SGLT2 Inhibitors: Two Glucose-Lowering Mechanisms?

Ipragliflozin, an SGLT2 inhibitor that is approved in Japan but not yet in the US or Europe, may have two separate glucose-lowering mechanisms, according to a Japanese study published online in Drugs in R & D.

“It appears that the glycemic efficacy of ipragliflozin is determined by the balance of its ability to modulate insulin resistance and beta-cell function depending on changes in body weight… [I]pragliflozin may have two distinct glucose-lowering mechanisms: reducing insulin resistance via weight loss and activating beta-cell function by reducing lipotoxicity,” wrote first author Eiji Kutoh, MD, PhD of the Biomedical Center (Tokyo, Japan) and colleagues.

In addition to their antihyperglycemic effects, SGLT2 inhibitors have been linked to a number of other effects that may benefit patients with T2DM, including weight loss, improved blood pressure, and renal protection. Early reports have suggested that ipragliflozin may improve free fatty acid levels, which could have an impact on lipotoxicity and beta cell function, according to background information in the article.

The study included 33 patients with newly diagnosed or untreated T2DM who were naïve to ipragliflozin at the start of the study. Participants were started on ipragliflozin monotherapy at 25-50 mg/day for three months. After that, they were divided into two groups: those with a significant decrease in BMI of 0.75 or less (n=17, P<0.00001)) and those who did not lose weight (n=16).

Key results:

• HbA1c: Similar decreases in both groups

♦ Weight loss group: 9.76–8.02%, P<0.00001

♦ Weight neutral group: 10.07–8.36%, P<0.0005

• Free fatty acids: Nonsignificant increase in the weight loss group, significant decrease in the weight neutral group (P<0.05)

• Beta cell function (HOMA-B): Increased in both groups, but was significantly more improved in the weight neutral group (P<0.05)

♦ Weight loss group: +38.91%

♦ Neutral group: +96.83%

• In the weight neutral group, as beta cell function improved, fasting blood glucose significantly decreased (P<0.05) and free fatty acids decreased (P<0.05)

• In the weight loss group, insulin resistance (HOMA-IR) significantly decreased (P< 0.04)

♦ As insulin resistance decreased, the weight loss group experienced greater changes in fasting blood glucose (P<0.02)

SGLT2 inhibitors likely shift metabolism from carbohydrate to lipid utilization, which could explain some of these results, according to the authors. For example, the increase in free fatty acids seen in the weight loss group was accompanied by a nonsignificant decrease in triglycerides. However, the mechanisms by which beta cell function may have improved in the weight neutral group remain unclear.

The authors noted several limitations: the observational nature of the study, small number of participants, relatively short duration, and the inclusion of only five female patients compared to 28 males.

Researchers are conducting an identical study, using canagliflozin, to determine if the results are specific to ipragliflozin or if they apply to the drug class.

Take-home Points

• A small study in Japan suggests that the SGLT2 inhibitor ipragliflozin may have two separate glucose-lowering mechanisms: reducing insulin resistance through weight loss and improving beta-cell function by reducing lipotoxicity.

• Patients who lost weight on three months of ipragliflozin showed significantly improved insulin resistance, and had greater changes in fasting blood glucose as insulin resistance improved.

• Patients who did not lose weight on three months of ipragliflozin showed significantly improved beta cell function; fasting blood glucose and free fatty acids decreased as beta cell function improved.

• Researchers are conducting an identical study with canagliflozin to determine if the results are specific to ipragliflozin or if they apply to the drug class.

The authors report no conflicts of interest.

Reference: Kutoh E, et al. Distinct glucose-lowering mechanisms of ipragliflozin depending on body weight changes. Drugs R D. 2016 Oct 31.