One of the mainstays of drug treatment for type-2 diabetes, the sulphonylureas, may carry significantly higher risks of death and heart failure than another standard therapy, metformin, a UK-based cohort study suggests.

In turn, though, metformin was associated with a substantially higher risk of mortality than pioglitazone (Actos, Takeda), whose safety profile scored favourably against rosiglitazone (Avandia, GlaxoSmithKline), its more harassed competitor in the newer thiazolidinedone class of diabetes treatments.

A research team led by Professor Paul Elliott from Imperial College London conducted the retrospective cohort study, publishing their findings on bmj.com. Using data from 91,521 men and women with diabetes (average age: 65 years) included in the UK General Research Practice Database between 1990 and 2005, they looked at the risk of myocardial infarction, congestive heart failure and death from any cause associated with prescribing different types of oral diabetes drugs.

The researchers found that metformin was the most commonly prescribed (to 74.5% of patients) drug for type 2 diabetes in this cohort, followed by monotherapy with second-generation sulphonylureas (63.5%). Just 9.2% of the patients were prescribed rosiglitazone as monotherapy, 10.5% rosiglitazone in combination and 4.2% pioglitazone either as monotherapy or in combination. The thiazolidinedones were introduced to the UK market around 2000.

The analysis identified 3,588 incident cases of myocardial infarction, 6,900 cases of congestive heart failure and 18,548 deaths. Compared with metformin, monotherapy with first- or second-generation sulphonylureas was associated with a significant 24-61% excess risk of all-cause mortality, while second-generation sulphonylureas were associated with a 18-30% excess risk of congestive heart failure, Elliott et al reported.

The thiazolidinedones – i.e., rosiglitazone and pioglitazone – were not associated with a risk of myocardial infarction and pioglitazone was linked to a significantly lower – 31-39% – risk of all-cause mortality than metformin. When the two thiazolidinedones were compared, rosiglitazone was associated with a 34-41% higher risk of all-cause mortality than pioglitazone.

That the sulphonylureas should compare unfavourably with metformin in their risk profile for all-cause mortality and congestive heart failure is consistent with the recommendations of the American Diabetes Association and the International Diabetes Federation, which lean towards metformin as the initial treatment for type 2 diabetes, the authors noted.

“We do not confirm previous reports of an excess risk of myocardial infarction associated with rosiglitazone compared with metformin,” Elliott et al commented. The observation that pioglitazone’s risk profile came out favourably compared with rosiglitazone “requires replication in other studies”, they said.