In this study of subjects with T2DM who had inadequate glycaemic control with diet and exercise, treatment with canagliflozin 100 and 300 mg provided clinically important and statistically significant improvements in glycaemic control compared with placebo over 26 weeks; these improvements were associated with weight loss with both doses of canagliflozin. Both canagliflozin doses were generally well tolerated and were associated with a low incidence of hypoglycaemia. Of note, this study included subjects with normal renal function as well as those with mild or moderate renal impairment (chronic kidney disease, Stages 2 and 3), with an exclusion criterion of eGFR <50 ml/min/1.73 m2.
In the main study, reductions in HbA1c, FPG and PPG were observed with both canagliflozin doses. A large proportion of subjects reached HbA1c <7.0% with canagliflozin, and few subjects required glycaemic rescue therapy. Relative to canagliflozin 100 mg, canagliflozin 300 mg provided greater effects on glycaemic endpoints, body weight and systolic BP; similar increases in HDL-C were observed with both doses. Because canagliflozin 300 mg provides more sustained maximal decrease in RTG
than canagliflozin 100 mg, the incremental efficacy observed was anticipated. Doses of canagliflozin >200 mg have been reported to decrease post-meal glucose excursions, potentially through delayed glucose absorption (related to transient inhibition of the gut SGLT1 transporter due to high gut luminal concentrations of drug prior to drug absorption) [12
], which could also contribute to the incrementally greater efficacy seen with canagliflozin 300 mg. Clinical mechanism of action studies [14
] have confirmed delayed gastrointestinal glucose absorption with canagliflozin 300 mg in healthy volunteers and subjects with T2DM.
Addressing obesity is an important part of T2DM management, helping to lower insulin resistance and contributing to improvements in glycaemic control [1
]. In addition to providing glycaemic improvements, canagliflozin treatment provided body weight reductions in this study. Because many of the traditional therapies for T2DM result in weight gain, the added benefit of weight loss with canagliflozin is clinically useful [17
]. Canagliflozin was also associated with significant decreases in systolic BP (with no compensatory increase in pulse rate) and increases in HDL-C, but showed modest, dose-related increases in LDL-C. Smaller increases than those in LDL-C were observed in non–HDL-C and Apo B; the LDL-C/HDL-C ratio was slightly decreased across groups. The mechanism for the LDL-C increase with canagliflozin is not known, but may be related to the metabolic changes associated with UGE. Improvements in HDL-C and triglycerides are likely related to the improved glycaemic control and weight loss associated with canagliflozin. Taken together, multiple CV risk factors were positively modified in patients treated with canagliflozin. However, the impact of these changes on the overall risk for CV events should be further evaluated in larger CV outcome studies.
Improvements in fasting measures of βCF (HOMA2-%B, proinsulin/insulin ratio and proinsulin/C-peptide ratio) and AUCC
ratio during the FS-MMTT were seen with canagliflozin, consistent with previous reports [11
]. Because SGLT2 transporters are not present on β-cells, a direct mechanism for this improvement is unlikely; the improvements in βCF likely reflect reversal of glucotoxicity [19
], and are possibly related to an ‘unloading’ of the β-cell as glucose is partitioned out of the system through increased UGE. In this study, sustained glucose lowering was observed through 26 weeks; because deterioration of βCF underlies disease progression, the sustained glucose lowering observed may suggest improved durability; however, longer term assessments are needed to clarify this issue.
Canagliflozin was generally well tolerated, with a safety profile consistent with expectations based on earlier reports for SGLT2 inhibitors [8
]. Slightly higher rates of overall AEs were seen with canagliflozin compared with placebo, primarily due to higher incidences of UTIs and genital mycotic infections, but these led to few discontinuations. Given the increase in UGE with canagliflozin, which induces an osmotic diuresis, the increased incidence of the related AEs of polyuria and pollakiuria was as expected. However, these events were generally mild or moderate in intensity and did not lead to discontinuations. Moreover, AEs related to reduced intravascular volume were infrequent and did not lead to discontinuations. Incidences of documented hypoglycaemia with canagliflozin were low and similar to those with placebo, with no report of severe hypoglycaemia in any group; this low incidence of hypoglycaemia was expected, as the reduction in RTG
with canagliflozin has been reported to be in the 4.4 to 5.0 mmol/l range – above the threshold for hypoglycaemia – so that minimal further loss of urinary glucose would occur with canagliflozin as glucose levels are lowered close to the hypoglycaemic threshold [8
In the high glycaemic substudy, both canagliflozin doses substantially improved glycaemic parameters and showed improvements in body weight, BP and HDL-C, similar to results from the main study. Notably, despite the markedly elevated baseline HbA1c (>10.0 and ≤12.0%) in this cohort, single-agent treatment with canagliflozin resulted in 11.6 to 17.4% of subjects reaching HbA1c <7.0%. Because UGE is proportional to the glucose concentration above RTG, subjects with higher baseline glucose levels might be expected to show greater osmotic diuresis and potentially increased safety and tolerability issues with canagliflozin treatment. Notably, the safety and tolerability profile of canagliflozin in the high glycaemic cohort was similar to that seen in the main study population, with minimal occurrence of AEs related to osmotic diuresis (e.g. pollakiuria) or reduced intravascular volume (e.g. postural dizziness).
In conclusion, canagliflozin 100 and 300 mg significantly improved glycaemic control, reduced body weight and were generally well tolerated compared with placebo over 26 weeks in subjects with T2DM inadequately controlled with diet and exercise, suggesting that canagliflozin may be a useful therapeutic option in this setting.