COVID-19 and SGLT2 inhibitors: what’s the risk and how to manage it?

A primary care review of how to manage patients on SGLT2 inhibitors in the coronavirus pandemic

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Introduction and background

Cotransporter-2 Inhibitors (SGLT-2i) are used in the treatment of diabetes and work by acting on the convoluted tubules of the kidney to prevent reabsorption of glucose. This results in higher levels of glucose being excreted in the urine and hence an improvement in diabetic control.

Clinically available SGLT2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin can be used as monotherapy as well as combination therapy in the treatment of diabetes.

The class of medications have been shown to result in positive effects on other areas such as the cardiovascular system, with patients showing weight loss, decreasing blood pressure, preserving renal function, reduction in triglycerides, natriuresis and improved endothelial dysfunction.1 Trial evidence has confirmed this. The EMPA-REG OUTCOME trial with empagliflozin reported that patients with type 2 diabetes and high CV risk who received empagliflozin as add-on therapy to standard-of-care drugs as compared to placebo showed a lower rate of occurrence of primary CV outcomes and overall mortality.2

The Canagliflozin Cardiovascular Assessment (CANVAS) Study looked at patients who had a prior history of cardiovascular disease (CV) or at least 2 risk factors for CV disease by studying canagliflozin in more than 10,000 patients with type 2 diabetes. Study results showed that canagliflozin reduced the CV and nonfatal myocardial infarction (26.9 vs. 31.5%) and also demonstrated potential renal protective effects. However, there was an increase in risk of amputation.3

Side effects

Due to the increase in glucose excretion in the urine, side effects such as an increased risk of genital mycotic infections has been seen. Some patients have also had episodes of diabetic ketoacidosis (DKA) due to the reduced availability of carbohydrates thought to be as a result of the glycosuria, a shift in the utilisation of substrate to fat oxidation from glucose and promotion of hyperglucagonaemia. This has the effect of stimulating ketogenesis. Some patients also have symptoms of postural hypotension due to the volume depletion.1 This group of medication should be used with caution in patients who are high risk such as those taking diuretic medication.4

Use of SGLT2 inhibitors in the coronavirus pandemic

There has been increasing evidence that patients who are taking this class of medications and are infected with COVID-19 are at increased risk of DKA, a side effect that has been seen with this class before (as above). Even patients who are euglycaemic have a significant risk of developing DKA or Hyperosmolar hyperglycaemic state (HHS).5

SGLT2 inhibitor treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses and ketone levels measured, preferably in blood rather than urine. Treatment may be restarted when the ketone values are normal and the patient's condition has stabilised.5

Regarding primary care management, advice is that patients should continue to take the SGLT2 medication during the pandemic but they should be reminded about what to do should they become unwell. It is important to provide support for patients regarding “sick day” rules. The Association of British Clinical Diabetologists has provided information and guidance on SGLT2 inhibitors in patients with type 2 diabetes.6

General advice is that SGLT2 inhibitors should be stopped when a patient becomes unwell especially when unable to eat or drink as this can reduce the risk of further deterioration or development of DKA. It is not necessary for them all to be given the ability to monitor their capillary blood glucose unless they are prescribed an additional medication which requires this already. It is important to note that glucose levels can be normal because of the way SGLT2 inhibitors work. Ketone levels can be high even with a normal glucose.6

There are small numbers of patients with type 1 diabetes who are taking SGLT2 inhibitors (only dapagliflozin is licensed) but they are usually managed in a secondary care setting. This group of patients are at high risk and are susceptible to DKA. Again, DKA may occur when the patient is euglycaemic. Therefore, this group of patients will have been contacted to ask them to stop the medication.

Patients should already have access to a testing meter that enables them to monitor their blood ketone levels. Stopping medication can cause a rise in the patient’s glucose levels so patients should be advised to closely monitor their blood glucose and adjust their insulin doses accordingly. Their SGLT2 inhibitor is likely to be restarted by their diabetologist once the pandemic is over and it is deemed safe to do so.

References

  1. Pradhan A, Vohra S, Vishwakarma P, et al. Review on sodium-glucose cotransporter 2 inhibitor (SGLT2i) in diabetes mellitus and heart failure. J Family Med Prim Care. 2019 Jun;8(6):1855-1862.
  2. Saiz LC. The EMPA-REG OUTCOME trial (empagliflozin). A critical appraisal. The power of truth, the truth of power. DTB Navarre. 2016, 24. 1-13.
  3. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657.
  4. Inagaki N, Kondo K, Yoshinari T, et al. Pharmacokinetic and pharmacodynamic profiles of canagliflozin in Japanese patients with type 2 diabetes mellitus and moderate renal impairment. Clin Drug Investig. 2014 Oct;34(10):731-42.
  5. SGLT2 inhibitors: monitor ketones in blood during treatment interruption for surgical procedures or acute serious medical illness. Medicines and Healthcare products Regulatory Agency, Drug safety update. March 2020.
  6. SGLT-2 inhibitors in people with type 2 diabetes: An educational resource for health professionals. Association of British Clinical Diabetologists. [Accessed May 2020]

Further reading

Patient resources

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