Judy L. Bahnson's research while affiliated with Wake Forest School of Medicine and other places

Introduction The Look AHEAD randomized clinical trial reported that an 8-year intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) in adults aged 45–76 years with type 2 diabetes and overweight/obesity delayed kidney disease progression. Here, we report long-term post-intervention follow-up for the trial’s secondary outcome of kidney disease. Research design and methods We examined effects of ILI (n=2570) versus DSE (n=2575) on decline in estimated glomerular filtration rate (eGFR) to <45 mL/min/1.73 m² or need for kidney replacement therapy (KRT: dialysis or kidney transplant) during intervention and post-intervention follow-up (median 15.6 years overall). Results Incidence of eGFR <45 mL/min/1.73 m² was lower in ILI during the intervention (HR=0.80, 95% CI=0.66 to 0.98) but not post-intervention (HR=1.03, 0.86 to 1.23) or overall (HR=0.92, 0.80 to 1.04). There were no significant treatment group differences in KRT. In prespecified subgroup analyses, age×treatment interactions were significant over total follow-up: p=0.001 for eGFR <45 mL/min/1.73 m² and p=0.01 for KRT. The 2205 participants aged >60 years at baseline had benefit in both kidney outcomes during intervention and overall (HR=0.75, 0.62 to 0.90 for eGFR <45 mL/min/1.73 m²; HR=0.62, 0.43 to 0.91 for KRT). The absolute treatment effects were greater post-intervention: ILI reduced the rate of eGFR <45 mL/min/1.73 m² by 0.46 and 0.76 cases/100 person-years during and post-intervention, respectively; and reduced KRT by 0.15 and 0.21 cases/100 person-years. The younger participants experienced no such post-intervention benefits. Conclusions ILI reduced kidney disease progression during and following the active intervention in persons aged ≥60 years. ILI should be considered for reducing kidney disease incidence in older persons with type 2 diabetes.

Objective This observational study investigated metabolomic changes in individuals with type 2 diabetes (T2D) after weight loss. We hypothesized that metabolite changes associated with T2D‐relevant phenotypes are signatures of improved health. Methods Fasting plasma samples from individuals undergoing bariatric surgery ( n = 71 Roux‐en‐Y gastric bypass [RYGB], n = 22 gastric banding), lifestyle intervention ( n = 66), or usual care ( n = 14) were profiled for 139 metabolites before and 2 years after weight loss. Principal component analysis grouped correlated metabolites into factors. Association of preintervention metabolites was tested with preintervention clinical features and changes in T2D markers. Association between change in metabolites/metabolite factors and change in T2D remission markers, homeostasis model assessment of β‐cell function, homeostasis model assessment of insulin resistance, and glycated hemoglobin (HbA1c) was assessed. Results Branched‐chain amino acids (BCAAs) were associated with preintervention adiposity. Changes in BCAAs (valine, leucine/isoleucine) and branched‐chain ketoacids were positively associated with change in HbA1c (false discovery rate q value ≤ 0.001) that persisted after adjustment for percentage weight change and RYGB ( p ≤ 0.02). In analyses stratified by RYGB or other weight loss method, some metabolites showed association with non‐RYGB weight loss. Conclusions This study confirmed known metabolite associations with obesity/T2D and showed an association of BCAAs with HbA1c change after weight loss, independent of the method or magnitude of weight loss. image

INTRODUCTION Diabetes and overweight/obesity are described as accelerating aging processes, yet many individuals with these conditions maintain high levels of cognitive and physical function and independence late into life. The Look AHEAD Aging study is designed to identify 20‐year trajectories of behaviors, risk factors, and medical history associated with resilience against geriatric syndromes and aging‐related cognitive and physical functional deficits among individuals with these conditions. METHODS Look AHEAD Aging extends follow‐up of the cohort of the former 10‐year Look AHEAD trial. The original cohort (N = 5145) was enrolled in 2001 to 2004 when participants were aged 45 to 76 years and randomly assigned to a multidomain intensive lifestyle intervention (ILI) or a diabetes support and education (DSE) condition. The trial interventions ceased in 2012. Clinic‐based follow‐up continued through 2020. In 2021, the cohort was invited to enroll in Look AHEAD Aging, an additional 4‐year telephone‐based follow‐up (every 6 months) enhanced with Medicare linkage. Standardized protocols assess multimorbidity, physical and cognitive function, health care utilization, and health‐related quality of life. RESULTS Of the original N = 5145 Look AHEAD participants, N = 1552 active survivors agreed to participate in Look AHEAD Aging. At consent, the cohort's mean age was 76 (range 63 to 94) years and participants had been followed for a mean of 20 years. Of the original Look AHEAD enrollees, those who were younger, female, or with no history of cardiovascular disease were more likely to be represented in the Look AHEAD Aging cohort. Intervention groups were comparable with respect to age, diabetes duration, body mass index, insulin use, hypertension, cardiovascular disease, and cognitive function. ILI participants had significantly lower deficit accumulation index scores. DISCUSSION By continuing the long‐term follow‐up of an extensively characterized cohort of older individuals with type 2 diabetes, Look AHEAD Aging is well positioned to identify factors associated with resilience against aging‐related conditions.

Background: Patients who have obesity seldom lose weight after total knee arthroplasty (TKA). The Look AHEAD trial randomized patients with type 2 diabetes who had overweight or obesity to a 10-year intensive lifestyle intervention (ILI) or diabetes support and education (DSE). Methods: Of the total 5,145 participants enrolled who had a median 14-year follow-up, a subset of 4,624 met inclusion criteria. The ILI aimed at achieving and maintaining a 7% weight loss and included weekly counseling the first 6 months, with decreasing frequency thereafter. This secondary analysis was undertaken to determine what effects a TKA had on patients participating in a known successful weight loss program and specifically if there was a negative impact on weight loss or their Physical Component Score (PCS). Results: The analysis suggests that the ILI remained effective for maintaining or losing weight after TKA. Participants in ILI had significantly greater percent weight loss than those in DSE both before and after TKA (ILI-DSE before TKA: -3.6% (-5.0, -2.3); after TKA: -3.7% (-4.1, -3.3); both P<.0001). When comparing percent weight loss before to after TKA, there was no significant difference within either the DSE or ILI group (LSMEAN±SE ILI: -0.36%±0.3, P=0.21; DSE: -0.41%±0.29, P=0.16). PCS scores improved after TKA (P<.001), but no difference was found between TKA ILI and DSE groups before or after surgery. Conclusion: Participants who had a TKA did not have an altered ability to adhere to intervention goals to maintain weight loss or obtain further weight loss. The data suggest patients who have obesity can lose weight after TKA on a weight loss program.

Aims: To evaluate the contribution of baseline and longitudinal changes in cardiometabolic health (CMH) towards heart failure (HF) risk among adults with type 2 diabetes (T2D). Methods and results: Participants of the Look AHEAD trial with T2D and without prevalent HF were included. Adjusted Cox models were used to create a CMH score incorporating target levels of parameters weighted based on relative risk for HF. The associations of baseline and changes in the CMH score with risk of overall HF, HFpEF and HFrEF were assessed using Cox models. Among the 5,080 participants, 257 incident HF events occurred over 12.4-years follow-up. The CMH score included 2-points each for target levels of waist circumference, GFR, urine-albumin-to-creatinine-ratio, and 1-point each for BP and HbA1c at target. High baseline CMH score(6-8) was significantly associated with lower overall HF risk (aHR[ref=low score(0-3): 0.31[95% CI=0.21-0.47]) with similar associations observed for HFpEF and HFrEF. Improvement in CMH was significantly associated with lower risk of overall HF (aHR per 1-unit increase in score at 4-years: 0.80[95% CI=0.70-0.91]). In the ACCORD validation cohort, the baseline CMH score performed well for predicting HF risk with adequate discrimination (C-index=0.70), calibration (chi-square=5.53, p-value=0.70), and risk stratification (aHR[high(6-8) vs. low score(0-3): 0.35[95% CI=0.26-0.46]). In the LookAHEAD subgroup with available biomarker data, incorporating NT-proBNP to the baseline CMH score improved model discrimination (C-index=0.79) and risk stratification (aHR[high(8-10) vs. low score(0-4): 0.18[95% CI=0.09-0.35]). Conclusions: Achieving target levels of more CMH parameters at baseline and sustained improvements were associated with lower HF risk in T2D.

OBJECTIVE Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P < 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.

Background Intentional weight loss is associated with lower risk of heart failure (HF) and atherosclerotic cardiovascular disease among patients with type 2 diabetes. However, the contribution of baseline measures and longitudinal changes in fat mass (FM), lean mass (LM), and waist circumference (WC) to the risk of HF and myocardial infarction (MI) in type 2 diabetes is not well established. Methods Adults from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. FM and LM were predicted using validated equations and compared with dual-energy x-ray absorptiometry measurements in a subgroup. Adjusted Cox models were used to evaluate the associations of baseline and longitudinal changes in FM, LM, and WC over 1- and 4-year follow-up with risk of overall HF, HF with preserved ejection fraction (EF; EF ≥50%), HF with reduced EF (EF <50%), and MI. Results Among 5103 participants, there were 257 incident HF events over 12.4 years of follow-up. Predicted and measured FM/LM were highly correlated ( R ² =0.87–0.90; n=1369). FM and LM decreased over 4-year follow-up with greater declines in the intensive lifestyle intervention arm. In adjusted analysis, baseline body composition measures were not significantly associated with HF risk. Decline in FM and WC, but not LM, over 1 year were each significantly associated with lower risk of overall HF (adjusted hazard ratio per 10% decrease in FM, 0.80 [95% CI, 0.68–0.95]; adjusted hazard ratio per 10% decrease in WC, 0.77 [95% CI, 0.62–0.95]). Decline in FM was significantly associated with lower risk of both HF subtypes. In contrast, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Similar patterns of association were observed for 4-year changes in body composition and HF risk. Longitudinal changes in body composition were not significantly associated with risk of MI. Conclusions In adults with type 2 diabetes, a lifestyle intervention is associated with significant loss of FM and LM. Declines in FM and WC, but not LM, were each significantly associated with lower risk of HF but not MI. Furthermore, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00017953.

Background: Type 2 diabetes mellitus (T2DM) is associated with higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF), and body mass index (BMI) on risk for HF is not well-established. Methods: Participants from the Look AHEAD (Action for Health in Diabetes) trial without prevalent HF were included. Time to event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention (ILI) vs. diabetes support and education (DSE) groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, BMI, and longitudinal changes in these parameters with risk of HF were evaluated using multivariable adjusted Cox models. Results: Among the 5,109 trial participants, there was no significant difference in the risk of incident HF (n = 257) between the ILI vs. DSE groups [HR (95% CI) = 0.96 (0.75 to 1.23)] over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit [Tertile 2: HR (95% CI) = 0.61 (0.44 to 0.83)] and high fit [Tertile 3: HR (95% CI) = 0.38 (0.24 to 0.59)] groups, respectively (referent group: low fit, Tertile 1). Among HF subtypes, after adjustment for traditional CV risk factors and interval incidence of MI, baseline CRF was not significantly associated with risk of incident HFrEF. In contrast, the risk of incident HFpEF was 40% lower in moderate fit and 77% lower in the high fit groups. Baseline BMI was also not associated with risk of incident HF, HFpEF, or HFrEF after adjustment for CRF and traditional CV risk factors. Among participants with repeat CRF assessments (n = 3,902), improvements in CRF and weight loss over 4-year follow-up was significantly associated with lower risk of HF [HR (95% CI) per 10% increase in CRF = 0.90 (0.82 to 0.99), per 10% decrease in BMI = 0.80 (0.69 to 0.94)]. Conclusions: Among participants with T2DM in the Look AHEAD trial, the ILI did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT00017953

Introduction: Type 2 Diabetes (T2DM) is associated with higher risk for HF. The contributions of baseline measures of and changes in fitness (CRF) toward HF risk in T2DM is not well-established. Methods: Participants of the Look AHEAD trial without prevalent HF randomized to the intensive lifestyle intervention (ILI) vs. usual care arms were included. Incident HF hospitalization and its subtypes [HF with preserved ejection fraction (EF>= 50%, HFpEF) & HF with preserved ejection fraction (EF < 50%, HFrEF)] were adjudicated through the end of 2014 using a validated approach. The associations of baseline CRF estimated from a maximal treadmill test and changes in CRF (from baseline to year 4) with risk of HF and its subtypes were evaluated using adjusted Cox models. Results: Among the 5,109 study participants, there was no significant difference in the risk of HF (n = 257 events) between the ILI vs. usual care groups [HR (95% CI) = 0.96 (0.75 - 1.23)] over 12.4 years follow up. In adjusted analysis, the risk of HF was 39% and 62% lower among moderate fit [Tertile 2] and high fit [Tertile 3] groups, respectively [vs. low fit (Tertile 1), Table]. Among HF subtypes, the risk of HFpEF was 40% lower in moderate fit and 77% lower in the high fit groups (vs. low fit). In contrast, baseline CRF was not associated with risk of HFrEF after adjustment for potential confounders (Table). BMI was also not associated with risk of HF after adjustment for CV risk factors. Among participants with repeat CRF testing (n = 3,902), improvements in CRF and weight loss over 4-year follow-up was significantly associated with lower risk of HF [HR (95% CI) per 10% increase in CRF = 0.90 (0.82 to 0.99), per 10% decrease in BMI = 0.80 (0.69 to 0.94)]. Conclusion: Higher baseline CRF is independently associated with lower risk of HF, particularly HFpEF, among individuals with T2DM. Improvements in CRF and weight loss can significantly lower risk of HF in this high-risk population. However, the ILI implemented in the LookAHEAD trial did not modify the risk of HF among the study participants.

Background: Evidence has established obesity as a risk factor for total knee replacement (TKR) due to osteoarthritis. Obesity is a risk factor for TKR. Randomized trials such as Look AHEAD (Action for Health in Diabetes) have shown long-term successful weight loss with an intensive lifestyle intervention (ILI). It is unknown, however, if intentional weight loss can reduce the risk of TKR. Methods: Look AHEAD randomized persons aged 45-76 with type 2 diabetes who had overweight or obesity to either an ILI to achieve/maintain 7% weight loss or to standard diabetes support and education (DSE). Reported knee pain was assessed using the Visual Analog Scale and Western Ontario McMaster University Osteoarthritis Index questionnaire in 5125 participants without previous TKR. Cox proportional hazard regression was used to model differences in risk of TKR in relation to randomization group assignment (ILI vs DSE) along with baseline body mass index category and baseline knee pain as potential confounders from baseline through Look AHEAD-Extension. Results: Baseline mean ± SD Western Ontario McMaster University Osteoarthritis Index knee pain scores did not differ by treatment assignment (ILI: 3.6 ± 2.9, DSE: 3.9 ± 3.0, P = .08); as expected due to randomization. During follow up, the 631 (12%) participants who reported having a TKR were more likely to have been heavier (P < .001) and older (P < .001) at enrollment, but risk of TKR did not differ by treatment group assignment (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.91-1.25, P = .43). Heterogeneity of treatment effect was observed according to baseline knee pain (interaction P = .02). In persons without knee pain at baseline, there was a 29% reduced risk of TKR in ILI compared to DSE (HR 0.71, 95% CI 0.52-0.96). However, in persons with knee pain at baseline, there was no statistically significant association of treatment assignment with respect to subsequent TKR incidence (HR 1.11, 95% CI 0.92-1.33). Conclusion: Findings suggest that intensive lifestyle change including physical activity, dietary restriction and behavioral changes to achieve weight loss for prevention of TKR may be most effective in preventing TKR prior to the development of knee pain.