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History of the SGLT2 Inhibitor Drug Class

Jan 17, 2014

Phuong Nguyen, PharmD Candidate, LECOM College of Pharmacy

Remarkable as it might sound, the SGLT2 inhibitor drug class arguably dates back 178 years. In 1835, French chemists first isolated a substance known as phlorizin from the bark of apple trees, and in 1886, German physician and early diabetes pioneer Joseph von Mering demonstrated that the ingestion of high doses of phlorizin caused people to expel glucose in their urine (glucosuria)….

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Phlorizin was found to improve glycemic control in diabetic animals, but a key factor precluding its use in humans concerned dosage: since the vast majority of phlorizin is converted to another compound in the gut before it can be of any use, massive doses are required to see any glucose-lowering benefit. Unfortunately, phlorizin is also associated with unpleasant gastrointestinal problems. Still, its underlying biological mechanism was sound, and so the history of the entire SGLT2 inhibitor class has really been about the search for compounds capable of replicating phlorizin’s ability to induce glucosuria while sidestepping the massive dosing requirement and unpleasant side effects.

As is not uncommon for new drug classes, the initial development of SGLT2 inhibitors saw multiple early candidates discontinued due to safety issues. Canagliflozin and dapagliflozin are now the first of their class to reach the US market.

How do SGLT2 inhibitors work?

One of the most basic biological factors driving the diabetes and obesity epidemics is that our bodies have evolved to never waste food and energy. For most species, including our hunter-gatherer ancestors who could never be entirely sure where their next meal would come from, such aggressive conservation of energy made perfect sense. But modern humans live in an era of plentiful food, where there’s far greater danger of eating too much rather than too little. SGLT1 and SGLT2 evolved to prevent the loss of seemingly vital sugar by transporting glucose from the kidney back into the bodys circulation, with SGLT2 reabsorbing 90% of glucose in the kidney and SGLT-1 accounting for the final 10% in the kidney.

In people without diabetes, there is a certain threshold at which glucose levels in the bloodstream are so high that the body begins to expel glucose in the urine – this level is determined by the number of SGLT2 proteins (when too much glucose filters through the kidneys, there are not enough available SGLT2s to bring glucose back to the blood, and glucose spills into the urine). Interestingly, in people with diabetes, the threshold is actually higher because diabetes patients have excess SGLT2 proteins, meaning that a greater amount of glucose can be reabsorbed before glucosuria occurs (this of course exacerbates hyperglycemia). SGLT2 inhibitors reduce the threshold to below-normal levels and thus promote glucosuria at lower blood glucose concentrations.

SGLT2 inhibitors work by preventing the reabsorption of glucose in the kidneys, and by reversing the fine-tuned biological process for storing energy. SGLT2 inhibitors cause glucosuria, but this is because the inhibitors decrease the number of available SGLT2, and thereby lower the threshold for glucose excretion. This can cause the expulsion of 100 to 300 calories of excess glucose each day. Indeed, clinical trials for canagliflozin and dapagliflozin, and other SGLT2 candidates have all shown weight loss, which may be beneficial if patients are also trying to lose weight.

As with many therapies however, the benefits of SGLT2 inhibitors are tempered by side effects. Some potential negative side effects include genital and urinary tract infections and decreases in bone density, though none of these were sources of significant concern for the FDA’s advisory committee. The infections most likely occur because fungi and bacterial cultures can grow more quickly in the sweeter, glucose-rich urine. The excretion of glucose through the urinary tract is clearly linked with an increase in infection, but clinical data and key endocrinologists suggest that these infections have thus far generally proven easily treatable with medication.

The true inconvenience of these infections will become clearer once people begin taking these medications, especially once it becomes clear whether or not these infections are a persistent, recurring issue for users over a longer time period than has thus far been explored in clinical trials. And while there isn’t yet the long-term data to assess this either way, it’s worth noting that chronic hyperglycemia often impairs the function of the body’s white blood cells, which are essential to fighting infection.

Long-term SGLT2 inhibition might not only lower glucose levels, but also strengthen the body’s white blood cells, which in turn would be more able to fight off urinary tract infections. Other potential side effects of SGLT2 inhibitors tend to be more specific to particular drugs rather than the class a whole, such as the increase in breast and bladder cancer risk associated with dapagliflozin but not seen in canagliflozin.