Editor's Note: Commentary based on Espeland MA, Luchsinger JA, Neiberg RH et al. Long term effect of intensive lifestyle intervention on cerebral blood flow. J Am Geriatr Soc 2018;66:120-6.

Please see the associated Expert Analysis on sarcopenic obesity.

Study Question: What is the effect of weight loss on cerebral blood flow in middle-aged and older adults with type 2 diabetes mellitus?

Funding: NIDDK, NIH, DHHS.

Study Design: Ancillary study of the Action for Health in Diabetes (Look AHEAD) trial. In brief, the main Look AHEAD study was a clinical trial that randomized 5,145 overweight or obese patients with type 2 diabetes mellitus to either an intensive lifestyle intervention (increased physical activity and decreased caloric intake; intervention group) versus diabetes education and support (control group). The maximal follow up in the main trial was 13.5 years. The primary outcome of the main trial was a four-point composite outcome (cardiovascular death, nonfatal MI, nonfatal stroke, angina resulting in hospitalization). The primary study found no benefit in the intensive lifestyle intervention group compared to the control group for the composite outcome.

Study Participants: Look AHEAD Brain MRI study participants were recruited from three Look AHEAD clinical trial sites between their 10-12-year enrollment anniversaries among those for whom an MRI was considered safe.

Intervention group: Caloric goal of 1,200-1800 calories/day (<30% total calories from fat, ≥15% of calories from protein) with a physical activity goal of ≥175 minutes/week of activity similar to brisk walking.

Control Group: Attended three group sessions each year with standardized protocols for diet, activity and support without goals for diet, physical activity or weight.

Primary Outcome for Current Ancillary Sub-study: Mean cerebral blood flow measured using a 3.0 Tesla brain MRI.

Statistical Analysis: Baseline variables compared with chi-square, t-tests. Primary outcome compared between the intervention and control group by a mixed effects model that adjusted for region, age, sex, education, race and ethnicity, clinic, systolic and diastolic blood pressure.

Results: The average age was 57.5 years in the control arm (N = 153) and 58.5 years in the intervention arm (N = 157). At baseline, all covariates were similar except for a higher prevalence of overweight (BMI 25-29.9) individuals in the intensive lifestyle intervention (ILI) arm, higher prevalence of moderate obesity (BMI 30-39.9) in the ILI arm and higher prevalence of extreme obesity (BMI ≥ 40) in the control arm; overall p-value 0.03 by chi-square.

The mean cerebral blood flow (at an average time from enrollment to imaging of 10.4 years) was higher in the intervention arm compared to the control arm (51.60 vs. 48.61 ml/100g/minute). The mean difference (intervention-control) was 2.99 (SE 1.43, 95% CI: 0.38-5.81; p = 0.04). In the intervention group, greater weight loss and increased physical activity were associated with greater cerebral blood flow.

Conclusion: In overweight or obese patients with type 2 diabetes mellitus enrolled in the ancillary brain MRI study of the Look AHEAD trial, those randomized to the intervention arm had higher cerebral blood flow compared with those randomized to the control group.

Limitations: The current study should be considered hypothesis generating. Baseline cerebral blood flow was not assessed, so it is unclear if the observed differences were attributable to the intervention. Other limitations include the possibility of differential selection bias and residual confounding.

Perspective: The Look AHEAD study was a well-designed ILI trial with considerable longitudinal follow-up.¹ It provided an opportunity for clinicians and researchers to conduct additional ancillary studies, including the current mechanistic sub-study done to enhance an understanding of the relationships between weight loss and cognition utilizing an imaging modality, brain MRI.² The authors demonstrated that an ILI may increase cerebral blood flow; in addition, marginal changes in selected cognitive subdomains based on standardized testing were also seen.

The study design failed to account for lean muscle mass changes or strength in the aging process that could significantly impact the results. The authors did not account or evaluate changes in waist circumference as a surrogate for central adiposity. Importantly, 20% of the ILI group were classified as overweight using BMI. Previous data suggest that a BMI in the overweight range is associated with the lowest risk of mortality in older adults, and that obesity treatments should be restricted to those with a BMI exceeding 30 or 33.³ Including overweight patients may have reduced the effect sizes observed. Other limitations of this study include the unavailability of baseline cerebral blood flow in both arms, which would have provided additional information about the effect of the intervention, the possibility of differential selection bias, and residual confounding. In addition, the intervention population was middle-aged (58.5 years) at baseline, so the applicability of the study findings to older adults is uncertain.

The current study should be considered as hypothesis generating. However, as future studies in this area emerge, changes in cognitive function as a function of aging and weight are key areas for the cardiovascular clinical team to keep in mind. Moreover, the advent of revolutionizing procedures, such as transcatheter aortic valve replacement, has brought to the forefront important issues of aging, such as frailty,⁴ cognitive changes and the role of BMI in modulating disease presentation and response to therapy in older adults with cardiovascular disease.^5,6

Using a framework of care of older adults with cardiovascular disease such as the 5Ms (mind, mobility, medications, multimorbidity, matters most)⁷ or the domain management model (medical/surgical domain, cognitive domain, physical domain and social domain),⁸ cardiovascular clinicians will become increasingly comfortable incorporating cognitive function (e.g., dementia) and physical function (frailty, activities of daily living) into clinical decision-making. Lastly, an understanding of the association of sarcopenic obesity and cardiovascular disease in older adults is ironically still in its infancy. Of particular importance is its role in the cardiac rehabilitation process (both pre-procedure and post-procedure rehabilitation).

References

1. Look AHEAD Research Group, Wing RR, Bolin P, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145-54.
2. Espeland MA, Luchsinger JA, Neiberg RH, et al. Long term effect of intensive lifestyle intervention on cerebral blood flow. J Am Geriatr Soc 2018;66:120-6.
3. Winter JE, MacInnis RJ, Wattanapenpaiboon N, Nowson CA. BMI and all-cause mortality in older adults: a meta-analysis. Am J Clin Nutr 2014;99:875-90.
4. Afilalo J, Lauck S, Kim DH, et al. Frailty in older adults undergoing aortic valve replacement: the FRAILTY-AVR study. J Am Coll Cardiol 2017;70:689-700.
5. Khan MM, Hermann N, Gallagher D, et al. Cognitive outcomes after transcatheter aortic valve implantation: a metaanalysis. J Am Geriatr Soc 2018;66:245-62.
6. Sannino A, Schiattarella GG, Toscano E, et al. Meta-analysis of effect of body mass index on outcomes after transcatheter aortic valve implantation. Am J Cardiol 2017;119:308-16.
7. Tinetti M, Huang A, Molnar F. The geriatric 5M's: a new way of communicating what we do. J Am Geriatr Soc 2017;65:2115.
8. Gorodeski EZ, Goyal P, Hummel SL, et al. Domain management approach to heart failure in the geriatric patient: present and future. J Am Coll Cardiol 2018;71:1921-36.

Keywords: Geriatrics, Weight Loss, Waist Circumference, Diabetes Mellitus, Type 2, Cardiac Rehabilitation, Transcatheter Aortic Valve Replacement, Body Mass Index, Activities of Daily Living, Blood Pressure, Obesity, Overweight, Body Weight, Obesity, Abdominal, Life Style, Cerebrovascular Circulation, Stroke, Magnetic Resonance Imaging, Outcome Assessment, Health Care

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