Treatment for Centrally Obese Patients With Type 2 Diabetes
What is the best treatment strategy for centrally obese patients with type 2 diabetes who experience secondary treatment failure, ie, once dietary plus maximum therapeutic oral hypoglycemic agents fail to maintain glucose control, considering that insulin may worsen central obesity?
Shahid Mahmood, MD
More than 90% of patients with newly diagnosed type 2 diabetes are overweight or obese. Most of these patients have excessive amounts of central or visceral adipose tissue. In addition, because type 2 diabetes is a progressive disease, most patients will eventually experience beta-cell failure and require insulin therapy. Therefore, the situation described in the question is not uncommon and can be addressed from 3 different perspectives: improving the hyperglycemia, minimizing weight gain, and early intervention.
Once a patient reaches the point of secondary treatment failure, with persistent hyperglycemia despite dietary alterations and maximally effective doses of oral hypoglycemic agents, it is time to start insulin therapy. Obesity in general, and visceral obesity in particular, is associated with insulin resistance. The metabolic disturbances that accompany abdominal obesity include dyslipidemia, hypertension, and a prothrombotic and proinflammatory state. There is evidence that the dyslipidemia associated with visceral adiposity is more strongly linked to the development of atherosclerosis than the dyslipidemia of peripheral adiposity. Although the mechanism underlying this effect has not been clearly defined, visceral obesity has been associated with a greater increase in free fatty acids, which is manifested as hypertriglyceridemia. When combined with insulin resistance, as well as the altered glucocorticoid and sex-steroid metabolism associated with visceral adiposity, this leads to an increase in the concentration and density of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles. Therefore, patients with type 2 diabetes and visceral adiposity are at a higher risk for developing atherosclerosis. Beta-cell failure and hyperglycemia may accentuate this risk.
When the patient's glycemic control becomes unacceptable, it needs to be corrected. This usually requires adding insulin, which often is associated with weight gain. This can be a frustrating circle of events. Although the targets for glycemic control may be loosened somewhat in situations where rapid and dramatic weight gain is occurring, they nonetheless require close vigilance.
Sulfonylureas, glinides (nonsulfonylurea insulin secretagogues), thiazolidinediones (TZDs), and insulin can all promote weight gain. However, there are steps that can be taken to minimize the amount of weight gain.
In the United Kingdom Prospective Diabetes Study, sulfonylurea monotherapy was associated with approximately 5 kg of weight gain over the 6-year study, whereas insulin monotherapy was associated with the greatest amount of weight gain (approximately 10 kg). The data on TZDs are less clear. Although monotherapy with both rosiglitazone and pioglitazone has been associated with weight gain, this is diminished when TZDs are combined with other oral antidiabetic agents. In addition, it is not clear how much of the weight gain is due to pedal edema and increased plasma volume. Several studies have suggested that TZDs may cause a redistribution of adipose tissue, promoting a net reduction in visceral fat. This would be expected to lead to a reduction in insulin resistance.
The drug with perhaps the best long-term data on weight gain is metformin, which is believed to be weight-neutral at worst, with many patients experiencing a modest weight loss. When metformin is added to insulin, there is a tendency for patients to gain less weight and achieve comparable or better glycemic control than with insulin alone. The alpha-glucosidase inhibitors acarbose and miglitol are also thought to be weight-neutral, although the side effects of these agents often prevent their use in high doses.
Finally, a strong case can be made for early intervention. Significant endothelial dysfunction and insulin resistance can usually be seen well in advance of the diagnosis of type 2 diabetes. Because many antidiabetic therapies are also associated with weight gain, it makes good sense to include weight control as part of the treatment regimen early in the course of diabetes. Furthermore, weight control measures are especially important for nondiabetic patients at increased risk for developing diabetes. Improvements in insulin sensitivity, blood pressure, cholesterol, triglycerides, and mortality can be readily demonstrated in diabetic patients who achieve even modest degrees of sustained weight loss.
Data are lacking, however, for long-term outcomes beyond improved metabolic parameters. This question is being addressed by the Study of Health Outcomes of Weight Loss (SHOW), an National Institutes of Health-funded placebo-controlled trial to examine the long-term effects of weight control in patients with diabetes. In addition, there is growing evidence that type 2 diabetes can be prevented, or at least delayed by weight loss. The Diabetes Prevention Program showed a 58% reduction in the incidence of diabetes in high-risk individuals through intensive lifestyle interventions that led to an average 5.6-kg weight loss over 2.8 years. This was approximately twice the reduction in incidence that was observed in patients who received metformin. If lifestyle changes, with an emphasis on a modest weight reduction through diet and exercise, were prescribed for every patient with a body mass index > 25 kg/m, fewer patients would probably face the tough choices described in the question.
What is the best treatment strategy for centrally obese patients with type 2 diabetes who experience secondary treatment failure, ie, once dietary plus maximum therapeutic oral hypoglycemic agents fail to maintain glucose control, considering that insulin may worsen central obesity?
Shahid Mahmood, MD
More than 90% of patients with newly diagnosed type 2 diabetes are overweight or obese. Most of these patients have excessive amounts of central or visceral adipose tissue. In addition, because type 2 diabetes is a progressive disease, most patients will eventually experience beta-cell failure and require insulin therapy. Therefore, the situation described in the question is not uncommon and can be addressed from 3 different perspectives: improving the hyperglycemia, minimizing weight gain, and early intervention.
Once a patient reaches the point of secondary treatment failure, with persistent hyperglycemia despite dietary alterations and maximally effective doses of oral hypoglycemic agents, it is time to start insulin therapy. Obesity in general, and visceral obesity in particular, is associated with insulin resistance. The metabolic disturbances that accompany abdominal obesity include dyslipidemia, hypertension, and a prothrombotic and proinflammatory state. There is evidence that the dyslipidemia associated with visceral adiposity is more strongly linked to the development of atherosclerosis than the dyslipidemia of peripheral adiposity. Although the mechanism underlying this effect has not been clearly defined, visceral obesity has been associated with a greater increase in free fatty acids, which is manifested as hypertriglyceridemia. When combined with insulin resistance, as well as the altered glucocorticoid and sex-steroid metabolism associated with visceral adiposity, this leads to an increase in the concentration and density of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles. Therefore, patients with type 2 diabetes and visceral adiposity are at a higher risk for developing atherosclerosis. Beta-cell failure and hyperglycemia may accentuate this risk.
When the patient's glycemic control becomes unacceptable, it needs to be corrected. This usually requires adding insulin, which often is associated with weight gain. This can be a frustrating circle of events. Although the targets for glycemic control may be loosened somewhat in situations where rapid and dramatic weight gain is occurring, they nonetheless require close vigilance.
Sulfonylureas, glinides (nonsulfonylurea insulin secretagogues), thiazolidinediones (TZDs), and insulin can all promote weight gain. However, there are steps that can be taken to minimize the amount of weight gain.
In the United Kingdom Prospective Diabetes Study, sulfonylurea monotherapy was associated with approximately 5 kg of weight gain over the 6-year study, whereas insulin monotherapy was associated with the greatest amount of weight gain (approximately 10 kg). The data on TZDs are less clear. Although monotherapy with both rosiglitazone and pioglitazone has been associated with weight gain, this is diminished when TZDs are combined with other oral antidiabetic agents. In addition, it is not clear how much of the weight gain is due to pedal edema and increased plasma volume. Several studies have suggested that TZDs may cause a redistribution of adipose tissue, promoting a net reduction in visceral fat. This would be expected to lead to a reduction in insulin resistance.
The drug with perhaps the best long-term data on weight gain is metformin, which is believed to be weight-neutral at worst, with many patients experiencing a modest weight loss. When metformin is added to insulin, there is a tendency for patients to gain less weight and achieve comparable or better glycemic control than with insulin alone. The alpha-glucosidase inhibitors acarbose and miglitol are also thought to be weight-neutral, although the side effects of these agents often prevent their use in high doses.
Finally, a strong case can be made for early intervention. Significant endothelial dysfunction and insulin resistance can usually be seen well in advance of the diagnosis of type 2 diabetes. Because many antidiabetic therapies are also associated with weight gain, it makes good sense to include weight control as part of the treatment regimen early in the course of diabetes. Furthermore, weight control measures are especially important for nondiabetic patients at increased risk for developing diabetes. Improvements in insulin sensitivity, blood pressure, cholesterol, triglycerides, and mortality can be readily demonstrated in diabetic patients who achieve even modest degrees of sustained weight loss.
Data are lacking, however, for long-term outcomes beyond improved metabolic parameters. This question is being addressed by the Study of Health Outcomes of Weight Loss (SHOW), an National Institutes of Health-funded placebo-controlled trial to examine the long-term effects of weight control in patients with diabetes. In addition, there is growing evidence that type 2 diabetes can be prevented, or at least delayed by weight loss. The Diabetes Prevention Program showed a 58% reduction in the incidence of diabetes in high-risk individuals through intensive lifestyle interventions that led to an average 5.6-kg weight loss over 2.8 years. This was approximately twice the reduction in incidence that was observed in patients who received metformin. If lifestyle changes, with an emphasis on a modest weight reduction through diet and exercise, were prescribed for every patient with a body mass index > 25 kg/m, fewer patients would probably face the tough choices described in the question.
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