Insulin's sweet spot sours as diabetes deaths
increase
3rd October 2019
In 1922, an anxious
father was waiting at Pyrmont Wharf in Sydney for a ship to come in.
At home, his
five-year-old daughter Phyllis, weighing just 8.5kg, was slowly starving to
death on a diet of butter and whey instituted after her diagnosis with type 1
diabetes six months earlier.
The ship’s cargo
included stocks of insulin and Phyllis Adams became the first Australian to
receive the life-saving drug.
By the time she
died in 1988, Phyllis had the dual distinctions of both living with diabetes
and being treated with insulin for longer than any other person in the world.
Today, insulin is a
daily lifesaver for an estimated 130,000 Australians living with type 1
diabetes.
However, globally,
it is estimated that half of the 100 million people needing insulin for type 1
or type 2 diabetes lack reliable access.1
In the US, the
soaring cost of insulin products is leading to deaths and has emerged as a hot
political topic.
Democratic
presidential candidate Bernie Sanders has put the drug centre-stage in his push
for universal healthcare and President Donald Trump is waging war on drug
pricing and has announced steps to allow importation of lower-priced
medications from Canada.
Americans are
reportedly resorting to measures such as buying dog insulin, rationing their
dose or using cheaper over-the-counter short-acting insulins with less
predictable effects.
An independent
report by Upwell Health published in January showed that one in four
insulin-dependent patients with diabetes in the US are cutting back on how much
insulin they use due to cost.2
And in August, a
young American with type 1 diabetes died from a series of strokes in his sleep.
Josh Wilkerson, 27,
from Northern Virginia, no longer eligible for his step-father’s insurance
plan, could not afford the $US1200-a-month prescription (about $1800) for
long-acting insulin and had switched to a cheaper formulation.
According to the
Union of Concerned Scientists, the price of insulin in the US has risen 1000%
since the mid-1990s.
There have been at
least six deaths attracting nationwide attention and dramatic civil action,
including a group of protesting parents who in late 2018 attempted to deliver
the ashes of their children to the headquarters of a leading insulin
manufacturer (see main photo).3
These events are a
sad indictment on the altruistic story of the drug’s development by a Canadian
doctor and his student in 1922.
Man's Best friend
Dr Frederick
Banting was a surgeon in a floundering practice in Ontario, Canada, when he
took on extra work as a demonstrator at a local medical school.
In 1920, while
preparing a lecture for students on the function of the pancreas, he hit on an
idea for an experiment to investigate the relationship between pancreatic
secretions and diabetes.
At the time, a
strict diet avoiding all carbohydrates was the only treatment for the disease
and parents of children such as Phyllis Adams were faced with the grim choice
of death by ketoacidosis or slow starvation.
At the time of
Banting’s eureka moment, European research had already hinted at an association
between the onset of diabetes and the degeneration of the tiny clusters of
pancreatic cells known as the ‘islets of Langerhans’, named for the German
medical student who discovered them.
Further research in
Europe into pancreatic secretions was hindered by WWI.
This proved
fortuitous for Banting, who took his idea to John Macleod, a Scottish physiologist
he had studied under at the University of Toronto.
Macleod had
published a series of papers on glycosuria and although initially sceptical of
Banting’s hypothesis, granted him a laboratory, some dogs and a student
assistant, Charles Best.
The pair began
building on former experiments on dogs that compared the results of either the
ligation of the pancreatic duct — serving to atrophy the acini cells that send
secretions into the gut but leaving the islets of Langerhans unaffected
— or a complete pancreatectomy.
They found that
where duct-ligated dogs did not develop diabetes, the dogs undergoing
pancreatectomy quickly developed glycosuria. Their next experiment involved
isolating the pancreatic secretions of a duct-ligated dog after the atrophy of
the acini cells.
Sold for a dollar
After multiple
set-backs and dead dogs, Banting and Best managed to keep a diabetic dog named
Marjorie alive for 70 days with injections of an extract made from a
duct-ligated dog pancreas and prepared in saline, a suggestion from Macleod.
The wider
scientific community remained sceptical but Macleod was determined to prepare a
solution for human testing, hiring biochemist James Collip to help.
They made an
extract from the secretions of dogs and cows but their first clinical test on a
14-year-old boy failed.
The second attempt,
using an extract Collip purified using alcohol, dramatically normalised the
teenager’s glycaemia, glycosuria and ketonuria.
Banting, Best and
Collip sold their patent for insulin to the University of Toronto for a dollar.
Within a year,
pharmaceutical manufacturer Eli Lilly was mass-producing insulin made from cow
and pig pancreases.
In 1923, Banting
and Macleod were awarded the Nobel Prize in Physiology or Medicine for the
discovery of insulin.
Banting split his
winnings with Best, and Macleod split his with Collip.
Treating
diabetes: A tale that spans centuries
|
Ayurvedic texts
from the sixth century BC are among the first to describe a disease
causing madhumeha, Sanskrit for ‘honey urine’, so named because
it attracted ants and flies.
The physicians of
Ancient Egypt also provide some early theories of a connection between diet
and the symptoms of diabetes.
An Egyptian
papyrus from 1550BC provides a prescription for excessive urination,
instructing patients to sip a cocktail of “water from the bird pond,
elderberry, fibres of the asit plant, fresh milk, beer-swill, flower of the
cucumber and green dates”.7
It wasn’t until
the first century, however, that the term diabetes, derived from the Greek
word for ‘siphon’, was used.
While there is
some debate over which eminent Greek scholar was the first to use the term,
Aretaeus of Cappadocia describes a disease of “melting down of the flesh and
the limbs into urine” resulting in a life that is “short, disgusting and
painful”.8
By the
Renaissance, European physicians advised tasting urine to confirm its
sweetness.
The most famous
of these was Oxford physician Thomas Willis — perhaps best known for
identifying the Circle of Willis — who provided the adjunct ‘mellitus’ from
the Greek ‘like honey’ in 1674.
Meanwhile, a
Swiss anatomist by the name of Johann Conrad Brunner was busy excising
the pancreas of his neighbour’s hunting dogs.
In 1683, Brunner
described classic symptoms of polyuria and polydipsia in pancreatectomised
dogs but he failed to make the association with earlier or contemporary
descriptions of the symptoms of diabetes.
This link was not
made until a landmark study in 1889 by Dr Joseph von Mering and Dr Oskar
Minkowski. The two German physicians are credited with the discovery of
glycosuria after their experiment inducing diabetes in yet another
unfortunate dog.
But the pair
was unable to obtain a pancreatic extract.
Minkowski,
however, became one of Europe’s leading physicians and was among those called
to Moscow in 1923 to attend to Vladimir Lenin after his final stroke, and Von
Mering went on to discover barbiturates.
Minkowski died
from bronchopneumonia in 1931 before the Nazi persecution of WWII.
His wife,
however, outlived him and managed to escape Germany in 1941 with the economic
support of Charles Best.
An
acknowledgement of the contribution made by her husband to the science of
diabetes and Best’s own research success is the discovery and manufacture of
insulin.
|
Who controls the
market?
By 1978, synthetic
human insulin was being developed from genetically engineered Escherichia
coli, avoiding the allergic reactions that came with animal extracts. By
the mid-1990s, long-acting analogue insulins became available.
Insulin’s status as
a biologic drug has kept the price of its production high and deterred
biosimilar manufacture.
Three manufacturers
together control 96% of the global insulin market — and they have been
able to avoid patent expiry through ‘evergreening’ (making slight modifications
to the product) and inventing new devices for delivery among other strategies.1
A 2018 report from
I-Mak.org, a non-profit organisation that works to lower drug prices, showed
that the price of Sanofi’s Lantus, the leading long-acting insulin for patients
with type 1 diabetes, increased by 18% each year from 2012 to 2016.4
And Lantus is not
alone. A report from the American Diabetes Association published in Diabetes
Care in 2018 showed the average price of the four insulin categories increased
by 15-17% between 2012 and 2016.5
Although Sanofi’s
primary patent on Lantus expired in 2015, the company has filed 70 secondary
patents since its first approval in the US in 2000.
As the insulin
affordability crisis in the US deepens, it has given rise to bio-hacking
start-ups such as openinsulin.org, a group dedicated to developing its own
generic and accessible alternatives.
Along with Eli
Lilly and Novo Nordisk, Sanofi has also pursued litigation against companies
offering cheaper biosimilar versions of patented biologic insulin that have
made insulin more affordable in Japan and Europe.
A review last year
in BMJ Global Health estimated a truly competitive biosimilar
market could supply a patient with insulin at a cost of $103-191 per year.6
Congressional
hearings have exposed the complexity of the insulin affordability crisis.
While drug
manufacturers have set up various access programs for the uninsured and created
their own cheaper ‘generic’ drugs in response to patient outcry, they also
point to other areas of the notorious US health insurance system, including the
way prescription drug pricing is managed by health plans.
The stories of the
young people who have died this year in the US because of the cost of insulin
is a long way from the image of that Australian father on the docks at Pyrmont
nearly a century ago, waiting for a lifeline for his daughter, made possible by
the doctor who sold his patent for a buck.
·
References on request, from jo.hartley@adg.com.au
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