AMSTERDAM – When patients with dysglycemia had severe hypoglycemia while on treatment with basal insulin glargine, the episodes did not trigger as many adverse cardiovascular outcomes as did severe hypoglycemia during standard care with oral glucose-lowering drugs but no insulin.
"Hypoglycemia caused by insulin glargine–mediated glucose lowering is unlikely to cause cardiovascular outcomes," Dr. Linda G. Mellbin said at the European Society of Cardiology Congress 2013. The link between hypoglycemia and cardiovascular outcomes was up to two- to threefold lower in patients receiving insulin glargine treatment, compared with patients on standard oral regimens in data from more than 12,000 patients with early type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance enrolled in a trial that compared insulin glargine with standard treatment, said Dr. Mellbin, a cardiologist at the Karolinska Institute in Stockholm.
Mitchel L. Zoler/IMNG Medical Media
Dr. Lars Rydén (left) and Dr. Peter Grant
"What was reassuring was that while insulin glargine caused more hypoglycemic events" compared with standard treatment in these patients, "the absolute number of fatal events was still lower with insulin, showing insulin is a very safe treatment," said Dr. Lars Rydén, professor of cardiology at the Karolinska Institute and a coinvestigator with Dr. Mellbin.
"The clinical implication is that you shouldn’t be afraid of insulin; patients should use it if they need it," Dr. Rydén said in an interview. "One reason people are afraid is because it causes hypoglycemia, but this [hypoglycemia] doesn’t seem to be very dangerous."
Dr. Mellbin, Dr. Rydén, and their associates studied data collected in the ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial. Last year, the primary outcome of the study showed that in 12,537 patients with early type 2 diabetes or other indications of dysglycemia and at high risk for cardiovascular outcomes, treatment with basal insulin glargine (Lantus) had a neutral effect during a median 6 years follow-up, compared with standard care on the incidence of several cardiovascular outcomes: death, myocardial infarction, stroke, any revascularization procedure, or heart-failure hospitalization (N. Engl. J. Med. 2012;367:319-28). The new analysis focused on the 3,518 patients in ORIGIN who had at least one hypoglycemic episode during follow-up+ and included 472 patients with at least one severe hypoglycemic event.
Hypoglycemic episodes were more frequent in insulin-treated patients, who accounted for about three-quarters of all hypoglycemic episodes and as well as about three-quarters of the severe events.
The nonsevere hypoglycemic episodes were benign. In a propensity-score adjusted analysis, nonsevere hypoglycemia had no significant association with total mortality, cardiovascular death, arrhythmic death, or cardiovascular death plus nonfatal MI or stroke.
But severe hypoglycemic episodes, as well as severe nocturnal episodes, were significantly linked with increased rates for all these outcomes in the adjusted analysis. For example, patients who had at least one severe hypoglycemic event had a 58% increased incidence of cardiovascular death, MI, or stroke, and a 74% higher rate of total mortality, Dr. Mellbin reported at the meeting. Concurrent with her report, an article with the results was published online (Eur. Heart J. 2013 [doi:10.1093/eurheartj/eht332]).
Although more patients who received insulin had severe hypoglycemia, patients who had these episodes while on glargine had a substantially lower rate of death and other cardiovascular outcomes than did the patients who became hypoglycemic while on standard treatment. The standard-treatment patients who had a severe hypoglycemic episode were 70% more likely to have a subsequent primary-outcome event, compared with the patients who had severe hypoglycemia, while on glargine. The rate of all-cause death following severe hypoglycemia was more than twice as common in the standard care patients, compared with those who had severe hypoglycemia on glargine, and the rate of arrhythmia death was nearly threefold higher in the standard-care patients.
These findings explain why patients on insulin glargine did not have excess cardiovascular and mortality endpoints over standard treatment: Each hypoglycemic event while on insulin had less adverse consequence than when hypoglycemia occurred in patients on standard treatment. In the standard-treatment group, 29% of patients received a sulfonylurea, 28% received metformin, and 3% received another oral hypoglycemic drug. In the insulin glargine group use of oral drugs was very similar, but all patients also received insulin.
The finding that severe hypoglycemic events differ in their clinical impact depending on the treatment context in which they occur in the patients enrolled in ORIGIN could have several possible explanations, Dr. Rydén said. First, it’s possible that the more frequent, repeated episodes of hypoglycemia in the patients on insulin pre-conditioned their myocardium and prevented more severe reactions to subsequent hypoglycemic episodes.