- Email: [email protected]
Insulin Rationing
The Journal for Nurse Practitioners xxx (xxxx) xxx
Contents lists available at ScienceDirect
The Journal for Nurse Practitioners journal homepage: www.npjournal.org
Insulin Rationing Leigh Hart, PhD, FNP-C a b s t r a c t Keywords: analog insulin diabetes mellitus insulin cost synthetic human insulin
The high cost of insulin in the United States has led to insulin rationing by some patients. This article presents a case of insulin rationing and discusses evidence supporting the use of lower-cost synthetic human insulin in some type 2 diabetics without a history of nocturnal hypoglycemia. Provider considerations for managing the switch from analog insulin to synthetic human insulin are presented. © 2019 Elsevier Inc. All rights reserved.
Jaye is a 34-year-old male patient with type 2 diabetes. A year ago he passed out at home and was admitted to intensive care with a blood sugar level of 1,200. Before this diagnosis, his medical history was negative, except for a 100-lb weight gain when he completed a rehabilitation program for substance use disorder 4 years earlier. He has been sober since that time. He was discharged from the intensive care unit on 25 U detemir once a day, metformin 1,000 mg twice a day, and lisinopril 10 mg once a day. His primary care nurse practitioner has titrated his insulin up to 40 U over the last year, but he continues to have very high hemoglobin A1c levels. He is employed and has health insurance through his employer. He is the sole provider for his family. He has a wife and a 1-year-old daughter, and he is expecting his second child in 6 months. He works in an industrial setting and averages 60 hours of work a week. Even with insurance and an income greater than $40,000 a year, he is having difficulty paying the copay for his current basal analog insulin. His nurse practitioner states he needs to add a rapidacting analog insulin at mealtimes because his last hemoglobin A1c was 14%. Jaye’s hemoglobin A1c is at this critical level because he has been rationing his insulin because of cost. Recently, while on the basal insulin alone, he had $100 to last 5 days until his next payday. He was out of his basal analog insulin, but the $80 copay to refill his prescription would not leave enough money for him to buy food for the family and diapers for his 1-year-old daughter. He decided to wait and go without his insulin until his next payday. By Thursday of his second week without insulin, his blood sugar was so high that his meter would not produce a reading and instead flashed “seek medical attention.” He felt horrible but could not miss any work so he “borrowed” 20 units of rapid-acting analog insulin from a coworker, took the medication, and continued to drive his forklift. Despite insurance and employment, this current plan of care is not working for this patient. The addition of the bolus analog insulin will help gain control of his hemoglobin A1c but not if he does not https://doi.org/10.1016/j.nurpra.2019.10.023 1555-4155/© 2019 Elsevier Inc. All rights reserved.
take it. The new rapid-acting insulin will increase his monthly copay to over $300. He cannot afford these medications. Is there a safe, less expensive alternative for this patient? The History of Insulin A diagnosis of type 1 diabetes was fatal until the production of the first commercial insulin in 1923.1 Dr. Frederick Banting discovered the process for insulin extraction from bovine pancreas, and Eli Lilly (Indianapolis, IN) was the first company to produce and market this miracle drug.2 In 1926, crystallization of insulin improved solubility, but the insulin was only available in a regular formulation, and patients required multiple injections a day.2 In 1936, a fish protein called protamine and zinc were added to insulin, providing the first much-needed extended-action insulin protamine zinc insulin.2 A reduction in the amount of protamine led to neutral protamine Hagedorn (NPH) insulin in 1946. NPH insulin has a shorter action time compared with protamine zinc insulin and could be combined with regular insulin to more closely mimic the basal/bolus pattern of insulin normally released by the human body. This was followed by the Lente series, which altered the amount of zinc and produced an intermediate-action insulin.2 Recombinant DNA technology led to a new human insulin formulation marketed in 1983.2 Recombinant DNA technology uses a common bacterium and inserts human genes into the genetic material of the microorganism. The microorganism subsequently produces the desired protein, in this case human insulin. In 1996, the analog insulin lispro, a lysine-proline analog insulin, was introduced as the fastest-acting insulin.3,4 This new rapid insulin has an onset of action of 5 to 15 minutes and a peak of 20 minutes to 90 minutes. This was followed by the basal insulins, glargine in 2000 and detemir in 2005. Analog basal insulin lasts for up to 24 hours and produces no or a very limited peak action time, reducing the risk of hypoglycemia.2-4 These new basal analog
2
L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx
insulins can be used with rapid-acting analog insulins such as insulin aspart or insulin glulisine at mealtime to closely mimic the natural patterns of insulin secretion. Two analog biosimilar insulins are now available. In 2015, Basaglar (Eli Lilly), a biosimilar form of the analog insulin glargine, was Food and Drug Administration approved followed by Admelog (Sanofi, Paris, France), the biosimilar formation of lispro in 2017. Extensive cost savings have not yet been realized with the addition of biosimilars. At the time of this writing, the GoodRx.com website lists 3 insulin 3 mL U-100 pens for the brand insulin Lantus (SanofiAventis US; insulin glargine) for $215.20 with a coupon, whereas the biosimilar Basaglar was $250.91. Many ask why insulin is so expensive when it is not a new product. The production of biosimilar medications is more costly than other nonbiological medications. In addition, there are 3 manufactures that provide insulin in the United States. These companies are Eli Lilly, Sanofi, and Novo Nordisk (Bagsvaerd, Denmark). These companies also produce the 2 available biosimilar formulations. The analog insulins have become the most widely used insulins in the United States.5 The JN Learning podcast titled “Health Care Spending Gone Wild: Using Expensive Insulin Analogs With Few Clinical Advantages” provides a good overview of the molecular modifications used to produce the onsets and duration of action for analog insulins.5
investigated by a bipartisan Senate Finance Committee with a goal to stabilize and lower the cost of insulin.8 As our case study illustrates, even with insurance, the copay for insulin analogs may be too high for some patients. Table 1 presents a summary of certain insulin types and their costs currently available in the US according to GoodRx.com. Lipska9 concludes that recent studies provide evidence that the expensive insulin analogs do not offer substantial benefits for some type 2 diabetics.9 The less expensive synthetic human insulins may lower the financial burden for certain individuals with type 2 diabetes while maintaining good patient outcomes. Lipska et al10 identify candidates for this change as people with type 2 diabetes without a history of severe nocturnal hypoglycemia. Switching a patient with type 2 diabetes on an analog basal bolus regimen to a premixed human 70/30 insulin could result in significant cost savings and reduce the risk for insulin rationing. In some patients, it may also lower daily injection burden.10 Human insulin may be an option for some patients with type 1 diabetes who are unable to afford analog insulin. However, there are identified advantages for patients with type 1 diabetes to be placed on analog insulins.10 The focus of this article is on insulin options for patients with type 2 diabetes who do not have a history of severe nocturnal hypoglycemia.
The High Cost of Insulin
Lipska et al11 completed a retrospective study of Kaiser Permanente of Northern California, Oakland, CA, clients.11 Although insulin analogs are used by more patients with diabetes than other forms of insulin, Kaiser Permanente of Northern California preferentially uses human insulin. This retrospective study compared the outcomes of patients with type 2 diabetes mellitus initiated on basal analog insulin (n ¼ 25,489) and patients initiated on NPH human insulin (n ¼ 23,561). This study did not find significant differences in emergency department visits or hospital admissions
The price for insulin analogs has increased dramatically in recent years. “Insulin prices tripled from 2002 to 2013 and then nearly doubled 2012 to 2016” for almost the exact same product.6 Similar to the case study presented earlier, there are increasing reports in the media about people with diabetes rationing their insulin to the point of severe illness and even death.7 The crisis has captured the attention of US Congress and is currently being
Review of Evidence
Table 1 Comparison of Insulin Prices for Commonly Used Insulins Generic Name
Trade Name
Type
Cost per Unit
Rapid Insulin aspart
Novolog® (Novo Nordisk)
Analog
Insulin glulisine
Apidra® (Sanofi-Aventis)
Analog
Insulin lispro U 100
Humalog® U100 (Lilly)
Analog
$294.86 (U-100/10-mL vial) $561.65 (5 pens u100/3ml) $271.93 (U-100/10-mL vial) $512.40 (5 pens U-100/3 mL) $122.87 (U-100/10-mL vial)a $230.27 (5 pens U-100/3 mL)a $224.77 (3 pens U-200/3 mL) $137. 85 (U-100/10-mL vial)
Insulin lispro U 200 Insulin lispro Regular Regular insulin U100 Regular insulin U 500
®
Humalog U 200 (Lilly) Admelog® (Sanofi-Aventis)
Analog Biosimilar Analog
Humulin R® U100 (Lilly) Humulin R® U 500 (Lilly)
Human Human
$24.88 (vial) $1,561 U-500 20-mL vial Not for ordinary use
Humulin N® (Lilly), Novolin N® (Novo Nordisk)
Human
$96.25 (U-100/10-mL vial) $24.88 (U-100/10-mL vial)
Long Acting Insulin detemir
Levemir® (Novo Nordisk)
Analog
Insulin glargine
Lantus® (Sanofi-Aventis)
Analog Biosimilar analog
$313.46 $465.99 $213.44 $215.20 $250.91
Analog Analog Analog
$324.04 (3 pens U-100/3 mL) $511.75 (3 pens U-100/3 mL) $612.41 (3 pens U-200/3 mL)
Intermediate NPH insulin
Insulin glargine Ultraelong Acting Insulin glargine U 300 Insulin degludec U 100 Insulin degludec U 200
®
Basaglar (Lilly) ®
Toujeo (Sanofi-Aventis) Tresiba® (Novo Nordisk) Tresiba® (Novo Nordisk)
(U-100/10-mL vial) (5 pens U-100/3 mL) (U-100/10-mL vial) (3 pens U-100/3 mL) (3 pens U-100/3 mL)
Prices listed are the lowest posted total cost from GoodRx (https://www.pharmacist.com/practice-insights-emerging-insulins and https://www.goodrx.com/admelog) without insurance at the time of this writing. a Retail prices listed at $170 per vial and $322 per 5-pen set.
L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx
for hypoglycemic events between the 2 groups. It is interesting to note that the average hemoglobin A1c level in both groups of patients was above the recommended value of 7%, with the basal analog cohort reaching a mean hemoglobin A1c of 8.2% (95% confidence interval [CI], 8.1%-8.2%) in 1 year and the NPH cohort reaching a mean hemoglobin A1c of 7.9% (95% CI, 7.9%-8.0%).11 Luo et al12 evaluated a health plan program designed to lower patient and company cost by switching people with type 2 diabetes from very high-cost analog insulin to lower-cost human insulins. This was a retrospective cohort study of 4,635 participants.12 Participants were given financial incentives to self-select human insulin regimens over the more expensive analogs. The switch was available across the health care plan, but the ideal candidate was an adult with type 2 diabetes on more than 2 injections a day, not prone to hypoglycemia, on more than 50 U a day, and/or a history of nonadherence. A dose conversion protocol was used to convert patients who selected to change from analog to human insulin. All analog insulins and secretagogues were stopped. The new premixed human 70/30 insulin or NPH insulin dosage was calculated at 80% of their former total daily dose (TDD) of analog insulin. For the participants switching to a premixed human 70/30 insulin, two thirds of the TDD was taken before breakfast, and one third of the TDD was taken before dinner. For some patients, this lowered the daily injection burden. Outcome measures were compared 12 months before and 12 months after the switch. A slight increase in hemoglobin A1c of 0.14 % (95% CI ,0.05%-0.23%) was found to be statistically significant (P ¼ .003) but not clinically significant. These authors conclude that to be clinically significant the change in hemoglobin A1c would be 0.5% or greater. There was not a significant change in serious hypoglycemic events between the 2 groups (P ¼ .61 for both groups). Nabrdalik et al13 completed an observational study (N ¼ 3,264) comparing patients on premixed human and analog insulin in relationship to efficacy, safety, and satisfaction. This study found that both groups had a reduction in hemoglobin A1c levels, but the hemoglobin A1c levels were significantly higher (P < .001) in the
3
human insulin group compared with the analog group (7.72% vs 7.57%). Nabrdalik et al found no difference between the groups in hypoglycemic events. This study also evaluated patient satisfaction using the Diabetes Treatment Satisfaction Questionnaire. Both groups were satisfied with their treatment regimen, with higher reports of patient satisfaction in the human insulin group. The authors did not elaborate or discuss what may have contributed to this increase in satisfaction.13 These studies provide evidence that synthetic human insulin may be an alternative for certain patients with type 2 diabetes who do not have a history of severe hypoglycemia.11-13 Hypoglycemia has been associated with macro- and microvascular disease and death from vascular and nonvascular causes.14 Patients identified as having an increased risk for hypoglycemia include “older age, longer duration of diabetes, higher creatinine levels, lower body mass index, lower cognitive function, use of two or more oral glucose-lowering drugs, history of smoking or microvascular disease, and assignment to intensive glucose control.”14 Insulin analogs are associated with a lower risk for hypoglycemia and are the recommendation to prevent hypoglycemia.15 Switching From Analog to Human Insulin One concern noted in the podcast “Health Care Spending Gone Wild: Using Expensive Insulin Analogs With Few Clinical Advantages” is that newer providers may not be familiar with prescribing the older human formulation of insulin because of the fact that currently 90% of diabetics on insulin are using the newer analog versions.5 The differences in action between the analogs and human insulin require close provider monitoring if it is decided to switch analogs to synthetic human insulin. Table 2 provides an overview of insulin type, dosing, and action profile and table.10 Lipska et al10 note that when switching patents from analog to human insulin, they should consider that patients may not have been taking their full prescribed dose of analog insulin. They recommend beginning the switch by reducing the current daily
Table 2 Insulin Type, Dosing, and Action Profile10,16 Synthetic Human Insulin Type
Onset
Peak
Duration
Dosing Frequency
NPH (Humulin N®a) (Novolin N®) Regular (Humulin R®a) (Novolin R®) Insulin NPH 70%/insulin regular 30% (Humulin® 70/30a) (Novolin® 70/30)
2-4 h 30-60 min 30-60 min
4-10 h 2-3 h 2-6 h
12-18 h 8-10 h 12-18 h
HS, BID 0-30 minutes before meals BID Before breakfast and dinner
Insulin Analogs Type Basal Insulins Degludec U-100 and U-200 (Tresiba®) Detemir U-100 (Levemir®) Glargine U-100 (Lantus®) Glargine U-300 (Toujeo®) Biosimular Glargine U-100 (Basaglar®)Rapid-acting Insulin Aspart U-100 (Novolog®) Glulisine U-100 (Apidra®) Lispro U-100 Pen U-200 (Humalog®) Premixed insulin aspart protamine 70% and insulin aspart 30% (Novolog® 70/30) 75% insulin lispro protamine 75% and insulin lispro 25% (Humalog® 75/25) 75% insulin lispro protamine 50% and insulin lispro 50% (Humalog® 50/50)
Onset
Peak
Duration
Dosing Frequency
1h 3-4 h 2-6 h
None identified 3-9 h None identified
> 40 h 6-24 h 20-24 h
QD QD, BID (for higher doses) QD, BID (for higher doses)
5-15 5-15 5-15 5-15
30-90 min 30-90 min 30-90 min 2-4 h
2-6 h 2-6 h 2-6 h 14-24
0-15 min before meals 0-15 min before meals 0-15 min before meals Before breakfast and dinner
min min min min
BID ¼ twice a day; HS ¼ hour of sleep; QD ¼ every day. a At the time of this writing, Novolin was approximately one third the cost of Humulin.
4
L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx
Table 3 Considerations for Using Human Insulin Instead of Analogs10 Concern
Consider
Injection techniques
Regular human insulin is recommended to be injected 30 minutes before a meal as opposed to with the meal for rapid-acting analogs. The least expensive human insulin does not come in a pen. Patients must have the physical and cognitive ability to accurately draw up and administer this insulin. 100 insulin syringes can be purchased for $24.00 at the time of this writing. Human N must be gently agitated to mix the suspension. May start at 10 U in the evening and titrate up by 2 units once or twice a week until target FBS and A1c is achieved. May titrate to 2 injections per day 1 at breakfast and 1 in the evening. Meal time R may be started at 6 U. Two injections: 1/2 daily dose before breakfast and 1/2 daily dose with dinner. If the A1c is greater than 9%, the start can be 0.3 U/kg/d for the total daily dose. Monitor for midday and midnight hypoglycemia. Reduce total daily dose on analogs by 20% when switching from analog to human insulin. For example, if the total daily dose on analogs is 50 U, start human insulin at 40 U. Premixed human insulins may allow for a reduction in total daily injection burden for people on a basal bolus analog pattern. The nocturnal hypoglycemia risk should be a consideration in the switch from analog to human insulin. Analog insulins may provide benefits to those with a history of nocturnal hypoglycemia. Consider in-office or telephone monitoring during the switch to monitor for hypoglycemia events. Patient education More frequent home glucose monitoring during dosage changes, illness, or change in dietary or activity patterns Consider less aggressive hemoglobin A1c targets when appropriate. Consider glucose monitoring before bed and a bedtime snack regimen.
Pen or vial
Human N and R
Premixed NPH 70/regular 30 Switching from analog to human
Nocturnal hypoglycemia
N ¼ NPH; NPH ¼ neutral protamine Hagedorn; R ¼ regular.
dose of insulin by 20%.10 Human insulins do not provide 24-hour coverage like the basal analogs. Because of this, 2 injections a day will be required.10 Table 2 presents an overview of the onset, peak, and duration for synthetic human and analog insulin. Table 3 presents a summary of provider considerations when prescribing switching a patient from analogs to synthetic human insulin.5 In the case presented at the beginning of this article, a decision was made to transition Jaye to a premixed human NPH 70%/regular 30% insulin. He is an ideal candidate because of his lack of nocturnal hypoglycemic episodes, his financial circumstances, and the daily injection burden a change to an analog basal bolus regimen would present. His analog TDD of insulin was reduced from 40 U of a basal analog to 32 of premixed human NPH 70/regular 30 insulin. Initially, 20 U will be given before breakfast and 12 U with the evening meal. The dosage will be titrated up by 2 U every 3 to 4 days until the target fasting glucose and A1c levels are obtained. Jaye was kept on the metformin and lisinopril. Extensive insulin education was provided to Jaye, including the frequency of glucose monitoring and how to recognize and prevent hypoglycemia. The risk for midday and nocturnal hypoglycemia was emphasized. Jaye was instructed not to skip meals, and while transitioning to the new insulin regimen, he checks his glucose before bed and eats a snack from a preapproved list if his glucose is less than 140. Jaye will report to the office by phone for the next few days and come in for a follow-up appointment in 1 week. Conclusion The cost burden for insulin is an urgent health care concern in the US. Although insulin analogs have been considered the preferred insulin in the US, the high cost and copays for this product may lead to insulin rationing and poor patient outcomes. Lower-cost synthetic human insulin may be a good alternative for certain people with type 2 diabetes without a history of severe nocturnal hypoglycemia. There are options for patients who are not candidates for the lower-cost human insulin alternatives. All 3 of the major insulin manufactures, Sanofi, Eli Lilly, and Novo Nordisk, have patient assistance programs advertised on their websites. These programs
provide coupons and discounts for insulin for patients who meet certain criteria. GoodRx.com is another source for coupons for drug discounts. There are efforts underway to lower the cost of insulin in the US. In addition to the Senate hearings on the high cost of drugs in the US, some states such as Florida are considering importing drugs from Canada.8 Until the efforts are successful, it is important to work with people with diabetes to find the insulin regimen that works best for them from both a financial and health outcomes measure. You can join in efforts to promote insulin accessibility and affordability by signing the petitions at https:// makeinsulinaffordable.org/. References 1. American Diabetes Association. Science, hope, progress. https://www.diabetes. org/resources/timeline. Accessed July 31, 2019. 2. White JR. A brief history of the development of diabetes medications. Diabetes Spectr. 2014;27(2):82-86. 3. Tibaldi JM. Evolution of insulin: from human to analog. Am J Med. 2014;127(10):S25-S38. 4. Quianzon CC, Cheikh I. History of insulin. J Community Hosp Intern Med Perspect. 2012;2(2). https://doi.org/10.3402/jchimp.v2i2.18701. 5. American Medical Association. JN Learning. Health care spending gone wild: using expensive insulin analogs with few clinical advantages [audio podcast]. May 16, 2019. https://edhub.ama-assn.org/jn-learning. Accessed July 31, 2019. 6. Weixel N. Drug pricing fight centers on insulin. The Hill. 2019. https:// thehill.com/policy/healthcare/430680-drug-pricing-fight-centers-on-insulin. Accessed July 31, 2019. 7. Smith-Sabel B. Insulin’s high cost leads to lethal rationing. Shots health news from NPR. 2018. https://ju.idm.oclc.org/login?url¼https://search. ebscohost.com/login.aspx?direct¼true&db¼ccm&AN¼103945600&site¼ehostlive. Accessed July 31, 2019. 8. Barrett J. Rising insulin costs addressed at Senate hearing on drug prices. Pharmacy Times. 2019. https://www.pharmacytimes.com/resource-centers/ diabetes/rising-insulin-costs-addressed-at-senate-hearing-on-drug-prices. Accessed July 31, 2019. 9. Lipska KJ. Insulin analogues for type 2 diabetes. JAMA. 2019;321(4):350-351. https://doi.org/10.1001/jama.2018.21356. 10. Lipska KJ, Hirsch IB, Riddle MC. Human insulin for type 2 diabetes: an effective, less-expensive option. JAMA. 2017;318(1):23-24. https://doi.org/10.1001/ jama.2017.6939. 11. Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA. 2018;320(1): 53-62. https://doi.org/10.1001/jama.2018.7993.
L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx 12. Luo J, Khan NF, Manetti T, et al. Implementation of a health plan program for switching from analogue to human insulin and glycemic control among Medicare beneficiaries with type 2 diabetes. JAMA. 2019;321(4):374-384. https://doi.org/10.1001/jama.2018.21364. 13. Nabrdalik K, Kwiendacz H, Sawczyn T, et al. Efficacy, safety, and quality of treatment satisfaction of premixed human and analogue insulin regimens in a large cohort of type 2 diabetic patients: PROGENS BENEFIT observational study. Int J Endocrinol. 2018;1(suppl):1-7. https://doi.org/10.1155/2018/653617. 14. Zoungas S, Patel A, Chalmers J, et al, ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15):1410-1418.
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15. Howard-Thompson A, Khan M, Jones M, George CM. Type 2 diabetes mellitus: outpatient insulin management. Am Fam Physician. 2018;97(1):29-37. 16. Woo TM, Robinson MV. Pharmacotherapeutics for Advanced Practice Nurse Prescribers. 4th ed. Philadelphia, PA: FA Davis; 2016.
Leigh Hart, PhD, FNP-BC, is a professor at Jacksonville University in Jacksonville, FL, and can be contacted at [email protected]. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.
Contents lists available at ScienceDirect
The Journal for Nurse Practitioners journal homepage: www.npjournal.org
Insulin Rationing Leigh Hart, PhD, FNP-C a b s t r a c t Keywords: analog insulin diabetes mellitus insulin cost synthetic human insulin
The high cost of insulin in the United States has led to insulin rationing by some patients. This article presents a case of insulin rationing and discusses evidence supporting the use of lower-cost synthetic human insulin in some type 2 diabetics without a history of nocturnal hypoglycemia. Provider considerations for managing the switch from analog insulin to synthetic human insulin are presented. © 2019 Elsevier Inc. All rights reserved.
Jaye is a 34-year-old male patient with type 2 diabetes. A year ago he passed out at home and was admitted to intensive care with a blood sugar level of 1,200. Before this diagnosis, his medical history was negative, except for a 100-lb weight gain when he completed a rehabilitation program for substance use disorder 4 years earlier. He has been sober since that time. He was discharged from the intensive care unit on 25 U detemir once a day, metformin 1,000 mg twice a day, and lisinopril 10 mg once a day. His primary care nurse practitioner has titrated his insulin up to 40 U over the last year, but he continues to have very high hemoglobin A1c levels. He is employed and has health insurance through his employer. He is the sole provider for his family. He has a wife and a 1-year-old daughter, and he is expecting his second child in 6 months. He works in an industrial setting and averages 60 hours of work a week. Even with insurance and an income greater than $40,000 a year, he is having difficulty paying the copay for his current basal analog insulin. His nurse practitioner states he needs to add a rapidacting analog insulin at mealtimes because his last hemoglobin A1c was 14%. Jaye’s hemoglobin A1c is at this critical level because he has been rationing his insulin because of cost. Recently, while on the basal insulin alone, he had $100 to last 5 days until his next payday. He was out of his basal analog insulin, but the $80 copay to refill his prescription would not leave enough money for him to buy food for the family and diapers for his 1-year-old daughter. He decided to wait and go without his insulin until his next payday. By Thursday of his second week without insulin, his blood sugar was so high that his meter would not produce a reading and instead flashed “seek medical attention.” He felt horrible but could not miss any work so he “borrowed” 20 units of rapid-acting analog insulin from a coworker, took the medication, and continued to drive his forklift. Despite insurance and employment, this current plan of care is not working for this patient. The addition of the bolus analog insulin will help gain control of his hemoglobin A1c but not if he does not https://doi.org/10.1016/j.nurpra.2019.10.023 1555-4155/© 2019 Elsevier Inc. All rights reserved.
take it. The new rapid-acting insulin will increase his monthly copay to over $300. He cannot afford these medications. Is there a safe, less expensive alternative for this patient? The History of Insulin A diagnosis of type 1 diabetes was fatal until the production of the first commercial insulin in 1923.1 Dr. Frederick Banting discovered the process for insulin extraction from bovine pancreas, and Eli Lilly (Indianapolis, IN) was the first company to produce and market this miracle drug.2 In 1926, crystallization of insulin improved solubility, but the insulin was only available in a regular formulation, and patients required multiple injections a day.2 In 1936, a fish protein called protamine and zinc were added to insulin, providing the first much-needed extended-action insulin protamine zinc insulin.2 A reduction in the amount of protamine led to neutral protamine Hagedorn (NPH) insulin in 1946. NPH insulin has a shorter action time compared with protamine zinc insulin and could be combined with regular insulin to more closely mimic the basal/bolus pattern of insulin normally released by the human body. This was followed by the Lente series, which altered the amount of zinc and produced an intermediate-action insulin.2 Recombinant DNA technology led to a new human insulin formulation marketed in 1983.2 Recombinant DNA technology uses a common bacterium and inserts human genes into the genetic material of the microorganism. The microorganism subsequently produces the desired protein, in this case human insulin. In 1996, the analog insulin lispro, a lysine-proline analog insulin, was introduced as the fastest-acting insulin.3,4 This new rapid insulin has an onset of action of 5 to 15 minutes and a peak of 20 minutes to 90 minutes. This was followed by the basal insulins, glargine in 2000 and detemir in 2005. Analog basal insulin lasts for up to 24 hours and produces no or a very limited peak action time, reducing the risk of hypoglycemia.2-4 These new basal analog
2
L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx
insulins can be used with rapid-acting analog insulins such as insulin aspart or insulin glulisine at mealtime to closely mimic the natural patterns of insulin secretion. Two analog biosimilar insulins are now available. In 2015, Basaglar (Eli Lilly), a biosimilar form of the analog insulin glargine, was Food and Drug Administration approved followed by Admelog (Sanofi, Paris, France), the biosimilar formation of lispro in 2017. Extensive cost savings have not yet been realized with the addition of biosimilars. At the time of this writing, the GoodRx.com website lists 3 insulin 3 mL U-100 pens for the brand insulin Lantus (SanofiAventis US; insulin glargine) for $215.20 with a coupon, whereas the biosimilar Basaglar was $250.91. Many ask why insulin is so expensive when it is not a new product. The production of biosimilar medications is more costly than other nonbiological medications. In addition, there are 3 manufactures that provide insulin in the United States. These companies are Eli Lilly, Sanofi, and Novo Nordisk (Bagsvaerd, Denmark). These companies also produce the 2 available biosimilar formulations. The analog insulins have become the most widely used insulins in the United States.5 The JN Learning podcast titled “Health Care Spending Gone Wild: Using Expensive Insulin Analogs With Few Clinical Advantages” provides a good overview of the molecular modifications used to produce the onsets and duration of action for analog insulins.5
investigated by a bipartisan Senate Finance Committee with a goal to stabilize and lower the cost of insulin.8 As our case study illustrates, even with insurance, the copay for insulin analogs may be too high for some patients. Table 1 presents a summary of certain insulin types and their costs currently available in the US according to GoodRx.com. Lipska9 concludes that recent studies provide evidence that the expensive insulin analogs do not offer substantial benefits for some type 2 diabetics.9 The less expensive synthetic human insulins may lower the financial burden for certain individuals with type 2 diabetes while maintaining good patient outcomes. Lipska et al10 identify candidates for this change as people with type 2 diabetes without a history of severe nocturnal hypoglycemia. Switching a patient with type 2 diabetes on an analog basal bolus regimen to a premixed human 70/30 insulin could result in significant cost savings and reduce the risk for insulin rationing. In some patients, it may also lower daily injection burden.10 Human insulin may be an option for some patients with type 1 diabetes who are unable to afford analog insulin. However, there are identified advantages for patients with type 1 diabetes to be placed on analog insulins.10 The focus of this article is on insulin options for patients with type 2 diabetes who do not have a history of severe nocturnal hypoglycemia.
The High Cost of Insulin
Lipska et al11 completed a retrospective study of Kaiser Permanente of Northern California, Oakland, CA, clients.11 Although insulin analogs are used by more patients with diabetes than other forms of insulin, Kaiser Permanente of Northern California preferentially uses human insulin. This retrospective study compared the outcomes of patients with type 2 diabetes mellitus initiated on basal analog insulin (n ¼ 25,489) and patients initiated on NPH human insulin (n ¼ 23,561). This study did not find significant differences in emergency department visits or hospital admissions
The price for insulin analogs has increased dramatically in recent years. “Insulin prices tripled from 2002 to 2013 and then nearly doubled 2012 to 2016” for almost the exact same product.6 Similar to the case study presented earlier, there are increasing reports in the media about people with diabetes rationing their insulin to the point of severe illness and even death.7 The crisis has captured the attention of US Congress and is currently being
Review of Evidence
Table 1 Comparison of Insulin Prices for Commonly Used Insulins Generic Name
Trade Name
Type
Cost per Unit
Rapid Insulin aspart
Novolog® (Novo Nordisk)
Analog
Insulin glulisine
Apidra® (Sanofi-Aventis)
Analog
Insulin lispro U 100
Humalog® U100 (Lilly)
Analog
$294.86 (U-100/10-mL vial) $561.65 (5 pens u100/3ml) $271.93 (U-100/10-mL vial) $512.40 (5 pens U-100/3 mL) $122.87 (U-100/10-mL vial)a $230.27 (5 pens U-100/3 mL)a $224.77 (3 pens U-200/3 mL) $137. 85 (U-100/10-mL vial)
Insulin lispro U 200 Insulin lispro Regular Regular insulin U100 Regular insulin U 500
®
Humalog U 200 (Lilly) Admelog® (Sanofi-Aventis)
Analog Biosimilar Analog
Humulin R® U100 (Lilly) Humulin R® U 500 (Lilly)
Human Human
$24.88 (vial) $1,561 U-500 20-mL vial Not for ordinary use
Humulin N® (Lilly), Novolin N® (Novo Nordisk)
Human
$96.25 (U-100/10-mL vial) $24.88 (U-100/10-mL vial)
Long Acting Insulin detemir
Levemir® (Novo Nordisk)
Analog
Insulin glargine
Lantus® (Sanofi-Aventis)
Analog Biosimilar analog
$313.46 $465.99 $213.44 $215.20 $250.91
Analog Analog Analog
$324.04 (3 pens U-100/3 mL) $511.75 (3 pens U-100/3 mL) $612.41 (3 pens U-200/3 mL)
Intermediate NPH insulin
Insulin glargine Ultraelong Acting Insulin glargine U 300 Insulin degludec U 100 Insulin degludec U 200
®
Basaglar (Lilly) ®
Toujeo (Sanofi-Aventis) Tresiba® (Novo Nordisk) Tresiba® (Novo Nordisk)
(U-100/10-mL vial) (5 pens U-100/3 mL) (U-100/10-mL vial) (3 pens U-100/3 mL) (3 pens U-100/3 mL)
Prices listed are the lowest posted total cost from GoodRx (https://www.pharmacist.com/practice-insights-emerging-insulins and https://www.goodrx.com/admelog) without insurance at the time of this writing. a Retail prices listed at $170 per vial and $322 per 5-pen set.
L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx
for hypoglycemic events between the 2 groups. It is interesting to note that the average hemoglobin A1c level in both groups of patients was above the recommended value of 7%, with the basal analog cohort reaching a mean hemoglobin A1c of 8.2% (95% confidence interval [CI], 8.1%-8.2%) in 1 year and the NPH cohort reaching a mean hemoglobin A1c of 7.9% (95% CI, 7.9%-8.0%).11 Luo et al12 evaluated a health plan program designed to lower patient and company cost by switching people with type 2 diabetes from very high-cost analog insulin to lower-cost human insulins. This was a retrospective cohort study of 4,635 participants.12 Participants were given financial incentives to self-select human insulin regimens over the more expensive analogs. The switch was available across the health care plan, but the ideal candidate was an adult with type 2 diabetes on more than 2 injections a day, not prone to hypoglycemia, on more than 50 U a day, and/or a history of nonadherence. A dose conversion protocol was used to convert patients who selected to change from analog to human insulin. All analog insulins and secretagogues were stopped. The new premixed human 70/30 insulin or NPH insulin dosage was calculated at 80% of their former total daily dose (TDD) of analog insulin. For the participants switching to a premixed human 70/30 insulin, two thirds of the TDD was taken before breakfast, and one third of the TDD was taken before dinner. For some patients, this lowered the daily injection burden. Outcome measures were compared 12 months before and 12 months after the switch. A slight increase in hemoglobin A1c of 0.14 % (95% CI ,0.05%-0.23%) was found to be statistically significant (P ¼ .003) but not clinically significant. These authors conclude that to be clinically significant the change in hemoglobin A1c would be 0.5% or greater. There was not a significant change in serious hypoglycemic events between the 2 groups (P ¼ .61 for both groups). Nabrdalik et al13 completed an observational study (N ¼ 3,264) comparing patients on premixed human and analog insulin in relationship to efficacy, safety, and satisfaction. This study found that both groups had a reduction in hemoglobin A1c levels, but the hemoglobin A1c levels were significantly higher (P < .001) in the
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human insulin group compared with the analog group (7.72% vs 7.57%). Nabrdalik et al found no difference between the groups in hypoglycemic events. This study also evaluated patient satisfaction using the Diabetes Treatment Satisfaction Questionnaire. Both groups were satisfied with their treatment regimen, with higher reports of patient satisfaction in the human insulin group. The authors did not elaborate or discuss what may have contributed to this increase in satisfaction.13 These studies provide evidence that synthetic human insulin may be an alternative for certain patients with type 2 diabetes who do not have a history of severe hypoglycemia.11-13 Hypoglycemia has been associated with macro- and microvascular disease and death from vascular and nonvascular causes.14 Patients identified as having an increased risk for hypoglycemia include “older age, longer duration of diabetes, higher creatinine levels, lower body mass index, lower cognitive function, use of two or more oral glucose-lowering drugs, history of smoking or microvascular disease, and assignment to intensive glucose control.”14 Insulin analogs are associated with a lower risk for hypoglycemia and are the recommendation to prevent hypoglycemia.15 Switching From Analog to Human Insulin One concern noted in the podcast “Health Care Spending Gone Wild: Using Expensive Insulin Analogs With Few Clinical Advantages” is that newer providers may not be familiar with prescribing the older human formulation of insulin because of the fact that currently 90% of diabetics on insulin are using the newer analog versions.5 The differences in action between the analogs and human insulin require close provider monitoring if it is decided to switch analogs to synthetic human insulin. Table 2 provides an overview of insulin type, dosing, and action profile and table.10 Lipska et al10 note that when switching patents from analog to human insulin, they should consider that patients may not have been taking their full prescribed dose of analog insulin. They recommend beginning the switch by reducing the current daily
Table 2 Insulin Type, Dosing, and Action Profile10,16 Synthetic Human Insulin Type
Onset
Peak
Duration
Dosing Frequency
NPH (Humulin N®a) (Novolin N®) Regular (Humulin R®a) (Novolin R®) Insulin NPH 70%/insulin regular 30% (Humulin® 70/30a) (Novolin® 70/30)
2-4 h 30-60 min 30-60 min
4-10 h 2-3 h 2-6 h
12-18 h 8-10 h 12-18 h
HS, BID 0-30 minutes before meals BID Before breakfast and dinner
Insulin Analogs Type Basal Insulins Degludec U-100 and U-200 (Tresiba®) Detemir U-100 (Levemir®) Glargine U-100 (Lantus®) Glargine U-300 (Toujeo®) Biosimular Glargine U-100 (Basaglar®)Rapid-acting Insulin Aspart U-100 (Novolog®) Glulisine U-100 (Apidra®) Lispro U-100 Pen U-200 (Humalog®) Premixed insulin aspart protamine 70% and insulin aspart 30% (Novolog® 70/30) 75% insulin lispro protamine 75% and insulin lispro 25% (Humalog® 75/25) 75% insulin lispro protamine 50% and insulin lispro 50% (Humalog® 50/50)
Onset
Peak
Duration
Dosing Frequency
1h 3-4 h 2-6 h
None identified 3-9 h None identified
> 40 h 6-24 h 20-24 h
QD QD, BID (for higher doses) QD, BID (for higher doses)
5-15 5-15 5-15 5-15
30-90 min 30-90 min 30-90 min 2-4 h
2-6 h 2-6 h 2-6 h 14-24
0-15 min before meals 0-15 min before meals 0-15 min before meals Before breakfast and dinner
min min min min
BID ¼ twice a day; HS ¼ hour of sleep; QD ¼ every day. a At the time of this writing, Novolin was approximately one third the cost of Humulin.
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L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx
Table 3 Considerations for Using Human Insulin Instead of Analogs10 Concern
Consider
Injection techniques
Regular human insulin is recommended to be injected 30 minutes before a meal as opposed to with the meal for rapid-acting analogs. The least expensive human insulin does not come in a pen. Patients must have the physical and cognitive ability to accurately draw up and administer this insulin. 100 insulin syringes can be purchased for $24.00 at the time of this writing. Human N must be gently agitated to mix the suspension. May start at 10 U in the evening and titrate up by 2 units once or twice a week until target FBS and A1c is achieved. May titrate to 2 injections per day 1 at breakfast and 1 in the evening. Meal time R may be started at 6 U. Two injections: 1/2 daily dose before breakfast and 1/2 daily dose with dinner. If the A1c is greater than 9%, the start can be 0.3 U/kg/d for the total daily dose. Monitor for midday and midnight hypoglycemia. Reduce total daily dose on analogs by 20% when switching from analog to human insulin. For example, if the total daily dose on analogs is 50 U, start human insulin at 40 U. Premixed human insulins may allow for a reduction in total daily injection burden for people on a basal bolus analog pattern. The nocturnal hypoglycemia risk should be a consideration in the switch from analog to human insulin. Analog insulins may provide benefits to those with a history of nocturnal hypoglycemia. Consider in-office or telephone monitoring during the switch to monitor for hypoglycemia events. Patient education More frequent home glucose monitoring during dosage changes, illness, or change in dietary or activity patterns Consider less aggressive hemoglobin A1c targets when appropriate. Consider glucose monitoring before bed and a bedtime snack regimen.
Pen or vial
Human N and R
Premixed NPH 70/regular 30 Switching from analog to human
Nocturnal hypoglycemia
N ¼ NPH; NPH ¼ neutral protamine Hagedorn; R ¼ regular.
dose of insulin by 20%.10 Human insulins do not provide 24-hour coverage like the basal analogs. Because of this, 2 injections a day will be required.10 Table 2 presents an overview of the onset, peak, and duration for synthetic human and analog insulin. Table 3 presents a summary of provider considerations when prescribing switching a patient from analogs to synthetic human insulin.5 In the case presented at the beginning of this article, a decision was made to transition Jaye to a premixed human NPH 70%/regular 30% insulin. He is an ideal candidate because of his lack of nocturnal hypoglycemic episodes, his financial circumstances, and the daily injection burden a change to an analog basal bolus regimen would present. His analog TDD of insulin was reduced from 40 U of a basal analog to 32 of premixed human NPH 70/regular 30 insulin. Initially, 20 U will be given before breakfast and 12 U with the evening meal. The dosage will be titrated up by 2 U every 3 to 4 days until the target fasting glucose and A1c levels are obtained. Jaye was kept on the metformin and lisinopril. Extensive insulin education was provided to Jaye, including the frequency of glucose monitoring and how to recognize and prevent hypoglycemia. The risk for midday and nocturnal hypoglycemia was emphasized. Jaye was instructed not to skip meals, and while transitioning to the new insulin regimen, he checks his glucose before bed and eats a snack from a preapproved list if his glucose is less than 140. Jaye will report to the office by phone for the next few days and come in for a follow-up appointment in 1 week. Conclusion The cost burden for insulin is an urgent health care concern in the US. Although insulin analogs have been considered the preferred insulin in the US, the high cost and copays for this product may lead to insulin rationing and poor patient outcomes. Lower-cost synthetic human insulin may be a good alternative for certain people with type 2 diabetes without a history of severe nocturnal hypoglycemia. There are options for patients who are not candidates for the lower-cost human insulin alternatives. All 3 of the major insulin manufactures, Sanofi, Eli Lilly, and Novo Nordisk, have patient assistance programs advertised on their websites. These programs
provide coupons and discounts for insulin for patients who meet certain criteria. GoodRx.com is another source for coupons for drug discounts. There are efforts underway to lower the cost of insulin in the US. In addition to the Senate hearings on the high cost of drugs in the US, some states such as Florida are considering importing drugs from Canada.8 Until the efforts are successful, it is important to work with people with diabetes to find the insulin regimen that works best for them from both a financial and health outcomes measure. You can join in efforts to promote insulin accessibility and affordability by signing the petitions at https:// makeinsulinaffordable.org/. References 1. American Diabetes Association. Science, hope, progress. https://www.diabetes. org/resources/timeline. Accessed July 31, 2019. 2. White JR. A brief history of the development of diabetes medications. Diabetes Spectr. 2014;27(2):82-86. 3. Tibaldi JM. Evolution of insulin: from human to analog. Am J Med. 2014;127(10):S25-S38. 4. Quianzon CC, Cheikh I. History of insulin. J Community Hosp Intern Med Perspect. 2012;2(2). https://doi.org/10.3402/jchimp.v2i2.18701. 5. American Medical Association. JN Learning. Health care spending gone wild: using expensive insulin analogs with few clinical advantages [audio podcast]. May 16, 2019. https://edhub.ama-assn.org/jn-learning. Accessed July 31, 2019. 6. Weixel N. Drug pricing fight centers on insulin. The Hill. 2019. https:// thehill.com/policy/healthcare/430680-drug-pricing-fight-centers-on-insulin. Accessed July 31, 2019. 7. Smith-Sabel B. Insulin’s high cost leads to lethal rationing. Shots health news from NPR. 2018. https://ju.idm.oclc.org/login?url¼https://search. ebscohost.com/login.aspx?direct¼true&db¼ccm&AN¼103945600&site¼ehostlive. Accessed July 31, 2019. 8. Barrett J. Rising insulin costs addressed at Senate hearing on drug prices. Pharmacy Times. 2019. https://www.pharmacytimes.com/resource-centers/ diabetes/rising-insulin-costs-addressed-at-senate-hearing-on-drug-prices. Accessed July 31, 2019. 9. Lipska KJ. Insulin analogues for type 2 diabetes. JAMA. 2019;321(4):350-351. https://doi.org/10.1001/jama.2018.21356. 10. Lipska KJ, Hirsch IB, Riddle MC. Human insulin for type 2 diabetes: an effective, less-expensive option. JAMA. 2017;318(1):23-24. https://doi.org/10.1001/ jama.2017.6939. 11. Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA. 2018;320(1): 53-62. https://doi.org/10.1001/jama.2018.7993.
L. Hart / The Journal for Nurse Practitioners xxx (xxxx) xxx 12. Luo J, Khan NF, Manetti T, et al. Implementation of a health plan program for switching from analogue to human insulin and glycemic control among Medicare beneficiaries with type 2 diabetes. JAMA. 2019;321(4):374-384. https://doi.org/10.1001/jama.2018.21364. 13. Nabrdalik K, Kwiendacz H, Sawczyn T, et al. Efficacy, safety, and quality of treatment satisfaction of premixed human and analogue insulin regimens in a large cohort of type 2 diabetic patients: PROGENS BENEFIT observational study. Int J Endocrinol. 2018;1(suppl):1-7. https://doi.org/10.1155/2018/653617. 14. Zoungas S, Patel A, Chalmers J, et al, ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363(15):1410-1418.
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15. Howard-Thompson A, Khan M, Jones M, George CM. Type 2 diabetes mellitus: outpatient insulin management. Am Fam Physician. 2018;97(1):29-37. 16. Woo TM, Robinson MV. Pharmacotherapeutics for Advanced Practice Nurse Prescribers. 4th ed. Philadelphia, PA: FA Davis; 2016.
Leigh Hart, PhD, FNP-BC, is a professor at Jacksonville University in Jacksonville, FL, and can be contacted at [email protected]. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.