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Expensive Insulin Analogs Perform No Better Than NPH Insulin for Type 2 Diabetes

An estimated 29 million Americans have diabetes, a chronic disease characterized by high blood sugar. The treatment of type 2 diabetes typically begins with lifestyle modifications and metformin, a pill that lowers the amount of sugar in the blood. However, up to 25 percent of diabetes patients will require insulin injections to control their blood sugar.

For decades, synthetic insulin has been a life-saving treatment for people with diabetes whose pancreas could not secrete adequate amounts of insulin. “Human insulin,” named to distinguish it from earlier preparations derived from animal sources, became widely available as neutral protamine Hagedorn (NPH) insulin in the 20th century.

“NPH insulin has been the standard of care for decades,” said Andrew J. Karter, PhD, senior research scientist with the Kaiser Permanente Division of Research. “However, in the 2000s, this changed in most health systems and the use of new insulin analog products rapidly surpassed the use of NPH insulin.”

Insulin is used by diabetes patients to help stabilize levels of blood sugar throughout the day. In clinical trials, insulin analogs had modestly lower risk of nocturnal hypoglycemia, or low blood sugar during sleep, compared with NPH insulin.

Now a large observational study conducted by Kaiser Permanente and the Yale School of Medicine, and published in JAMA (Journal of the American Medical Association), has found that people with type 2 diabetes who initiated treatment with insulin analogs — such as glargine and detemir — did not have substantially better blood sugar control or lower risk of hypoglycemia than those initiating treatment with NPH insulin.

“We were able to compare newly prescribed NPH insulins and insulin analogs in a large and diverse population of Kaiser Permanente type 2 diabetes patients, under real-world conditions with uniquely detailed data about possible confounding factors and long-term outcomes,” said lead author and endocrinologist Kasia J. Lipska, MD, MHS, of Yale School of Medicine.

Comparing NPH insulin and insulin analogs

With funding provided by the National Institutes of Health, the researchers reviewed the electronic medical records of 25,000 patients diagnosed with type 2 diabetes in Kaiser Permanente’s Northern California region over a 10-year period.

“NPH insulin is the standard of care for type 2 diabetes patients initiating insulin treatment at Kaiser Permanente,” said Richard Dlott, MD, endocrinologist and medical director of population care for Kaiser Permanente Northern California. “Over 90 percent of those initiating insulin treatment in Kaiser Permanente are started on the NPH insulin. In contrast, approximately 90 percent of privately insured patients with type 2 diabetes from other health systems in the United States are using insulin analogs.”

The researchers followed each patient for an average of 1.7 years after they initiated insulin, and recorded all emergency department visits or hospitalizations related to severe hypoglycemia, as well as changes in their blood sugar (hemoglobin A1c) control.

“Outcomes following initiation of the two types of insulin were compared using state-of-the-art statistical modeling techniques to adjust for any differences between NPH and analog initiators,” said Karter, an epidemiology and health services researcher studying diabetes and its complications.

“What we found is that for patients with type 2 diabetes in usual practice, the use of the more expensive insulin analogs did not appear to result in better safety or better blood sugar control compared with NPH insulin,” Lipska said. “This suggests that many people with type 2 diabetes should consider starting with NPH insulin, instead of insulin analogs, especially if cost is an issue for them.”

Costly alternative

Analogs cost up to 10 times more than NPH insulins, contributing to a tripling of the total cost for insulin nationally between 2002 and 2013.

The rising cost of insulin may directly affect health outcomes for people with diabetes, Karter said. His research has shown that high out-of-pocket costs for medications increases the likelihood that the patient fails to initiate a newly prescribed drug or takes less than prescribed over the long term.

“Poorer adherence leads to poorer future health outcomes,” Karter said.

“Some people with type 2 diabetes may find the potential benefits of insulin analogs worth the additional cost. But we found no population-level evidence to suggest that the extra expenditure is warranted for most people with type 2 diabetes, particularly when the high cost could prevent some of them from ever starting the treatment they need or divert resources away from other, potentially beneficial clinical interventions.”

Lisa Gilliam, MD, clinical lead for diabetes care in Kaiser Permanente Northern California, said, “This is an important study, supporting the approach taken at Kaiser Permanente to use NPH as the first-line insulin in patients with type 2 diabetes. This approach is both effective and cost-conscious, an important consideration in an era with ballooning costs of medical treatments.”

In addition to Karter and Lipska, co-authors of the study were Melissa Parker, MS, and Howard H. Moffet, MPH, Kaiser Permanente Division of Research; and Elbert S. Huang, MD, MPH, University of Chicago Department of Medicine.

“Association of initiation of basal insulin analogs vs neutral protamine Hagedorn (NPH) insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes,” appeared June 23 in JAMA.

This research was presented at the American Diabetes Association 2018 conference in Orlando, Fla., June 23-25, 2018, poster 1311-P.

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