Cross-sectional and longitudinal associations among healthcare costs and deficit accumulation.

BACKGROUND: Type 2 diabetes mellitus and overweight/obesity increase healthcare costs. Both are also associated with accelerated aging. However, the contributions of this accelerated aging to increased healthcare costs are unknown. METHODS: We use data from a 8-year longitudinal cohort followed at 16 U.S. clinical research sites. Participants were adults aged 45-76 years with established type 2 diabetes and overweight or obesity who had enrolled in the Action for Health in Diabetes clinical trial. They were randomly (1:1) assigned to either an intensive lifestyle intervention focused on weight loss versus a comparator of diabetes support and education. A validated deficit accumulation frailty index (FI) was used to characterize biological aging. Discounted annual healthcare costs were estimated using national databases in 2012 dollars. Descriptive characteristics were collected by trained and certified staff. RESULTS: Compared with participants in the lowest tertile (least frail) of baseline FI, those in the highest tertile (most frail) at Year 1 averaged $714 (42%) higher medication costs, $244 (22%) higher outpatient costs, and $800 (134%) higher hospitalization costs (p < 0.001). At Years 4 and 8, relatively greater increases in FI (third vs. first tertile) were associated with an approximate doubling of total healthcare costs (p < 0.001). Mean (95% confidence interval) relative annual savings in healthcare costs associated with randomization to the intensive lifestyle intervention were $437 ($195, $579) per year during Years 1-4 and $461 ($232, $690) per year during Years 1-8. These were attenuated and the 95% confidence interval no longer excluded $0 after adjustment for the annual FI differences from baseline. CONCLUSIONS: Deficit accumulation frailty tracks well with healthcare costs among adults with type 2 diabetes and overweight or obesity. It may serve as a useful marker to project healthcare needs and as an intermediate outcome in clinical trials.

Associations that Cardiorespiratory Fitness and Body Mass Index Loss Have with Deficit Accumulation Frailty.

INTRODUCTION/PURPOSE: Lower cardiorespiratory fitness and obesity may accelerate aging processes. The degree to which changes in fitness and body mass index (BMI) may alter the rate of aging may be important for planning treatment. We assessed cross-sectional and longitudinal associations that cardiorespiratory fitness and BMI had with a deficit accumulation frailty index (FI). METHODS: Fitness, based on standardized graded exercise tests, and weight to calculate BMI at baseline and year 4 were collected from 3944 participants aged 45-76 yr in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial. A validated 38-item deficit accumulation FI was used as a marker of aging. Associations between baseline and changes in fitness and BMI with changes in FI were assessed using linear models. RESULTS: Both baseline and 4-yr changes in fitness and BMI were independently associated with 4-yr changes in frailty (all P < 0.001). Mean (95% confidence interval) changes in FI ranged from -0.019 (-0.024, -0.013) for participants in the group with the greatest fitness increase and BMI loss to 0.029 (0.024, 0.034) for participants in the group with the greatest fitness loss and BMI gain. Associations of 4-yr changes in fitness and BMI with FI changes were similar across subgroups based on age, sex, baseline BMI, diabetes duration, and cardiovascular disease history. Increased fitness across 4 yr was associated with less FI accumulation independent of baseline fitness. CONCLUSIONS: Adults with type 2 diabetes and overweight or obesity may slow aging processes captured by an FI by increasing their cardiorespiratory fitness and losing weight.

Long-term Impact of a 10-Year Intensive Lifestyle Intervention on a Deficit Accumulation Frailty Index: Action for Health in Diabetes Trial.

BACKGROUND: Multidomain lifestyle interventions may slow aging as captured by deficit accumulation frailty indices; however, it is unknown whether benefits extend beyond intervention delivery. METHODS: We developed a deficit accumulation frailty index (FI-E) to span the 10 years that the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial delivered interventions (a multidomain lifestyle intervention focused on caloric restriction, increased physical activity, and diet compared to a control condition) and to extend across an additional 8 years post-delivery. The study cohort included 5 145 individuals, aged 45-76 years at enrollment, who had type 2 diabetes and either obesity or overweight. RESULTS: Overall, FI-E scores were relatively lower among lifestyle participants throughout follow-up, averaging 0.0130 [95% confidence interval: 0.0104, 0.0156] (p < .001) less across the 18 years. During Years 1-8, the mean relative difference between control and lifestyle participants' FI-E scores was 0.0139 [0.0115, 0.0163], approximately 10% of the baseline level. During Years 9-18, this average difference was 0.0107 [0.0066, 0.0148]. Benefits were comparable for individuals grouped by baseline age and body mass index and sex but were not evident for those entering the trial with a history of cardiovascular disease. CONCLUSIONS: Multidomain lifestyle intervention may slow biological aging long term, as captured by an FI-E. Clinical Trials Registration Number: NCT00017953.

An Examination of Whether Diabetes Control and Treatments Are Associated With Change in Frailty Index Across 8 Years: An Ancillary Exploratory Study From the Action for Health in Diabetes (Look AHEAD) Trial.

OBJECTIVE: The aim of this study was to describe cross-sectional and longitudinal associations between glycated hemoglobin (HbA1c) levels and strategies to control type 2 diabetes with baseline levels and 8-year changes in a deficit accumulation frailty index (FI), a commonly used marker of biological aging. RESEARCH DESIGN AND METHODS: We conducted exploratory analyses from 4,169 participants, aged 45-76 years, who were followed in the Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial, pooling data across intervention groups. We related baseline and 8-year levels of HbA1c with FI scores using analyses of variance and covariance. Associations between 8-year changes in FI and the use of diabetes medication classes and weight changes were assessed with control for HbA1c levels. Inverse probability weighting was used to assess bias associated with differential follow-up. RESULTS: Baseline and average HbA1c levels over time of <7%, as compared with ≥8%, were associated with less increase in FI scores over 8 years (both P ≤ 0.002). After adjustment for HbA1c, use of metformin and weight loss >5% were independently associated with slower increases in frailty. CONCLUSIONS: Lower HbA1c levels among individuals with diabetes are associated with slower biological aging as captured by a deficit accumulation FI. Strategies to control diabetes through weight loss or metformin use may also slow aging.

Psychological resilience in older adults with type 2 diabetes from the Look AHEAD Trial.

BACKGROUND: There is growing interest in identifying factors associated with healthy aging. This cross-sectional study evaluated associations of psychological resilience with factors associated with aging in older adults with type 2 diabetes mellitus (T2DM). METHODS: Participants were 3199 adults (72.2 ± 6.2 years of age, 61% female, 61% White, body mass index [BMI] = 34.2 ± 8.2 kg/m2 ) with T2DM enrolled in Look AHEAD (a multi-site randomized clinical trial comparing an intensive lifestyle intervention for weight loss to diabetes education and support). Participants were followed observationally after the 10-year intervention was discontinued. The following items were assessed approximately 14.4 years post-randomization in a cross-sectional analysis: Brief Resilience Scale; overnight hospitalizations in past year; physical functioning measured objectively (gait speed, grip strength) and via self-report (Pepper Assessment Tool for Disability; physical quality of life [QOL; SF-36]); a measure of phenotypic frailty based on having ≥3 of unintentional weight loss, low energy, slow gait, reduced grip strength, and physical inactivity. Depressive symptoms (PHQ-9) and mental QOL (SF-36) were also measured. Logistic/linear/multinomial regression was used to evaluate the association of variables with resilience adjusted for age, race/ethnicity, and gender. RESULTS: Greater psychological resilience was associated with lower BMI, fewer hospitalizations, better physical functioning (i.e., lower self-reported disability, better physical QOL, faster gait speed, greater grip strength, lower likelihood of frailty), fewer depressive symptoms, and greater mental QOL (all p < 0.05). Psychological resilience moderated the relationship of number of hospitalizations in the past year with self-reported disability and grip strength. CONCLUSIONS: Psychological resilience is associated with better physical function and QOL among older adults. Results should be interpreted cautiously given cross-sectional nature of analyses. Exploring the clinical benefits of resilience is consistent with efforts to shift the narrative on aging beyond "loss and decline" to highlight opportunities to facilitate healthy aging.

Eight-Year Changes in Multimorbidity and Frailty in Adults With Type 2 Diabetes Mellitus: Associations With Cognitive and Physical Function and Mortality.

BACKGROUND: Indices of multimorbidity and deficit accumulation (ie, frailty indices) have been proposed as markers of biological aging. If true, changes in these indices over time should predict downstream changes in cognition and physical function, and mortality. METHODS: We examined associations that 8-year changes in (i) a multimorbidity index comprised of 9 chronic diseases and (ii) a frailty index (FI) based on deficit accumulation in functional, behavioral, and clinical characteristics had with subsequent measures of cognitive and physical function over 10 years. We drew data from 3 842 participants in the Action for Health in Diabetes clinical trial. They were aged 45-76 years at baseline and at risk for accelerated biological aging due to overweight/obesity and type 2 diabetes mellitus. RESULTS: A total of 1 501 (39%) of the cohort had 8-year increases of 1 among the 9 diseases tracked in the multimorbidity index and 868 (23%) had increases of ≥2. Those with greatest increases in multimorbidity tended to be older individuals, males, and non-Hispanic Whites. Greater FI increases tended to occur among individuals who were older, non-Hispanic White, heavier, and who had more baseline morbidities. Changes in multimorbidity and FI were moderately correlated (r = 0.26; p < .001). Increases in both multimorbidity and FI were associated with subsequently poorer composite cognitive function and 400-m walk speed and increased risk for death (all p < .001). CONCLUSIONS: Accelerated biological aging, as captured by multimorbidity and frailty indices, predicts subsequent reduced function and mortality. Whether intensive lifestyle interventions generally targeting multimorbidity and FI reduce risks for downstream outcomes remains to be seen. Clinical Trials Registration Number: NCT00017953.

Does the impact of intensive lifestyle intervention on cognitive function vary depending baseline level of frailty? An ancillary study to the Action for Health in Diabetes (Look AHEAD) Trial.

AIMS: To assess whether there is an opportune window when intensive lifestyle intervention (ILI) benefits cognitive function. METHODS: Standardized cognitive assessments were collected following ≥8 years of either ILI or a control condition of diabetes support and education (DSE) in 3708 individuals, ages 45-76 years at enrollment, with type 2 diabetes and overweight or obesity. Frailty index (FI) scores were used to group individuals at baseline into tertiles according to their age-related health status. Linear models were used to describe intervention adherence and cognitive function, with interaction terms to examine the consistency of relationships among tertiles. RESULTS: Worse baseline FI scores were associated with poorer subsequent performance in tests of attention, processing speed, and executive function. No differences in any measure of cognitive function were observed between intervention groups within any FI tertile (all p > 0.10). Among individuals with worse baseline FI scores, weight gain was associated with poorer global cognitive function among participants assigned to DSE. There was no association between weight changes and cognitive function among participants assigned to ILI. CONCLUSIONS: Among adults with type 2 diabetes and overweight/obesity, we found no evidence that there is a window of opportunity based on FI when ILI benefits cognitive function.

Does the Impact of Intensive Lifestyle Intervention on Cardiovascular Disease Risk Vary According to Frailty as Measured via Deficit Accumulation?

BACKGROUND: Individuals are often counseled to use behavioral weight loss strategies to reduce risk for cardiovascular disease (CVD). We examined whether any benefits for CVD risk from weight loss intervention extend uniformly to individuals across a range of underlying health states. METHODS: The time until first occurrence of a composite of fatal and nonfatal myocardial infarction and stroke, hospitalized angina, or CVD death was analyzed from 8 to 11 years of follow-up of 4,859 adults who were overweight or obese, aged 45-76 years with Type 2 diabetes. Individuals had been randomly assigned to either an intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Participants were grouped by intervention assignment and a frailty index (FI) based on deficit accumulation, ordered from fewer (first tertile) to more (third tertile) deficits. RESULTS: Baseline FI scores were unrelated to intervention-induced weight losses and increased physical activity. The relative effectiveness of ILI on CVD incidence was inversely related to baseline FI in a graded fashion (p = .01), with relative benefit (hazard ratio = 0.73 [95% CI 0.55,0.98]) for individuals in the first FI tertile to no benefit (hazard ratio = 1.15 [0.94,1.42]) among those in the third FI tertile. This graded relationship was not seen for individuals ordered by age tertile (p = .52), and was stronger among participants aged 45-59 years (three-way interaction p = .04). CONCLUSIONS: In overweight/obese adults with diabetes, multidomain lifestyle interventions may be most effective in reducing CVD if administered before individuals have accrued many age-related health deficits. However, these exploratory analyses require confirmation by other studies. CLINICAL TRIAL REGISTRATION: NCT00017953.

Impact of an 8-Year Intensive Lifestyle Intervention on an Index of Multimorbidity.

BACKGROUND/OBJECTIVES: Type 2 diabetes mellitus and obesity are sometimes described as conditions that accelerate aging. Multidomain lifestyle interventions have shown promise to slow the accumulation of age-related diseases, a hallmark of aging. However, they have not been assessed among at-risk individuals with these two conditions. We examined the relative impact of 8 years of a multidomain lifestyle intervention on an index of multimorbidity. DESIGN: Randomized controlled clinical trial comparing an intensive lifestyle intervention (ILI) that targeted weight loss through caloric restriction and increased physical activity with a control condition of diabetes support and education (DSE). SETTING: Sixteen U.S. academic centers. PARTICIPANTS: A total of 5,145 volunteers, aged 45 to 76, with established type 2 diabetes mellitus and overweight or obesity who met eligibility criteria for a randomized controlled clinical trial. MEASUREMENTS: A multimorbidity index that included nine age-related chronic diseases and death was tracked over 8 years of intervention delivery. RESULTS: Among individuals assigned to DSE, the multimorbidity index scores increased by an average of .98 (95% confidence interval [CI] = .94-1.02) over 8 years, compared with .89 (95% CI = .85-.93) among those in the multidomain ILI, which was a 9% difference (P = .003). Relative intervention effects were similar among individuals grouped by baseline body mass index, age, and sex, and they were greater for those with lower levels of multimorbidity index scores at baseline. CONCLUSIONS: Increases in multimorbidity over time among adults with overweight or obesity and type 2 diabetes mellitus may be slowed by multidomain ILI. J Am Geriatr Soc 68:2249-2256, 2020.

Impact of Multidomain Lifestyle Intervention on Frailty Through the Lens of Deficit Accumulation in Adults with Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes and obesity increase the accumulation of health deficits and may accelerate biological aging. Multidomain lifestyle interventions may mitigate against this. METHODS: Within a large, randomized clinical trial of intensive lifestyle intervention including caloric restriction, increased physical activity, dietary counseling, and risk factor monitoring compared with diabetes support and education, we examined the accumulation of health deficits across 8 years. We used two complementary frailty indices (FIs) based on deficit accumulation, one modeled on work in the Systolic Blood Pressure Intervention Trial and the other including additional deficits related to obesity and type 2 diabetes mellitus. Differences between intervention groups and their consistency among subgroups were assessed with re-randomization tests. RESULTS: Data from 4,859 adults (45-76 years at baseline, 59% female) were analyzed. Random assignment to intensive lifestyle intervention was associated with lower FI scores throughout follow-up as captured by areas under curves traced by longitudinal means (p ≤ .001), over which time mean (SE) differences between intervention groups averaged 5.8% (0.9%) and 5.4% (0.9%) for the two indices. At year 8, the percentage of participants classified as frail (FI > 0.21) was lower among intensive lifestyle intervention (39.8% and 54.5%) compared with diabetes support and education (42.7% and 60.9%) for both FIs (both p < .001). Intervention benefits were relatively greater for participants who were older, not obese, and without history of cardiovascular disease at baseline. CONCLUSIONS: Eight years of multidomain lifestyle intervention create a buffer against the accumulation of age-related health deficits in overweight or obese adults with type 2 diabetes.ClinicalTrials.gov Identifier: NCT00017953.