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Cardiovascular safety of antidiabetic drugs

ESC Congress Report

  • Glitazones improve cardiovascular risk markers but have no evidence for change of cardiovascular morbidity and mortality
  • Regulatory agency view: Safety not enough, new drugs must improve outcome
  • Cardiovascular risk in diabetics related to plasma levels of natriuretic peptides
  • Current data and trials likely inadequate to identify relationship between glycaemic control and outcome

View the Slides from this session in ESC Congress 365

For me, this was one of the highlight sessions of the ESC conference in 2014. Four excellent speakers gave four excellent talks with substantial audience participation from more than 200 delegates.

Professor Ryden (Stockholm, Sweden) focussed on glitazones, highlighting their ability to improve many cardiovascular (CV) disease risk markers but the paucity of evidence that this translates into a reduction in CV morbidity or mortality. He reviewed the evidence for an increased risk of heart failure, possibly mediated by renal salt and water retention rather than a change in cardiac function, and the scaremongering over an increased risk of bladder cancer. He berated, equally, those who were too quick to accept or condemn novel interventions before robust scientific evidence of either benefit or harm has been obtained.

Dr Rosano (Rome, Italy), who previously worked in the European Medicines Agency, provided some personal insights into the regulatory process for approval of hypoglycaemic agents. He concurred with Dr Ryden that surrogate measures were no longer an appropriate reason for approval of treatments for T2DM. New studies must not only show that treatments are safe (placebo could be considered safe) but that they reduce CV disability and death by a clinically meaningful amount. 

Dr Scirica (Boston, USA) presented new data on the SAVOR and EXAMINE trials that compared, respectively, saxagliptin and alogliptin (DPP4 inhibitors) to placebo in >20,000 patients. The studies showed no CV benefit. The risk of heart failure did increase but did not appear to be due to fluid retention and, unlike with giltazones, was associated with a substantial increase in mortality. Overall, CV risk, including heart failure, was strongly related to plasma concentrations of natriuretic peptides (a finding also reported in a large community screening project by Dr Helen Fazlalizadeh).

Dr Tamargo (Madrid, Spain) reported that there are now about 200,000 patients in trials investigating the possibility that improved glycaemic control will improve outcome. He was concerned that by concept or design these trials were likely to fail. He showed that there was little robust evidence from randomised trials to support the belief that improved glycaemic control would improve outcome. However, study designs have generally failed to test the hypothesis adequately; increases in conventional therapy in the placebo groups often lead to little difference in glucose control between the control and active arms of studies. Trial durations are too short. Whether the legacy effects (benefits observed after the end of the trial) are real awaits pre-specified evaluation.

In summary, our understanding and study of glycaemia in cardiovascular disease is a mess. There is no robust evidence that improved glucose control reduces micro- or macro-vascular disease in patients with T2DM.  We do not know that initiating hypoglycaemic therapy before the fasting plasma glucose is above 15mmol/L (UKPDS control arm) is of any benefit. We should encourage doctors and patients to be less aggressive about glucose control until evidence of real clinical benefit is demonstrated. Cardiac stress hormones, such as natriuretic peptides, rather than glycaemic control identify risk and may be a better target for therapy than glucose. Clearly, T2DM and its treatment is an emotive subject surrounded by a great deal of mythology, prejudice and misconception.  A healthy dose of iconoclasm is required to make progress.  

If we begin with certainties, we shall end in doubts; but if we begin with doubts, and are patient in them, we shall end in certainties.
Francis Bacon, De Augmentis (bk. I)


Science has proof without any certainty. Creationists have certainty without any proof.
Charles Edward Montague




Cardiovascular safety of antidiabetic drugs

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.