A Brief History of the Insulin Pill

A Brief History of the Insulin Pill


There’s nothing convenient about insulin injections, and if you’ve ever wondered why you can’t just pop a pill to control your blood sugar, you’re certainly not alone. Doctors and scientists have been working on an insulin pill since almost the very moment that insulin was discovered.

Every year or two, it seems, there’s another new report that the insulin pill is just around the corner. We applaud every advance, but in reality, major developments have been slow to come. Snags and setbacks are common. People with diabetes can be forgiven if they’re now a touch skeptical about supposed breakthroughs. Nevertheless, researchers do keep making patient progress; perhaps we will see an insulin pill in the foreseeable future.

Here’s an update on where things stand, including the latest innovation: a team of doctors that say they’ve created a pill that will only release insulin when blood sugar is high.

 

Why a Pill?

The attraction of an insulin pill, as opposed to the syringe, is so obvious that it hardly needs to be described. Many patients hate administering their daily injections, and a fear of needles has caused too many people with diabetes to delay or avoid prescribed insulin treatment. Even for those without a serious aversion to needles, a pill could be more convenient and less troublesome, potentially eliminating the random ouches, bruises and more serious complications that come along with regular injections. There’s a reason why a reliable insulin pill is often called the Holy Grail of diabetes technology.

Scientists have been working on an insulin pill now for very nearly a century. In 1922, only a year after the discovery of insulin, pioneering diabetes expert Dr. Elliott Joslin conducted the world’s first (unsuccessful) experiments on oral insulin delivery. In 1924, the first scientific consideration of oral insulin was published, and 1965 saw the first patent issued. But we’re still waiting for the first insulin pill to hit the market.

An insulin pill would seem to be especially attractive to the doctors who treat Type 2 diabetes and their patients. In Type 1 diabetes, insulin is non-negotiable: if you want to live, you have to make some kind of peace with syringes, pens or insulin pumps. In Type 2, however, insulin is just one of several possible therapies, one that may be stopped or started as conditions merit, and missing an injection or two is less likely to result in immediate noticeable harm. As a result, many patients with T2D lobby their doctors to avoid insulin, or don’t take it as prescribed. Doctors would love to be able to prescribe a form of insulin that might be more willing adopted by their patients.

Some experts, it should be stressed, might instead be alarmed by the possibility of a more approachable insulin treatment. Our contributor Dr. Mariela Glandt, for example, has argued that the use of insulin actually exacerbates the root cause of Type 2 diabetes, and that drug ultimately causes more harm than good. And nearly every expert agrees that the condition should, if possible, be treated primarily through dietary and lifestyle changes changes.

 

How an Insulin Pill Might Work

You might suppose that taking insulin through the stomach shouldn’t work, but it turns out that oral delivery of insulin might actually be better than insulin injections. In the healthy body, insulin secreted by the pancreas is transported to the liver, the body’s metabolic hub. But subcutaneously injected insulin bypasses the liver and circulates peripherally, an inexact mimicry of the body’s natural process. This “suboptimal” arrangement, by the way, helps explain why people with Type 1 diabetes tend to experience higher levels of insulin resistance than expected, and may also help explain why insulin can lead to weight gain. Insulin taken through the gastrointestinal tract, by contrast, can pass through the liver more or less like nature intended. This more natural metabolism may well also lead to improved glucose control and reduced risk of hypoglycemia.

Getting insulin from the stomach into the bloodstream is the hard part. Stomach acids deactivate insulin swiftly; the insulin needs to be protected until it reaches the intestine, where most mineral and nutrient absorption takes place. Researchers have made great strides in solving this first issue, designing multiple ways of effectively protecting the insulin on its journey through the stomach.

Just getting insulin safely into the intestine doesn’t solve the problem, though, because only a tiny fraction of insulin will naturally permeate the intestinal lining. The next huge problem to solve is how to package insulin in a manner that will somehow boost absorption, or transport insulin across the intestinal lining.

The solutions to this sticky problem can be so creative as to be almost unbelievable. Imagine swallowing a tiny tortoise-shell shaped applicator device with a spring-loaded needle made entirely of freeze-dried insulin. Imagine swallowing a pill that dissolves in the intestine, inflating a minuscule balloon covered in minuscule needles. Many other complex options have been studied: insulin is combined with absorption and penetration enhancers, or is entrapped within nanoparticles, liposomes or polymeric micelles, diverse microscopic structures that can better pass through the intestinal lining.

Most attempts thus far have failed. The history of oral insulins is, generally speaking, one of frustration and disappointment. Even within the last decade, many promising approaches have been abandoned because they simply didn’t work. But as long as there are billions to be made, businesses will keep trying.

 

A Recent Innovation

The Academic Times recently profiled an innovation by an international group of scientists working on the issue. The technology, described in the journal Chemical Science, uses a specific type of nanoparticle that may be capable of solving the two major problems associated with oral insulin delivery. These tiny crystalline carriers, loaded with insulin, both resist the harsh conditions in the stomach and pass through the intestinal barrier.

These nanoparticles add another revelatory feature: they release insulin in response to hyperglycemia. Once the hardy nanoparticles have survived the stomach acids and have penetrated the intestinal membrane, they begin to take a beating in the presence of high blood glucose. Sugar molecules literally bust into the micropores of the structure, displacing insulin and allowing it to escape into the bloodstream. The hope—confirmed, so far, by studies in rats—is that this glucose-responsive release will decrease the likelihood of hypoglycemia and promote nice, steady blood sugars. The pill would itself act almost like a tiny temporary closed loop insulin system, sensing blood sugar levels and dosing insulin as appropriate.

Anyone following diabetes science knows that rodent diabetes has already been cured about a million times, and that there is a very long and challenging path between animal study and human application. Even if everything goes well for the technology, which its leader called “revolutionary,” one can only guess how many years away it might be from conducting human trials and winning FDA approval.

 

Insulin Pills on the Horizon

Israel’s Oramed is the group closest to actually putting a product on the market. Oramed was founded by Dr. Miriam Kidron, a scientist with Jerusalem’s Hadassah Ein Kerem Medical Center, along with her son, CEO Nadav Kidron. Inspired by a 2006 scientific breakthrough—the drug employs an “enteric coat” to protect the insulin in the stomach, and then a powerful absorption enhancer to help it get through the gut wall—the Oramed team long ago committed to commercializing the product “as soon as possible.”

We profiled Oramed way back in 2012. At the time, a company spokesman admitted that it would “probably be a number of years until the oral insulin is on the market.” Today, nearly a decade later, Oramed is still churning through the lengthy FDA approval process. At the moment they are conducting two different phase three trials, a final testing stage that could at last lead to federal approval in the United States and then elsewhere. Phase two trials were a success, showing that the pill safely and effectively regulated the blood glucose of participants, and the company remains optimistic. In November 2020, it predicted to The Times of Israel that its product would be available for people with Type 2 diabetes “in just over three years.”

Oramed’s first product will be a daily pill for patients with Type 2 diabetes. This is the most natural place for pharmaceutical research and development to focus—both because patients with Type 2 tend to have simpler blood sugar management issues, and because the potential market is so much larger. The business is also working on a daily solution for Type 1 diabetes, but we should expect a product for T1D to have a longer path to development. Patients with Type 1 diabetes have more volatile blood sugar levels, and many (especially insulin pump users) prefer the ability to tweak basal insulin rates throughout the day anyway, and may therefore be less interested in a 24-hour insulin pill.

Several other companies are a step or two behind Oramed. Tech firms Biocon, Diasome, and Diabetology all have their own insulin pill products in long development, having experienced ups and downs along the way. Years can pass between significant trials and press releases, as scientists patiently plug away behind the scenes.

There are still unknowns that require larger and lengthier experiments to test. Insulin, for example, is a powerful growth promoter, and repeatedly forcing it through the gut may have cause unforeseen damage. Low uptake in the intestine could require manufacturers to put apparently excessive amounts of insulin in each pill. And any novel drug can have side effects and unintended consequences. Oramed’s phase three trials, now underway, will be one of the most significant tests of the drug’s potential to date.



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