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Story of Discovery: SGLT2 inhibitors: harnessing the kidneys to help treat diabetes

Existing treatments are helping many people with diabetes live healthier lives, but there is still an urgent demand for new diabetes medications. Many years of research have enhanced understanding of diabetes and its effects on the body, including its role in kidney damage. Likewise, research into how the kidneys function has led to a better understanding of how the kidney manages glucose (sugar) and fluid in the body. Collectively, this research has led to the discovery of a new class of drugs that targets the kidneys to help control blood glucose in people with diabetes.

Glucose is a sugar that serves as the body’s chief energy source. For those with diabetes, their cells have difficulty using glucose properly, leading to hyperglycemia (high blood glucose). Some people with type 2 diabetes can control their condition with physical activity and diet, while others require diabetes medications. As the disease progresses, many require injections of insulin, a hormone which helps the body utilize glucose. Existing diabetes drugs can help people with diabetes maintain their blood glucose levels in a healthy range, reducing their chances of complications later in life. However, these existing treatments sometimes carry side effects (such as hypoglycemia, or low blood glucose) and/or restrictions that can limit their usefulness. Moreover, even with the expanded choice of treatments now available, meeting recommended blood glucose level targets can be challenging.

From many years of dedicated research, a new approach to reducing blood glucose levels has emerged: a new class of diabetes drugs, called SGLT2 inhibitors, that allows the kidneys to dispose of excess blood glucose in the urine. Clinical studies in people with type 2 diabetes have shown that these medications can safely and effectively lower blood glucose levels and improve glycemic control.

The path of discovery from basic research to effective, U.S. Food and Drug Administration (FDA)-approved diabetes drugs was paved with decades of work by many scientists, including NIDDK-supported researchers. The SGLT2 inhibitors are a prime example of how discovery research into how the body works can result in new disease treatments.

The Kidneys and Diabetes

Every day, a healthy adult’s two kidneys, each about the size of a fist, together filter 120 to 150 quarts of blood. Blood carrying wastes enters the kidneys, and the kidneys’ millions of filtering units, called nephrons, filter that blood in a two-step process. First, blood passes through the glomerulus, a structure which keeps blood cells and larger molecules, such as proteins, in the blood, while allowing wastes and excess fluid to pass through. The filtered fluid then passes through the tubule, which reclaims needed minerals and glucose, sending them back to the bloodstream. Wastes and extra fluid continue on to the bladder as urine. In this way, the kidneys maintain blood’s healthy composition, keep levels of electrolytes such as sodium and potassium stable, and (through fluid management) contribute to healthy blood pressure.

The kidneys play an important role in managing glucose levels in the body. Because glucose is small enough that it can pass through the glomerulus, it will end up in the urine if it is not reclaimed or “reabsorbed.” Because the body uses glucose as fuel, losing significant amounts of glucose in the urine would be wasteful for a healthy person. To prevent this loss, healthy kidneys in people without diabetes recapture virtually all the filtered glucose and return it to the bloodstream.

After the blood is filtered through the glomerulus, the filtered fluid (or “filtrate”) moves on to the tubule, where the business of glucose reabsorption takes place. In the tubule wall, one side of each cell faces the filtrate and the other faces the circulation. In this way, tubule cells can act as both sensors monitoring the components of the filtrate, and conduits that can move materials from the filtrate back into the blood. The filtrate flows over the tubule cells, and transport proteins on the tubule cell surface recapture the glucose, much like workers plucking items from a conveyor belt. Glucose is transported into the tubule cells and then pumped out the other side, back into the blood.

However, the kidneys’ glucose reabsorption system is optimized to work best when blood glucose concentrations are in a normal range. In people with poorly controlled diabetes, who have increased blood glucose levels, this system begins to break down. The amount of glucose in the blood exceeds the kidneys’ ability to recapture it, and some glucose continues through the tubules and is lost in the urine, a condition called glucosuria.

The Identification of SGLTs—Novel Proteins That Transport Glucose in the Kidney and Other Tissues

For many years, the exact details of how kidney cells reabsorb glucose were unknown. The first clue as to how the kidneys accomplish this task was discovered in the early 1980s by NIH-supported researchers who noticed differences in glucose transport capacity throughout the rat kidney tubule: the early part of the tubule could absorb more glucose more quickly than the downstream part of the tubule. Understanding of how this worked on the molecular level emerged from studies of how glucose from food is absorbed by the cells lining the intestine. NIDDK-supported researchers studying the cells lining the intestine discovered the gene for the intestinal glucose transport protein. The protein belonged to a new class of glucose transporters called sodium-glucose cotransporters, or SGLTs. The intestinal transport protein was named SGLT1. Scientists then found a second, closely related protein, SGLT2. Both SGLT1 and SGLT2 are responsible for glucose transport in the kidney.

SGLT1 and SGLT2 are proteins on the cell surface of the tubule cells. Both reclaim glucose from the kidney filtrate, moving glucose together with sodium into the tubule cells, where they can then be returned to the blood. SGLT2 is found earlier in the tubule and is a very high-capacity glucose transporter, while SGLT1 is found later in the tubule and is a lower‑capacity transporter. Thus, filtered glucose will first encounter SGLT2 before encountering SGLT1. SGLT2 is responsible for 90 percent of the total glucose absorption as urine is made, while SGLT1 is responsible for the remaining 10 percent. In addition to the kidney and intestine, SGLT1 is also found in many other tissues of the body.

Because of their key role in glucose reabsorption, the SGLTs, particularly SGLT2, were promising drug targets to alter blood glucose levels. Healthy kidneys can reabsorb up to 180 grams (roughly 0.40 pounds) of glucose per day. If a medication could safely block SGLT2 activity and encourage the kidneys to pass that glucose out with the urine rather than reclaim it back into the blood, that might be an elegant solution to persistently high blood glucose levels. In fact, a condition called familial renal glucosuria (FRG) already demonstrated this approach in nature. This condition is caused by changes in the gene coding for SGLT2, resulting in reduction in SGLT2 activity. This reduced activity prevents most glucose in the filtrate from being reclaimed, and people with FRG lose significant amounts of glucose in the urine. Interestingly, for reasons that are not entirely understood, this condition does not seem to cause hypoglycemia or any serious side effects. Therefore, researchers asked, could SGLT2 inhibitors be safe and effective for use in people with diabetes?

Treating Diabetes with the Help of the Kidneys

By the time the SGLT proteins were discovered, an SGLT inhibitor called phlorizin had been studied for over 150 years, although only in recent decades have scientists discovered its mechanism of action. Phlorizin came from the root bark of the apple tree. As early as 1933, it was briefly tested in a very small number of people, and scientists found that it could increase glucose in the urine, lower blood glucose levels, and prevent reabsorption of glucose. However, its effects were not limited to the kidney. Because it inhibited glucose absorption in the intestine, was poorly absorbed when taken orally, and interfered with glucose transport in other parts of the body, it was not suitable for use in people. Nonetheless, studies of phlorizin were important to understanding how sodium-glucose transporters worked, and scientists suspected that it might inhibit the SGLTs. Indeed, in 1995, NIDDK-funded researchers found that phlorizin inhibited both SGLT1 and SGLT2. Because SGLT1 is found in many tissues and plays a key role in absorbing glucose in the intestine, this explains some of phlorizin’s side effects.

As more became known about phlorizin and SGLTs, scientists became interested in using phlorizin as a starting point to develop a treatment for diabetes. Work over the next few decades focused on developing phlorizin derivatives that were more potent, more specific to SGLT2, and that lasted longer in the bloodstream. This research resulted in the discovery and testing of improved SGLT2 inhibitors.

The SGLT2 inhibitors have been extensively studied in industry-supported clinical trials and were found to be safe and effective at improving glucose control in adults with type 2 diabetes. This research has culminated in FDA approval of several drugs for treatment of type 2 diabetes. The first SGLT2 inhibitor to be FDA-approved was canagliflozin (marketed as Invokana®) in March 2013, followed by the approval of dapagliflozin (marketed as Farxiga®) in January 2014 and empagliflozin (marketed as Jardiance®) in August 2014. These medications provide new tools to help control blood glucose levels in adults with type 2 diabetes.

The approved SGLT2 inhibitors are effective in reducing hemoglobin A1c (HbA1c), a measure of blood glucose levels. SGLT2 inhibitors can be used with other oral or injectable diabetes medications, including insulin. This is important because diabetes is a progressive disease which often requires additional medicines over time as insulin production decreases. Another advantage of SGLT2 inhibitors is that they do not cause hypoglycemia (low blood sugar) in the absence of other drugs with this side effect. Because sodium, like glucose, is reabsorbed by the SGLTs, SGLT inhibition also increases loss of sodium in the urine. SGLT2 inhibitors can cause a modest reduction in systolic blood pressure, but because this effect is so small it may not be clinically meaningful, and these drugs are not indicated for the control of blood pressure.

One recent industry-supported clinical trial found that people with type 2 diabetes and cardiovascular disease had a lower rate of death from cardiovascular causes when they added the SGLT2 inhibitor empagliflozin to their standard care. Cardiovascular death was reduced by 38 percent, although there was no significant effect on nonfatal heart attacks or strokes. Of note, the study was limited to participants with established cardiovascular disease and a previous cardiovascular event such as a heart attack or stroke. Also, most participants were older (average age 63) and had long-standing diabetes (57 percent had diabetes for more than 10 years). Studies are ongoing to determine the effects of other SGLT2 inhibitors on cardiovascular disease. More research is also needed to determine the effect of empagliflozin on cardiovascular disease in the broader population with diabetes—those who are younger, have shorter durations of diabetes, and do not have pre-existing cardiovascular disease. Research is also needed to understand whether the reduction in cardiovascular death was due to reduced blood pressure, lower fluid volume, or other mechanisms.

SGLT2 inhibitor use does have some restrictions and side effects, however. The glucose-lowering action of these drugs is dependent on adequately functioning kidneys. People should not take SGLT2 inhibitors if they have severely impaired kidney function. Some of the SGLT2 inhibitors are not effective and may have more side effects in people with moderate kidney dysfunction. SGLT2 inhibitors are also not approved to treat patients with type 1 diabetes. Because SGLT2 inhibitors are diuretics, common side effects include increased thirst and urination. People taking SGLT2 inhibitors may develop low blood pressure when going from lying down or sitting to standing. Older people are particularly susceptible to this drop in blood pressure, called orthostatic hypotension, which can cause dizziness and falls. People taking SGLT2 inhibitors also have an increased risk for genital fungal infections (such as yeast infections in women) and urinary tract infections. At least one SGLT2 inhibitor (canagliflozin) increases both the risk of loss of bone density in the hip and lower spine and the risk of bone fractures. The FDA has warned that fractures can occur as early as 12 weeks after starting this drug and with only minor trauma. Because these drugs impact mineral metabolism and may increase the risk of falls, health care providers should be vigilant regarding bone health. There have also been reports that these medications may cause ketoacidosis, a potentially dangerous metabolic condition, and the FDA has warned patients and caregivers to be alert for the signs and symptoms of this condition. Diabetic ketoacidosis is usually seen only with very high blood glucose levels, but ketoacidosis has been reported to occur with only mild or moderately increased glucose in people taking SGLT2 inhibitors. This side effect may be more common in people taking insulin who reduce their insulin dose, and in those with acute illness, infection, alcohol use, or reduced food and fluid intake.

The Future of SGLT Inhibitors

Building on the successful use of existing SGLT2 inhibitors in people with type 2 diabetes, more research is being done on this class of medications. SGLT2 inhibitors provide a significant reduction in blood glucose levels, but they do not reduce blood glucose to healthy levels in all people who have been given these medications. Thus, some compounds that inhibit both SGLT2 and SGLT1 are under investigation to increase glucosuria even more than can be achieved with SGLT2 inhibitors alone. Additionally, several new SGLT2-specific inhibitors are in pre-clinical development, and some have been approved for type 2 diabetes treatment in other countries. Ongoing studies will provide information about whether SGLT2 inhibitors are safe and effective in people with type 1 diabetes.

After drugs receive FDA approval, new information about risks and benefits often emerges as more people receive the drug. As described above, the SGLT2 inhibitors’ risks and benefits will require further study. More research will determine the magnitude of the risks (such as bone fractures) and benefits (such as reductions in cardiovascular‑related deaths), in which patients they occur, and whether these effects are specific to certain drugs or are common to all SGLT2 inhibitors. The FDA continues to work closely with manufacturers to monitor emerging information about the safety of the three drugs in the SGLT2 inhibitor class that have now been approved and to alert caregivers and patients to the latest information.

Better Treatments Through Research

Diabetes is a costly, chronic disease that can be difficult to manage effectively. People with diabetes can find it difficult to keep their blood glucose levels within a healthy range, and new medications that help them achieve these goals are needed. SGLT2 inhibitors, a new class of medications for the treatment of diabetes, are the result of decades of dedicated research by many scientists across the globe. The development of the SGLT2 inhibitors built upon years of research into how the kidneys function, and their story is a wonderful example of how research in one area can lead to advances in another. The NIDDK and the NIH have supported many stages of this research: basic inquiries into how the kidneys function, discovery of the SGLT proteins, pre-clinical development and testing of SGLT inhibitory compounds, and elucidation of how SGLT2 inhibitors work to help those with diabetes meet their health goals. Until recently, people with type 2 diabetes had only a few classes of drugs to choose from when diet and exercise were not sufficient to control their blood glucose. Basic research expanding our knowledge of how the body works has paid off by laying a firm foundation for the discovery of new medicines that are helping people with diabetes build a healthy future.

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