Incretin mimetics have been called “the darlings of diabetes treatment” and they may soon also be licensed for treating obesity. But a BMJ investigation has found growing safety concerns linked to the drugs’ mechanism of action. Deborah Cohen asks why patients and doctors have not been told.
They’ve been touted as the “new darlings of diabetes treatment”—the biggest breakthrough since the discovery of insulin nearly a hundred years before. The so called incretin therapies—glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors—looked as if they might change the face of type 2 diabetes. Their dual action of switching on insulin and suppressing glucagon to help control blood glucose was the ultimate in diabetes care.
The promise of a Nobel prize for the investigators loomed large. Scientists had discovered a treatment that could potentially modify disease progression. Studies in experimental animals showed that GLP-1 caused a proliferation in new insulin producing β cells. The hope was that these new cells might be able to replace those that died off in the course of human diabetes.
Nor did the promise end there. GLP-1 acts on the brain to makes people feel less hungry and the more powerful drugs aid weight loss—rather than weight gain like many antidiabetic drugs before them.
It’s an effect companies are seeking to market in its own right. Spurred on by the US Food and Drug Administration’s willingness to license new obesity treatment, Novo Nordisk’s chief science officer Mads Krogsgaard Thomsen said last year that the “political establishment in the US now knows that behaviour change alone is not enough.”1
His company’s drug, liraglutide, is in the process of late stage clinical tests, which Thomsen says show promising results.
But an investigation by the BMJ suggests Thomsen’s confidence might be optimistic. Concerns held by some specialists about the potential side effects of GLP-1 drugs have emerged into the mainstream after both the FDA and the European Medicines Agency announced in March that they would launch a review into whether the drugs may cause or contribute to the development of pancreatic cancer.
As yet neither agency has reached any conclusions, but they are meeting to discuss the matter later this month. And, as this investigation has found, for the regulators it is not a new concern. Over the years, drug assessors have become increasingly concerned that the incretin drugs have the potential for unwanted proliferative effects.
Concerns long held by some experts about the potential side effects of incretin mimetics have gathered momentum with three publications this year. An independent analysis of health insurance data published in February found that people taking exenatide and sitagliptin were at twice the risk of hospital admission for acute pancreatitis compared with people taking other antidiabetic drugs2—the absolute risk 0.6%. And in April an analysis of data from the US Food and Drug Administration’s adverse event reporting system showed an increase in reports for pancreatitis and pancreatic cancer in people taking incretin mimetics compared with those taking other antidiabetic drugs.3
The FDA and EMA have both confirmed to the BMJ that their own analyses also show increased reporting or signals of pancreatic cancer with incretin mimetics. But they emphasise that this does not mean the relation is causal.
Both agencies announced in March that they will review data from a study just published showing pre-cancerous and dysplastic changes to the pancreas in organ donors exposed to incretin mimetics.4
The evidence is fiercely contested, with manufacturers stoutly defending the safety of their products. Merck, for example, told the BMJ that independent observational studies and a meta-analysis of clinical trials involving 33 881 patients found no association between DPP-4 inhibitors and pancreatic cancer. Bristol-Myers Squibb says that “post-marketing data does not confirm a causal relationship between saxagliptin or exenatide and pancreatitis and/or pancreatic cancer” (see bmj.com for full questions and answers with manufacturers).
But a “Dear Doctor” letter from Bristol-Myers Squibb and AstraZeneca on the UK Medicine and Healthcare Products Regulatory Agency’s website says: “A review of reports of pancreatitis from post-marketing experience revealed that signs of pancreatitis occurred after the start of saxaglitpin treatment and resolved after discontinuation, which is suggestive of a causal relationship. Moreover, pancreatitis has been recognized as an adverse event for other DPP-4 inhibitors.”5 A spokeswoman for Boehringer Ingelheim told the BMJ: “Pancreatitis has been reported in clinical trials and spontaneous post marketing sources. Guidelines for the use of linagliptin in patients with suspected pancreatitis are included in the prescribing information of the treatment.”
The increasingly fractious debate among scientists and doctors was played out last month in the specialty journal Diabetes Care.
Experienced GLP-1 investigator, Professor Michael Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany, and a consultant to many of the manufacturers, argued that the published evidence against the drugs is weak. “The potential harms and risks typically refer to rare events and are discussed in a controversial manner,” he wrote.6 But a team of four academics from the US and UK (one an expert witness in litigation against one of the manufacturers) suggested that neither the safety nor the effectiveness of the class can be assumed. “The story is familiar. A new class of antidiabetic agents is rushed to market and widely promoted in the absence of any evidence of long-term beneficial outcomes. Evidence of harm accumulates, but is vigorously discounted,” they wrote in their response. 7
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 pointing to unwanted proliferative or inflammatory pancreatic effects.
The BMJ has also found that, despite published reports that indicated safety concerns, companies have not done critical safety studies; nor have regulators requested them. And access to raw data that would have helped resolve doubts about the safety of these drugs has been denied.
On their own, the individual pieces of unpublished evidence may seem inconclusive — increases in size and abnormal changes in animal pancreases, raised pancreatic enzyme concentrations in humans, reports of thyroid neoplasms, and pancreatitis in early clinical trials.
But when considered alongside other emerging and long standing evidence—such as concerns about the effect of GLP-1agonists on α cells first published in 19998; the presence of the GLP-1 receptor on cells other than the target pancreatic β cell; and increasing signals from regulatory databases2 9—a more coherent and worrying picture emerges, posing serious questions about the safety of this class of drug.
What’s going on in the pancreas?
In a world where the prevalence of type 2 diabetes is increasing rapidly, finding new targets for therapy is a high priority for drug companies. The discovery by scientists in the 1970s and the then publication in 1993 by Michael Nauck of the double action of GLP-1 (glucagon-like peptide-1) provided just such a target.
GLP-1 is a hormone-like peptide released by the intestine in response to a meal; its functions include regulating insulin and blood glucose and slowing gastric emptying. In his study, Nauck found that GLP-1 both increased the insulin made in the pancreas and, by inhibiting the secretion of glucagon, reduced the glucose released by the liver. Excessive glucose release by the liver underpins the high circulating glucose that defines type 2 diabetes. Following secretion, GLP-1 is quickly inactivated by an enzyme, dipeptidyl peptidase-4 (DPP-4). The GLP-1 drugs are either analogues that are not inactivated by DPP-4, taken by injection (exenatide, liraglutide) or oral drugs that inhibit DPP-4 (sitagliptin, saxagliptin, and linagliptin).
The saliva of the desert dwelling Gila monster was the source for the first GLP-1 analogue on the market, exenatide. A heavy slow moving lizard, it eats once or twice a year, and uses the secretion of its salivary hormone exendin-4—which displays similar properties to GLP-1—to induce proliferation of its pancreas and gut to assimilate a meal. Some say this should have provided a valuable clue to the unwanted effects of raised circulating levels of a hormone that usually lasts for only minutes before it is broken down.
But now that most of the other treatments for type 2 diabetes are off patent, these are valuable drugs. Merck’s market leading drug sitagliptin generated about $4.1bn (£2.6bn; €3bn) in sales in 2012 with liraglutide’s 2012 sales of $1.7bn coming in behind. The profit margins mean there is much at stake for the companies and the organisations and doctors who depend on their support.
However, serious doubts about the wisdom of basing treatments on GLP-1 agonists have existed since the beginning. And the companies and regulators have, on reflection, had in their hands ample warning signs—and chance to resolve some of the emerging controversies.
In 2005, the New England Journal of Medicine published a study that showed pancreatic changes in patients who had a type of gastric bypass surgery called Roux-en-Y. The authors noted hypertrophy and hyperplasia of the islet cells, also affecting the cells in the pancreatic ducts. They thought this might be due to raised levels of the hormone GLP-1, which were known to occur after this type of procedure.21 (A later study on this type of surgery also showed a “pronounced” increase in α cell mass22).
Senior executives from Amylin and Lilly wrote to the New England Journal to distance their drug from the paper and to stress the lack of evidence of a pathological effect on the islets in animal studies. “A study of nine months’ duration in healthy cynomolgus monkeys at doses of more than 400 times those used in humans showed minimal-to-mild islet hypercellularity with no increase in islet size (data on file, Amylin Pharmaceuticals),” they said.
The suppression of glucagon by incretin mimetics was highlighted by companies in their drug licensing applications and was noted by regulators. Billions of dollars of sales later, after concerns have been raised about the safety of glucagon suppression and its effect on glucagon producing α cells, the extent to which they do this is being contested.
Butler and colleagues’ finding of α cell hyperplasia in humans taking GLP1 based drugs4 was not the first. In 1999 GLP-1 researcher Joel Habener and a team at Harvard found that exendin-4 (exenatide) induced an increase in α cells in rats.8
But evidence of α cell hyperplasia has come from multiple models and sources—including the companies themselves. Whether this is applicable to GLP-1 based treatments is subject to fierce debate.
Only last October, Professor Dan Drucker, a long standing consultant to many of the companies, gave a keynote lecture at European Association for the Study of Diabetes conference. “The therapeutic window for reduction of glucagon action to manifest beneficial effects for glucose control while avoiding enhancement of hepatic lipid storage, dyslipidemia, hepatocyte injury, and α-cell proliferation in diabetic subjects is unclear,” the official conference journal reported.23
Others in industry have previously highlighted the important role of glucagon suppression in the control of diabetes. In 2005 at a session entitled “GLP-1s: the new darlings of diabetes treatment” Jens Holst, scientific director of the Novo Nordisk Foundation for Metabolic Research at Copenhagen University and a long standing consultant to the company, told the American Diabetes Association annual conference that GLP-1 agonists were a powerful inhibitor of glucagon secretion, adding that he thought this would be “a very important action to diabetes patients.”
A spokesperson for Novo Nordisk acknowledged an effect on α cells but only from full not partial glucagon suppression. She told the BMJ: “Complete removal or blocking of the glucagon receptor, or important signalling components, have caused α cell hyperplasia. This is separate from the relatively modest lowering of glucagon secretion induced by GLP-1.”
The BMJ asked Drucker about this. In response he sent a copy of an article he had written in Cell Metabolism, but this did not describe α cell effects.24 Yet the BMJhas found that the companies were aware of the unwanted effects of the full and partial suppression of glucagon before the incretin mimetics came onto the market.
At the turn of the century, Holst, working with scientists from Novo Nordisk, reported that glucagon suppression in mice resulted in massive enlargement of the pancreas and the proliferation of α cells (α cell hyperplasia).25 They concluded that α cells appear not just in the islets but in the pancreatic ductal epithelium—something that Butler and colleagues found. Importantly, this effect did not require complete blocking of glucagon receptors or the stopping of glucagon production. Even a partial reduction in the hormone signalling resulted in α cell hyperplasia, as shown by Eli Lilly in 2004.26 The Lilly team acknowledged that they hadn’t seen any neoplasia; the studies up until that point had been short—only four months long. They suggested that both glucagon and its receptor must be functional in order to maintain a feedback loop that restrains α cell growth “but the exact nature of this feedback loop is unclear.”26
Over the years, evidence of the effects of modifying glucagon signalling has mounted. In 2009 Run Yu, codirector of the carcinoid and neuroendocrine tumour programme at Cedars Sinai Hospital in Los Angeles, published a report in patients with a rare condition causing deficiencies in glucagon signalling.27 He found α cell hyperplasia and neuroendocrine tumours.
“In type 2 diabetes glucagon plays a role but there is a price to pay with reducing it,” he told the BMJ.
Yu said that he had shared his view with certain companies after the study came out. Because of agreements with the companies, he was unable to say which they were.
He then did a study in mice with decreased glucagon signalling that was far longer than any conducted by the companies. He found that neuroendocrine tumours invariably developed after formation of α cell hyperplasia and eventually led to death. Yu concluded that glucagon suppression was not a safe way to treat diabetes.28But whether this applies to GLP-1based therapies is still uncertain.
In the course of this investigation, the BMJ has looked at thousands of pages of regulatory documents from both the FDA and the EMA. There seems to be little discussion about the potential adverse effects of interfering with glucagon signalling on the α cell, even though the manufacturers spelt out —and the regulators noted—that glucagon suppression was one of the effects of the drugs. Michael Elashoff, a former FDA reviewer who has analysed the safety of the drugs, believes the regulators should have been more cautious in approving them.
“If some of the side effects can be anticipated in advance, then it seems incumbent upon the FDA to really force the companies to do real significant investigation of these potential side effects before the drug goes on the market and not leave it to experiment with actual patients taking the drug,” he said.
The FDA maintains that: “Long-term studies of incretin mimetics in rodents, dogs, and monkeys failed to demonstrate adverse pancreatic pathology or other toxicology reflective of a glucagon deficit that could be interpreted as a clear risk to human subjects.”
The BMJ asked the five companies who market incretin mimetics if they have ever studied the effects of glucagon suppression on the proliferation of α cells. Only Novo Nordisk responded to the question. It stressed that it had never seen α cell hyperplasia in any of its studies.29 30 31 “Alpha-cell hyperplasia is not mediated by the GLP-1 receptor,” a spokeswoman said. Behind the scenes, concerns also started to emerge about the potential inflammatory effects on the pancreas. Effects on pancreatic enzymes: Internal industry documents show that in 2005, one industry key opinion leader reported “extremely high” lipase levels in a patient taking exenatide. He was concerned that the company had missed signs of potential inflammation in its clinical trials.
Dennis Kim, then executive director at Amylin, wrote in an email that the doctor’s report was a “bit concerning” and confirmed that pancreatic amylase and lipase were not measured systematically in the company’s clinical trials.
The BMJ has found that companies have measured these enzymes for “safety issues,” but in many cases the data have not been reported in the published studies.
For example, in one Lilly funded trial comparing weekly exenatide with sitagliptin and two other diabetes treatments—insulin and pioglitazone—enzyme levels increased in a higher percentage of people taking incretin mimetics after 26 weeks of treatment.
Regulatory documents show the mean (SD) lipase concentration in the exenatide group increased from 42.0 (23.77) U/L on day 1 to 60.8 (38.39) U/L at week 26. Sitagliptin also increased lipase from 40.3 (21.3) U/L to 48.7 (30.7) U/L. The levels in the pioglitazone control dropped. However, when the trial was published in theLancet, these data did not make the final cut.32 The company did not say why when the BMJ put it to them. Neither did lead author, Richard Bergenstahl, answer theBMJ’s queries.
Earlier this year, the Lancet published another study funded by Eli Lilly and Amylin in which enzyme levels were measured but not reported.33 “Routinely measured concentrations of pancreatic lipase and total amylase varied in both groups and were not predictive of gastrointestinal symptoms,” the paper said.
The FDA says that the clinical value of routine amylase and lipase monitoring in asymptomatic patients is not clear. But pancreatologists, have told the BMJ that reporting enzyme levels is important because they may reflect a subclinical effect of the drug.
“Many large phase III trials report findings of significant biochemical abnormalities, even though the clinical significance may be uncertain at the time, and in this case where the drug is known to exert effects on the pancreas, I would find such information of value,” Thor Halfdanarson, a pancreatic surgeon, at the Mayo Clinic in Arizona said.
Indeed, writing in support of incretin mimetics in Diabetes Care last month, Michael Nauck said that the effect on pancreatic enzymes may be important.6 “Effects of GLP-1 receptor stimulation on pancreatic enzyme synthesis, potential leakage into the circulation rather than direct secretion into pancreatic digestive juice, and a potential induction if a chronic inflammatory response need to be studied,” he said.