About SGLT2 Diabetes Drugs

Without proper medical management, patients with diabetes are at an increased risk of severe complications, some of which may be life-threatening. Doctors often prescribe diabetes medications to patients who cannot control their blood glucose levels through diet and exercise alone. Like all medications, diabetes drugs such as SGLT2 inhibitors carry a risk of complications.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors may be prescribed to patients with type 2 diabetes. These diabetes drugs work by blocking the ability of the kidneys to reabsorb glucose. This can result in the body expelling 100 to 300 calories of excess glucose on a daily basis.

SGLT2 diabetes drugs

Currently, there are about half a dozen SGLT2 inhibitors including:

• Invokana
• Invokamet
• Farxiga
• Xigduo XR
• Jardiance
• Glyxambi

In January 2014, the FDA approved Farxiga (dapagliflozin) to treat type 2 diabetes in adults when used in conjunction with diet and exercise. The FDA advisory panel had voted 13-1 to approve the drug, although the vote that considered whether the drug had an acceptable safety profile was somewhat more divided at 10-4.

Initially, dapagliflozin was denied FDA approval in 2012. At that time, the FDA stated that the drugmakers had not provided enough data about the benefit/risk profile. When Farxiga was approved in 2014, the FDA issued the caveat that manufacturers Bristol-Myers Squibb and AstraZeneca conduct six post-market clinical studies. The studies to be conducted included a cardiovascular outcomes trial and a bladder cancer trial, along with studies on pediatric risks, pregnancy risks, liver abnormalities, and urinary flow.

Not long after the initial denial of Farxiga in 2012, the FDA approved canagliflozin (Inovakana), manufactured by Janssen Pharmaceuticals. Invokana was the first SGLT2 inhibitor in this class to be approved for use in the U.S. Invokana was hailed as being an innovator in the field of diabetes treatment, given that SGLT2 inhibitors do not affect insulin levels, but rather affect the reabsorption of glucose. Upon approval of Invokana, the FDA required Janssen Pharmaceuticals to conduct clinical trials regarding pediatric safety, bone safety, cardiovascular outcomes, and pregnancy safety.

Cardiovascular safety was of particular concern, since Invokana was approved not long after an FDA advisory panel met to evaluate the risk of heart failure in other diabetes drugs such as Actos (pioglitazone) and Avandia (rosiglitazone).

The FDA approved Invokamet (Janssen Pharmaceuticals) in August 2014. Invokamet is a combination of Invokana and metformin hydrochloride, the latter of which is an older generation of diabetes medications. Invokamet is intended to treat type 2 diabetes in adults whose blood glucose is not adequately controlled by metformin or Invokana alone.

In 2014, the FDA also approved Xigduo XR for adults. Like Invokamet, Xigduo is a combination medication. It uses dapagliflozin (Farxiga) combined with metformin hydrochloride.

Glyxambi is the latest combination SGLT2 inhibitor to gain FDA approval. In 2015, the agency approved the use of this combination of empagliflozin and linagliptin, manufactured by Boehringer Ingelheim Pharmaceuticals. It is the first drug to combine an SGLT2 inhibitor with a dipeptidyl peptidase-4 (DPP-4) inhibitor. The DPP-4 inhibitor, linagliptin, works by stimulating the production of hormones that trigger the pancreas into making more insulin. It also acts upon the liver to reduce the production of glucose.

Another drug in the SGLT2 inhibitor category is empagliflozin (Jardiance), which was approved by the FDA in August 2014. The medication is distributed by Boehringer Ingelheim Pharmaceuticals. In its approval notice, the FDA stated that it requires the manufacturer to complete four post-market clinical studies for Jardiance, including trials involving cardiovascular outcomes, pediatric safety, and a nonclinical trial on renal development, bone development, and growth among juvenile patients.

Development of SGLT2 diabetes drugs

Although SGLT2 inhibitors are relative newcomers to the U.S. market, the mechanism of action of the substance that inspired the drugs, phlorizin, was actually first isolated by French chemists in 1835. The compound was extracted from the bark of apple trees. However, it wasn’t until 1886 that Joseph von Mering – a German physician known for his groundbreaking work on diabetes research – conducted studies that demonstrated that phlorizin resulted in glucosuria among human patients. Glucosuria refers to the expulsion of blood sugar in the urine.

Despite this early discovery, researchers were unable to find a way to safely and effectively administer this compound to patients with diabetes. Most phlorizin is converted into another substance in the gastrointestinal tract before it can act effectively on glucose. Subsequently, patients required massive doses of the substance to control blood sugar. This resulted in a high potential for side effects, particularly gastrointestinal complications.

Until relatively recently, drug developers had been unable to find a safer and more effective compound that would duplicate the desired effects of phlorizin.

How SGLT2 diabetes drugs work

In a typical healthy adult, the kidneys are capable of filtering about 180g of glucose each day. Nearly all of that glucose is reabsorbed into the body, with less than one percent being expelled in urine. The reabsorption of glucose requires multiple transport mechanisms to carry the glucose from the kidney tubules into the tubular epithelial cells. SGLTs act as these transporters in the body.

SGLTs are a range of different membrane proteins (including SGLT1, SGLT2, and SGLT3) that escort glucose from the kidney tubules back into the gastrointestinal tract. SGLT2 carries about 90 percent of the glucose from the kidneys, making it an ideal target for diabetes medications. By administering a drug such as Invokana or Farxiga that works by inhibiting the actions of SGLT2, diabetic patients can expel a significantly higher amount of glucose in the urine than they normally would, thereby stabilizing blood sugar levels.

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