Commentary on EASD commentary on the publication by Elashoff et al., published online in Gastroenterology, February 2011: Increased Incidence of Pancreatitis and Cancer among Patients Given Glucagon Like Peptide-1–Based Therapy.
To Gastroenterology journal
Dr. Abdulameer Abdullah Alashbal; FACHARTZ Int. Med.1
1 Clinical Professor of Medicine; Consultant Diabetologist
Almustansiriya medical college, Department of Medicine, Alyermouk Teaching Hospital, Bagdad, Iraq
Commentary on EASD commentary on the publication by Elashoff et al., published online in Gastroenterology, February 2011: Increased Incidence of Pancreatitis and Cancer among Patients Given Glucagon Like Peptide-1–Based Therapy.
Dr. Abdulameer Abdullah Al-Ashbal; FACHARTZ Int. Med.1
1Associate Clinical Professor of Medicine; Consultant Diabetologist
Almustansiriya medical college, Department of Medicine, Alyermouk Teaching Hospital, Bagdad, Iraq
Summary
The data of the recent publication by Elashoff et al certainly raise concern regarding the safety aspects associated with exenatide (Byetta) as glucagon-like peptide-1 analogs and sitagliptin (Januvia) as DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. The recent European Association for Study of Diabetes commentary criticized the main reported findings and raised a question of whether that these findings don’t allow for far-reaching conclusions. In this counterpoint, many unanswered questions regarding potential side effects associated with the long-term use of glucagon-like peptide-1-based drugs are discussed and the purpose is to suggest that EASD’s conclusion is premature.
Keyword: Diabetes Mellitus, glucagon-like peptide-1, Pancreatitis, Cancer
In light of the recently emerging and proliferating discussion about the clinical use and the associated risks of glucagon-like peptide-1-based therapy, I would like to comment on EASD commentary (1) on the publication by Elashoff et al. (2). The data of the publication by Elashoff et al certainly raise concern regarding the safety aspects associated with exenatide and sitagliptin for the treatment of type 2 diabetes mellitus (T2DM). The EASD commentary criticized the main reported findings and raised the question of whether that these findings don’t allow for far-reaching conclusions, which, in turn, may cause negative consequences to the use of glucagon-like peptide-1-based drugs.
While the authors of EASD commentary recognize the importance of randomized control trials as the only strong way of measuring comparative risk, they advise patients not to stop any medication and reassure them that there is no need for any immediate action. However, the authors of the commentary did not tell us when we have to take action and what did they mean by action? They also used the term “any medication” and “any circumstance”. This means that there is no need to monitor patients carefully for the development of pancreatitis after initiation or dose increases of sitagliptin or sitagliptin/metformin in order to achieve acceptable standards for making a diagnosis of pancreatitis, to discontinue sitagliptin or sitagliptin/metformin if pancreatitis is suspected while using these products and to be cautious in patients with a history of pancreatitis. Because acute pancreatitis is associated with considerable morbidity and mortality, and early recognition is important in reducing adverse health outcomes, the FDA recommended healthcare professionals be alert to this potentially serious condition (3). The glucagon-like peptide-1 receptor is a G-protein–coupled receptor that is expressed in pancreatic islets and exocrine duct cells (4,5).
Animal studies (5, 6) suggest that asymptomatic chronic pancreatitis may not be an uncommon consequence of glucagon-like peptide-1-based therapy. The number of published reports of pancreatitis following treatment with exenatide and of cases reported to the FDA as adverse events are increasing (7-10). Therefore, it would be most welcome to have the EASD authors’ considerations for both patients and their physicians to report any unexpected adverse or serious events associated with the use of these drugs. Interest has recently been focused on the potential adverse effects of these new therapies (11,12). Thus, the problem is that this is a hormone that drives cellular replication and no other therapy [for diabetes] drives cellular replication. If there is public awareness for certain events, then physicians and patients will feel more inclined to report such events to the database. Therefore, both patients and their physicians should be alert about the possibility of increased incidence of acute pancreatitis or chronic asymptomatic pancreatitis as potential side effects.
The paper by Nachnani et al. is a timely addition to an area of growing interest and controversy in which, at present, there are more questions than answers (6). Moreover, this paper is a welcome addition to others as yet limited (13, 14). Studies analysis showed an increased risk of infections and post-marketing reports of anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions such as Stevens-Johnson syndrome have occurred with sitagliptin (Januvia), up to 3 months after starting treatment (15).
The broad spectrum of DPP-IV enzyme activity and a large number of potential bioactive peptide substrates are some of the unanswered questions as well. Other unanswered questions of glucagon-like peptide-1-based therapy are optimal pharmacokinetic, frequency of administration, sustained vs. transient GLP-1 effects, responders vs. nonresponders, their use in sulfonylurea failure and in patients with insulin-requiring T2DM, human vs. rodents’ data.
DPP-4 inhibitors have some theoretical advantages over existing therapy with oral antidiabetic drugs but should currently be restricted to individual patients. Despite all the promise of glucagon-like peptide-1-based drugs, no randomized, controlled trials demonstrating that GLP-1–based therapy improves patient-relevant endpoints such as myocardial infarction or stroke have been reported. Database of systematic reviews has indicated that long-term data especially on cardiovascular outcomes and safety are urgently needed before the widespread use of these agents.
Prevention of microvascular and macrovascular complications rests on the timely institution of drug therapy by the prescribing physician, usually a general practitioner (GP), and the patient’s compliance with the treatment regimen and willingness to make lifestyle changes.
Optimal use of clinical practice guidelines (CPGs) in general practice demands specific implementation strategies aiming at the reduction of barriers to high-quality care. Clinical practice guidelines are potentially useful for health services and health workforce planning but would be more valuable for this aim if they contained more detail about care protocols and specific skills and competencies especially for general practitioners who would be expected to have reduced capacity for effective high-quality care. The general practitioners lack the required and reliable knowledge in deciding accurately to which patient and when to give glucagon-like peptide-1-based drugs and what are the precautions, warnings, and potential adverse effects that they themself be aware of it and must be explained to the patient. In addition, many of these general practitioners are not ready to detect and deal properly and timely with the potentially serious adverse effects. Subsequently, many patients will not receive such a level of care despite the availability of international treatment guidelines describing the supposed optimal management of patients with diabetes. Hence, a clear understanding of how to overcome this knowledge-action gap in diabetes seems to be lacking, despite previous studies which outlined the obstacles that prevent GPs from following the CPGs. So, the only winner in such a battlefield is the pharmaceutical companies. Because we as healthcare professionals control the market for products that we neither pay for nor consume, and whose unwanted consequences are experienced by patients. So, my suggestion is that the time has come to put limits between the role of general practitioners and that of diabetes specialized physicians particularly in highly serious medical issues like the use of glucagon-like peptide-1-based drugs. As we all know that the current practice diabetes guidelines are mostly consensus. This means that the general practitioners are not able to use these guidelines in a proper way. What makes the situation worse are the well-known limitations of post-marketing adverse event reporting. Available reports were sponsored by pharmaceutical companies and arguably have a limited capacity to detect adverse outcomes. Hence, drug regulatory agencies are unlikely to receive data on drug safety (i.e., an administrative, healthcare database.) that are independent of industry ties.
Until surveillance tools are free of industry influence have been established to provide more strong data, such dilemmas of uncertainty regarding adverse effects will remain unsolved. Hence, physicians will need to carefully review the prescribing information and decide whether the benefit-risk profile is beneficial for each individual patient. Improper bias in the CPGs production process can have a potentially more widespread adverse effect on patient care than individual practitioners’ COIs.
The purpose of my counterpoint is to suggest that EASD’s conclusion is premature. History has taught us that enthusiasm for new classes of drugs, heavily promoted by the pharmaceutical companies that market them, can obscure the caution that should be exercised when the long-term consequences are unknown.
Declaration of interest: The author has no conflicts of interest.
References:
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