What is 2 DG?
This is the new drug approved for use in COVID patients, approved for use by the DCGI in May 2021.
How is it believed to work?
2DG is taken up cells similar to glucose (Studies have mentioned uptake both by glucose transporters (GLUTs) and SGLT-2 receptors). Once inside the cell, it is phosphorylated to 2DG -6 phosphate similar to what happens to glucose. However, 2DG-6P is not able to undergo further glycolysis and accumulates within the cell, inhibiting normal metabolic pathways for glucose utilisation. Continued accumulation of 2DG6P within the cell ultimately leads to cell death. (1)
What is it’s use at present?
Cancer cells are metabolically very active and take up more glucose as compared to non-cancerous cells. Therefore, 2DG is currently used in the fluorinated form as 18-FDG for diagnostic purposes in PET CT scans (FDG-PET).
What dose has been used in human trials (predominantly as an anticancer agent)?
One trial done in patients with advanced cancer, (n=12) (3), used doses of 30-60 mg/kg/day for 2 weeks. This works out to 1.8-2 gm /day for a 60 or 70 kg person. Doses of 60mg/kg have been shown to cause QT prolongation, so the study concluded that 45 mg/kg was a safe, well tolerated dose. It should be noted that the study excluded people with diabetes, heart disease and a long list of other medical conditions.
Another phase 1 trial used escalating doses of 2DG, starting at 2 mg/kg and building up to tolerated doses. The study concluded that “The most significant adverse effects noted at 63-88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response.”
What is the half-life?
Reference 3 determined the T1/2 of 2-DG to be between 4-8 hours.
What do the Indian Studies show with regards to use in COVID?
No data available in public domain, not on ICMR or CTRI websites.
What does 2 DG do to blood glucose and insulin?
Though 2-DG induces a state of glucose deprivation inside the cells, the blood glucose rises to > 200-300 mg/dl (3,4) This is believed to occur due to activation of the adrenal glands and inducing norepinephrine mediated response to a perceived hypoglycaemia state. Of note, this is not an insulin mediated response. Insulin levels were shown to be low in monkeys pretreated with 2DG, even in the hyperglycemic state.
How does it work as an anti-viral agent?
“Regarding 2-deoxyglucose’s antiviral activity, it prevents the glycosylation of specific proteins and lipids as well as prevents proper penetration of the virus into the target cells.” (2)
Invitro studies have shown that deprivation of glucose and glutamine from the cellular medium prevented replication of RNA Viruses. Specific use of 2DG has been shown to inhibit the growth of HSV-1 and HCMV viruses (Both DNA viruses) and Rhinovirus (A RNA Virus similar to SARS CoV2 virus). (6)
So what have I learnt?
Promising data available from invitro studies that show 2 DG as a potent antiviral agent.
- Efficacy: No in vivo studies so far in humans regarding anti-viral efficacy (cannot access the Indian data)
- Safety – specially as higher doses have been shown to cause QT prolongation
- Tolerability: few human subjects studied and published show rise in blood glucose but symptoms of hypoglycaemia.
- Potential effect of SGLT-2 inhibitors on efficacy
- What will happen in patients with significant hyperglycemia to begin with, and on steroids?
Urgently need more data and access to studies before practicing physicians can use it with confidence.
- 2-Deoxy-D-glucose and its analogs: From Diagnostic to Therapeutic agents; Pajak B et al, Int J Med Sci, 2020, 21, 234
- TargetingTumor MetabolismWith 2-Deoxyglucose in Patients With Castrate-Resistant Prostate Cancer and Advanced Malignancies. Stein M et al, , doi: 10.1002/pros.21172
- A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Raez LE et al, Cancer Chemother Pharmacol., 2013 Feb;71(2):523-30, doi: 10.1007/s00280-012-2045-1. Epub 2012 Dec 11.
- Effect of 2–Deoxy—D—Glucose on Insulin Response to Glucose in Intact and Adrenalectomized Monkeys. Smith GP et al, Endocrinology, Volume 92, Issue 3, 1 March 1973, Pages 750–754, https://doi.org/10.1210/endo-92-3-750
- Hijacking the Supplies: Metabolism as a Novel Facet of Virus-Host Interaction. Mayer KA et al, Front. Immunol., 03 July 2019 | https://doi.org/10.3389/fimmu.2019.01533