Study indicates diabetes drug linked to cardiovascular death
BMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39224.364630.DB (Published 24 May 2007) Cite this as: BMJ 2007;334:1073
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The recent report from and colleagues reporting excess myocardial
infarctions in people with diabetes treated with rosiglitazone provides
cause for concern for patients and their health professionals using such
therapy [1]. Since their launch, the glitazones have a chequered history,
with the first in class, troglitazone, being withdrawn prematurely due to
hepatotoxicity. Excess heart failure has been noted in patients treated
with glitazones, and more recently, further concerns have been raised
about increased fracture risk [2].
The accompanying editorial in the New England Journal of Medicine,
however, is overly critical of glitazones, and lacks balance [3]. An
important point that should be emphasised is that the power of the meta-
analysis to detect significant effects on the basis of 158 events is weak,
and just a small number of events in either direction could have led to
completely different results. Data was not specifically collected or
independently confirmed, and patient level data was not analysed. It is
also important to note a significantly greater number of men in the
rosiglitazone treated group, compared to the non-rosiglitazone treated
group, which may have further skewed the results. Exclusion of studies
that did not report cardiovascular events may also be of importance as
their inclusion may have changed the results.
The conclusion that rosiglitazone leads to increased cardiovascular
disease is not convincing based on the data presented, although it may be
reasonable to surmise that glitazones are unlikely to afford significant
protection against vascular disease. More convincing data will be provided
large randomised studies looking at cardiovascular outcomes. One such
study involving rosiglitazone is the Rosiglitazone Evaluated for Cardiac
Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study [4]. This
has randomised 4,458 patients with type 2 diabetes to rosiglitazone or
metformin, with a primary end point of time to first CV hospitalisation or
death, and is due to report in 2008. An interim analysis of the RECORD
study data should be urgently undertaken to determine whether any similar
trend in increase in cardiovascular disease is noted.
A final point that should be made is that not all glitazones are the
same. Rosiglitazone has for some time been noted to cause a mild elevation
in LDL cholesterol, and indeed conversion from rosiglitazone to
pioglitazone results in improved lipid profiles in diabetic subjects [5].
This may be due to the greater PPAR alpha agonist activity of pioglitazone
compared to rosiglitazone, and hence a modest LDL and triglyceride
lowering effect. Furthermore, a major cardiovascular outcomes study has
been published using Pioglitazone in high risk diabetic patients, showing
a 16% reduction in cardiovascular death [6].
Glitazones have been a major therapeutic advance in the therapy of
type 2 diabetes, and a number of newer therapeutic options are becoming
available in the treatment of type 2 diabetes. Whilst the presented data
provide an important signal for patients and clinicians to continue
careful pharmacovigilance with new drugs for diabetes, more robust data
are required before assigning glitazones to the pharmaceutical dustbin.
1. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007 May 21; [Epub ahead of print].
2. Hampton T. Diabetes drug tied to fractures in women. JAMA 2007; 297: 1645.
3. Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. N Engl J Med 2007 May 21. [Epub ahead of print].
4. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Dargie H, Komadja M, Gubb J, Biswas N, Jones NP. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia. 2005; 48: 1726-35.
5. Berhanu P, Kipnes MS, Khan MA, Perez AT, Kupfer SA, Spanheimer RC, Demissie S, Fleck PR. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy. Diab Vasc Dis Res 2006; 3: 39-44.
6. Dormandy JA, Charbonnel B, Eckland DJ. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (Prospective Pioglitazone Clinical Trial in Macrovascular Events): a randomised controlled trial. Lancet 2005; 366: 1279-89.
Competing interests:
None declared
Competing interests: No competing interests
Tight control of HbA1c levels has assumed great importance in
diabetes
management. It has been enshrined in the QOF (Quality and Outcomes
Framework) of the New GP Contract as being an evidence based proposal.
Multiple drugs are licenced on the understanding that they reduce HbA1c
levels and that this is a good thing. So should it surprise us that a meta
-
analysis of trials of roisiglitazone shows a raised risk of myocardial
infarction
and an increase in cardiovascular deaths? (1)
I think the evidence to support tight glylcaemic control in reducing
complications of type 2 diabetes is poor. In fact the reduction in
diabetes
related endpoints, mortality and stroke from using metformin is not
explicable on the basis of glycaemic control. This isn’t just my opinion,
it is
what was written in the original paper of UKPDS 34, which is still the
paper I
see quoted as showing that tight glycaemic control reduces diabetic
complications. (2)
Should you choose to review the data of UKPDS 33 which compared tight
glycaemic control with sulphonylureas or insulin with conventional
treatment
you will see little benefit from tight control. (3) Tight control made no
difference to absolute rates of angina, heart failure, stroke, renal
failure, nor
vitreous haemorrhage. Tight control reduced the risk of going blind in one
eye, of suffering a fatal MI or of having an amputation by fewer than 1
per
1000 patient years, and then with no statistical significance. The
outcomes
which did show some clinical benefit were cataract extractions, retinal
photocoagulation and non-fatal MI and all –cause mortality, that is if you
can
call absolute risk reductions of between 1 and 3 per 1000 patient years as
being clinically relevant. Would you make the major lifestyle changes
required
by these two groups of treatment if after 10 years your largest single
risk
reduction was a 1 in 30 chance of not needing retinal photocoagulation? I
wouldn’t.
The wonder with drug licencing is that we continue to accept
surrogate
endpoints in trials to licence new treatments for conditions for which we
already have treatments. Our patients deserve better than they are
currently
being offered by those who promote tight glycaemic control. Show me better
data or accept that the control of blood glucose means metformin –anything
else is merely for symptom control.
References
1. Study links diabetes drug to heart deaths. BMJ 2007; 334: 1073
2. Effect of Intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34).
Lancet
1998; 352: 854-865
3. Intensive blood-glucose control with sulphonylureas or insulin
compared with conventional treatment and risks of complications in
patients
with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837- 853
Competing interests:
I have co-authored with Adrian
Edwards , Glyn Elwin and Rhys
Williams a paper on explaining
risk information over the
internet to patients with
diabetes. That project was
funded by the BMJ group
Competing interests: No competing interests
Rosiglitazone: where do we stand?
Dr. Sujoy Ghosh* ,Dr. Nabanita Bose, Dr. Andrew Collier, Dr. Iqbal
Malik
The Ayr Hospital, Ayr, Ayrshire, Scotland, United Kingdom
* Corresponding author. E-mail: drsujoyghosh@rediffmail.com
We have read with interest the news article suggesting possible
raised myocardial infarction and increased cardiovascular deaths in type 2
diabetes patients treated with rosiglitazone.[1-3] It was only recently
that another glitazone/glitazar (Muraglitazar) was found to increase the
risk of cardiovascular events (MI/Stroke/TIA).[4]
In a prospective randomised trial pioglitazone (PROACTIVE) showed
reduction of cardiovascular events.[5] This could be due to its more
favourable effects on lipids.
We observe that in the meta-analysis 15,560 patients were randomly
assigned to a regimen that included rosiglitazone while 12,283 were not
given rosiglitazone (control). There were 86 cases of MI and 39 deaths
from cardiovascular diseases in the rosiglitazone group compared to 72
cases of MI and 22 deaths from cardiovascular diseases in the control
group. It was on the basis of these differences that the authors concluded
that rosiglitazone increases the risk of MI and deaths from cardiovascular
diseases.
The results, if true would be cause for great concerns. What could be
the possible underlying mechanism for the apparent effect? The reasons are
unclear. Could it be because of effects of rosiglitazone on serum lipids
(particularly LDL-cholesterol)? In addition it produces a modest reduction
of haemoglobin levels and is know to precipitate congestive cardiac
failure in susceptible patients.
The authors admit that the study had several flaws. The analysis was
based on limited access to trial results from publicly available sources
and not on patient-level source data. In addition a relatively small
number of events occurred. Hence even random small changes in the number
of events could result in alteration of the statistical analysis. The
studies analysed included some small studies as well as short term trials
that were not originally intended to explore cardiovascular outcomes.
However the results would suggest ruling out of any possible cardio-
protective effect of rosiglitazone. The ongoing Rosiglitazone Evaluated
for Cardiac Outcomes and Regulation of glycaemia in Diabetes (RECORD)
trial may provide useful insight into the cardiovascular effects of
Rosiglitazone.
So where do we stand right now? What advice do we give our patients?
We would agree with the Diabetes UK statement: "Glitazones are not
presently recommended for people who have had, or who are at high risk of
having, heart failure……….. Any suggested link into an increased risk of
stroke and death from cardiovascular complications for people taking
rosiglitazone needs much more research.”[6]
REFERENCES
[1] Tanne JH. Study indicates diabetes drug linked to cardiovascular
death. BMJ. 2007 May 26;334 (7603):1073
[2] Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of
Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med.
(doi: 10.1056/NEJMoa072761)
[3] Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. N
Engl J Med (doi: 10.1056/NEJMe078099)
[4] Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death
and major adverse cardiovascular events in patients with type 2 diabetes
mellitus. JAMA. 2005 Nov 23;294(20):2581-6.
[5] Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti
M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox
RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L,
Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W,
Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive
investigators. Secondary prevention of macrovascular events in patients
with type 2 diabetes in the PROactive Study (PROspective pioglitAzone
Clinical Trial In macroVascular Events): a randomised controlled trial.
Lancet. 2005 Oct 8;366 (9493):1279-89.
[6] Rosiglitazone heart attack risk “not cause for alarm”. Diabetes
UK. 22 May 2007 (News: Press enquires).
http://www.diabetes.org.uk/About_us/News_Landing_Page/Rosiglitazone-heart-
attack-risk-not-cause-for-alarm/ (last accessed 31st May 2007)
Competing interests:
None declared
Competing interests: No competing interests