What Invokana’s Day at the FDA Means for the Future of SGLT-2s

learning curve
January 31, 2013

By Alasdair Wilkins

Earlier this month, an FDA advisory panel voted 10 to 5 in favor of approving a new treatment for type 2 diabetes called canagliflozin, which will likely be sold under the brand name Invokana. This drug was developed by Johnson & Johnson (the maker of LifeScan blood glucose strips and Animas pumps) and belongs to a new type (class) of diabetes drugs called sodium-glucose linked transporter-2 (SGLT-2) inhibitors. The FDA could announce final approval for the drug as soon as this March, which would make Invokana the first member of the SGLT-2 inhibitor drug class to become available in the United States. Meanwhile, a different SGLT-2 inhibitor, called Forxiga (dapagliflozin) from AstraZeneca and Bristol-Myers Squibb, has already been approved in Europe and is expected to reach the market there in the near future. In this learning curve, we’ll explore how this new drug class reached this point, as well as what role it might play in diabetes care in the coming years.

The History Underlying the SGLT-2 Inhibitor Drug Class

Remarkable as it might sound, the SGLT-2 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). Of course, it would take over a century before researchers recognized the potential usefulness of a substance that induces glucosuria for the treatment of type 2 diabetes.

Phlorizin was indeed 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 SGLT-2 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 SGLT-2 inhibitors saw multiple early candidates discontinued due to safety issues. Forxiga and Invokana are now set to be the first of their class to reach the European and US markets, respectively.

How do SGLT-2 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.

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. SGLT-1 and SGLT-2 evolved to prevent the loss of seemingly vital sugar by transporting glucose from the kidney back into the body’s circulation, with SGLT-2 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 SGLT-2 proteins (when too much glucose filters through the kidneys, there are not enough available SGLT-2s 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 SGLT-2 proteins, meaning that a greater amount of glucose can be reabsorbed before glucosuria occurs (this of course exacerbates hyperglycemia). SGLT-2 inhibitors reduce the threshold to below-normal levels and thus promote glucosuria at lower blood glucose concentrations.

SGLT-2 inhibitors work by preventing the reabsorption of glucose in the kidneys, and by reversing the fine-tuned biological process for storing energy.

SGLT-2 inhibitors work by preventing the reabsorption of glucose in the kidneys, and by reversing the fine-tuned biological process for storing energy. SGLT-2 inhibitors cause glucosuria, but this is because the inhibitors decrease the number of available SGLT-2, 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 Invokana, Bristol Myers Squibb and AstraZeneca’s Forxiga, and other SGLT-2 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 SGLT-2 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 Invokana, 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 of course essential to fighting infection. Long-term SGLT-2 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 in the long run. Other potential side effects of SGLT-2 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 Forxiga.

When to Use SGLT-2 Inhibitors for Type 2 Diabetes?

There are two main ways in which SGLT-2 inhibitors like Invokana can become part of the type 2 diabetes treatment paradigm: as a first-line treatment or as part of a combination therapy. In isolation, SGLT-2 inhibitors would seem to have considerable potential as a first-line therapy, but the class looks less impressive when compared to other treatment options, particularly metformin. Even in the roughly 20% of people with type 2 diabetes who cannot tolerate metformin, SGLT-2 inhibitors will likely have difficulty replacing DPP-4 inhibitors, which provide slightly lower reductions in A1c but have the benefits of fewer side effects, more long-term safety data, and potentially lower cost. While there likely is a patient population for whom SGLT-2 inhibitors really are the best choice as a first-line therapy, identifying them would be a challenge for our current healthcare system – see this month’s letter from the editor for more thoughts on this tricky topic.

We mainly expect Invokana and future SGLT-2 inhibitors to be used as part of a combination type 2 diabetes therapy, either as a second- or third-line therapy. An SGLT-2 inhibitor in conjunction with a DPP-4 inhibitor could be a strong pairing for those who cannot tolerate metformin, although the cost of both medications could well prove prohibitive for many. Last year’s ADA/EASD Position Statement, which provided a framework for prescribing medications for type 2 diabetes, did not include SGLT-2 inhibitors, which is not surprising considering that at the time, no SGLT-2 inhibitor had gained regulatory approval in either the United States or Europe.

In the early going, we believe physicians will tend to consider SGLT-2 inhibitors only after more established treatment options prove unsuccessful. Whether a person can benefit from SGLT-2 inhibitors will also heavily depend on the state of his or her kidney – the FDA will likely disallow the drug’s use in patients with impaired kidney function, with the precise cutoff to be determined at the time of approval. Since impaired kidney function tends to worsen the longer one has type 2 diabetes, this may limit SGLT-2 inhibitors’ usefulness as a later-stage therapy.

While SGLT-2 inhibitors have an uncertain place in the already crowded field of type 2 medications, 2013 should still be a big year for the class. Invokana’s approval by the FDA isn’t quite finalized, but there’s good reason to think it could come as early as this March, with a launch perhaps as soon as mid-year. Forxiga should be available in Europe in the near future, and the FDA is expected to reconsider and announce a new decision for this drug in the middle of 2013. Pfizer’s ertugliflozin and Eli Lilly and Boehringer Ingelheim’s empagliflozin are both currently in Phase 3 trials, setting them up for FDA approval perhaps as early as 2014 or 2015. SGLT-2 inhibitors have been a long time in the making – almost 200 years – and they are definitely not a perfect, one-size-fits-all solution. But for type 2 patients who have had little success lowering their blood glucose and A1c levels with existing medications, this new group of drugs might just be a reason for renewed optimism.

Could SGLT-2 Inhibitors Be Used in Type 1 Diabetes?

In terms of SGLT-2 inhibitors and type 1 diabetes, it should be stressed that the FDA is currently only considering Invokana’s potential as a treatment for type 2 diabetes. J&J has informed us that an indication for the use of Invokana with type 1 is a long-term possibility, but they have not set a timeline for clinical trials, so this remains several years away. Like GLP-1 agonists and DPP-4 inhibitors, the SGLT-2 inhibitor class is thought to have some potential as a way for people with type 1 to reduce their A1c levels, stabilize their blood glucose levels, and potentially lower their insulin requirements.

After the FDA Advisory Committee, influential FDA Panel Member Dr. Sanjay Kaul expressed optimism for the potential of SGLT-2 inhibitors in type 1 diabetes. Specifically, he noted that the limited therapeutic choices in type 1 diabetes (i.e., only insulin), combined with SGLT-2 inhibitors’ unique mechanism of action with no weight gain or hypoglycemia, could make the drugs an ideal choice for type 1 patients. We look forward to studies on this front, hopefully in the next couple of years.

FAQ on Kidneys

What do the kidneys do?

The kidneys serve multiple crucial functions in the human body. Their primary purpose is to filter waste products out of the blood and other bodily fluids. This process creates urine and allows the body to reabsorb glucose. The kidneys also help maintain the optimal blood pressure and produce several vital hormones.

What is chronic kidney disease?

Also known as chronic renal disease, chronic kidney disease (CKD) occurs when the kidneys are unable to properly filter all the fluids that pass through them. CKD can present a wide variety of symptoms, with most being traced to the buildup of waste products in the blood that should have been excreted in urine. Since CKD is a chronic condition, this decrease in kidney function is observed over months or years.

How is diabetes related to chronic kidney disease (CKD)?

Diabetes is the primary cause of chronic kidney disease, accounting for 38% of all CKD cases in the United States in 2012. The other major cause of CKD is hypertension (25%), which itself is an extremely common complication of diabetes. More than 35% of people with diabetes aged 20 years or older have chronic kidney disease. CKD is a common complication for both type 1 and type 2 diabetes.

How can CKD be treated?

The majority of CKD cases involve damage to the kidney’s blood vessels, although there are several possible underlying causes for the progressive loss of renal function. Indeed, this makes treating CKD complicated – while certain forms of CKD can be treated depending on the specific cause, there are no universally successful treatments known to slow down or reverse the loss of kidney function. CKD can ultimately result in kidney failure, which can only be treated with dialysis or a kidney transplant.

How can kidney function be improved?

Several lifestyle factors can potentially improve kidney health. According to the CDC, these include maintaining good glucose control, keeping blood pressure below 130/80 mm Hg, keeping cholesterol in the target range, exercising and generally being physical active, eating healthily, and cutting down salt intake. These can all potentially slow down the loss of kidney function, especially when combined with the right medications.

What is GFR?

GFR stands for glomerular filtration rate. This simply refers to the rate at which filtered fluids move through the kidney. Since CKD involves a slowdown of the movement of filtered fluids through the kidney, GFR is the main measuring stick used to determine how well the kidneys are working. GFR is measured in ml/min/1.73m2 – those units simply refer to how many milliliters (ml) are filtered every minute (min), adjusted for the standard value for the body’s surface area (1.73m2).

What is eGFR?

The early phases of chronic kidney disease often do not present any noticeable symptoms – this makes blood tests that can calculate GFR and thus kidney function extremely important, as they are one of the only ways to detect CKD. Such a blood test produces an estimated GFR, or eGFR for short. This value is used as the basis for assessing a person’s kidney function.

How is renal health defined?

In adults, the healthy GFR range is 100-130 ml/min/1.73m2. CKD is divided into five stages based both on eGFR score and kidney damage. Stage 1 of CKD is slight renal impairment, defined as visible kidney damage with GFR at or above 90 ml/min/1.73m2. Stage 2 is mild impairment, or GFR of 60-89 ml/min/1.73m2. Stage 3 is moderate impairment, or GFR 30-59 ml/min/1.73m2. Stage 4 is severe impairment, or GFR of 15-29 ml/min/1.73m2. Kidney failure occurs when GFR is below 15 ml/min/1.73m2, which is also known as Stage 5 or end stage renal disease. Anyone with a GFR below 60 ml/min/1.73m2 for at least three months is considered to have chronic kidney disease, regardless of whether there is visible evidence of kidney damage.  

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