Novo Nordisk’s Levemir (insulin detemir) has been classified as Category B for pregnant women. “This is the most thrilling news since the discovery of insulin,” says Dr. Lois Jovanovic, CEO and Chief Scientific Officer of the Sansum Diabetes Research Institute and world-renowned expert in diabetes and pregnancy. “I am thrilled.”
Given that Dr. Jovanovic is so unequivocally positive, the news deserves a bit more explanation for those of us who aren’t experts and aren’t pregnant. Levemir is the first long-acting insulin other than NPH to be classified as Category B. But what exactly does that mean? And why are we so worried about insulin in pregnancy anyway?
The FDA, Dr. Jovanovic explains, needs to make sure drugs taken by women during pregnancy are safe for the baby, and not going to cause any birth defects or abnormalities. The FDA therefore assigns drugs to a category that indicates how they should be used in pregnancy. Category A drugs are things like vitamins—not just okay to use, but actually good for the pregnant woman and the fetus. Category B drugs are not necessarily positive for pregnancy, but all animal and human studies must indicate that the drug is safe for the mother and the baby. Category C drugs are not known to cause birth defects, but have not been sufficiently tested in humans to really be certainly safe. Up until now, untested insulin analogues, and all long-acting insulin analogues other than NPH, fell into Category C—not known to be harmful, but not known to be safe either.
Now, normal, non-diabetic women produce their own insulin, and that insulin is obviously safe for fetuses. What, then, makes insulin analogues different and riskier? The answer is that insulin analogues may behave similarly to human insulin in the body, but they are different chemically, and each has a unique molecular composition. That is meaningless to the human eye, but can be very significant to the human immune system, which is designed to produce antibodies, a type of protein that other cells in the body can recognize, that bind to foreign molecules in the body. Insulin alone—analogue or otherwise—does not cross the placenta and reach the fetus, but insulin molecules bound by these antibodies can cross the placenta, where they can act on the cells of the fetus, resulting in an overabundance of insulin (a growth hormone) affecting the fetus.
So, if an insulin analogue causes the body to produce a lot of binding antibodies, it can get carried across the placental barrier and harm the fetus, and thus each new insulin analogue has to go through a battery of tests to determine whether it is safe for use in pregnancy. These tests must be done in both animals and humans, and must show that there are no adverse effects on babies born to mothers using the drug. Insulin aspart (NovoLog), insulin lispro (Humalog), and NPH have all been previously tested and classified as Category B, and now insulin detemir (Levemir) is joining the elite group after a series of human trials enrolling more than three hundred subjects.
Does this reclassification open the gate for other basal insulin analogues? Unfortunately for the fans of Lantus, the answer is no—even if insulins are similar in terms of action, their molecular makeup is different, meaning their impact on antibody production is potentially different. Dr. Jovanovic points out that insulin glargine (Lantus) in particular has been shown to cause high levels of antibody production, and she would therefore never recommend a pregnant woman use Lantus, and would ideally require women to be off Lantus even before getting pregnant.
Even if Lantus were comparable to Levemir in terms of antibody production, though, its flat profile of action- without any peaks—is actually a disadvantage during pregnancy. Because of the nature of hormone production, requirements of insulin in pregnancy vary throughout the day, making peaking preferable in basal insulins. NPH, in fact, is pretty good in this regard in Dr. Jovanovic’s eyes; the problem with NPH, though, is that it doesn’t last long enough, and requires patients to take at least three shots a day to get full basal coverage. That might be okay under normal circumstances, but “pregnant women are tired,” Dr. Jovanovic explains, and if a woman happened to fall asleep before taking her late-night NPH dose, she and her fetus would be severely endangered; the risk of going into ketoacidosis with hyperglycemia is much greater during pregnancy, and ketoacidosis can cause sudden death in utero. This risk makes the twice-daily Levemir hugely important in Dr. Jovanovic ’s mind—that bit of insurance against forgotten doses and ketoacidosis cannot be underestimated. In fact, Dr. Jovanovic even recommends using Levemir injections at night to women using insulin pumps, as she prefers the assurance of a basal shot to the possibility that the pump infusion set might fall out during the night, leading to hyperglycemia and harm to the fetus.
Given how helpful the twice-daily, slightly peaky Levemir can be according to Dr. Jovanovic, it is not surprising that doctors have been prescribing and using Levemir insulin in pregnancy even in the absence of the Category B classification. Will this reclassification really change anything, then? Dr. Jovanovic thinks it absolutely will—many doctors, she finds, have been switching women to NPH despite the nighttime risk, and, further, many insurance companies fight reimbursement of medication that is not approved for the prescribed use. With the new classification, doctors can prescribe Levemir with confidence that it is safe and that they won’t be risking malpractice suits, and patients will be able to purchase Levemir without having to fight tooth and nail for reimbursement every time.
This reclassification of Levemir, then, is not only a win for Novo Nordisk—but it is also a big win for doctors and their patients. Hopefully more women and their babies will sleep safely and euglycemically now that another tool has been added to their diabetes toolbox.