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© JAPI • january 2012 • VOL. 60
Point of View
The Cage in Search of a Bird
Sanjay Kalra*
T
he last few years have seen a sudden spurt in interest
in malignancy related to diabetes and diabetes related
medications.
When modern diabetology began about a century ago, the
aim of clinicians was just to keep their patients alive for as long
as possible. With the discovery and use of insulin, emphasis
shifted to avoiding acute complications such as hypoglycemia
and symptomatic hyperglycemia. As diabetes care improved,
and the understanding of pathophysiology and natural
history of the disease deepened, physicians expanded their
ambit to include the prevention and management of chronic
complications. A gluco-centric approach was supplanted by a
more comprehensive attitude towards diabetes, including focus
on macrovascular and microvascular complications.
These changes were driven, in part, by a greater realization
of the various mechanisms involved in glycemic metabolism.
From a simplistic insulin deficiency-based model, diabetes has
progressed to a multipronged pathophysiologic model, also
known as the Ominous Octet.1 Newer culprits, such as dopamine,
‘the forgotten felon’, are also being added to this list.2
In parallel, newer drug targets were studied and evaluated
for their potential in diabetes management. Much of this
research has led to the development, and marketing, of novel
drugs. The GLPI analogues, DPP-4 inhibitors and newer insulin
analogues, all of which are used in diabetes management, were
introduced with the past decade. With all these changes, the
horizon of diabetes pharmacotherapy changed dramatically.
From a bleak, spartan choice limited to sulfonylureas and
biguanides, the practicing physicians was suddenly confronted
with a virtually unlimited number of combinations and
permutations of antidiabetic therapy. The sky line was full of
exciting and promising therapeutic options, which physicians,
and guidelines, embraced enthusiastically.3,4 The birds had come
to roost. But where there are birds, there will be bird hunters.
cases) as compared to those on placebo (5 cases), this finding
was not given much prominence. The observation was over
shadowed by the beneficial effects of pioglitazone on glycemia,
and by its cardiovascular safety.7 This was in sharp contrast to the
hype created over malignancy related to estrogen replacement
therapy, which followed publication of the Women’s Health
Initiative Trial.8
In 2010, though, papers were published on the relationship
of insulin glargine with malignancy. Glargine use was found to
be linked with a higher risk of breast cancer in post menopausal
women, though the methodology of these papers was widely
criticized.9 These publications created worldwide interest in
cancer and diabetes. Reviews were published on this topic, and
researchers began to look at all anti diabetic and metabolic drugs
with what can only termed as a paranoid index of suspicion.
Moreover, at odds with a controversial 2010 meta-analysis by
Sipahi et al, the bird hunters had come out in force. Recently,
in 2011, data linking pioglitazone with bladder cancer was
published.10,11 Though the authors themselves point out the
methodological limitations (and flaws) of their work, this report
led to a Trans-Atlantic debate on the use of pioglitazone.12 Similar
reports on cancer have been published for GLP-I analogues
(medullary thyroid carcinoma), dapaglifozin (cancer of bladder
and breast), telmisartan, and insulin. The only antidiabetic drug
shown to have favorable effects on proliferation is metformin.13
For telmisartan, too, two new Danish-cohort findings (70 clinical
trials and almost 3,25,000 patients) published in April 2011
completely refuted the incidence and risk of cancer associated
with ARBs.14,15
The cage, i.e. cancer, is in search of a bird, viz, the antidiabetic
drugs. This situation is similar to the situation described by the
writer Franz Kafka “I am a cage, in search of a bird”. This quote
brings to mind a corrupt judge who keeps on trying to find fault
with an innocent poor man, until he succeeds.
Diabetes has always been known to be a pro-carcinogenic
state. High levels of glucose, insulin and insulin like growth
factor 1 have been implicated in the development of various
glucose-dependent malignancies. These include cancers of
the breast, colon, prostate, uterus and ovary. Various other
mechanisms for this have been mentioned in the occasional
reviews on the relationship of diabetes and malignancy
published earlier.5 Analysis of data by some authors also
revealed that use of insulin per se was a factor which promoted
malignancy.6 No hype, however, was created, either in scientific
journals or in lay media regarding this.
Is the current controversy on diabetes and cancer an echo
of this story? Is it created by researches and medical writers
including in statistical jugglery and manipulation, until a
particular statistical method reveals a significant finding?
A few years ago, the Pro-Active trial reported beneficial
results of pioglitazone on glycemic control as well as
cardiovascular safety. Though the study documented higher
rates of bladder cancer in subjects treated with pioglitazone (14
Cancer is a serious matter. There is no denying this fact. And
if cancer is iatrogenic, it becomes an even more serious matter.
But can one stop using all drugs because they have some adverse
effect or the other? The traditional methods of management
have proved inadequate to handle the burgeoning burden of
the diabetes pandemic. This is why we have found the need to
develop newer drugs and technology to tackle diabetes.
*
Executive Editor, Indian J Endocrinology and Metabolism; Editorin-chief, Intl J Clinical Cases and Investigations; Bharti Hospital and
B.R.I.D.E., Karnal 132001, India
Is it created by vested interests, which target competing
drugs, hoping that negative publicity will hit their sales. Is the
controversy fuelled by a ‘’tabloid like’’ mentality, rather than
pure scientific attitude, on part of medical journal editors? In
search of wider readership, higher impact factors, and the elusive
capital factor, do journals encourage sensational news, at the cost
of less glamorous findings?
Leaving the bird hunters unchecked with their cages in
© JAPI • january 2012 • VOL. 60 75
search of innocent birds, will thwart efforts at newer and safer
drug development. This is something we, rather, our patients
can ill afford. Then, what is the solution? We should strengthen
ourselves with current data, trends and techniques, to ensure
optional utilization of drugs. Methods of suspecting, screening
and diagnosing malignancy should be taught to physicians and
endocrinologists. Rational choice of specific hypoglycemic drugs
and their combinations should be discussed and assessed in
continuing medical education symposia, as well as in journals
such as JAPI.
Do not cage the bird. Instead, regulate the bird hunters.
6.
Schiel R, Müller UA, Braun A, Stein G, Kath R. Risk of malignancies
in patients with insulin-treated diabetes mellitus: results of a
population-based trial with 10-year follow-up (JEVIN). Eur J Med
Res 2005; 10:339-44.
7.
The official ProActive results website. http://www.proactive-results.
com/. Accessed on 29 July 2011.
8.Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg
C, Stefanick ML, et al; Writing Group for the Women’s Health
Initiative Investigators. Risks and benefits of estrogen plus progestin
in healthy postmenopausal women: principal results From the
Women’s Health Initiative randomized controlled trial. JAMA 2002;
288:321-33.
9.
References
1.
Defronzo RA. Banting Lecture: From the triumvirate to the ominous
octet: a new paradigm for the treatment of type 2 diabetes mellitus.
Diabetes 2009; 58:773–795
2.
Kalra S, Kalra B, Agrawal N, Kumar S. Dopamine: The Forgotten
Felon in Type 2 Diabetes. Recent Patents on Endocrine, Metabolic
and Immune Drug Discovery 2011; 5:61-65.
3. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR,
Sherwin R, et al. Management of hyperglycemia in type 2 diabetes
mellitus: A consensus algorithm for the initiation and adjustment
of therapy. Update regarding the thiazolidinediones. Diabetologia
2008; 51:8-11.
4.
Bray GA. Pharmacological treatment of the overweight patient. In:
Bray GA, editor. The Metabolic syndrome and Obesity. Tatowa,
New Jersey: Humana 2007; 203-56.
5.
Kath R, Schiel R, Müller UA, Höffken K. Malignancies in patients
with insulin-treated diabetes mellitus. J Cancer Res Clin Oncol 2000;
126:412-7.
Simon D. Diabetes treatment with insulin glargine and risk of
malignancy: methodological pitfalls and ethical issues. Diabetologia
2010; 53:204-205.
10. Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the
association of pioglitazone use and bladder cancer through drug
adverse event reporting. Diabetes Care 2011; 34:1369-71.
11. Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry
CP Jr, et al. Risk of bladder cancer among diabetic patients treated
with pioglitazone: Interim report of a longitudinal cohort study.
Diabetes Care 2011; 34:916-22.
12. Unnikrishnan AG, Kalra S, Bantwal G. Every rose has it’s thorn!.
Indian J Endocr Metab 2011; 15:3-4.
13. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR and Morris
AD Metformin and reduced risk of cancer in diabetic patients. BMJ
2005; 330:1304–1305.
14. Pasternak B, Svanström H, Callréus T, et al. Use of angiotensin
receptor blockers and the risk of cancer. Circulation 2011; 123:17291736.
15. The ARB Trialists Collaboration. Effects of telmisartan, irbesartan,
valsartan, candesartan and losartan on cancers in 15 trials enrolling
138 769 individuals. J Hypertens 2011;29:623-635.
STATEMENT OF OWNERSHIP
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