Physicians hear a common refrain from patients with Type 2 diabetes: “Not the needle! Not yet. Give me three more months. I’ll be good!” So they try with renewed vigor to control their disease without insulin through diet, exercise and oral medications. Inevitably, many patients lapse and their diabetes again slips out of control, doing invisible damage to their kidneys, nervous systems and cardiovascular health.
This cycle of fear and denial has little to do with insulin itself, a normal human protein, but rather its method of delivery: a hypodermic needle.
Many patients are afraid of needles or embarrassed at the prospect of carrying syringes and the associated stigma of ” shooting up” before a meal. But pain and inconvenience aside, injectable insulin also carries a medical risk — hypoglycemia. This occurs when blood glucose falls too low, a common occurrence in people who’ve injected insulin that acts longer than needed, and one that can, in extreme circumstances, prove fatal.
For the nation’s 23 million diabetics and 57 million pre-diabetics, many of whom use insulin, a better way to deliver insulin could be life-changing, enabling them to use insulin therapy earlier in the progression of their disease and reducing the long-term damage. And it could be possible.
Two products that could get insulin into the bloodstream without needle sticks are in the latter stages of clinical trials, with their makers hoping for Food and Drug Administration approval in the next two years.
One is administered via oral spray; the other is delivered via inhaler. Still more are in earlier phases of development. Together they offer the potential for treating the disease in a less onerous, less obvious, less painful fashion.
“Soon after insulin was discovered in the 1920s, doctors immediately recognized that it would be an advantage if they could get it into the body without injection,” says Dr. Gerald Bernstein, vice president for medical affairs for Generex, which developed the spray.
But getting insulin, a very large protein, past the body’s protective barriers and absorbed across small patches of surface area has proved difficult.
Better Delivery System
Injectable insulin is familiar — it’s been around for 80 years — but it has drawbacks. The hormone must be injected multiple times throughout the day to help the body store glucose properly and keep bloodstream levels low. Uncontrolled high blood-sugar can destroy eyesight, nerves and kidney function.
But insulin injected under the skin has to work its way through fat, muscle and connective tissue to reach the bloodstream. Because of this, insulin activity can persist long after a meal, shuttling too much sugar out of the blood and creating hypoglycemia. Fear of the resulting dizziness, fainting or possible coma can keep some patients from using injectable insulin.
There have been many attempts historically to create an insulin pill, but the digestive tract is, well, digestive to large proteins like insulin; after all, the stomach is designed to break down the proteins in our meals.
The new products would speed insulin to the bloodstream in a more consistently absorbed fashion without being destroyed by the digestive system.
The oral spray, called Oral-lyn, delivers liquid bubbles containing insulin to the lining of the mouth, also called the buccal mucosa. “It goes right into the bloodstream; there’s no place to hang out,” Bernstein says. “The advantage is that [its activity] peaks much faster than even the most rapid-acting injectable insulin. It’s got a two-hour window, and when it’s finished, it’s finished.”
That, he says, enables patients to take it immediately before a meal, with a reduced risk of experiencing low blood sugar hours later. Oral-lyn is delivered in a puff of medicine much like an asthma inhaler.
Afrezza, the other product in the latter stages of testing, also uses a small inhaler device but one that directs the medication toward the lungs. Its maker, MannKind Corp., believes it can succeed where other inhaled insulins have failed.
One inhaled insulin, called Exubera, was actually approved by the FDA in 2006, but it failed to generate sufficient sales and was pulled from the market by Pfizer the next year.
The Exubera device was about the size of a tennis ball canister — almost as embarrassing to whip out at a restaurant table as a syringe — and calculating the insulin dose proved confusing and complex. In addition, some patients and doctors were concerned that the relatively large insulin particles delivered by Exubera might leave deposits in the lungs that would increase cancer risk.
Peter Richardson, chief scientific officer of Valencia-based MannKind, says his company learned from the Exubera missteps. Afrezza comes in a palm-sized inhaler with simple four- or eight-unit doses.
Afrezza’s insulin catches a ride on nanoparticles. The nanoparticles and the insulin get absorbed rapidly through the lung’s air sacs into the bloodstream, and the inert nanoparticles eventually are eliminated from the body via urine, he says.
Data from ongoing Phase III trials on both devices were presented at a meeting of the American Diabetes Assn. in June. And an Afrezza study was published in the medical journal the Lancet in June. In that research, 448 patients took either Afrezza or injected insulin at mealtimes for one year. Afrezza controlled blood sugar levels as well as injected insulin and resulted in less of the weight gain associated with starting injected insulin — about 2 pounds for patients on Afrezza compared with 5.5 pounds for patients on injected insulin. In addition, Afrezza patients experienced fewer episodes of mild-to-moderate hypoglycemia (48% of the group, compared with 69% of the injected insulin group) and fewer episodes of severe hypoglycemia (4%, compared with 10%).
Oral-lyn is still enrolling people in Phase III trials, scheduled to be completed early next year, but the preliminary results announced in June showed similar benefits when compared with injected insulin — less weight gain and fewer episodes of severe hypoglycemia. MannKind says it expects Afrezza to become available in 2011.
Both companies say their products do a better job of mimicking the natural, fast-acting spike of insulin released from the pancreas during mealtimes.
“Faster yet than injectable insulin is a good thing,” says Dr. Daniel Lorber, an endocrinologist in Queens, N.Y., who completed the published trial of Afrezza and has consulted for MannKind. Also, unlike injected insulin, neither product must be refrigerated.
Dr. Richard Bergenstal, president of medicine and science for the diabetes association, notes that other insulin products are also being developed — for delivery through the nasal membranes and as oral pills.
“The biggest problem we have with insulin is hypoglycemia,” he says. “If these mimic more closely how insulin is delivered from the pancreas and avoid that, to me that’s the potential benefit here.”
But whether the convenience factors along with the potential of these products to lower the risk for hypoglycemia will translate into a real advantage over injected insulin has yet to be proved, Bergenstal says. Further, he notes, the new devices are somewhat wasteful in that they need to use more insulin to deliver the same dose as an injection, which will push their cost up.
Still, he’s pleased to see progress in making insulin more convenient. “Even as we develop other therapies, insulin is still our tried and true. It’s a valuable treatment that has been around for 80 years, and we know what it does.”
Thank you Kendall Powell/ latimes.com