Human Insulin Could Be Front-Line for Many With Type 2 Diabetes

June 24, 2018

ORLANDO — Patients with type 2 diabetes starting insulin therapy for the first time who were prescribed a basal insulin analog, compared with human neutral protamine Hagedorn (NPH) insulin, did not have a lower risk of serious hypoglycemia, nor did they have improved glycemic control, in a new real-world study.

The findings suggest that the use of basal insulin analogs in usual practice settings may not be associated with clinical advantages for these outcomes, say Kasia J. Lipska, MD, of Yale University School of Medicine, New Haven, Connecticut, and colleagues in their article just published online in JAMA. Lipska also presented the results in a poster here at the American Diabetes Association (ADA) 2018 Scientific Sessions.

"We did this study because there are lingering questions about whether or not basal insulin analogs are really superior for the management of type 2 diabetes," Lipska told Medscape Medical News.

"In type 1 diabetes," she explained, "I think the situation is a little different, the evidence [for basal insulin analogs] is a little more convincing but in type 2 diabetes the randomized clinical trials comparing NPH insulin versus insulin glargine or detemir showed very little benefit in terms of outcomes."

"Despite these relatively small benefits of insulin analogs, they have really become the default insulins to use in patients with [type 2 diabetes]. That wouldn't necessarily be a problem if it wasn't for the fact that they are so expensive," she observed.

"Patients are struggling to be able to afford insulin, so in that setting it's really important to know whether there is additional value to the more expensive insulins and whether such value exists in usual clinical practice, as opposed to a clinical trial, so that's why we did this study."

"The clinical value of using basal analogs as front-line insulins for type 2 diabetes is unclear," agree Matthew J. Crowley, MD, MHS, Division of Endocrinology, Duke University Medical Center, Durham, North Carolina, and Matthew L. Maciejewski, PhD, Center for Health Services Research in Primary Care, Durham Veterans Affairs Medical Center, in an editorial in JAMA accompanying the article by Lipska and colleagues.

The results from this study help "address this evidence gap" and corroborate "findings from prior comparative trials in a clinical practice environment," they state.

"Along with pursuing measures to help control increasing insulin costs, reemphasizing NPH insulin as a front-line insulin option for most patients with type 2 diabetes could begin to bend the insulin cost curve for patients and insurers," they assert.

Over 90% of Patients in Kaiser Permanente System Received NPH Insulin

Lipska and colleagues conducted a retrospective observational study using data from Kaiser Permanente of Northern California from January 1, 2006, through September 30, 2015, on more than 25,000 patients with poorly controlled type 2 diabetes (mean HbA1c was 9.4% at baseline) who initiated a long-acting insulin analog (glargine or detemir; n = 1928) compared with those who started NPH insulin (n = 23,561). The mean age of patients was 60 years, the cohort was 51.9% white, and 46.8% were female.

Lipska told Medscape Medical News that the data from Kaiser "is kind of unique because in that system people still use NPH preferentially. In most [healthcare] systems it's difficult to do this study because there is so little NPH use."

The primary outcome was time to a hypoglycemia-related emergency department (ED) visit or hospital admission, and the secondary outcome was change in HbA1c within 1 year of starting insulin.

The overall rate of hypoglycemia-related ED visits or hospital admissions was low.

During a mean follow-up of 1.7 years, there were 39 hypoglycemia-related ED visits or hospital admissions among 1928 patients who initiated insulin analogs (11.9 events/1000 person-years) compared with 354 hypoglycemia-related ED visits or hospital admissions among 23,561 patients who initiated NPH insulin (8.8 events/1000 person-years) (between-group difference, 3.1 events/1000 person-years; P = .07).

Among 4428 patients matched by propensity score, the adjusted hazard ratio was 1.16 for hypoglycemia-related ED visits or hospital admissions associated with insulin analog use.

Patients starting NPH insulin experienced a modestly larger reduction in HbA1c after 1 year compared with those taking basal analogs. Within 1 year of insulin initiation, HbA1c decreased from 9.4% to 8.2% with insulin analogs and from 9.4% to 7.9% after beginning therapy with NPH insulin

"We found no difference in the rates of severe hypoglycemia with the use of NPH versus analogs, and we found no clinically significant difference in terms of glycemic control between the two. There was actually a greater fall in HbA1c with the use of NPH compared with analog insulin — it was in favor of NPH and statistically significant but in terms of clinical effect it was small," Lipska said. 

More Data Needed to Drill Down Who Will Benefit from Analogs

In their editorial, Crowley and Maciejewski note a number of strengths and limitations of the study.

For example, clinicians' greater familiarity with NPH insulin in this healthcare system "may have reduced the likelihood of hypoglycemia among NPH insulin users, which may partly explain the low event rates," they note, also observing that only the most serious hypoglycemia events were documented.

Indeed, Lipska told Medscape Medical News that previous clinical trials have shown a reduction in nocturnal hypoglycemia in favor of insulin analogs (versus NPH), which "should not be pushed aside because it's important."

And because this analysis focused on initiation of basal insulin in patients with poorly controlled type 2 diabetes, "the findings may not be generalized to other populations such as patients with better-controlled type 2 diabetes...or those using complex basal-prandial insulin regimens," the editorialists note.

Nevertheless, the ADA working group on insulin pricing has suggested "human insulin may be an appropriate alternative to more expensive analog insulins for some people with diabetes," they note.

Lipska acknowledged: "There are potentially people who will do better on these more expensive insulins. What we don't want is this kind of evidence to restrict access for those patients who may benefit."

"But on the other hand, the use of the more expensive insulin as the absolute default for most people doesn't make sense given these data," she stressed. "I think we should generate the evidence — who is going to benefit [from more expensive analogs] and in what ways...rather than just spend more money."

In general, analogs can cost up to 10 times the amount of NPH insulin, she said. "That's a big difference," she told Medscape Medical News. "A lot of people in our country are paying a portion of this price. Even if they have insurance, there are co-pays, or they get into the 'donut hole.' "

Lipska has received support from the Centers for Medicare & Medicaid Services. Coauthor Moffet has received grant funding from Eli Lilly, AstraZeneca, and Regeneron/Sanofi. Coauthor Karter has received grant funding from AstraZeneca. Maciejewski has received grants from the National Institute on Drug Abuse and Department of Veterans Affairs and a contract from the National Committee for Quality Assurance to Duke University for research. Both authors acknowledge support from the Durham Veterans Affairs Health Services

American Diabetes Association 2018 Scientific Sessions. June 22, 2018; Orlando, Florida. Abstract 1311-P.

JAMA. Published online June 23, 2018. Abstract, Editorial

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