always possible to predict the course of COVID-19 and who will develop severe disease, the most practical advice for patients is discontinue the drug at the onset of any symptoms consistent with a viral syndrome.
• Other side of story: There is a growing argument that dapagliflozin in particular has shown to decrease lactic acidosis and thus has the potential to reverse acid-base balance inside the cells during hypoxia, which can prevent cell injury during the cytokine storm of COVID-19 illness, in patients with diabetes. DARE19 trial in 900 sickest patients is ongoing to answer this.

GLP-1 RA

• Liraglutide has shown to increase ACE2 expression in lungs and heart and has improved right ventricular hypertrophy in rats with type 1 diabetes.
• Experimental study has also suggested an anti-inflammatory effects and therapeutic benefit in acute lung injury with liraglutide.
• Increase in ACE2 expression raise a theoretical concern in patients with COVID-19.
• GLP-1RAs have been associated with increased gastrointestinal adverse events, it is suggested avoiding this class of drugs during the sick days.
• Several GLP-1RAs have shown a significant cardiovascular benefit in CVOTs, stopping these drugs may be disadvantageous.

Insulin

• Insulin is always a preferred modality in any emergent situation irrespective of the degree of renal and hepatic dysfunction and thus it can be used at any stage of COVID-19.
• Subcutaneous (SC) insulin in patients with diabetes and mild to moderate COVID-19, in those taking food orally, is not a challenging issue.
• However, most hospitalized COVID-19 patient with diabetes with poor oral intake or on mechanical ventilator will eventually need intravenous insulin infusion with hourly or 2-hourly monitoring and frequent adjustment of infusion rates.
• This would increase the chance of exposure of health care providers (HCP). To minimize frequent exposure, use of SC short acting insulin analogues can be one approach, however, its role in critically ill patients is not fully known.
• Alternatively, to minimize the exposure, even a single per day SC dose of long-acting basal insulin could be an attractive option
• Models of Insulin pump or continuous subcutaneous insulin infusion (CSII), where insulin rates can be remotely adjusted via a Bluetooth can be useful to minimize exposure of HCP.
• Insulin treatment should never be stopped.
• Ideal BG levels: 108-180 mg/dl.
• BG levels monitoring:
  • >180-270 mg/dl: every 2-4hrs.
  • >270 mg/dl: every 2 hrs (also check blood ketones every 4hrs).

New onset diabetes in COVID

• Increasingly, all evidence currently available hints that both new-onset hyperglycaemia without diabetes and new-onset diabetes in COVID-19 is associated with a poorer outcome compared with normoglycemic individuals and people with pre-existing diabetes.
• An international group of leading diabetes researchers participating in the COVIDIAB Project, haS established a global registry of patients with COVID-19-related diabetes.
• Nevertheless, emerging data increasingly suggests that ‘‘new-onset” hyperglycemia is a frequently observed finding especially in admitted patients with COVID-19, who had no history of dysglycemia or diabetes in the past and were currently not on corticosteroids.
• This entity of ‘‘new-onset” hyperglycaemia could be classified as:
  1. ‘‘stress-induced” hyperglycaemia,
  2. ‘‘new-onset diabetes” in previously unrecognized prediabetes,
  3. hyperglycaemia possibly related to SARS-CoV-2 direct effect on pancreas and,
  4. drug-induced hyperglycaemia or ‘‘secondary diabetes” during the course of treatment for COVID-19, especially with frequent use of corticosteroids.
• How you define New onset Hyperglycaemia?
  • ADA defines new-onset hyperglycaemia without diabetes when fasting plasma glucose (FPG) is between 100–125 mg/dL and/or HbA1c is between 5.7 and 6.4%, in absence of dysglycemia in past.
  • New-onset diabetes would be defined in presence of two abnormal samples either FPG is more than 126 mg/dL) or HbA1c more than 6.5% or a random glucose level more than 200 mg/dL) with symptoms of hyperglycaemia, in absence of any history of diabetes in past

Possible pathogenic mechanism of new-onset hyperglycaemia in patients with COVID-19

(Proposed by Ceriello et al. and Apicella et al.)

• It is possible that during COVID-19, due to the huge production of cytokines, insulin resistance may be exacerbated or de novo induced. This phenomenon may also contribute to the appearance of hyperglycaemia.
• Interestingly, cytokines may, in turn, also affect β-cell function, contributing to a further decrease of insulin secretion. SARS-CoV-2 may affect β-cells producing a reduction of insulin secretion.
• SARS-CoV-2 infection is also accompanied by a huge production of cytokines, which can induce insulin resistance. Both, reduced insulin secretion and insulin resistance, may hesitate in hyperglycaemia, which in turn, may further decrease insulin secretion and increase insulin resistance. Hyperglycaemia is also generating non-enzymatic glycosylation.
• Glycosylation of the ACE2 receptor can facilitate the entry of the SARS-CoV-2 in the host cells. On the other hand, glycosylation of antithrombin III may favour thrombus formation.
• Acute hyperglycaemia, through cytokines production or directly may provoke endothelial dysfunction and thrombus formation, which in turn can lead to organ damage and fatal outcome of the disease.

CME INDIA Learning Points:

• Diabetes and associated complications can increase the risk of morbidity and mortality during acute infections due to suppressed innate and humoral immune functions.
• The levels of glycated haemoglobin (HbA1c) >9% have been linked to a 60% increased risk of hospitalization and pneumonia-related severity during bacterial infection. Effect of SARS CoV2 is associated with a twofold increase in severity and mortality with COVID-19 based on current evidence.
• The susceptibility of people with DM to COVID-19 infection does not necessarily appear to be increased as compared to the patients without diabetes.
• Most patients with mild infection and with normal oral intake can continue the usual antihyperglycemic medications.
• It is advisable to discontinue SGLT-2 inhibitors because of the risk of dehydration and euglycemic ketosis.
• Metformin also need to be stopped if there is vomiting or poor oral intake.
• Doses of other antihyperglycemic drugs like sulfonylureas and insulin may have to be altered depending upon the blood glucose levels.
• Patients with new onset hyperglycaemia even without a frank diabetes due to any cause (Stress-induced/ COVID-19-induced/ pre-existing dysglycemia), are associated with a poorer outcome compared to the normoglycemic individuals as well as those with pre-existing diabetes and COVID-19.
• New-onset diabetes has been increasingly being reported as a case series during the pandemic of COVID-19, sometime presenting with acute diabetic ketoacidosis.

Source:

1. Diabetes and Metabolic Syndrome Clinical Research and Reviews. April 2020 DOI: 10.1016/j.dsx.2020.04.004.
2. Hyperglycemia without diabetes and new-onset diabetes are both associated with poorer outcomes in COVID-19 Awadhesh Kumar Singh, Ritu Singh, diabetes research and clinical practice 167 (2020) 108382.
3. Ceriello A, Nigris VD, Prattichizzo F. Why is hyperglycemia worsening COVID-19 and its prognosis? Diabetes Obes Metab. 2020 May 28: 10.1111/dom.14098.
4. Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. COVID-19 in people with diabetes: understanding the reasons for worse outcomes. Lancet Diabetes Endocrinol. https://doi.org/10.1016/S2213-8587(20) 30238-2.
5. Bode B, Garrett V, Messler J, McFarland R, Crowe J, Booth R, et al. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States. J Diabetes Sci Technol 2020;14(4):813–21.

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