Ask the Experts - Role of Pharmacologic Agents in the Prevention of...
Ask the Experts - Role of Pharmacologic Agents in the Prevention of...
Can pharmacologic agents be used in patients with impaired glucose tolerance (IGT) to slow or stop the progression to frank diabetes mellitus?
R. Gopinath, MD
This question is certainly very important and currently the subject of great debate. .The prevalence of type 2 diabetes is rising all over the world, as a result of an aging population living an increasingly sedentary lifestyle and consuming, in relation to their energy expenditure, foods high in fat and refined carbohydrates. Many developing countries already show epidemic rates of type 2 diabetes due to "modernization" and industrialization, indicating an urgent need for prevention in those at greatest risk.
People with IGT certainly fit into that category. Studies in a number of populations, including Europeans; Native Americans; Indian, Chinese, and African-born Mauritians; Samoans, Nauruans; and Melanesian Papua New Guineans, show that individuals with IGT have a higher (between 2- and 7-fold higher) risk of progressing to type 2 diabetes than persons with normal glucose tolerance.
Healthy lifestyle practices, such as exercise, appropriate nutrition, and maintenance of ideal body weight, may be effective in preventing type 2 diabetes in people with IGT. The efficacy of primarily nonpharmacologic interventions, such as those used in the first major population-based intervention reported, the DaQing Study in China, provides support for the view that interventions directed at improving glucose tolerance in individuals with IGT should be given a high priority. This is supported by the preliminary findings of the Finnish Prevention Study.
In the DaQing Study, the incidence of IGT converting to type 2 diabetes was reduced by one third in the intervention group compared with controls. Of interest is the fact that many people did not respond to the lifestyle intervention. In one sense, this is not surprising because type 2 diabetes is a heterogeneous disease with a number of pathways that lead to insulin resistance, some of which don't respond to weight reduction and/or exercise. This raises the issue of whether pharmacologic intervention is warranted.
Two British trials conducted in the 1960s were the first studies to use oral hypoglycemic agents, along with dietary modifications, to prevent progression of IGT. One study, from Bedford, used tolbutamide and the other study, from Whitehall, used phenformin. Neither study showed any benefit over 10 years or 5 years of follow-up, respectively. Another study in women with postgestational IGT found that the addition of chlorpropamide to a diet treatment did not change later rates of glucose intolerance.
These negative results are in contrast to the findings of a Scandinavian study conducted by Sartor and colleagues, who showed that diet alone or with tolbutamide significantly reduced the incidence of type 2 diabetes in males with IGT. However, this trial had a number of flaws, including poor randomization of control and treatment groups. Moreover, when analyzed properly according to "intention to treat" analysis, there did not appear to be any advantage in using tolbutamide.
In the United States, the National Institutes of Health (NIH) is addressing this challenge by funding a major multicenter IGT intervention study (The Diabetes Prevention Program) to examine the potential benefit of lifestyle changes on the prevention of type 2 diabetes, as well as whether there is a role for pharmacologic intervention with the biguanide metformin. The Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) will assess the role of the alpha-glucosidase inhibitor acarbose in preventing type 2 diabetes in individuals with IGT.
The new therapeutic compounds of the thiazolidinedionegroup have created considerable interest in this regard. Troglitazone had been shown to improve insulin sensitivity in people with type 2 diabetes and the glycemic response after a glucose load in people with IGT. However, because of reports of potential liver toxicity, troglitazone was withdrawn from the market. Thomas Buchanan and his colleagues in Los Angeles, California, gave troglitazone (before it was withdrawn) to a group of women with gestational diabetes, who are certainly a high-risk group for developing future diabetes. Troglitazone-treated patients demonstrated a 60% reduction in the progression to type 2 diabetes. These results are certainly worthy of confirmation with pioglitazone and rosiglitazone.
Therefore, although more evidence may be needed, there appears to be a place for pharmacologic compounds, such as biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, in preventing the deterioration from IGT to type 2 diabetes.
Can pharmacologic agents be used in patients with impaired glucose tolerance (IGT) to slow or stop the progression to frank diabetes mellitus?
R. Gopinath, MD
This question is certainly very important and currently the subject of great debate. .The prevalence of type 2 diabetes is rising all over the world, as a result of an aging population living an increasingly sedentary lifestyle and consuming, in relation to their energy expenditure, foods high in fat and refined carbohydrates. Many developing countries already show epidemic rates of type 2 diabetes due to "modernization" and industrialization, indicating an urgent need for prevention in those at greatest risk.
People with IGT certainly fit into that category. Studies in a number of populations, including Europeans; Native Americans; Indian, Chinese, and African-born Mauritians; Samoans, Nauruans; and Melanesian Papua New Guineans, show that individuals with IGT have a higher (between 2- and 7-fold higher) risk of progressing to type 2 diabetes than persons with normal glucose tolerance.
Healthy lifestyle practices, such as exercise, appropriate nutrition, and maintenance of ideal body weight, may be effective in preventing type 2 diabetes in people with IGT. The efficacy of primarily nonpharmacologic interventions, such as those used in the first major population-based intervention reported, the DaQing Study in China, provides support for the view that interventions directed at improving glucose tolerance in individuals with IGT should be given a high priority. This is supported by the preliminary findings of the Finnish Prevention Study.
In the DaQing Study, the incidence of IGT converting to type 2 diabetes was reduced by one third in the intervention group compared with controls. Of interest is the fact that many people did not respond to the lifestyle intervention. In one sense, this is not surprising because type 2 diabetes is a heterogeneous disease with a number of pathways that lead to insulin resistance, some of which don't respond to weight reduction and/or exercise. This raises the issue of whether pharmacologic intervention is warranted.
Two British trials conducted in the 1960s were the first studies to use oral hypoglycemic agents, along with dietary modifications, to prevent progression of IGT. One study, from Bedford, used tolbutamide and the other study, from Whitehall, used phenformin. Neither study showed any benefit over 10 years or 5 years of follow-up, respectively. Another study in women with postgestational IGT found that the addition of chlorpropamide to a diet treatment did not change later rates of glucose intolerance.
These negative results are in contrast to the findings of a Scandinavian study conducted by Sartor and colleagues, who showed that diet alone or with tolbutamide significantly reduced the incidence of type 2 diabetes in males with IGT. However, this trial had a number of flaws, including poor randomization of control and treatment groups. Moreover, when analyzed properly according to "intention to treat" analysis, there did not appear to be any advantage in using tolbutamide.
In the United States, the National Institutes of Health (NIH) is addressing this challenge by funding a major multicenter IGT intervention study (The Diabetes Prevention Program) to examine the potential benefit of lifestyle changes on the prevention of type 2 diabetes, as well as whether there is a role for pharmacologic intervention with the biguanide metformin. The Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) will assess the role of the alpha-glucosidase inhibitor acarbose in preventing type 2 diabetes in individuals with IGT.
The new therapeutic compounds of the thiazolidinedionegroup have created considerable interest in this regard. Troglitazone had been shown to improve insulin sensitivity in people with type 2 diabetes and the glycemic response after a glucose load in people with IGT. However, because of reports of potential liver toxicity, troglitazone was withdrawn from the market. Thomas Buchanan and his colleagues in Los Angeles, California, gave troglitazone (before it was withdrawn) to a group of women with gestational diabetes, who are certainly a high-risk group for developing future diabetes. Troglitazone-treated patients demonstrated a 60% reduction in the progression to type 2 diabetes. These results are certainly worthy of confirmation with pioglitazone and rosiglitazone.
Therefore, although more evidence may be needed, there appears to be a place for pharmacologic compounds, such as biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, in preventing the deterioration from IGT to type 2 diabetes.