Type 2 Diabetes Outcomes

Both the degree and the duration of obesity are risk factors for type 2 diabetes ((1), (2)). The majority of patients with type 2 diabetes are obese ((3)). Diabetes incidence rates are steadily rising in this country, and some of the responsibility is clearly related to the increase in obesity that is also occurring ((4), (5), (6), (7)). Caloric restriction ((8)) and weight loss ((9), (10)) improve the hyperglycemia. Whether weight loss is successful and glycemia is decreased or whether it is not, obese patients with type 2 diabetes need to control the risk factors that lead to morbidity and mortality in this disease. For microvascular disease, the risk factor seems to be primarily the hyperglycemia. If this can be controlled, there are significantly fewer and less severe microvascular complications in patients with either type 1 or type 2 disease ((11), (12), (13), (14)). For macrovascular disease, the data are much less clear. The rate of cardiovascular disease (CVD) in type 2 diabetes patients is extremely high. Compared with their nondiabetic counterparts, the relative rate of CVD for men with diabetes is two to three, and for women with diabetes it is three to four ((15), (16), (17), (18), (19)). The annual risk of fatal and nonfatal CVD in middle-aged diabetic patients is 2% to 5% ((15), (20), (21), (22), (23), (24)). The risk for the effect of obesity on CVD is independent of the risk associated with other risk factors such as hypercholesterolemia, smoking, and hypertension ((25)). Large prospective epidemiological studies have consistently shown that in patients with diabetes, the higher the glucose, the higher the incidence of CVD ((26), (27), (28), (29), (30), (31), (32)). These studies suggest that the risk of a cardiovascular event rises by ∼10% to 30% for every 1% rise in hemoglobin A1c (HbA1c). Recent epidemiological studies have shown that the lower the glucose the lower the risk of CVD ((33), (34), (35)). In contrast to the evidence cited above, the possibility that glycemic control may worsen CV outcomes was raised by the feasibility phase of the Veterans Affairs Cooperative Study on Diabetes Mellitus (VACS-DM) trial, in which the intensive group had a nonsignificant change in the risk of CV events ((36)). This observation remains unexplained but may have been related to the short duration of this trial, the use of a sulfonylurea class drug (or of the sulfonyurea used, glipizide) in the intensive group but not in the conventional group, or the relatively few events. Nevertheless, it highlights residual uncertainty regarding the potential CVD benefits of glycemic control. As a result of the fact that obese patients with type 2 diabetes suffer from both microvascular and macrovascular disease, it is important to control all of the risk factors that could lead to the increased morbidity and mortality. With regard to glycemic control, the best marker to follow is the glycosylated hemoglobin, also referred to as glycated hemoglobin, glycohemoglobin (Ghb), HbA1c, or HbA1. It is a term used to describe a series of stable minor hemoglobin components formed slowly and nonenzymatically from hemoglobin and glucose. The rate of formation of Ghb is directly proportional to the ambient glucose concentration. Because erythrocytes are freely permeable to glucose, the level of Ghb of a blood sample provides a glycemic history of the previous 120 days, the average erythrocyte lifespan ((37)). Ghb most accurately reflects the previous 2 to 3 months of glycemic control. The Ghb has been shown to predict the risk for the development of many of the chronic complications in diabetes, analogous to using cholesterol determinations to predict the risk for development of cardiovascular disease ((11), (12), (13), (14)). Ghb values in patients with diabetes are a continuum: they range from normal in a small percentage of patients whose blood glucose levels are in or close to the normal range to markedly elevated values, e.g., 2- to 3-fold increases in some patients, reflecting an extreme degree of hyperglycemia. There is broad consensus that Ghb testing should be performed routinely in all patients with diabetes: first, to document the degree of glycemic control at initial assessment, and second, as part of continuing care ((38), (39), (40)). Measurement approximately every 3 months is required to determine whether a patient's metabolic control has remained continuously within the target range. Thus, regular measures of Ghb permit detection of departures from the target range in a timely fashion. For any individual patient, the frequency of Ghb testing should be dependent on the treatment regimen used and on the judgment of the clinician. In the absence of well-controlled studies that suggest a definite testing protocol, expert opinion recommends Ghb testing at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control) and more frequently (quarterly assessment) in patients whose therapy has changed or are not meeting glycemic goals ((41)). Specific treatment goals should be individualized, but one must take into account the results of studies, such as the Diabetes Control and Complications Trial (DCCT), showing a direct relationship between Ghb values and the risk of many of the chronic complications of diabetes ((11)). The American Diabetes Association recommends that “the goal of therapy should be an A1c of <7% and that the physician should reevaluate the treatment regimen in patients with A1c values consistently >8%. Again, these specific A1c values apply only to assay methods that are certified as traceable to the DCCT reference method” ((41)). The DCCT was the first major multicenter randomized clinical trial that showed that improving long-term glycemic control in type 1 diabetes ((11)) reduced the long-term complications. These included microvascular complications: retinopathy, neuropathy, and kidney disease. The study was not powered to show the effect of macrovascular complications. The United Kingdom Prospective Diabetes Study (UKPDS) was the second large multicenter randomized clinical trial investigating the relationship between tight control and complications in type 2 patients ((9), (42)). Again, it showed a decreased incidence of microvascular diabetic complications in patients on tight glucose control. It was also not powered to show a macrovascular effect in terms of number of years of follow-up and number of patients followed. Two smaller studies in type 2 patients are worth reporting. The first is a randomized clinical trial done in Japan, showing that tight glucose control significantly decreased the incidence of microvascular complications of type 2 diabetes (although these were not obese patients) ((43)). The second was a Scandinavian study reporting the same thing ((13)). All of these randomized clinical trials used HbA1c as the marker of good glucose control. The appearance or progression of microvascular events were decreased in the intensively treated patients. Specifically, retinopathy, neuropathy, and nephropathy were significantly improved. However, macrovascular events (myocardial infarction, congestive heart failure, and stroke) improvement did not reach significance. Thus, whereas Ghb is the primary outcome marker recommended for use in assessing the degree of glucose control of a diabetic patient, other markers must also be followed. These are markers that point to the progression of macrovascular disease, which is the primary cause of the mortality in type 2 diabetic patients. The additional outcome markers that need to be used in following obese diabetic patients, in addition to Ghb, are weight, waist circumference, blood lipids, blood pressure, and albuminuria. As mentioned above, obesity is a risk factor for the development of type 2 diabetes ((1), (2)), and in patients already diagnosed, it makes their disease more severe ((6)). Weight loss leads to an improvement of glucose control ((8), (9), (10)) and is an accepted standard of care for treatment of the disease. Patients should try to lose weight and maintain a body mass index below 25 kg/m2 whenever possible ((44), (45), (46)). Central body fat distribution has been found to be an independent risk factor for the development of type 2 diabetes ((47), (48)) and of cardiovascular disease ((49), (50)). The impact of fat distribution is independent and additive to the impact of total fat burden ((51), (52)). A reduction of central fat improves diabetes control ((52)). Diabetic women should aim to maintain waist circumference below 35 inches and diabetic men below 40 inches ((45)). The typical blood lipid abnormalities shown by patients with diabetes are an increase in triglycerides and a decrease in high-density lipoprotein-cholesterol (HDL-C) ((53)). Low-density lipoprotein-cholesterol (LDL-C) may be elevated but is often normal ((53), (54)). However, even when LDL-C is not elevated, the LDL particles are smaller and denser (so-called phenotype B) ((55)), and these particles are much more atherogenic ((56)). As a result, blood lipid levels should be controlled in diabetic patients ((57)). Primary therapy should be directed first at lowering LDL-C concentrations to levels recommended for patients with preexisting coronary heart disease (CHD; ≤100 mg/dL) ((57), (58), (59)). Triglycerides should be lowered to ≤ 200 mg/dL, and an effort should be made to try to increase HDL-C to >35 mg/dL in women and >45 mg/dL in men ((57), (58)). The prevalence of hypertension increases with increasing weight ((60), (61)). Persons with type 2 diabetes are often hypertensive, and figures from the second National Health and Nutrition Examination Study (NHANES) indicate a prevalence of ∼25% among type 2 diabetic patients 20 to 44 years, 48% among those 45 to 64 years, and 58% among those of 65 to 74 years((62)). The control of blood pressure is crucial to prevention of complications in diabetes ((63)). Diabetes increases the risk of cardiovascular events 2- to 6-fold higher at every level of systolic blood pressure or diastolic blood pressure ((64)). In diabetic persons there is a graded increase in risk across the entire range of blood pressure ((15)). Therefore, diabetes and hypertension combined confer a much higher risk than either one alone. In part because of this higher risk, even at high-normal levels of blood pressure, the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure VI (JNCVI) recommended beginning drug treatment in diabetic patients if the systolic blood pressure is >130 mm Hg or the diastolic blood pressure is >85 mm Hg ((65)). The United Kingdom Prospective Diabetes Study has shown that morbidity and mortality can be greatly reduced if blood pressure is controlled ((63)). The goal for blood pressure control is therefore recommended to be 130 mm Hg systolic and 80 mm Hg diastolic ((65)). Microalbuminuria is usually the first sign of renal complications in a diabetic person. Increasing albuminuria is predictive of both the incidence of CAD and of mortality ((66), (67)). The level of microalbuminuria is therefore a good marker of subsequent heart disease, as well as renal disease. As such, it is a very good measurement to follow with regard to adequate metabolic control of diabetes ((67), (68)). Diabetes patients should have a dilated eye exam done once a year by a qualified practitioner to assess for retinopathy. Also, a comprehensive foot exam should be done a minimum of once per year to check for any vascularity, neuropathy, joint changes, toe nail infections, and possible ulcers. Obesity is closely associated with type 2 diabetes and as a result the majority of diabetic patients are obese. To manage obese diabetic patients adequately, a number of markers of disease and mortality outcomes must be followed routinely. These include glycated hemoglobin, blood pressure, lipids, weight, waist circumference, and microalbuminuria. Partly supported by NIH Grant DK26687.