A review of 39 randomized controlled trials with more than 60,000 patients found that diabetic ketoacidosis (DKA) events were more common among patients taking sodium-glucose co-transporter-2 (SGLT2) inhibitors compared to control medications (0.18% vs. 0.09%). The effect was larger in patients age 60 years or older and those who had been taking the drugs for longer than a year, leading the authors to suggest that SGLT2 inhibitors be used with caution in these situations.
The review was published on May 4 by Diabetes, Obesity and Metabolism. The following commentary by Tomás P. Griffin, MB, BCh, BAO, MSc, Dip Clin Ed, and Sean F. Dinneen, MD, was published in the ACP Journal Club section of the Oct. 20 Annals of Internal Medicine.
The use of SGLT2 inhibitors will probably increase given the growing evidence to support their cardiovascular and renal benefits in patients with and without diabetes, and guidelines advocating SGLT2 inhibitors as a second-line agent in patients with type 2 diabetes plus cardiovascular disease, renal disease, or obesity. As a result, clinicians need to be aware of the risk for DKA.
The systematic review and meta-analysis by Liu and colleagues confirm that, although rare, risk for DKA is increased in patients with type 2 diabetes who use SGLT2 inhibitors compared with patients who do not. The increased rate of DKA seen in clinical trials has also been reported in some real-world, population-based cohort studies, which have shown that SGLT2 inhibitors are associated with an approximately 3-fold increase in risk for DKA.
Liu and colleagues showed that increased rates of DKA were seen specifically in patients aged ≥60 years and as duration of follow-up increased. The decline in β-cell function that occurs with advancing age and prolonged duration of diabetes probably plays an important role. Metabolically stressful activities (e.g., history of alcohol intake, dehydration, decreasing insulin doses, surgery, sepsis, cardiovascular events, and prolonged exercise/fasting) are other potent precipitants for DKA. Further, patients with diabetes due to impaired β-cell function (e.g., pancreatitis or latent autoimmune diabetes) who are mistakenly managed as having type 2 diabetes are at increased risk for DKA.
Although the mechanism of SGLT2 inhibitor–induced euglycemic DKA is not completely understood, several pharmacokinetic properties of SGLT2 inhibitors play roles. SGLT2 inhibitors increase the quantity of urinary glucose excreted, lowering blood glucose levels. Consequently, there is a decline in insulin secretion leading to increased glucagon production, stimulating lipolysis and ketone production. In addition, SGLT2 inhibitors may enhance glucagon production through their action on pancreatic α-cells, further increasing lipolysis and ketosis.
In clinical practice, euglycemic DKA is a diagnostic challenge. Its timely recognition and appropriate management mandates that discerning physicians remain vigilant when patients using SGLT2 inhibitors present with vague symptoms, such as nausea, vomiting, abdominal pain, or fatigue, in the presence of relatively normal blood glucose levels. To prevent this rare (yet potentially fatal) complication of SGLT2 inhibitor therapy, clinicians should consider withholding SGLT2 inhibitors during periods of volume depletion or prolonged fasting, or in preparation for elective surgery.