Janssen-Cilag Ltd. is pleased to announce that Invokana (canagliflozin) has received European approval for the treatment of adults with type 2 diabetes mellitus to improve glycaemic control.
Invokana is a member of a new class of drugs known as sodium glucose co-transporter 2 (SGLT2) inhibitors. SGLT2 inhibitors contribute to controlling blood glucose levels via the kidney. As glucose is filtered from the blood into the kidneys, it is reabsorbed back into the bloodstream. Canagliflozin selectively inhibits SGLT2, an important transport carrier in the renal proximal tubule responsible for this reabsorption, and as a result, promotes the loss of glucose via the urine, lowering blood glucose levels in adults with type 2 diabetes. This mechanism of action is independent of b-cell function and insulin.1
Canagliflozin is indicated as a once-daily oral medication to improve glycaemic control in adults with type 2 diabetes mellitus. It is for use as a monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance; or as an add-on therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.1
The marketing authorisation is based on the results of an extensive, phase 3 clinical trial programme which enrolled 10,285 patients with type 2 diabetes in nine double-blind, controlled clinical efficacy and safety studies.1-3 Several of these phase 3 studies have directly compared Invokana to current standard treatments. One such head-to-head comparative study evaluated the efficacy and safety of Invokana as an add-on therapy versus sitagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy.2
Study design
After a 2 week single-blind, placebo run-in period, type 2 diabetes patients who had inadequate glycaemic control on metformin therapy (n=1,284) were randomised to receive canagliflozin 100mg or 300mg, sitagliptin 100mg, or placebo for a 26 week, placebo- and active-controlled, double-blind period followed by a 26 week, active-controlled, double-blind period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Secondary endpoints included changes in HbA1c at week 52, body weight, fasting plasma glucose (FPG) and systolic blood pressure (BP) at weeks 26 and 52. Baseline demographic and disease characteristics were similar across treatments groups.2
Invokana 300mg demonstrated statistical superiority to sitagliptin in reduction of HbA1c
At week 26, canagliflozin 100mg and 300mg significantly reduced HbA1c from baseline compared with placebo (difference in least squares [LS] mean changes of −0.62% and−0.77%, respectively; p <0.001 for both); the change in HbA1c with sitagliptin was −0.66% relative to placebo (Figure 1A). A greater proportion of patients treated with canagliflozin 100mg and 300mg achieved HbA1c <7.0% than with placebo (45.5%, 57.8% and 29.8%, respectively; p =0.000 for both); 54.5% of sitagliptin-treated patients achieved HbA1c <7.0%. Both canagliflozin doses significantly reduced FPG at week 26 vs placebo (p <0.001 for all). FPG was also reduced from baseline with sitagliptin.
Canagliflozin 100mg and 300mg demonstrated non-inferiority, and canagliflozin 300mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (−0.73%, –0.88%,–0.73%, respectively) at week 52; differences (95% CI) vs sitagliptin were 0% (−0.12, 0.12) and −0.15% (−0.27, –0.03) for the 100mg and 300mg doses respectively (Figure 1B). A higher proportion of patients treated with canagliflozin 300mg achieved HbA1c <7.0% compared with those treated with canagliflozin 100mg or sitagliptin (54.7%, 41.4% and 50.6%, respectively). The proportion of patients reaching HbA1c <6.5% was 26.9%, 21.9% and 24.9% for those treated with canagliflozin 300mg, canagliflozin 100mg and sitagliptin, respectively. Over 52 weeks, canagliflozin 100mg and 300mg provided greater reductions in FPG than sitagliptin (difference in LS mean changes of −0.5 and −1.0 mmol/l, respectively; p <0.001 for both).2
Patients experienced secondary benefits of reductions in body weight and blood pressure with Invokana
At week 26, canagliflozin 100mg and 300mg significantly reduced body weight compared with placebo (p <0.001); body weight change was −1.2% with both sitagliptin and placebo. Both canagliflozin doses were associated with significant decreases vs placebo in systolic BP (p <0.001 for both). Reductions from baseline in diastolic BP were also observed with both canagliflozin doses. Sitagliptin was associated with decreases from baseline in systolic and diastolic BP.
At 52 weeks, canagliflozin 100mg and 300mg significantly reduced body weight compared with sitagliptin, with differences in LS mean per cent changes vs sitagliptin of −2.4% (-2.1kg) and −2.9% (-2.5kg), respectively (p <0.001 for both) (Figure 1C). Both canagliflozin doses significantly decreased systolic BP relative to sitagliptin at 52 weeks (difference in LS mean changes of −2.9 and −4.0 mmHg, respectively; p <0.001 for both).2
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Safety and tolerability
Canagliflozin treatment was generally well tolerated, but was associated with a higher proportion of patients reporting genital mycotic infections and osmotic diuresis-related adverse events than with sitagliptin or placebo/sitagliptin. These were generally mild or moderate in severity, occurred at a low incidence and infrequently led to discontinuation. The incidence of documented hypoglycaemia was low but was slightly higher with both canagliflozin doses (6.8%) than with sitagliptin (4.1%) or placebo/sitagliptin (2.7%). The incidence of urinary tract infections was similar with canagliflozin 100mg and 300mg and the control groups (i.e. sitagliptin and placebo/sitagliptin).2 Results from this trial was included in a pooled analysis of placebo-controlled, phase 3 studies to assess the safety and tolerability profile of canagliflozin in a broad range of type 2 diabetes patients on various background anti-hyperglycaemic treatments; the type and incidence of adverse events associated with canagliflozin was similar across all studies. Dose-related increases in the incidence of hypoglycaemia episodes were seen with canagliflozin vs placebo in patients on background sulfonylurea. Hypoglycaemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin vs placebo.4
Invokana 300mg demonstrated statistical superiority to sitagliptin in HbA1c reduction in triple therapy
The results of the current study complement and support findings from a similar head-to-head, 52 week, phase 3 trial comparing canagliflozin 300mg with sitagliptin 100mg in patients with type 2 diabetes inadequately controlled with metformin plus sulfonylurea.3 In that study, canagliflozin 300mg demonstrated non-inferiority and statistical superiority to sitagliptin in HbA1c-lowering effect at 52 weeks (difference in LS mean changes of −0.37%). Greater reductions in body weight (difference of −2.8%), FPG and systolic BP were observed with canagliflozin relative to sitagliptin. Overall adverse events incidence was similar with canagliflozin and sitagliptin but the incidence of genital mycotic infection and osmotic diuresis-related adverse events was higher with canagliflozin. The incidence of hypoglycaemia was similar with canagliflozin and sitagliptin but was higher than that observed in the current study, which is likely related to the additional sulfonylurea treatment.2,3
Conclusion
Canagliflozin is the third SGLT-2 inhibitor for type 2 diabetes available in Ireland. Canagliflozin vs sitagliptin as add-on to metformin improved glycaemic control from baseline and showed statistical superiority to sitagliptin at 52 weeks. It also demonstrated a low but slightly higher risk of hypoglycaemia than with sitagliptin. Treatment with canagliflozin resulted in significant reductions in bodyweight and blood pressure vs sitagliptin, and was well tolerated.2 The efficacy and safety results from this study are consistent with the findings from other trials for canagliflozin.2-4
References:
1. Invokana Summary of Product Characteristics, April 2014. Available from www.medicines.ie
2. Lavalle-González FJ et al. Diabetologia 2013;56:2582–2592.
3. Schernthaner G et al. Diabetes Care 2013;36:2508-2515.
4. Usiskin K et al. Postgraduate Medicine 2014;126(3):16-34.