The prevention of diabetes assumes increasing importance for the growing elderly population in the United States and elsewhere. Other studies have also demonstrated that diabetes can be prevented (or delayed) by lifestyle change (23
) and medication (25
), but the DPP provides unique information about prevention in older adults. DPP data indicate that there are significant age differences in response to either lifestyle modification or metformin, which appear to reflect variation in both behavior and biology.
Age-related deterioration in glucose tolerance reflects both impaired insulin secretion and declining insulin sensitivity (27
). Insulin resistance is closely linked to obesity, and changes in body composition that are typical of aging (increased visceral fat and decreased skeletal muscle mass) are thought to be the major determinants of increasing insulin resistance with age. Diet-induced weight loss improves insulin sensitivity and insulin secretion in older patients (30
), but data are conflicting about whether exercise can enhance insulin action and improve glucose tolerance, independent of weight loss (31
). Several studies in older patients with type 2 diabetes suggested that resistance training can improve glycemic control and insulin sensitivity, independent of weight loss (32
). Improvements in insulin action and reduction in hyperinsulinemia have also been reported in older, nondiabetic men following short-term strength training (35
). In contrast, the effect of aerobic (endurance) training on insulin sensitivity in the elderly population is uncertain, with some reporting a clear benefit (36
) and others no effect, despite increased muscle GLUT4 and mitochondrial oxidative capacity (38
). Most DPP ILS participants achieved their exercise goal through low-level aerobic activity, such as brisk walking or cycling, with a small contribution from resistance training. The DPP ILS program was not designed to determine the individual effectiveness of diet change versus exercise or to determine the most effective form of exercise. However, our data suggest that the effectiveness of a comprehensive ILS program in preventing deterioration of glucose tolerance is enhanced in older adults. These results appear to be due to more active participation in ILS activities by the older group, although other (biological) factors are suggested by their better baseline body size and glycemic profile and the stronger effect on postchallenge glycemia.
The reasons for differences in ILS participation among the age groups were not formally assessed in DPP. As expected, younger participants were more likely to be employed (85% vs 82% vs 39%) and to live in households with four or more members (50% vs 29% vs 12%). These data would support anecdotal evidence that younger participants had family and work responsibilities that could interfere with lifestyle changes, whereas older participants had fewer competing obligations and more time to devote to the ILS program. Older individuals may also be more aware of disease vulnerability, now being the same age when parents or good friends died or experienced serious illness.
We observed a trend (in comparison to ILS) toward decreased effectiveness of metformin with increasing age, despite greater weight loss and comparable (if not enhanced) medication adherence among older metformin-treated participants. Although baseline glucose variables were almost identical in the three age groups, the strength of the association between age and declining metformin effect was attenuated when the small differences in baseline fasting glucose values (106 vs 107 mg/dL, in the 25–44 and 60–85 year age groups, respectively) were included in the model. This finding suggests that the older metformin group may have had a somewhat higher risk of diabetes at baseline, which could account for some of the observed difference in treatment effect. Nonetheless, the pattern of decreased metformin effect with age suggests that there may be true differences in physiology and pharmacologic response.
The three age groups were generally well matched at baseline for glucose parameters, but the older group was significantly more insulin-sensitive and had greater impairment of insulin secretion than the young or middle-aged groups. This observation is in contrast to data from some cross-sectional studies, which have reported increased obesity and insulin resistance with aging (39
). One explanation for these results is a “survivor effect”—that is, those persons who survived to a later age without developing diabetes tended to be somewhat leaner and less insulin resistant than were age-mates who did become diabetic. As reported previously (9
), baseline insulin sensitivity and secretion were strong and independent predictors of diabetes risk in the DPP. Within the metformin group, those participants with the highest insulin sensitivity and lowest insulin secretion (the pattern typical of older adults) had a greater hazard ratio for diabetes than did those participants with the lowest insulin sensitivity and greatest insulin secretion (typical of younger adults) (9
). However, this pattern was not observed in the placebo or lifestyle groups, suggesting that metformin effectiveness is tied to metabolic profile, being most effective in insulin-resistant individuals and less so in those individuals whose predominant metabolic defect is impaired insulin secretion.
The primary mechanism for the antidiabetic effect of metformin is through suppression of hepatic glucose production, which is the major determinant of fasting plasma glucose levels but plays a more minor role in postchallenge (or postprandial) hyperglycemia (21
). Although elevated hepatic glucose production is a classic feature of type 2 diabetes, some have reported that this may be less of a factor in older diabetic persons (39
), thus providing another potential explanation for reduced metformin effect. Among those persons who progressed to diabetes within DPP, we observed that younger participants were more likely to convert by fasting glucose criteria, and older participants by 2-hour criteria. This pattern was most apparent in the metformin group, and is consistent with the relative ineffectiveness of this agent in reducing postchallenge hyperglycemia. Age differences in patterns of diabetes conversion have been reported by others (6
) and may be related to the varying contributions of defects in insulin secretion and sensitivity. In the Rancho Bernardo Study, isolated postchallenge hyperglycemia was much more common than fasting hyperglycemia as a diagnostic criterion for diabetes (4
). Data from the Baltimore Longitudinal Study of Aging suggest that there may be two distinct phenotypes for the development of diabetes—one through increased fasting glucose and the other through elevated 2-hour glucose levels (22
). In that study, older adults (>65 years) had substantially accelerated rates of progression to abnormal 2-hour glucose compared to younger persons. We propose that reduced metformin effectiveness in preventing diabetes in the elderly population may be due to the interaction of a specific metabolic profile (insulin secretory defect, leading to postchallenge hyperglycemia) with the drug's pharmacologic action. However, metformin may be useful in treating elderly patients with established diabetes, when both fasting and postprandial hyperglycemia are typically present.
Some limitations to these analyses should be acknowledged. Ethnic and sex distributions were not equal in all age groups, with men and Caucasians over-represented among older participants. Male ILS participants lost more weight and reported more exercise than did female ILS participants, although diabetes risk reduction did not differ significantly (62% for men vs 52% for women; p = .25). Similarly, although Caucasians and Hispanics lost more weight than African Americans did, diabetes risk reduction did not differ by ethnic group. Among metformin participants, diabetes risk reduction was similar in men and women (37% and 27%; p = .41) and among ethnic groups, suggesting that the observed age differences in treatment effects are unlikely to be explained solely by variations in sex and ethnic composition of the age groups. Although age differences in response to intervention was a predetermined secondary outcome in DPP, the study had limited power to detect these differences, and this may have been a factor in the borderline statistical significance of some of our findings. The numbers also preclude meaningful stratified analyses to examine the effect of unequal ethnic and sex distributions in some age groups.
As noted, the DPP cohort was a relatively healthy and motivated group, so these results may not apply to frail or disabled elderly persons. Individuals with significant physical limitations (i.e., those unable to walk at a moderate pace) were not enrolled in DPP. However, the DPP ILS program was successfully modified for participants who developed such limitations (for example, due to injury or arthritis) during the course of the study. On the whole, the DPP ILS program of low-intensity aerobic activity and low-fat, reduced-calorie diet was well-tolerated by older participants and has broad potential applicability for community-dwelling seniors.
In conclusion, results of the DPP demonstrate that an intensive lifestyle modification program is exceptionally effective in preventing diabetes in older individuals with IGT. This robust response is in large part due to greater weight loss and more active participation in ILS activities among the older participants. The limited effectiveness of metformin, in contrast, may reflect true age-related differences in glucose metabolism and glycemic patterns at diabetes conversion. These results indicate that a program of moderate-intensity exercise and modest weight loss should be recommended for older individuals at high risk for type 2 diabetes. Implementation of these recommendations has the potential to reduce or delay the burden of diabetes in the growing elderly population.