Adipokines as Predictive Biomarkers for Training Adaptation in Subjects with Multimorbidity-A Hypothesis-Generating Study.

BACKGROUND: Physical exercise exerts a positive effect on many chronic conditions, specifically lifestyle-related diseases such as overweight and obesity, type 2 diabetes mellitus (T2DM), cardiovascular conditions and osteoarthritis (OA). As a result of common risk factors, most of these patients present with multiple conditions. Exercise- and disease-related biomarkers, such as adipokines, are emerging tools in training supervision and regulation; however, their significance in subjects with multimorbidities is unknown. SUBJECTS AND METHODS: To address this issue, adipokines leptin, adiponectin and resistin were assessed in a cohort of subjects with multimorbidities (n = 39) presenting with at least two of the abovementioned conditions or relevant risk factors before and after a six-month exercise and lifestyle intervention program ('MultiPill-Exercise'), and correlated with training adaptation, namely changes in relative maximum oxygen uptake (V·O2max). RESULTS: There was a significant negative correlation between baseline leptin concentrations and training effect for relative V·O2max (after three months: rho = -0.54, p = 0.020 *; after six months: rho = -0.45, p = 0.013 *), with baseline leptin explaining 35% of the variance in delta relative V·O2max after three months and 23% after six months. CONCLUSIONS: Leptin might be a suitable surrogate biomarker in the context of exercise-based lifestyle intervention programs in subjects with multimorbidity.

Proof of Concept of a 6-Month Person-Oriented Exercise Intervention 'MultiPill-Exercise' among Patients at Risk of or with Multiple Chronic Diseases: Results of a One-Group Pilot Trial.

Physical exercise has been shown to be effective in the treatment of non-communicable chronic diseases. However, patients with multiple chronic diseases (multimorbidity) have received little attention in health policy. This pilot trial served as a proof of concept of a 6-months person-oriented exercise intervention for people at risk of or with diagnosed cardiovascular diseases, diabetes mellitus type 2, overweight and/or hip/knee osteoarthritis, regarding effects on health outcomes as well as adherence and safety. The intervention ('MultiPill-Exercise') was designed to promote physical exercise participation, considering an individual perspective by addressing personal and environmental factors. Outcomes were assessed at baseline (t0) and after three- (t3) and six-months (t6). The primary outcome was self-reported physical exercise participation in minutes/week comparing t3 and t6 vs. t0. Secondary outcomes included cardio-respiratory fitness (maximum oxygen uptake VO2peak during incremental cycling ergometry), isometric peak torque of knee extensors and flexors, health-related quality of life (Veterans Rand 12 with its subscales of perceived general health (GH), mental health (MCS), and physical health (PCS)) and blood levels. Adherence to exercise (% of attended sessions during the first 12-weeks of the intervention) and adverse events were monitored as well. Data were analyzed using a non-parametric procedure for longitudinal data, estimating rank means (MRank) and relative treatment effects (RTE) as well as linear-mixed effect models for parametric data. The primary endpoint of physical exercise participation was significantly higher at t3 and t6 compared to baseline (t3 vs. t0: MRank = 77.1, p < 0.001, RTE: 0.66; t6 vs. t0: MRank = 70.6, p < 0.001, RTE = 0.60). Improvements at both follow-up time points compared to t0 were also found for relative VO2peak (t3 vs. t0 = 2.6 mL/kg/min, p < 0.001; t6 vs. t0 = 2.0 mL/kg/min, p = 0.001), strength of knee extensors (t3 vs. t0 = 11.7 Nm, p = 0.007; t6 vs. t0= 18.1 Nm, p < 0.001) and GH (t3 vs. t0 = 16.2, p = 0.003; t6 vs. t0 = 13.4, p = 0.008). No changes were found for MCS, PCS and for blood levels. Overall exercise adherence was 77%. No serious adverse events were recorded. Results of this pilot trial represent a first proof of concept for the intervention 'MultiPill-Exercise' that will now be implemented and evaluated in a real-world health care setting.

Implementation and evaluation of an individualized physical exercise promotion program in people with manifested risk factors for multimorbidity (MultiPill-Exercise): a study protocol for a pragmatic randomized controlled trial.

BACKGROUND: Multimorbidity is a major problem in Europe, increasing the need for prevention and rehabilitation programs. In Germany no guidelines have been developed that focus on patients with multiple chronic non-communicable diseases (NCDs). Benefits of physical activity (PA) and exercise in NCDs have been proven, but most interventions focus on single conditions. The evaluation of the effectiveness, efficiency and safety of PA programs in patients suffering from multiple NCDs and the feasibility of the implementation within the health care service remain open research questions. METHODS: The multi-site randomized controlled pragmatic trial includes 320 sedentary subjects with at least two of the following NCDs, either manifested or in a pre-stage with evident risk factors: Cardio-vascular disease, Diabetes mellitus type 2, knee/ hip osteoarthritis and obesity. Participants will be recruited from general practitioners and medical specialists and randomized to standard care of a statutory health insurance or MultiPill-Exercise. Standard care includes a choice of one or a maximum of two 8- to 12-week health programs, including nutrition, exercise, relaxation or special disease management programs. MultiPill-Exercise is based on the bio-psycho-social health model, considering a person-oriented perspective in light of given individual characteristics and context factors. The 24-weeks intervention focuses on aerobic and strengthening exercises in line with the WHO PA recommendations. Psychological and pedagogical elements along with behavior change techniques are implemented to ease the initiation and maintenance of exercise participation and lifestyle change, including nutrition. Primary outcome will be short- and long-term PA measured with the European Health Interview Survey-Physical Activity Questionnaire (EHIS-PAQ). Secondly, the effectiveness of the program on generic, disease specific, economic, and exercise behavioral parameters, as well as program adherence and safety will be evaluated. DISCUSSION: Results of this trial evaluate the PA intervention program in people with multiple NCDs in a real-life scenario. It will serve as a proof of concept with the opportunity of translation into routine practice. This approach, as a multi-site RCT with its rigorous methods and standardized operating procedures for the conduction of the intervention, will allow valid conclusions for the implementation of PA interventions in people with multimorbidity. TRIAL REGISTRATION: The trial was registered at www.drks.de (ID: DRKS00025033 ) on 30th September 2021.

Physical activity promotion for multimorbid patients in primary care settings: a protocol for a systematic review evaluating health benefits and harms.

BACKGROUND: To date multimorbidity has not received much attention in health policies, even though multiple chronic diseases put high demands on the health care system in industrial nations. Enormous costs of care and a physically, mentally, and socially reduced quality of life are common consequences of multimorbidity. Physical activity (PA) has a positive preventive and therapeutic effect on common non-communicable diseases. The objective of this study will be to evaluate the health benefits and harms of PA interventions for sedentary adults with multimorbidity in primary care settings. METHODS: This is the study protocol for a systematic review. We will search PubMed, MEDLINE (Ovid), Web of Science, CINHAL, and the Cochrane Library (from inception onwards). In addition, clinical trial registers and reference lists of included studies will be searched. We will include randomized controlled trials, quasi-experimental, and non-randomized trials examining the health benefits and harms of PA interventions with or without additional lifestyle interventions for sedentary adult patients with multimorbidity (e.g., two or more chronic non-communicable diseases) in primary care. Eligible control groups will be standard care, placebo, or medications. Two reviewers will independently screen all citations, abstracts data, and full-text articles. The primary outcomes will be health-related quality of life and mortality. Secondary outcomes will include cardiovascular fitness, muscular strength and disease-specific outcomes (e.g., depression score), biomarkers as well as control of metabolic risk factors (e.g., blood pressure, HBA1c, body weight) and any adverse event. The methodological quality of the studies will be appraised using appropriate tools. If feasible, we will conduct random effects meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity (e.g., study design, geographical location, or type of intervention). Strength of the body of evidence will be assessed according to the Grading of Recommendations Assessment (GRADE). DISCUSSION: This review will evaluate the evidence on health benefits and harms of PA interventions for sedentary adults with multimorbidity in primary care settings. We anticipate our findings to be of interest to patients, their families, caregivers, and healthcare professionals in selecting and conducting optimal health promotion programs. Possible implications for further research will be discussed. SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (registration identifier: osf.io/ka8yu).