Sanofi announced results from the landmark ORIGIN trial (Outcome Reduction with Initial Glargine Intervention), which showed that Lantus (insulin glargine [rDNA] injection) had no statistically significant positive or negative impact on cardiovascular (CV) outcomes versus standard care during the study period. Results also showed 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.

The study findings were presented at the American Diabetes Association 72nd Scientific Sessions and also published online in the New England Journal of Medicine (NEJM).

ORIGIN was a six-year randomized clinical trial designed to assess the effects of treatment with insulin glargine versus standard care on CV outcomes. The study involved over 12,500 participants worldwide with pre-diabetes or early type 2 diabetes mellitus and high CV risk, with 6,264 participants randomized to receive insulin glargine titrated to achieve fasting normoglycemia. The co-primary endpoints were the composite of CV death, or non-fatal myocardial infarction, or non-fatal stroke; and the composite of CV death, or non-fatal myocardial infarction, or non-fatal stroke, or revascularization procedure, or hospitalization for heart failure.

“We now know more about insulin glargine than about any other glucose lowering drug with respect to future health outcomes,” commented Dr. Hertzel Gerstein, McMaster University, Hamilton, Ontario/Canada and Principal Investigator of the ORIGIN trial. “Specifically, it maintains excellent glycemic control, slows progression of dysglycemia and has no long-term serious health effects. Moreover, this academically led and analyzed trial is an excellent example of collaboration between industry and academia.”

The study demonstrated that achieving fasting normoglycemia did not affect CV outcomes in these participants with early dysglycemia during the study period (first co-primary endpoint: Hazard Ratio [HR]: 1.02; p = 0.63, NS; and second co-primary endpoint: HR: 1.04; p = 0.27, NS).

Insulin glargine achieved targeted long-term glycemic control (median fasting plasma glucose 5.2 mmol/L and HbA1c 6.2%), which was sustained over the 6.2 years of follow-up.

There was no association between insulin glargine and increased risk of any cancer (HR: 1.00; p = 0.97, NS). Neither analysis of all cancers combined, nor analysis of any organ-specific type of cancer, suggested an increased risk for the users of insulin glargine.

Results showed that insulin glargine delayed progression from pre-diabetes (IFG or IGT) to type 2 diabetes mellitus by 28% (HR: 0.72; p = 0.006). Other secondary outcomes included a composite microvascular outcome (metrics of kidney or eye disease; (HR: 0.97; p= 0.43), and all-cause mortality (HR: 0.98; p= 0.70).  

“In patients with pre-diabetes or early type 2 diabetes and high CV risk, ORIGIN shows that it is possible to maintain low and stable HbA1c levels that are close to normal over a long time, and to potentially delay the progression from pre-diabetes to diabetes. Sanofi is proud to have sponsored this trial as a vital contribution to improving understanding of diabetes and the impact of long-term glycemic control,” commented Riccardo Perfetti, MD, vice president medical affairs, Global Diabetes, Sanofi.

Hypoglycemic events were infrequent. In the insulin glargine arm, the rate of severe hypoglycemia was 0.01 episodes per patient-year of exposure versus 0.003 episodes per patient-year for standard care. Rates for overall hypoglycemia with insulin glargine were 16.7 patients with events per 100 patient-years of exposure versus 5.2 patients with events per 100 patient-years for standard care. In addition, weight gain was modest for participants in the insulin glargine arm, at an average of 3.5 pounds over the duration of the study.

ORIGIN investigated the use of insulin glargine in a population in which insulins are not typically used,1 providing new data on the potential benefits and risks of initiation of insulin glargine therapy earlier in the course of diabetes (average disease duration since diagnosis at entry in trial: 5.8 years).

“Our commitment to funding this vitally important long-term trial exemplifies our aim to help identify new ways of treating and understanding diabetes,” commented Pierre Chancel, senior vice president, Global Diabetes, Sanofi. “I am pleased to announce that Sanofi will extend the observations of ORIGIN by an additional two years. All of these data will build on the extensive Lantus evidence in more than 47 million real-life patient-years and over 10 years of clinical experience involving 80,000 participants in clinical development programmes.”

The extension of the observations of ORIGIN will be called ORIGINALE (Outcome Reduction with an Initial Glargine Intervention and Legacy Effect).

ORIGIN (Outcome Reduction with Initial Glargine Intervention) is a unique, six-year landmark cardiovascular (CV) outcomes trial, evaluating Lantus (insulin glargine) versus standard care in over 12,500 individuals who are at high CV risk with pre-diabetes or early type 2 diabetes mellitus. Spanning 40 countries worldwide, it is the world’s longest and largest randomized clinical trial of its type in this population, and the first to formally evaluate the effects of insulin on CV outcomes. The trial used a 2x2 factorial design to determine whether using insulin glargine to target fasting normoglycemia (FPG = 95mg/dL), and separately omega-3 polyunsaturated fatty acids (PUFA), could reduce cardiovascular morbidity and/or mortality. Participants assigned to standard care were treated on the basis of the investigator’s best judgment and local guidelines, including lifestyle measures, dietary modifications, metformin, sulfonylureas and other oral anti-diabetic agents.