Synergy Effect of the Appetite Hormone GLP-1 (LiragluTide) and Exercise on Maintenance of Weight Loss and Health After a Low Calorie Diet - the S-LiTE Randomized Trial

Obesity is associated with increased risk of developing cardiovascular disease and type 2 diabetes (T2D), along with increased risk of all-cause mortality [1,2]. Obesity management guidelines recommends weight loss of more than 5 % of initial body weight to improve cardiometabolic risk factors, with greater weight loss producing greater benefits [3,4]. A 5 to 10 % weight loss improves lipid profile (~20% reduction in triglycerides, ~15 % reduction in LDL-cholesterol, ~8 % increase in HDL-cholesterol levels) [1,4,5], reduces systolic and diastolic blood pressure (~5 and ~4 mmHg, respectively) [3,6], reduces HbA1c [3,4], and improves insulin sensitivity [7-9]. However, weight regain reverse these health benefits [10,11]. Furthermore, intentional weight loss is typically followed by a 30 to 50 % regain of lost weight within the first year [12-14]. The main biological reasons for the rapid weight regain may be that weight loss causes a decrease in total energy expenditure to a degree that is greater than predicted from the decrease in fat and lean mass [15,16] in combination with increased appetite in the weight-reduced state [17,18].

Increasing energy expenditure by increasing physical activity is the first-line lifestyle modification in the treatment of obesity along with reducing food intake. For exercise interventions targeting general public health recommendations (at least 150 min/week of moderate intensity aerobic exercise), the associated weight loss is often modest (0-3 %) without concomitant calorie restriction [19-21]. However, independent of weight loss, increasing physical activity improves body composition, glycemic control, low grade inflammatory profile, and cardiorespiratory fitness in individuals with overweight and obesity [22-25]. In addition, exercise may preserve lean mass during weight loss [26] and thereby counteract the associated decrease in resting metabolic rate [27], which may explain the observation that individuals performing regular exercise have less body weight regain after weight loss compared to participants that do not exercise [28,29].

Glucagon-like peptide-1 (GLP-1) is an incretin hormone primarily secreted from enteroendocrine L-cells in the gut after food intake. GLP-1 stimulates glucose-dependent insulin secretion thereby lowering blood glucose and reduces appetite and thereby food intake [30,31]. Treatment for 56 weeks with the GLP-1 receptor agonist (GLP-1 RA), liraglutide (3.0 mg), as an adjunct to regular diet and physical activity recommendations has been shown to improve glycemic control and induce moderate weight loss of 4.0 % in patients with T2D [32] and 5.4 % in non-diabetic individuals with overweight or obesity [33] compared to placebo. In addition, liraglutide has been shown to maintain a diet-induced weight loss over 56 weeks [34] and maintain very low-calorie diet-induced improvements of fasting plasma glucose and triglycerides over 52 weeks of weight loss maintenance superior to similar diet-induced weight loss maintenance in obese nondiabetic individuals [18].

Obesity is associated with chronic low-grade inflammation [35,36] which is linked to the development of atherosclerosis and insulin resistance [37-39]. Physically active individuals have lower inflammatory biomarker concentrations than their inactive counterparts [24], possibly explained by antiinflammatory effects of an acute bout of exercise [40] and lower levels of visceral adipose tissue [41]. GLP-1 has also emerged as an immunomodulatory agent [42,43]. In mice, GLP-1 RA administration reduces macrophage accumulation and inflammatory markers in the arterial wall [44], adipose tissue [45], and heart [46]. Similarly, GLP-1 RAs have shown antiinflammatory effects in human coronary artery endothelial cells and aortic endothelial cells [47]. In humans with T2D, short term GLP-1 RA treatment exert antiinflammatory actions, reflected in reduced levels of the macrophage activation molecule sCD163 [48] and reduced production of several proinflammatory markers, such as TNF-α, IL1β, and IL-6 in peripheral blood mononuclear cells [48,49]. Another study showed no improvement of obesity-associated adipose tissue dysfunction in T2D patients after GLP-1RA treatment [50]. One year treatment with GLP-1 RAs reduce the inflammation marker, high-sensitivity C-reactive protein, in overweight and obese individuals [33] and T2D patients [51]. Notably, in patients with T2D and high cardiovascular risk, GLP-1 RAs reduced the rate of occurrence of first major cardiovascular event [52,53].

Thus, both physical activity and GLP-1 RA treatment seem to facilitate weight loss maintenance, improve metabolic health, and reduce systemic inflammation. However, diet-induced weight loss decreases energy expenditure and increases appetite. The investigators hypothesize that the combination of physical activity and liraglutide treatment improves weight loss maintenance and immunometabolic health since the decreased energy expenditure is targeted with exercise and the increased appetite with liraglutide.