Monday June 10 2013
Incretin mimetic drugs may have adverse effects on the pancreas
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".
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.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.