CANVAS Program shows reduced heart events but increased risk of side effects.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drugs that lower blood glucose by increasing the excretion of glucose via urine. It’s been proven that SGLT2 inhibitors (empagliflozin and canagliflozin) are associated with reducing the risk of major adverse cardiovascular events in patients with type 2 diabetes. Therefore, SGLT2 inhibitors are considered a second-line therapy option for the treatment of diabetes when metformin alone fails to lower hyperglycemia to goal. While SGLT2 inhibitors are a valuable new therapy option, they appeared to have some concerning adverse effects, such as increased risk of amputation and bone fracture.
A previous study, called CANVAS Program, was conducted to assess and report the effects of canagliflozin (Invokana) on cardiovascular, renal, and safety outcomes. Results of CANVAS Program indicated that participants in the canagliflozin group had a significantly higher rate of side effects, including amputation of a lower limb (HR 1.97, 95% CI 1.41-2.75) and bone fracture (HR 1.26, 95% CI1.04-1.52) in comparison to the placebo group.
A recently published study focused on measuring the safety risks, specifically the risks of amputation and bone fracture linked to SGLT2 inhibitors. This study included all the randomized clinical trials (EMPA-REG OUTCOME and CANVAS Program) with cardiovascular events as their primary endpoint, comparing SGLT2 inhibitors with placebo in patients with type 2 diabetes. They re-evaluated EMPA-REG OUTCOME and CANVAS Program trials by estimating restricted mean survival times (RMST) based on the reconstructed individual patient data for each time-to-event outcome from publicly available information.
The result of this study showed that differences of RMSTs for lower-extremity amputations were -20days and for minor fracture were -15 days. Also, in regard to major adverse cardiac events, both empagliflozin and canagliflozin appeared to have statistically significant effects on reducing the risk compared with placebo. This study concluded that based on the difference in RMST, canagliflozin has shown to elevate the risks of amputation and bone fracture compared to placebo.
To further investigate previously reposted side effects associated with SGLT2 inhibitors, especially canagliflozin, a new study evaluated the risk for nonvertebral fracture in patients who newly initiated treatment with canagliflozin in comparison to glucagon-like peptide-1 (GLP-1) agonist.
This study was designed as a population-based, new-user cohort study. The data used in this study was on over 70 million patients, pooled from two U.S commercial health care databases, between March 2013 to October 2015. They included patients with type 2 diabetes who began treatment with canagliflozin and patients with type 2 diabetes who were started on a GLP-1 agonist. There were 79,964 individuals in the canagliflozin group who were propensity score–matched in a 1:1 ratio to 79,964 individuals in the GLP-1 agonist group. The baseline characteristics of the patients in this study are: average age of 55, average HbA1C of 8.7%, 48% of patients were females, and, 27% of patients were on insulin therapy.
The primary outcomes in the study were considered as a composite endpoint of fracture, demanding medical attention in areas of forearm, humerus, pelvis, or hip. Secondary outcomes comprised any fracture in other areas than ones included in the primary outcome. The overall hazard ratio (HR) used in this study was provided from a fixed-effects meta-analysis that combined results from the two databases.
The results of data analysis for this cohort study showed that the rate of the primary outcome among canagliflozin (2.2 events per 1000 person-years) was similar to GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75-1.26). Moreover, risk of fracture in pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle was similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) with overall HR of 0.92 (CI, 0.83-1.02).
In conclusion, according to the data analysis of this study, canagliflozin is not shown to increase risk for fracture in middle-age patients with type 2 diabetes and slightly lower fracture risk when compared with GLP-1 agonists.
- Canagliflozin is associated with a significant reduction in CV events for patients with type 2 diabetes.
- Risk of bone fractures was similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) with an overall HR of 0.92.
- Canagliflozin is not associated with increased risk for fracture compared with GLP-1 agonists.
Neal B, Perkovi V, Mahaffey KW, et al. CANVAS Program Collaborative Group Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57. 10.1056/NEJMoa1611925
Kaneko, M. & Narukawa, M. Clin Drug Investig (2019) 39: 179. https://doi.org/10.1007/s40261-018-0731-4
Fralick M, Kim SC, Schneeweiss S, Kim D, Redelmeier DA, Patorno E. Fracture Risk After Initiation of Use of Canagliflozin: A Cohort Study. Ann Intern Med. ;170:155–163. doi: 10.7326/M18-0567
Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy