On June 15, 2015, a case serious detailing the association between sodium-glucose cotransporter 2 (SGLT2) and a serious side effect of euglycemic diabetic ketoacidosis (DKA) in nine patients, seven of whom had type 1 diabetes and two with type 2 diabetes, was published online in Diabetes Care.
This report provides details about a potentially life-threatening side effect. This side effect is particularly concerning because in this instance, the DKA is euglycemic, meaning those affected have near normal glucose and few symptoms.
SGLT2 inhibitors are a new class of drug that treats type 2 diabetes, but they are also being used off label in patients with type 1 diabetes.
With the two patients with type 2 diabetics, euglycemic DKA developed postoperatively. In most of the seven patients with type 1 diabetes, euglycemic DKA developed in the setting of reduced insulin dose.
The most concerning aspects of this euglycemic DKA is that patients don’t realize it’s happening. Because glucose levels are not significantly increased, they keep the insulin dose the same, sometimes even reducing it, which worsens the acidosis.
DKA is characterized by decreased insulin secretion along with increased secretion of cortisol, glucagon, catecholamines, and growth hormone. Common symptoms include headache, nausea, vomiting, malaise, and abdominal pain.
The case report suggests that the SGLT2 inhibitors increase glucose loss through the urine. They have also been linked to increase glucagon levels, which could cause gluconeogenesis, free-fatty-acid release, and increased serum-ketone levels. The volume depletion that is associated with the inhibitor use could exacerbate the problem by further increasing glucagon, cortisol, and epinephrine.
Senior author of the case series report, Irl Hirsch, explained “the disconnect between hepatic ketogenesis and blood glucose is not something we teach in medical school, and especially not in people with type 2 diabetes. If insulin levels are low and glucagon and other counter regulatory hormones are high, a perfect storm exists as renal glycosuria masking the hepatic ketosis, and euglycemic DKA can occur.
According to Dr. Hirsch, the two biggest concerns include patients having surgery and those with type 1 diabetes receiving SGLT2 inhibitors off label. He suggests stopping the SGLT2 inhibitors 3 days before elective surgery. For urgent or emergent surgeries in patients on SGLT2 inhibitors, he advises anesthesiologists to infuse enough insulin and dextrose to ensure low or immeasurable b-hydroxyburyrate levels.
One of the motivations for using SGLT2 inhibitors off label patients with type 1 diabetes is to reduce the insulin dose and possibly decrease the risk of hypoglycemia; however there may be a price to pay if the insulin dose is decreased.
Another issue that may be driving use of SGLT2 inhibitors off label in patients with type 1 diabetes is preliminary research that suggests this drug class may reduce the risk of diabetic kidney disease. However, it would be premature or ill advised to prescribe these drugs to patients with type 1 diabetes for kidney protection. Doctors should stick to approved drugs like ACE inhibitors and angiotensin-receptor blockers.
While studies with SGLT2 inhibitors in patients with type 1 diabetes are ongoing, SGLT2 inhibitors are not approved for treatment of type 1 diabetes. The advice against off-label use is motivated in great measure by concerns about the risk of ketoacidosis, but also by the absence of any proven benefit for patients with type 1 diabetes.