Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis

Abstract

Objective: To evaluate the longer-term safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).

Methods: The safety/tolerability of canagliflozin 100 and 300 mg were assessed using data pooled from seven placebo- and active-controlled studies of 52–104 weeks in duration that enrolled a broad range of patients with T2DM (N = 5598). Canagliflozin 100 and 300 mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non-canagliflozin treatments (i.e. placebo, sitagliptin, glimepiride). Safety was assessed based on adverse event (AE) reports, including the incidence of AEs related to the mechanism of SGLT2 inhibition.

Results: Overall AE incidence was similar with canagliflozin 100 and 300 mg and non-canagliflozin (73.7%, 74.5%, and 73.7%). The incidence of AE-related discontinuations and serious AEs was low and balanced across groups. The incidence of male and female genital mycotic infections, urinary tract infections, and AEs related to osmotic diuresis or volume depletion was higher with canagliflozin versus non-canagliflozin; these AEs generally occurred early with decreased incidence over time and incidence was similar across baseline HbA1c subgroups. The incidence of fractures and diabetic ketoacidosis was low and similar across groups. Canagliflozin was associated with a low incidence of hypoglycemia when used with background AHAs that are not associated with hypoglycemia; the incidence was higher among patients on background AHAs associated with hypoglycemia (i.e. insulin, sulfonylurea, glinide).

Limitations: Limitations of this analysis include its post hoc nature. While this analysis included a broad population of patients, including those with a history or risk of cardiovascular disease or chronic kidney disease, the longer-term safety in these patient populations was not specifically evaluated. Ongoing outcome studies will provide data on the long-term safety of canagliflozin in these populations.

Conclusions: Longer-term exposure to canagliflozin as monotherapy or in combination with other agents was generally well tolerated in patients with T2DM.

Trial registration: ClinicalTrials.gov identifiers: NCT01106625, NCT01081834, NCT01106677, NCT00968812, NCT01106651, NCT01106690, NCT01137812.

Keywords:

• Canagliflozin
• safety
• sodium glucose co-transporter 2
• type 2 diabetes mellitus

Transparency

Declaration of funding

The studies described in this manuscript were sponsored by Janssen Research & Development, LLC, Raritan, NJ, USA. The sponsor had a role in the study design and conduct, and in data collection, analysis, and interpretation. The authors prepared this report with editorial assistance funded by the sponsor. All authors had full access to study data; were responsible for the integrity of the data and the accuracy of the data analysis; and reviewed, edited, and approved the report for publication.

Author contributions: R.Q., M.D., and G.M. contributed to the design and conduct of the study; the acquisition, analysis, and interpretation of data; and drafted, reviewed, and approved the manuscript. D.B., J.X., and M.J.D. contributed to the analysis and interpretation of data and drafted, reviewed, and approved the manuscript.

Declaration of financial/other relationships

R.Q., D.B., J.X., M.D., and G.M. have disclosed that they are full-time employees of Janssen Research & Development, LLC. M.J.D has disclosed that he is a full-time employee of Janssen Scientific Affairs, LLC.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors acknowledge Ujjwala Vijapurkar, PhD, of Janssen Research & Development, LLC for her contribution to the data analyses. The authors additionally acknowledge all patients and investigators that contributed to these analyses and the understanding of the canagliflozin safety and tolerability profile. Medical writing support was provided by Felicia Gray, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.