Insulin info for internists

A talk at Tuesday's “Diabetes for the Internist” precourse reviewed some of the most significant recent advances in insulin, including new concentrations and combinations with other medications, new delivery mechanisms, and biosimilars.


It's easy for physicians and patients to take insulin for granted, even though 100 years ago, it wasn't even an option, M. Sue Kirkman, MD, ACP Member, told attendees at Tuesday's “Diabetes for the Internist” precourse.

“It's important to remember what a miracle insulin is,” said Dr. Kirkland, who is an endocrinologist and professor of medicine at the University of North Carolina in Chapel Hill. “Type 1 diabetes was really a death sentence.”

Insulin was first extracted from animals in the 1920s, and human insulin was developed in the 1980s, followed by insulin analogues in the 1990s and even more new discoveries in recent years. “Since the turn of the millennium, we've had a plethora of new insulins that have come out,” said Dr. Kirkland.

During her talk on new insulin products and technology, she reviewed some of the most significant recent advances, which include new insulin concentrations and combinations with other medications, new delivery mechanisms, and biosimilars. She noted that she has received research grants from Novo Nordisk, Theracos, and Bayer, but none related to the information in her lecture.

Another recent change is medical experts' perspective on the use of insulin for type 2 diabetes. Although the majority of patients taking insulin in the U.S. today have type 2 diabetes, insulin was downgraded as a treatment option for type 2 in the most recent guidelines from the American Diabetes Association and the European Association for the Study of Diabetes.

“It used to be insulin was a second-line option once metformin didn't work. Now it's moved down to a third-line,” said Dr. Kirkman. One reason for this is concern about hypoglycemia, she noted.

The guidelines now recommend glucagon-like peptide-1 (GLP-1) receptor agonists as the first choice of injectable medication for type 2 diabetes. After GLP-1s, the next drug in line is old-fashioned neutral protamine Hagedorn (NPH) insulin.

“NPH insulin is much cheaper” than basal analogues, Dr. Kirkland said. “You might think it's a lot worse, right? It turns out there's no difference in HbA1c lowering.” That makes NPH the right choice for any type 2 diabetes patients facing cost barriers, she explained.

The advantage of basal analogues is their lower risk of hypoglycemia. “If hypoglycemia is a big concern, you should probably use a basal analogue in your patient with type 2 diabetes,” Dr. Kirkland said.

In type 1 diabetes, hypoglycemia is generally more of a concern, so basal analogues should be preferred to regular insulin. “If you have a type 1 who cannot get insulin any other way [than paying full price], then they might have to use NPH. I try to do everything I can to get analogues for my type 1s,” she said.

Treatment with analogue insulin has become slightly cheaper thanks to the development of biosimilar drugs. “We actually don't have a mechanism to get true generic insulins in the U.S.,” noted Dr. Kirkland.

The first biosimilar on the market was for insulin glargine, and it costs about 15% less than the original. “Still very expensive out of pocket,” she said. Still, the price difference is enough that a lot of insurance companies have switched. The FDA also recently approved a biosimilar to insulin lispro.

Dr. Kirkland's preferred analogue, however, especially for patients with type 1 diabetes, is insulin degludec. It's an insulin analogue with fatty-acid side chain, which prolongs both absorption and clearance. It comes in U100 and U200 pens. “It's not available in vials,” which may be a downside to patients who prefer syringes to pens, she noted.

Degludec has a very long duration of action (42 hours) and comparable efficacy to insulin glargine, but patients using it have less variability in their glucose levels, she reported. Another advantage is that the pens can be used for up to eight weeks after they're opened. “Many other pens once you start using it, you have to throw it away after 28 days,” she said. The U200 pen also allows delivery of a lot of insulin: 160 units with one injection.

A trial published in the New England Journal of Medicine in August 2017 compared insulin degludec and insulin glargine in patients with type 2 diabetes, many of whom also had cardiovascular disease. It found similar glycemic control and cardiovascular events, but lower rates of hypoglycemia with degludec. “You'd have to treat about 30 patients with degludec as opposed to glargine to prevent one episode of hypoglycemia,” Dr. Kirkland reported.

“I'm very quick to try to move people to degludec. If [other insulins] are on the same tier, I'll preferentially use degludec,” she said.

It's not just basal insulins that have seen improvements in recent years. Researchers have been working to make prandial insulin function more like the pancreas. “Before anything actually gets to affecting our blood glucose, even just looking at food, tasting food, there is secretion of insulin from the pancreas,” Dr. Kirkland explained.

Even rapid-acting insulin does not take effect that quickly. “What's really the Holy Grail in terms of mealtime insulin is to have some kind of ultra-fast insulin,” she said. There are three approaches to achieving this goal: administering insulin in some different way, changing its formulation, or somehow altering the injection site (such as applying heat or hyaluronic acid).

A new, very fast way to administer insulin was already discovered and approved back in the early 2000s, but inhaled insulin didn't catch on the first time around. “It was actually taken off the market by the company just for commercial reasons,” said Dr. Kirkland. One issue was that the insulin inhaler was very large. “It kind of looked like they were using a bong. It wasn't very discrete.”

The new insulin inhaler is much more subtle, more like an asthma inhaler, Dr. Kirkland said. Its effects come and go very quickly, with peak levels in 20 minutes and a half-life of an hour.

There are a number of caveats to its use, though. “You have to do spirometry before you start it, and at six months, and annually thereafter,” she said. It's also contraindicated in patients with chronic obstructive pulmonary disease or asthma. The doses come in blister packs of four, eight, or 12 units, so there are not a lot of options for titrating. Adverse reactions—in addition to hypoglycemia, of course—include cough, throat irritation, and throat pain.

Dr. Kirkland also worries about the possibility of more serious effects, such as lung cancer. “I have some concerns about inhaling a growth factor into the alveoli,” she said. She doesn't prescribe inhaled insulin but noted that some endocrinologists “love it” and it could be good for patients who are needle-phobic or particularly attuned to their postmeal glucose levels.

Innovations in the formulation of insulin have brought us Fiasp, manufactured by Novo Nordisk, a speedier version of insulin aspart. “It is quicker acting—faster on and faster off,” said Dr. Kirkland. “The problem is that in the trials, it wasn't that impressive.”

According to a study published in Diabetes, Obesity and Metabolism in December 2018, the faster formulation did reduce postprandial hyperglycemia compared to regular insulin aspart, but there was no significant difference in HbA1c. It was approved on the basis that it was noninferior to existing insulin, and again, might be most useful in those concerned about postprandial hyperglycemia, Dr. Kirkland noted.

“Outside of some specific conditions, such as pregnancy, we don't know that treating postprandial hyperglycemia is going to improve outcomes,” she said.

What does definitely improve outcomes is getting patients the insulin they need, and Dr. Kirkland closed her review of insulin hot topics with some tips for ensuring access to this suddenly costly drug.

“Insulin costs are going up really disproportionally compared to other drugs,” she said. “There's not really a clear reason for that.”

To deal with this problem, internists should remember that human insulins are cheaper than analogues and that vials are cheaper than pens. Another option to consider is that Walmart and Sam's Club sell human insulin over the counter for about $25 a vial, which may be less than some patients' insurance copays.

For patients taking that approach to buying insulin, Dr. Kirkland says, “I'm not even going to write a prescription. I'm going to write out the words of what you need to tell the pharmacist.”