UK researchers have questioned the current algorithm for diabetes treatment after their study showed using a glitazone second-line with metformin was more effective than adding sulfonylureas at this stage.
Their long-term study in primary care patients found that metformin plus pioglitazone significantly reduced the risk of all-cause mortality by a third, and serious cardiovascular events by over a quarter, when compared to metformin plus a sulfonylurea.
The study retrospectively analysed data of 26,278 patients with type 2 diabetes from the General Practice Research Database who had received metformin monotherapy as their first treatment.
Patients were classified by second-line treatment if they switched within 180 days of ceasing metformin and followed for 10 years.
HbA1c improved significantly with all combinations by a median of 1.0%, bar metformin and DPP4-inhibitors. However, the mean HbA1c did not fall below 7.0% for any of the regimens.
Patients receiving metformin plus pioglitazone had a significant reduction of 29% in all-cause mortality when compared to metformin plus a sulfonylurea.
This combination also significantly reduced the risk of a combined endpoint, defined as the first occurrence of death, myocardial infarction, stroke or cancer by 26%, compared to metformin plus a sulfonylurea.
No significant differences were found with combinations of metformin plus rosiglitazone or metformin plus DPP4-inhibitors when compared with metformin plus a sulfonylurea.
The meformin-pioglitazone combination was significantly better at preventing death, myocardial infarction, stroke or cancer compared with all other regimes, except metformin plus a DPP4-inhibitor.
NICE guidelines currently recommend a sulfonylurea as second-line treatment when metformin fails to adequately control blood glucose, with other therapies third line.
The authors concluded that alternative therapies to metformin plus sulfonylurea may provide superior clinical outcomes.
They concluded: ‘These findings provide some intriguing insights into the optimal approach to intensifying glucose-lowering therapy after the failure of metformin.
‘Data from our study indicates that alternative treatment regimens may provide superior clinical outcomes, in particular metformin plus pioglitazone or metformin plus a DPP4 inhibitor.’
Dr Colin Kenny, a GP in County Dromore and a member of Primary Care Diabetes Society, said: ‘I feel this will be helpful for practices that have cohorts of patients on the metformin-pioglitazone combination.
‘In practice I do consider using pioglitazones or DPP4-inhibitors as second-line over sulfonylureas, but it is not in NICE or SIGN guidance currently – it will be interesting to see if this changes.’
Mortality risk
Sulfonylurea monotherapy – 45% increase
Metformin-pioglitazone – 30% decrease
Meformin + DPP4 – 39% decrease (not significant)
Metformin + Rosiglitazone – 9% decrease (not significant)
*compared with metformin-sulfonylurea
Journal of Clinical Endocrinology and Metabolism 2012, available online 17 October
