Large amounts of glucose are filtered by the kidneys daily, all reabsorbed with sodium via Sodium glucose Co-transporter 2 SGLT on the luminal border of the proximal convoluted tubule. No glucose is excreted in the urine of non-diabetics. Suppressing glucose reabsorption through blockade of SGLT increases overall urinary glucose excretion, reducing plasma glucose levels, independent of insulin and with a low hypoglycaemia risk. SGLT2 inhibitor trials showed reductions in HBA1c levels.
Other benefits include weight reduction likely due to loss of calories in the form of glucose in the urine and a diuretic effect with fluid loss resulting in subtle blood pressure lowering. Uric acid levels are also reduced.
Recent experience at our institution confirms the potentially serious risk of diabetic ketoacidosis (DKA) with these agents. In randomised clinical trials of SGLT2 inhibitors DKA incidence was very low but real world data (FDA adverse event reporting) shows a much higher risk.
Investigation of use of SGLT2 inhibitors includes ‘off label’ use in type I diabetics and DKA might occur more commonly in this group. In the literature, some type I patients previously diagnosed as type II were unmasked.
Pathophysiological mechanisms for DKA
Urinary glucose losses cause lower blood glucose levels which in turn decreases insulin secretion. The lower insulin levels, and increased glucagon secretion (by direct effect of SGLT2 inhibitors on pancreatic α-cells) leads to an increased glucagon/insulin ratio, which favours a metabolic shift to fatty acid use and ketogenesis. As well, SGLT2 inhibitors increase renal ketone reabsorption.
Mild ketosis is not necessarily a problem and may even have beneficial effects. However, under stressful situations (e.g. surgery, infections or alcohol use), DKA may be precipitated.
Moreover, this diagnosis may be delayed or missed as urinary glucose losses may preclude markedly elevated serum glucose levels. Serum glucose levels may be normal (euglycaemic DKA). Renal ketone reabsorption means urinary ketone levels may not be elevated, with the ketosis diagnosis missed if only urinary ketones are checked.
Maintain a high index of suspicion if a patient taking SGLT2 inhibitors has clinical features consistent with DKA (nausea, vomiting and abdominal pain), even with a normal blood glucose level. Assess serum acid-base parameters and ketone levels.
Management is similar to DKA management in general, with intravenous fluid and insulin. Cease the SGLT2 inhibitor until the patient’s condition has stabilised. Consider withholding these agents in those acutely unwell or undergoing elective surgery.
Other potential negative effects include increased risk of genital mycosis and UTI’s. Slight increases in serum potassium, magnesium and phosphate levels may occur. Osmotic diuresis induced hypovolaemia can cause a reversible reduction in GFR resulting in acute kidney injury (or potential increased falls risk in the elderly, although this diuretic effect would likely benefits heart failure patients).
Avoid concomitant use of loop diuretics and NSAIDs.
- SGLT2 inhibitors are not side effect free but their positive effect on blood sugar, weight and CVS risk make them useful.
- Use is likely to increase in the future.
- DKA risk is low but important. It must be considered in appropriate clinical settings.
Author competing interests: nil relevant. Questions or references? Please contact the editor.
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