The Days of Animal Insulin May be Numbered – Should Corporations Make the Decision?

The future of animal insulin looks grim. Now that 90 percent of people with type I diabetes are taking human insulin, no one denies that the era of animal insulin may be coming to a close. But for those who have come to depend on it, the availability of animal insulin is vital.

The pharmaceutical companies who manufacture insulin in the U.S.-Eli Lilly and Novo Nordisk-say they will continue to supply animal insulin into the next century, but are quick to point out that demand continues to fall each year. Both assure physicians and patients that their companies would never pull animal insulin from the market without consulting consumers first.

“We would work with patient groups to help people prepare,” for the discontinuation of animal insulin, said Kelly Sego, a spokesperson for Eli Lilly. “This isn’t something that we would spring on the market.”

Steven Lazarus, a 33-year type I diabetes veteran, scoffs at such assurances. “That’s crap,” he said. “Gee, they care about humanity? I just don’t believe that.”

Lazarus is a sceptic for good reason. In 1993, Eli Lilly halted production of animal ultralente insulin, a long-acting basal insulin. A year later, on September 2, 1994, Novo Nordisk discontinued its entire bovine source insulin line, including animal ultralente, the type Lazarus was taking. “Both Novo and Lilly pulled (animal ultralente) without so much as a hello,” he said. When he found out about Novo Nordisk’s plan to pull animal ultralente, Lazarus said he called corporate headquarters, “made a stink,” but was just given the run-around. “I was told it was strictly a business decision.”

Physicians are also wary of pharmaceutical company claims of goodwill. Dr. Irl Hirsch, a Seattle endocrinologist, said he was furious when past animal insulins were pulled from the market without proper warning. In response to their latest guarantees that patients will continue to have a choice, Hirsch said, “that’s what I was assured by Novo Nordisk about the beef ultralente insulin-I was assured it would be around into the next century.” But that did not prove to be the case.

Currently, there is no animal ultralente insulin available in the U.S. Other animal insulins, extracted from the pancreases of pigs and cows, are still on the market. Novo Nordisk only makes purified pork insulin for U.S. distribution, while Eli Lilly makes six formulations, but no animal ultralente. Animal ultralente is thought to have the longest action, lasting from 36 to 40 hours with virtually no peaks. By contrast, human ultralente insulin lasts anywhere from 20 to 24 hours, with an extremely variable peak occurring four to 16 hours after injecting.

Dr. John Hunt, a Canadian physician with 40 years of insulin experience, notes that other insulins have a shorter duration of action than animal ultralente, with progressively earlier peaks. The approximate order from longest to shortest-acting, according to Hunt, is as follows: animal ultralente, animal lente, animal NPH, human ultralente, human lente, human NPH, animal semilente, animal regular, human regular and Lispro.

When animal ultralente was pulled human ultralente was offered as the alternative. An option Lazarus calls “no alternative at all,” because it does not provide for the long action that animal ultralente had.

The pharmaceutical companies “have an obligation to provide a complete line of insulin,” said Dr. Nicholas Mezitis, a New York City diabetologist. “It’s a little cavalier to deny practitioners the opportunity to decide which insulins to prescribe. I don’t see how they can phase out animal insulin when it’s very well documented that there are differences between (animal and human) insulin,” he said.

Is Newer Necessarily Better?

Before 1982, when Genentech engineers first used recombinant DNA technology to make human insulin from E. coli bacteria, animal insulin was the only choice for people with diabetes. With the advent of human insulin, many physicians stopped prescribing animal insulin, having been convinced that human was a purer alternative, a technological advance and a leap for medicine. (Current animal insulins are very pure-far purer than they were several years ago.) Now these assumptions are being called into question.

In 1989 animal insulin still constituted 45 percent of Novo Nordisk’s insulin sales worldwide. This figure has fallen dramatically each year. In 1995 animal insulin made up only nine percent of the insulin market. Despite these numbers, Novo Nordisk spokesperson Susan Jackson said the company has no plans to discontinue their remaining animal insulin.

As with any new product, advertising had a lot to do with human insulin’s seemingly overnight domination of the market. Dr. Andrew Farquhar, a long-time Canadian physician with diabetes, noted one particular advertisement in the Canadian Diabetes Association publication which featured a superfit “Iron-Man” triathlete encouraging patients to ask their physicians about the better control attainable with human insulin. The message: be healthy-use human.

But the health of patients hasn’t necessarily been the cause for the switch. One main reason so many physicians have been prescribing human insulin, especially for new type I patients, is because they fear animal insulin will one day be discontinued. All animal insulins have already been pulled from pharmacy shelves in other countries such as Italy, Norway, Sweden, Denmark and Australia.

In countries where it is still available, pharmacies are often reluctant to stock animal insulin simply because the demand isn’t what it used to be. Dr. Hirsch noted that some of his patients have to place special orders for animal insulins and that pharmacies are not always happy to accommodate. Availability, he said, “is particularly a problem in rural areas, where the typical corner drug stores just don’t stock it.”

In his practice, Hirsch said, between 96 and 98 percent of his patients are using human insulin not because it’s better but “because it’s become clear that animal insulins are being phased out.” This rationale is common among practitioners.

“Do I start new patients on human insulins? Yes I do,” said Dr. Howard McEwen, a Canadian diabetes specialist. “Mostly because I expect that animal insulins will not be available in the future.”

Animal vs. Human-The Debate Continues

Lately the safety of human insulin has been called into question. Critics of human insulin often cite two particular shortcomings. They say human insulin does not provide for the smooth glycemic control that can be achieved with longer-acting animal insulin. The other oft-heard complaint is that human insulin may be linked to hypoglycemia unawareness-an abrupt onset of hypoglycemia without the typical warning signs.

Even if problems like hypoglycemia unawareness occur in a minority of patients using human insulin, “for these people it seems reasonable to have them switch to animal insulin,” said American Diabetes Association president Dr. Philip Cryer. He believes that the same degree of glycemic control can be achieved with either animal or human insulin.

Animal insulins, because they are a foreign substance, act more slowly in the body. When first injected, antibodies attach themselves to the animal insulin molecules, but later release them into circulation. When human insulin is injected, no such antibodies are produced. This allows for a faster mode of action within the body.

“A few years ago I succumbed to the persuasive advertising and made the change from beef/pork NPH to ‘human’ NPH,” wrote Dr. Farquhar in a April 3, 1995 letter to the B.C. Medical Journal. “My personal experiences (as a patient) convinced me there is a very significant difference in the (actions) of the two insulin preparations and discussions with many other individuals indicated the difficulties I encountered were not at all unique,” he wrote. “After three very frustrating months (taking human insulin) I finally reverted back to animal insulin and feel this may have been one of the best decisions of my medical career.”

June Biermann, an author who has written extensively about diabetes, had trouble when she switched to human source insulin in the early ’80s. “Instead of having my regular good blood sugar control, I was all over the place.” She laments the passing of the animal ultralente. “It was really great therapy,” she said. “We called it the poor man’s pump,” because of the consistent blood sugar control it offered.

It is not uncommon for patients to benefit from a change in insulin therapies. Dr. Farquhar related one such experience of a patient who had lived for years with severe episodes of hypoglycemia unawareness. “As a practicing pharmacist, she felt human insulin was the best product,” he said. “After finally convincing her to switch to animal insulin, within a couple of weeks her life had changed dramatically” for the better.

Dr. McEwen, who has supervised an intensive diabetes program in Canada since 1986, believes that animal ultralente is what patients liked most about the program. Patients took human regular insulin before meals and beef-pork ultralente once a day as a basal insulin. “The ultralente beef-pork insulin became one of the selling points of the program and was loved by the diabetics, who often remarked that for the first time they were able to control the diabetes rather than have the diabetes control their lives.”

Forced to switch to human ultralente when the animal ultralente was pulled from the market, McEwen’s patients began having problems. “The human ultralente…was found to peak and be unpredictable and result in frequent episodes of hypoglycemia.”

Since its release, the official FDA labeling of human insulin bottles has carried a warning which reads: “A few patients who experienced hypoglycemic reactions after transfer from animal source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin.”

Hypoglycemia unawareness is one of the reasons why Dr. McEwen hopes animal insulins will remain on the market. “Human insulins are useful in a few rather rare situations such as insulin allergy, insulin resistance and insulin atrophy,” according to Dr. McEwen. “That has to be balanced against a rather high incidence of hypoglycemia unawareness which does exist.”

Cost is another complaint some practitioners have with human insulin. Though “synthetic human insulin is cheaper to mass produce, this savings has not been passed on to the consumer, who must pay, on average, $2 more per vial of insulin,” said Dr. Farquhar. “In the U.K. it has been estimated that the switch to synthetic human insulin has cost the National Health Service an additional 19 million pounds ($41 million dollars) per year,” he said.

Sego, Eli Lilly’s spokesperson, said a manufacturing cost comparison between animal and human insulins “is hard to determine. It isn’t easy to simplify because of the technology involved.” She could not quote a cost per vial of each insulin type, but said that animal insulins were increasingly expensive to manufacture because of the decline in demand.

An informal survey of insulin prices at San Francisco pharmacies revealed that Eli Lilly’s standard animal regular insulin is, on average, $2.00 cheaper per vial than human regular insulin.

Defenders of Human Insulin

For every animal insulin advocate, there are just as many human insulin proponents ready to discount any claims that human insulin may be to blame for fluctuating blood glucose levels or hypoglycemia unawareness.

Many physicians believe the charges against human insulin are simply overstated. Dr. Hirsch says the data regarding human insulin and hypoglycemia unawareness is “just not all that convincing.”

Carol Robertson, a certified diabetes educator who has roughly 600 patients in her practice, said she has yet to see any incidence of hypoglycemia unawareness connected to human insulin use. She believes hypoglycemic episodes have more to do with unstable blood sugars. “Does that explain every single report of hypoglycemia unawareness? Not necessarily. I say, OK there’s a potential,” that human insulin may be the cause, “but I haven’t seen it in my practice.”

Robertson does blame human insulin for the development of lipohypertrophy, or fat deposits at the site of injection. She calls this condition “an almost expected side-effect of human insulin use,” and for this reason, often switches patients to purified pork animal insulin.

One of the most vehement defenders of human insulin is Dr. Richard Bernstein, a long-time physician and author with diabetes. He said he’s switched hundreds of patients at a time to human insulin. “I don’t have a single patient who complains of hypoglycemia unawareness or a greater frequency of hypoglycemia,” he said.

Bernstein said he welcomes the day when animal insulins are pulled from the market. He believes animal insulin, not human, is to blame for unpredictable blood sugars. Animal insulins cause the body to produce antibodies which then attach themselves to the insulin. But, reasons Dr. Bernstein, there is no way to predict when these antibodies will release the insulin into the bloodstream. For this reason, patients may experience unexpected episodes of hypoglycemia, he said. “Human insulin takes care of this problem. Because there are no antibodies, there are no unexpected lows.”

Another element of Dr. Bernstein’s preference for human insulin involves his belief that less insulin causes fewer complications. When they switch to human insulin, patients are able to cut their dosages by one-third. Excessively high doses of human insulin, said Dr. Bernstein, probably explain the problems patients and physicians have associated with human insulin use.

For his patients, Bernstein advocates an extremely low carbohydrate diet as a means to avoid taking higher dosages of insulin. As a long-time physician with type I diabetes, Dr. Berstein practices what he preaches and has not eaten a slice of bread in 35 years.

“From the beginning, when human insulin was first released, Lilly never advised the users to decrease the dose,” Dr. Bernstein said. “They said (animal and human insulins) were bio-equivalent and they’re not.”

Ben Weyhing, an executive board member of the Washington branch of the American Diabetes Association who has a 39-year history with type I diabetes said he’s tried a number of insulin regimens over the years. Now Weyhing uses human ultralente and said he’s suffered no ill side-effects.

Like Bernstien, he believes complications come from inappropriate use of different insulins. “If you understand the program of intensive therapy, it works quite well,” he said. But, he added, in his experience, many physicians have expressed an unwillingness to exert the time and effort needed to educate patients about newer, more involved therapies using human insulin. “It’s not rocket science, you just have to pay attention for a while,” after switching regimens, he said.

Which Insulin Regimen is Right for You?

Whichever one works best is the logical answer, say many physicians who have taken up the animal insulin cause. They maintain that, all debate aside, animal insulins should remain on the market for the benefit of those patients who prefer it.

Dr. Hunt believes finding the proper insulin regimen involves matching the metabolism of the patient against the peak and duration of action of specific insulins to achieve the best 24-hour control. “Since no two diabetic individuals are identical, any physician who states that `this is my insulin schedule’ just does not understand diabetes,” said Dr. Hunt.

He noted that studies and scientific medicine are one thing, but clinical experience speaks for itself. “It is my contention that a good clinician works 10 to 20 years ahead of science,” Dr. Hunt said. “No self-respecting clinician would willingly accept poor control of blood sugars since self b
ood testing was introduced in the 1970s. However, I faced many audiences who asked the question; ‘is it proven that good control is important?’ When I had to state that I believed it, but that it was not proven, I was to told to go away and come back when the proof was available.” The landmark 1993 Diabetes Control and Complications Trial finally proved him right.

Dr. Hunt is concerned about the future of animal insulin availability. “I have recently had some of my key insulins removed. It is distressing. I understand that some more are in danger of being removed. This would be enough to make me retire.”

The issue of choice and keeping animal insulins available has led to the founding of three patient advocate groups-the Insulin Dependent Diabetes Trust in England, the Alberta Committee for Diabetic Rights in Canada and the Swiss Association for the Preservation of Natural Insulin (see accompanying page one story). Jenny Hirst, co-chair of the IDDT, said their organization was formed “because patient experiences weren’t really being listened to.”

Hirst noted that in England many patients were switched from animal to human insulins without even being told. Doctors did so, said Hirst, because like so many in the early 1980s, they believed human was better.

Some physicians are listening and they, like the advocacy groups, believe in the importance of maintaining choice. “Physicians have a responsibility to ensure that each patient receives that insulin which is best suited to that patient,” wrote Dr. Farquhar in an Oct. 1995 letter to the Globe & Mail, a Canadian publication. “Drug companies have decided to restrict that choice and, with a few notable exceptions, physicians appear to have been more supportive of them than of their patients.”

Dr. McEwen is not one of those physicians. “I have made it a rule that I do not change any patient over to human insulins if they have good control and are comfortable on insulins of animal origin,” wrote McEwen. “We should be exploring other insulins but we must remember that not all people are the same and what suits one does not always suit another. There should be a choice.”

In the end, said Dr. Hirsch, “patients want what works for them; they just want a good glycemic profile. Some find that animal insulin works best for this smoother control. Patients make the decision about what insulin to use themselves-they read up, do their own investigating.”

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