A PRIMER ON INSULIN AND POSSIBLE PRICING SOLUTIONS

Zeena Nackerdien

Photo by The original uploader was Takometer at English Wikipedia / CC BY 2.5

Contents

• Structure

• Basics

• Biology

• General principles of insulin therapy during diabetes

• Timeline (1920s to 1930s)

• Timeline (1940s to 1980s)

• Timeline (1990s to 2000s)

• Sources of Insulin

• Different Types

• Some of the subcutaneous insulin delivery devices (1)

• Some of the subcutaneous insulin delivery devices (2)

• Why so many insulins and devices?

• Cost

• Possible solutions (ADA)

Structure

• “Insulin is a hormone consisting of 2 polypeptide chains. Each chain is composed of a specific sequence of amino acid residues connected by peptide bonds. In humans, chain A has 21 amino acids, and chain B has 30. Post translational modifications result in the connection of these two chains by disulfide bridges. Cysteine residues on A7 and B7, as well as A20 to B19 are covalently connected by disulfide bridges. Chain A also has an internal disulfide bridge connecting A6 to A11. The 3D structure of insulin is composed of 3 helices and the three disulfide bridges. Hydrophobic amino acid residues are clustered on the inside of the molecule while the polar amino acids residues are located on the outer surface. This arrangement of amino acid residues lends stability to the overall molecule. A single molecule of insulin can form a dimer with another insulin molecule, but the most active form is a single unit. The chemical formula for the insulin monomer is: C256H381N65O79S6.”1

Photo by Isaac Yonemoto. / CC BY 2.5;

1. https://en.wikibooks.org/wiki/Structural_Biochemistry/Protein_function/Insulin#Structure

Basics

• Excess blood glucose is taken up by cells per instruction of the pancreatic hormone, insulin

• Average normal blood glucose (blood sugar) control for the past 2 to 3 months, as measured by the A1C test, is about 7% , according to the American Diabetes Association (ADA)

– Core metabolic disorder of the highly prevalent chronic disease, type 2 diabetes, is insulin resistance

– A combination of tests can confirm insulin resistance e.g., fasting insulin blood test, glucose tolerance testing, and clinical evaluations

• Insulin is the most potent glucose-lowering agent1

– Patient motivation, cardiovascular and end-organ complications, age, general well-being, risk of hypoglycemia, and overall health status, as well as cost considerations can impact decisions to intensify insulin therapy

1. Garber AJ, et al. Endocrine Practice: 2017;23(2):207-238.

Biology

• Insulin is coded for on the short arm of chromosome 11

• Synthesized in -cells of pancreatic islets of Langerhans as its precursor, proinsulin

1. Wilcox G. Clin. Biochem. Rev. 2005;26(2):19-39.

Proinsulin is synthesized in the ribosomes of the rough

endoplasmic reticulum (RER) from mRNA as pre-proinsulin.

Pre-proinsulin is formed by sequential synthesis of a signal

peptide, the B chain, the connecting (C) peptide and then the A chain comprising a single

chain of 100 amino acids.

Removal of the signal peptide forms proinsulin, which acquires its characteristic 3-dimensional

structure in the ER.

Secretory vesicles transfer proinsulin from the RER to the

Golgi apparatus, whose aqueous zinc and calcium rich

environment favours formation of soluble zinc-containing

proinsulin hexamers

As immature storage vesicles form from the Golgi, enzymes

acting outside the Golgi convert proinsulin to insulin and C-

peptide.

Insulin forms zinc-containing hexamers which are insoluble,

precipitating as chemically stable crystals at pH 5.5.

When mature granules are secreted into the circulation by

exocytosis, insulin, and an equimolar ratio of C-peptide are

released.

General Principles of Insulin Therapy during Diabetes

• Used in diabetes treatment of all types

Type 1a

• All patients

• Physiologic replacement should ideally mimic secretary pattern of non-diabetic pancreas

• Diabetic ketoacidosis at first presentation usually indicates a need for lifelong treatment

Type 2b

• Manage hyperglycemia in many patients

• High-risk patients e.g., Afro-Caribbean populations may present with ketoacidosis

a. The body makes very little or no insulin due to autoimmune destruction of the cells that produce insulin.

b. With the more common form of diabetes, the body does not make or use insulin well.1. McCulloch DK. UpToDate 2017.

Timeline(1920s to 1930s)

1. Perkins A. Nursing made Incredibly Easy. 2017;15(3):30-35.

Timeline(1940s to 1980s)

1. Perkins A. Nursing made Incredibly Easy. 2017;15(3):30-35.

Timeline(1990s to 2000s)

1. Perkins A. Nursing made Incredibly Easy. 2017;15(3):30-35.

Sources of Insulin1

• Insulin can be isolated from the pancreases of animals, usually cows, pigs, or even horses

• Nowadays, animal insulins have been replaced with human insulins and analogs

• Since the 1980s, recombinant insulins were manufactured using bacteria and yeast

• Plants (Arabidopsis Thaliana) are also being investigated as “factories” for the production of insulin

1. Ahmad K. J.Tradit.Chin. Med.. 2014;34(2):234-237.

Different Types1

• Insulin helps the body or store

or use the blood glucose it gets

from food

• There are 4 different types of

commercially available insulins

– Rapid-acting insulin

– Regular or Short-acting insulin

– Intermediate-acting insulin

– Long-acting insulin

1. American Diabetes Association. Insulin Basics. 2017

Some of the

Subcutanenous

Insulin

Delivery

Devices

CSII (Successful use depends on patient education and motivation)1

Advantages:Glycemic control with continuous delivery of insulin; Patient

compliance and acceptance

Disadvantages:Cost; Risk of diabetic ketoacidosis if pump fails

Pens (No superiority vs. syringes for glycemic control)1

Advantages: Convenient; Pain versus syringes; Accurate and precise versus

syringes

Disadvantages Expensive than syringes; Cannot mix 2 insulins:

Vial and Syringe (Most frequently used method)1

Advantages: Costly than pen and continuous subcutaneous insulin infusion

(CSII)

Disadvantages:Pain than pen; Psychosocial issues; Inconvenient to carry; Accurate than pens; Patient-friendly

1. Shah RB, et al. Int. J. Pharm. Investig. 2016;6(1):1-9..

Some of the

Subcutanenous

Insulin

Delivery

Devices

Inhaled (Exubera withdrawn from the market; Technosphere under review*)1

Advantages: Noninvasive; Patient compliance; Onset of control within 10 to 15

min,; Postprandial blood glucose control

Disadvantages:Bioavailability; Inhalational device issues; Lung function; Transient cough

Threshold-suspend (TS) pump1 (FDA-approved; Phase 4 survey

underway; Long-term data not available)

All the advantages of SAP + glycemia by 30% versus SAP

Disadvantages: Same as CSII and SAP; Hypoglycemia algorithms not predictive

Sensor-augmented pump therapy (SAP; Better glycemic control

requires contentious continuous glucose monitor use)1

Advantages: Same as continuous subcutaneous insulin infusion (CSII) + better

glycemic controlDisadvantages: Same as CSII; CGM accuracy

*The FDA has recently approved a human insulin, Afrezza, for type 1 and 2 diabetes.1. Shah RB, et al. Int. J. Pharm. Investig. 2016;6(1):1-9..

Why so many insulins and devices?

Insulin replacement therapy is lifesaving and reduces complications associated with diabetes. However, it remains a challenge to implement effective glycemic control in patients with advanced insulin deficiency.1

1Quest for more physiologic insulins mimicking the pharmacodynamics of normal prandial and basal insulin secretion, led to the development of various insulin analogs. Insulins with more consistent biological activities, ease-of-use, and better safety profiles are currently in use; Unobtrusive, user-friendly devices have also been designed to make the life of patients with insulin-dependent diabetes more tolerable.1

2The first biosimilar insulin, glargnine (U100) was introduced into the USA in 2015; Because biosimilars are not exact copies of the original, large recombinant insulin product, inherent differences may result in differences in immunological responses by patients.1

3

1. Meneghini LF, McNulty JN. Diabetes Technol. & Ther. 2017;19(2):76-78.

Cost“More than 90% of privately insured patients with type 2 diabetes in the USA who

are prescribed insulin receive the latest and most expensive insulin analogs.

Although these newer insulin products might be substantially better than the

purified pancreatic extracts that Banting, Best, and Collip isolated 95 years ago,

the data are not definitive on whether insulin analogs being used today are safer or

more effective for most patients with type 2 diabetes than human insulins used

widely in the 1990s, for which the main patents have expired.” 1

1. Luo J, et al.The Lancet Diab. & Endocrinol.. 2017;5(3):158-159.

2015: US patients (≥65 years old) using Medicare Part D spent more than $4.3 billion on one type of insulin alone i.e., the second-largest expenditure for part D drugs for that year.1

Possible Solutions (ADA)

Want to see all off-patent diabetes

medications, including insulin, in

the lowest cost-sharing tier on all

formularies1

Support the authorization of the

Centers for Medicare and

Medicaid Services (CMS) to negotiate

prices for prescription drugs

under Medicare Part D1

Support the move toward value-based benefit design from the current fee-for-

service system to incentivize better

outcomes, in addition to promoting

adherence to recommended

therapy to reduce emergency

department visits and

hospitalizations1

ADA, American Diabetes Association1. Tsai A. The Rising Cost of Insulin. In. Diabetes Forecast. The Healthy Living Magazine.2016.