Patients with diabetes have a 2-4 times higher risk of heart disease and stroke.1 To help reduce a diabetic’s cardiovascular risk, the American Diabetes Association provides therapeutic goals for blood pressure and cholesterol levels.2 The impact of glycemic control on cardiovascular events and mortality is not clear, however it is known that maintaining good glycemic control lessens the risk and prevents the progression of microvascular events.2,3 The American Diabetes Association and European Association Study of Diabetes recently published an update on the management of hyperglycemia.4 Based on these guidelines, insulin remains an option as initial therapy or as add-on therapy with oral agents. Insulin therapy was used in trials evaluating the impact of intensive control on cardiovascular outcomes, so it can be difficult to separate the efficacy and safety of insulin from the findings of these trials.2,3 Some benefits of insulin include its efficacy, lack of a maximum dose, and ability to titrate to response. However, insulin is associated with concerns, particularly hypoglycemia and weight gain; therefore, use of insulin is generally seen later in the course of diabetes. With insulin glargine, there have also been reports of cancer risk raising the concern for the safety of this option in the management of type 2 diabetes.5-8
The Outcome Reduction with an Initial Glargine Intervention or ORIGIN trial was a randomized, double-blind trial that compared insulin glargine to standard care and n-3 fatty acids to placebo (results reported separately). The purpose was to determine the effect of insulin glargine on cardiovascular outcomes in Type 2 diabetics and in reducing the incidence of diabetes in patients at risk of diabetes. Patients were 50 years or older, at high risk of cardiovascular events and had a diagnosis of Type 2 diabetes (stable control on 0-1 oral agents) or impaired glucose tolerance/impaired fasting glucose (IGT/IFG). For those with Type 2 diabetes, the A1C had to be <9% on no agents and <8% on medication. The insulin glargine group was started on 2, 4, or 6 units each evening and self-titrated to a fasting blood glucose (FBG) of <95mg/dL; the standard care group received treatment based on the investigator and treatment guidelines. The co-primary outcomes were the composite of death from cardiovascular cause, myocardial infarction or nonfatal stroke; and the composite of the previous outcomes plus revascularization procedures, or hospitalization for heart failure.9
A total of 12,537 patients were enrolled with a mean age of 63.5 years and a duration of diabetes of 5.3-5.5 years. The baseline median FBG was 124-125 mg/dL and A1C was 6.4%; 11-12% of patients had IGT/IFG. Patients were followed for a median of 6.2 years. Use of insulin glargine early in the course of diabetes was found to have a neutral effect on cardiovascular outcomes compared to standard care. For the primary outcomes, there was no difference in the composite endpoint of myocardial infarction, stroke, or death from cardiovascular cause (HR 1.02, 95% CI 0.94 to 1.11) or the composite of cardiovascular endpoints plus revascularization and heart failure hospitalizations (HR 1.04, 95% CI 0.97 to 1.11). There was no difference in mortality or microvascular events. The insulin glargine group was more likely to experience hypoglycemia (16.72 vs. 5.16 per 100 person-years with standard care, p<0.001) and experience weight gain (1.6 kg vs. -0.5kg with standard care). However while there was more hypoglycemia with insulin glargine, overall there was a low incidence in the insulin treated patients of 1 severe episode per 100 person-years. For patients with IGT/IFG, there was less progression to diabetes with insulin glargine (HR 0.72, 95% CI 0.58-0.91, p=0.006), however there was no difference in regression to normal glycemic indices. The reduction in new cases of diabetes came with the cost of weight gain and hypoglycemia. The study found no difference in the incidence of any cancer (HR 1.00, 95% CI 0.88 to 1.13), death from cancer (HR 0.94, 95% CI 0.77 to 1.15) or cancer at specific sites. At study end, the A1C was 6.2% in the insulin glargine group vs. 6.5% with standard care.
In summary, the ORIGIN investigators found that early use of insulin glargine had no effect on cardiovascular outcomes and attainment of normal to near normal glycemic ...