By: Ben Eastman
Eli Lilly, the manufacturer of 80 percent of America’s insulin is planning to take Iletin I (beef/pork) insulins off of the market.
Lilly has made no formal public announcement of these plans, but since May of this year anyone who calls Lilly’s 800 customer service line is politely informed that, “Production will cease in 1998, and it is expected that the stock will be completely depleted some time in 1999.”
What does this mean for the estimated 300,000 in the United States who depend on Iletin I? It all depends on who you ask.
Pros and Cons
For years the benefits and disadvantages of animal and human insulins have been debated. Many argue that animal insulins are an outdated form of insulin therapy that presents a number of potential complications, and that the problems some patients claim to experience on human insulin are unsubstantiated. From as far back as 1987 it has been believed that human insulins are the insulins of choice for “Patients with a history of animal source insulins … women with type 1 of child bearing age, pregnant women with type 1 or 2 … type 2 patients who require insulin temporarily … (and) type 2 patients who develop the need for insulin due to loss of islet cell mass,” among others. (Arthur Krosnick, MD, Consultant, July 1987;27(7); 78-87)
Still, patients and doctors have reported to have found clinical advantages using animal insulin.
James R. Hart, Jr. of Corning California is one of these patients. For 37 years Hart was a well controlled type 1 on NPH Iletin I (50 units per day). Then he switched to human insulin.
“I started suffering from poor control and hypoglycemic unawareness,” he says. After hearing that others had experienced similar problems Hart “demanded to be put back on Iletin I.” Since switching back he reports being “under control again, and my hypoglycemic warning signs have returned to the level that I had known all those previous years.”
Hart is not alone in his experiences with human insulins. Still, some members of the diabetes care community are reluctant to give much weight to anecdotal reports like his. Some believe that this reluctance may be partially responsible for Eli Lilly’s plans to discontinue the production of Iletin I in the near future.
Matthew Kiln, MB, BS, DRCOG, FRSH, notes that many medical professionals disregard claims against human insulins (especially regarding adverse reactions) that are based on anecdotal evidence. “Unfortunately, when looking at this point, official bodies (i.e. the BDA, ADA, drug companies, etc.) do not consider reports from patients to be evidence. I am afraid to say that even if thousands of patients report problems with certain types of human insulin, this is not evidence,” he says.
This hesitancy to accept anecdotal reports of problems with human insulin could stem from the belief of some medical professionals that people’s preferences for certain medications and practices are often emotionally charged rather than grounded in fact. They claim that once people have decided that a particular practice or medication is problematic for them, no amount of objective evidence to the contrary will change their minds.
Andrew Farquhar, MD, relates a story of his own that illustrates the lack of respect some members of the medical community have for anecdotal evidence. At a recent meeting of diabetes care professionals, Farquhar and other medical associates who are insulin dependent voiced their problems with human insulins and preferences for animal insulins. A participant in the meeting then suggested that any such problems result from a lack of understanding of how to design proper insulin treatment regimens.
“At first I laughed at the suggestion. But then after I thought about it I became incensed,” says Farquhar. Not only was his clinical, medical experience and understanding called into question because of his preference for animal insulin in certain situations, but his personal experiences were completely discounted. While this may be a somewhat shocking affront to a medical doctor, countless people on insulin who are not medical professionals can no doubt relate to this sort of interaction.
“Call it anecdotal [problems with human insulin] if you like, but there is a real problem here. It truly upsets me that some physicians disregard what their patients are telling them,” he adds.
Farquhar is not alone in these beliefs. “Spontaneous reporting of adverse events is recognized as the most effective way of detecting relevant side-effects,” reads, “Valuable Lessons in Insulin Anecdotes,” by Laurence Gerlis, MA, MB, BChir (Cantab), MRCP, FFPM, in the February 1996 issue of Hospital Update.
In fact, “physicians and consumers are encouraged to report all suspected adverse drug experiences (ADE), not just those that are already known to be caused by the drug,” reads the FDA’s Annual Adverse Drug Experience Report: 1995. (Reports should be made to MedWatch, the FDA’s medical products reporting program at (800) 332-1088.) From voluntary reports provided by health care professionals and consumers, Humulin insulin was ranked number eight on the FDA’s “Postmarket Adverse Drug Experience Reports by Top-10 Ranked Suspect Drugs” in 1995.
Still, many medical professionals believe that if most animal insulin users were blinded to the type of the insulin they were taking and were provided with a new injection schedule that took the insulins’ differences in action into account, they would have a very hard time determining which was which. Nancy Bohannon, MD, likens the situation to people with diabetes who claim that they don’t need to test BGs because they can sense when they are too high or too low. They vigorously defend that they are capable of doing this, but when they have been clinically tested, they are not able to do it at all.
Pharmacist Keith Campbell, RPh, CDE, who has had type 1 diabetes for 48 years agrees. “I understand the emotions involved with switching insulins very well.” He says that it took him two years to make the switch from U80 to U100 because he was so reluctant to “fix what wasn’t broken.” In the end, however, he made the change and has done just fine.
Why Is It Being Pulled?
After repeated requests, Eli Lilly declined to comment on the proposed discontinuation of Iletin I. Despite this, many have their own ideas as to Lilly’s motivation. Almost every person contacted for this article, regardless of their stance on the reported differences between insulin species, agrees that Iletin I is being pulled for economic reasons.
For some this makes perfect sense. “Why should they [insulin manufacturers] go through the process [extracting beef pork insulin] when it is totally unnecessary and cost ineffective,” says Campbell.
Nicholas Mezitis, MD, notes that the insulin companies have a monopoly like position in the insulin market. He wishes that these companies would “respect their ‘monopoly’ position,” and not make decisions to cut products and services based strictly on numbers.
“Financially, yes I see it [pulling animal insulins]. But there is a subset of people out there who does well on beef/pork insulin. Why should they have to suffer?” asks Mezitis.
Farquhar agrees and points out that, “The only option available for people like me, who may wish to continue using animal insulin, is to import it from the United Kingdom where it is still being produced.”
Many argue that human insulin improves metabolic control. “The results of this study demonstrate that a significant number of [type 1] patients who are being treated with animal insulins will improve their metabolic control and decrease their insulin antibody response when they are transferred to human insulin,” reads a paper by John K. Davidson, MD, PhD (Clinical Therapeutics, vol. II no. 3, 1989).
Jaime A. Davidson, MD, FACP, “demonstrated a significant improvement in blood glucose control,” after comparing HbA1c values before and after the switch from animal to human insulins in a study published in the February, 1989 issue of Resident and Staff Physician.
However, a number of others insist that human insulin has no effect on metabolic control. “Obviously, the change from animal to human insulin, per se, does not improve metabolic control,” reads “Clinical Pharmacology of Human Insulin,” a paper by Heinemann and Richter, published in the December 1993 issue of Diabetes Care.
“Manufacturers may in the future have to think carefully about bringing new drugs to the marketplace unless they are anticipated to have a clinical advantage, which human insulin does not,” reads a commentary in the April 2, 1992 issue of Nature by Simon P. Wolff.
Proof or Spoof
Some feel that trying to prove that a particular insulin species has universal advantages is pointless, and that Iletin I should remain available simply because no two people react to insulin in the same way.
“Since every individual with diabetes is different — with different weight, height, calorie requirements, meal plans, general level of activity and metabolic and psychological activity — each person needs different insulin actions, or type and amount, to meet their specific needs,” says John A. Hunt, MB, BS, FRCP(C).
Hunt is not alone in this belief. “The choice of insulins with appropriate pharmacological characteristics, purity and origin of the insulin preparations are important prerequisites for optimal therapy,” reads the Heinemann and Richter paper.
Length of Action
“Human insulin tends to have a faster absorption and shorter duration of action compared with animal insulin,” reads the Heinemann and Richter paper.
The ADA agrees and goes on to rank the actions of the various insulin species. “Human insulins have a more rapid onset and shorter duration of activity than pork insulins, whereas beef insulins have the slowest onset and longest duration of activity,” reads the ADA’s article, “Insulin Administration,” published in the January 1997 issue of Diabetes Care. (For a listing of insulin action profiles see page 14 of our October, 1997 issue.)
The Heinemann and Richter paper also points out that the first clinical trial with diabetic patients found that, “significantly higher blood glucose levels were observed with human insulin before the morning and evening injection compared with the levels when treated with animal insulin. This was attributed to the more rapid absorption of the human NPH insulin.” (Clark et al. The Lancet ii: 354-57, 1982)
Human insulins’ shorter duration means that people switching from animal to human insulins may have to add more injections to their daily insulin regimen to compensate for these increased BG levels.
“Sometimes, switching to human insulin means increased injections. If patients are under control with beef/pork insulin and don’t want more injections, that’s another reason for staying with animal insulin,” reads the Canadian Diabetes Association’s (CDA), “Report on Beef-Pork Insulins,” originally published in the summer, 1996, special edition of Diabetes Dialogue.
Hunt adds that, “Animal insulins, used logically, can often keep excellent control over 24 hours using mixed short and long acting insulins just twice daily. The human insulin usually must be given three times daily, and if the NPH has to be shifted to bedtime [to avoid high BGs in the early morning], then four injections must be used.”
For many this extra shot can prove to be inconvenient. Kemp Randolph, PhD, has had diabetes for 44 years and currently uses beef/pork insulin. For thirty years he was well controlled on one shot of mixed insulin per day. More recently, he has been well controlled on two shots per day. If he is forced to go onto human insulin he realizes he will need to increase to three to four shots each day. For Randolph, this is no small inconvenience.
“Not having to shoot up at lunch time is really nice. It gives me a lot more freedom,” he says. The fact that he will be forced to disrupt his insulin regimen because Lilly wants to discontinue an insulin line has him more than a little frustrated, “I am outraged,” he says.
Hunt points out another potential problem with adding shots to one’s insulin regimen. He cites a principle in medicine that the less often a person has to take a pill, the less chance there is any single dose will be forgotten. Thus, in recent years, there has been a general move in medicine toward long-acting drugs that can be taken at breakfast and will last all day. Hunt believes that, “In diabetes we have gone in the opposite direction, increasing the number of injections and increasing the risk of forgetting an insulin dose.”
Still, here again opinions differ. Campbell notes that many of the patients and physicians that want to see Iletin I production continued, “base their desire for beef insulin on its longer action.” Rather than giving great weight to the convenience of taking fewer shots of insulin each day, he believes the more important thing is to, “maintain close control with flexibility. So why not take two shots with human insulin as a basal.”
“It is not a point of the number of shots per day, but the smoothness of basal control,” claims Farquhar. He notes that a smooth basal control is especially important now that more and more people are using the rapid acting Humalog insulin. If some patients will need to take as many as, “three shots of ‘basal’ insulin a day then it is not really a good basal,” he argues.
Insulin Antibodies — Friends or Foes?
Several studies, as well as the experiences of many physicians and insulin users, have shown that animal insulins last longer. But why is this? Antibodies may be part of the reason.
The body often produces antibodies to animal insulins that bind to the insulin and, in effect, take up the insulin’s time as it is working to lower blood sugars. There is no way to be sure of this, but many suggest that this results in the insulins’ prolonged duration of action.
The formation of antibodies is one of the many issues that helps to form differences of opinion among health care professionals.
According to Campbell, studies have shown that the formation of antibodies (especially in reaction to beef insulin) can be problematic. “If insulin is bound to antibodies, its action is unreliable — the predictability is gone.”
Others feel that using the presence of antibodies to argue against animal insulins is without merit. “Even injected synthetic human insulins cause antibody formation to a small degree,” reports Michael Bryer-Ash, MD, of the Division of Endocrinology, University of Tennessee, Memphis.
He goes on to say that even the new lispro insulin could stimulate antibody production, “We don’t yet have follow-up data from a large population taking lispro insulin over a long period of time. It’s a bit of an over simplification to say lispro is a human insulin. Changing the order of the lysine and proline molecules changes the physiochemical properties which could have the potential to cause an antibody reaction — much like the ones we see in some persons who take animal insulins.”
Hunt adds that, “Antibodies have been grossly overb
own and have been used for commercial purposes. Animal insulin has been used since 1921, and no one has made a fuss about antibodies until human insulin was made available. At the same time antibodies to human insulins have been downplayed.”
Hunt also points out that antibodies to one’s own naturally produced human insulin are present in a number of people with diabetes. These insulin antibodies are formed long before any type of injected insulin therapy begins.
Still others feel that the formation of antibodies can even be helpful when developing injection schedules. Mezitis has experienced that animal insulin not only has a longer duration of action, but that it has a smoother peak. While he sights no clinical studies to substantiate his claim, he feels that the action of the antibodies make the insulin work in a smoother, more predictable way in some patients.
“It is probable that antibodies are a huge advantage for me because they smooth the insulin peak and make its action much more predictable,” says Farquhar, who tried to switch to human NPH but stopped using it after a “very frustrating four months of fluctuating blood sugars.”
Stephen Leichter, MD, FACP, FACE, believes that people on both sides of the debate are right. Leichter points out that all patients are different. He notes that some patients may experience similar courses of action on human and animal insulins, but others may not. Unfortunately, there is currently no way to know how a person will react to the antibodies besides trial and error.
Not every argument for or against animal insulin springs from its length of action. What follows are purported differences between animal and human insulins that are much more contested.
The ADA’s Complete Guide to Diabetes defines lipoatrophy as when, “fatty tissue under the skin disappears and causes dents in the skin at the injection site … Lipoatrophy is probably caused by an immune reaction, although its exact cause is not known. Your body is responding to insulin as an injected ‘foreign’ substance.”
Carolyn Robertson, RN, CDE, MSN, has experienced “a problem with lipoatrophy” in her practice and believes there is a definite connection between lipoatrophy and the use of human insulin.
However, “All patients on animal insulin who present with immunological problems such as … lipoatrophy should be transferred to human insulin,” reads the CDA’s, “Report on … Beef-Pork Insulins.”
Despite this, it has been Robertson’s experience that lipoatrophy comes on faster with the use of human insulin, and she has had success treating the condition by switching patients to animal insulins.
She also voices a commonly heard frustration when discussing the differences between insulin species — There has been a lack of large, well designed studies investigating the differences between insulin species in terms of their clinical benefits and their influences on reported complications.
One of the most important problems that may occur when patients are changed over to human insulin is a change in dosing.
While some state that, “After transfer from animal to human insulin, the mean total daily insulin dose for the entire group (481 individuals) did not change significantly,” reads the J. K. Davidson study sited earlier.
But others claim that patients will frequently require much lower doses of human insulin than animal insulin. The CDA’s “Report … on Beef-Pork Insulins” points out that, “Insulin dose changes seen in transferring patients from animal to human insulin are often minimal, except for approximately 15 percent of patients who may require more significant dosage adjustments.”
If these patients are not well prepared by their physicians to deal with possible reductions in their daily insulin requirements, serious hypoglycemic episodes may result.
Leichter published a case to demonstrate this problem. One of Leichter’s patients became the first person to receive a commercial injection of human insulin. This patient had been taking 105 units of animal insulin each day prior to being switched to human insulin.
“After 48 hours on human insulin he was down to taking 60 units per day,” says Leichter. If this patient was not under close supervision, or was changed without being informed as to the differences, “this large a dose change could cause severe hypoglycemia,” says Leichter.
Hypoglycemia and Hypoglycemic Unawareness
Perhaps the most controversial difference of opinion about human and animal insulins revolves around hypoglycemia and hypoglycemic unawareness. Some patients and health care professionals claim that using human insulin leads to increased bouts of hypoglycemia, and a substantial loss of warning signs of approaching hypoglycemia. These claims are anything but universally supported, however.
The first report associating human insulin with changes in hypoglycemic warning signs was published in 1987. In this work the authors, “described in The Lancet what we termed ‘human insulin hypoglycaemia unawareness,’ seen in 66 out of 176 diabetic patients transferred from beef/pork insulin to human insulin … Patients on human insulin experienced less often the classical warning symptoms such as sweating, tremor and hunger. These symptoms recurred when the patients were transferred back to animal insulin. On the other hand, neuroglycopenic symptoms such as a lack of coordination, visual disturbances and headache were more often mentioned as warning symptoms with human insulin,” write Teuscher and Egger of the study “Hypoglycemic Unawareness in Diabetics Transferred to Human Insulin.” (The Lancet, 1987; ii: 382-85)
Studies followed supporting the claim that human insulins are associated with a decrease in hypoglycemic warning signs. The findings of a study by Kern et al., “suggest that hypoglycemia induced by human insulin can be more detrimental to early sensory processing in humans as compared to [pork] insulins.” (Clinical Physiology and Biochemistry, 1990:8:122-127)
Other studies claim switching to human insulin might increase the frequency of hypoglycemic reactions. “Transfer of treatment from animal insulin to human insulin was associated with an increased risk of severe hypoglycemia. Caution should be exercised when transferring diabetic patients to human insulin,” reads a case control study by Egger et al. published in the September 14, 1991 issue of the British Medical Journal.
Several other studies and papers have been published that counter the human insulin hypoglycemia connection. “We could find no statistically significant differences between the insulin species with respect to glycemic control or the frequency, timing, severity or awareness of hypoglycemia,” reads a study by Colagiuri, Miller and Petocz. (“Double-Blind Crossover of Human and Porcine Insulins in Patients Reporting Lack of Hypoglycemia Awareness,” The Lancet, 1992; 339: 1432-35)
“This study shows that hypoglycemic warning symptoms and the incidence of severe hypoglycemia are comparable between patients on treatment with human and animal preparations,” reads a study by Muhlhauser et al., published in the August 1991 issue of Diabetes Care.
As can be seen from these few studies, there is anything but a consensus on the effects of different insulin species on hypoglycemia and hypoglycemic unawareness. Regardless of the disagreement in research circles, many patients claim to have experienced differences between insulin species.
“I have used animal insulin for over 40 years, and I find that I do not do well with human insulin,” writes insulin user Marilyn R. Schnabl Guenther, from Lakeport, California. “I cannot ‘feel’ my lows, which is not a good thing! Changes from the old reliables … have not been favorable for me,” she adds.
Some patients have even found that they experience differences between different species of animal insulins. Randolph has never taken human insulin at any time in his life and says he has HbA1cs, “in the 6% range.”
During his 44 years of insulin dependence he was switched from the older beef insulin to Iletin I. His doctor later switched him to Iletin II (purified pork), but he began to suffer from hypoglycemic unawareness. He then demanded to be transferred back to the Iletin I.
“Even though I am a long-term diabetic and my hypoglycemic awareness threshold is low, my threshold has been raised by approximately 15 to 20 mg/dl,” Randolph says of his switch back to Iletin I. But stories like Randolph’s are not sufficient evidence of a problem for many in the diabetes community.
What Will the Future Bring?
A recent article, entitled “Insulin Lispro: The Next Step,” by Christian D. Herter, MD, CDE, suggests that the future of insulins may be dominated by the use of insulin analogs like lispro, and that “there may come a time when the use of ‘real’ insulins becomes unusual.” (March/April, 1997 edition of Clinical Diabetes)
But Herter goes on to say that, “Until then, our success in helping our patients approach euglycemia depends on the artful application of many types of insulin products.”
Heinemann and Richter also note that patients’ understanding of the differences between insulins is crucially important, “most important, the patients must receive instruction on the time-action profiles of the insulins they use, and information on how to adapt the doses to achieve good metabolic control while avoiding hypoglycemic episodes,” they write.
The ADA concurs. “Pharmacists and health care providers should not interchange insulin species or types without the approval of the prescribing physician and without informing the patient of the type of insulin change being made,” reads its January 1997 article in Diabetes Care.
Some point out that even if all animal insulins are eventually pulled, there are synthetic insulins being developed that should fill the void. “HOE 901 is now in clinical trials for FDA approval. It is a long acting basal insulin unlike the human UltraLente. It is more like the old animal UltraLente,” says Bohannon. She adds that “One shot at night should provide good 24 hour coverage … if it works the way it is supposed to.” However, Bohannon estimates that it will “probably take about three years” for HOE 901 to be put on the market—if everything goes according to plan.
Similarities and Differences
When it comes to the animal vs. human insulin debate there are a number of opinions as to the importance, and even the existence, of differences between insulin species. To make the matter even more confusing, there is continuing debate over the importance of anecdotal reports of such differences.
However, all this means little to the people who feel that they have an easier time on Iletin I and other animal insulins. They simply believe that certain insulin species are easier for them to handle and others appear to cause problems.
If there is anything in the debate over insulin species that is agreed upon, it would most likely be the fact that some people can be changed from one insulin species to another without incident, and that others claim that such a change presents them with numerous problems. Because no two people are alike and reactions to switching insulins are unpredictable, many would like to see that the current insulin choices remain available.
Steven Lazarus, an investment banker from New York City, is one of these people. He used to be on animal insulin and had troubles when he was switched to human. When he went back to animal insulin many of those problems were solved. A few years later, however, he switched back to human and has since successfully stayed on human now that Humalog is available.
“Every time there is a bit of adjustment in an insulin regimen, there is a bit of getting used to,” says Lazarus. He notes, however, that he has had diabetes since infancy and takes a very proactive role in the management of his condition. In addition, he claims he has a good working relationship with his physician so the adjustments and questions that come up can be handled with relative ease.
He also realizes that he is not necessarily the typical diabetes patient. He points out that some people with diabetes are very reluctant to discuss their condition and do not necessarily take as active a role in developing their insulin regimens. Many people also may not have insurance coverage and may have only minimal contact with a physician. It is these people that Lazarus and others worry about the most.
Leichter points out that the relationships between generalist and specialists are strained at best and add to the problem. “How can we be sure that those who may have a hard time with a switch to human will be referred to a specialist who can give them the attention and expertise they need?” he wonders.