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A British Medical Journal (BMJ) investigation into two
classes of type
2 diabetes drugs has prompted headlines in the Daily Mail. The newspaper
claims, 'Diabetes drugs taken by thousands linked to cancer of the pancreas and
other serious health problems,' going on to allege that drug
manufacturers may be trying to hide potentially harmful side effects. It is important to stress that there is no
evidence of any legal or regulatory wrongdoing by any of the drug companies
mentioned in the BMJ article.
The BMJ investigation focused on two relatively
new classes of type
2 diabetes drugs collectively known as "incretin mimetics". There
are two main types of incretin mimetic:
- glucagon-like
peptide-1 (GLP-1) agonists, such as exenatide, which help boost insulin
production while decreasing blood sugar levels – the drug also has the
added benefit of leading to modest weight loss
- dipeptidylpeptidase-4
inhibitors (DPP-4), such as sitagliptin, which block the effects of an
enzyme that can have a harmful impact on blood sugar levels
Neither of these drugs are first-line treatments for
people with type 2 diabetes. Instead, they tend to be used if first-choice
drugs are not working well enough by themselves.
As both types of drugs act on the pancreas, concerns have
been raised that they may also have adverse effects on the organ. The article
discusses these concerns and the evidence behind them.
This evidence includes the results of animal studies
and reports from medicines regulatory agencies which suggest that the
drugs may increase the risk of inflammation of the pancreas (pancreatitis)
and could also lead to cancerous changes in the tissue of the pancreas,
triggering pancreatic
cancer.
From the evidence discussed, it does appear
that there may be an increased risk of these drugs having adverse
effects, but further safety studies are needed to confirm this. People may
be reassured that the bodies that regulate medication are aware of the
potential risks and will be carefully reviewing the safety of these drugs.
For now, anyone with diabetes who has concerns about
their treatment should speak with the healthcare professionals involved in
their care. The risk to your health of suddenly stopping treatment for type 2
diabetes are likely to far outweigh any potential risk of harm to your
pancreas.
Where did the story come from?
The news stems from an article published in the peer-reviewed
British Medical Journal (BMJ) written by Deborah Cohen, the
BMJ investigations editor. The article has been made available on an open access
basis, so it is free to read or download.
No sources of funding or conflicts of interest are
reported.
The article states that, "In the course of this
investigation, the BMJ has reviewed thousands of pages of regulatory documents
obtained under freedom of information and found unpublished data."
Specific methods for identifying and selecting these
documents are not presented in the article, so it is not clear whether all the
evidence related to this issue has been considered. The BMJ investigation also
raised specific questions directly with drugs manufacturers.
What is the BMJ article about?
Cohen discusses two types of diabetes medication
that both work in two main ways:
- increasing
the production of insulin, a hormone produced by the
pancreas that helps the body's cells take up blood sugar (glucose) to
use it for energy
- suppressing
glucagon secretion, another hormone released by the pancreas which
has the opposite effect of insulin, causing the liver to release its
glucose stores to increase blood sugar
The two types of medication under the spotlight are
glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4)
inhibitors. Neither of these drugs are first-line treatments for type 2
diabetes, but may be considered if first-line treatments are not working
effectively on their own.
The GLP-1 agonist group includes two drugs called
exenatide and liraglutide. In addition to increasing insulin release and
suppressing glucagon, these drugs also slow stomach emptying. For this reason
they can also help prevent weight gain.
Currently, GLP-1 agonists may be considered for people
whose diabetes has not been controlled by standard first-line treatments, such
as metformin and sulfonylurea, and who are obese (BMI above
35kg/m2).
The National Institute for Health and Care Excellence
(NICE) currently recommends that treatment with these drugs should only be
continued if the person demonstrates adequate blood sugar control and has lost
at least 3% of their body weight within six months.
The DPP-4 inhibitor group includes the drugs linagliptin,
saxagliptin, sitagliptin and vildagliptin. There are specific types of people
who are considered suitable to take these drugs.
Broadly, they may also be prescribed when standard
treatment with a combination of first-choice drugs for diabetes (metformin and
sulfonylurea) has either failed to control blood sugar, is inappropriate, or
alternative diabetes drugs are inappropriate. Again, these drugs should only be
continued if there is adequate blood sugar control.
What does the BMJ article say
about these diabetes drugs?
Because incretin mimetics stimulate the cells of the
pancreas, there is the potential that they may also have adverse effects on the
organ.
Recently, experts have had increasing concerns about the
safety of incretin mimetics. In February 2013 an independent analysis of health
insurance data found that people taking exenatide and sitagliptin were at twice
the risk of being admitted to hospital with inflammation of the pancreas (acute
pancreatitis) compared with people taking other diabetic drugs.
The actual size of the risk to the individual was low –
only 0.6%, or six in every 1,000 people taking the drugs. But even if individual
risk is low, health watchdogs have to consider the fact that these types of
drugs are taken by hundreds of thousands of people.
In April 2013, analysis of data from the US Food and Drug Administration (FDA) also showed
increases in cases of pancreatitis and pancreatic cancer among people taking
incretin mimetics compared with those taking other diabetic drugs.
Both the FDA and the European Medicines Agency (EMA) are
said to have confirmed to the BMJ that their own analyses also show increased
reports of pancreatic cancer with these drugs.
However, the agencies have emphasised that this does not
necessarily mean that the drugs directly cause these adverse effects. It could
possibly be the case that it is type 2 diabetes itself, rather than the drugs,
that is increasing the risk of pancreatic cancer.
In March 2013, both agencies said that they would review
study data showing that some organ donors who had taken incretin mimetics have
demonstrated pre-cancerous changes in the pancreas.
Despite these findings, the risks are said to be fiercely
contested by manufacturers. The drug company Merck has presented data from a
pooled review of almost 34,000 people who have taken DPP-4 inhibitors and found
no connection with pancreatic cancer.
However, other manufacturers appear to have some concerns
about inflammation of the pancreas (pancreatitis) related to the use of these
drugs. Bristol-Myers Squibb and AstraZeneca have sent a letter to the UK Medicine and
Healthcare products Regulatory Agency (MHRA) saying: "A review of
reports of pancreatitis from post-marketing experience revealed that signs of
pancreatitis occurred after the start of saxagliptin treatment and resolved
after discontinuation, which is suggestive of a causal relationship. Moreover,
pancreatitis has been recognised as an adverse event for other DPP-4
inhibitors."
The BMJ article goes on to further discuss the
"increasingly fractious debate among scientists and doctors played out
last month in the specialty journal Diabetes Care", before going on to
discuss the problems that have been observed in animals given the drugs:
- Diabetic
rats were given sitagliptin, metformin, or a combination of both drugs.
Rats given sitagliptin had problems in their pancreas – enlargement,
pancreatitis, or changes in the cells that could indicate early cancerous
changes. At an ensuing meeting between experts and manufacturers held at
the American Diabetes Association, one expert stated that the results in
rats could suggest an increase in the risk of pancreatic cancer and that
if the results were true, the future of the drugs could be in doubt.
However, he said that, "concern had to be balanced against the lack
of data indicating similar effects in humans." Other experts
suggested that the rat model used was not reliable.
- A study in
mice genetically predisposed to developing pancreatitis and pancreatic
cancer found that they developed pancreatitis and pre-cancerous changes
more quickly when given exenatide. Another study in non-diabetic rats also
showed overgrowth in the cells of their pancreatic ducts when given
exenatide. Supporters of the drugs question the methods used in these
studies.
- There is
disputed evidence from monkeys that suggests that there may be an increase
in pancreas weight among young healthy monkeys given liraglutide.
The BMJ article also discusses lawsuits in the USA
related to the possible link between exenatide and acute pancreatitis. This led
to a judge allowing an independent pathologist to review the manufacturer's
slides of slices of pancreas from monkeys treated with exenatide – the
manufacturer reportedly initially refused access to these slides. The
pathologist found more chronic inflammation and pancreatic disease in the
treated monkeys than untreated controls.
A team from the University of California, Los Angeles
(UCLA) analysed data from 2004-09 recorded in the FDA adverse event database.
It found that the odds of pancreatitis were increased about six- to tenfold
with exenatide and sitagliptin, and the odds of pancreatic cancer increased
just under threefold with both drugs. The team noted the limitations of their
study and advised that it was interpreted with caution.
Industry representatives and medical societies were
reported to have heavily criticised the methods of the original
study – for example, saying that it did not include information about
other factors that could affect the results (potential confounders)
A later analysis by the US Institute for Safe Medication
Practices (ISMP) found that all five incretin mimetics were together associated
with more than 25 times the rate of pancreatitis than that seen in people with
diabetes taking other drugs. The DPP-4 inhibitors were associated with 13.5
times higher rates of pancreatic cancer, and the GLP-1 agonists had rates 23
times higher than other diabetic drugs.
For some of the drugs (linagliptin and saxagliptin) there
was only a single case of pancreatic cancer, and changes in risk were not
significant.
What did the BMJ article conclude?
The BMJ article raises concerns their investigation found
that, despite misgivings about the safety of these drugs, "companies have
not done critical safety studies; nor have regulators requested them", and
that, "access to raw data that would have helped resolve doubts about the
safety of these drugs has been denied".
It says that although the individual pieces of evidence
may seem inconclusive, a "more coherent and worrying picture emerges"
when they are "considered alongside other emerging and longstanding
evidence".
Conclusion
This article presents important concerns that
glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4)
inhibitors could potentially increase the risk of inflammation and cancerous
changes in the pancreas.
The agencies that regulate medicines in Europe and the
USA are aware of these issues, and told the BMJ that their analyses show
increased reporting of pancreatic cancer among people taking these types of
drugs.
However, the agencies note that it has not been
established whether these drugs directly cause the adverse effects seen in
the pancreas. Both agencies are reviewing emerging evidence on safety in this
area.
For now, anyone with diabetes who has
been prescribed these drugs and has concerns should speak with the
healthcare professionals involved in their care.
Do not stop taking any diabetes medication unless you are
advised to do so by the doctor in charge of your care. If you stop taking this
medication without medical advice, you are at a much higher risk of developing complications
related to diabetes, such as heart
disease, stroke, kidney
damage and even blindness, than
you are at risk of developing pancreatic cancer.
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