A patient with Diabetes Type 2 (or prediabetes) is more likely to have congestive heart failure (CHF) when receiving rosiglitazone or pioglitazone, but his/her risk of cardiovascular death (CVD) is not raised. You can read about this in an article in The Lancet, published this week.

In the same issue of The Lancet an Editorial and two accompanying Comments explain the importance of basing clinical decisions on trials which assess outcomes, which are of most relevance to patients, such as micro- and macro-vascular complications and quantity and quality of life, instead of simply basing them on ‘surrogate outcome’ of blood glucose control (which all trials in the Article’s analysis are based).

Dr Richard Nesto, Lahey Clinic Medical Centre, Burlington, MA, USA and team carried out an analysis of seven randomized double-blind trials of drug related CHF in individuals with diabetes type 2 or prediabetes – they had all been given rosiglitazone or pioglitazone, from a family of drugs known as TZDs (thiazolidinediones). These seven trials involved 20,191 patients. Main outcome measures were development of CHF and CVD.

The scientists found that the 72% increase in relative risk for CHF was observed across a extensive 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. The authors explained that the absolute CFH risk varied greatly across those patient groups. This should help doctors choose suitable patients for TZDs when prescribing these drugs.

The authors believe the excess of CHF events linked to TZDs was probably because of TZD-related fluid retention and diastolic dysfunction in vulnerable patients. However, the authors add that nobody knows what the natural history of congestive heart failure when caused by TZD-related fluid retention is.

“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 glycemic 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,” the authors wrote.

“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 characterization 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,” the authors conclude.

The First Comment
“All the meta-analyses fail to spot the elephant in the room. Treatments should be effective, rather than merely innocuous. Improved glycemic 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.”
Dr John Cleland and Dr Stephen Atkin, Department of Cardiology, Castle Hill Hospital, University of Hull

The Second Comment
Drugs based on surrogate outcomes represent a false economy, even though they initially save money and allow new drugs to enter the market rapidly. “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.”
Dr Victor Montori, Mayo Clinic of Medicine, MN, USA, and colleagues

” The Linked Editorial
“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.”

Update 2013, June 7th – an FDA advisory panel recommended loosening the restrictions on Avandia (rosiglitazone), which have been in force since 2010.

Written by: Christian Nordqvist