Sulfonylureas combined with insulin increased mortality risk more than metformin plus insulin, according to recent study findings published in Diabetologia.

Ulrik M. Mogensen, MD, of the department of cardiology at University Hospital Rigshospitalet in Denmark, and colleagues evaluated 11,081 patients receiving sulfonylurea with insulin and 16,910 patients receiving metformin with insulin to determine the differences in outcomes of treatment combinations. Outcome endpoints measured included all-cause mortality, cardiovascular death, hypoglycemia and a composite endpoint of myocardial infarction, stroke and CV death.

The metformin plus insulin group was younger, had experienced less comorbidity and a longer duration of monotherapy treatment, and used metformin more often before insulin therapy vs. the sulfonylurea plus insulin group.

There was a two to five times greater risk for mortality among the sulfonylurea group compared with the metformin group. Glibenclamide, tolbutamide and glipizide plus insulin led to the greatest odds of all outcome endpoints compared with metformin plus insulin. Compared with metformin plus insulin, there was an increased risk for mortality among all sulfonylurea plus insulin combinations. When using glimepiride plus insulin as a reference, researchers found no significant differences of mortality for combinations of insulin plus glibenclamide (RR=1.13; 95% CI, 0.91-1.54), gliclazide (RR=0.84; 0.64-1.09), glipizide (RR=1.24; 95% CI, 0.96-1.58) and tolbutamide (RR=1.2; 95% CI, 0.83-1.74).

Increased mortality (RR=1.7; 95% CI, 1.48-1.95), CV death (RR=1.35; 95% CI, 1.07-1.7) and the combined endpoint (RR=1.25; 95% CI, 1.05-1.49) were all associated with the use of sulfonylurea plus insulin.

One percent of patients had been hospitalized with hypoglycemia at baseline. During follow-up, 3.5% were hospitalized with hypoglycemia; 85% once, 10.6% twice, 3.4% three times and 3% more than three times. Compared with the sulfonylurea plus insulin groups, the metformin plus insulin group had a lower incidence of hypoglycemia. The sulfonylurea plus insulin group had a higher incidence of having a hypoglycemic event after baseline compared with the metformin plus insulin group (RR=2.06; 95% CI, 1.62-2.61). There was an increased risk of all-cause mortality (RR=2.16; 95% CI, 1.94-2.4), CV death (RR=2.18; 95% CI, 1.85-2.56) and the combined endpoint (RR=1.82; 95% CI, 1.56-2.12) for having hypoglycemia before baseline.

“In conclusion, a combination of [sulfonylurea plus insulin] is being used less frequently, in accordance with guidelines,” the researchers wrote. “In adjusted analyses, [sulfonylurea plus insulin] was associated with increased mortality compared with [metformin plus insulin]. There were no statistically significant differences in risk between individual [sulfonylureas] in combinations with insulin. Hypoglycemia was more frequent with [sulfonylurea plus insulin] compared with [metformin plus insulin] and was associated with an increased risk. Differences in baseline characteristics between treatment groups and the observational design should be considered when interpreting the results.”