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ORIGIN: Long-term data show no increased CV, cancer risks from daily insulin glargine use
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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 ORIGIN Trial Investigators. N Engl J Med. 2012;doi:10.1056/NEJMoa1203859.
- The ORIGIN Trial Investigators. N Engl J Med. 2012;doi:10.1056/NEJMoa1203858.
- The ORIGIN Trial Investigators. ORIGIN trial – Final results. Presented at: the American Diabetes Association’s 72nd Scientific Sessions; June 8-12, 2012; Philadelphia.
Disclosures:
- 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.
Perspective
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Michael H. Davidson, MD
The ORIGIN trial started 10 years ago to evaluate the effects of 1 g of ethyl ester omega-3s (Lovaza/Omacor) on CV outcomes in 12,536 high-risk patients with either prediabetes or diabetes. This study failed to demonstrate a clinical benefit for 1 g of omega-3s over a median follow-up of 6.2 years.
The results are disappointing but not surprising due to the low dose of omega-3s used in the trial. Many omega-3 experts believe that clinical benefits of omega-3s are derived from antagonizing the effects of arachidonic acid on prostaglandin production, resulting in less thrombosis, vasoconstriction or inflammation. In the setting of a Western diet, which is rich in the precursor omega-6 fatty acids of arachidonic acid, a low dose of EPA and DHA have very little effect on modifying prostaglandin synthesis. Studies have shown that in conjunction with a Western diet, much higher doses of marine sources of omega-3s are required to reduce thrombosis or other potential pleiotropic effects that may modify CV risk.
Although 1 g of Omacor/Lovaza lowered triglycerides by 10% in the ORIGIN trial, this modest reduction in triglycerides is unlikely to result in a significant CV benefits. At least 4 g of Lovaza/Omacor are needed to lower triglycerides by 25% to 30% and non-HDL by 5% to 10%, which may provide a CV benefit. Unfortunately, there are three other large ongoing outcome trials that are also evaluating a 1-g dose of Omacor/Lovaza. These trials are also very unlikely to work. The REDUCE-IT trial is evaluating 4 g of pure EPA in an 8,000 patients at high CV risk. This trial has a dose of omega-3s that has been proven to significantly lower triglycerides and arachidonic acid levels and, therefore, has a much better chance of proving a CV benefit. Other higher-dose omega-3 trials are being planned as well. An important lesson in clinical trials is to determine if the therapy tested is adequately dosed based on surrogate endpoints (ie, lipids, BP, changes in inflammation, platelet function) before launching into a long-term outcome trial. There is clear evidence that a 1-g dose of omega-3s is inadequate in a Western population to significantly modify any surrogate that is linked to CV events.
Perspective
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Zachary T. Bloomgarden, MD
ORIGIN was a remarkable study of 12,537 patients for a median of 6.2 years carried out by dedicated investigators who, in 2002, asked what was then an interesting question: Would early treatment of diabetes with insulin improve CV outcome in high-risk patients? Much was subsequently learned from ACCORD, ADVANCE, and VADT, so that today, a decade after its inception, our expectations for ORIGIN were low, and, indeed, it was largely a negative study. Nonetheless, there are important points to be made.
It is interesting and noteworthy that, among the 1456 patients with prediabetes, maintaining fasting glucose under 95 mg/dL for 6 years reduced the likelihood of progression to diabetes in the prediabetic subset of the study. Of around 725 patients on standard care, about 250 developed diabetes during the course of the 6 years. Among those who were treated with insulin, 3 months after stopping insulin, about 220 had developed diabetes, yielding a reduction of 20%. Of course, treating 725 persons at risk of developing diabetes with insulin for six years in impractical as a way of avoiding diabetes. It is, however, an interesting finding from the point of view that achieving normal blood fasting glucose may allow beta cells rest in such a fashion as to improve their function.
A negative finding is that intensive insulin therapy over 6 years increased weight by about 1 BMI point, with tripling in the likelihood of developing hypoglycemia, both total and severe. Crucially, the hypothesized reduction in macro- and microvascular endpoints was not seen, leading to the question of whether once people with diabetes actually have CVD it may be too late to prevent CVD with intensive glucose treatment.
There is some danger that an interpretation will be put forward that treating people with insulin for 6 years and lowering their blood sugar to normal and their A1c to a non-diabetic range is of no benefit. Rather, we must recognize that the study randomized people already having CVD and at high likelihood of events (a 5% annual CV event rate) to A1c at goal level, around 6.5%, or to levels <6%. A more positive interpretation would be that these people may have received intensive glycemic treatment too late for benefit to occur. We can argue that the correct study to do is not to take people with very high risk, but instead to take those who have developed diabetes or are just developing diabetes, and who do not at that time have the high CV risk which we know will develop over the next decade. Treating such a group of patients to normal blood glucose might well give benefit over the long-term – although the number of patients needed, and the time of observation required, would truly be daunting.
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