2nd September 2009
Two recently published Canadian cohort studies have assessed cardiovascular safety and fracture risk with pioglitazone▼ and rosiglitazone. The BMJ study found pioglitazone▼ was associated with a lower risk of heart failure and death than rosiglitazone. The Archives of Internal Medicine study found both glitazones were associated with an increased risk of fractures (in both men and women), but pioglitazone▼ may be more strongly associated with fractures than rosiglitazone. These findings are interesting but, as they are from observational data, they should be viewed as providing a basis for further research and interpreted cautiously.
Level of evidence:
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria.
Health professionals should continue to follow MHRA advice published in October 2007 and December 2007. Neither pioglitazone▼ nor rosiglitazone should be used in people with heart failure or a history of heart failure. Rosiglitazone should be used in patients with previous or current ischaemic heart disease only after a careful evaluation of the individual patient’s risk. Neither glitazone should be commenced or continued in people at higher risk of fractures.
In people with type 2 diabetes, priority should be given to reducing cardiovascular risk – lifestyle interventions (stopping smoking, losing weight, and taking more exercise as appropriate), controlling blood pressure, taking a statin, and taking metformin. In some patients, additional hypoglycaemic drugs may be considered to control blood glucose. However, NICE guidance should be followed and individual targets for HbA1c should be agreed with each patient. These could be above that of 6.5% (48mmol/mol) set for people with type 2 diabetes in general and should take into account patient preferences and the balance of likely benefits and harms (such as hypoglycaemia) as well as the medicines management issues.
What is the background to this?
There are three main safety concerns with glitazones: heart failure, myocardial ischaemia and fractures. There is consistent evidence that both rosiglitazone and pioglitazone▼ can cause weight gain, fluid retention and lead to new or worsening heart failure. This is not a rare occurrence, and can be serious and sometimes fatal. There is also evidence that rosiglitazone might be associated with a small increased risk of cardiac ischaemia, particularly in combination with insulin. The third safety concern relating to an increased risk of fractures has been seen with both pioglitazone▼ and rosiglitazone. See the ‘So what?’ section below for details.
The two recently published Canadian cohort studies discussed in this blog aimed to further clarify safety issues with glitazones, and ascertain whether there were any particular differences between treatment with pioglitazone▼ or rosiglitazone. The BMJ study compared the risk of acute myocardial infarction (MI), heart failure and death in patients with type 2 diabetes treated with pioglitazone▼ or rosiglitazone. Whereas, the Archives of Internal Medicine study compared rates of peripheral fractures in men and women with type 2 diabetes exposed to glitazones or sulphonylureas.
What do these studies claim?
The retrospective BMJ cohort study found pioglitazone▼ was associated with a lower risk of heart failure and death than rosiglitazone. Over a 6-year study period, significantly fewer patients reached the primary composite outcome of death or hospital admission for acute MI or heart failure with pioglitazone▼ compared with rosiglitazone (5.3% vs. 6.9%, adjusted hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.76 to 0.90). In terms of absolute risk, this was estimated to equate to one additional composite event each year for every 93 patients treated with rosiglitazone rather than pioglitazone▼. In secondary analyses of each individual outcome, pioglitazone▼ had a lower risk of death (adjusted HR 0.86; 95% CI 0.75 to 0.98) and heart failure (adjusted HR 0.77; 95% CI 0.69 to 0.87), but there was no significant difference in the risk of MI (adjusted HR 0.95; 95% CI 0.81 to 1.11).
The prospective Archives of Internal Medicine cohort study found glitazones were associated with an increased risk of fractures in both men and women with type 2 diabetes, and pioglitazone▼ may be more strongly associated with fractures than rosiglitazone. There was a statistically significantly increased risk of peripheral fractures in men and women exposed to any duration of glitazone treatment compared with sulphonylurea treatment (adjusted HR 1.28; 95% CI 1.10 to 1.48). In absolute terms, this was estimated to equate to one additional peripheral fracture for every 86 patients being treated with a glitazone rather than a sulphonylurea for three years.
Subgroup analyses suggested that pioglitazone▼ was associated with a statistically significantly increased risk of fractures compared with sulphonylureas in both men (adjusted HR 1.61; 95% CI 1.18 to 2.20) and women (adjusted HR 1.77; 95% CI 1.32 to 2.38). Whereas, rosiglitazone compared with sulphonylureas was not (men: adjusted HR 1.00; 95% CI 0.75 to 1.34, women: adjusted HR 1.17; 95% CI 0.91 to 1.50). However, any subgroup analysis needs to be treated with caution, and the confidence intervals from the subgroup analyses for pioglitazone▼ and rosiglitazone overlap, so no firm conclusions can be drawn as to whether these two drugs really do have different fracture risks.
The authors of BMJ study suggest their findings show clinically important differences in the cardiovascular safety profiles of rosiglitazone and pioglitazone▼, with pioglitazone▼ being associated with a lower risk. They conclude that as rosiglitazone lacks a distinct clinical advantage over pioglitazone▼, continued use of rosiglitazone may not be justified. The findings are from an observational study, which by nature, has inherent limitations – therefore, this requires further investigation, ideally in prospective RCTs. However, this does add to previous concerns about rosiglitazone not only being associated with heart failure (as pioglitzone▼ is too) but also with a small increased risk of cardiac ischaemia.
At the very least, these latest results provide additional support for a strategy of reviewing patients taking rosiglitazone, considering their hypoglycaemic medication and making adjustments where appropriate in the light of recently updated NICE guidance. However, very importantly, this study was only designed to compare the safety of pioglitazone▼ and rosiglitazone. It does not provide any information on the safety of pioglitazone▼ relative to other hypoglycaemic drugs, and the authors quite rightly state that their findings should not be interpreted as evidence that pioglitazone▼ is without cardiotoxicity. There is good evidence that pioglitazone▼, as well as rosiglitazone, increases the risk of heart failure, and it may be that pioglitazone is more strongly associated with fracture risk than rosiglitazone (see below).
With regard to what we already know about the cardiovascular safety of glitazones the major clinical outcome studies with pioglitazone▼ (PROACTIVE) and rosiglitazone (RECORD) both found an increased risk of heart failure. In addition, a meta-analysis of seven randomised controlled trials (n=20,191) of pioglitazone or rosiglitazone, found these drugs increased the risk of congestive heart failure compared with controls across a wide range of cardiac risk, with no heterogeneity between studies (relative risk [RR] 1.72, 95% CI 1.21 to 2.42). However, there was no increased risk of cardiovascular death (RR 0.93, 95% CI 0.67 to 1.29; P=0.68).
With regard to myocardial ischaemia, the December issue of Drug Safety Update stated that “a meta-analysis of data from clinical trials showed that the overall incidence of cardiac ischaemic events was higher for rosiglitazone than for comparators (1·99% vs.1·51%; hazard ratio 1·31 [95% CI 1·01–1·70]). However, there was no increase in overall mortality. The risk of cardiac ischaemic events seems to be particularly marked when rosiglitazone is combined with insulin, or in patients with a previous or current ischaemic heart disease. Analysis of pioglitazone▼ trials did not suggest an increased risk of cardiac ischaemia. [A meta-analysis of 19 randomised controlled trials (n=16,390) of pioglitazone found a statistically significantly lower risk of the combined outcome of death, myocardial infarction or stroke [HR 0.82, 95% CI 0.72 to 0.94] for pioglitazone▼ compared with controls, but not for the individual outcome components.] However, comparative data do not provide good evidence of a difference between rosiglitazone and pioglitazone▼ for risk of cardiac ischaemia events.”
The authors of the Archives of Internal Medicine study suggest their findings show that both men and women are at increased risk of fracture from glitazones, and that pioglitazone▼ may be more strongly associated with fractures than rosiglitazone. As would be expected, there are limitations with this observational study and, as discussed above, the findings from the subgroup analyses in particular should be treated with caution. However, the study does raise the possibility that glitazones may increase fracture risk in men, not just in women as we have seen previously, and that there may be differences between pioglitazone▼ and rosiglitazone in fracture risk. An earlier meta-analysis of 10 randomised controlled trials (n=13,715) found that pioglitazone or rosiglitazone combined increased fracture risk compared with controls (odds ratio [OR] 1.45 (95% CI 1.18 to 1.79). However, when men and women were analysed separately in five RCTs (n=11,401 patients), a statistically significant increased risk of fractures was seen among women (OR 2.23, 95% CI 1.65 to 3.01) but not among men (OR 1.00, 95% CI 0.73 to1.39).
The authors of this latest study state that in the absence of mitigating clinical benefits with glitazones, mounting evidence of harm should discourage physicians from prescribing these drugs. Again, at the very least, these latest results provide additional support for a strategy of reviewing patients taking glitazones, considering their hypoglycaemic medication and making adjustments where appropriate in the light of recently updated NICE guidance.
In terms of clinical benefits, Cochrane reviews for both pioglitazone▼ and rosiglitazone, have concluded that there is no convincing evidence that patient orientated outcomes, such as mortality, morbidity, adverse effects, costs or quality of life, are positively influenced by either drug. In addition, both key clinical outcome studies with pioglitazone▼ and rosiglitazone raise questions.
The PROACTIVE study with pioglitazone▼ found there was no significant difference between pioglitazone and placebo in the primary endpoint, a composite of all-cause mortality, non-fatal MI, stroke, acute coronary syndrome, vascular interventions or amputation. There was a benefit with regard to the more narrowly defined secondary endpoint of all-cause mortality, non-fatal MI or stroke. However, secondary endpoints should be viewed with caution in trials where primary endpoints do not achieve conventional levels of statistical significance. The RECORD trial with rosiglitazone, found dual therapy with rosiglitazone plus metformin or a sulfonylurea was non-inferior to dual therapy with metformin plus a sulfonylurea with regard to major cardiovascular outcomes. However, questions over the analysis limit the degree of confidence which can be placed in this conclusion.
NICE type 2 diabetes guidance recommends that glitazones can be considered instead of insulin as triple therapy with metformin and a sulphonylurea if insulin is unacceptable or inappropriate. They can also be considered for second-line use as dual therapy with either metformin or a sulphonylurea when either of these latter drugs is contraindicated, not tolerated or (in the case of sulphonylureas) there is a significant risk of hypoglycaemia. However, NICE reiterates the safety advice about glitazones and states that up to date advice from the EMEA and MHRA should be taken into account before prescribing.
With regard to the three main safety issues with glitazones: heart failure, myocardial ischaemia and fractures, current MHRA advice is as follows (see Drug Safety Update October 2007 and December 2007):
- Rosiglitazone and pioglitazone▼ should not be used in people with heart failure or history of heart failure; incidence of heart failure is increased when rosiglitazone or pioglitazone▼ are combined with insulin. Closely monitor patients during treatment for signs and symptoms of fluid retention, including weight gain or oedema.
- Rosiglitazone might be associated with a small increased risk of cardiac ischaemia, particularly in combination with insulin; rosiglitazone should be used in patients with previous or current ischaemic heart disease only after careful evaluation of individual risk.
- The risk of fracture should be considered in the care of patients, especially women, treated with pioglitazone▼ or rosiglitazone. NICE recommends that glitazones should not be started or continued in people at higher risk of fractures.
The possible safety differences between rosiglitazone and pioglitazone▼ raised by the two recently published studies are interesting. However, as the findings are from observational data they should be viewed as providing a basis for further research and interpreted cautiously.
Study details –
Design: retrospective cohort study of 39,736 outpatients in Ontario, Canada aged 66 years and older who were started on rosiglitazone or pioglitazone between 1 April 2002 and 31 March 2008
Outcomes and results: see above
Sponsorship: supported by a grant from the Ontario Ministry of Health and Long Term Care
Design: prospective cohort study of 84,339 patients from British Columbia, Canada, who began treatment with a glitazone or a sulphonylurea between 1 January 1998 and 31 December 2007
Outcomes and results: see above
Sponsorship: funded in part by a grant to the University of British Columbia from the BC Ministry of Health
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