medwireNews: The dipeptidyl peptidase (DPP)-4 inhibitor linagliptin and the sulfonylurea glimepiride have similar cardiovascular safety profiles, show the results of the CAROLINA trial.
“We are addressing in this trial a lingering debate that has been going on for many, many years in terms of the safety of the sulfonylureas,” Julio Rosenstock (University of Texas Southwestern Medical Center, Dallas, USA) told journalists at the 79th ADA Scientific Sessions in San Francisco, California, USA.
The debate goes back to the UGDP trial in the 1960s, which showed a significantly increased cardiovascular death risk for patients taking tolbutamide, leading to a warning being placed on the product labels of all sulfonylureas since then.
However, the medication class remains in widespread use, despite other drawbacks including limited glycemia durability and increased risk for hypoglycemia, because of its effectiveness and low cost.
The findings of the CAROLINA trial, which is the first cardiovascular outcomes trial to use an active comparator medication, may remove cardiovascular risk from the list of sulfonylureas’ drawbacks.
The trial pitted linagliptin, with its established neutral cardiovascular safety profile, against glimepiride, and shows the two to be equivalent.
Over a median follow-up of 6.3 years, the rates of the 3-point major adverse cardiovascular event outcome (nonfatal myocardial infarction or stroke, or cardiovascular death) were 11.8% in the linagliptin group and 12.0% in the glimepiride group – no significant difference. The same was true for the individual endpoints, and for heart failure hospitalization, non-cardiovascular death, and all-cause mortality.
There was no evidence of a superior cardiovascular safety profile for linagliptin, which is what the trial was designed to detect.
The two medications produced similar glycemic control, with glycated hemoglobin levels deteriorating in both groups after initial improvements, and although bodyweight changes favored linagliptin, the difference was only modest – around 1.5 kg on average.
As expected, the sulfonylurea was associated with a higher risk for hypoglycemia than the DPP-4 inhibitor, with rates of 11.1 versus 2.34 per 100 person–years for any hypoglycemia, 8.4 versus 1.4 per 100 person–years for moderate/severe hypoglycemia, and 0.18 versus 0.01 per 100 person–years for hypoglycemia-related hospitalization.
The 6033 study participants had type 2 diabetes of a median 6.3 years’ duration and either had established cardiovascular disease (42%) or were at increased risk. Most (83%) were on metformin, but none were insulin-dependent.
Rosenstock noted that there will be debate about the extent to which the CAROLINA findings can be extrapolated to other sulfonylureas, but said: “Other than cost considerations, CAROLINA supports the use of a DDP-4 inhibitor, in this case linagliptin, before a sulfonylurea – if hypoglycemia and weight gain are the considerations.
“We do believe that cardiovascular safety should no longer be a consideration in the decision-making process for selecting between either of these two agents.
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79th ADA Scientific Sessions; San Francisco, California, USA: 7–11 June 2019