July 2008 - Introduced this decade, the long-acting insulin medications glargine and detemir have largely replaced the older intermediate-acting insulin NPH in the treatment of type 1 diabetes. However, a review of studies reveals that the newer drugs offer only a slight benefit over NPH in terms of blood glucose control.
The researchers did see a clear benefit of long-acting insulin in the risk for hypoglycemia - dangerously low blood glucose that can result from insulin injections - particularly at night.
The review comprised 23 studies of more than 6,500 people.
"Long-acting insulin preparations have gained much popularity in recent years for the treatment of type 1 diabetes mellitus," said review author Moshe Vardi, M.D. "Our objective was to assess whether there is a significant clinical advantage for these drugs."
Vardi, a physician in the internal medicine department at Carmel Medical Center in Haifa, Israel, said pharmaceutical companies have waged a tremendous marketing campaign to promote these newer insulin medications.
The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.
Type 1 diabetes - formerly called juvenile diabetes because of its early onset in children, teenagers and young adults - accounts for only about 5 percent of all cases of diabetes. Patients with type 1 diabetes have a defect in the pancreas that prevents them from making enough insulin. All patients with type 1 diabetes require insulin treatment to control blood glucose.
The newer therapies allow for insulin replacement that more closely mimics how the body releases insulin. To do this, injected insulin needs to replace basal or "background" insulin secretion that occurs at a continuous level in the body, as well as to replace the spike in insulin that occurs after eating a meal.
Most people with type 1 diabetes inject basal (long- or intermediate-acting) insulin once or twice a day under the skin, with additional boluses of short- or rapid-acting insulin at meals. Insulin pumps are an alternative option.
The intermediate-acting insulin NPH has served to help replace basal insulin secretion since the 1950s; however, some physicians consider the newer long-acting insulin analogues glargine and detemir to be clinically superior to NPH. Most of the review studies compared glargine or detemir with NPH.
To determine effectiveness, the researchers looked at the results for hemoglobin A1c, a widely used measure of long-term blood glucose control. They also looked at fasting glucose levels in the blood.
To assess safety, they evaluated rates of hypoglycemia and adverse events. In severe cases, hypoglycemia can lead to seizures or coma if left untreated. Because type 1 patients often need large amounts of insulin, the risk of hypoglycemia is much greater in type 1 patients than in insulin-treated type 2 patients.
The researchers found that long-acting insulin medications offered only a slight improvement in A1c and blood glucose levels over intermediate-acting options.
"We were surprised to find such a minor advantage in the overall glucose-lowering abilities of the long-acting drugs compared to the older, intermediate-acting drugs," Vardi said.
However, when compared with intermediate-acting insulin, long-acting insulin medicines decreased the risk for severe nighttime hypoglycemia by 30 percent. The review noted no additional differences between the two types of insulin for other adverse events.
Irl Hirsch, M.D., an expert in type 1 diabetes from the University of Washington School of Medicine's Diabetes Center in Seattle, said that currently there is very little use of NPH in the treatment of type 1 diabetes in the United States, primarily because the newer insulin medications are much less likely to cause severe hypoglycemia.
"The reduction in the frequency of hypoglycemia has been profound," Hirsch said. "Insulin analogues have totally revolutionized our ability to reduce hypoglycemia in adults with diabetes in the U.S."
Despite the review findings, Hirsch said, "NPH is not a good basal insulin," because it has an unnatural peak in its action that the long-acting medications glargine and detemir do not have. This difference becomes more important in patients aggressively trying to reduce their A1c levels to a target normal level, which many diabetic patients do not try to achieve. This could explain why many studies do not find differences in blood glucose control between intermediate- and long-acting insulin choices, he said.
However, the review authors concluded, "When compared to intermediate-acting insulin, their effect on glucose control appears to be subtle, if at all." Vardi cautioned that none of the studies examined risks for development of long-term diabetes-related complications, such as heart disease, blindness or kidney disease.
Vardi M, et al. Intermediate acting versus long acting insulin for type 1 diabetes (Review). Cochrane Database of Systematic Reviews 2008, Issue 3.