From the vault: Everything drugs
The promise of SGLT2 inhibitors
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Natália Coelho Mendonça writes about the promise of SGLT2 inhibitors.
Most drugs get approved to do one thing. In rare cases, drugs get multiple indications, allowing their manufacturers to advertise them as treatments for a range of conditions. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, also called flozins, began as diabetes drugs. Surprisingly, they turned out to also be very effective at improving heart health. Then they were discovered to slow the progression of chronic kidney disease, one of the leading causes of death and disability worldwide. Preliminary evidence indicates that they show promise in helping several other conditions, but no one knows exactly how they achieve this yet. Could SGLT2 inhibitors be a new medical Swiss Army knife?
The backstory of flozins
SGLT2 is a protein found in the kidneys that stops the body from wasting calories. It works like a pump that extracts glucose from urine and moves it back into the blood. The sodium in the name refers to how that pump is powered: like a water wheel using a gradient in water height to move machinery, SGLT2 uses the gradient in sodium concentration between the urine and the blood as an energy source.
Phlorizin was the first drug that blocks SGLT2 to be isolated, in 1835. This compound was extracted from the root bark of the apple tree by French chemists and studied in the hopes that it would be useful for stopping fevers. It wasn’t.
It took a long time before anyone found a use for phlorizin. About 50 years after its original discovery, German physician Josef von Mering discovered that it stimulates excess sugar excretion in the urine of animals. It likely didn’t strike many people at the time as a good treatment for diabetes – after all, excess sugar in the urine is a symptom of diabetes, as are some of the other effects caused by phlorizin, such as weight loss and excessive thirst. In fact, the effects of phlorizin administration in animals have in the past been called ‘phlorizin diabetes’.
The paradigmatic sign of type 2 diabetes is high blood sugar. In a healthy person, the pancreas releases the hormone insulin in response to increases in blood sugar. Insulin, in turn, tells various cells in the body to absorb the excess sugar. But when someone has type 2 diabetes, the cells do not listen as well: they become resistant to the effect of insulin and let sugar build up in the blood. This is a problem because very high blood sugar, known as hyperglycemia, causes damage to multiple organs.
In 1987, phlorizin was used to clarify the role of high blood sugar in type 2 diabetes. Researchers at Yale University found that phlorizin restored insulin sensitivity in a rat model of diabetes, effectively curing them of the disease, whereas stopping the phlorizin treatment made insulin resistance return. This showed that high blood sugar is not just a result of insulin resistance, but also plays a role in worsening it once it begins.
This kindled interest in using flozins – the name of the group of drugs that block SGLT2, also called SGLT2 inhibitors – as antidiabetic medications. But phlorizin has other effects as well. It doesn’t just block SGLT2 – it also blocks SGLT1, the main protein that’s responsible for glucose absorption in the small intestines. This blockage leads to substantial gastrointestinal side effects, like diarrhea (similar to antidiabetic drugs metformin and acarbose). Moreover, only small amounts of phlorizin are absorbed by the digestive system, meaning that patients would need to inject it or take large oral doses (and these large doses are associated with more severe side effects).
These issues created problems with the feasibility of using flozins medically. But in 2000, Japanese researchers solved the absorption problem by developing synthetic flozins that were easily absorbed into the blood after taking them orally. These drugs also increased the release of glucose in the urine, implying they were working as expected. But like phlorizin, they also blocked SGLT1, and caused the same side effects.
Soon this problem was solved too. More work by Japanese researchers on synthesizing flozins led to the development of canagliflozin and dapagliflozin, which are both absorbable and selective – blocking SGLT2 much more than SGLT1.
Meanwhile, evidence grew that indirectly supported the safety of flozins for long-term use. In the 2000s, researchers discovered the cause of familial renal glycosuria, a condition that runs in families where patients have abnormally and persistently high levels of glucose in their urine, but have otherwise normal kidney function. They also have normal blood glucose levels and life expectancies, and report no complaints related to the condition.
It turned out that familial renal glycosuria was caused by genetic mutations in the SGLT2 gene that reduced the effectiveness of the SGLT2 pump, creating an effect similar to that of flozins. The fact that people could live completely normal lives with an impaired SGLT2 gene (and thus sweeter urine than everyone else) provided evidence that flozins, which artificially mimicked the condition, could be safely used in the long run.
The diabetes trials
It was time for clinical trials. In the late 2000s, the two synthetic flozins developed by Japanese researchers, canagliflozin and dapagliflozin, were bought by Johnson & Johnson and AstraZeneca respectively, and both began clinical trials for the drugs.
These trials were for diabetes, following the train of research since the 1980s that had established that inhibiting SGLT2, and thus lowering blood sugar, can help control type 2 diabetes. But rather than looking at how the compounds affected survival or the symptoms or complications of diabetes, the trials were based on surrogate endpoints, meaning that they only had to show that they directly affected biomarkers of the disease, such as high blood sugar. Surrogate endpoints were introduced to speed up drug research and encourage more research into compounds that take a long time to impact the things we care about directly.
The results were conclusive, though unsurprising. By stopping SGLT2 from extracting sugar from the urine into the blood, both flozins directly reduced rates of hyperglycemia, which by this point was known to be a major symptom of diabetes, and also a contributory cause.
The heart trials
After flozins were approved as diabetes drugs, on the basis that they lower the markers of diabetes, they had to go through further trials to be sure that they did not increase the risk of heart attacks, strokes, or deaths due to cardiovascular disease. This requirement was imposed by the FDA in 2008, after a meta-analysis published in 2007 found that rosiglitazone, another diabetes drug approved on the basis of surrogate endpoints, increased the risk of heart attacks by 43 percent.
These trials were imposed to confirm the benefits of the drugs were not outweighed by cardiovascular side effects.
Yet something unexpected happened: the trial for empagliflozin – which, like dapagliflozin and canagliflozin, inhibits SGLT2 much more strongly than SGLT1 – showed a 14 percent reduction in major cardiovascular events, a 35 percent reduction in hospitalizations for heart failure, and a 38 percent reduction in cardiovascular deaths overall – all statistically significant.
Other flozins followed suit, backing up their diabetes trials with heart health trials. Not only did they get to stay on the market as antidiabetic drugs, but between 2020 and 2023, the FDA gave three of them indications for heart failure as well.
As discussed, SGLT2 is a protein primarily found in the kidneys which prevents sugar and sodium chloride from being passed into the urine. It is obvious how the inhibition of SGLT2 decreases blood sugar, making flozins good medications for type 2 diabetes. But we’re not sure why they’re so good for the heart.
We know that flozins reduce blood pressure, but this effect is small – nowhere near enough to account for their protection against heart diseases. Conventional blood pressure therapy reduces the risk of heart failure by 28 percent for every 10 millimeters of mercury (mm Hg) decrease in blood pressure. But in one of the large flozin trials mentioned above, patients on canagliflozin had 39 percent lower rates of heart failure despite blood pressure reductions of only 3.5 mm Hg – almost three times the ratio of heart failure reductions to blood pressure reductions. Post hoc analyses of the same trial found that the blood pressure–lowering effect of canagliflozin explained only four percent of its effect on kidney function.
It similarly has been found that the cardiovascular benefits of flozins cannot be explained by their effect on blood sugar alone.
There have been a whole range of additional proposed explanations, including the fact that the drugs increase diuresis (urination) and natriuresis (salt passing through to the urine); or that they improve cardiac energy metabolism, potentially encouraging the heart to fuel itself with lipids.
You can read the rest of the piece here.
This story first appeared in Issue 14 of Works in Progress.
Natália Coelho Mendonça is a software engineer and blogger based in San Francisco.
Interesting drug with potentially huge implications for health care spending. Not only is kidney dialysis incredibly annoying for patients, it’s about 1% of total federal spending.
Nice piece here, Works in Progress.
One of the "side effects" of human progress, specifically, our ability to produce more food from limited land since the Industrial Revolution, is the disconnect between our biology and technology.
For example, our advances in agriculture, food production, and storage, led us to select against foods that were high in Omega-3 fatty acids before we even knew they existed. We now know, but don't fully understand, that Omega-3s are essential for our health. We don't get enough of them.
Similarly, the industrial era favors foods that are easily grown, transported, and stored, which lends itself to low-nutrient, but calorie-dense carbohydrates. As a consequence, we get too many carbs and sugars, leading to many chronic illnesses, like kidney disease, obesity, and diabetes.
It probably shouldn't be surprising that drugs that target this pathology, the insulin resistance/overconsumption of carbohydrates issue, lead to a myriad of health benefits beyond the disease they are intended for. We are finding, for example, that Semaglutide doesn't only treat diabetes and obesity, but may also improve alzheimers, parkinsons, heart disease, among a host of others.