https://www.ajmc.com/journals/evidence-based-diabetes-management/2014/july-august-2014/benefits-risks-of-sglt2-inhibitors-explored-at-session
Benefits, Risks of SGLT2 Inhibitors Explored at Session

Mary K. Caffrey

If the size of the crowd at the Moscone Center on June 15, 2014, in San Francisco, California, was any sign, interest is high in the new class of drugs to treat type 2 diabetes (T2DM), the sodium-glucose co-transporter 2 inhibitors (SGLT2s). These drugs, the focus of a symposium at the 74th Scientific Sessions of the American Diabetes Association (ADA), have gained notice for their role in eliminating glucose from the body while helping patients lose weight.

The symposium, “The Role of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes,” gave attendees an overview of how these new drugs harness the renal system to improve health measures, and how they can be used both alone and in combination with other drugs.

Edward C. Chao, DO, associate clinical professor of medicine at the University of California San Diego, walked the audience through the drug’s physiological process. Clifford J. Bailey, PhD,
FRCP, professor of clinical sciences and director, Biomedical Sciences Research, University of Birmingham, United Kingdom, reviewed recent studies on the drugs’ benefits; Lawrence A. Leiter, MD, FRCP, FACP, FAHA, professor of medicine and nutritional sciences, University of Toronto, Canada, discussed safety issues; and Zachary T. Bloomgarden MD, MACE, clinical professor of medicine, Mount Sinai School of Medicine, laid out “unanswered questions” surrounding this new class.

While multiple SGLT2 inhibitors are under development, the session focused largely on canagliflozin and dapagliflozin, which have been approved by the FDA; presenters offered some data on empagliflozin, which has been approved in Europe and awaits FDA action.

Understanding the potential of SGLT2 inhibitors in T2DM starts with understanding the role of kidney in glucose metabolism, Chao said. Normally, the kidney reabsorbs glucose and returns it to the body; when glucose exceeds the body’s reabsorption capacity, it passes out through the urine. However, this “job” of the kidney can result in hyperglycemia when too much glucose is reabsorbed, especially when glucose remains at chronically high levels. The role of the kidney in contributing to hyperglycemia was suspected in the time of the ancient Greeks, Chao said, but it took until the 1930s for this mechanism to be confirmed.

Sodium-coupled glucose co-transporters, especially SGLT2, are active in the reabsorption process. Chao said SGLT2 is normally responsible for 90% of the glucose absorption, with SGLT1 handling the remaining 10%. Thus, new drugs in the SGLT2 inhibitor class work to limit this process, allowing glucose to pass out in urine. It’s becoming clear, Chao said, that SGLT2 inhibitors do not have an unlimited capacity to eliminate glucose.

Studies show that once a maximum level of glucose excretion is reached, higher doses of these new drugs do not eliminate more glucose. That’s why there is interest in studying a combination of inhibiting SGLT2 and SGLT1, he said. It’s also clear that because SGLT2 inhibitors have a distinct role, apart from the effects of insulin or another relatively new drug class, the incretin mimetics, that SGLT2 inhibitors can be used in combination with other therapies for additional benefits.

The weight loss benefit of SGLT2 inhibitors is especially profound, said Bailey. If patients who need to lose weight can stick to a diet of 1500 to 2000 calories a day, and up to 300 calories of glucose are passed out through the urine, the effect on weight loss can be rapid, he said. However, there are some indications that the weight loss effect may bottom out, in part because after a while, patients become hungry and eat more.

It’s the primary benefit, reduced levels of glycated hemoglobin (A1C) that interests clinicians the most, Bailey said. SGLT2 inhibitors are especially beneficial in patients who cannot take
metformin, which is often the first drug prescribed for T2DM. However, Bailey said, the SGLT2 inhibitor class should be considered early on, even if metformin is used. “If you give these to newly diagnosed patients, the combination of dapagliflozin and metformin, the results are better,” he said, adding that combinations of dapagliflozin and insulin can also be effective.

Benefits of canagliflozin for reducing both A1C levels and weight are also evident, Bailey said. “It’s more likely that you’re going to see these agents in combination with metformin. We can also
use as a triple therapy,” along with insulin, he said. He repeated a theme heard at several sessions at ADA: acting aggressively early on, instead of waiting until T2DM progresses to add drug combinations, will be the right call for certain patients, especially if they need to lose weight.

Leiter addressed side effects, especially vaginal irritation in women and urinary tract infections (UTIs), which would be the result of higher glucose in the urine. However, Leiter said, thus far studies show that the side effects are not severe, that UTIs occur in the lower and not the upper urinary tract, and that generally, side effects have not been severe enough to cause patients
to stop taking the drug.

“The highest occurrence is in the first 4 months, with less than 1% withdrawal from clinical trials as a result of infections,” Leiter said. What about volume depletion, which can result if patients become dehydrated? Leiter said these symptoms, along with skeletal risks, generally occur only in the oldest patients. As for cardiovascular risks, Leiter said trials going on right now will yield data that will tell clinicians much about longerterm effects.

What are the next questions in SGLT2 research? Bloomgarden said there are many, including why the drug class isn’t more potent. Additional studies will examine relationship between SGLT2 inhibitors and glucagon, as well as the possible need for controlling dietary sodium to thoroughly understand the effects of this new class.
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