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DKA Not Associated With SGLT-2 inhibitors

Study reported SGLT-2 Inhibitors monotherapy might not lead to DKA events as opposed to insulin therapy.

A study had suggested that adults with type 2 diabetes who take sodium–glucose cotransporter 2 (SGLT-2) inhibitors are less likely to experience diabetic ketoacidosis (DKA) when compared with those who are on insulin treatment. However, the U.S. Food and Drug Administration (FDA) alerts SGLT-2 inhibitors may lead to DKA. SGLT-2 inhibitors work by helping the kidneys to lower blood glucose levels, with excess blood glucose removed through urine. DKA is a potentially life-threatening acute situation, particularly in the elderly patients that would require hospital admission and intensive treatment. It is a rare condition in type 2 diabetes and its incidence is decreasing.

In a retrospective cohort study, patients diagnosed with type 2 diabetes or patients who had filled antidiabetes prescription medications were identified from the national registers from 1995 to 2014 and their data were included in the study. To establish a baseline occurrence of DKA in type 2 diabetes, the national registries in Denmark was used to estimate incidence rates and the data were linked to information on the prescriptions filled to determine treatment exposure, specifically the use of SGLT2 inhibitor. These subjects were followed up from the time of diagnosis until the end of the study, 31 December 2014, or until death or relocation. DKA incidents were described as a primary or secondary diagnosis and patients were excluded if they were diagnosed with type 1 diabetes or diabetes medications were filled before the age of 30 years. Incidence rates were analyzed with Poisson regression, adjusted for sex, current age, calendar time, and duration of diabetes, with natural splines (5 knots) describing the time effects. Since SGLT-2 inhibitors were introduced in Denmark in December 2012, it was essential to include calendar time to avoid confounding.

Scientists from the Steno Diabetes Center, Copenhagen, Denmark examined patients with type 2 diabetes, all of who were treated with medication, including insulin. They evaluated the rates of DKA to assess any possible association between DKA and SGLT-2 inhibitors. The first event of DKA was reported in 4,045 patients out of 415,670 subjects during the follow-up period in 3 million person-years. This corresponds to a rough incidence rate of 1.34 per 1,000 person-years, and the incidence went on to decrease by 5.6% (95% CI 5.0– 6.2%) per year. Relative to patients without pharmacological treatment, exposure to noninsulin glucose-lowering drugs carried a hazard ratio for DKA of 1.3 (95% CI 1.2–1.5), insulin monotherapy 6.0 (95% CI 5.3–6.8), and the combination 3.0 (95% CI 2.7–3.4). More importantly, for SGLT2 inhibitor monotherapy, no events of DKA were registered (31 person-years), and in any treatment combination using SGLT2 inhibitors, there were only six events of DKA in a total of 3,811 person-years of observation, corresponding to an insignificant hazard ratio of 1.6 (95% CI 0.7– 3.5).

According to the author, this is the first study to estimate nationwide incidence of DKA in type 2 diabetes with 20 years of follow-up and three million person-years of observation combined with prescription data. The risk of DKA was lesser in patients taking SGLT-2 inhibitors as a single treatment or in combination with another drug. The risk of DKA was higher in patients on insulin, followed by those who were on a combination of insulin and oral diabetes medications. Subjects who filled SGLT-2 inhibitors prescriptions had not registered DKA events, whereas six events of DKA were reported in subjects who were treated with SGLT-2 combination treatments. Thus, the patients on insulin monotherapy had the highest occurrence, and there were few events among those prescribed SGLT-2 inhibitors and only among those concomitantly prescribed other glucose-lowering drugs and insulin.

The DKA incidence rates in the group treated with SGLT2 inhibitor were higher when compared with canagliflozin trials, but the DKA rates indicated what were likely to be faced in clinical practice; one out of 1,000 patients with type 2 diabetes were hospitalized with DKA each year due to life-threatening complications that may occur.

In conclusion, the excess risk associated with SGLT-2 inhibitor treatment was, however, not significant and is hardly clinically relevant.

Practice Pearls:

  • Adults with type 2 diabetes who take SGLT-2 inhibitors were less likely to experience DKA than those who are on insulin treatment.
  • Excess risk associated with SGLT-2 inhibitor treatment was not significant and hardly clinically relevant.
  • The study showed that no DKA events were listed for SGLT-2–inhibitor monotherapy (in 31 person-years).

References:

  1. Brooks M. SGLT2 Inhibitor diabetes drugs may cause ketoacidosis:FDA. Medscape. 2015, May 15.
  2. Jensen ML, Persson F, Andersen GS, Ridderstrale M, Nolan JJ, Carstensen B, and Jorgensen ME. Incidence of Ketoacidosis in the Danish Type 2 Diabetes Population Before and After Introduction of Sodium–Glucose Cotransporter 2 Inhibitors—A Nationwide, Retrospective Cohort Study, 1995–2014. Diabetes Care.  2017, Feb 12.
  3. Woodfield J. SGLT2 inhibitors show no significant risk of DKA, study reports. Diabetes News. 2017, Mar 17.

Tenzing Dolkar, BSc., PharmD Candidate 2017, Lake Erie College of Osteopathic Medicine, School of Pharmacy

Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD