What have we learnt from the rosiglitazone saga?
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d1354 (Published 17 March 2011) Cite this as: BMJ 2011;342:d1354
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Montori and Shah investigated what we can have learn from the
rosiglitazone "saga".(1)
Sagas are epic tales in prose of heroic deeds of days long gone,
"tales of worthy men" that are usually realistic.
Here the men are from Big Pharma, regulatory agencies, medical
journals, university plus the prescribers and ... the patients. Qualifying
are a mix of cupidity, lack of professionalism, incompetence, laziness,
naivety ... and deadly harm.
What happened is unrealistic. There is one principle "primum non
nocere". It is simple to apply. Regulatory agencies must protect the
patient: the approval process needs studies with a fair active comparator
on clinical endpoints, surrogate endpoints are just tricks. Why
prescribers can't keep in mind that " the eldest, the safest"?
This tragic drama was avoidable, as for the selective COX-2 inhibitor
and so many ...However we do not want to learn from past experiences. The
language is a crucial strategy. Again, here there is a huge clash of
discourses between the language we use and the language we should be using
to reach the level of consciousness needed for the beginning of corrective
actions.
1 Montori VM Shah ND. What have we learnt from the rosiglitazone
saga? BMJ 2011; 342:d1354
Competing interests: No competing interests
I read with interest the authors' scathing judgment of physicians who
still prescribe thiazolidinediones for patients with type 2 diabetes. I
further note the disdain for those bodies who still advocate for "tight"
glycemic control. As a practicing endocrinologist, but also a student of
"evidence-based medicine", I take exception to these rather strident
views.
"Tight" glycemic control in the UKPDS was defined as an A1c of 7%
(vs. 7.9% achieved in the standard group)1. This strategy did not lead to
an increase in mortality. "Very tight" glycemic control in the ACCORD
trial was associated with a very small increase in mortality, but the
reasons for this finding remain unknown2 and the results are not
generalizable to patients early in the course of their disease. We still
await an analysis from the ACCORD trial that examines the effects of
rosiglitazone on mortality, which was widely used in the intensive group
(92% of participants in the intensive arm were treated with
rosiglitazone)3. Some guidelines now advocate for a target A1c of 7%, with
lower targets for some groups eg diabetic nephropathy, but more relaxed
targets in those at high risk of hypoglycemia eg the elderly or those with
cardiovascular disease4; therefore, the contempt for the "guidelines"
expressed in this editorial seems misleading. While the evidence that
"tight" control reduces cardiovascular outcomes is sparse, the reduction
in the risk of microvascular complications cannot be entirely discounted.
Blindness and renal failure are important clinical outcomes that matter to
patients, as is hypoglycemia5.
There are many other factors including patients' values that need to
be considered6 when devising guidelines for the management of diabetes,
over and above simply the "evidence" from observational studies or poorly
conducted metaanalyses7. Physicians who treat patients with type 2
diabetes will attest to the challenges that arise when advising patients
to start insulin therapy. In practice, it is more than the "occasional"
patient that is reluctant or unable to take insulin (personal
observation). Patients' "resistance to insulin therapy" is not unfounded8.
Insulin therapy is certainly effective, but it requires injections,
frequent glucose testing, causes weight gain and hypoglycemia and it can
be challenging for many patients to manage (personal observation).
Resources in terms of diabetes education are required to teach patients to
use and adjust insulin safely. Many patients view having to take insulin
as a "failure" to manage their diabetes appropriately8. Insulin is a safe
and effective therapy to manage diabetes, when used appropriately and I
use it often. However, I suspect most people when questioned, would choose
a pill over an injection, if given the choice (personal observation).
The authors' point out that there are important differences between
rosiglitazone and pioglitazone in terms of mechanism of action and safety,
so perhaps we should not be so quick to throw the baby out with the
bathwater. The ACCORD trial showed that many patients with diabetes will
require multiple therapies, including insulin, to control glycemia3,
making the development of oral drugs that are safe and effective for
managing type 2 diabetes an important goal. These drugs should, however,
be properly tested in long term trials examining clinically important
outcomes including measures of safety, before their use becomes
widespread.
1. UK Prospective Diabetes Study Group: Intensive blood-glucose
control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 1998; 352:837-853,
2. The ACCORD Study Group. Long-Term Effects of Intensive Glucose
Lowering on Cardiovascular Outcomes. N Engl J Med 2011; 364:818-828
3. The Action to Control Cardiovascular Risk in Diabetes Study Group.
Effects of Intensive Glucose Lowering in Type 2 Diabetes N Engl J Med
2008; 358:2545-2559
4. Canadian Diabetes Association Clinical Practice Guidelines Expert
Committee, Canadian Diabetes Association 2008. Clinical practice
guidelines for the prevention and management of diabetes in Canada. Can J
Diabetes. 2008;32 (suppl 1)
5. Pramming S, Thorsteinsson B, Bendtson I, Binder C. Symptomatic
hypoglycaemia in 411 type 1 diabetic patients. Diabetic medicine 1991; 8:
217 -22
6. Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello
P, Sch?nemann HJ, for the GRADE Working Group. Rating quality of evidence
and strength of recommendations GRADE: an emerging consensus on rating
quality of evidence and strength of recommendations.
BMJ 2008;336:924-926
7. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of
myocardial infarction and death from cardiovascular causes. N Engl J Med.
2007; 356(24):2457-71. Erratum in: N Engl J Med. 2007; 357(1):100
8. Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews
DR, Landgraf R,
Kleinebreil L; International DAWN Advisory Panel. Resistance to insulin
therapy among patients and providers: results of the cross-national
Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care. 2005
Nov;28(11):2673-9.
Competing interests: I participate in clinical trials of novel agents in type 2 diabetes that are sometimes funded by pharmaceutical companies. I was a site investigator for the ACCORD trial. I was a member of the Expert Committee for the 2008 Canadian Diabetes Association Clinical Practice Guidelines for the Management of Diabetes in Canada. Finally, I treat patients with diabetes.
Perhaps we are too conservative, but that is what we learned.
We appreciate Dr. McDonald's comments and engagement in this
discussion. We agree with her that achieving glycemic control is a tough
task for clinicians and patients, parties that need high quality evidence
to guide their care, and a strong regulatory framework.
Regarding the safety of rosiglitazone, we think that the Nissen meta-
analyses -- with all its methodological shortcomings -- yielded results
that other more rigorous meta-analyses have reproduced, and that new
evidence has not contradicted. We do not expect the sub-analyses of ACCORD
to contribute importantly to this issue.
Dr. McDonald makes a strong case for the central role of patient
preferences and values in choosing antihyperglycemic drugs. Our group is
conducting research and implementing shared decision making for diabetes
medications. This research will contribute to achieve the model that Dr.
McDonald and we prefer to guide the choice of diabetes medications. Tools
to promote shared decision making in diabetes are available in an open
access fashion at http://kercards.e-bm.info and we expect to make these
available in other formats soon.
Finally, taking all the evidence into account (rather than selecting
studies by their results), we believe that the strength of evidence
supporting a tight glycemic goal (i.e., aiming at HbA1c < 7-7.5%) is
weak and therefore precludes any party from dogmatically promoting or
rejecting it. The associated burdens and costs, potential harms, and low
likelihood of benefit from pursuing such control with currently available
drugs makes it an unattractive proposition for most of our informed
patients. Perhaps we are too conservative, but that is one of the lessons
we learned from the rosiglitazone saga.
Competing interests: No competing interests