Diabetes Forecast

Insulin Innovations

New forms of insulin at your pharmacy and on the horizon

By Andrew Curry , ,
needle sticking into insulin vial

ballyscanlon/Getty Images

For many people with diabetes, insulin is an integral part of life. So integral that it's easy to forget insulin hasn't always been around. Less than a century ago, doctors had no idea what caused diabetes, only that it killed: The average patient with what we now call type 1 diabetes lived for just three years after the diagnosis.

In the early 1920s, two young Canadians named Frederick Banting and Charles Best, building on the work of scientists all over the world, made a crucial breakthrough: They discovered that insulin, a protein produced by the pancreas, helped signal the body's cells to absorb glucose circulating in the blood. Without insulin, the body couldn't use blood glucose for energy.

The discovery of insulin in 1921 helped define diabetes as an endocrine disease. The field of endocrinology looks at how hormones such as insulin influence critical processes in the body. When the first patients were given insulin, the results were dramatic. "Those who watched the first starved, sometimes comatose, diabetic receive insulin and return to life saw one of the genuine miracles of modern medicine," historian Michael Bliss wrote in his book The Discovery of Insulin.

But insulin still had a long way to go. The first insulins were harvested from rabbits and pigs. They were tricky to produce, and problems with purification could make people dangerously sick. Needles that required sharpening and glass syringes were crude compared with what people use today; testing glucose was imprecise and difficult.

Over the decades, scientists have made tremendous strides. Since the early 1980s, most insulin has been produced using genetically modified bacteria or yeast. Scientists slip a piece of highly engineered human DNA into the bacteria's or yeast's genetic code, causing it to produce insulin.

Nearly a century after Banting and Best's discovery, insulin is very different than it was in those early days: There are a dizzying array of different formulations and varieties, each designed to act in a slightly different way.

And there's more innovation on the way. The steady rise of type 2 diabetes around the world presents major unmet medical needs and business opportunities in the form of diabetes treatments—including new ways to deliver insulin.

Unsurprisingly, pharmaceutical companies are pouring research dollars and personnel into coming up with the next big thing in diabetes treatment. "It's not only that we're technologically able to do these things more precisely and easily, but that there's a huge market for diabetes drugs," says MCPHS University professor Alissa Segal, PharmD, who's also the Joslin Diabetes Center's clinical pharmacist. "The push for companies to get involved in modifying insulin is huge."

In fact, the constant progress may have a downside, as two doctors recently argued in The New England Journal of Medicine. They explained that, while most drugs are discovered once and then eventually cheapen when they're available as generics, insulin is more of a moving target. As improved insulins go on the market, their predecessors—often perfectly safe and effective—are no longer produced. "There is still no inexpensive supply of insulin for people living with diabetes in North America," the authors write, "and Americans are paying a steep price for the continued rejuvenation of this oldest of modern medicines."

Here's a look at what's new in insulin—and what's just over the horizon.

Now Available » Just Breathe

While some researchers are working on ways to make injected insulin last as long as possible in the body, others are coming up with ways to put it to work fast—and painlessly. In February, Sanofi released an inhalable mealtime insulin called Afrezza.

Afrezza is a very finely powdered rapid-acting insulin that gets into the body via the lungs, which are made up of millions of tiny airways. Unfolded, they'd cover half a tennis court. When you breathe in, the powder is distributed through these airways and quickly moves into the blood. "As you are pulling air in, you're also getting insulin particles so small they reach the deep lungs," says Stefan Schwarz, PhD, MBA, head of the Afrezza brand for Sanofi. The powder is absorbed almost as soon as it hits the lungs, passing over into the bloodstream within five to six seconds, he says.

Click here for a list of insulins available in the United States.

That, Sanofi claims, makes Afrezza extremely convenient: Breathe in as you're sitting down for a meal, not 20 to 30 minutes before as with injections, for example. "As a patient, you can [inhale] the minute you start eating and see peak insulin within 12 to 15 minutes," Schwarz says. "It's very fast and gets out of your system very quickly. Within 180 minutes, it's all out of your system." That way, while your meal is digesting, there is less of a chance you'll have too much circulating insulin, which puts you at risk for hypoglycemia.

Before getting a prescription, adults will have to show that their lungs are up to inhaling by undergoing spirometry, a common test of lung power. The drug isn't recommended for certain people—such as smokers and those with asthma or chronic obstructive pulmonary disease—because of risks of adverse effects. It hasn't been tested in children.

Afrezza's not the first inhalable insulin. Nearly a decade ago, the pharmaceutical company Pfizer introduced an inhalable insulin called Exubera. The drug had a tough time catching on because of high costs compared with traditional insulin, what patients at the time said was confusing dosing levels, and an awkward breathing apparatus the size of a flashlight.

Pfizer pulled Exubera from the market in 2007, after barely a year. Several other companies with inhalables in the works followed suit, backing away from the idea.

Sanofi is hoping this time will be different. The Afrezza inhaler is much smaller than Exubera's device, and resembles a whistle. And Sanofi paid attention to the Exubera story when developing its dosing cartridges, which contain 4 or 8 standard units, designed to be enough for a typical meal.

The product, which has been cleared for adults with type 1 and type 2 diabetes, is aimed at "two very specific patient segments," says Schwarz: "people who are not in control and really need to make the step into insulin but don't want to because of injections and people on basal insulin who don't want to add three more [mealtime] injections into their busy lives each day."

The first group includes many people with type 2 diabetes reluctant to move to the next level of treatment because they don't want to deal with needles. Independent studies have shown that up to half of all people with diabetes wait too long to begin insulin injections, sometimes procrastinating for five years or more after their doctor recommends they start. "People are trying to stay on orals as long as possible, and sometimes longer than healthy," Schwarz says. "Afrezza is a great option to initiate or intensify insulin."

Segal is skeptical that the inhalable will be particularly useful for those initiating insulin: She says most people's first step into insulin is a once daily long-acting basal insulin, not mealtime injections. But she sees a third group that might really appreciate Afrezza: people with type 1 who have been dealing with numerous needle-based injections for years. "Inhaled insulin provides an option for type 1 patients who might need a rest for their injection sites," she says. They'd still need to take basal insulin, however.

Coming Soon » The Next Lantus?

Sanofi introduced Lantus, a long-acting insulin, to the U.S. market about 15 years ago. Known generically as insulin glargine, Lantus is now one of the most widely used insulin products in the world: An estimated 3.5 million people with diabetes use Lantus to keep their basal (background) insulin levels steady over the course of a full day, earning Sanofi upwards of $7.4 billion a year.

Lantus has been protected by a patent since its release in 2000, but that patent ran out earlier this year. That's expected to open up the basal insulin market to generic versions of insulin glargine.

The diabetes drug market may be making room for biosimilar insulins in the near future. Much like generic versions of oral medications, biosimilars are cheaper versions of brand-name biological drugs such as insulin. Before they get to you, though, they must be tested and reviewed for safety by the Food and Drug Administration.

That's spurred an effort to make a product that improves on insulin glargine's effectiveness. Sanofi is hoping to keep building on Lantus' dominance with an improved insulin glargine called Toujeo, more highly concentrated than Lantus and designed to release more slowly, meaning one dose will last even longer. The drug was cleared by the Food and Drug Administration (FDA) earlier this year.

Other companies are revisiting the chemistry of the insulin molecule to come up with entirely new basal insulins. One of the most promising projects is insulin degludec, a new formulation developed by Novo Nordisk that's available in Europe now and in the final phases of review by the FDA. According to Todd Hobb, MD, Novo Nordisk's chief medical officer in North America, the company's goal was to produce a basal insulin that could be dosed at any time of day, once a day.

To change the way insulin works, scientists tweaked the insulin molecule itself. "If you look at the insulin molecule, you can make minor changes that have significant effects in how quickly it comes apart," Hobb says.

Degludec is a case in point. Chemists coaxed insulin molecules to hang together in long chains, which uncouple one at a time from the end of the chain. "That way, it slowly and consistently releases into the bloodstream," says Hobb.

Novo's new insulin isn't available in the United States yet. Federal regulators wanted to see more evidence that it was safe for people with cardiovascular conditions first. The earliest it would be available—under the trade name Tresiba—is late 2015, but sometime in 2016 is more likely, Hobb says.

While dosing instructions aren't clear for the unapproved drug, there's some interest in flexible dosing. The company's testing suggests that the new insulin works for well over 24 hours, possibly reducing the number of injections needed and the waning effectiveness at the tail end of the dose.

Take Hobb's 10-year-old son, who has type 1 diabetes and takes Levemir, Novo Nordisk's answer to Lantus: "From Monday to Friday, when he gets up to go to school, he's injecting at 6:45 [a.m.]," Hobb says. "On Saturday and Sunday, he wants to sleep till 10. But on the weekends, his blood sugars are higher because his basal insulin doesn't go past that 24-hour window."

Down the Road » Lasting Longer

Even as Tresiba and Toujeo push the envelope for long-acting insulin past the 24-hour mark, researchers are hard at work trying to find formulations that will extend basal insulin's staying power even further. "Three to four days without injecting is the Holy Grail for everyone who designs basal insulin," says Nelson Phillips, PhD, a biochemist at Case Western Reserve University trying to find new ways to shape the insulin molecule.

In 2014, the American Diabetes Association gave Phillips an innovation grant, funding designed to help move promising ideas from the lab to a stage where they could be developed for people with diabetes to actually use. "People with diabetes have Lantus and Levemir," Phillips explains. "We are trying to make something even longer lasting."

One way long-lasting insulins work is by keeping insulin molecules stuck together in clumps. Zinc is a sort of glue that keeps them together. When insulin is injected into the body, the zinc is absorbed and the insulin clumps fall apart, allowing the insulin to be absorbed and begin working to signal the body tissues to absorb glucose.

The challenge for Phillips was to find a way to hook the insulin molecules together so they'd stay connected even after their gluey zinc was gone. At first, he managed—but the resulting adjustments he had to make to the insulin molecules reduced their effectiveness.

In the lab, Phillips fiddled with a different part of the insulin molecule. "What we did was add another residue that would increase potency," he says. "The design also includes stability, so it doesn't break down."

The formulation is still years away from marketable form, but Phillips has been testing the new insulin in rats and dogs, and so far "it's much [longer lasting] than Lantus," he says. "This is a promising candidate."

On the Horizon » Insulin With Brains

University of Utah chemist Danny Chou, PhD, is even further out on the forefront of insulin science. He's looking beyond fast-acting and slow-release insulin to what he calls "smart" insulin.

"We'd like to try to have insulin that's controlled by circulating blood sugar levels," Chou explains. "It's active when you need it, but when you go to 100 or 80 mg/dl, it will shut off. It would be an insulin that would control blood sugar in the right range, which could reduce long-term complications."

Chou's not the first person to tackle this problem. One approach coated the insulin molecules with a chemical layer that dissolved when blood glucose reached certain levels, releasing the insulin to do its work. Others were like tiny cages with holes too small for insulin to escape; as blood glucose rose, the bars got farther apart and let the insulin out.

Chou says there are problems with that idea. Over time, the coating or "cages" would build up in the body, for example. "If you have the material to encapsulate, over time, you have bioaccumulation problems," says Chou. "And wherever you have foreign materials, there's concern about immune response," with the body's immune system reacting in harmful ways to the coatings.

Instead, Chou is trying to modify the insulin molecule itself, adding a string of proteins that act as a sort of glucose sensor. Once in the body, the individual insulin molecule would act as its own continuous glucose monitor. "In an ideal scenario, it would be good for two days, or even a week," he says. "You wouldn't have to worry about what you're eating."

Chou published his first results earlier this year, showing that his experimental insulin could out-perform Levemir in mice. If things go well, he says, it might be ready for clinical trials in people with diabetes in the next five years. A similar smart insulin, which begins working when blood glucose is too high and then turns off when glucose reaches a safe level, is being developed by Merck and is in Phase 1 human trials.

Reality Check

Any look at the new insulin formulations available to people with diabetes has to come with a caveat: Much depends on your health insurance. "There are a lot of options, but they're not necessarily open to everybody," says Segal.

Insurance companies negotiate deals directly with drug makers, pushing hard for the lowest price to maximize their profits. Often entire insurance plans will mandate one type of basal insulin—then switch everyone on the plan to a different type when the insurer gets a better deal. That means many patients don't have access to the latest insulins for financial reasons.

Pharmacists and doctors' priority is getting people on insulin as needed and making sure they take it regularly, period. A cutting-edge formulation a patient can't afford does no good. "We often have to do what we have to do to have patients be able to take insulin, rather than try to find the best formulation," Segal says. She has watched the rush to come up with better insulin with both a scientist's appreciative eye and a practitioner's sense of what's possible. "What they're doing is really cool, but we also have to be realistic about the world most patients live in," she says.



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