Can tofoglifozin overcome patient adverse events to join the SGLT2 inhibitor market?
SGLT2 inhibitors, the “new kid” on the scene of oral hypoglycemic medications, are rapidly growing as a class of medications with a recent explosion of research.
A recent study, published in July 2015, introduced another novel SGLT2 inhibitor (tofoglifozin) to the scene, demonstrating efficacy, safety, and tolerability of this new agent, resulting in improved glycemic control and lower body weight. In this 12-week multi-center randomized, dose-finding trial, subjects with poor glycemic control from diet/exercise or diet/exercise plus a stable dose of metformin were randomized to placebo vs. 5 escalating doses of tofogliflozin (2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg) once daily.
The drug, like others in its class, was efficacious and reduced HbA1c in a dose-dependent manner at all doses except the 2.5 mg dose; body weight and fasting blood glucose were also reduced in a dose-dependent manner, similar to its predecessors. There appeared to be no interaction between tofoglifozin and metformin with respect to safety or efficacy. Although the drug was relatively well tolerated overall, with two or less patients withdrawing due to adverse effects (AE), the overall rate of AE in each arm was quite high: 35.9%-46.3% with SGLT2 inhibition; 37.9% with placebo.
Therefore, although technically a “positive” study, we must take this with a grain of salt (or sugar!). The high rate of adverse events is rather alarming. One could reason that was a high signal in the placebo arm as well, so this high AE rate could simply be a function of the patients selected for this trial. Although this is partially true, AE rate with SGLT2 inhibitors was still higher than placebo in this study. Similarly, other studies with high AE rates have demonstrated that the side-effect profile of SGLT2 inhibitors (especially the urogenital mycotic effects and increased risk of volume depletion and orthostatic hypotension) may continue to pose a significant obstacle to the widespread integration of these drugs into the anti-diabetic armamentarium. The role of these drugs, therefore, will most likely be as an adjunctive agent (to metformin) in highly selected populations (i.e., those with edema and normal renal function). However, larger outcome-trials (such as the DECLARE-TIMI trial, which will randomize approximately 17,150 patients with type 2 diabetes mellitus and either known cardiovascular disease (secondary prevention cohort) or at least two risk factors for cardiovascular disease (primary prevention cohort) with follow up for estimated 4.5 years will provide definitive results on their safety and efficacy.
Reference: Ikeda S, et al. A novel and selective SGLT2 inhibitor, tofogliflozin, improves glycemic control and lowers body weight in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2015 Jul 14. [Epub ahead of print]