Exploring the interplay of pharmacotherapy and dietary weight loss interventions with whole body health including physical activity, physical function and body composition

Background

The overall health benefits of weight loss are well known; however, there are important areas that require further investigation such as the effects of pharmacotherapy induced weight loss on physical activity, cardiorespiratory fitness, physical function and body composition which are not well understood. Furthermore, dietary energy restriction is known to improve glycaemic outcomes and lead to type 2 diabetes remission, but the acute time-course of glucose levels following energy restriction and whether physical markers of health are key predictors to these early glycaemic responses are unknown. This thesis aims to further develop the collective evidence surrounding the interplay between physical markers of health and weight loss interventions.

Aims

1) To conduct a systematic review and meta-analysis to investigate the effects of weight-lowering pharmacotherapies on physical function, physical activity and cardiorespiratory fitness.

2) To conduct a systematic review and meta-analysis to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter-2 inhibitors (SGLT2is) on lean body mass in humans.

3) To investigate whether the addition of dapagliflozin 10mg once-daily alters physical activity levels in adults with type 2 diabetes mellitus.

4) To explore whether baseline levels of lean body mass, cardiorespiratory fitness, physical activity and hand-grip strength predict the acute reduction in glucose levels, following the initiation of a meal replacement product diet in young adults with type 2 diabetes mellitus.

Key findings

1) Pooled findings from 14 randomised-controlled trials highlighted an improvement in self-reported physical function, favouring the pharmacotherapy intervention groups (standardised mean difference: 0.27; 95% CI: 0.22 to 0.32). Results were consistent whether physical function was reported using the Short-Form 36-Item questionnaire (SF-36) (0.24; 0.17 to 0.32) or Impact of Weight on Quality of Life-Lite (IWQOL-Lite) (0.29; 0.23 to 0.35). Furthermore, meta-regression highlighted a significant association between pharmacotherapy induced weight loss and improved physical function for IWQOL-Lite (p=0.003). However, overall effects were lower than those observed for dietary interventions.

2) Pooled meta-analysis of 36 trials showed a loss of lean body mass in the direction of the GLP-1RAs (mean difference: -1.51kg [95% CI: -2.00 to -1.01]) and SGLT2is (mean difference: -1.04kg [95% CI: -1.45 to -0.64]) intervention groups. Sub-group analysis highlighted consistent results when stratified by type of body composition outcome, type of body composition measurement technique and disease status. Results were not modified by sex. Further pooled meta-analysis highlighted that lean body mass accounted for 28% of overall weight loss induced by GLP-1RAs and SGLT2is.

3) Initiation of dapagliflozin 10mg once-daily led to reductions in total physical activity of 0.91mg and in moderate-to-vigorous physical activity (MVPA) of 9.12 min/day. Individual change responses in total physical activity from baseline to week 12, highlighted that 53% of participants randomised to dapagliflozin 10mg, underwent minimum clinically important reductions in total physical activity.

4) The initiation of a low-calorie meal replacement product (MRP) diet led to an immediate reduction in continuously measured average glucose levels and improvements in associated continuous glucose metrics; standard deviation of glucose (SDglucose), glucose co-efficient of variation (%CV), time-above range (TAR%), time in range (TIR%) and time-below range (TBR%). The acute glucose responses were modified by baseline physical health markers including lean body mass %, cardiorespiratory fitness, total physical activity, MVPA and handgrip strength (p<0.001 for all interactions).

Conclusions

The findings highlighted in this thesis further understanding of the interplay between physical markers of health and weight loss interventions. Results suggest that when weight loss interventions are initiated, a multifactorial approach may be necessary to enhance the limited effects on physical function, preserve lean body mass and mitigate reductions in physical activity. Future trials should also consider incorporating objective measures of physical activity and physical function within their designs, to ensure the observations described in this thesis are further researched within larger heterogenous study samples and with newer generations of weight loss pharmacotherapies.