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Feature Diabetes Drugs

Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed?

BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f3680 (Published 09 June 2013) Cite this as: BMJ 2013;346:f3680

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

In the early 70s Dr. Archie Cochrane, in his landmark publication “Effectiveness and Efficiency,” wisely stated: We need to ask three key questions about any kind of medical intervention:
1. Can it work?
2. Does it work in practice?
3. Is it worth it?

He also stated that: “A medical intervention is considered “effective” only if it has been demonstrated, preferably by a Randomised Clinical Trial, that the intervention does more good than harm. This criterion should be applied, not only to new treatments, but also to old treatments, the use of diagnostic tests and screening procedures”.

Cerivastatin, Dronedarone, Flecainide, and Milrinone are just a few of the drugs initially favoured for positive effects on surrogate cardiovascular outcomes. Now all these drugs either have severe restrictions in place on their use, or have simply been removed from the market. Milrinone, thought to be a promising drug for heart failure when measured by surrogate outcomes, has been shown to increase mortality by 28% when compared to placebo.

Unfortunately, in the world of diabetes drugs, newer classes of agents are still getting onto the market at a very high speed. This is mainly due to soft regulatory requirements that give undue importance to HBA1C as a reliable surrogate outcome for even the most common diabetes complication – cardiovascular disease. An example of these soft rules: one of the safety criteria when licensing a new anti-diabetic drug is that it does not cause an increase in cardiovascular risk.

For a disease like type 2 diabetes, which usually lasts decades in most patients, is it sufficient to only rely on short term studies which demonstrate a lowering of HBA1C levels with no apparent increase in cardiovascular risk?

Recent RCTs and meta-analyses about intensive glycaemic control confirm that HBA1C is a poor surrogate for the main cardiovascular complications of type 2 diabetes such as stroke, heart failure, coronary artery disease with or without myocardial infarction, and ischaemic cardiomyopathy.

GLP-1 receptor agonists - the main ones being exenatide, liraglutide, and sitagliptin - are indeed legal for use in clinical practice; however, this is despite there being no hard proof that they are considered safe nor that they reduce hard endpoints complications that mostly matter to diabetic patients, such as heart failure, stroke, myocardial infarction, renal failure, amputations, vision loss and premature CVD deaths.

The use of GLP-1 agonists has consistently shown signs of increased chronic sub-clinical pancreatitis, acute pancreatitis, pancreatic cancer, and thyroid cancer in animals and humans. So far these serious effects of GLP-1 agonists have been mostly monitored slowly and bureaucratically by the manufacturers of these drugs.

These drugs should have followed the correct licensing path of any new drug, just as Dr. Archie Cochrane implied about 40 years ago. I.e., GLP-1 agonists needed randomised long-term clinical trials looking at their side-effects and their efficacy on diabetic complications, before getting into the market.

Let's not forget about the recent Rosiglitazone saga!

References:

1. Archie Cochrane. Effectiveness&Efficiency. Nuffield Provincial Hospital Trust 1971.
2. Use of GLP-1 analogues needs great caution. BMJ 2011;342:d1478
3. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150-6 .BMJ 2012;344:e1451.
4. Utility of GLP-1R agonists in diabetes requires long term study. BMJ 2012;344:e1451
5. GLP-1 based agents and pancreatitis. BMJ 2013;346:f1263
6. Glucagonlike Peptide 1–Based Drugs and Pancreatitis: Clarity at Last, but What About Pancreatic Cancer?: Comment on “Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus” JAMA Intern Med. 2013;():1-3
7. GLP-1–Based Therapies: The Dilemma of Uncertainty Gastroenterology 2011 Jul;141(1):20-3
8. Effects of Intensive Glucose Lowering in Type 2 Diabetes. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358:2545-2559
9. Licensing drugs for diabetes. BMJ 2010;341:c4805
10. Impact of the U.S. Food and Drug Administration Cardiovascular Assessment Requirements on the Development of Novel Antidiabetes Drugs Diabetes Care May 2011 vol. 34 no. Supplement 2 S101-S106

Competing interests: No competing interests

19 June 2013
Jose Mario Franco de Oliveira
Associate Professor of Medicine
Universidade Federal Fluminense
Rua Senador Vergueiro # 2 apt. 202