Prevention Or Delay Of Type Diabetes

Prevention efforts may start with promotion of healthy lifestyle and appropriate screening in those at higher risk: individuals > 45 years of age and those with a BMI > 25 kg/m2 (22). Screening should also be considered for people who are <45 years of age and are overweight if they have another risk factor for diabetes: physical inactivity, first-degree relative with diabetes, members of high-risk ethnic populations (e.g., African American, Latino, Native American, Asian American, Asian American, and Pacific Islander), women who delivered a baby weighing > 9 lb or were diagnosed with gestational diabetes, hypertension, low HDL cholesterol, high triglycerides, women with polycystic ovarian syndrome, IGT, or IFG on previous testing, other clinical conditions associated with insulin resistance (e.g., severe obesity and acanthosis nigricans), and history of cardiovascular disease (CVD). Repeat testing may be carried out at 3-year intervals.

Lifestyle modification (i.e., weight loss through diet and increased physical activity) has proven effective in reducing incident T2D in high-risk groups. The Da Qing Study (China) randomly allocated 33 clinics (557 persons with IGT) to 1 of 4 study conditions: control, diet, exercise, or diet plus exercise (23). Compared with the control group, the incidence of diabetes was reduced in the three intervention groups by 31, 46, and 42%, respectively, and with a modest weight loss in study participants. The Finnish Diabetes Prevention Study evaluated 522 obese persons with IGT randomly allocated on an individual basis to a control group or a lifestyle intervention group that emphasized physical activity, weight loss, limited total dietary intake and intake of saturated fat, and increased intake of dietary fiber (24). During the trial, the incidence of diabetes was reduced by 58% in the lifestyle group compared with the control group. The US Diabetes Prevention Program is the largest trial of primary prevention of diabetes to date and was conducted at 27 clinical centers with 3,234 overweight and obese participants with IGT randomly allocated to 1 of 3 study conditions: control, use of metformin, or intensive lifestyle intervention (25). The goal of lifestyle intervention was to achieve and maintain 7% or greater weight loss through a low-calorie, low-fat diet and 150 or more minutes of moderate physical activity weekly. Nearly half the participants were African American, Hispanic American, Asian American, or Native American. Over 3 years, the incidence of diabetes was reduced by 31% in the metformin group and by 58% in the lifestyle group; the latter value is identical to that observed in the Finnish Study. To prevent 1 case of diabetes, only 7 patients needed to be treated with lifestyle change, compared with 14 patients treated with met-formin. The magnitude of risk reduction in the lifestyle intervention group was similar across all ethnic groups, and participants in all age and BMI subgroups achieved a clinically significant reduction in risk. In contrast, met-formin was relatively ineffective in older and less obese participants.

Type 2 diabetes prevention trials using other forms of pharmacological therapy have also reported a significant lowering of the incidence of diabetes. The a-glucosidase inhibitor acarbose reduced the risk by 32% in the STOP-NIDDM trial (26), and the thiazolidinedione troglitazone reduced the risk by 56% in the TRIPOD Study (27).

More recently, the investigators from the DREAM trial, a study in 5,269 adults with IGT, IFG, or both and no previous CVD were recruited from 191 sites in 21 countries and randomly assigned in a 2-by-2 factorial design to receive rosiglitazone 8 mg/day and/or ramipril 15 mg/day. There was no statistical evidence of an interaction between the ramipril and the rosiglita-zone arms. After a mean follow-up of 3 years, the use of ramipril did not reduce the incidence of diabetes (28), while the treatment with rosiglitazone reduced by almost 60% the incidence of T2D and increased the likelihood (+70%) of regression to normoglycemia (29).

Whether diabetes prevention strategies also ultimately prevent the development of diabetic vascular complications is unknown, but cardiovascular risk factors are favorably affected (30). Preventive strategies that can be implemented in routine clinical settings have been developed and evaluated. Widespread application has, however, been limited by local financial considerations, even though cost-effectiveness might be achieved at the population level.

MANAGEMENT Prevention of Complications

Chronic poor glycemic control is associated with the development of diabetic vascular complications, including microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (coronary, cerebrovascular and peripheral vascular disease). CVD is the cause of 65% of deaths in patients with T2D (31).Epidemiologic studies have shown that the risk of a myocardial infarction (MI) or CVD death in a diabetic individual with no prior history of CVD is comparable to that of an individual who has had a previous MI (32, 33).

Microvascular complications can be delayed or prevented by maintaining excellent chronic glycemic control, as has been demonstrated in a number of interventional trials, including the Diabetes Control and Complications Trial (DCCT), the United Kingdom Prospective Diabetes Study (UKPDS), the Kumamoto Study, and the Stockholm Diabetes Intervention Study (34-39). Further, even in acute illness, several studies have shown that intensive insulin therapy and improved glycemic control are associated with better outcomes (40, 41).

Intensive glycemic control also results in reduced macrovascular complications, i.e., CVD, as demonstrated in a number of epidemiological studies (42-44). From the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study of type 1 diabetes, it is clear that intensive glycemic control prior to the onset of vascular disease has long-term beneficial effects on the risk of CVD in this population (45). Patients with newly diagnosed T2D, aged 25-65 years at baseline, whose HbAlc was reduced from 7.9 to 7% in the UKPDS, did not exhibit a reduction in cardiovascular events, although a subgroup of patients treated with metformin showed a trend to a lower incidence of events (46). However, 10-year follow-up data from this study showed persistence of microvascular benefits and long-term appearance of macrovascular benefits in the insulin and sulfonylurea groups despite the fact that the differences in HbAlc between the groups had disappeared (47).

Three recent trials in older adults with T2D have assessed the effect of lowering blood glucose to near-normal levels on cardiovascular risk. First, patients in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (n = 10,251) had a mean age of 62.2 years at entry and 10 years of diabetes duration. Sixty-two percent were men, and 30% had prior macrovascular disease and a baseline median HbA1c level of 8.1% (48). Study patients were assigned to receive intensive therapy (median HbA1c level achieved of 6.4%) or standard therapy (median HbA1c level achieved of 7.5%). After a median follow-up of 3.4 years, compared to the standard-therapy group, those in the intensive-therapy group had higher overall mortality (4% vs. 5%) and cardiovascular mortality (1.8% vs. 2.6%) and greater-number of hypoglycemic events (1% vs. 3.1%). Second, patients in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study (n = 11,140) had a mean age of 66 years at entry and 8 years of diabetes duration. Fifty-seven percent were men and 32% had prior macrovascular disease and a baseline median HbA1c level of 7.2% (49). Study patients were assigned to receive intensive therapy (median HbAlc level achieved of 6.4%) or standard therapy (median HbAlc level achieved of 7%). After a median follow-up of 5 years, compared to the standard-therapy group those in the intensive-therapy group achieved a reduction in the incidence of nephropathy (5.2% vs. 4.1%), although severe hypoglycemia was more common (1.5% vs. 2.7%). There were no differences in overall mortality (9.6% vs. 8.9%), cardiovascular mortality (5.2% vs. 4.5%), or major macrovascular events (10.6% vs. 10%). Finally, patients in the Veterans Affairs Diabetes Trial (VADT) (n = 1,792) had a mean age of 60.4 years at entry and 11.5 years of diabetes duration. Ninety-seven percent were men and 40% had prior macrovascular events and a baseline mean HbA1c level of 9.4% (50). They were assigned to receive intensive therapy (median HbA1c level achieved of 6.9%) or standard therapy (median HbA1c level achieved of 8.4%). After a median follow-up of 6 years, there was no significant difference in the rate of the composite primary endpoint (MI, congestive heart failure, invasive revascularization, inoperable coronary artery disease, amputation for ischemia, stroke, or cardiovascular death) between the intensive- and the standard-therapy groups (25.9% vs. 29.3%, p = 0.12). Fewer cardiovascular events than expected were observed in both groups, in part because of the aggressive management of blood pressure (reduction from 131/77 to 127/70 mmHg) and lipids (LDL-cholesterol and triglycerides fell from 106 and 157 mg/dl to 78 and 135 mg/dl, respectively, while HDL rose from 34 to 40 mg/dl) as well as lifestyle changes (40-57% exercised regularly, 60-68% adhered to diet, and cigarette smoking was reduced from 16% to 10%) and the increased use of antiplatelet/anticoagulants (from 76% at entry to 92% at the end of the study). Intensive therapy was associated with lower risk of the primary endpoint only in those with diabetes for less than 15 years and those who had low arterial calcium (AC) scores (AC < 100). Severe hypoglycemia requiring medical assistance was higher than expected and more frequent in the intensive than in the standard group (21.1% vs. 9.7%, p < 0.01). In fact, hypoglycemic events that led to impaired or loss of consciousness were independent predictors of major cardiovascular events and cardiovascular and total mortality.

Glycemic Goals

Based on results from clinical trials of glycemic control and the impact on diabetic microvascular complications, recommendations for targets of glycemic control have been put forth (1). Glycemic control is fundamental to the management of diabetes. The HbAlc is the most accepted indicator of chronic control, reflecting fasting and postprandial glucose concentrations. The goal of therapy is to achieve an HbAlc as close to normal

Table 2 Glycemic goals

HbAlc goal for patients in general <7% HbAlc goal for the frail elderly patient <8% Pre-prandial capillary plasma glucose* 90-130 mg/dl Peak postprandial capillary plasma glucose* <180 mg/dl

* Capillary plasma glucose = fingerstick glucose.

Adapted from American Diabetes Association (1) and Brown et al. (75).

as possible in the absence of hypoglycemia. Recommended glycemic goals for non-pregnant individuals are shown in Table 2. Less stringent treatment goals may be appropriate for patients with limited life expectancies and in individuals with co-morbid conditions (51). Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals.

Nutrition and Physical Activity

Overweight and obesity are strongly linked to the development of T2D and can complicate its management. Moderate weight loss improves glycemic control and reduces CVD risk. Therefore, weight loss is an important therapeutic strategy in all overweight or obese individuals who have T2D. All patients with diabetes should be encouraged to maintain a healthy lifestyle by exercising and following an appropriate diet (52). The primary approach for achieving weight loss is therapeutic lifestyle change, which includes a reduction in energy intake and an increase in physical activity.

Oral Antidiabetic Agents

A variety of antidiabetic pharmaceutical agents for the treatment of T2D are available, which target different mechanisms in the underlying pathogenesis of the disease (53-56) (Fig. 2). There are five categories of oral agents on the market, which can be used initially in most cases of T2D, until insulin deficiency becomes severe and insulin replacement is required. Sulfonylureas and the glitinides (repaglinide, nateglin-ide) are insulin secretagogues that stimulate release of insulin from the P-cells of the pancreas. Metformin, a biguanide, improves insulin sensitivity chiefly by reducing insulin resistance in the liver, thereby decreasing hepatic glucose production. The thiazolidinediones (rosiglitazone, pioglita-zone) improve insulin sensitivity primarily in the muscle, thereby increasing peripheral uptake and utilization of glucose. The a-glucosidase inhibitors (acarbose) prevent the breakdown of carbohydrates to glucose in the gut, by

Increased by: Sulfonylureas, Glitinides Insulins Exenatide

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