Real-World Evidence on Canagliflozin: A1C Declines, Some Patients Can Replace Other Drugs

The SGLT2 inhibitor canagliflozin, sold as Invokana by Janssen Pharmaceuticals, has produced significant real-world declines in glycated hemoglobin (A1C) for patients with type 2 diabetes (T2D), with some patients able to stop taking other drugs, according to a presentation by Silvio Quaglia, MD, a Millburn, New Jersey-based physician who is board-certified in internal medicine. Quaglia was the luncheon speaker at Patient-Centered Diabetes Care, presented by The American Journal of Managed Care and Joslin Diabetes Center on April 8, 2016.

Canagliflozin was the first of the sodium-glucose co-transporter- 2 (SGLT2) inhibitors to gain FDA approval in 2013,¹ and more than 7 million prescriptions have been sold, according to Quaglia. According to Janssen data, canagliflozin is used both as a monotherapy (19%) and as part of multi-drug regimens, including 26% of patients who have used it alongside insulin.

Canagliflozin and other drugs in the SGLT2 inhibitor class have a unique mechanism of action that allows the therapy to function separately from the rest of a T2D regimen. Normally, the SGLT2 protein operates in the proximal convoluted tubule of the kidneys and controls 90% of glucose reabsorption, after filtration. Canagliflozin and others in the SGLT2 inhibitor class block this protein, allowing excess glucose to be expelled in the urine and for the body to use remaining glucose more efficiently. Patients taking canagliflozin can lose weight and increase insulin sensitivity.

Thus, besides improving glycemic control, canagliflozin can allow patients to eliminate other drugs from their T2D regimen, especially diuretics. Canagliflozin is available in 100-mg and 300-mg doses; the lower dose is recommended for all patients starting therapy.

SGLT2 inhibitors now appear in guidelines from the American Association of Clinical Endocrinologists/American College of Endocrinology, Quaglia said, and this class is now the leading oral therapy option after metformin. SGLT2 inhibitors can be used as monotherapy, although they are more typically prescribed as an add-on therapy after metformin or perhaps a drug combination. (Glugacon-like peptide-1 [GLP-1] receptor agonists are also highly recommended, but this class is available only by injection.²)

Quaglia reviewed both clinical trials, the results of which show canagliflozin outperforms another popular T2D medication, and real-world evidence, which shows the therapy is helping patients achieve A1C results seen in trials—while allowing some of them to stop taking other drugs.

CANAGLIFLOZIN VS SITAGLIPTIN

Quaglia presented results of a 2013 study by Schernthaler et al in Diabetes Care³ comparing 377 patients taking 300 mg of canagliflozin with 100 mg of sitagliptin. Both groups were taking metformin and sulfonylurea background therapy and had a baseline A1C of 8.1%. The group taking 300 mg of canagliflozin experienced an average 1.03% drop in A1C compared with an average of 0.66% for sitagliptin. Nearly half (47.6%) of the canagliflozin group achieved an A1C goal of 7%, while only 35.3% of those taking sitagliptin achieved this goal.³

Although not prescribed for weight loss, canagliflozin produced more weight loss in the study than sitagliptin. After a year, patients taking canagliflozin had an average weight loss of 2.5%, or 5.1 pounds, while those taking sitagliptin lost 0.3% of their weight, or 0.2 pounds.

REAL-WORLD RESULTS

Real-world patients who took canagliflozin have had results consistent with clinical trials, Quaglia said. In December 2015, a claims analysis of 4017 patients who took canagliflozin appeared in BMC Endocrine Disorders.⁴ As was the case in the study by Schernthaner, those who started with the highest A1C levels showed the most dramatic results.

Among 826 patients with a mean baseline A1C of 8.59%, there was an average drop in A1C of 0.81%. Of these, 715 patients who started the study with an A1C of at least 7.0% (mean 8.92%) fell 0.97%. Of these, 501 patients started with a mean A1C of at least 8.0% (average 9.54%) and had a drop of 1.3%. And in the group of 270 patients who started with an A1C of at least 9.0% (average 10.51%), the mean drop in A1C was 1.81%.⁴

This same study also examined whether patients who started canagliflozin were able to discontinue other diabetes medications.³ The results were:

• Of the 2091 patients taking metformin, 235 stopped taking it, for an 11.0% reduction.

• Of the 1113 patients taking sulfonylureas, 140 stopped therapy, for a 12.6% reduction.

• Of the 934 patients taking a dipeptidyl peptidase-4 inhibitor, 139 stopped therapy, for a 14.9% reduction.

• Of the 786 patients using basal insulin, 121 stopped, for a 15.4% reduction. • Of the 654 patients using GLP-1 receptor agonists, 107 stopped, for a 16.4% reduction.

• Of the 372 patients taking thiazolidinediones (TZDs), 41 stopped taking them, for an 11% reduction.

• Of the 344 patients using bolus insulin, 73 stopped using it, for a 21.2% reduction.

• Of 96 patients using pre-mixed insulin, 13 stopped, for a 13.5% reduction.

The potential for canagliflozin to allow some patients to stop taking another therapy is notable in light of the position statement from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD). Quaglia presented the ADA/EASD matrix for adding second- or third-line therapy, which notes that the SGLT2 inhibitor class presents a low risk of hypoglycemia relative to basal insulin, with opportunity for weight loss and relatively few side effects (dehydration and genitourinary infections). Older classes of therapy, such as TZDs and sulfonylureas, are associated with weight gain and more serious side effects.⁵ 1. FDA approves Invokana to treat type 2 diabetes [press release]. Silver Spring, MD: FDA; March 29, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm345848.htm. Accessed June 2, 2016.

2. Garber AJ, Abrahamson MJ, Bazilay JI, et al. Consensus statement by AACE/ACE on the comprehensive type 2 diabetes management algorithm—2016 Executive Summary. Endocr Pract. 2016;22(1):84-113. doi:10.4158/EP151126.CS.

3. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea [published correction in Diabetes Care. 2013;36(12):4172]. Diabetes Care. 2013;36(9):2508-2515. doi:10.2337/dc12-2491.

4. Buysman EK, Chow W, Henk HJ, Rupnow MTF. Characteristics and outcomes of patients with type 2 diabetes mellitus treated with canagliflozin: a real-world analysis. BMC Endocr Disord. 2015;15(67):1-10. doi:10.1186/s12902-015-0064-8.

5. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi:10.2337/dc14-2441.

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