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Glitazones: Fluid Retention, Cardiac Failure and Macular Oedema

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Prescriber Update 28(1): 8-10.
November 2007

Ruth Savage, Medical Assessor, New Zealand Pharmacovigilance Centre, Dunedin

Glitazones (thiazolidinediones) can cause fluid retention, which is dose related and more likely to occur when they are used in combination with insulin or sulphonylureas. Consequences include new or worsening cardiac failure and macular oedema. Pioglitazone and rosiglitazone are contraindicated in patients with NYHA Class III and IV heart failure, and not recommended in patients with symptomatic heart failure. All patients taking glitazones need to be informed of possible symptoms, and monitored for fluid retention and associated complications. If signs or symptoms develop, prescribers should consider stopping or reducing the dose of glitazone.

The glitazones (also known as thiazolidinediones or TZDs) are used in the treatment of Type 2 diabetes mellitus. They are the first class of medicines to primarily target insulin resistance. Rosiglitazone and pioglitazone are the two glitazones currently available in New Zealand; only pioglitazone is funded (under Special Authority).

Fluid retention and oedema reported locally and internationally

The Centre for Adverse Reactions Monitoring (CARM) has received reports of peripheral oedema, pulmonary oedema, pleural effusion and exacerbation of cardiac failure with pioglitazone and rosiglitazone. A review of the WHO International Drug Monitoring database in December 2006 revealed that reports of fluid retention leading to oedema and related conditions made up the greatest proportion of adverse reactions to glitazones. In clinical trials, fluid retention was commonly reported by patients taking these medicines; oedema was reported more often when insulin or a sulphonylurea was also prescribed.¹

Development of oedema is dose-related and, in most patients, is mild to moderate.¹ However, it can be severe as illustrated in reports to CARM. One patient was admitted to hospital with oedema extending from the legs to the chest while taking pioglitazone 15mg daily. Another developed oedema of the legs and abdomen, and shortness of breath on exertion three weeks after starting rosiglitazone 4mg daily. There was no evidence of cardiac failure. He recovered with frusemide treatment and discontinuation of rosiglitazone.

Fluid retention may lead to pulmonary oedema and cardiac failure

Fluid retention due to glitazones may lead to, or exacerbate, cardiac failure in some patients. Patients with ischaemic heart disease, valvular heart disease or hypertension are already at risk of developing cardiac failure and it is thought that glitazones may increase the likelihood of this occurring.

Risk higher with combined insulin and glitazones

In clinical trials, heart failure and pulmonary oedema occurred commonly in patients taking rosiglitazone and insulin; this was more frequent than in those taking insulin alone. Patients with heart failure were, on average, older, had a longer duration of diabetes and were mostly taking the higher 8mg dose.¹

Pre-existing heart failure may worsen

In a trial comparing pioglitazone and glibenclamide in patients with moderate to severe heart failure and uncontrolled Type 2 diabetes, 9.9% of patients taking pioglitazone, compared with 4.7% taking glibenclamide, were admitted to hospital because of heart failure. As with rosiglitazone, this was more likely to occur in older patients and those using insulin.

Heart failure precipitated in macrovascular disease

The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study² examined the incidence of heart failure in patients taking pioglitazone compared with placebo. Patients enrolled had Type 2 diabetes with macrovascular disease. Heart failure, and heart failure leading to hospital admission, occurred significantly more often in patients taking pioglitazone compared with placebo (11% v 8% and 6% v 4%) but there was no difference in the incidence of fatal heart failure.

Mechanism likely to be fluid retention rather than left ventricular dysfunction

Some patients have developed pulmonary oedema without evidence of ischaemic heart disease, or systolic or diastolic dysfunction. Marked peripheral oedema has been a feature in some case reports.^3,4 Studies of rosiglitazone indicate that a dose-related effect on pulmonary endothelial permeability, rather than alterations in left ventricular mass or ejection fraction, is probably responsible for the development of pulmonary oedema and, in susceptible patients, cardiac failure.⁵

Consider background risk, use low doses and monitor patients closely

Use of rosiglitazone or pioglitazone is contraindicated in patients with NYHA Class III and IV heart failure, and not recommended in patients with symptomatic heart failure.¹ It would be prudent to use the lowest possible doses of glitazones in patients with oedema and breathlessness without confirmed clinical evidence of cardiac insufficiency.

Due to an increased risk of heart failure and myocardial ischaemia when rosiglitazone is added to insulin therapy, rosiglitazone must not be initiated in patients already using insulin.¹

In patients taking a sulphonylurea who also require a glitazone, initiation of the glitazone should be at the lowest recommended dose with cautious increases only after appropriate clinical evaluation of the patient's risk of fluid retention and cardiovascular events.¹

All patients (especially those with cardiac disease putting them at risk of heart failure) taking glitazones should be monitored for signs and symptoms of fluid retention and heart failure following initiation of the glitazone and again following any subsequent dose increases. If signs and symptoms suggestive of heart failure develop, prescribers should either stop or reduce the dose of glitazone. Patients and their carers should also be informed of the symptoms of fluid retention and heart failure.¹

Macular oedema can be exacerbated by glitazone use

Among patients with Type 2 diabetes, the prevalence of macular oedema is 15% in those who use insulin and 4% in those who do not.⁶ Post-marketing reports have been received of worsening diabetic macular oedema in association with glitazone use, probably because of fluid retention.¹ These reports led to a review of 30 patients who had macular oedema while taking pioglitazone or rosiglitazone.⁷ It was observed that these patients also had lower limb oedema. Eleven of these patients were observed for three months after glitazones were discontinued. Mean weight gain after commencing a glitazone in these patients was 13.5 kg and mean weight loss after discontinuation was 8.5 kg. Rapid reduction in macular oedema occurred in four of the eleven patients when glitazones were discontinued.

Disturbances in visual acuity may indicate macular oedema. If macular oedema occurs or worsens during treatment with glitazones, this may be due to disease progression, but also consider whether the glitazone could be implicated. Patients should be advised to seek medical advice if they develop symptoms of visual impairment, and prescribers should give consideration to stopping the glitazone.

Caution and vigilance warranted

In summary, prescribers need to be aware that glitazones commonly cause oedema and related conditions. Pioglitazone and rosiglitazone are contraindicated in patients with NYHA Class III and IV heart failure, and not recommended in patients with symptomatic heart failure. Initiation of glitazone therapy should be at the lowest recommended dose; subsequent dose increases should only occur following evaluation of the patient's risk of fluid retention and cardiovascular events. It is recommended that patients be informed of the symptoms and be monitored, particularly for cardiovascular decompensation.

Competing interests (author): none declared.

References

Eli Lilly and Company (NZ) Ltd. Actos™ data sheet. www.medsafe.govt.nz/profs/Datasheet/a/Actostab.htm
GlaxoSmithKline NZ Ltd. Avandia™ data sheet. 7 August 2007. www.medsafe.govt.nz/profs/Datasheet/a/Avandiatab.htm
Dormandy JA, Charbonnel B, Eckland DJA, et al. 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;366:1279-1289.
Shah M, Kolandaivelu A, Fearon WF. Pioglitazone-induced heart failure despite normal left ventricular function. American Journal of Medicine 2004;117(12):973-974.
Fernando DJ, Bulugahapitiya U, Prior K. Delayed onset of rosiglitazone-induced pulmonary oedema. Eur J Intern Med 2006;17(8):590.
Idris I, Gray S. Donnelly R. Rosiglitazone and pulmonary oedema: an acute dose-dependent effect on human endothelial cell permeability. Diabetalogia 2003;46(2):288-290.
Kendall C, Wooltorton E. Rosiglitazone (Avandia) and macular oedema. CMAJ 2006;174(5):623-624.
Ryan EH, Han DP, Ramsay RC, et al. Diabetic macular oedema associated with glitazone use. Retina 2006;26:562-570.