At a session held during the AOA/ACOFP 105th Convention, a panel of experts discussed the epidemiology, pathophysiology, and treatment of type 2 diabetes.
This poster session was supported by an unrestricted educational grant from Bristol-Myers Squibb Company.
The Epidemiology of Diabetes and Its Chronic Complications
"Type 2 diabetes is increasing in prevalence," said Nathan Tolchin, DO, clinical professor of medicine, Upstate Medical University, Syracuse, New York. A recent study revealed a 33% increase in the prevalence of diabetes in the U.S. between 1990 and 1998 (Diabetes Care 2000;23:1278-1283). There are over 16 million diabetics in the U.S., 95% of whom have type 2 diabetes. Type 2 diabetes is primarily a disease of older adults, and it is associated with obesity.
Dr. Tolchin noted that diabetes is very expensive to treat, not only because of the metabolic abnormality but also the microvascular and macrovascular complications. Approximately 10% to 15% of Medicare patients have diabetes, and they consume about 25% to 30% of the total Medicare expenditures. "Medicare is paying the greatest share of the cost of treating diabetes in this country," said Dr. Tolchin.
Dr. Tolchin noted that diabetic patients with poor glycemic control suffer more acute and chronic complications than patients who are under tight control, and they therefore are more costly to treat. "It's the vascular complications that lead to the morbidity and mortality of the disease," said Dr. Tolchin.
Type 2 diabetes is caused by two main pathophysiologic defects: insulin resistance and abnormal insulin secretion. The insulin resistance in diabetic patients causes increased glucose production by the liver and inefficient glucose utilization by peripheral tissues. Initially, the pancreas responds by increasing insulin production in an attempt to overcome the insulin resistance. However, insulin secretion becomes increasingly inadequate as beta cell dysfunction progresses. By the time a patient is diagnosed with type 2 diabetes, hyperglycemia has most likely been going on for several years.
The vascular effects of diabetes are either microvascular or macrovascular. Diabetic nephropathy, the leading cause of end-stage renal disease, is a microvascular disease. Urinary albumin excretion represents a marker for this and other vascular diseases. Diabetic retinopathy, also a microvascular disease, is the primary cause of blindness in the U.S. "Hyper-glycemia appears to drive the microvascular complications," said
Dr. Tolchin.
Hyperglycemia leads to the production of advanced glycation end products (AGEs), which have been associated with vascular disease in diabetic patients. AGEs bind to receptors on various cell types, including endothelial cells, and may contribute to the development of vascular lesions. Glucose ties up with proteins of the blood vessel wall, which causes atherosclerotic damage to those blood vessels. "AGEs seem to facilitate the damage of microvascular disease," said Dr. Tolchin.
Studies have shown that microvascular complications can be reversed or prevented with tight glucose control. Dr. Tolchin cited the DCCT Trial in which type 1 diabetics who received an intensive insulin regimen had marked reduction in both retin-opathy and nephropathy (N Engl J Med 1993;329:977-986). A Japan-ese study looked at type 2 diabetes and found that intensive therapy reduced the incidence of retinopathy and nephropathy by keeping patients at a HbA1C level that is considered acceptable (less than 7%).
People with diabetes are also at increased risk for developing macro-vascular complications, including coronary artery disease, peripheral vascular disease, and stroke. The risk of coronary artery disease is increased two- to four-fold in people with type 2 diabetes; cardiovascular disease is the cause of death in almost 80% of these patients. Dr. Tolchin cited studies showing that hyperglycemia is an independent risk factor for macrovascular complications. "There's no question that hyperglycemia has an impact on the vascular damage in these patients," he said.
Dr. Tolchin also discussed the insulin resistance syndrome, which includes hypertension and hyperlipidemia. "The constellation of heart disease, hypertension, and diabetes has been the scourge of every practicing physician who treats these patients," said Dr. Tolchin. The combination of lipid abnormalities, hypertension, glucose abnormalities, and excess weight contribute to the development of macrovascular complications; all of these conditions must be addressed in the therapeutic program to effectively reduce mortality and morbidity.
Pathophysiology of Diabetes
Robert Green, DO, chief of family practice and chief of pharmacy and therapeutics, Hollywood Medical Center, and clinical instructor, Nova Southeastern College of Osteopathic Medicine, Hollywood, Florida, discussed the pathophysiology of diabetes, specifically beta cell dysfunction and insulin resistance.
Beta cell dysfunction as a cause of diabetes has been well known for many years. In the last five to seven years, insulin resistance has been further investigated and characterized. Insulin resistance is multifactorial, leading to excess glucose production by the liver, reduced glucose uptake by skeletal muscle, and excess lipolysis by adipose tissue, which results in hyperlipidemia. If untreated, these in concert launch an attack on the body's vasculature, which leads to an acceleration of atherosclerosis and a decrease in overall perfusion.
In a nondiabetic person, as plasma insulin levels rise, the glucose metabolism correspondingly elevates, thus metabolizing glucose and lowering blood sugar and feeding the cells of the body. Two distinct defects occur in a type 2 diabetic patient. First, insulin secretion is blunted, leading to impaired glucose metabolism and hyperglycemia. This is coupled with insulin resistance that occurs both peripherally and hepatically, also leading to marked hyperglycemia, which, if untreated, results in devastating end organ damage.
Being overweight can further complicate this process. At 20% above ideal body weight, insulin sensitivity can be approximately 50% of normal. At 150% over ideal body weight, insulin sensitivity is about 20% of normal. Therefore, maintaining proper weight is important for slowing the progression of, or even preventing, diabetes.
"Beta cell failure is a critical part of the equation that must be addressed," Dr. Green continued. When a normal person is given a glucose load, insulin is released by the pancreas within a few minutes, thus bringing the blood sugar down and returning plasma insulin levels to normal. When a type 2 diabetic is given a glucose load, there is no initial spike of insulin to help metabolize the glucose; plasma glucose does not return to baseline as it would in a normal person. "As beta cell function declines in the context of continued insulin resistance, both fasting postprandial plasma glucose levels become elevated," said Dr. Green. All patients with type 2 diabetes have both insulin resistance, which remains relatively constant, and beta cell dysfunction, which progressively worsens. The majority of patients eventually require multiple agents to maintain glycemic control.
"In order to achieve tight glucose control, we need to address the beta cell dysfunction and the insulin resistance concomitantly," said Dr. Green. When tight control is achieved, the risk of complications can be significantly reduced. "Tight control can be achieved with oral medications that are now available," concluded Dr. Green.
Treating the Metabolic Defects of Type 2 Diabetes
Lawrence Blonde, MD, director, Ochsner Diabetes Clinical Re-search Unit, Ochsner Clinic and Ochsner Medical Foundation, New Orleans, reviewed some new therapeutic approaches to potentially improve outcomes for patients with type 2 diabetes.
The American Diabetes Association has developed goals for glycemic control in patients with diabetes; these recommendations include a HbA1c of less than 7%. The current treatment paradigm for type 2 diabetes usually starts with diet and exercise; oral antidiabetic agents are added when nonpharmacologic interventions fail. Dr. Blonde noted that the United Kingdom Prospective Diabetes Study (UKPDS) found that only 20% of the diet policy participants were able to reach the goal of a fasting plasma glucose (FPG) of less than 270 mg/dL with diet alone (Lancet 1998;352:837-853). The other 80% required pharmacologic treatment.
"Diet and exercise remain cornerstones of treatment, but in most cases they alone won't succeed in achieving glycemic goals," said Dr. Blonde. Most patients will also require pharmacologic intervention to meet glycemic goals. He noted that over the last several years, several new treatments for type 2 diabetes have emerged. The current armamentarium includes insulin secretagogues, the alpha-glucosidase inhibitor agents that delay carbohydrate absorption, and two classes of insulin sensitizers-thiazolidinediones and the biguanide metformin.
Many clinicians initiate treatment of type 2 diabetes with medical nutrition therapy and exercise. If an acceptable HbA1c level is not achieved, monotherapy with metformin or a
sulfonylurea is usually initiated. However, many patients will not attain and/or maintain glycemic goals with monotherapy. "In the UKPDS fewer than 50% of patients had a HbA1c of less than 7% after three years, irrespective of the monotherapy agent they received," remarked Dr. Blonde.
Dr. Blonde then reviewed studies demonstrating the benefits of combining antidiabetic agents with complementary mechanisms of action. He cited a study by DeFronzo in which patients who were not at goal on glyburide alone were randomized to continued treatment with glyburide or metformin therapy or treatment with both glyburide and metformin (N Engl J Med 1995;333:541-549). Those switched to metformin had a minor improvement in glycemic control. However, when metformin was added to glyburide, there was a marked improvement in both HbA1c and FPG. Similar results have been seen with the combination of metformin and other sulfonylureas and with metformin and repaglinide. Thiazolidinediones can also be combined with sulfonylureas. An improvement in efficacy over either agent alone is also observed when a thiazolidinedione is added to metformin even though both agents are insulin sensitizers.
The explanation for this benefit is that the thiazolidinediones primarily enhance insulin sensitivity in adipose tissue and muscle whereas metformin has its greatest effect on insulin sensitivity in the liver. Thus combining the two agents provides added benefit. "You can also add one of the alpha glucosidase inhibitors to any of the other agents and get added benefit," said Dr. Blonde. The most frequently used antidiabetic combination is metformin plus one of the sulfonylureas.
A study by Harris and colleagues showed that 60% to 70% of patients on pharmacotherapy for type 2 diabetes have HbA1c levels above 7%, about 50% have a HbA1c above 8%, and 30% have values above 9% (Diabetes Care 1999;22:403-408). Furthermore, by the time a patient has sufficient hyperglycemia to diagnose type 2 diabetes, they manifest both insulin resistance and an insulin secretory deficit. "It's possible that earlier diagnosis and treatment that is designed to correct both of these dual impairments and that more vigorously attempts to meet glycemic targets using combination therapy earlier, or even from the outset may be more effective at meeting treatment goals," said Dr. Blonde.
Blonde described a prospective, randomized, double-blind study of a novel single-tablet glyburide/metformin combination conducted by Garber et al. (Abstr 432. Diabetes. 2000;49 (Suppl 1): A107). With a combination of metformin and glyburide, the metformin can decrease insulin resistance by increasing peripheral glucose uptake and decreasing hepatic glucose production, while the glyburide enhances insulin secretion.
"The two together can improve glycemic control," said Dr. Blonde. Eight hundred and six patients with type 2 diabetes and inadequate glycemic control on diet and exercise alone (with an FPG of 240 mg/dL or less and a HbA1c between 7% and 11%) were randomized to receive placebo, glyburide, metformin, or one of two doses of the glyburide/metformin combination (1.25 mg/250 mg or 2.5 mg/500 mg). The primary endpoint was mean change in HbA1c from baseline to week 20. The secondary endpoints were mean change in FPG, two-hour postprandial glucose, and glucose excursions (difference between FPG and the two-hour postprandial glucose).
Both glyburide and metformin were more effective than placebo and both glyburide/metformin doses were more effective than either agent used alone (see Table 1). After 20 weeks of double-blind therapy, more than two-thirds of patients treated with glyburide/metformin achieved an HbA1c less than 7%. Glyburide/metformin administration was associated with reductions in mean HbA1c of 1.48% and 1.53% for the lower and higher doses of glyburide/metformin, respectively. Both combination doses were associated with a greater reduction in two-hour postprandial glucose than with either monotherapy. "This reduction was a function of both reducing the FPG and the postprandial glucose excursion, so there was a lower value to begin with and then a diminished excursion after the meal," said Dr. Blonde. With the combination treatment, there was also a greater improvement in insulin secretion after the meal.
In terms of adverse events, there were no episodes of severe hypoglycemia reported for any group in the trial. The frequency of hypoglycemia was 11% for patients on the lowest dose combination, 21% for patients treated with glyburide alone, and 38% for patients on the highest dose combination. There were fewer gastrointestinal side effects with the lower dose combination than with metformin alone. Therefore, the study demonstrated that the use of a fixed dose glyburide/metformin combination agent can be a very effective therapeutic approach.
Dr. Blonde subsequently described a study that evaluated the use of glyburide/metformin in type 2 diabetic patients who were already on
monotherapy (with at least half maximal doses of a sufonylurea) but had not achieved adequate glycemic control. These patients had more severe hyperglycemia (mean baseline HbA1c 9.4% to 9.6%) and a longer duration of diabetes. Six hundred thirty- nine patients were randomized to receive glyburide (20 mg/day), metformin (500 mg to 2 g/day), or the glyburide/ metformin combination at one of two doses (2.5 mg/500 mg or 5 mg/500 mg) which were then titrated as necessary.
In terms of HbA1c, neither glyburide nor metformin offered a benefit for these patients who had already failed on at least half the maximum dose of a sulfonylurea. Both combinations achieved a marked improvement in HbA1c and FPG. There was a difference in mean HbA1c of 1.7% in favor of glyburide/metformin therapy over glyburide monotherapy, and a difference in mean HbA1c of 1.9% favoring the combination over metformin alone. Dr. Blonde noted that both combination doses worked equally well.
There was no adverse effect on lipids and mean weight gain was less than two pounds. The most common adverse effects were gastrointestinal. There were no reports of severe hypoglycemia.
Dr. Blonde concluded by describing an open label cohort of the first glyburide/metformin trial he discussed. One hundred seventy-three patients who did not qualify for the double-blind study because their lack of glycemic control prohibited them from participating in a study with a placebo arm (FPG > 240 mg/dL or HbA1c 11% to 12%) were treated with glyburide/metformin tablets. The mean HbA1c at baseline was 10.6%. After 13 weeks of glyburide/metformin treatment, the HbA1c was reduced by 3.45% to a value of 7.15 %. After 26 weeks the mean HbA1c value had declined further to a value of 7.09%. Mean FPG after 26 weeks was reduced by 121 mg/dL with glyburide/ metformin therapy.
In summary, improving outcomes for people with diabetes requires achieving and maintaining glycemic, blood pressure, and lipid goals. Type 2 diabetes continually worsens due to progressive beta cell failure and continued insulin resistance. In the majority of patients monotherapy fails to provide adequate glycemic control over time, necessitating addition of medications with complementary mechanisms of action. "Simultaneous rather than sequential administration of agents that address both insulin resistance and beta cell failure may be appropriate for a significant number of patients who do not get to goal with medical nutrition therapy and exercise," concluded Dr. Blonde.
.
All contents Copyright © 1999 - 2001 Medical Association Communications