“Kiss NPH Goodbye”

The evolution of insulin has taken a turn that even Banting and Best could not have foreseen when they discovered the hormone back in the 1920s.

In little more than five years, the advent of insulin analogs—or “designer insulins,” as they are called—has significantly altered the way many doctors are prescribing insulin. First, the release of Humalog (insulin lispro) in 1996 resulted in a rapid changeover from Regular to the faster-acting insulin among many insulin users. More recently, the release of NovoLog (insulin aspart) has given people with diabetes a second rapid-acting insulin.

But what’s causing a “buzz” in the diabetes community today is the introduction of Lantus (insulin glargine).

An Important Milestone

“Kiss NPH Goodbye” proclaimed a slide projected behind the podium where Julio Rosenstock, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center at Dallas, was speaking at the American Diabetes Association’s 49th Annual Postgraduate Course on February 2.

The slide drew chuckles from the audience, as did Dr. Rosenstock’s dead-pan comment about using Lantus: “It’s a no-brainer.”

At the same meeting, Irl B. Hirsch, MD, of the University of Washington in Seattle, called the advent of Lantus “an important milestone.”

“With this new, long-acting insulin, prandial and basal insulins can be identified more accurately, and initial dosing is simplified.”

Prandial insulin, or bolus insulin, refers to the insulin taken with meals to offset the glucose-raising effects of food. Basal insulin is the “background” insulin needed to maintain fasting metabolism. In people without diabetes, small amounts of insulin are being released all the time to keep the body in balance. The total daily dosage of insulin is roughly divided into half basal (a long-acting insulin) and half bolus (generally a rapid-acting insulin).

Hailing the New Insulins

With the advent of Humalog, NovoLog and Lantus, some endocrinologists are saying they no longer find as much use for the older insulins such as Regular and NPH. (For comparisons of the various insulins, see the chart on pages 46-47.)

“Insulin analogs are more physiologic,” says M. Sue Kirkman, MD, of the Indiana University Medical Center in Indianapolis. “Physiologic” means that the activity of the rapid-acting insulins is closer to normal insulin action, which peaks rapidly after food is ingested and then disappears quickly from the body.

Kirkman says that in addition to using rapid-acting insulin analogs for type 1s, “I would also use them in a type 2 who needs short-acting insulin and who has trouble with low blood glucose or inadequate coverage of post-meal high blood glucose.”

Before Lantus was available, Kirkman most frequently had her patients take two injections of NPH a day to act as their basal insulin. Now, however, she’s switched most of her type 1 patients who are not using insulin pumps to the newest insulin analog.

“Lantus seems to be a truly physiologic basal insulin and is a big improvement over Ultralente, NPH or Lente in terms of smooth action,” she says.

She’s also using Lantus for some of her type 2 patients, “but often they do fine with less physiologic insulins and don’t need the additional expense of Lantus. It’s about twice as expensive as NPH.”

Daniel Einhorn, MD, FACE, medical director for the Scripps/Whittier Diabetes Institute in La Jolla, California, also believes that Lantus “is our optimal basal insulin.”

“Lantus is the basal insulin I use in virtually all of my patients [with diabetes]. both type 1 and type 2. There is no particular patient I wouldn’t put on Lantus.”

Einhorn says he can find “almost no use for [Regular insulin] today.” However, Kirkman says she uses Regular for the occasional type 1 who won’t take a rapid-acting insulin and for some type 2s. Once again citing stability and cost, she notes that “sometimes type 2s have enough stability in their blood glucose to get decent control on [premixed Regular and NPH],” an alternative that is “significantly less expensive” than the premixed insulin analogs.

Not Taught in the Textbooks

How do doctors determine insulin regimens? While textbooks can provide guidelines, much of what determines the best insulin regimen for a person with either type 1 or 2 diabetes has to do with that person’s own, unique situation.

For example, there is variability in insulin absorption depending on the person and on where the insulin is injected. Some people are more sensitive to Humalog than to NovoLog—and vice versa. The delayed gastric emptying caused by gastroparesis may call for the slower-acting Regular insulin. Hirsch notes that Regular insulin may also better handle meals that are higher in fat and protein.

Rosenstock says he might suggest that someone who eats lunch at noon and does not eat dinner until 7 or 8 p.m. take Regular at lunchtime. Elderly people also might do better on an insulin that is not as rapid-acting as Humalog or NovoLog.

When discussing the two rapid-acting insulins, Rosenstock commented that NovoLog is leading the race with delivery systems, including the Innovo pen, which displays the amount and time of the last dosage, and the InDuo system, which combines an insulin delivery system with a blood-glucose testing meter. While he did not note any differences in insulin action between the two analogs, there is mounting anecdotal evidence that NovoLog has a longer “tail” than Humalog, meaning that although it peaks as quickly as Humalog, it lasts a bit longer.

Endocrinologists have to look at the problems an individual is having with a particular regimen and then must decide what adjustments would best address those problems.

“Very few people are the same, and very few people are the same two days in a row,” says Einhorn. “There is no more a formula for how to give insulin than there is a formula for how to live your life.”

Kirkman uses “clinical experience—remembering what did or did not work for other patients, or just trying something in this patient that seems like it should work”—combined with data collected from home blood-glucose monitoring to determine an insulin regimen.

The type of diabetes can make a difference, too.

“With type 2s, you have more flexibility,” explains Robert Tanenberg,MD, professor of medicine, section of endocrinology, at East Carolina University in Greenville, North Carolina. “You might just give them a little NPH at bedtime. But once a type 2 has had diabetes for a long period of time, they get to be more like a type 1. I feel very strongly that type 2 people need insulin, and the problem is that they wait too long to get it.”

The newer insulin analogs are making it easier for doctors to design insulin regimens.

“With NPH-based regimens, it becomes difficult to separate the basal from the prandial (meal-time) insulin because NPH may act as both,” Hirsch says. “For example, if NPH is administered in the morning, it would serve as basal insulin in the late morning. as prandial insulin. for the lunch meal, and then as basal insulin again for the time period after lunch is absorbed.”

With Lantus, however, he explains, “prandial and basal insulins can be identified more accurately, and initial dosing is simplified.”

Changing How Insulin Is Used in Pumps

While Regular insulin was the gold standard for insulin pump users prior to 1996, that changed when Humalog—with its rapid action—was released.

Both Einhorn and Kirkman said they have discontinued the use of Regular insulin for their patients who use insulin pumps.

Recently, Novo Nordisk announced that the FDA has approved NovoLog for use in insulin pumps. Eli Lilly says it expects similar approval for Humalog later this year.

Even before FDA approval, however, Einhorn and others were prescribing the rapid-acting insulins for pump use.

Humalog and NovoLog “are more predictable, and there are fewer episodes of low blood glucose,” says Einhorn. “Humalog is not even approved for use in pumps, but endocrinologists have been using it in pumps all along. There is just no rationale that I know of for using Regular over NovoLog or Humalog in the pump.”

Is This the End?

It’s certainly not the end of the evolution of insulins, no matter how “perfect” they might seem today—especially when compared to that first, rough, albeit life-giving, “magic elixir.”

Inhaled insulins are on the foreseeable horizon. Perhaps the future will bring implantable chips that release insulin with the sending of a signal. Maybe there will be insulins that automatically activate according to need.

David R. Owens, FRCP, and colleagues at the Diabetes Research Unit at Liandough Hospital in Wales wrote in the September 1, 2001, issue of The Lancet that less than one decade ago available insulin preparations “made it almost impossible to achieve good glycemic control without substantial disruption to the patient’s lifestyle.” They add that recombinant DNA technology contributed to the most recent analogs, which better mimic normal insulin action.

Today, with diabetes education and a more intensive approach to insulin therapy, people have the tools and the capability to help themselves live longer and healthier lives.

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