The Food and Drug Administration (FDA) recently approved a drug called Inpefa to reduce the risk of heart failure in people with Type 2 diabetes. The drug took a long and winding road to get its regulatory approval. That “road” gives us a glimpse, not only at the approval process, but how regulators considered concerns about the compound’s safety. Understanding how the trials were designed and how regulators considered the risks and benefits of the drug can help us evaluate whether or not we want to take it.
“I generally am relatively enthusiastic about this new medication to be honest,” says Sanket Dhruva, MD, a cardiologist at the Veterans Affairs Medical Center in San Francisco, CA. Similar drugs have shown important benefits for patients, according to the American Heart Association. But, he adds, “I think there are still, obviously, risks to patients, and I think they are important caveats to the benefit.”
For decades, scientists suspected that inhibiting SGLTs (sodium glucose cotransporters) could help treat diabetes, because SGLTs ferry glucose—or sugar—and sodium into and out of your cells. SGLT proteins exist in several forms naturally in the body, but the ones that researchers have been interested in for treating diabetes are called SGLT1 and SGLT2. SGLT1 is found in the kidneys, as well as many other places in the body, such as the intestines, while SGLT2 is found only in the kidneys.
Researchers hoped to help treat diabetes by limiting the glucose that SGLTs ferry into cells. They studied a molecule, phlorizin, that inhibited (or slowed the activity of) both SGLT1 and SGLT2, but they found that because the drug acted on SGLT1 all over the body, it caused too many side effects.
In 2013 and 2014, three different drugs that instead inhibited only SGLT2 (which is only found in the kidneys) were FDA approved for diabetes: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). The SGLT2 inhibitors work by preventing the cells in your kidney from taking in too much glucose. Instead, your body eliminates that glucose in your urine. Later research suggested these drugs might also reduce the risk of cardiovascular problems in patients with Type 2 diabetes who were at heightened risk for heart failure—a significant beneficial side effect.
Still, researchers suspected that, if they could target certain SGLT1 receptors more specifically(for example, only those in the intestines), the drugs could become even more effective at helping people with diabetes manage blood sugar levels and prevent heart failure.
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An SGLT1/SGLT2 Inhibitor That Just Might Work
In June of 2018, researchers published the results of three clinical trials using sotagliflozin, a drug that inhibits both SGLT1 and SGLT2 to manage blood sugar in people with Type 1 diabetes who were already using insulin. The trials showed that the drug not only improved blood sugar control but the participants also lost weight and improved their blood pressure.
There was one major caveat though. In addition to side effects such as diarrhea and fungal infections, the drug seemed to raise the risk of diabetic ketoacidosis—a life-threatening complication of diabetes—more than eight-fold. Diabetic ketoacidosis is a known risk of all SGLT2 inhibitors currently on the market. Out of 1,748 participants who took the drug, 56 (or 3%) experienced diabetic ketoacidosis, compared to only five (0.4%) out of the 1,229 who were given a placebo. This was despite the fact that the company provided participants with warnings and tools to monitor their ketones.
Still, the two pharmaceutical companies, Lexicon and Sanofi teamed up and applied for FDA approval later that year. They called the drug Zynquista.
Zynquista Comes with A Very Big Danger
Before the FDA issued its decision on whether or not to approve the drug, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed the clinical trial data. The committee voted on whether or not it recommends that the FDA approve the drug. While the FDA is not required to follow the committee’s advice, it typically does. The committee was split on Zynquista. Eight members voted for approval of the drug, and eight voted against. Those that voted against were particularly concerned about the risk of diabetic ketoacidosis.
“I think it’s impossible to understate the concern about DKA (diabetic ketoacidosis) really just because the absolute increase is really remarkable,” Michael Blaha, MD, of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease in Baltimore told MedPage Today at the time. “I am concerned about the prospect that this could be worse in the real world [outside of the trial setting].”
In March of 2019, the FDA officially rejected the approval of Zynquista (sotagliflozin). Lexicon and Sanofi ended their collaboration, and only Lexicon kept working on the drug. The company appealed the FDA’s decision, but the FDA stood firm and rejected that appeal in December of 2019. Meanwhile, the European Medicines Agency (EMA)—the European Union’s FDA equivalent—decides to approve the drug as an add-on to insulin treatment for those with Type 1 diabetes in April 2019.
Trials Begin Anew
About a year after the FDA rejected Zynquista for the second time, researchers published two new clinical trials, in January of 2021. This time, scientists tested whether the drug would help people with Type 2 diabetes who were at risk for heart failure.
One study enrolled people with type 2 diabetes who also had kidney disease, a risk factor for heart failure. The other study enrolled patients with Type 2 diabetes who were already hospitalized for worsening heart failure.
Both trials suggested that the drug, which the companies were now calling Inpefa (instead of Zynquista) could reduce the risk of heart failure in these at-risk participants. In the kidney disease trial, sotagliflozin reduced the risk of heart failure by 26%. It also reduced the risk of heart attacks, strokes, and worsening kidney function.
Side Effects of Inpefa
In the kidney disease trial, diabetic ketoacidosis was about twice as common in participants who took Inpefa (30 out of 5,291) as those who took a placebo (14 out of 5,286). It’s possible that the risk is lower than it was in the 2018 studies because diabetic ketoacidosis is more common in people with Type 1 diabetes than those with Type 2.
“Type one diabetes also is fundamentally different in many ways from type two diabetes” says Dhruva. “In type one diabetes, patients are at significant risk for diabetic ketoacidosis (DKA). And, that risk is much, much, much smaller in type two diabetes.”
In the trial of patients who had been hospitalized for worsening heart failure, nine out of 605 participants who took Inpefa experienced severe hypoglycemia, compared to only two out of 611 who took a placebo. Severe hypoglycemia is low blood sugar, which can be caused by overtreatment of diabetes. At first, it can lead to shakiness and a pounding heart, but if it isn’t treated it could lead to a seizure, a coma, or even death.
In both trials, those who took Inpefa had a greater risk of diarrhea, fungal genital infections, and volume depletion, a condition in which you don’t have enough blood plasma. It can cause fatigue, weakness, dizziness, fainting, and can even be fatal. You may need intravenous (IV) fluids to treat volume depletion.
Both trials ended early, due to loss of funding in March 2020, that the company attributed to COVID-19. The kidney disease trial tracked participants for an average of 16 months, while the trial on those that had been hospitalized for heart failure tracked patients for an average of nine months. The goal of the research (called the endpoint) was to determine how many patients died from cardiovascular causes during the studies. But since the studies were shorter than planned, very few people actually died during the brief window during which they were studied. That makes it difficult to compare those who used the drug to those who didn’t. Instead, the researchers ended up assessing how often patients required urgent treatment or hospitalization for cardiovascular events, even if they survived.
Trials can end early for different reasons, explains Dhruva. Some may be for more concerning reasons than others.
“If the trials were stopped due to COVID-19 or another shock to the [medical] system, that’s one thing,” says Dhruva, but there are two other reasons that trials are often stopped early. First, the results suggested a positive impact even sooner than researchers expected. Dhruva warns that sometimes longer studies after approvals of these types of drugs suggest that they don’t provide as great a benefit as was initially thought in the short trial.
Alternatively, a trial can be ended early because the results look negative. Companies want to cut their losses, but then, “we get some sort of post hoc analysis that shows that there’s a benefit to the drug, and then all of a sudden everyone’s very enthusiastic,” says Dhruva.
As of right now, we know that Lexicon did change the endpoints of the trials from death due to cardiovascular events, to cardiovascular events that required urgent treatment, but there is not currently any evidence that the trials ended because of any observed benefit or lack thereof in the studies.
Heart Failure Drug, Inpefa, Gets the Green Light
The company marketing Zynquista in the European Union requested that the EMA withdraw its marketing authorization for treating Type 1 diabetes in March of 2022. The company, Guidehouse Germany GmbH, wrote that this was for “commercial reasons.” The EMA obliged, and made its marketing authorization no longer valid.
Lexicon asked the FDA to approve Inpefa to prevent heart failure in people with Type 2 diabetes and chronic kidney disease or previous heart failure in 2022, but ended up pulling the application. The company said it did so because of issues with paperwork, but in May 2023, both the company and the FDA said the issues had been resolved. On May 30, the FDA approved Inpefa.
Questions to Ask Your Doctor About Inpefa
Dhruva says that while he’s generally enthusiastic about this type of medication, there are questions you should ask your clinician before you take it.
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Why do you think Inpefa will help me?
It’s important to note that the clinical trials didn’t actually show that they’ll help you live longer.
“I want patients to be aware that the reason that we’re treating them with Inpefa is because the primary endpoint looked positive. The primary endpoint was supposed to be fewer deaths, but the new one, based on the shorter trial time was a sum of cardiovascular death, plus hospitalizations for heart failure, plus urgent visits per heart failure,” says Dhruva. He emphasizes that the trials did not demonstrate that people who took Inpefa were likely to live longer than those who did not.
“If I was counseling a patient, I would say there is uncertainty if this medication will help you to live longer. It’s possible, and I hope so…but I would like to see data before that claim is made.”
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How will Inpefa interact with other medications I’m taking?
Dhruva also points out that almost anyone who is prescribed Inpefa will already be taking other medications for diabetes or other conditions, so it’s crucial to pay attention to how the drug might interact with those drugs.
“This is going to be an add-on medication,” says Dhruva, so polypharmacy—a situation in which you’re taking more than five medications at once—is a concern.
