The Troglitazone in the Prevention of Diabetes Study

The Troglitazone in the Prevention of Diabetes (TRIPOD) study evaluated 236 Hispanic women with gestational diabetes and a mean BMI of 30 kg/m2. This trial used 400 mg/day of troglitazone, and demonstrated a 55% relative risk reduction of diabetes with a number needed to treat of 15 patients for 2.5 years. The 121 women on placebo developed diabetes at a rate of 12% yearly, compared with 5% among the 114 that received troglitazone. Additionally, lowered plasma insulin levels were found in 89% of individuals on troglitazone. The decreased secretory demands on the P-cells caused by the reduction in insulin resistance not only delayed the development of diabetes, but preserved P-cell function (14).

An interesting observation from this study occurred with the removal of troglitazone from the market. This necessitated reapproval for use of a different glitazone (pioglitazone).

In an analysis of the 84 women who were still nondiabetic 8 months after the study medications had to be stopped, the rate of progression to type 2 diabetes was 21% in the placebo group and 3% in the troglitazone group, for a 92% risk reduction. This would not have been seen if the glitazone was simply masking the disease.

The role of glitazones in preventing diabetes and P-cell regeneration will be discussed in Chapter 6.

Clearly, these trials have demonstrated the important role of lifestyle changes including both diet and exercise in altering the progression of glycemic tolerance. Further discussion of the importance of these studies in outcome reduction for cardiovascular disease will be discussed in Chapter 12.

Currently, hemoglobin A1-C (glycated hemoglobin) or fructosamine are not advocated as screening tests for diabetes. The fructosamine measures the average blood sugar over a 2-week period, whereas the hemoglobin A1-C measures the average glucose over a 60-day period.

Various assays measure the hemoglobin A1-C (glycated hemoglobin) but they do not reflect the glucose level at the time the blood sample is tested. Thus, these measurements are more efficacious in guiding glycemic control on a long-term basis rather than a day-to-day basis. The process of glycation (glycosylation) refers to a protein/carbohydrate linkage. This process is irreversible and occurs as plasma combines with the hemoglobin component of red blood cells. These assays reflect average blood glucose concentration over a 2-3 months period because the lifespan of the red blood cells is approximately 120 days. Therefore, the amount of the circulating glucose concentration to which the red blood cell is exposed will affect the amount of the glycosylated hemoglobin (17).

In addition to its oxygen-carrying capacity, hemoglobin molecules allow the red blood cells to facilitate the flow of glucose into and out of the red blood cell. Muscle and liver cells possess insulin-controlled gated mechanisms, regulating the influx and efflux of glucose.

This is not the case with the red blood cell. The value of the A1-C is given as a percentage to indicate what percent of the A1-C molecules are linked to glucose. A variety of terms has been used to describe this test. These include "the glycosylated hemoglobin," "the glycated hemoglobin," and "the glycohemoglobin." Even the nomenclature has been changed recently to "A1-C" from "HbA1-C."

The process of glycosylation refers to the linkage of a molecule to a glycosyl group. This process can by facilitated by coenzymes. When accomplished nonenzymatically, the process is referred to as glycation. Glucose links itself to hemoglobin nonenzymatically.

It is important to understand that there are certain conditions that can interfere with the accuracy of the hemoglobin A1-C result. Falsely low concentrations can be present in those conditions that decrease the life of the red blood cell, such as sickle cell trait, excessive bleeding (particularly on a chronic basis), and hemolytic anemias. Falsely high concentrations are likely in situations that increase the lifespan of the red blood cell. This can be seen specifically in splenectomy states. Other conditions associated with a falsely elevated hemoglobin A1-C include persistence of fetal hemoglobin, uremia, high concentrations of ethanol, and high aspirin doses (> 10 g/day).

Regular monitoring of glycosylated hemoglobin is critical to follow the patient's progress and can be correlated with microvascular outcomes. The hemoglobin A1-C represents a sum of the fasting blood sugar and the postprandial sugars. Many individuals can present with elevated hemoglobin A1-C with normal fastings, indicating that the patient is having postprandial excursions to a significant degree (9).

Other proteins, however, are glycated and can be measured as an indicator of glycemic control. Serum proteins have a shorter half-life (17-20 days) compared with hemoglobin (50 days), thus, measurement of serum fructosamine represents a shorter amount of average glucose control (2-3 week). Fructosamine measurements can be useful for patients with gestational diabetes. Fructosamine units (micromoles per liter) can be correlated with levels of hemoglobin A1-C; a fructosamine of 320 ^mol/L is equivalent to an 8% hemoglobin A1-C, whereas 250 ^mol of fructosamine is equivalent to a hemoglobin A1-C of 10%.

Because the prevalence rate of type 2 diabetes increases dramatically with age, screening becomes an important part of the primary care physician's surveillance for this condition. For every diagnosed case of type 2 diabetes, 0.6 cases are undiagnosed according to the National Health and Nutrition Examination Survey-2 data. Glucose intolerance increases from approximately 9% at age 20-44 to 42% at age 65-74. Because the macrovascular complications of this disease develop with glucose tolerance, it is hoped that significant mortality and morbidity could be prevented with more aggressive early detection (18).

Recent data from the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe trial indicate that as many as one-third of diabetic patients can be missed by simply using a fasting blood sugar, because postprandial glucose elevations precede the development of fasting hyperglycemia. Therefore, the following patient types should be considered for diabetic screening with postprandial sugars:

1. Individuals who are equal to or greater than 140% of their ideal body weight.

2. Patients that have previously been identified as having impaired fasting or glucose tolerance.

3. Those individuals that are Hispanic, African American or other ethnic groups predisposed to diabetes.

4. Individuals with hypertension and hyperlipidemia, particularly those with elevated triglycerides, low HDL, and a preponderance of small, dense LDL.

5. Women with high-birthweight babies, equal to or greater than 9 lb (19).

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