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New AACE Guidelines for Glycemic Control in Type 2 Diabetes: A Strategy for Success

Introduction

The new American Association of Clinical Endocrinologist (AACE) guidelines for the treatment of diabetes were developed to educate clinicians on the need for earlier detection and intervention of diabetes. Prior to the publication of these guidelines, the AACE polled several physicians and were surprised to find that many clinicians thought a A1C greater than 8% was when intervention should begin.“Well, that’s too late,” stated the chair of the symposium, Jaime A. Davidson, MD, FACE, Co-Chair, Diabetes Mellitus Consensus Conference, American College of Endocrinology Consensus Statement on Guidelines for Glycemic Control, adding “in the U.S. we already make the diagnosis of diabetes seven years too late and if we wait until the A1C is 8% or higher to do something, the complications and cost will be incredible.”

The guidelines state that normal preprandial glucose levels should be less than 110 mg/dL; normal 2-hour postprandial glucose levels less than
140 mg/dL; and A1C less than 6.5%. Combining these aggressive goals with a better screening procedure to detect high- risk patients can allow for earlier diagnosis and treatment.

The purpose of this symposium was to gather leaders in the field of diabetes to discuss the role that lifestyle modification and pharmacotherapy have in slowing or attenuating the progression of type 2 diabetes.

Diabetes Prevention Program: The Impaired Glucose Tolerance Component of the Diabetes Continuum

There are several risk factors for the development of type 2 diabetes, including obesity, physical inactivity, elevated fasting glucose levels, impaired glucose tolerance, age, race/ethnicity, previous gestational diabetes, and a family history of diabetes. Of these, obesity and physical inactivity are the two risk factors that can be modified and were the focus of the presentation by David Marrero, PhD, a principal investigator of the Diabetes Prevention Program (DPP).

Obesity: How Serious is theProblem and Can It Be Modified?
Over the past decade, surveys by the Centers for Disease Control (CDC) have shown a dramatic increase in obesity throughout the United States and it has been well established that “the larger the person, the more likely they are to develop type 2 diabetes,” said Dr. Marrero.

The primary goal of the DPP was to prevent or slow the development of type 2 diabetes in patients with documented impaired glucose tolerance (IGT). In this longitudinal study, 3,234 IGT patients (postprandial glucose, 140–199 mg/dL; fasting glucose, 95–125 mg/dL; BMI > 24 kg/m2; age >25 yrs) were randomized to one of 3 interventions: intensive lifestyle modification, metformin 850 mg BID, or placebo (a 4th intervention with troglitazone was discontinued secondary to idiosyncratic hepatotoxicity). The average BMI in this population was 34kg/m2.

The intensive lifestyle therapy was designed to achieve a 7% loss of body weight. This was attempted by keeping fat intake <25% of the total calories (1200–1800 kcal/day) in combination with increased physical activity (150 minutes/week). The program also included a 16 session course on diet, exercise, and behavioral modification skills. This was followed by 4 years of programs designed to encourage patients to maintain program goals. The intensive lifestyle maintenance phase included monthly contact with patients along with visits at least every 2 months. The results of this study found significant improvements in body weight, A1C, and number of minutes of leisure physical activity. More importantly, there was a significant reduction in the number of patients who progressed to type 2 diabetes. There was an overall 58% reduction in the development of diabetes in those patients randomized to intensive lifestyle modification while metformin therapy demonstrated a 31% reduction in the development of diabetes. Metformin therapy was particularly effective in patients < 60 years old while intensive lifestyle modification was particularly effective in patients greater than or equal to 60 years old (Figures 1, 2).

Based on this study and the Finnish Diabetes Prevention study, Dr. Marrero listed some of the techniques that have proven to be successful in obesity management, including:

• Behavioral modification
• Self-monitoring (food diary, body weight diary, exercise diary)
• Stimulus control (eat when hungry, stop when full, always eat at table, no unhealthy snack food, lay out exercise clothes)
• Cognitive restructuring (realistic goals, changing internal response to slip-ups)
• Stress management (outlets for stress other than eating, e.g., exercise, meditation, hobby)
• Social support (family, peer support groups)

In discussing diet and exercise with your patient, Dr. Marrero stressed the need to focus on health rather than numbers. Dr. Marrero said “a 290-pound man who met our goal still weighed 270 pounds,” adding “I think patients’ ideas of satisfactory weight loss are likely unattainable and we need to change their thinking about what is adequate weight loss especially when they’ve had a long history of obesity and dietary failure experiences.” Dr. Marrero also statedWhether these intensive lifestyle changes can be performed in a general practice setting is unclear. Dr. Marrero confessed that lack of insurance reimbursements and time constraints by the physician make this intervention difficult. However, Dr. Marrero was optimistic that a simple program where the patient is strongly encouraged to keep a diet/exercise diary, regular office visits, and work with nurses/dieticians can be very helpful.

Dr. Marrero concluded by stating that as clinicians, we need to be stronger advocates for insurance reimbursements, healthy menus in schools/workplaces, more physical education in schools, and pedestrian/ bicycle friendly communities, in order to make such interventions more successful.

 

Prediction of Cardiovascular Risk Using the UKPDS Risk Assessment Program

The principal investigator for the UK Prospective Diabetes Study (UKPDS), Rury Holman, FRCP, professor of Diabetic Medicine, Diabetes Trials Unit at the Oxford Center for Diabetes ,University of Oxford in Oxford, England provided the audience with a thorough discussion of the risk factors for coronary heart disease (CHD) in type 2 diabetes patients and how intervention can help reduce these risks.

Four of the risk factors for CHD in the non-diabetic population are often referred to as the deadly quartet (LDL-cholesterol, HDL-cholesterol, smoking, and blood pressure). In the type 2 diabetes, the same risk factors apply but the risk values are higher. Furthermore, there is a fifth risk factor, A1C (Figure 3).

The Importance of Reducing the Risk Factors for CHD
The UKPDS confirmed that statistically significant independent risk factors for CHD were an increase in LDL-cholesterol, a decrease in HDL-cholesterol, an increase in A1C, an increase in systolic blood pressure, and smoking. By improving these parameters in each individual, the risk of developing CHD can decrease greatly. For example, regression analysis has shown that a 1 mMol (39 mg/dL) decrement of LDL-cholesterol predicts a 29% risk reduction of CHD. An 0.1 mMol HDL-cholesterol increment (4 mg/dL) predicts a 9% risk reduction and a 1% decrement in A1C predicts a 14% decrease in risk of CHD.

A Model to Calculate the Risk of CHD in Type 2 Diabetics
There are several calculators available to estimate the risk of CHD risk in type 2 diabetes. The problem with most of these models is that the calculations are based on data from the Framingham Heart Study, which did not have many diabetic patients, nor were any measures of glycemia or diabetic duration included. In contrast, the UKPDS study had over 5,000 diabetic patients who were representative of a newly diagnosed type 2 diabetes population. A model was developed utilizing the data and is referred to as the UKPDS Risk Engine. The model was found to be robust when tested against actual data from the UKPDS, accurately predicting CHD and stroke rates for different levels of glycemia, blood pressure, and lipids. Using this model, a clinician can enter patient specific data (e.g., age, age at diagnosis, sex, ethnicity, smoking status, A1C, systolic blood pressure, total cholesterol, and HDL) to calculate CHD risk. As an example, a type 2 diabetic patient with A1C of 7%, blood pressure 140 mmHg, total cholesterol of 200 mg/dL, and HDL-cholesterol of 44 mg/dL, would have a 25% risk of developing CHD within the next 10 years and a 12% risk of stroke employing this model.

The clinical significance of this model is that the calculations can be shown to patients and the clinician can determine with the patient which risk factors should be addressed more aggressively to help reduce their risk of CHD.

Conclusion
Dr. Holman ended his presentation by stating that this model is specific for type 2 diabetes and should not be used for the general population, nor for patients with impaired glucose tolerance (IGT). This model is free and can be downloaded from the web (www.dtu.ox.uk/ riskengine). The UKPDS Risk Engine has wide applicability and will be of particular use to healthcare providers, insurers, planners, clinicians and patients.

Pathophysiological Approach to Achieving Optimal Glycemic Control

Type 2 diabetics have two major abnormalities. First, the amount of insulin which is secreted by the pancreatic beta cell is deficient and second, tissues are resistant to insulin, stated Dr. Ralph DeFronzo, professor of medicine and chief of the Diabetic Division and deputy director of the Diabetes Institute at the University of Texas Health Science Center at San Antonio, San Antonio, Texas and father of the glucose clamp technique. In early stages of the disease, the major problem is hyperinsulinemia as the beta cells increase insulin secretion in response to increased postprandial glucose levels. Eventually, beta cells become more dysfunctional and insulin secretion declines leading to a hyperglycemic state. During hyperinsulinemia, the strategy is to provide pharmacotherapy that improves insulin sensitivity and later as type 2 diabetes develops, adding drugs that augment insulin secretion.

Insulin Resistance in the Liver and Muscle
Patients with type 2 diabetes have markedly increased fasting insulin levels. Such levels should suppress hepatic gluconeogenesis but studies have shown hepatic glucose production increases. “As hepatic glucose production goes up, so goes up the fasting glucose,” said Dr. DeFronzo, adding “if you have a drug that doesn’t work on the liver, you probably don’t have a very good drug for the treatment of type 2 diabetes.” While the liver appears to drive morning fasting glucose levels, insulin resistance in the skeletal muscle affects postprandial hyperglycemia.

Treatment of Mild Type 2 Diabetes
“The key is to go after the fasting glucose concentration,” stated Dr. DeFronzo. Fasting glucose accounts for the majority of the glucose and furthermore, if a person begins each morning with abnormal fasting glucose levels, intervention becomes more difficult throughout the day. Therefore, treatment should generally begin the night before to insure that morning fasting glucose levels are close to normal. There are several oral agents available that can work at the beta cell (sulfonylurea; meglitinides), the liver (metformin; thiazolidinediones), and the muscle (thiazo- lidinediones; metformin).

According to Dr. DeFronzo, “metformin should be the first drug unless there’s some contraindication in the treatment of individuals with type 2 diabetes.” Metformin corrects the insulin resistance and hyperinsulinemia but it also lowers LDL-cholesterol and promotes weight loss to further lower the risk of CHD.

The sulfonylureas are similar to metformin in terms of efficacy but work directly on the beta cells by binding to the sulfonylurea receptor which stimulates insulin release. A newer drug (Glucovance) that combines the sulfonylurea glyburide with metformin has been shown to be highly effective as the two drugs appear to complement each other. “What seems to happen is the metformin is potentiating the effect of glyburide to kick out insulin,” said Dr. DeFronzo, and further stated that this is likely due to the preparation as well as “some kind of potentiating effect at the level of the beta cell.” The additive effect of the drugs allows the dose of each drug to be halved and still be more effective than component monotherapy at normal therapeutic doses.

Treatment of Moderate to Severe Diabetes
In persons who do not respond, or no longer respond, to other oral agents there are two options available for primary care physicians, and a third option for endocrinologists. First, you can add bedtime NPH insulin which will overcome the insulin resistance, lower hepatic glucose production, and lower the fasting glucose. The second option would be to add a third oral agent such as a thiazolidinedione. Dr. DeFronzo said this is the regimen preferred in his clinic and “we favor pioglitazone because it has a more favorable lipid profile.” Furthermore, the thiazolidinedione drugs can be safely added to the sulfonylureas and metformin. The third option would be to start insulin therapy.

Beta Cell Preservation
Studies with thiazolidinediones have shed some light on b-cell physiology during the course of diabetes. After 26 weeks of therapy with pioglitazone, the insulin sensitivity index is significantly improved. At the same time, the insulinogenic index, a measure of b-cell function, was also improved. The effect of glyburide/metformin combination therapy on insulin secretion and insulin sensitivity was studied in patients with poorly controlled type 2 diabetes. After 16 weeks of therapy, b-cell function in the glyburide/metformin group was also measured by the insulinogenic index, and was similar to that in the glyburide monotherapy group. The index was lowest in the metformin monotherapy group. Therefore, b-cell function in the glyburide/metformin tablet group was improved to the same degree as in the glyburide monotherapy group, although less than half the dose of sulfonylurea was used. This indicates that optimal glycemic control with glyburide/metformin tablets can improve b-cell function.

Conclusion
Treatment for type 2 diabetes must focus on the pathophysiological changes that are occurring during the progression of the disease. By using early treatment regimens that are designed to preserve beta cell function and decrease hepatic glucose output, the physician can improve the long term outcome of these patients and lower the risk of developing further complications associated with type 2 diabetes.

 

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