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Feature Diabetes Drugs

Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?

BMJ 2013; 346 doi: (Published 09 June 2013) Cite this as: BMJ 2013;346:f3680

Re: Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?

Dear Sir/Madam,

We write as academic clinicians who have worked with Industry on studies of incretin based therapies. We declare this interest, but also an overriding interest in evidence that the historical treatment of type 2 diabetes by sulphonylureas and insulin in escalatingly large doses is far from optimal and not without serious risk from hypoglycaemia, weight gain and possibly increased cardiovascular risk.

Cohen (1) and the BMJ are right to highlight that it is unethical to withhold results of experimental work from the scrutiny of independent clinicians and academics, particularly where there may be concerns regarding safety of pharmacotherapeutic agents. That said, it is unfortunate that so much of this article was one-sided and could lead to decisions to withhold treatment based more on hearsay than evidence and engender anxiety in patients and health care professionals. To be associated in this way with the biased and sensationalistic “Dispatches” television programme made matters worse. We question whether it is right for a medical journal to employ an “investigation” journalist to not only search out “stories” for the medical press, but to be associated with such a programme - ndeed be the main person featured in it - with further inflammatory headlines resulting in the National press. This is a recipe for fear, anxiety and non-adherence with disastrous consequences.

Given the progressive nature of Type 2 Diabetes, we need treatments to add to metformin that will improve glycaemia but avoid hypoglycaemia and weight gain (2-4). Thus, any review of the efficacy/safety balance in new treatments should start with an appraisal of the status quo. The UKPDS has been taken as endorsement of safety of sulphonylureas and escalating doses of insulin and, despite the assertions of your editorial(5), most physicians accept that improving glycaemia will reduce microvascular complications. Achieving glycaemic goals with currently available treatments, however, does not reduce cardiovascular events at least in high risk, longer duration patients(6,7).

There have been concerns that the treatments themselves, or the hypoglycaemia and weight gain they produce, may explain failure to reduce cardiovascular events. Large meta-analyses of sulphonylurea treatment indeed suggest that they may increase cardiovascular risk(8,9). In contrast, a large meta-analysis of DPP-4 inhibitors suggests significant cardiovascular benefit(10). Whilst there is no definitive answer regarding cardiovascular outcomes, a balanced review would have at least considered the potential benefits of newer agents versus the older, established therapies.

In direct contrast to the evidence presented, and despite the fact it was recently published by the BMJ, Cohen ignores the large insurance cohort study of 72723 patients which reported no increase in cardiovascular admissions or mortality and no increase in pancreatitis with sitagliptin (11). Instead, she only refers to the less well controlled cohort using patients only up to the age of 65 that reported an increase in hospitalisations from pancreatitis, but does not comment on cardiovascular events(12).

Retrospective cohort studies have their limitations because of confounding and bias. It is surprising that Cohen did not look at the definitive Cochrane meta-analysis provided by the group from Warwick Evidence. They reviewed 28 RCTS from 170 articles and involving 10910 patients treated with GLP1 analogues and found only 2 cases of pancreatitis (13). Even allowing for some underreporting, clinical pancreatitis appears rare and balanced by the benefits in glycaemic control without hypoglycaemia and with weight loss.

There is no human data on increased risk of pancreatic cancer. The data from animal work has been reviewed by experts and by the regulators and the science and relevance to man is disputed and based on interpretations of dysplasia. The hypothesis that a “subclinical pancreatitis” is being produced in man is not backed up by credible evidence and needs far more balanced scrutiny.

The autopsy histology is in only 8 patients(14) and the findings and their interpretation need confirmation in far greater numbers and with independent scrutiny before they can be taken as good evidence of potential harm. The significant concerns regarding the data interpretation in this study are well reviewed (Kahn SE ; Diabetes 2013-published on-line ahead of print April 17th).

Once allegations of a potential for cancer are raised for any drug class, they can only be refuted by long term follow-up. The cardiovascular safety studies with these drugs may, when pooled, go some way to providing this. For the time being, if the hypothesis is that pancreatitis promotes carcinogenic changes then the clinical safety data reporting that pancreatitis is very rare should be reassuring.

It seems not enough for the BMJ that the EMA and FDA are actively studying these issues, that clinicians are aware of possible pancreatitis risk, that all SPCs for these drugs caution regarding pancreatitis and that there is little hard evidence for increased risk of pancreatic cancer. As healthcare professionals, we discuss with our patients the pros and cons of various drug combinations and agree with them the best management plan for that individual. There is no drug which is free of side-effects and perfectly safe. An efficacy/safety balance must be struck and will depend on factors such as age, disease duration, co-morbidities, hypoglycaemia risk, weight gain etc.

In an attempt to discredit “Big Pharma” are we to see as "fall-out" loss of useful drug classes? Should we go back to the days when only metformin, sulphonylureas and insulin were available? Should we then just be using drugs in combination with metformin which promote weight gain and hypoglycaemia? What do we tell our HGV licence holder - sorry I can’t help improve your diabetes control because my only option is to give a drug which increases your risk of hypoglycaemia. Or the elderly lady with angina and osteoporosis - sorry about the fall and hip fracture because of hypoglycaemia. Or our overweight patient who is putting on more weight (and making his sleep apnoea worse) because weight neutral/losing therapies are no longer available. Or our patient with renal failure who has greatly increased risk of severe hypoglycaemia if we give him insulin or a sulphonylurea. Where is individualised care in all this?

As evidenced by the National Press, it is easy to get a “sensationalistic” story off the ground. Much more difficult is limiting the “fall-out”. The safety issues regarding incretin-based drugs are being fully investigated by the proper authorities - why is this not acceptable to your Journal?

1. Cohen D et al BMJ 2013;346:f3680
2. Turner R et al UKPDS 17 Ann Int Med 1996;124:136-145
3. Stratton IM et al UKPDS 35 BMJ 2000;321:405-412
4. UK Hypoglycaemia Study Group.Diabetologia 2007;50:1140-1147
5. Montori V BMJ 2013;346:f3692
6. Accord N Engl J Med 2008;358:2545-59
7. Duckworth W VADT N Engl J Med 2009;360:129-139
8. Tzoulaki I et al BMJ,2009;339:b4731
9. Schramm T et al Eu Heart J ,2011:32:1900-1908
10. Monami m et al Curr Med Res Opin 2011;27:57-64
11. Eurich D T et al BMJ 2013;346:f2267
12. Singh S et al JAMA Intern Med.2013;173(7):534-539
13. Shyangdan D , Royle P, Clar C ,Sharma P, Waugh N. BMC Endocrine disorders 2010,10:20
14. Butler A , Cambell-Thompson M, Gurlo T, Dawson D,Atkinson M, Butler D Diabetes 2013 March 22 on line

Competing interests: Honoraria received for lectures and advisory work from MSD, Novartis, Boehringer-Ingelheim, BMS/Astra-Zeneca,Takeda,Roche,Sanofi-Aventis,Eli Lilly and Novo Nordisk

26 June 2013
Anthony H. Barnett
Emeritus Professor of Medicine and Consultant Physician
J.Paul O'Hare
Heart of England NHS Foundation Trust and University of Birmingham
Diabetes Centre,Birmingham Heartlands Hospital,Birmingham,B9 5SS,United Kingdom