This article is more than 5 years old. Information may no longer be current.
Canagliflozin: The first SGLT2 inhibitor on the market
Click Here to Manage Email Alerts
The first sodium-glucose cotransporter 2 inhibitor, canagliflozin, recently reached the market.
These drugs reduce the reabsorption of glucose through inhibition of renal sodium-glucose cotransporter (SGLT). SGLT2 is responsible for mediating about 90% of renal glucose reabsorption in the S1 segment of the proximal convoluted tubule. SGLT1 accounts for the other 10%. Thus, inhibition of SGLT2 will inhibit most renal glucose reabsorption, resulting in glucosuria.
The CANTATA-M trial investigated the safety and efficacy of canagliflozin monotherapy in addition to diet and exercise in patients with type 2 diabetes. The primary outcome was the change in HbA1c from baseline to week 26 between canagliflozin and placebo. Researchers analyzed 584 patients. After 26 weeks of treatment, canagliflozin 100 mg and 300 mg reduced the baseline HbA1c by 0.77% and 1.03%, respectively, which led to a mean difference of –0.91% and –1.16%, respectively, compared with placebo (P<.001 for both doses). In the high glycemic cohort, the baseline HbA1c was reduced by 2.13% with canagliflozin 100 mg and 2.56% with canagliflozin 300 mg in the 91 patients included for analysis.
James Taylor
Secondary outcomes also improved with canagliflozin compared with placebo, including a higher proportion of patients reaching an HbA1c <7%, larger reductions in fasting glucose (mean decrease of 27 mg/dL with canagliflozin 100 mg and 34 mg/dL with canagliflozin 300 mg), and a mean difference in body weight of –1.9 kg and –2.9 kg for canagliflozin 100 mg and 300 mg, respectively. Systolic blood pressure and HDL were also improved with canagliflozin, whereas triglycerides and diastolic BP were not statistically different compared with placebo. LDL was marginally increased in those receiving canagliflozin.
A 12-week randomized, double blind, placebo-controlled, parallel-group, dose-ranging study evaluated the safety and efficacy of canagliflozin in patients with type 2 diabetes who were receiving stable doses of metformin. The primary outcome was the change in HbA1c from baseline at 12 weeks. After 12 weeks of treatment, canagliflozin 100 mg and 300 mg reduced the baseline HbA1c by 0.76% and 0.92%, respectively, compared with a 0.2% reduction with placebo (P<.001 for both doses compared with placebo). Sitagliptin 100 mg daily produced a 0.74% reduction in the HbA1c. Canagliflozin 100 mg and 300 mg reduced the baseline body weight by 2.6 and 3.4 kg, respectively, and both doses reduced fasting glucose by 25.2 mg/dL. The weight loss produced by canagliflozin was progressive throughout the study and did not appear to plateau by study end. Treatment with canagliflozin also improved HDL and triglycerides but caused a minor increase in LDL; BP was also modestly improved.
Schernthaner and colleagues studied canagliflozin in a 52-week, randomized, noninferiority, double blind, phase 3 study. The objective of this study was to determine the efficacy in using canagliflozin in patients taking metformin and a sulfonylurea compared with sitagliptin in uncontrolled patients. The primary endpoint, change in HbA1c from baseline, was found to be 1.03% and 0.66% in the canagliflozin 300 mg daily and sitagliptin 100 mg daily groups, respectively, with a difference of 0.37% (95% CI, –0.5 to –0.25). Schernthaner and colleagues noted that this result not only met the criteria for noninferiority but also indicates that canagliflozin 300 mg daily may actually be superior to sitagliptin 100 mg daily in these patients. Along with the reduction in glucose, a significant reduction in body weight (–2.6 kg vs. –0.1 kg; P<.001), systolic BP (–5.1 mm Hg vs. 0.9 mm Hg; P<.001) and diastolic BP (–3 mm Hg vs. –0.3 mm Hg) was seen with canagliflozin vs. sitagliptin. Also, both HDL (7.6% vs. 0.6%) and LDL (11.7% vs. 5.2%) were increased in the canagliflozin group compared with sitagliptin.
Canagliflozin carries a low risk for hypoglycemia but increases the risk for genital mycotic infections in both men and women; other potential adverse events include increased urination, increased blood urea nitrogen and serum creatinine, hyperkalemia, diarrhea and headache. Canagliflozin is unlikely to have drug interactions but requires dose adjustment in patients with a creatinine clearance between 45 mL/min and 60 mL/min; it should not be used in patients with a creatinine clearance <45 mL/min. Cash price is about $9 per day, which is comparable to many other newer antihyperglycemic agents. Insurance coverage will vary. It is being positioned to compete against agents like sitagliptin as a second-line choice. Long-term effects, such as cardiovascular outcomes, are unknown but being studied.
For more information:
- Rosenstock J. Diabetes Care. 2012;35:1232-1238.
- Schernthaner G. Diabetes Care. 2013;36:2508-2515.
- Stenlöf K. Diabetes Obes Metab. 2013;15:372-382.
- James R. Taylor, PharmD, CDE, is a clinical associate professor in the department of pharmacy practice at the University of Florida, Gainesville. He can be reached at University of Florida, College of Pharmacy, P.O. Box 100486, Gainesville, FL 32610-0486; email: jtaylor@cop.ufl.edu. He reports no relevant financial disclosures.