ORIGIN - A Major Diabetes Study that Failed   (June 14, 2012)

In early 2001, a new insulin was first marketed in the United States: Lantus (insulin glargine). It was the first of the long-acting insulin analogs, is usually effective when given once daily, and it rapidly became the insulin-of-choice to use when a “basal” insulin is needed.

Soon after, in 2003, the first of 12,537 patients entered the ORIGIN (Outcome Reduction with Initial Glargine Intervention) study. This study, which was funded by the manufacturer of Lantus, was based on earlier studies suggesting that lowering the blood sugar levels to normal with basal insulin might reduce the chance of serious cardiovascular outcomes, and might reduce the chance of developing diabetes in people who do not have diabetes, and might slow the progression of bad things due to high sugar -- what the study authors called “dysglycemia.” Other studies had suggested that the use of omega-3 fatty acids might also reduce the risk of these problems, so the manufacturer was persuaded to add a study of O3FA to be done at the same time on the same patients.

The primary objectives of ORIGIN were: “to determine whether insulin glargine-mediated normoglycemia can reduce cardiovascular morbidity and/or mortality in people at high risk for vascular disease with either IFG, IGT, or early type 2 diabetes [(people who are not normally prescribed insulin) and] to determine whether omega-3 polyunsaturated fatty acids can reduce cardiovascular mortality in people with IFG, IGT, or early type 2 diabetes.” In other words, the study aimed to find out if giving Lantus and O3FA in patients with prediabetes or patients with early T2DM, would reduce cardiovascular risk.

Patients who were randomized to Lantus added a once-daily subcutaneous injection of Lantus; the dose was adjusted to obtain a fasting BG of ≤95 mg/dL (5.3 mM). People with diabetes who were randomized to standard care managed their glucose levels based on their physician’s judgment; nondiabetic participants randomized to standard care were watched for the development of diabetes. All patients were also randomly assigned to receive either an omega-3 polyunsaturated fatty acid (Omacor® brand) or placebo.

The results have just been published in a pair of articles in the New England Journal of Medicine, Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia and n–3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia and were presented at the recent ADA Scientific Sessions meeting in Philadelphia, which I attended.

Sitting in the audience, and listening to the study's experts reviewing the data from the 12,537 participants in 40 countries on six continents over six years, it became obvious that the results were underwhelming. Giving Lantus simply did not have any statistically significant impact on cardiovascular outcomes when compared to standard care. Also, there was no difference in the incidence of cardiovascular death between the omega-3 fatty acid supplement and placebo groups, although the O3FA did reduce triglyceride levels.

The graphs showing these outcomes were shown on huge screens in the meeting room, and were spectacular, and it’s a bit of a shame that they can’t be reproduced here. (They are available at the NEJM website, at http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMoa1203858&iid=f02 for insulin and http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMoa1203859&iid=f02 for O3FA.)

Result by result, the curves showing the outcomes for Lantus or for O3FA were superimposed on the curves for the outcomes with standard care: no differences!

Although not the main reason for doing the study, the results did show that insulin glargine delayed progression from pre-diabetes to type 2 diabetes, and there was no association between insulin glargine use and increased risk of any cancer. No new unexpected side effects of Lantus were uncovered. But there was a cost. The risk of severe hypoglycemia was 0.7% higher in the Lantus group (1% versus 0.3% per year), and one death attributed to hypoglycemia occurred in a participant taking Lantus. And patients on Lantus gained a median of 1.6 kg, while those in the standard-care group lost a median of 0.5 kg.

The title of the press release that the ADA put out about ORIGIN (Study Finds No Increased Heart, Cancer Risk from Daily Insulin Glargine Use) was lipstick on a pig. Strictly speaking, that title was true, but clearly was not the reason the manufacturer was willing to part with millions of dollars to underwrite the study: they were hoping to find that early use of Lantus would decrease cardiovascular risk. It didn't. The press release title should have been "Huge Diabetes Study Shows Insulin Glargine is Ineffective at Lowering Cardiovascular Risk When Given to People with Early T2DM or Prediabetes."