Published: 26 November, 2021
A century of insulin
100 years ago at the University of Toronto, researchers began experiments that would revolutionise the management of patients with diabetes. Insulin, as it was soon called,
was a life-saving treatment and the early trials were described as “nothing short of miraculous”. The impact of this discovery for millions of people with diabetes cannot be
overemphasised. The crucial role of researchers at the University of Toronto is documented
here and provides an interesting insight into the initial work and also
the ongoing advancements in medicine that resulted.
2021 marks a notable milestone in the history of management of people with diabetes. 100 years ago a group of four men
working in Toronto, Canada, were credited with the discovery of insulin. This was a continuation of research into the links
between the pancreas and diabetes that had begun when the islets of Langerhans were discovered in 1869 by medical student,
Paul Langerhans. The role of the islets was isolated in 1901 and work by several researchers continued over the next two
decades in an attempt to pinpoint the secretions responsible for the control of blood glucose. During 1921, Sir Fredrick
G. Banting and his assistant Charles Best, under the guidance of Professor John J.R. Macleod, were able to extract insulin
from the pancreas and show that it could lower blood glucose in dogs with induced diabetes. With the later assistance of
biochemist James Collip, the extract (now obtained from cattle) was purified and by the end of 1921, judged ready for a
human trial. Several sources state that Banting and Best experimented with the extract on themselves, inducing symptomatic
Prior to 1921, a diagnosis of type 1 diabetes, particularly in children meant patients often survived only days or weeks.
Management was admission for dietary restriction, fasting and bed rest in an unsuccessful effort to avoid diabetic ketoacidosis.
Patients were also prone to fatal infections.
The first patient to receive an insulin injection derived from oxen on 11 January, 1922 was 14 year old Leonard Thompson
who had type 1 diabetes and was an inpatient at Toronto General Hospital. Despite improvements in both blood glucose and
urinary ketones, he experienced an allergic reaction due to the continuing impurity of the ox-pancreas extract. After further
purification of the extract, he received another injection later that month and continued to have regular injections with
good effect until he died, aged 26 years, of pneumonia.
The patent for insulin was transferred to the University of Toronto for a token payment of $1 so that insulin would be
accessible to all and a non-commercial public health institution, Connaught Laboratories oversaw the start of large-scale
manufacturing of the medicine, with Eli Lilly & Co. later taking over production. In 1923, Banting and MacLeod received
the Nobel Prize in Physiology and Medicine for their discovery and gallantly shared the prize money with Best and Collip.
A number of papers and editorials discussing this notable milestone have featured in recent medical journals; a selection
of open access articles are listed below:
- Buse JB, Davies MJ, Frier BM, Philis-Tsimikas A. 100 years on: the impact of the discovery of insulin on clinical outcomes.
BMJ Open Diabetes Res Care. 2021 Aug;9(1):e002373. doi:
10.1136/bmjdrc-2021-002373. (A comprehensive overview of a century
of insulin use and its impact on clinical outcomes)
- Attie AD, Tang QQ, Bornfeldt KE. The Insulin Centennial-100 years of milestones in biochemistry. J Lipid Res. 2021 Oct
doi: 10.1016/j.jlr.2021.100132. Online ahead of print. (A review of the insulin centennial with links to milestone
- Hooper K M. What lies beyond 100 years of insulin. Dis Model Mech. 2021 Nov 1; 14(11): dmm049361. Published online 2021
Nov 9. doi: 10.1242/dmm.049361 (An editorial with links to other similar articles)
COVID-19 vaccination in pregnancy: no safety concerns with Pfizer vaccine
Medsafe and the COVID-19
Vaccine Independent Safety Monitoring Board (CV-ISMB) have found no safety concerns when the Pfizer vaccine is administered during pregnancy.
There are significant risks associated with COVID-19 infection in pregnancy to both the mother and baby including an increased risk of severe infection,
death and pre-term birth. The infant is also more likely to require neonatal intensive care and pregnant women are three times more likely to require ICU treatment compared with non-pregnant women.
In New Zealand approximately 10 – 20% of pregnancies result in miscarriage. The Centre for Adverse Reactions Monitoring (CARM) received 17 reports (up to 27 October, 2021) of miscarriage in women who received the vaccine while pregnant which is lower than the expected rate. The CV-ISMB has found no evidence to suggest that the Pfizer vaccine increases the risk of miscarriage.
The available safety information supports routine vaccination with the Pfizer COVID-19 vaccine during pregnancy.
here for further information on COVID-19 vaccination during pregnancy, breastfeeding and for those planning pregnancy. The
Ministry of Health and Immunisation
Advisory Centre (IMAC) also have an information page covering some common queries about vaccination during pregnancy and breastfeeding.
N.B. Medsafe and the COVID-19 Vaccine Independent Safety Monitoring Board (CV-ISMB) have also
a statement about the lack of any evidence of a link between administration of the Pfizer vaccine and menstrual disorders or unexpected vaginal bleeding.
Thrombosis versus thrombosis with thrombocytopenia (TTS) following COVID-19 vaccination
produced a resource for healthcare professionals to distinguish between thrombosis and thrombosis with thrombocytopenia syndrome (TTS) following COVID-19 vaccination.
TTS has been associated with adenovirus vector-based vaccines, e.g. AstraZeneca and Janssen, and is not currently associated with mRNA vaccines, e.g. Pfizer.
From 26 November, 2021, the AstraZeneca
vaccine will be available to people in New Zealand aged 18 years and older who cannot receive the Pfizer vaccine or for those who would like
a different vaccine. Although TTS is rare (approximately 1 in 100,000 people), it is important that clinicians know how to identify and manage the condition, and that patients are
aware of the symptoms and signs to look out for. Click
here for a patient handout.
The Centre for Adverse Reactions Monitoring (CARM) received 107 reports* of thrombosis after COVID-19 vaccination up to 28 September, 2021, which is lower than the expected
background rate in New Zealand (approximately 800 per 1,000,000 people). Thrombosis is not currently considered to be an adverse effect of the Pfizer vaccine.
*A report following vaccination does not necessarily imply a causal link to the vaccine, often these events occur coincidently
What is TTS and when should it be suspected?
TTS, also known as vaccine-induced immune thrombotic thrombocytopaenia (VITT), is defined as any patient presenting
with both acute venous or arterial thrombosis and new onset thrombocytopaenia and no known recent exposure
to heparin. N.B. Not all thrombocytopaenia post vaccination is TTS, immune thrombocytopenia has also been reported.
When to suspect TTS?
- Vaccination with an adenovirus vector-based vaccine 4 – 42 days ago
- Thrombosis, most often in the cerebral venous sinus or splanchnic veins – can be severe and progressive
- Thrombocytopenia (< 150 × 109); platelets may be normal at presentation but drop within four to six hours
- Reduced fibrinogen
- High D-Dimer result
- Positive PF4 ELISA test (available at LabPlus in Auckland City Hospital)
- No alternative explanation for symptoms and signs, e.g. no heparin exposure in the previous 100 days
Treatment for TTS is different to the standard treatment of thrombosis and should not include heparin,
for screening and treatment advice see: https://www.thanz.org.au/documents/item/590.
To read more about the risk of thrombosis and TTS with the AstraZeneca vaccine,
Preparations containing bufexamac should be disposed of
Medsafe has announced that the consent to distribute topical products containing bufexamac was revoked on 9 November, 2021, following a recommendation
from The Medicines Adverse Reaction Committee (MARC), based on safety concerns related to serious skin reactions. Bufexamac is a topical NSAID contained in creams used for the treatment of insect bites, stings, itches, minor burns and sunburn. Two products were previously available in New Zealand (Antiseptic Soothing Cream and Paraderm Plus Topical Cream), however, these are no longer available. Patients should be advised to return any unused product to their pharmacy for disposal, including any product they have acquired directly from overseas.
PHARMAC to fund biosimilar adalimumab
has announced that they are to fund Amgevita, a biosimilar adalimumab from 1 March, 2022. A biosimilar is a comparable version of a biological medicine (the innovator – in this case Humira) that already has regulatory approval, i.e. the reference medicine. From 1 March, 2022, patients currently taking Humira should be changed to Amgevita and for any new patient, Amgevita will be the only funded option. Changes to Special Authority criteria for Amgevita include widened access criteria, removal of dosing restrictions and extension of the renewal time period to two years. Amgevita is an approved medicine in New Zealand and is widely prescribed internationally. It is a citrate-free formulation which is likely to reduce the injection site pain that some patients experience with Humira.
For further information on biosimilars see “Biosimilars:
the future of prescribing biological medicines"
PHARMAC has set the following timeline of events:
- Now until 28 February, 2022
- No change to current funding
- Begin to identify people taking adalimumab to discuss the changes
- From 1 March, 2022
- An automatic Special Authority number will be issued for people currently taking adalimumab (Humira)
- Existing patients on Humira should be changed to Amgevita, with some exceptions (see below)
- Amgevita will be the only funded option for new patients
- Prescriptions should be for the specific branded medicine and not written generically as both brands will be funded
initially, although each will have differing funding criteria
- From 1 October, 2022
- Amgevita will be the funded option for new and current patients, other than those who are eligible for an exception
or have intolerable adverse effects or loss of control of their condition for which they
are prescribed adalimumab
- Patients who need ongoing funded access to Humira will require a new Special Authority number
Patients who can continue to take Humira, without a trial of Amgevita, include those who have Crohn’s disease or ocular inflammation who may be at risk of
destabilisation of their condition or a loss of vision if their treatment was altered. These patients will require a new Special Authority number prior to 1 October,
2022 as all existing Special Authorities will be cancelled.
Patients who develop intolerable adverse effects or a loss of disease control after trialling at least two doses of Amgevita will be able to restart
funded treatment with Humira. A new Special Authority will also be required for these people.
A brand switch fee will be available for pharmacists who are supporting patients through the change.
PHARMAC medicine supply issues
The following issues relating to medicine supply have recently been announced by PHARMAC
PHARMAC has announced that the funded brand
of prednisone tablets is changing. The current funded brand is Apo-Prednisone and this will change to
Prednisone Clinect over the next few months. Stock of Apo-Prednisone is expected to run out by April, 2022. Both medicines are made by the same
manufacturer and will continue to look the same, contain the same ingredients and there is no change to the strengths of the tablets or the pack size.
Salbutamol with ipratropium bromide (Duolin)
The supplier of Duolin has
advised PHARMAC that some stock will be arriving in early December, 2021 and more expected in mid-December. Stock of
Duolin has been unavailable since late 2020. The co-payment waiver that has been in place for most of 2021, that meant only one co-payment was
needed for the two individual component inhalers required to replace Duolin on prescription, will end on 1 December, 2021.
Paper of the Week: ACE inhibitors and ARBs can prevent new-onset type 2 diabetes
Lowering blood pressure is a well-known strategy to prevent the vascular complications of type 2 diabetes. Until now, the role of blood pressure lowering in the
prevention of diabetes has been uncertain.
An individual participant data meta-analysis was performed from 19 randomised controlled trials (including 145,939 participants) between 1973 and 2008 and concluded that
blood pressure lowering was effective at preventing new-onset type 2 diabetes; angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)
showed the strongest protection, whilst beta-blockers and thiazide diuretics increased the risk of new-onset type 2 diabetes.
Summary of key findings:
- The effects of five major classes of antihypertensives on the risk of new-onset type 2 diabetes were studied: ACE inhibitors,
ARBs, beta-blockers, thiazide diuretics and calcium channel blockers
- After a median follow-up of 4.5 years, 9,883 participants were diagnosed with new-onset type 2 diabetes. The incidence
rate for developing new-onset diabetes per 1000 person-years was 16.44 and 15.94 in the comparator and intervention group,
- A 5 mm Hg reduction in systolic blood pressure reduced the risk of type 2 diabetes by 11%
- ACE inhibitors (RR: 0.84) and ARBs (RR: 0.84) reduced the risk of new-onset type 2 diabetes, compared to placebo
- Beta-blockers (RR: 1.48) and thiazide diuretics (RR: 1.20) increased the risk of new-onset type 2 diabetes, compared
to placebo; no significant effect was observed for calcium channel blockers (RR: 1.02)
- Findings were confirmed in an independent complementary analysis using genetic data
- It is unknown as to what extent the reduction in type 2 diabetes risk is due to the blood pressure reduction versus
the specific inhibition of the renin-angiotensin-aldosterone system
The findings from this meta-analysis and an
editorial support ACE inhibitors and ARBs for the prevention of type 2 diabetes. Beta-blockers and thiazide diuretics should generally be avoided
when treating hypertension in patients at high risk of diabetes. Clinicians may choose to modify the risk of diabetes through selecting an appropriate
antihypertensive, or by encouraging patients to engage in physical activity to maintain a healthy weight and consume a nutritionally balanced diet.
For information on non-pharmacological strategies to prevent type 2 diabetes, see:
Naxarzadeh M, Bidel Z, Canoy D, et al. Blood pressure lowering and risk of new-onset type 2 diabetes:
an individual participant data meta-analysis. Lancet 2021;398:1803-10.
This Bulletin is supported by the South Link Education Trust
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