Prevention - Delay of Type 2 Diabetes

Recommendations

* Individuals at high risk for developing diabetes need to become aware of the benefits of modest weight loss and participating in regular physical activity. (A)
* Patients with IGT should be given counseling on weight loss as well as instruction for increasing physical activity. (A)
* Patients with IFG should be given counseling on weight loss as well as instruction for increasing physical activity. (E)
* Follow-up counseling appears important for success. (B)
* Monitoring for the development of diabetes in those with pre-diabetes should be performed every 1??2 years. (E)
* Close attention should be given to, and appropriate treatment given for, other CVD risk factors (e.g., tobacco use, hypertension, dyslipidemia). (A)
* Drug therapy should not be routinely used to prevent diabetes until more information is known about its cost-effectiveness. (E)

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Studies have been initiated in the last decade to determine the feasibility and benefit of various strategies to prevent or delay the onset of type 2 diabetes. Five well-designed randomized controlled trials have been reported. The strategies shown to be effective in preventing diabetes relied on lifestyle modification or glucose-lowering drugs that have been approved for treating diabetes.

In the Finnish study, middle-aged obese subjects with IGT were randomized to receive either brief diet and exercise counseling (control group) or intensive individualized instruction on weight reduction, food intake, and guidance on increasing physical activity (intervention group). After an average follow-up of 3.2 years, there was a 58% relative reduction in the incidence of diabetes in the intervention group compared with the control subjects.

In the Diabetes Prevention Program (DPP), enrolled subjects were slightly younger and more obese but had nearly identical glucose intolerance compared with subjects in the Finnish study. About 45% of the participants were from minority groups (e.g., African American, Hispanic), and 20% were 60 years of age. Subjects were randomized to one of three intervention groups, which included the intensive nutrition and exercise counseling ("lifestyle") group or either of two masked medication treatment groups: the biguanide metformin group or the placebo group. The latter interventions were combined with standard diet and exercise recommendations. After an average follow-up of 2.8 years, a 58% relative reduction in the progression to diabetes was observed in the lifestyle group and a 31% relative reduction in the progression of diabetes was observed in the metformin group compared with control subjects. On average, 50% of the lifestyle group achieved the goal of 7% weight reduction and 74% maintained at least 150 min/week of moderately intense activity. In the troglitazone arm of the DPP (discontinued after a mean of 0.9 years when the drug was withdrawn from the market), troglitazone markedly reduced the incidence of diabetes during the period the drug was given.

In the Da Qing Study, men and women from health care clinics in the city of Da Qing, China, were screened with OGTT, and those with IGT were randomized by clinic to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. Subjects were reexamined biannually, and after an average of 6 years?? follow-up, the diet, exercise, and diet plus exercise interventions were associated with 31, 46, and 42% reductions in risk of developing type 2 diabetes, respectively.

Three other studies, each using a different class of glucose-lowering agent, have shown a reduction in progression to diabetes with pharmacological intervention. In the Troglitazone in Prevention of Diabetes (TRIPOD) study, Hispanic women with previous GDM were randomized to receive either placebo or troglitazone (a drug now withdrawn from commercial sale in the U.S. but belonging to the thiazolidinedione [TZD] class). After a median follow-up of 30 months, troglitazone treatment was associated with a 56% relative reduction in progression to diabetes. In the STOP-IDDM trial, participants with IGT were randomized in a double-blind fashion to receive either the -glucosidase inhibitor acarbose or a placebo. After a mean follow-up of 3.3 years, a 25% relative risk reduction in progression to diabetes, based on one OGTT, was observed in the acarbose-treated group compared with the placebo group. If this diagnosis was confirmed by a second OGTT, a 36% relative risk reduction was observed in the acarbose group compared with the placebo group.
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Finally, in the XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study, orlistat was examined for its ability to delay type 2 diabetes when added to lifestyle change in a group with BMI 30 kg/m2 with or without IGT. After 4 years of treatment, the effect of orlistat addition corresponded to a 45% risk reduction in the IGT group, with no effect observed in those without IGT.

Our knowledge of the early stages of hyperglycemia that portend the diagnosis of diabetes, and the recent success of major intervention trials, clearly show that individuals at high risk can be identified and diabetes delayed, if not prevented. The cost-effectiveness of intervention strategies is unclear, but the huge burden resulting from the complications of diabetes and the potential ancillary benefits of some of the interventions suggest that an effort to prevent diabetes is worthwhile.

Lifestyle modification

In well-controlled studies that included a lifestyle intervention arm, substantial efforts were necessary to achieve only modest changes in weight and exercise, but those changes were sufficient to achieve an important reduction in the incidence of diabetes. In the Finnish Diabetes Prevention Study, weight loss averaged 9.2 lb at 1 year, 7.7 lb after 2 years, and 4.6 lb after 5 years; “moderate exercise,” such as brisk walking, for 30 min/day was suggested. In the Finnish study, there was a direct relationship between adherence with the lifestyle intervention and the reduced incidence of diabetes.

In the DPP, the lifestyle group lost 12 lb at 2 years and 9 lb at 3 years (mean weight loss for the study duration was 12 lb or 6% of initial body weight). In both of these studies, most of the participants were obese (BMI >30 kg/m2).

A low-fat (<25% fat) intake was recommended; if reducing fat did not produce weight loss to goal, calorie restriction was also recommended. Participants weighing 120??174 lb (54??78 kg) at baseline were instructed to follow a 1,200-kcal/day diet (33 g fat), those 175??219 lb (79??99 kg) were instructed to follow a 1,500-kcal/day diet (42 g fat), those 220??249 lb (100??113 kg) were instructed to follow an 1,800-kcal/day diet (50 g fat), and those >250 lb (114 kg) were instructed to follow a 2,000-kcal/day diet (55 g fat).

Pharmacological interventions

Three diabetes prevention trials used pharmacological therapy, and all have reported a significant lowering of the incidence of diabetes. The biguanide metformin reduced the risk of diabetes by 31% in the DPP, the -glucosidase inhibitor acarbose reduced the risk by 32% in the STOP-IDDM trial, and the TZD troglitazone reduced the risk by 56% in the TRIPOD study.

In the DPP, metformin was about half as effective as diet and exercise in delaying the onset of diabetes overall, but it was nearly ineffective in older individuals ( 60 years of age) or in those who were less overweight (BMI <30 kg/m2). Conversely, metformin was as effective as lifestyle modification in individuals aged 24??44 years or in those with a BMI 35 kg/m2. Thus, the population of people in whom treatment with metformin has equal benefit to that of a lifestyle intervention is only a small subset of those who are likely to have pre-diabetes (IFG or IGT).

There are also data to suggest that blockade of the renin-angiotensin system may lower the risk of developing diabetes, but more studies are necessary before these drugs can be recommended for preventing diabetes.

Lifestyle or medication?

The DPP is the only study in which a comparison of the two was made, and lifestyle modification was nearly twice as effective in preventing diabetes (58 vs. 31% relative reductions, respectively). The greater benefit of weight loss and physical activity strongly suggests that lifestyle modification should be the first choice to prevent or delay diabetes. Modest weight loss (5??10% of body weight) and modest physical activity (30 min daily) are the recommended goals. Because this intervention not only has been shown to prevent or delay diabetes, but also has a variety of other benefits, health care providers should urge all overweight or sedentary individuals to adopt these changes, and such recommendations should be made at every opportunity.

When all factors are considered, there is insufficient evidence to support the use of drug therapy as a substitute for, or routinely used in addition to, lifestyle modification to prevent diabetes. Public health messages, health care professionals, and health care systems should all encourage behavior changes to achieve a healthy lifestyle. Further research is necessary to understand better how to facilitate effective and efficient programs for the primary prevention of type 2 diabetes.

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AMERICAN DIABETES ASSOCIATION
DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004

References
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May 27, 10 • Diabetes mellitus