Successful Treatment of Prediabetes in Clinical Practice
Successful Treatment of Prediabetes in Clinical Practice
Objective: To determine the effectiveness of targeted pharmacologic interventions to reverse documented pathophysiologic abnormalities in prediabetes.
Methods: Patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) were treated with insulin sensitizers (pioglitazone + metformin) or insulin sensitizers + exenatide on the basis of oral glucose tolerance testing–derived indices of insulin resistance and impaired β-cell function. Patients who declined pharmacologic therapy received lifestyle modification only.
Results: One hundred five patients with IGT and/or IFG were treated with insulin sensitizers (pioglitazone + metformin) (n = 40), insulin sensitizers + exenatide (n = 47), or lifestyle modification only (n = 18). After a mean follow-up period of 8.9 months, the lifestyle modification group demonstrated no significant changes in fasting plasma glucose, plasma glucose area under the curve during oral glucose tolerance testing, insulin sensitivity, or β-cell function. In the pioglitazone + metformin group (24 hours off medication), fasting plasma glucose fell from 109 to 102 mg/dL; plasma glucose area under the curve decreased by 12.0%; insulin sensitivity and β-cell function improved by 42% and 50%, respectively (all P<.001); 14.3% converted to normal glucose tolerance; and no patient developed diabetes. In the pioglitazone + metformin + exenatide group (24 hours off medication), fasting plasma glucose fell from 109 to 98 mg/dL; plasma glucose area under the curve decreased by 21.2%; insulin sensitivity and β-cell function improved by 52% and 109%, respectively (all P<.001); 59.1% of patients with IGT reverted to normal glucose tolerance; and no patient developed diabetes.
Conclusions: Targeted pathophysiologic therapy based on oral glucose tolerance test–derived measures of insulin sensitivity and β-cell function can be implemented in general internal medicine and endocrine practice and is associated with marked improvement in glucose tolerance and reversion of prediabetes to normal glucose tolerance in more than 50% of patients.
Approximately 26 million Americans have type 2 diabetes mellitus and more than twice this number, approximately 79 million, have prediabetes. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are well-characterized prediabetic conditions and about half of such individuals progress to type 2 diabetes over their lifetime. However, about 40% of persons who develop type 2 diabetes have neither IGT nor IFG. We have shown that a 1-hour plasma glucose concentration of 155 mg/dL or higher during an oral glucose tolerance test (OGTT) is highly predictive of type 2 diabetes even in the absence of IGT or IFG. Both insulin resistance and β-cell failure are strong predictors of future type 2 diabetes. Persons with IFG are characterized by impaired early insulin response during an OGTT and hepatic insulin resistance with normal or near-normal late insulin response and muscle insulin sensitivity. In contrast, persons with IGT have severe muscle insulin resistance and impaired late insulin response during the OGTT. These pathogenic differences explain the very distinct shapes of the plasma glucose concentration curves in people with IGT vs IFG. By the time overt diabetes develops, approximately 80% of β-cell function has been lost and individuals are maximally insulin resistant. Currently, the American Diabetes Association recommends lifestyle intervention (diet plus exercise) as initial therapy for patients with prediabetes and the addition of metformin in patients at high risk. The use of metformin to treat prediabetic patients is based on the results of the US Diabetes Prevention Program. Thiazolidinediones, including troglitazone, rosiglitazone, and pioglitazone, have consistently been shown to be twice as effective as metformin in preventing IGT/IFG conversion to type 2 diabetes and in inducing reversion to normal glucose tolerance. The benefit of thiazolidinediones is related both to their insulin-sensitizing effect and their ability to augment and/or preserve β-cell function. The glucagonlike peptide 1 (GLP-1) receptor agonists promote weight loss and augment β-cell function and have been shown to be effective in reverting prediabetes to normal glucose tolerance. Although neither the thiazolidinediones nor the GLP-1 receptor agonists have been approved for the treatment of prediabetes, they have been shown to prevent the progression of IGT/IFG to type 2 diabetes, and many physicians have begun to use these antidiabetic agents to slow or prevent the progression of prediabetes to diabetes in persons at high risk.
From measurement of the plasma glucose, insulin, and C-peptide concentrations during the OGTT, one can derive measures of β-cell function and insulin sensitivity that correlate well with the euglycemic insulin and hyperglycemic clamp techniques. In the present report, we describe a practical therapeutic approach to the treatment of high-risk prediabetic individuals based on the pathophysiology of the disease. This approach is easy to implement in every day clinical practice and is based on sound pathophysiologic principles and well-established physiologic mechanisms of action of antidiabetic agents.
Abstract and Introduction
Abstract
Objective: To determine the effectiveness of targeted pharmacologic interventions to reverse documented pathophysiologic abnormalities in prediabetes.
Methods: Patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) were treated with insulin sensitizers (pioglitazone + metformin) or insulin sensitizers + exenatide on the basis of oral glucose tolerance testing–derived indices of insulin resistance and impaired β-cell function. Patients who declined pharmacologic therapy received lifestyle modification only.
Results: One hundred five patients with IGT and/or IFG were treated with insulin sensitizers (pioglitazone + metformin) (n = 40), insulin sensitizers + exenatide (n = 47), or lifestyle modification only (n = 18). After a mean follow-up period of 8.9 months, the lifestyle modification group demonstrated no significant changes in fasting plasma glucose, plasma glucose area under the curve during oral glucose tolerance testing, insulin sensitivity, or β-cell function. In the pioglitazone + metformin group (24 hours off medication), fasting plasma glucose fell from 109 to 102 mg/dL; plasma glucose area under the curve decreased by 12.0%; insulin sensitivity and β-cell function improved by 42% and 50%, respectively (all P<.001); 14.3% converted to normal glucose tolerance; and no patient developed diabetes. In the pioglitazone + metformin + exenatide group (24 hours off medication), fasting plasma glucose fell from 109 to 98 mg/dL; plasma glucose area under the curve decreased by 21.2%; insulin sensitivity and β-cell function improved by 52% and 109%, respectively (all P<.001); 59.1% of patients with IGT reverted to normal glucose tolerance; and no patient developed diabetes.
Conclusions: Targeted pathophysiologic therapy based on oral glucose tolerance test–derived measures of insulin sensitivity and β-cell function can be implemented in general internal medicine and endocrine practice and is associated with marked improvement in glucose tolerance and reversion of prediabetes to normal glucose tolerance in more than 50% of patients.
Introduction
Approximately 26 million Americans have type 2 diabetes mellitus and more than twice this number, approximately 79 million, have prediabetes. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are well-characterized prediabetic conditions and about half of such individuals progress to type 2 diabetes over their lifetime. However, about 40% of persons who develop type 2 diabetes have neither IGT nor IFG. We have shown that a 1-hour plasma glucose concentration of 155 mg/dL or higher during an oral glucose tolerance test (OGTT) is highly predictive of type 2 diabetes even in the absence of IGT or IFG. Both insulin resistance and β-cell failure are strong predictors of future type 2 diabetes. Persons with IFG are characterized by impaired early insulin response during an OGTT and hepatic insulin resistance with normal or near-normal late insulin response and muscle insulin sensitivity. In contrast, persons with IGT have severe muscle insulin resistance and impaired late insulin response during the OGTT. These pathogenic differences explain the very distinct shapes of the plasma glucose concentration curves in people with IGT vs IFG. By the time overt diabetes develops, approximately 80% of β-cell function has been lost and individuals are maximally insulin resistant. Currently, the American Diabetes Association recommends lifestyle intervention (diet plus exercise) as initial therapy for patients with prediabetes and the addition of metformin in patients at high risk. The use of metformin to treat prediabetic patients is based on the results of the US Diabetes Prevention Program. Thiazolidinediones, including troglitazone, rosiglitazone, and pioglitazone, have consistently been shown to be twice as effective as metformin in preventing IGT/IFG conversion to type 2 diabetes and in inducing reversion to normal glucose tolerance. The benefit of thiazolidinediones is related both to their insulin-sensitizing effect and their ability to augment and/or preserve β-cell function. The glucagonlike peptide 1 (GLP-1) receptor agonists promote weight loss and augment β-cell function and have been shown to be effective in reverting prediabetes to normal glucose tolerance. Although neither the thiazolidinediones nor the GLP-1 receptor agonists have been approved for the treatment of prediabetes, they have been shown to prevent the progression of IGT/IFG to type 2 diabetes, and many physicians have begun to use these antidiabetic agents to slow or prevent the progression of prediabetes to diabetes in persons at high risk.
From measurement of the plasma glucose, insulin, and C-peptide concentrations during the OGTT, one can derive measures of β-cell function and insulin sensitivity that correlate well with the euglycemic insulin and hyperglycemic clamp techniques. In the present report, we describe a practical therapeutic approach to the treatment of high-risk prediabetic individuals based on the pathophysiology of the disease. This approach is easy to implement in every day clinical practice and is based on sound pathophysiologic principles and well-established physiologic mechanisms of action of antidiabetic agents.
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