Glitazones: Don't throw the baby out with the bath water.
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with the first in class, troglitazone, being withdrawn prematurely due to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.
Rapid Response:
Glitazones: Don't throw the baby out with the bath water.
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