PHILADELPHIA — Daily insulin glargine injections, started during the early stages of type 2 diabetes, neither increased nor reduced the risks for myocardial infarction, stroke, cancer, or CV-related mortality, according to results of the ORIGIN trial.
According to principal investigator Hertzel Gerstein, MD, of McMaster University, insulin glargine had a “neutral effect” on adverse CV outcomes, cancer and mortality, as compared with placebo.
“People have been debating the question of whether there are adverse consequences to long-term insulin use for years. This study provides the clearest answer yet to that question: No, there are not,” Gerstein stated in a press release.
The largest and longest study of its kind, the Outcome Reduction with Initial Glargine Intervention (ORIGIN) study included more than 12,500 patients (mean age, 63.5 years; 35% women) at high risk for, or in the early stages of, diabetes. The trial was conducted at 573 sites in 40 countries.
Patients were randomly assigned to daily insulin glargine (Lantus, Sanofi-Aventis) with a target fasting blood glucose level ≤95 mg/dL or to standard care (no insulin), and to omega-3 fatty acid supplementation or placebo. Follow-up was conducted for a median of 6.2 years.
Effects of basal insulin on adverse outcomes
Rates of incident CV outcomes were similar in the insulin glargine and standard care groups at the end of the study. The co-primary outcome of nonfatal MI, nonfatal stroke or death from CV causes was 2.94 per 100 person-years in the insulin glargine group vs. 2.85 per 100 person-years in the standard care group (HR=1.02; 95% CI, 0.94-1.11). The rate of the aforementioned events plus revascularization or HF hospitalization was 5.52 per 100 person-years in the insulin glargine group vs. 5.28 per 100 person-years in the standard care group (HR=1.04; 95% CI, 0.97-1.11).
About 1,000 cancers occurred during the study period (HR=1.00; 95% CI, 0.88-1.13).
“This is the longest, most extensively done study on the effect of insulin vs. no insulin on cancer. There was no evidence whatsoever of the effect of [insulin glargine] on cancers or cancer death,” Gerstein said during a press conference.
The study did confirm the presence of two previously known adverse effects of insulin — hypoglycemia and weight gain. However, both of these were minor, with patients gaining an average of 3.5 lb during the study and experiencing a low rate of hypoglycemia, on average just over one episode per participant per year.
“We now know what the risks are of taking insulin on a long-term basis, and they are low,” Gerstein said.
Effect on progression to diabetes
The ORIGIN investigators also examined whether daily insulin use would prevent or slow progression to diabetes in high-risk patients. They studied this in 1,456 patients who were at risk for diabetes at baseline. At the end of the trial they stopped their insulin and had an oral glucose tolerance test 1 month later. At that time, there was a 28% reduction in new diabetes in patients who had been randomized to insulin vs. usual care. A second OGTT done at 3 months showed a 31% reduction in new diabetes.
“Using insulin for about 6 years does seem to slow the progression of diabetes in these individuals,” Gerstein said at the press conference.
“We believe this is because giving insulin to those with somewhat elevated glucose levels allows the pancreas to rest during this period, essentially helping it to work longer,” he said. However, the durability of this effect for more than 3 months after stopping insulin remains unknown, the researchers cautioned.
Effects of omega-3 fatty acids
The study also examined whether administering daily doses of 1-g omega-3 fatty acid capsules (Omacor, Pronova BioPharma) to patients with type 2 diabetes could help prevent cardiac-related deaths. Results showed that daily supplementation did not reduce the rate of CV events in the high-risk patients studied (9.1% vs. 9.3%; HR=0.98; 95% CI, 0.87-1.10). Use of n-3 fatty acids also had no significant effect on the rates of major vascular events (16.5% vs. 16.3%; HR=1.01; 95% CI, 0.93-1.10); death from any cause (15.1% vs. 15.4%; HR=0.98; 95% CI, 0.89-1.07); or death from arrhythmia (4.6% vs. 4.1%; HR=1.1; 95% CI, 0.93-1.30).
Triglyceride levels were reduced by 14.5 mg/dL more in the n-3 fatty acid group vs. those assigned placebo (P<.001). Researchers observed no significant effects on other lipids.
“Whether similar results would have been observed at higher doses is unknown,” the researchers wrote in The New England Journal of Medicine.
Researchers said the n-3 fatty acids were well tolerated and associated with high adherence — 88% of patients were still taking their omega-3 supplement at the end of the study. Adverse events were similar between the two groups.
“This is the first study to look specifically at the potential CV benefit of omega-3 fatty acids for people with diabetes or prediabetes,” Jackie Bosch, MSc, associate professor at McMaster University and Hamilton Health Sciences, stated in the release. “We saw no benefit or harm in taking the supplement.”
Potential implications and future research
Next, the investigators will conduct a follow-up study — ORIGIN and Legacy Effects (ORIGINALE) — which will continue to 2 years and, hopefully, to 10 years, Bosch said.
In the meantime, “ORIGIN’s findings should reassure patients and clinicians regarding the long-term health impact of using basal insulin therapy to target normoglycemia,” Gerstein said. “Ninety years after it was first used to treat diabetes, we can say that when you need an effective glucose-lowering drug there is no reason to be concerned about undiscovered long-term risks of using basal insulin early in the course of diabetes.” – by Katie Kalvaitis
For more information:
- The trial was supported by Sanofi, with study drugs provided by Pronova BioPharma Norge. Ms. Bosch reports no other relevant financial disclosures. Dr. Gerstein reports participating on the scientific advisory board and payment for lectures including service on speakers bureaus from Sanofi-Aventis.