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The longest trial to study insulin has concluded it has a neutral effect on cardiovascular outcomes and cancer incidence, researchers said.

The 6-year trial involving more than 12,000 patients found that patients with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes who were randomized to insulin glargine had an incidence rate of cardiovascular outcomes of 2.94 per 100 person-years compared with 2.85 for those receiving standard care, according to Hertzel Gerstein, MD, from McMaster University in Hamilton, Ontario, and colleagues.

The risk of developing cancer was statistically the same in both arms (HR 1.00, 95% CI 0.88 to 1.13, P=0.97), Gerstein reported here at the American Diabetes Association. The study was also simultaneously published in the New England Journal of Medicine.

“This is the longest, most extensively conducted study to examine the effect of insulin versus no insulin, and we found no evidence at all for a risk of cancer,” Gerstein said at a press briefing.

The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death. The second coprimary outcomes included those above plus revascularization and hospitalization for heart failure. The researchers also looked at microvascular outcomes, incident diabetes, hyperglycemia, weight, and cancer incidence.

The Kaplan-Meier curves regarding cardiovascular events between the two arms were virtually superimposable, Gerstein said.

The only real difference was the “modest” weight gain (3 lbs. versus 1 lb.) and “modest” rate of hypoglycemia (6% versus 2%) associated with glargine during the study period.

“After 90 years of uncertainty regarding the safety of insulin in type 2 diabetes, we now know its long-term effect on serious and important outcomes,” Gerstein said.

Similar excitement for the results was shared among the other investigators at the dais.

“In my world as a cardiologist, I’m more interested in mortality and morbidity regarding glucose-lowering drugs, and with these results we now have better background knowledge,” said investigator Lars Rydén, MD, from the Karolinska Institute in Stockholm. “It’s quite reassuring to know that over the long period we don’t see any drawbacks of this treatment.”

However, whether these results will lead to expanded use of insulin in those at risk of diabetes is unclear. Gerstein and others mainly said the data are reassuring that insulin is safe.

In particular, the glycated hemoglobin A1c levels for the two arms were similar throughout the trial.

At baseline, they were 6.4% for each group. At 4 years, they were 6.1% and 6.4% for the glargine and standard care arms, respectively, and at the conclusion of the study they were 6.2% and 6.5%, respectively.

The ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial recruited 12,537 patients from 40 countries. The median follow-up was 6.5 years, the mean age of participants was 63, and 35% were women. At the conclusion of the study, researchers knew the primary outcome status of 99% of participants.

At 2 years, 90% of those in the glargine arm were compliant; that dropped to 85% at 5 years.

Of those without diabetes at baseline, those assigned to insulin glargine were 28% less likely to develop diabetes at the time of the first oral glucose tolerance test. At this point, they were taken off glargine and by the next glucose tolerance test (median 100 days), they were 20% less likely to develop diabetes compared with standard care participants.

“Our trial showed that near-normal fasting plasma glucose and glycated hemoglobin levels can be achieved and maintained for more than 6 years with a daily injection of basal insulin with or without an oral agent when self-monitored fasting glucose levels are used by high-risk patients to adjust the dose of insulin glargine,” researchers noted.

More than half of the participants in the glargine arm were able to maintain a fasting plasma glucose level of 95 mg/dL for at least 5 years compared with a median fasting glucose level of 123 mg/dL of those in the standard care group who were taking oral agents.

The study is limited because nearly 50% of those in the glargine arm ultimately used metformin, which could have contributed to the cardioprotective benefit, researchers said.

Also, the findings pertain to the effect of insulin therapy and not the effect of glucose lowering, they said.


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