Insulin – structure,
discovery and obtaining it.
What is insulin?
• Insulin is a hormone central regulating carbohydrate and fat
metabolism in the body.
• Insulin causes liver cells, muscle cells and fat tissue to take up glucose
from the blood and store it as glycogen in the liver and muscle.
Production of insulin
• Insulin is producted by the pancreas, which has two important
functions :
1. Producing hormones – insulin and glucagon which regulate blood
sugar levels.
2. Producing pancreatic digestive enzymes.
• Insulin is released when any of the several stimuli are detected–
stimuli include ingested protein and glucose in the blood from
digested food.
Insulin structure
• Insulin is a peptide hormone composed of 51 amino acids and has a
molecular weight of 5808 Da.
Insulin is
produced and
stored in the
body as a
hexamer ,
while the active
form is the
monomer.
• Hexamer is more stable then the monomer, which is better for
practical reasons.
• Monomer is a much faster-reacting drug, it means that insulin
injections do not have to precede mealtimes by hours.
• Insulin is produced by beta cells in the islets of Langerhans, which
release insuln in two phases: The first phase release is triggered in
response to rising or increased blood glucose levels. The second
phase is a sustained, slow release of newly formed vesicles triggered
independently of sugar.
• Beta cells in the islets of Langerhans take up as much as 60%-80% of
all the cells.
Insulin mutations
• Mutations in the insulin gene can cause type I or type II diabetes.
Reserchears have found at least 10 mutations - they suspect that the
mutations alter the way insulin folds during its synthesis. Reserchears
suggest that these improperly folded proteins interfere with other
cellular processes in ways that eventually kill the cells that produce
insulin.
• Most strongly influenced by insulin are the muscle cells and fat cells.
These cells are important because of their central role in movement,
breathing and circulation.
• Together these cells account about two-thirds of all cells.
• Avarage life of insulin is 3-6 min.
Actions of insulin
on the human metabolism
• Control of the cellural intake of certain substances.
• Increase of DNA replication and protein sythesis.
• Modification of the activity of numerous enzymes.
Insulin for medical purposes
• Insulin is being produced biosynthetically using recombinant DNA
technology. More recently, reserchers have succeded in introducing
the human insulin gene into plants and in producing insulin in them.
This technique is set to reduce production costs.
• Before it was possible to produce insulin biosynthetically it wa aquired
from animals and purified so it could be used as injections.
Although insulin
which is aquired
biosynthetically is
a precise copy of
the human insulin
gene, they have
been designed to
have an effect
much faster.
History of insulin
Paul Langerhans
Paul Langerhans was
a medical student in
Berlin in 1869. He
was studying the
structure of pancreas
under the microscope
when he noticed
tissue clumps
scatarred throughout
the pancreas. He
named them as the
islets of Langerhans.
Oscar Minkowski
In 1889, Polish-German
physician Oscar
Minkowski in
collaboration with
Joseph von Mering,
removed the pancreas
from a healthy dog to
test its assumed role in
digestion. On testing the
urine , they found sugar
in the dog’s urine,
establishing for the first
time a relationship
between the pancreas
and diabetes.
• In 1916, a Romanian professor of physiology Nicolae Paulescu, was
the first to isolate insulin.
• In 1921. Nicolae published four papers explaining his research.
• 8 months later his work was confirmed by doctor Frederick Grant
Banting and biochemist J.J.R. Macleod, who were later awarded the
Nobel prize.
Nicolae Paulescu
Nicolae Paulescu
was the dicoverer
of insulin,
however because
of his anti-semitic
views he has been
ereased from the
history of
medicine as the
discoverer of
isnulin.
In 1920, Canadian Frederick Banting was reading one of Mikowski’s
papers and concluded that it was the digestive secretions that
Minkowski had originally studied that were breaking down the islet
secretions, thereby making it impossible to extract successfully. The
idea was the pancrea’s internal secretions, which, it was supposed,
regulates sugar in the bloodstream, might hold the key to the
treatment of diabetes. A surgeon by training, Banting knew certain
arteries could be tied off that would lead to atrophy of most the
pancreas, while leaving the islets of Langerhans intact.
• In 1921, Banting travaled to Toronto to explain his idea to
[Link], who was Professor of Physiology at the University of
Toronto. He asked Macleod if he could use his lab to test his idea.
Eventually he agreed to let Banting use his lab and supplied him with
ten dogs on which to experiment and a lab assistant Charles Best.
John James
Rickard
Maclod
When the Professor
returned from his
summer vacation to
the University of
Toronto and saw the
progress Banting and
Best had made, he
decided to let Banting
contionue his
research, supplied
him with more dogs,
bigger lab and
pointed out the flaws
in his research.
Frederick Banting
After Bantings
discovery, the
Canadian
goverment
funded Bantings ,
so he could
continue his
research. King
George V
crowned Banting
Ser.
Chales Best
Macleod supplied
Banting with two lab
assistants – Charles Best
and Clark Noble. Since
Banting required only
one lab asisstant, Best
and Noble flipped a coin
to see which would
assist Banting for the
first half of the summer.
Best won, and took the
first shift as Banting’s
asisstant. Unfortunate
for Noble Banting
decided to keep Best for
the entire summer.
The first insulin injection
The first insulin injection was made on January 11, 1922, Leonard
Thomson, a 14-year-old diabetic who lay dying at the Toronto
General Hospital. However, the extract was so impure Thompson
suffered a severe allergic reaction, and further injections were
canceled. Over the next 12 days, Collip developed a second dose –
purified exctract, which Banting injected Thompson on January 21.
The second injection was succesful, with no side-effects and also in
completely eliminating the glycosuria sign of diabetes.
James Collip
James helped
Banting to purify
the insulin
exctract, but
Banting, Best and
Collip didin’t work
well together so
after a year Collip
left the group.
In 1922, Best managed to improve his techniques to the point where
large quantities of insul could be exctracted on demand, but the
preparation remained impure. The drug firm “Eli Lily and Company”
united with Basting and in November, “Eli Lily and Company” made
a major breakthrough and were able to produce large quantities of
highly refined insulin. Insulin was offered for sale shortly after.
Herbert Boyer
Herbert Boyer
was the scientist
first who
succeded in
making a
synthetic
“human” insulin
through gene-
engeneering in a
laboratory in
1977.
• “Eli Lily and Company” partnered up with “Genetech” the company
founded by Boyer, went on in 1982 to sell the first commercionally
available biosynthetic human insulin under the brand name “Humilin”.
• The patent for insulin was sold to the University of Toronto for one
half-dollar.
Nobel prizes
• In 1923 the Nobel prize committee awarded Frederick Banting and
[Link]. They were awarded the Nobel Prize in Physiology for
the discovery of insulin. Banting, isulted that Best was not metioned,
shared his prize with him and Macleod immediately shared his with
James Collip.
Frederick Banting and his lab
partner Charles Best
Dorothy
Crowfoot
Hodgkin
In 1969, Dorothy
determined the
spatial
conformation of the
molecule, the so-
called tertiary
structure. She had
been awarded a
Nobel Prize in
Chemistry in 1964
for the
development of
crystallography.
Frederick Sanger
In 1958 british molecular
biologist Frederick
Sanger determined the
primary structure of
insulin. It was the first
protein to have its
sequence be
determined. He was
awarded the Nobel Prize
in Chemistry for his
work.
Rosalyn
Sussman
Yalow
1977 Rosalyn
received the Nobel
Prize in Medicine
for the
develpoment of
radioimmunoassay
for insulin.
Insulin Economics
The Cost of Diabetes Therapy
To understand where we are
one needs to know how this all started………
•By 2005 more than US $7.3 billion was spent globally on
the purchase of insulin products
• Thought due to increased prevalence/need, increase
cost, increased use of analogues
No one could have predicted what would happen over the next decade
Pharm Pract 2006;22(12):44-9.
Price of Insulin: 1960-2015 US-per unit
(Regular and RapidActing Analogue)
Diabetes Prevalence, % Insuln-Rx’ed
Patients, Share of Sales
Gal A: Bernstein Research September 24, 2013
Average Wholesale Price (AWP)
•AWP: “list prices” reported by manufacturers
•AWP has often been compared to the “list price” or “sticker price”,
meaning it is an elevated drug price that is rarely what is actually paid
•AWP is not a government-regulated figure, does not include discounts or
rebates often involved in prescription sales, and is subject to fraudulent
manipulation by manufacturers or even wholesalers. As such, the AWP,
while used throughout the industry, is a controversial pricing benchmark
Accessed May 23, 2015 from [Link]/article/[Link]
Sticker Shock
January, 2016 (after deductibles)
•Co-pay for insulin aspart: $150/vial (the “preferred insulin” for a
physician in NY City) $190 on [Link]
•Co-pay for a box of 5 insulin glargine pens: $185 (for a college
professor in Everett, WA) $381 on [Link]
•Co-pay for a vial of NPH insulin, $40 (student in Eugene, OR)
$135 on [Link]
Insulin Financial Primer
•In 2013, insulin was a $21 billion global market with compound
annual growth rate of 15% for the previous 5 years.
•Secular volume growth: 6-7%/year 2008-2018
•Revenue = unit SALES + unit PRICE
•For all 3 companies, the reliance on the US is problematic: role
of biosimilars?
•These may attenuate growth, yet both Sanofi and Eli Lilly will be
in the biosimilar market
Gal A: Novo Nordisk, an insulin primer; where is the market headed? Bernstein Research September 24, 2013
Price Increases
• On May 30, 2014 the price of insulin glargine was increased by 16.1%
by Sanofi
• The next day, Novo Nordisk increased the price of insulin detemir by
16.1%
• The pattern repeated itself 6 months later and this has actually
happened 13 times for these two products with total sales of $11
billion US
Langreth R: Hot drugs show sharp price hikes in shadow market. Bloomberg Business May 6, 2015
Lantus and Levemir Price per vial - USD
Langreth R: Hot drugs show sharp price hikes in shadow market. Bloomberg Business May 6, 2015
What About Insulin Revenue?
C. Canipe and J. Walker, WSJ, Oct 5, 2015
Comparing Prices of Insulin Around the World (Feb, 2016)
My Take
• For the typical patient with type 2 diabetes, while I prefer analogues
due to decreased hypoglycemia risks, most do well with human
insulin
• NPH (2009 Cochrane Review): no difference from analogues with
HbA1c; there was no difference in severe hypoglycemia although
increased risk of symptomatic and nocturnal hypoglycemia
• Regular insulin-no difference in glycemic control and no increased risk
of hypoglycemia compared to rapid-acting analogues (in T2D)
• Analogues should always be used as much as possible with T1D
*Cochrane Database Syst Rev. 2007;(2): CD005613 **Diabetes Obesity Metab 2009;11:53-59
However…
• Younger physicians without experience with NPH and Regular require
training-simply switching insulins without understanding the caveats
could result in poor outcomes
• Training for the use of human insulin for both postgraduate
physicians, fellows, residents, and students should be a priority
• Shouldn’t this be the role of our professional and advocacy societies
(ADA, Endocrine Society, and AACE)?
Tylee T, Hirsch IB: JAMA [Link]-666
So Are We Using More Human Insulin?
• Between 2011 and 2015 human Regular insulin sales have decreased
from 5.8% to 3.9% and all NPH insulin has decreased from 6.2% to
4.5% (pre-mix human insulin has decreased from 6.2% to 4.5%)
• WHY (one reason)?
• In 2015 promotional detailing for human Regular and NPH were 0.5%
and 0.3% of all calls respectively; long-acting analog is 34% with rapid-
acting analog 24% of detailing (pre-mix analogues > 30% for both
companies)
Warburg Pharma Rx January, 2016
Why Did This Happen?
• Costs from developing current insulins were paid years (decades) ago; can we attribute the slope
of the increase in price all to R&D of new insulins?
• Does the benefit of a 10, 20, or 30% reduction of mild hypoglycemia justify even greater costs?
• The actual cost of insulin manufacturing is extremely cheap; is it ethical to charge such a price for
a medication required for survival by some?
• The emerging role of biosimilar insulins
• “Supply and Demand” economics is not at work
• Insulin is not alone in its cost increase
Possible Solutions?
• Develop diabetes (insulin) guidelines that incorporate cost/benefit
analysis
• “Value-based pricing”-physician panels to recommend target prices
based on magnitude of benefit
• But panels doing these two need to be all inclusive, including an
economist and endocrinologist
• Allow importation of drugs from abroad for personal use
• Unlikely to be allowed
Prescription Medicines:
Insulin Costs in Context
Prescription Medicines: Insulin Costs in Context [Link]/insulin
Medical innovation has transformed the lives of diabetes
patients.
A century ago, patients were treated with animal insulins. Today, patients have access to insulins that
operate at the molecular level that more closely resemble insulin release as it naturally occurs in the body.
More recent advances have driven much of this transformation.
Maintenance of stable and consistent blood sugar levels is better than ever before, helping
to avoid serious complications and reduced weight gain.
Longer-acting insulins provide coverage for over 24 hours and enable greater flexibility in
dosing and reduced risk of dangerous blood sugar drops.
Rapid-acting insulins—including an inhaled form—enable dosing directly before or even
after meals, rather than in anticipation of meals
Insulin pens offer greater convenience, including some that reduce injections for high
doses or ease use in children.
*NOTE: Modern insulin treatment protocol often requires long-acting insulin to provide a base level of coverage all day along with meal-time administration of insulin to modulate spikes in blood glucose.
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Prescription Medicines: Insulin Costs in Context [Link]/insulin
Better diabetes management saves money and improves health outcomes.
Improving Medication Adherence
Among Diabetes Patients Could:
22 Result in 1 million less ER visits and
hospitalizations annually
million
Save $8.3 billion for the U.S. health
Americans live with care system each year
uncontrolled diabetes.
SOURCE: American Diabetes Association
SOURCE: Jha, et al. “Greater Adherence to Diabetes Drugs is Linked to Less Hospital Use and Could Save Nearly $5 Billion Annually.” Health Affairs
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Prescription Medicines: Insulin Costs in Context [Link]/insulin
After discounts and rebates, prices for the most commonly used insulin classes are declining.
70% 30%
Amount discounts can Amount prices after Net prices for long-acting
lower the list price of discounts and rebates insulins are less expensive
insulin, according to have fallen in the last two now than in 2010
industry analysts years for long-acting
insulins
SOURCE: Bloomberg Businessweek, June 29, 2017; Bloomberg. June 29, SOURCES: SSR Health. “US Brand Net Pricing Growth 0.2% in 3Q17,” December 2017. SOURCE: SSR Health. “US Rx net prices fall 4.8 percent y/y in 4Q18.”
2016. Eli Lilly, Press Release, March 2019. March 18, 2019.
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Prescription Medicines: Insulin Costs in Context [Link]/insulin
Diabetes patients face soaring out-of-pocket costs.
Middlemen expose insulin patients to list prices through coinsurance
or deductibles. Over the past 10 years in the commercial market:
The share of patient out-of-pocket medicine The share of patient out-of-pocket medicine
spending represented by coinsurance has grown spending represented by deductibles has grown
2x 3x
Source: Kaiser Family Foundation, October 2016.
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Prescription Medicines: Insulin Costs in Context [Link]/insulin
Insurers and PBMs have a lot of leverage to hold down medicine
costs.
Negotiating power is increasingly concentrated among
fewer pharmacy benefit managers (PBMs). Insurers determine:
FORMULARY
if a medicine is covered
23%
24% TIER PLACEMENT
patient cost sharing
Top 3
Market Share: ACCESSIBILITY
76%
utilization management through
prior authorization or fail first
23%
30% PROVIDER INCENTIVES
preferred treatment guidelines
and pathways
OptumRx (UnitedHealthGroup)
CVS Health (Caremark)
Express Scripts
All Other
Source: Drug Channels Institute, March 2019.
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Prescription Medicines: Insulin Costs in Context [Link]/insulin
Negotiated savings are often not shared with patients.
More than half of commercially insured
Cost sharing for nearly 1 in 5 brand
patients’ out-of-pocket spending for brand
prescriptions is based on list price
medicines is based on the full list price
29%
44%
55%
Copay
26%
Deductible
Coinsurance
Source: IQVIA. May 2018.
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Prescription Medicines: Insulin Costs in Context [Link]/insulin
Sharing negotiated rebates would lower Medicare Part D patient costs.
For a typical Part D patient with diabetes taking five
medicines, including insulin:
Out-of-pocket spending could
decrease nearly $900 a year
If we don’t reform the rebate
system, diabetes patients could
pay twice what their insulin costs
Premiums would only increase to their insurer when they are in
$3 to $6 a month, as little as a
dime a day the deductible.
SOURCES: Avalere Analysis, 2019; OACT, Milliman and Wakely Analysis, February 2019.
NOTE: Plan cost includes medical and pharmacy claims
59
Prescription Medicines: Insulin Costs in Context [Link]/insulin
Sharing negotiated rebates could save commercially insured patients as well.
Example: High-Deductible Health Plan with a Copay Example: High-Deductible Health Plan with Coinsurance
Mary has diabetes and spends Kevin has diabetes and several
$1,000 each year on medical and other health conditions and spends
pharmacy expenses $5,000 each year on medical and
pharmacy expenses
She would save $359 a year She would save about $800 a year
Her premium would increase Her premium would increase
less than 1% less than 1%
Source: Milliman Analysis, October 2017.
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Prescription Medicines: Insulin Costs in Context [Link]/insulin
Policy solutions to address insulin affordability challenges.
FINALIZE PROPOSED RULE TO REFORM REBATE SYSTEM IN MEDICARE PART D
• Replace the current system of rebates in Part D with a system where discounts are passed directly on to patients
at the pharmacy counter
DELINK SUPPLY CHAIN PAYMENTS FROM THE LIST PRICE OF A MEDICINE
• Advance reforms that prevent PBMs and other supply chain entities from having their compensation calculated as
a percent of the list price of a medicine and instead based on a fee based on the value their services provide
ENSURE PATIENTS WITH STATE-REGULATED INSURANCE ALSO DIRECTLY BENEFIT
FROM REBATES
• Support legislation at the state-level that would reduce patients’ out-of-pocket costs by sharing discounts and
rebates with patients at the pharmacy counter
SUPPORT FIRST DOLLAR COVERAGE OF INSULIN FOR HIGH-DEDUCTIBLE HEALTH
PLAN PATIENTS
• Clarify Department of Treasury rules to make sure high-deductible health plans must provide coverage of
insulin and other chronic disease medicines prior to the deductible
COUNT THIRD-PARTY DISCOUNT PLANS TOWARD DEDUCTIBLES
• Change private health insurance rules to require health plans to count the cost of prescriptions purchased
through third-party programs, like Blink Health and GoodRx, toward patient maximum out-of-pocket limits
SUPPORT FLAT COPAYS FOR INSULIN FOR PATIENTS RECEIVING COST-SHARING
SUBSIDIES IN THE EXCHANGES
• Make regulatory changes to ensure plans put at least one of each type of insulin on a copay-only tier
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