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Association Between Use of Sodium Glucose Cotransporter 2 Inhibitors and Serious Adverse Effects

Jan 5, 2019
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy

Study findings warrant cautious consideration and discussions about risk vs benefit when considering therapy.

The number of medications used to treat type 2 diabetes has increased dramatically in recent years. One of the newest classes to be added is the sodium glucose cotransporter 2 (SGLT-2) inhibitors. This class of medication has gained interest due in part to the proven reduction in cardiovascular risk it affords. However, there have been a growing number of reports of severe adverse effects associated with its use. For instance, some studies have documented higher incidence of bone fracture, lower limb amputation, diabetic ketoacidosis, serious urinary tract infections, and acute kidney injury when compared to other antidiabetic medications. Currently, this subject has not been well-researched, and the studies that exist have concerning limitations. Consequently, the aim of this study is to determine if an association exists between use of SGLT-2 inhibitors and some of the more commonly reported severe adverse effects.

A register-based cohort study design was selected in order to determine if an association exists. The primary outcome of interest was the occurrence of: lower limb amputation, diabetic ketoacidosis, bone fracture, acute kidney injury, serious urinary tract infection, pancreatitis, and venous thromboembolism. Study data was procured from the national health registers in Denmark and Sweden. Individuals were considered for inclusion if they were at least 35 years of age and had filled their first prescription of an SGLT-2 inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist during the study period (July 2013 to December 2016). Individuals were excluded if they had no record of using any prescription drugs or no hospital contact within the previous year, if there was any previous exposure to any drug in the study classes, had a history of dialysis or kidney transplantation, drug misuse, end-stage disease, or hospital stays lasting longer than 30 days. For those deemed eligible, propensity scores were calculated for the probability of starting an SGLT-2 inhibitor based on 66 covariates. These scores were then used to match SGLT-2 inhibitor and GLP-1 agonist users in a 1:1 ratio in order to control for potential confounding variables and bias. Incidence of the previously mentioned adverse events were recorded and compared against the usage of the study medications. Subgroup analysis was performed (by sex, age group, country, and history of major cardiovascular event) for all outcomes of interest. Statistical significance was determined via the use of Cox proportional hazards regression model.

From a preliminary search, 64,850 potential participants were identified. However, 17,564 were excluded, which left 21,372 in the SGLT-2 inhibitor group and 27,278 in the GLP-1 receptor agonist group. After propensity score matching was conducted, the final tally was 34,426 participants (17,213 in both the SGLT-2 inhibitor and GLP-1 agonist groups). When the data was analyzed, it was found that use of SGLT-2 inhibitors was associated with higher risk of lower limb amputation (hazard ratio of 2.32) and diabetic ketoacidosis (hazard ratio of 2.14) than use of GLP-1 receptor agonists. No statistically significant difference was observed with any of the other adverse events of interest.

While SGLT-2 inhibitors have their benefits (oral dosage form and cardiovascular risk reduction) it appears that they are not without their risk. When compared against other antidiabetic medications (GLP-1 receptor agonists) SGLT-2 inhibitors are associated with a higher risk of diabetic ketoacidosis and lower limb amputation. These findings are concerning and should warrant a more cautious consideration and discussion of clinical benefits vs possible risks.

Practice Pearls:

  • SGLT-2 inhibitors are a class of oral antidiabetic medications that have been shown to reduce the risk of cardiovascular events in patients who have diabetes.
  • Evidence suggests that use of SGTL-2 inhibitors are associated with increased risk of lower limb amputation and diabetic ketoacidosis when compared to GLP-1 receptor agonists.
  • Evidence suggests that use of SGTL-2 inhibitors are associated with increased risk of lower limb amputation and diabetic ketoacidosis when compared to GLP-1 receptor agonists.
  • These findings warrant more cautious consideration and discussions about risk vs benefit when considering this therapy.
  • These findings warrant more cautious consideration and discussions about risk vs benefit when considering this therapy.

Reference:

Ueda, Peter, et al. “Sodium Glucose Cotransporter 2 Inhibitors and Risk of Serious Adverse Events: Nationwide Register Based Cohort Study.” Bmj, 2018, doi:10.1136/bmj.k4365.

Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy