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.
Rapid Response:
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