Importance of Identifying the Overweight Patient Who Will Benefit the Most by Losing Weight

Public awareness of the untoward effects of excess weight has not led to an effective approach for dealing with the problem. Perhaps the problem should be looked at from a different perspective that examines the nature of the relationship between overweight and obesity and the development of coronary heart disease, type 2 diabetes, and hypertension. All three of these conditions are characterized by resistance to insulin-mediated glucose disposal (1, 2). Furthermore, the hyperinsulinemia that is associated with insulin resistance has been shown to be an independent predictor of these syndromes (3). Because overweight and obese individuals tend to be insulin resistant and become more insulin sensitive with weight loss (4), it is often assumed that obesity equals insulin resistance. However, studies in Pima Indians and persons of European ancestry demonstrated that physical fitness was as powerful a modulator of insulin resistance as was body weight; each variable accounted for approximately 25% of the differences in insulin-mediated glucose disposal in nondiabetic persons (5). The strongest evidence that insulin resistance is not a simple function of overweight and obesity comes from the report from the European Group for the Study of Insulin Resistance (6). The researchers analyzed specific measures of insulin resistance in 1146 nondiabetic, normotensive volunteers and found that only about 25% of the volunteers who were obese were classified as insulin resistant. Parenthetically, neither waist circumference nor waist-to-hip ratio was related to insulin sensitivity after adjustments for age, sex, and body mass index (BMI). However, the conclusion that approximately 75% of obese persons were not classified as insulin resistant does not imply that they were free of health-related problems. The view that overweight and obese persons are at increased risk for type 2 diabetes, hypertension, and coronary heart disease as a result of insulin resistance is supported by results from prospective intervention studies indicating that improved insulin sensitivity and the associated metabolic benefits are limited to persons defined as being insulin resistant before losing weight (7-10). For example, in a 12-month study of weight loss (10) in overweight persons classified as being either insulin resistant (high triglyceride and low high-density lipoprotein [HDL] cholesterol concentrations) or insulin sensitive (low triglyceride and high HDL cholesterol concentrations), a weight lossassociated decrease in plasma insulin concentration and an improvement in dyslipidemia were confined to the insulin-resistant group. Evidence that not all overweight and obese persons are insulin resistant (5-10) and that the metabolic benefits from weight loss are predominantly seen in those who are defined as being insulin resistant before losing weight [7-10] suggests that strategies to overcome the untoward health-related effect of overweight and obesity become more focused. A decision to begin treatment efforts by stratifying overweight and obese persons by their degree of insulin resistance and to emphasize disease risk reduction rather than simple weight loss requires 1) the ability to recognize the appropriate subpopulation of obese persons in a relatively straightforward manner and 2) evidence that weight loss in this selected group will be of clinical benefit. Identifying Overweight Persons Who Are Insulin Resistant The importance of identifying insulin-resistant persons to be the focus of weight-loss programs is supported by the results of two prospective studies that measured insulin-mediated glucose disposal. The studies found that persons in the upper tertile of insulin-mediated glucose disposalthat is, the most insulin-resistant personswere at a statistically significantly increased risk for developing type 2 diabetes, coronary heart disease, or hypertension (11, 12). Another prospective study (3) showed that when insulin was used as a surrogate measure of insulin resistance, all three syndromes developed to a substantially greater degree in the 25% of the population with the highest insulin levels. Directly quantifying insulin-mediated glucose disposal is not clinically practical, and plasma insulin measurements are not standardized. However, once focus is shifted to the downstream consequences of insulin resistance and hyperinsulinemia, the task becomes simpler. A BMI greater than 25.0 kg/m2 is currently used to define being overweight; a BMI greater than 30.0 kg/m2 merits the designation of obese. Based on these definitions, it would be prudent to evaluate any person with a BMI greater than 25.0 kg/m2 for the manifestations of insulin resistance. Persons with a BMI greater than 27.0 kg/m2 are considered to be at such great risk that antiobesity drugs approved by the U.S. Food and Drug Administration can be prescribed. These persons certainly require risk factor evaluation. In the presence of a family history of type 2 diabetes, hypertension, or coronary heart disease, identifying risk factors is even more imperative. There are no unequivocal cut-points for identifying overweight persons most likely to be at increased risk for type 2 diabetes, coronary heart disease, and hypertension. However, several simple measurements described in the following sections can provide considerable clinical insight. Dyslipidemia People who are insulin resistant have a characteristic atherogenic lipoprotein profile, including a high plasma triglyceride and a low HDL cholesterol concentration (1, 2, 13), a shift in the diameter of the low-density lipoprotein (LDL) particles (14), and an increase in the postprandial accumulation of remnant lipoproteins (15, 16). Although LDL particle diameter and postprandial lipemia cannot be routinely determined, plasma triglyceride and HDL cholesterol concentrations are measured by reasonably well-standardized methods. Plasma triglyceride concentrations will usually be greater than 1.7 mmol/L (>150 mg/dL) (1, 2) in insulin-resistant persons; when this level is exceeded, LDL particles become smaller and denser (17) and the postprandial accumulation of remnant lipoproteins becomes accentuated (16). Thus, once the plasma triglyceride concentration exceeds 1.7 mmol/L (150 mg/dL), three of the four atherogenic lipoprotein abnormalities associated with insulin resistance are probably present. A low HDL cholesterol concentration is the fourth lipoprotein abnormality in insulin-resistant and hyperinsulinemic persons; a value less than 1.04 (<40 mg/dL) is associated with both the insulin resistance syndrome (1, 2) and increased risk for coronary heart disease (18). Thus, overweight persons with a triglyceride concentration greater than 1.70 mmol/L (>150 mg/dL) and an HDL cholesterol concentration less than 1.04 mmol/L (<40 mg/dL) are almost certainly insulin resistant to the degree that predicts substantial clinical benefit with weight loss. Although both a high triglyceride and a low HDL cholesterol concentration have been identified as risk factors for coronary heart disease (18, 19), the ratio of their plasma concentrations may be an even more useful predictor. Thus, the observation (20) that the triglyceride-to-HDL cholesterol concentration ratio was as powerful a predictor of coronary heart disease as the more conventional ratios of LDL cholesterol to HDL cholesterol or total cholesterol to HDL cholesterol is supported by evidence that the risk for ischemic heart disease was much greater when the conventional risk factors (high LDL cholesterol concentration, hypertension, smoking, and physical inactivity) were associated with a high triglyceride-to-HDL cholesterol concentration ratio (21). Evidence also shows that the untoward effects of these four conventional risk factors were substantially attenuated in persons with a low triglyceride-to-HDL cholesterol ratio. Hypertension Because only about 50% of hypertensive patients are insulin resistant and hyperinsulinemic (22), the presence or absence of hypertension is not as powerful a predictor of insulin resistance as is a high triglyceride and low HDL cholesterol concentration. However, patients with high blood pressure who are at greatest risk for coronary heart disease have the characteristic lipoprotein profile of the insulin resistance syndrome (23, 24). A high triglyceride (>1.70 mmol/L [>150 mg/dL]) and a low HDL cholesterol (<1.04 mmol/L [<40 mg/dL]) concentration in an overweight person with hypertension identifies a person who is both insulin resistant and at greatly increased risk for coronary heart disease and one who needs intensive intervention. Glucose Intolerance Although insulin resistance is the basic defect in patients with type 2 diabetes, most insulin-resistant persons can maintain the degree of compensatory hyperinsulinemia needed to prevent gross decompensation of glucose homeostasis. In patients with a normal fasting plasma glucose concentration (<6.11 mmol/L [<110 mg/dL]), a plasma glucose concentration 120 minutes after a 75-g oral glucose load greater than 11.1 mmol/L (200 mg/dL) is diagnostic of type 2 diabetes; a value of 7.77 to 11.1 mmol/L (140 to 200 mg/dL) indicates impaired glucose tolerance (25). In both instances, it is highly probable that the glucose intolerance will be associated with insulin resistance, hyperinsulinemia, and the atherogenic lipoprotein profile characteristic of the insulin resistance syndrome. Fasting plasma glucose concentration is a less sensitive guide to the presence or absence of insulin resistance, and a normal fasting plasma glucose concentration (<6.11 mmol/L [<110 mg/dL]) does not mean that a person is insulin sensitive. A fasting plasma glucose concentration greater than 6.99 mmol/L (>126 mg/dL) is diagnostic of type 2 diabetes (25) and almost certainly identifies an insulin-resistant person. Patients with a fasting plasma glucose concentration between 6.11 and 6.99 mmol/L (110 and 126 mg/dL) are classifi