To the Editor: We found Dr. Vouyiouklis’s article about the recently approved sodium-glucose cotransport 2 (SGLT) inhibitor canagliflozin very useful. However, we strongly believe there are some issues that should be addressed.
In discussing the canagliflozin trials, Dr. Vouyiouklis did not mention a phase III randomized, double-blind, double-arm study, in which canagliflozin (100 and 300 mg) in addition to metformin was compared with placebo and sitagliptin (100 mg) in patients with type 2 diabetes. 1 This study recruited 1,284 participants in 22 countries. At week 52, hemoglobin A 1c levels had declined by 0.73% in the sitagliptin group, 0.73% in the canagliflozin 100 mg group, and 0.88% in the canagliflozin 300 mg group. Thus, canagliflozin 100 mg demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority. In addition, as previously described by other trials, a significant statistical reduction was observed in weight and blood pressure with modest elevations in LDL cholesterol and the incidence of mycotic urinary infections.
Current guidelines and recommendations give a wide variety of therapeutic options as the second step if lifestyle interventions and metformin fail to achieve glycemic control. 2 The best combination regimen is still debated and, because of their excellent side-effect profile, dipeptidyl peptidase-4 inhibitors (gliptins) are one of the most used therapeutic classes. We believe this study adds important evidence that could help with decision-making in routine clinical practice.
Also, canagliflozin’s favorable effects on weight and blood pressure inevitably lead to the question, Are the weight loss and decreased systolic blood pressure due to osmotic diuresis or to lean or body fat weight loss? The mechanism of action of SGLT2 inhibitors, per se, favors osmotic diuresis, and several trials have demonstrated this same effect, as well as postural dizziness and orthostatic hypotension. 3,4 Until now, the exact cause of this weight loss has not been elucidated, and no trial has demonstrated with precision a reduction in lean or fat body weight as a direct effect of SGLT2 inhibitors. This, in addition to LDL elevation, could have important clinical implications, as diuretic osmosis will subsequently activate the renin-angiotensin-aldosterone system. This might initially blunt this blood pressure reduction and promote parasympathetic inhibition, sympathetic activation, and myocardial and vascular fibrosis that can potentially lead in the long term to adverse cardiovascular outcomes. 5