Canagliflozin Added to Insulin: a Japanese Study

In Japanese individuals, 16 weeks of treatment with canagliflozin combined with insulin is well tolerated and effective in improving glycemic control and decreasing body weight, according to results published online in Cardiovascular Diabetology.¹

“The decrease in HbA1c levels [with canagliflozin] was slightly greater than that observed in a previous study in non-Japanese patients, including Caucasians…suggesting that the effects of canagliflozin are independent of the pathologic features among races,” wrote first author Nobuya Inagaki, MD, PhD, of Kyoto University Graduate School of Medicine (Kyoto, Japan), and colleagues.

The usage profile of insulin and pathophysiology of T2DM in Japanese individuals differs from Caucasians. Japanese patients with T2DM tend to have a longer duration of disease and higher baseline HbA1c when they initiate insulin, according to background information in the article.

Past results from the Cardiovascular Assessment Study (CANVAS) found significant decreases in fasting plasma glucose, weight, and blood pressure, and increased hypoglycemia with canagliflozin compared to placebo added to insulin.² However, that analysis did not include Japanese individuals.

Because of their effect on weight loss, SGLT2 inhibitors may be a reasonable addition to insulin therapy, which can cause weight gain and exacerbate insulin resistance, leading to increased insulin requirement.  However, recent reports have raised concerns about diabetic ketoacidosis (DKA) with SGLT2 inhibitor use, especially when combined with insulin.³ In May 2015, the US Food and Drug Administration (FDA) issued a warning about increased risk for DKA with SGLT2 inhibitor use.⁴   

The double-blind placebo-controlled study included patients with inadequately controlled T2DM despite insulin (mean HbA1c 8.85-8.89), diet, and exercise therapies. Researchers randomized participants to placebo (n=70) or canagliflozin 100 mg daily (n=76), combined with existing insulin therapy. Daily insulin dosages ranged from 8 to 60 units. The study followed patients up to week 16.

Key results:

• HbA1c change from baseline:  Significantly decreased with canagliflozin (−0.97) vs placebo (0.13) (P<0.001)

♦ Canagliflozin result was independent of the insulin regimen

• Fasting plasma glucose change from baseline: Significantly decreased with canagliflozin (-34.1 mg/dL) vs placebo (−1.4 mg/dL) (P<0.001)

• Percent body weight change from baseline: Significantly decreased with canagliflozin (-2.13%) vs placebo (0.26 %) (P<0.001)

• HDL change from baseline: Significantly increased with canagliflozin (3.3 mg/dL) vs placebo (3.3 mg/dL) (P=0.007)

• HOMA2- %B (a marker of beta cell function): Significantly increased with canagliflozin (10.15%) vs placebo (0.88%) (P<0.001)

• Overall incidence of adverse events: Similar for both groups (64.8% for placebo, 68% for canagliflozin)

♦ Slight increase in ketone bodies in the canagliflozin group

• Hypoglycemia: Slightly higher with canagliflozin (40.0 %) vs placebo (29.6 %)

♦ No severe hypoglycemia reported

The authors noted that most hypoglycemia events occurred between 6 AM and noon, and suggested that patients on SGLT2 inhibitors plus insulin may need to be more cautious in the morning. 

They also highlighted the slightly increased HOMA2- %B with canagliflozin, which may suggest improved beta cell function perhaps because of decreased glucotoxicity.

Finally, they noted the slight increase in ketone bodies in the canagliflozin group. However, this result was not accompanied by hyperglycemia or clinical symptoms like malaise. No participant was released from the study due to increased ketone bodies. 

“The elevation of ketone bodies was not accompanied by hyperglycemia and is therefore likely attributable to a compensatory increase in fatty acid metabolism in response to loss of calories because of canagliflozin-induced urinary glucose excretion,” the authors wrote.

“Therefore adjusting the insulin dose may be performed with care, particularly in T2DM patients with diminished capacity to secrete insulin,” they added.

They noted that the main limitation was the short duration of treatment, and mentioned that the study has been extended to 52 weeks. Because of the small number of patients in each insulin group, and because the study did not include patients on intermediate- or rapid-acting insulin, the study could not evaluate which type of insulin fits best with canagliflozin.

Take-home Points

• A Japanese study of canagliflozin added to insulin found that the combination is well tolerated and effective in improving glycemic control in Japanese patients.

• Canagliflozin plus insulin was associated with significantly increased HOMA2- %B, suggesting improved beta cell function.

• Ketone bodies were slightly increased with canagliflozin plus insulin; the authors suggest adjusting the insulin dose with care.

• Hypoglycemia was slightly higher with canagluflozin than placebo added to insulin and tended to occur in the morning; more caution may be needed between 6AM and noon.

• A 52-week study is planned.

The study was funded by Mitsubishi Tanabe Pharma Corp

Nobuya Inagaki reports consulting fees, research support, serving in speaker bureaus XXX from one or more of the following: Mitsubishi Tanabe Pharma Corp., Astellas Pharma Inc., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Japan Diabetes Foundation, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Roche Diagnostics K.K., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Shiratori Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. And/or Abbott Japan Co.

All other authors are employees of Mitsubishi Tanabe Pharma Corp.

References:

1. Inagaki N, et al. Efficacy and safety of canagliflozin in combination with insulin: a double-blind, randomized, placebo-controlled study in Japanese patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2016 Jun 18;15:89.

2. Neal B, et al for the CANVAS Trial Collaborative Group. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015 Mar; 38(3):403-411.

3. Taylor SI, et al. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015 Aug; 100(8):2849-2852.

4. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Accessed September 6, 2016 at: http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm