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Efficacy and Safety of an SGLT-2 Inhibitor with Insulin for Type 2s

May 29, 2015

Canagliflozin appears to offer significant benefits when used in conjunction with insulin therapy.…

The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined.


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Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m2, estimated glomerular filtration rate of 75 mL/min/1.73 m2, fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were −0.62% (95% CI −0.69, −0.54; −6.8 mmol/mol [95% CI −7.5, −5.9]; P < 0.001) and −0.73% (95% CI −0.81, −0.65; −8.0 mmol/mol [95% CI −8.9, −7.1]; P < 0.001) at 18 weeks and −0.58% (95% CI −0.68, −0.48; −6.3 mmol/mol [95% CI −7.4, −5.2]) and −0.73% (95% CI −0.83, −0.63; −8.0 mmol/mol [95% CI −9.1, −6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses.

The researchers concluded that canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment. There were clear beneficial effects on HbA1c of adding canagliflozin to background insulin therapy. These benefits were apparent at 18 weeks and were sustained through 52 weeks for both doses of canagliflozin compared with placebo. The reductions in HbA1c were accompanied by favorable effects on body weight and blood pressure, which were also observed for both doses and over 52 weeks. These benefits were accompanied by the adverse effects anticipated for the drug class. Effects on lipid metabolism were inconsistent, but the broad pattern was similar to that reported previously. The net impact of the changes in lipid parameters produced by canagliflozin is uncertain, with the elevation in LDL cholesterol accompanied by a rise in HDL cholesterol that leaves the ratio of LDL cholesterol to HDL cholesterol unchanged. The hazard ratio for cardiovascular events reported during the regulatory review process prior to marketing was not suggestive of harm and ruled out large adverse effects of the compound.

The observed additive effects of canagliflozin on top of insulin are anticipated on the basis of the different mechanism of action of the compound. Because canagliflozin acts independently of insulin, it should be an effective treatment choice at most stages of the disease and also when used in conjunction with most other glucose-lowering therapies. Furthermore, the combination of canagliflozin with insulin may offer advantages compared with the combination of insulin with other oral agents because the use of canagliflozin may mitigate against the risks of hypoglycemia and weight gain that can be exacerbated by some other drug classes. The subset of patients among whom glucose-lowering efficacy might be reduced is those with renal impairment, and this might explain the lesser effect of canagliflozin among older individuals in this study.

Practice Pearls:

  • A key strength of this study is its large size and its robust randomized and controlled design.
  • The completeness of follow-up for the main efficacy and safety outcomes was good and the findings were robust to a series of sensitivity analyses.
  • In conclusion, canagliflozin appears to offer significant benefits when used in conjunction with insulin therapy.

Bruce Neal. 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. Published online before print December 2, 2014, doi: 10.2337/dc14-1237
Diabetes Care March 2015 vol. 38 no. 3 403-411