Rosiglitazone and Pioglitazone increase risk of congestive heart failure but not the risk of cardiovascular death

Patients with type 2 diabetes or prediabetes are more likely to develop congestive heart failure (CHF) when given rosiglitazone or pioglitazone, as compared with controls. However these drugs did not increase the risk of cardiovascular death (CVD) for these patients.

These are the conclusions of authors of an Article published in The Lancet.

Additionally, a linked Editorial and two accompanying Comments discuss the importance of basing clinical decisions on trials which assess outcomes which most matter to patients - such as micro- and macro-vascular complications and quality and quantity of life - rather than simply the “surrogate outcome” of blood glucose control which all trials in the Article’s analysis are based.

In the Article, Dr Richard Nesto, Lahey Clinic Medical Centre, Burlington, MA, USA and colleagues did a meta-analysis (a combined analysis of previous studies) of seven randomised double-blind clinical trials of drug related congestive heart failure in patients with type 2 diabetes or prediabetes, who were given rosiglitazone or pioglitazone, from a family of drugs known as thiazolidinediones (TZDs). These trials featured 20191 patients. The main outcome measures were development of CHF and the risk of CVD.

The researchers found that the 72% increase in relative risk for CHF was observed across a wide background of cardiovascular risk – in patients with prediabetes, those with type 2 diabetes but no cardiovascular disease, those with both type 2 diabetes and cardiovascular disease, and those with type 2 diabetes and documented CHF. According to the authors, the absolute risk for CFH varied a great deal across these patient groups which should help clinicians select appropriate patients for TZDs when these drugs are prescribed.

The authors say that since the drug exposures in these trials were relatively short, and most patients did not have previous histories of CHF or evidence of left ventricular dysfunction at entry, the excess of CHF events related to TZDs was probably the result of TZD-related fluid retention and diastolic dysfunction in susceptible patients. They add, however, that the natural history of congestive heart failure when caused by TZD-related fluid retention is unknown.

They say: “Despite the glucose-lowering effect of TZDs, our data indicate that these drugs should not be used in patients with heart failure and should be cautiously used for glycaemic control in patients with cardiovascular disease who do not have heart failure. In patients with type 2 diabetes without cardiovascular disease in whom the absolute risk for CHF is much lower, the use of TZDs should be weighed against the risks and benefits of other antidiabetic medications.”

They conclude with a note of caution, saying: “Insufficient follow-up durations could have affected our conclusions about the association between CHF and cardiovascular mortality. We also did not have sufficient data to assess whether the risk of congestive heart failure differed between the two TZDs. We need longer follow-up and better characterisation of patients in whom CHF develops because of fluid retention to determine the effect of TZDs on overall cardiovascular outcome and whether CHF should be regarded as an adverse event or a characteristic cardiovascular endpoint.”

In the first Comment, Dr John Cleland and Dr Stephen Atkin, Department of Cardiology, Castle Hill Hospital, University of Hull, UK, say: “All the meta-analyses fail to spot the elephant in the room. Treatments should be effective, rather than merely innocuous. Improved glycaemic control is not a surrogate for effective care of patients who have diabetes, which should be to reduce disability and increase lifespan…the regulatory authorities need greater emphasis on ensuring that drugs have effects that are clinically relevant, both in their actions and extent, without stifling innovation in an industry that is valuable to society.”

In the second Comment, Dr Victor Montori, Mayo Clinic of Medicine, MN, USA, and colleagues say drugs based on trials with surrogate outcomes represent a false economy despite saving money initially and allowing new drugs more rapid access to the market. They say: “Any savings are quickly overwhelmed by expenses associated with potentially ineffective or even harmful (yet heavily advertised) expensive therapies….patients and society may end up paying dearly for drugs that cause more harm than good.

“The medical community should insist that we invest the resources needed to do trials that ascertain the effect of interventions on patient-important outcomes.”

The linked Editorial says that future trials need to be designed with the issues pointed out by the commentators in mind. It concludes: “Manufacturers must do - in a timely fashion - postmarketing studies that assess the long-term safety of their drugs, and regulatory agencies must hold manufacturers’ feet to the fire to ensure that these are performed, performed properly, and thoroughly evaluated and made available to guide decisions about prescribing…unless limitations on the understanding, analysis, and communication of drug safety issues are addressed, the TZDs will simply become the latest in a series of preventable drug disasters.”