Incretins are the newest and most expensive class of blockbuster diabetes drug but according to a remarkably through investigation just published by the BMJ (British Medical Journal) the risk that they could cause pancreatic cancer is much greater than patients and doctors have been told. The biggest sellers in the UK are Byetta (exenatide), Victoza (liraglutide) and Januvia (sitagliptin).
It’s a story that is both alarming and horribly familiar. New wonder drug targets a different pathway and, it is claimed, is more effective than older ones as well as being safer. However it turns out there is a dark and dangerous side, which the companies and the regulator have kept quiet about for years.
This revelation also highlights another familiar theme. There is now abundant evidence that diet and life style, which don’t carry these dangers, can be an effective way of controlling, or even reversing, diabetes for many. Yet we spend over 600 million pounds a year on drugs (120 million pounds on incretins) and very little on implementing or refining a lifestyle approach. The drugs, unlike lifestyle, don’t even cut your risk of stroke or heart disease.
Only three years ago the one-time wonder diabetes drug Avandia was withdrawn because it raised the risks of heart attacks. It had emerged earlier that the company and the American drug regulator (the FDA) had known about the danger as far back in 2003 but the patients didn’t get to hear about it until 2007 thanks to research by an independent scientist.
Something alarming going on
The drug companies deny there is a problem. “There is absolutely no evidence of a risk of our drug and pancreatic cancer,” says a spokesperson for the makers of Liraglutide.
But what is so impressive about the BMJ article is the way it carefully assembles the evidence to show that at the very least there are strong suggestions that something alarming going on; that this had been known about for years and that neither the companies involved nor the regulator has been at all proactive in trying to get to the bottom of it.
For instance back in 2007, soon after sitagliptin was launched, researchers at the University of California Los Angeles found abnormalities in the pancreas of rats given the drug. All were enlarged and one had signs of a type of change in the cells that could potentially be a precursor to cancer.
(All incretins increase the amount of a naturally occurring peptide called GLP-1 that raises insulin production when needed. They come in two types. Sitagliptin does it by blocking an enzyme called DPP-4 which rapidly clears GLP-1 from the blood.)
The researchers offered to look at data on the pancreases of monkeys, also used to test sitagliptin, to see if the danger showed up there but the makers – Merck – weren’t interested. Documents seen by the BMJ show there were private discussions about aggressively pursuing the rat study to show that the results were spurious. In 2009 Merck was asked by the FDA to run a new trial to test the safety of sitagliptin in rats. The results didn’t arrive until earlier this year and have still not been published.
Undeterred by this apparent lack of interest, the UCLA team wondered if there were any signs of pancreatic problems in humans. To find out they analysed the reports of drug side effects sent in by doctors and collected by the FDA – this is similar to the Yellow Card scheme run in the UK. These showed that reports of pancreatic problems were six times more likely in diabetics given one of the incretins compared with those getting other types of diabetic drugs.
(The other type of incretin is a synthetic version of GLP-1 that also makes higher levels available for longer – the two best-selling ones are Exenatide and Liraglutide. )
The significance of all these studies are all still hotly disputed but the point is that the debates have almost exclusively been taking place behind closed doors. Meanwhile the evidence there could well be a problem keeps coming. The latest exhibit comes from a study that looked at pancreases that had come from organ donors who had type 2 diabetes. Those who had been prescribed an incretin type drug had a pancreas that was 40 per cent larger with more changes in some cells of the sort that could turn into cancer
But why should patients on these drugs be at raised risk of pancreatic problems – both a nasty and painful inflammation called pancreatitis –and possibly early signs of cancer. The FDA has said that there is no “established link” between the drugs and pancreatic damage.
Gila monster connection
There may not be an “established” one but the fact that these drugs can affect the pancreas has been known they were first discovered, says Edwin Gale, emeritus professor of diabetic medicine at Southmead Hospital, Bristol. “Initially it was hoped they would be a way of reversing diabetes by replacing the insulin-producing beta-cells that begin to fail in diabetes.” Mice in early trials did begin to grow new ones, but they remained immature.
Gail, who wrote the editorial that went with the BMJ investigation, says this effect on the pancreas should be no surprise to the experts. “Exenatide is a synthetic version of a type of GLP-1 found in the saliva of the Glia Monster and it’s there for a reason.”
This poisonous lizard eats very rarely – maybe less than once a month. Without food its stomach and pancreas shrivel up. “Besides pushing up insulin levels, the lizard’s GLP-1, also acts as a growth promoter, prompting its stomach and pancreas rapidly to expand when food arrives. Growth promoters frequently raise cancer risk”.
But you don’t need to go poking into Glia Monsters remarkable physiology to find a potential cancer connection with these drugs. You just need to be curious with access to the internet. For instance back in 2009 a blog run by diabetic and author Jenny Ruhl was raising the issue of a cancer risk with sitagliptin.
Tumour suppressing activity
She pointed out that it works by blocking the protein produced by the DPP-4 gene, which increases the amount of GLP-1. But DPP4 is also known to have tumour suppressing activity. She also claimed that none of the studies supporting sitagliptin’s safety had looked at its possible effect on tumour growth.
While concerned members of the public were spotting a potential cancer connection official bodies such a the UK drug watchdog, the MHRA and NICE were being reassuring. They identified pancreatitis as a real but rare risk of both types of incretins but made no mention of cancer.
However it’s too easy to blame the regulators, says Professor Gale, who also rejects casting pharma as the evil empire. “The problem is the system that subordinates the public interest to commercial secrecy.”
The result is that the companies have a perverse incentive not to find out about a risk. They are responsible for monitoring the safety of their drugs but if they don’t know about a problem they can’t be blamed for not tackling it. “The three monkeys, who neither hear, see nor speak, have been allowed to flourish at the heart of our system for protecting the public,” says Gale. One top of that the regulators rely on the companies to provide the evidence of safety and risk.
These revelations also highlight a fundamental problem common to a number of drugs – ignoring the underlying physiology. GLP-1 is a very active peptide that is normally released into the blood stream and cleared away within a matter of minutes. Patients taking incretins have it in their bloodstream round the clock; the possibility that this could have a serious knock-on effect can’t come as surprise.
There are non-drug ways to raise GLP-1.Several grams of cinnamon is one, prebiotics is another. Could they have a helpful effect on lowering blood sugar without the risks? I’ve no idea but I’m certain that research to tease out more details is unlikely to get serious funding.