Can Exenatide Be Substituted for Insulin?

In the current issue of Diabetes Care, Davis et al. report on a small study exploring the safety of substituting exenatide for insulin therapy in an attempt to take patients off insulin. 

The recent American Diabetes Association/European Association for the Study of Diabetes consensus treatment algorithm for type 2 diabetes has advanced basal insulin treatment as a much earlier therapeutic option following a structured target-driven strategy. However, the misconception by both providers and patients that insulin should be regarded as the therapy of last resort still prevails and is perhaps the main barrier to insulin treatment, even at the price of many years of poor glycemic control. Insulin is the most effective diabetes agent, only limited by hypoglycemia; however, when used inappropriately in non-physiological and non-optimized regimens, many patients treated with insulin remain poorly controlled.

In the last decade, several new treatments have been developed for treating type 2 diabetes. New agents have been tested in combination with insulin with the main purpose of establishing a "proof of concept" of an independent effect by keeping insulin therapy unchanged or not optimized. However, this "regulatory approval approach" often resulted in relatively small A1C reductions, and at the end of the trials the mean levels often remained far above the desired A1C targets. Although some of these combinations may provide benefits such as reduced insulin resistance, less weight gain, lower insulin requirements, and possibly less hypoglycemia, none of these secondary gains can substitute for the primary objective of reaching the recommended glycemic targets.

The concept of adding a new therapy to insulin was the initial strategy employed with troglitazone to get fast regulatory approval in 1997. The concept of using an insulin sensitizer along with insulin to improve glycemic control and reduce insulin requirements was quickly embraced following the study of add-on troglitazone.. Although subsequent trials with glitazones in combination with insulin showed only modest improvements in glycemic control, this strategy also led to misguided attempts to substitute newer agents for insulin treatment with the false concept of "rescuing" patients from insulin therapy. Since then, attempts have been made with other drugs to replace insulin therapy.

In the current issue of Diabetes Care, Davis et al report on a small study exploring the safety of substituting exenatide for insulin therapy in an attempt to take patients off insulin. The scientific value is rather unclear. In this study, success in the exenatide group was predefined as the ability to "maintain" glycemic control, allowing for a worsening of A1C no greater than 0.5%, despite the fact that the glucose control was poor to begin with. Presumably, the concept of coming off insulin, as if this was the main purpose in and of itself, appeared very appealing to patients and marketing strategists. However, we wonder whether the patients were really "successful" in stopping insulin and switching to exenatide if baseline A1C went up from 8.1 to 8.4%. Let us not forget that our main mission when managing patients with diabetes is to improve glycemic control and that the definition of real clinical success should be the achievement of A1C <7% or as close to normal as possible without unwanted side effects.

Incretin-related therapies are an important addition to our current treatment armamentarium for type 2 diabetes. However, what has made the marketing of exenatide most attractive to clinicians and patients is the associated weight reduction, which is rather modest in the controlled clinical trials but seems to be overemphasized in the periodically reported, uncontrolled, long-term follow-up of a smaller population of responders.

This pilot study clearly demonstrates negative results at best. Although withdrawal of insulin therapy led to some weight loss, which was further compounded by the weight-reducing effects of exenatide, the overall effect on glycemic control was rather disappointing. The level of glycemic control was no different in patients who continued on insulin, but it is important to recognize that the insulin regimen used in this study was often nonphysiological and that no attempt was made to optimize insulin therapy. This is a serious design flaw in the study that could be construed to have been intentionally set up to demonstrate superiority of exenatide, which was used at its maximum dose, whereas there was considerable room for adjusting up the insulin therapy.

Most importantly, the glycemic control at the end of the study was poor with exenatide therapy. In the intention-to-treat group, A1C increased by 0.3% from a baseline of 8% and almost 40% of patients (nonresponders to exenatide) experienced a significant deterioration in glycemic control as shown by a 1.6% rise in A1C. Obviously, if one looks just at the "successful" 60% group of responders, the A1C decreased by 0.5% from a baseline of 8.1%, and weight was reduced by ˇ­4 kg. However, 4 of 18 of these "successful" patients dropped out of the study between weeks 8 and 16, which does not bode well for the long-term success of such therapy. Were these patients really successful by the gold standards of clinical care? Was it worth it? Of course not! This was clearly a negative trial, with a flawed study design and a conclusion that perhaps should have been stronger against substituting exenatide for insulin.

Rather than building strategies to replace insulin, we urge the study sponsors to devote efforts in well-designed studies to explore the use of exenatide with insulin to achieve true treatment success with excellent glycemic control, some weight loss, and less hypoglycemia.

Source: Diabetes In Control: Diabetes Care. 2007;30(11):2972-2973.