Do SGLT2 inhibitor medications increase ketoacidosis risk?

This review looked at whether SGLT2 inhibitors increase the risk of ketoacidosis in patients with type 2 diabetes (T2D). It found that long-term use of these medications increases the risk of ketoacidosis, particularly for older patients.

Type 2 diabetes (T2D) is a disorder involving high levels of glucose (sugar) in the blood. Over time, high blood glucose can cause damage to blood vessels and to other areas including the kidneys. 

As the kidneys filter the blood, small channels, known as SGLT2, reclaim glucose. SGLT2 inhibitors are a type of diabetes medication which block these channels. This causes glucose to pass out of the body in the urine. This helps control blood glucose levels. Also, SLGT2 inhibitors reduce the risk of diabetic kidney disease. Examples of SGLT2 inhibitors include canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). 

Studies have indicated SGLT2 inhibitors may increase the risk of diabetic ketoacidosis (DKA). DKA is a rare but serious side effect of diabetes which occurs when the body cannot produce enough insulin. This signals to the body that there is not enough glucose. Instead, fat is converted into ketones to use as fuel. High levels of ketones cause the blood to become acidic, which can be life-threatening if it is not treated quickly. The association between the use of SGLT2 inhibitors and DKA is still not clear.

This review included 39 studies with 60,580 patients with T2D. They included three large trials of the effect of SGLT2 inhibitors on heart health, and 5 trials of the effect on kidney function. All of the trials used a control group to compare to the patients taking SGLT2 inhibitors. 27 trials used a placebo (inactive pills) as a control, and 13 trials used another medication such as metformin (Glucophage).

16 trials (41%) reported at least one case of DKA. There were 85 DKA events in total. Significantly more patients taking SGLT2 inhibitors had a DKA event compared to controls (0.18% vs. 0.09%). Patients taking SGLT2 inhibitors had 2.13 times higher odds of a DKA event.

After adjusting for other factors, patients over the age of 60 had 2.4 times higher odds of DKA. The risk of DKA was also higher when SGLT2 inhibitors were used for a longer period of time, particularly in studies over 52 weeks.

This study found that SGLT2 inhibitors increased the risk of DKA for patients with T2D. The risk was particularly increased when SGLT2 inhibitors were used for a longer period of time, and for patients over age 60.

The study was not able to look at how the use of insulin injections influenced the SGLT2 inhibitors’ effect on DKA.