SGLT-2 inhibitors, or gliflozins, are a newer and still expensive class of anti-diabetic drug. They work by interfering in the trafficking of glucose, preventing the kidney from reclaiming glucose and introducing it back into the bloodstream. The glucose is instead excreted. Analogously to metformin, another anti-diabetic drug, it is proposed that inhibition of SGLT-2 in some ways mimic the effects of calorie restriction, triggering beneficial cellular housekeeping mechanisms that usually only turn on during periods of fasting or low calorie intake. Size of effect and degree of side-effects are always the questions in these matters, however. One should hold back any nascent enthusiasm until able to find reliable answers in the literature.

Evidently, a faction of the research community thinks that metformin has a large enough effect size to run a human trial versus aging, in order to push the FDA into accepting aging as an indication. Following that same line of thinking, these researchers would probably also consider this strategy for one or more SGLT-2 inhibitors. That said, one of the points of using metformin as the lever, to try to make the FDA reconsider aging as a medical condition that can be treated, is that metformin is very widely used and has a long history of use. Not that it is particularly effective in the grand scheme of things. It is hard for the FDA to object to it on any grounds other than aging not being a formally defined and approved medical condition that people are permitted to treat, which is exactly the battle that researchers wish to take place.

SGLT-2 inhibitors induce a fasting state that triggers metabolic benefits

SGLT-2 inhibitors are a relatively new class of diabetes drugs that have shown many benefits for people with type 2 diabetes who have not responded well to previous interventions. Researchers set out to understand how these benefits happen. They found that SGLT-2 inhibitors induce a fasting state in the body without requiring the patient to sharply cut back on food intake. The researchers studied SGLT-2 inhibitors in a series of animal studies. First, they split the animals into two groups. One ate a normal diet and the other consumed a high fat diet. The high fat diet induced an insulin-resistant, diabetes-like state. They then split the animals into the three different cohorts. One group maintained their original diets. The second group maintained their original diets but also took SGLT-2 inhibitors. The third group matched the weight loss of group two through other methods, to confirm that any beneficial effects seen in group two were a result of SGLT-2 inhibitors and not weight loss in general. The researchers confirmed that the group given 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. 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. SGLT-2 inhibitors also blocked a pathway that can cause insulin resistance. The researchers also identified a new hormone mediator of SGLT-2 inhibitor treatment. Mice treated with SGLT-2 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. One mystery still remains, however: what are the specific mechanisms behind the reduction in cardiovascular disease risk observed in humans? This will be an important question for future studies.

SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms