Determining Predictors of Response to Exenatide in T2DM
Objectives: To determine predictors of glycemic response to exenatide and to assess change in glycosylated hemoglobin (A1C) and whether a correlation exists between weight loss and glycemic response.
Design: Retrospective observational cohort study.
Setting: United States in 2009.
Patients: 100 adult patients with type 2 diabetes prescribed exenatide.
Intervention: Retrospective chart review of patients to collect demographic data, weight, serum creatinine, diabetes education, and concurrent diabetes medications.
Main outcome measures: Patients were categorized as responders or nonresponders based on change in A1C. Responders had an A1C decrease of 0.5% or more and nonresponders had an A1C decrease of less than 0.5% from baseline to post–exenatide initiation. Demographic data for each cohort were analyzed.
Results: 100 patients met inclusion criteria (61 responders and 39 nonresponders). Responders had a mean A1C decrease of 1.6%, whereas nonresponders had a mean A1C increase of 0.23% (P < 0.001). Post hoc linear regression analysis revealed that baseline A1C was a predictor of response to exenatide (P < 0.001). Binary logistic regression analysis demonstrated that no other variables were predictors of response to exenatide (P > 0.05 for all). No correlation was found between weight loss and exenatide and glycemic response (P = 0.99).
Conclusion: Our data indicate that patients with a higher baseline A1C are more likely to have a glycemic response to exenatide than patients with a lower baseline
Exenatide (Byetta—Amylin) is a synthetic incretin mimetic that exhibits effects similar to human glucagon-like peptide (GLP)-1, which is a gut-derived incretin hormone. The effects include glucose-dependent insulin secretion from pancreatic beta cells, suppression of inappropriately elevated glucagon secretion, and slowing of gastric emptying. Exenatide was initially approved as adjunctive therapy for patients with type 2 diabetes with suboptimal glycemic control despite treatment with oral medications (e.g., metformin, sulfonylurea, thiazolidinedione, combination of metformin with either sulfonylurea or thiazolidinedione). In October 2009, exenatide also received Food and Drug Administration (FDA) approval as monotherapy.
At the time of this study and publication, twice-daily exenatide was the only exenatide product currently on the market. However, a once-weekly exenatide product (Bydureon) is in the process of gaining FDA approval. The original new drug application for once-weekly exenatide was submitted in May 2009, but the approval process was stopped following an FDA request for a thorough QT study to assess cardiovascular risks of the drug. Amylin anticipates responding to FDA's request by the end of 2011.
Based on data from the U.K. Prospective Diabetes Study (UKPDS), the American Diabetes Association currently recommends a glycosylated hemoglobin (A1C) goal of less than 7% for patients with type 2 diabetes (level A recommendation). UKPDS demonstrated that every 1% decrease in A1C resulted in a 25% reduction in microvascular endpoints. The potential for reduction in macrovascular endpoints related to decreases in A1C has been demonstrated in epidemiological studies and meta-analyses but has not been demonstrated in a randomized clinical trial. Two recently published meta-analyses that included data from ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) provided evidence that decreases in A1C significantly decrease macrovascular disease, with statistically significant 17% reductions in myocardial infarction and 10% to 15% reductions in CAD events but still no reduction in overall mortality. In clinical studies in which exenatide was added to oral therapy, decreases in A1C have ranged from 0.4 to 1.1%. Adding exenatide to thiazolidinedione therapy, with or without concurrent metformin use, resulted in similar decreases in A1C.
Exenatide therapy also is associated with weight loss. Weight loss achieved in clinical trials ranged from –1.6 ± 0.2 kg to –3.8 ± 1.4 kg. Moderate weight loss (5–10% body weight) in overweight and obese patients with insulin resistance has been shown to improve insulin sensitivity.
Pivotal exenatide studies have included patients with an average duration of diabetes of 10 years or fewer. The influence that disease duration has on exenatide therapy is not completely clear. However, it is well accepted that over time, beta cell function declines and thus insulin secretion decreases. Both UKPDS and the Belfast Diet Study showed that beta cell function declined during the 5 to 10 years postdiagnosis and that this decline was associated with worsening glycemic control. Because the diagnosis of type 2 diabetes does not occur at a consistent point in the course of the disease (i.e., it can occur early, middle, or late in the disease), the amount of beta cell function cannot be predicted accurately by date of diagnosis. However, patients diagnosed with type 2 diabetes 10 to 12 years earlier likely represent a cohort with limited beta cell function. Because one mechanism of exenatide is glucose-dependent insulin secretion from pancreatic beta cells, it is hypothesized that decreased beta cell function hinders the effects of exenatide on glycemic control in patients with type 2 diabetes of long duration. However, a clinical conundrum exists because despite previous demonstration that beta cell function declines over time in patients with type 2 diabetes, function can persist in others; no two patients are the same in this regard.
Overall, data are lacking regarding patient characteristics that are predictors of response to antihyperglycemic medications. The limited data that do exist include a meta-analysis of 604 Japanese patients with type 2 diabetes taking troglitazone (Rezulin—Parke-Davis/Warner-Lambert) that showed female gender, higher pretreatment fasting plasma glucose, higher body mass index (BMI), and higher C-peptide were associated with a better response to medication. In addition, a prospective study evaluating predictors of response to glimepiride in 849 patients demonstrated that duration of diabetes and previous treatment with oral antihyperglycemic agents were negative predictors of response.
Abstract and Introduction
Abstract
Objectives: To determine predictors of glycemic response to exenatide and to assess change in glycosylated hemoglobin (A1C) and whether a correlation exists between weight loss and glycemic response.
Design: Retrospective observational cohort study.
Setting: United States in 2009.
Patients: 100 adult patients with type 2 diabetes prescribed exenatide.
Intervention: Retrospective chart review of patients to collect demographic data, weight, serum creatinine, diabetes education, and concurrent diabetes medications.
Main outcome measures: Patients were categorized as responders or nonresponders based on change in A1C. Responders had an A1C decrease of 0.5% or more and nonresponders had an A1C decrease of less than 0.5% from baseline to post–exenatide initiation. Demographic data for each cohort were analyzed.
Results: 100 patients met inclusion criteria (61 responders and 39 nonresponders). Responders had a mean A1C decrease of 1.6%, whereas nonresponders had a mean A1C increase of 0.23% (P < 0.001). Post hoc linear regression analysis revealed that baseline A1C was a predictor of response to exenatide (P < 0.001). Binary logistic regression analysis demonstrated that no other variables were predictors of response to exenatide (P > 0.05 for all). No correlation was found between weight loss and exenatide and glycemic response (P = 0.99).
Conclusion: Our data indicate that patients with a higher baseline A1C are more likely to have a glycemic response to exenatide than patients with a lower baseline
Introduction
Exenatide (Byetta—Amylin) is a synthetic incretin mimetic that exhibits effects similar to human glucagon-like peptide (GLP)-1, which is a gut-derived incretin hormone. The effects include glucose-dependent insulin secretion from pancreatic beta cells, suppression of inappropriately elevated glucagon secretion, and slowing of gastric emptying. Exenatide was initially approved as adjunctive therapy for patients with type 2 diabetes with suboptimal glycemic control despite treatment with oral medications (e.g., metformin, sulfonylurea, thiazolidinedione, combination of metformin with either sulfonylurea or thiazolidinedione). In October 2009, exenatide also received Food and Drug Administration (FDA) approval as monotherapy.
At the time of this study and publication, twice-daily exenatide was the only exenatide product currently on the market. However, a once-weekly exenatide product (Bydureon) is in the process of gaining FDA approval. The original new drug application for once-weekly exenatide was submitted in May 2009, but the approval process was stopped following an FDA request for a thorough QT study to assess cardiovascular risks of the drug. Amylin anticipates responding to FDA's request by the end of 2011.
Based on data from the U.K. Prospective Diabetes Study (UKPDS), the American Diabetes Association currently recommends a glycosylated hemoglobin (A1C) goal of less than 7% for patients with type 2 diabetes (level A recommendation). UKPDS demonstrated that every 1% decrease in A1C resulted in a 25% reduction in microvascular endpoints. The potential for reduction in macrovascular endpoints related to decreases in A1C has been demonstrated in epidemiological studies and meta-analyses but has not been demonstrated in a randomized clinical trial. Two recently published meta-analyses that included data from ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) provided evidence that decreases in A1C significantly decrease macrovascular disease, with statistically significant 17% reductions in myocardial infarction and 10% to 15% reductions in CAD events but still no reduction in overall mortality. In clinical studies in which exenatide was added to oral therapy, decreases in A1C have ranged from 0.4 to 1.1%. Adding exenatide to thiazolidinedione therapy, with or without concurrent metformin use, resulted in similar decreases in A1C.
Exenatide therapy also is associated with weight loss. Weight loss achieved in clinical trials ranged from –1.6 ± 0.2 kg to –3.8 ± 1.4 kg. Moderate weight loss (5–10% body weight) in overweight and obese patients with insulin resistance has been shown to improve insulin sensitivity.
Pivotal exenatide studies have included patients with an average duration of diabetes of 10 years or fewer. The influence that disease duration has on exenatide therapy is not completely clear. However, it is well accepted that over time, beta cell function declines and thus insulin secretion decreases. Both UKPDS and the Belfast Diet Study showed that beta cell function declined during the 5 to 10 years postdiagnosis and that this decline was associated with worsening glycemic control. Because the diagnosis of type 2 diabetes does not occur at a consistent point in the course of the disease (i.e., it can occur early, middle, or late in the disease), the amount of beta cell function cannot be predicted accurately by date of diagnosis. However, patients diagnosed with type 2 diabetes 10 to 12 years earlier likely represent a cohort with limited beta cell function. Because one mechanism of exenatide is glucose-dependent insulin secretion from pancreatic beta cells, it is hypothesized that decreased beta cell function hinders the effects of exenatide on glycemic control in patients with type 2 diabetes of long duration. However, a clinical conundrum exists because despite previous demonstration that beta cell function declines over time in patients with type 2 diabetes, function can persist in others; no two patients are the same in this regard.
Overall, data are lacking regarding patient characteristics that are predictors of response to antihyperglycemic medications. The limited data that do exist include a meta-analysis of 604 Japanese patients with type 2 diabetes taking troglitazone (Rezulin—Parke-Davis/Warner-Lambert) that showed female gender, higher pretreatment fasting plasma glucose, higher body mass index (BMI), and higher C-peptide were associated with a better response to medication. In addition, a prospective study evaluating predictors of response to glimepiride in 849 patients demonstrated that duration of diabetes and previous treatment with oral antihyperglycemic agents were negative predictors of response.