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Raised risk of MI and mortality when starting sulfonylurea

Continuing metformin when introducing sulfonylureas in type 2 diabetes safer than switching

Louise Prime

Thursday, 19 July 2018

People with type 2 diabetes had a greater risk of major complications – myocardial infarction (MI), all-cause mortality and severe hypoglycaemia – after they started taking a sulfonylurea, whether it was in addition to or instead of metformin, compared with those who stayed on metformin monotherapy, research using UK general practice data has shown. The authors of the study*, published today on bmj.com, said patients who continued with metformin when starting a sulfonylurea still had a relatively increased risk of MI and all-cause mortality, but continuing metformin when introducing sulfonylureas appeared to be safer than switching.

Researchers in Montréal, Canada pointed out that although sulfonylureas are the most commonly prescribed second-line drugs to treat type 2 diabetes after first-line metformin has failed, and their safety with respect to adverse cardiovascular and hypoglycaemic events has been studied extensively, there have been only “sparse and limited” studies focusing specifically on cardiovascular and hypoglycaemic safety as a second-line drug in patients with poorly controlled diabetes in need of adding or switching to other drugs.

They conducted a population-based cohort study, using data from the UK Clinical Practice Research Datalink, Hospital Episode Statistics (HES) and Office for National Statistics (ONS) databases, to assess whether adding or switching to sulfonylureas is associated with an increased risk of MI, ischaemic stroke, cardiovascular death, all-cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes.

They matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions, and compared the two groups to estimate adjusted hazard ratios (HR) for the study outcomes.

The study authors reported that among 77,138 metformin initiators, 25,699 added or switched to sulfonylureas during the mean follow-up period of 1.1 years. Sulfonylureas were associated with a significantly increased risk of MI (HR 1.26), all-cause mortality (HR 1.28), and severe hypoglycaemia (HR 7.60) compared with continuing metformin monotherapy. There was a trend, though not quite reaching statistical significance, towards increased risks of ischaemic stroke (HR 1.24) and cardiovascular death (HR 1.18).

They also found that compared with adding sulfonylureas, switching to sulfonylureas was associated with a significantly increased risk of MI (HR 1.51) and all-cause mortality (HR 1.23); but they observed no differences for ischaemic stroke, cardiovascular death, or severe hypoglycaemia.

They noted that as their study was observational it could not show cause and effect, and their follow-up period was only short and so could not compare long-term differences between the groups. But they concluded: “Sulfonylureas as second-line drugs are associated with an increased risk of myocardial infarction, all-cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.”

The authors of an accompanying editorial** commented that this study supports the beneficial effects of metformin, by showing that the increased risk from sulfonylurea use was primarily among those who switched, and completely stopped metformin. They also pointed out that perhaps the observed difference in risk between adding and switching could have been driven by the possibility that higher doses of sulfonylureas were needed by those who switched; and that this needs further study.

They concluded: “This new evidence helps to individualise treatment decisions and minimise harm.”

*Douros A, Dell’Aniello S, Oriana Hoi Yun Yu, et al. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ 2018; 362: k2693 doi: 10.1136/bmj.k2693
**D’Agostino McGowan L, Roumie CL. Editorial: Sulfonylureas as second line treatment for type 2 diabetes. BMJ 2018; 362: k3041 doi: 10.1136/bmj.k3041

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