Opinion

VIEWPOINT
Costs Associated With Using Different Insulin
Preparations
Tracy Tylee, MD In 2012, an estimated 29 million individuals, or 9.3% sured adults with type 2 diabetes using insulin, 19% were
University of of the US population, had diabetes, with 30.8% of using analog insulins in 2000 compared with 96% who
Washington School of these patients using insulin.1 For patients with type 2 were using these products by 2010, accompanied by a
Medicine, Seattle.
diabetes, many options for insulin therapy are avail- 142% increase in out-of-pocket costs for diabetes
able, challenging clinicians to find appropriate insulin medications.2 Not only have patient co-payments for in-
Irl B. Hirsch, MD
University of regimens that best fit with their patients lifestyles. sulin increased, but prices for insulin have been substan-
Washington School of However, the affordability of insulin is becoming an tially increasing as well. From 2001 to 2015, the price of
Medicine, Seattle. important factor in decision making, and clinicians insulin lispro increased 585% (from $35 to $234 per vial),
should be aware of the lower-cost options that may be with a 555% increase for human insulin (from $20 to $131
available for their patients. per vial).3,4 For comparison, the inflation rate during this
For patients with type 2 diabetes requiring insulin, same period was only 33.7%.
the ideal regimen would be one that most closely mim- Despite the increased use of insulin analogs, their
ics physiologic insulin secretion. This would provide a superiority compared with human insulin with regard to
consistent, peakless intermeal insulin level to provide clinical outcomes is not well established, particularly for
continuous between-meal glucose control, combined type 2 diabetes. A 2009 Cochrane Review that in-
with a prandial insulin that has a rapid onset and dura- cluded 6 studies that compared NPH with the basal ana-
tion of action to match the postprandial glucose peak. logs found no clinically significant difference in hemo-
Over the last few decades, insulin analogs have been globin A1c levels. Moreover, there was no difference in
developed to match this physiologic profile better than rates of severe hypoglycemia, although the risk of symp-
human insulins. Recently, the insulin analog prices have tomatic and nocturnal hypoglycemia was reduced with
soared, however, making the cost-benefit ratio unclear. the analogs.5 Although most of the studies comparing
the effectiveness of rapid-acting ana-
logs compared with regular human insu-
lin have been in patients with type 1 dia-
The affordability of insulin is becoming
betes, several groups have reviewed the
important in decision making, and data for patients with type 2 diabetes. A
clinicians should be aware of the review from 2009 found no clinically sig-
nificant difference in glycemic control
lower-cost options that may be available. and no increased risk of hypoglycemia
with regular insulin compared with the
Human insulin was introduced in 1982 to replace ani- rapid-acting analog insulins.6 There is also no evidence
mal insulin. The original regular insulin has a duration of that the new analogs provide any advantage over hu-
action of approximately 8 hours, which makes it poorly man insulin in preventing diabetes-related vascular com-
suited to provide 24-hour basal coverage. From the late plications.
1930s through the 1950s, longer-acting insulins were de- Together these data suggest that in type 2 diabe-
veloped by adding protamine and zinc to regular insu- tes, there is little clinical benefit to using insulin analog
lin, although only neutral protamine Hagedorn (NPH) is compared with regular human insulin and NPH. The ana-
still used today. All of these insulins were imperfect be- logs provide a more physiologic insulin profile but, to
cause of less than ideal kinetics. The current era of basal date, no study has shown this potential advantage to be
insulin analogs was introduced in 2001 with modifica- beneficial with regard to hemoglobin A1c levels or long-
tions resulting in decreased solubility (insulin glargine) term outcomes. There appears to be a small improve-
or increased albumin binding (insulin detemir), which ment in hypoglycemia, although rates of severe hypo-
provide a long-acting basal insulin. glycemia, defined as needing the assistance of another
Regular insulin also lacks the rapid onset of action person, were very low with analogs and human insu-
necessary for an optimal prandial insulin. Thus, rapid- lins. As cost becomes a more important consideration,
acting insulin analogs were developed that prevent self- many patients will have no choice but to use a less ex-
Corresponding aggregation (clumping) of the insulin molecules, allow- pensive alternative and some patients may stop or ra-
Author: Irl B. Hirsch,
MD, University of
ing for quicker absorption and shorter duration of action. tion their insulin because of costs.
Washington School Although not perfect, these insulin analogs more closely There are no current guidelines regarding the use
of Medicine, replicate physiologic insulin patterns in humans. of human insulins for treatment of diabetes, nor are there
4245 Roosevelt Way
With the newer insulins promising a more physi- published recommendations for switching a patients
NE, Third Floor,
Seattle, WA 98105 ologic profile, the proportion of patients using insulin treatment regimen from an analog to human insulin.
(ihirsch@uw.edu). analogs has substantially increased. Among privately in- Thus, physicians often rely on their clinical experience

jama.com (Reprinted) JAMA August 18, 2015 Volume 314, Number 7 665

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/ by a Harvard University User on 09/16/2017

 Opinion Viewpoint

to determine the best options for their patients. Given the predomi-
nant use of insulin analogs over the last decade, younger clinicians
may not be as well versed in the use of these older insulins, and hav-
ing some guidance can be helpful to increase comfort level with pre-
scribing more affordable alternatives.
When transitioning a patient from analog basal insulin to NPH,
the main difference in dosing is timing. While both glargine and de-
temir can provide basal coverage with once-daily dosing, NPH usu-
ally needs to be given twice daily to provide adequate coverage. To
minimize the risk of nocturnal hypoglycemia, this dose is usually split
so that one-third of the total dose is given at bedtime, with the larger
dose given in the morning. Because the peak insulin activity of a
morning NPH dose would occur at lunchtime, the dose of lunch-
time insulin should be lower to avoid insulin stacking and to mini-
mize the risk of afternoon hypoglycemia. When starting this regi-
men, patients need to be encouraged to check blood glucose levels
in late morning and early evening to confirm safety. Consistency with
mealtimes also helps to minimize hypoglycemia.
Another concern with NPH insulin is its variable absorption.
Neutral protamine Hagedorn needs to be suspended in solution
by gentle mixing of the vial prior to administration. One study
involving 109 patients found that only 9% of patients mixed their
insulin prior to use, which resulted in significant variation in insu-
lin doses and glycemic response. After appropriate education,
however, more than 80% of patients were resuspending their
insulin.7 Thus, education about insulin use is important when
switching patients treatment regimens to NPH insulin to ensure
adequate dosing, and it appears that patients are capable of
appropriate administration.
With regular insulin, the issue of the insulin-meal interval, or lag
time, is a concern because of its slow onset of action. The general
recommendation has been for all patients to take regular insulin at
least 20 to 30 minutes before a meal. However, a study of 100 pa-
tients with type 2 diabetes found no clinical benefit to using a 20-
minute lag time compared with no lag time with mealtime regular
insulin.8 Based on this study, the lag time typically recommended
with use of regular insulin may not be necessary, which would sim-
plify the switch from rapid-acting insulin analogs at mealtime. Still,
given the slow absorption of regular insulin, more data on this topic
are needed.
The discovery of insulin in 1922 revolutionized the treatment
of diabetes. The modifications of the insulin molecule over the years
have provided clinicians with the ability to treat patients with physi-
ologic insulin regimens. The volume of insulin sold worldwide has
increased 6% to 7% over the last 5 years, with 60% of the growth
of insulin revenue coming from the US market. However, the ma-
jority of the revenue growth in the United States has not been re-
alized from higher volumes of insulin sold but rather is primarily
driven by the willingness of the US health care system to pay for mod-
est modifications in insulin formulations and repeated price in-
creases, resulting in insulin prices that are 3 times higher in the United
States than in the rest of the world.
Despite having only 15% of the global insulin market, the United
States generates almost 50% of the revenue related to insulin.9 How-
ever, increasing numbers of patients may find it difficult to afford
the newest insulins. The older insulins, while less commonly used,
are as effective as the analogs at controlling blood glucose for most
patients with type 2 diabetes at a lower price. Clinicians will need
to make adjustments to their patients regimens to minimize risk of
hypoglycemia, but with some understanding of how to use these in-
sulins properly, clinicians can help patients achieve adequate glyce-
mic control at a more reasonable cost.

ARTICLE INFORMATION
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Hirsch has received research grants from Sanofi
USA, Novo Nordisk, and Halozyme. He has
consulted with Abbott Diabetes Care, Roche, and
Valeritas. No other disclosures were reported.
REFERENCES
1. Centers for Disease Control and Prevention.
National Diabetes Statistics Report, 2014.
http://www.cdc.gov/diabetes/pubs/statsreport14
/national-diabetes-report-web.pdf. Accessed
November 2014.
2. Lipska KJ, Ross JS, Van Houten HK, Beran D,
Yudkin JS, Shah ND. Use and out-of-pocket costs of
insulin for type 2 diabetes mellitus from 2000
through 2010. JAMA. 2014;311(22):2331-2333.
3. Mendosa D. Is the cost of insulin skyrocketing?
April 2001. http://www.mendosa.com/insulin
_cost.htm. Accessed March 10, 2015.
4. GoodRx. http://www.goodrx.com. Accessed
June 29, 2015.
5. Horvath K, Jeitler K, Berghold A, et al.
Long-acting insulin analogues vs NPH insulin
(human isophane insulin) for type 2 diabetes
mellitus. Cochrane Database Syst Rev. 2007;(2):
CD005613.
6. Mannucci E, Monami M, Marchionni N.
Short-acting insulin analogues vs regular human
insulin in type 2 diabetes: a meta-analysis. Diabetes
Obes Metab. 2009;11(1):53-59.
7. Jehle PM, Micheler C, Jehle DR, Breitig D, Boehm
BO. Inadequate suspension of neutral protamine
Hagedorn (NPH) insulin in pens. Lancet. 1999;354
(9190):1604-1607.
8. Mller N, Frank T, Kloos C, Lehmann T, Wolf G,
Mller UA. Randomized crossover study to examine
the necessity of an injection-to-meal interval in
patients with type 2 diabetes and human insulin.
Diabetes Care. 2013;36(7):1865-1869.
9. Gal A, Blanckley A, Sonnenfeld A. Novo Nordisk:
An Insulin Primer: Where Is the Market Headed?
New York, NY: Bernstein Research; 2013.

666 JAMA August 18, 2015 Volume 314, Number 7 (Reprinted) jama.com

Copyright 2015 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/ by a Harvard University User on 09/16/2017