Gliptins do not have any impact on the risk of major cardiovascular events compared with placebo, say researchers.
In results described as ‘disappointing’, two large, placebo-controlled trials found the drugs did not impact on the risk of major CV events, with one of them suggesting additional caution may be needed over heart failure and severe hypoglycaemia.
The trials – unveiled at the European Society of Cardiology and published in the New England Journal of Medicine this month– were primarily designed to satisfy a US Food and Drug Administration requirement for new diabetes drugs to undergo CVD safety studies, set up in the wake of controversies over rosiglitazone.
Both saxagliptin and alogliptin showed non-inferiority to placebo in terms of their effect on combined major CV endpoints.
The SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53) study included 16,492 patients with type 2 diabetes and either a history CVD or multiple CVD risk factors.
Over the two-year trial, similar numbers of patients assigned to saxagliptin and placebo (7.3% and 7.2%, respectively) experienced the primary endpoint, a composite of CV death, myocardial infarction (MI) and ischemic stroke.
However, there was a small but highly significant increase in the rate of hospitalisations with heart failure in the saxagliptin group, at 3.5% compared with 2.8% in the placebo group, equating to a 27% increased relative risk of this endpoint.
And hypoglycaemia was significantly more common with saxagliptin than placebo; although this was mainly due to minor events, the risk of major hypoglycaemic events requiring intervention was also statistically higher.
The authors concluded: ‘In this randomized, placebo-controlled trial, the DPP-4 inhibitor saxagliptin neither reduced nor increased the risk of the primary composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, when added to the standard of care in patients at high risk for cardiovascular events, thus meeting the criterion for noninferiority to placebo but not providing any cardioprotective benefit.’
They added that the increased risk of hospitalisation from heart disease ‘merits further investigation’.
The other trial, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) study, included 5,380 patients with a recent acute coronary event.
Over the median 18-month follow-up, there was again no difference between the alogliptin and placebo groups in terms of the primary combined endpoint, this time defined as cardiovascular death, nonfatal MI or nonfatal stroke.
In this study, however, there was no increase in hypoglycaemic events. Neither saxagliptin nor alogliptin was associated with any increased risk of pancreatic adverse events – which have become the bugbear of the glucagon-like peptide (GLP)-1 type incretin mimetics.
NICE guidance currently recommends DPP-4 inhibitors as second- or third-line options for patients struggling to control glucose levels.
Dr Alan Begg, member of the SIGN guidelines steering committee and a GP in Montrose, told Pulse the findings were ‘disappointing’ and that GPs should be mindful of the potential heart failure hospitalisation risk.
He said: ‘The heart failure issue is important and needs further assessment – we all need to be aware of this potential problem. Overall the trials were disappointing in respect of not improving cardiovascular outcomes.
However, he added: ‘Improving glycaemic control is more important for microvascular disease.’
Dr Terry McCormack, editor of the British Journal of Cardiology and a GP in Whitby, said: ‘Basically these [trials] showed there was no evidence they were harmful in terms of cardiovascular outcomes such as MIs and strokes.
‘Yes there was a signal of more problems with heart failure, but that was always a problem with the glitazones. Also it’s difficult to know to be sure of this, because it depends how you diagnose heart failure.’
He added: ‘It was reassuring there was no signal for pancreatic cancer.’
This article was updated to reflect that the increase in heart failure hospitalisations was seen in the saxagliptin study, and not the other study