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Christine Klemp of West Bend, Wisconsin, received a shock when she opened her box of insulin on August 16. A message printed in red ink said, "This insulin will be discontinued. Contact your physician to change to another insulin." Klemp was horrified, because this particular insulin (Iletin I beef-pork) is the only insulin that works well for her. "My life is about to come to an end. I just could not believe this was happening."
Klemp has had diabetes for 25 years and, like many, she was changed over to human insulin several years ago. That is when her troubles began.
On the human insulin she progressed from taking two shots per day to five. And still her control declined. "I could no longer drive, as I was so dizzy that if I turned my head I would be in the other lane of traffic." Then she tried switching back to the beef-pork insulin. "Within three days (of switching to beef-pork insulin) I was again feeling like a human being and in a week I had complete confidence to drive - the dizzy feeling was gone." She was also able to go back to two shots per day.
Leslie Stillman is another beef-pork (Iletin I) insulin user who contacted Diabetes Health seeking help. Stillman, an art teacher and mother from Newark, Delaware, says, "I will do anything to keep this insulin. I have been on it for a long time, and this is the insulin that works for me."
"I contacted everybody: my senators, my state representatives and the governor. I even wrote to Clinton and included letters of support for this issue, but he never responded. I contacted the American Diabetes Association and they were not able to help either.
Like Klemp, when she tried human insulin she was in trouble. "I cannot use the human insulin because it makes me pass out too easily without any symptoms," she says. "I can tell better when I am low on the beef-pork insulin. I get more symptoms, like sweating, so I can get sugar in time."
In June 1998 Eli Lilly and Company began circulating flyers to both U.S. and Canadian Iletin I users, formally announcing their intent to stop manufacturing all three types of mixed beef-pork insulin: Regular, NPH and Lente. Lilly predicts that supplies of Iletin I should be available into 1999.
Who Uses Beef-Pork Insulin?
The Canadian Diabetes Association (CDA) estimates that one-quarter of Canadian insulin users rely on animal insulin. The U.S. Centers for Disease Control and Prevention estimates that roughly half of the 10.3 million Americans with diabetes inject insulin. Precise figures on the extent of animal insulin use are difficult to obtain. In 1997 sources at Eli Lilly told Diabetes Health that approximately 300,000 people with diabetes in the United States use beef-pork insulin.
The information given on the health care professional's version of Lilly's discontinuation notice conflicted with the patient's version. The patient version claims that, "In the United States, only 6 percent of patients who use insulin today use animal insulin." The citation given for this figure was "Data on file. Eli Lilly and Company." Upon asking for a copy of the data cited, Diabetes Health was told by a Lilly customer service representative that the "citation was cross-listed in a medical letter," which can only be dispatched to health care professionals.
A discontinuation letter sent to health care professionals states that, "Today, fewer than 6 percent of insulin users in the United States use Iletin I." Six percent of 5 million insulin users equal roughly 300,000 beef-pork users. Whether the 6 percent figure applies to all animal insulin users or the subset of insulin users who inject Iletin I mixed beef-pork, there is clearly a population using animal insulins.
The Lilly discontinuation materials do not mention that pork insulin (Iletin II) is still available. It states, "Lilly believes that human insulin is a good alternative to Iletin I," and further recommends that, "Patients who use Iletin I should speak with their physicians as soon as possible about transferring to human insulin." Lilly's customer service representatives confirm that Iletin II will continue to be available, but it seems that the only way to find out is through a direct phone call to Lilly.
For diabetes consumers and professionals, the issue is choice. In facing a debilitating chronic illness, allowing a patient the treatment option that works best for him or her increases the ability to successfully implement that treatment. The ADA's "Standards of Medical Care for Patients with Diabetes Mellitus (Diabetes Care: Volume 21, Supplement 1)" recommends "achieving near normal or normal blood glucose levels in patients." It suggests a "self-management program" that includes a component of "physiologically-based insulin regimens" tailored to "individual patient need." The individualized nature of diabetes clearly requires a full range of insulin formulations, rather than what seems almost exact duplication of species (human and pork) and variety (short and intermediate acting insulins such as Regular, NPH and Lente) by only two manufacturers.
Andrew Farquhar, MD, has a family practice in Canada and uses insulin for his own diabetes. "The ability to synthesize human insulin was an incredible achievement," but "the product falls far short of being a suitable replacement for animal-derived basal insulin." He continues, "I cannot think of another single episode in the history of medicine where a life-sustaining drug was cursorily withdrawn and its substitute provided by the drug companies was more expensive and less user-friendly."
Farquhar is a physician and endurance athlete who tests eight to ten times a day. He prefers beef-pork because he found his "diabetes control had never been so erratic" as when he switched to human insulin. After suffering a particularly frightening episode of hypoglycemia, he changed back to beef-pork insulin, with an almost immediate return of hypoglycemia symptoms and overall smoother control. He argues that "countless others have similar stories," and counts a nurse, pharmacist and fellow physician among those he knows personally who have responded adversely to human insulin.
Another medical professional expressing compassion for patients who rely on animal insulin is Alan Schorr, DO, FACE, whose practice is located in a suburb of Philadelphia. As a self-described "patient advocate," he feels that "there should be choice" for those he treats. "Anytime choice is limited, patients suffer and a physician's job is much more difficult," says Schorr. He also notes that children represent a particular subset of insulin users who respond well to the natural animal formulations.
There are a growing number of insulin consumers who were never offered a choice beyond various types of human insulin, and thus have no basis of comparison for their experiences. Many who started on human and later switched to animal do not wish to go back to human because they feel that animal provides better control and greater stability in their diabetes care.
Deborah Green of Alabama is the mother of two type 1 diabetic children, Robert and Pamela. Green says her son was "experiencing severe hypos in his sleep, slipping into comas and having seizures once a week." She recalls being told repeatedly by doctors, "This is the way it is with diabetes so get used to it!" Robert, then 10 years old, became so despondent over his poor diabetes control that Green insisted upon both children switching to animal insulin. "The results were incredible! Robert was smiling, joking around and happy again," says Green.
Robert is now 11 and in the sixth grade. He believes that his diabetes control has improved. He is proud to note that "I feel when I am low, and I only have to get two shots a day." His sister Pamela did not suffer such severe problems with human insulin, but has reduced her total daily injections from three to two.
The experiences of the Radley family from Canada were similar. Lucille Radley's identical twin sons, Peter and Marc, both have type 1 diabetes. Peter was diagnosed with diabetes in 1990, just after his fourth birthday. Ten months later, he suffered a severe hypo that temporarily left him partially paralyzed and unable to speak. He later described the feeling as "being trapped inside a body that would not respond." Although the debilitating physical effects of the episode lasted less than a day, it left an indelible mark on Peter's memory. He was terrified of a recurrence, and eventually began to suffer anxiety attacks. His glucose levels fluctuated with the increasing severity of the anxiety attacks.
Radley researched the issue and decided that a change from human to animal insulin might help Peter to regain control of his diabetes. Peter's endocrinologist did not believe a change of insulin would do any good. It was not until Radley "broke down completely" in his office early this year that he agreed to the switch. Peter improved almost immediately, beginning with his mood and grades. His blood glucose levels have stabilized, and both he and his mother are pleased to observe that his HbA1c readings took a nose dive from the mid-10 range to the low-8 range, and have stayed there ever since. She says that the doctor now agrees that switching was the best thing for Peter, and regrets having put it off for so long.
Peter's twin brother Marc has had diabetes since 1996. Like Peter, Marc was started on a regimen of human insulin. "Once his honeymoon phase cut out, and his pre-puberty hormones cut in, managing his diabetes became a nightmare," explains Radley. "He would drop like a rock, and shoot up like a rocket." His doctor kept insisting that the poor control was due to lack of compliance. Marc became so depressed over the situation that he told his mother he "wanted to die" rather than continue with diabetes.
Once again Radley sprang into action and had Marc transferred to animal insulin. She noted that within days, "his mood had improved tenfold." On his next visit to the clinic, his HbA1c reading had dropped from 10.2 to 8.1. The doctor and nurses asked if Marc had finally started being more responsible and mature in regards to his diabetes management. "Nope," Marc replied, "I switched to animal insulin like Peter." Radley is glad to once again have her "happy, goofy, fun loving" identical twins back.
Why Use Beef-Pork Insulin?
Why is beef-pork insulin an important treatment choice to many insulin users? Most using beef-pork agree that the primary reasons are slower absorption and greater stability of blood glucose levels. Each species of insulin differs slightly in structural composition. A molecule of beef insulin differs by three amino acids from a human insulin molecule, porcine by one. This leads to the quicker absorption of human insulin and the formation of fewer insulin antibodies than beef. The other side of quicker absorption is a stronger peak and shorter duration, which can lead to greater fluctuation of blood glucose levels and more injections. The ADA's Buyer's Guide To Diabetes Products '98 - Insulin cautions that "human insulins are absorbed more quickly than other forms" and notes that the source of an insulin "affects how fast the insulin is absorbed, peaks and lasts."
Some feel that animal insulin offers the benefit of more easily detected hypoglycemia symptoms. There is no definitive consensus as to why this is so. As early as 1982, Schluter et al. reported that "homologous insulin produces in vivo effects which are different from those produced by heterologous insulin" (Diabetes Care, 5 Suppl 2:78-81 1982 Nov-Dec). Comparing the biological effect of purified pork insulin to recombinant DNA human insulin by inducing hypoglycemia in non-diabetic volunteers, they noted that conterregulatory responses to the two kinds of insulin were different. Those using pork insulin had "higher output of epinephrine, growth hormone and cortisol." They believed that "an elevated incidence of sweating," an early warning symptom of hypoglycemia, "was related to epinephrine secretion."
Kern et al. have published a number of studies on the different influences of human insulin and pork insulin on sensory function during hypoglycemia. They postulate that "differences, occurring during early hypoglycemia, could contribute to the differential awareness of hypoglycemic warning symptoms" between patients using human insulin and pork insulin (Diabetes, 39:1091-8, 1990 Sep).
Given sparse evidence that human insulin offers significantly higher benefits than animal, insulin manufacturers commonly cite "immunologic improvement" in promoting synthetic human over natural animal insulins. Although Lilly emphasizes the lesser "antibody response" associated with human insulin in justifying the discontinuation of mixed beef-pork insulin, antibody levels do not appear to have a negative effect upon one's treatment experience with animal insulin, unless one is disposed to reaction or allergy with it. The CDA asserts that with modern animal insulin, less than 5 percent had bad reactions.
A minority do fare better on human insulin. Candace Chamberlain, a diabetes activist from London, Ontario, is one person who experienced serious side effects while taking animal insulin. She used mixed beef-pork from 1976 to 1995, and was extremely resistant to it, requiring 200 to 300 units per day. The injections damaged tissue in her legs and arms. She feels that the benefits of her transfer to human insulin are lower insulin requirements and improved HbA1c levels. However, she does find she suffers more hypoglycemic episodes in the early morning hours, and worries that the human insulin has led to weight gain. She says, "I have gone from animal insulin that was not lowering the sugar levels to human that is making the sugar levels go so low they crash through the floor." She hopes that a recent switch to Humalog will help to improve her situation.
Chamberlain is still adamant about the preservation of insulin choice for diabetes consumers. She believes that people with diabetes "should and must have a choice. We need to be educated on the choices out there, not railroaded."
Insulin manufacturers and some diabetes care professionals believe there is a lack of scientific evidence for continuing a wide range of insulin choice. A study cited by Lilly on the Iletin I discontinuation flyer in support of using human (Garber, JA, ET al., Clinical Therapeutics, 1991; 13:627-636) found "an improvement in glycemic control parameters" in patients who changed from animal to human. However, it also notes "a significant increase in the number of insulin injections."
A recent French study, "Transferring Aged Type 1 Patients From Animal to Human Insulin," funded by a grant from Novo Nordisk, appeared in the August 1998 Diabetes Forecast. The researchers claim "that Type I diabetic patients were efficiently and safely switched from animal to human insulin without aggravating the risk of hypoglycemia." Information on which species or type of animal insulin was not published. Data was collected via observer report and patient observation. The results are used as a basis for stating, "There is no evidence in the literature that biosynthetic human insulin increases the incidence of hypoglycemia or to suggest that it has the intrinsic ability to reduce the awareness of hypoglycemia."
Teuscher and Berger conducted a comparable, self-reported study, "Hypoglycemia unawareness in diabetics transferred from beef/porcine insulin to human insulin (Lancet, 1987 Aug. 15)." They followed a larger number of patients who switched to human from beef-pork up to 48 months after the change. Thirty-six percent of the patients reported that their hypo symptoms had worsened on human.
Manufacturer-supported research is not necessarily suspect but in many cases it does not jibe with the reports of insulin users themselves, which are often called "only anecdotal."
Diabetes is a synergistic disease. Clearly human insulin is not the only cause of lack of hypoglycemia awareness. Other contributing factors may include duration of diabetes, maintaining tight control, autonomic neuropathy and frequency of hypoglycemic episodes. The debate rages on, and no absolute consensus has been reached in the medical community. Dr. M. R. Kiln of the Paxton Green Health Center in London unsuccessfully attempted to convert to human insulin twice. In a letter to the editor of a British medical journal (Journal of Roy. Soc. Health) he wrote, "I do not understand why I have had far fewer severe nighttime hypoglycaemic attacks whilst on animal insulin therapy. I know that most research has not confirmed these differences, but many patients have found such a difference." His answer is, "That is highly controlled scientific research, and I am a relaxed diabetic patient not living in a controlled trial."
Preparation for Iletin I Withdrawal
Common sense dictates that beef-pork users not wait until they can no longer obtain Iletin I before making alternative arrangements. Choosing your new insulin depends on a variety of factors, including your time, money and energy available for investment in the endeavor. Some will likely do best to select existing domestic insulin formulations, human or pork. Others will wish to explore wider possibilities.
Animal insulin users should note that only Iletin I mixed beef-pork insulin is being discontinued. Mary Hunt is a diabetes activist from Detroit. She and others called a sampling of retail pharmacies across the United States and discovered that some mistakenly believe that all of the animal insulins have been discontinued. This is simply not true. Pork insulins will remain available for the time being. Lilly Iletin II pork is sold in Regular, NPH, and Lente; Novo's Purified Pork is available in Regular and NPH varieties.
Talk to your doctor as soon as possible about what insulin sources and types are available to you. Dr. Schorr is easing the transition of his beef-pork patients by giving them a choice between Iletin II pork, Novo Purified Pork, and synthetic human insulin. He encourages patients to "monitor closely with new insulin," and to carefully watch diet and exercise in order to communicate with their physicians.
The CDA recommends that patients switching from beef-pork to human insulin should lower their initial dosage by 10 to 20 percent. You may need to add additional shots to maintain the same level of control, particularly at bedtime.
Some beef and beef-pork insulin devotees feel that other insulins are unsuitable or unequivalent. Others may find that negative experiences with available U.S. insulins outweigh the convenience. These people may choose to research means of obtaining their insulin abroad.
Dave Groves of Birmingham, Alabama, is the operator of "Diabetes Forum" on Compuserve. Since the discontinuation of Novo Nordisk's beef Ultralente in 1995 Groves has been importing long-acting Hypurin Bovine Protamine Zinc (beef PZI) insulin from the U.K. It is manufactured by CP Pharmaceuticals and shipped to him by express mail. He says he has been pleased with the quality of the product and has experienced no problems getting his shipments cleared by customs authorities. Groves will be switching his short-acting insulin from Iletin I Regular to CP's Hypurin Bovine Neutral (beef Regular) when the beef-pork is no longer available. The only disadvantage to CP insulin that Groves notes is the higher price of roughly $45 per bottle, which his insurance does not cover.
The FDA allows its field offices some discretion over the importation of drugs in "personal use" quantities, but generally does not allow more than a three-month supply. Any drug that has not been approved in the United States is technically considered illegal.
An insulin shipment for personal use stands the highest likelihood of being deemed appropriate for release. The drug must be intended for a serious condition for which effective treatment may not be available domestically, and must not represent an unreasonable risk. Your shipping documentation should include your doctor's prescription for a three-month supply of your insulin, and a letter from you or your doctor stating that you are importing your insulin as a medical necessity given the lack of equivalent insulins in the United States. If the labeling for the insulin package is not in English, you should request a translation.
What Kind of Insulin(s) Will My Health Insurance Cover?
There are several considerations regarding insulin coverage. People who consider switching to domestically available pork or imported beef or beef-pork insulins should contact their health insurers immediately to find out what the rules are.
The price of pork insulin has almost doubled in the past year while beef-pork remained the least expensive of all insulins. Pork now costs 1 1/2 times as much as synthetic human insulin. It also exceeds the cost of prescription-only Humalog.
Insulin users from some HMOs or from states that do not mandate coverage of insulin are sometimes only allowed to choose from a preferred list of insulins, if they are covered for insulin at all. Human insulins seem to be recommended over animal, and some refuse to cover any sort of animal insulin.
Residents from states with mandatory coverage of diabetes supplies appear to fare slightly better. Individuals from two such states contacted their insurers for this article to find if they can receive coverage for their imported beef or beef-pork insulins after removal. They were told that this might be a possibility if two conditions were met:
What Does the Future Hold for Animal Insulin Users?
"For any other disease in the world there would be a public outcry at removing an effective, affordable medication, says Deborah Green. "We all need to speak up and insist that we, at the very least, be allowed the choice of insulin treatments."
Says Leslie Stillman, "I would think that living in the United States, I would have access to the insulin I need."
Robin Harrison, a North Carolina resident, has been a diabetes advocate for ten years. She holds two bachelor's degrees, in psychology and sociology.