SGLT2 Inhibitors Work by Inducing Fasting State, Joslin Center Scientist Says

Researchers said that they discovered the underlying mechanisms that allow sodium glucose co-transporter-2 (SGLT2) inhibitors to reduce excess glucose, thereby uncovering the processes behind the other metabolic changes that happen in patients with type 2 diabetes (T2D) who use the treatment.

The finding, published Thursday in JCI Insight, illuminates how the weight loss, reduction in fatty liver disease, and a decreased risk for cardiovascular disease happens in patients taking SGLT2 inhibitors. In this animal study, researchers said they found that SGLT2 inhibitors work by inducing a fasting state, even without requiring patients to sharply cut back on food intake.

SGLT2 inhibitors—sold under the names canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), among others—are indicated for people whose T2D has not responded to diet changes, exercise, and metformin.

The SGLT2 inhibitor drug class has a completely different mechanism from other antidiabetic therapies. The drugs target a protein that normally reabsorbs glucose in the kidney, and instead blocks this function and causes excess glucose to be expelled in the urine. Until now, scientists did not fully understand how they worked.

Researchers set out to understand how the metabolic changes happen. "The reduction in glucose has very profound effects on lots of tissues in the body," Mary Elizabeth Patti, MD, FACE, a researcher at the Joslin Diabetes Center, an associate professor at Harvard Medical School, and the lead investigator of the study, said in a statement. "Ultimately, we wanted to know how lowering glucose affected the metabolism of cells."

Since SGLT2 inhibitors lower glucose through the urine, they do not result in increased insulin levels. In groups of mice, the researchers were able to examine the effects of lowered glucose on metabolic processes.

First, they split the mice into 2 groups, with one eating a regular diet and the other eating a diet high in fat. The high-fat diet induced an insulin-resistant, diabetes-like state.

From there, the mice were separated into 3 different groups:

• One group stuck with their original diets.
• The second group maintained their original diets, but also took canagliflozin.
• The third group matched the weight loss of the second group through other methods, to confirm that any beneficial effects seen in the second group were a result of the SGLT-2 inhibitor and not weight loss in general.

The mice treated with the medication saw a large boost to their metabolic processes due to the activation of pathways associated with fasting.

"Lowering glucose by this mechanism shifts metabolism toward beneficial pathways that help to reduce fat accumulation in tissues," Patti said. "It causes the liver to think that it's in a fasting state and therefore a lot of pathways and genes are turned on that are similar to what you would see when someone is fasting."

These include pathways typically activated during situations that cause a lack of available nutrients in the body, such as exercise or calorie intake reduction. SGLT2 inhibitors also blocked a pathway that can cause insulin resistance.

The researchers also identified a new hormone mediator of SGLT2 inhibitor treatment. Mice treated with SGLT2 inhibitor medication had elevated levels of FGF-21, a hormone known to induce beneficial metabolic effects. Using mice lacking FGF-21, they found that FGF-21 was required for the weight loss and reduced body fat. FGF-21 did not play any role in the reduction of fat deposition in the liver.

However, the specific mechanisms behind the reduction in cardiovascular disease risk seen in humans was not discovered in this study and needs further research, the researchers said.

Janssen Pharmaceuticals, which makes canagliflozin, was one of the funders of the study.

Reference

Osataphan S, Macchi C, Singhal G, et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms [published online March 7, 2019]. JCI Insight. doi: 10.1172/jci.insight.123130.