Combination of exercise and GLP-1 receptor agonist treatment reduces severity of metabolic syndrome, abdominal obesity, and inflammation: a randomized controlled trial | Cardiovascular Diabetology

Study population

At inclusion, before the low-calorie diet, the study population was 215 participants (63% women), 42 ± 12 years of age, and a mean BMI of 37.0 ± 2.9. See baseline characteristics in Table 1 and Additional file 1: Table S1. Smoking and alcohol consumption at inclusion are shown in Additional file 1: Table S2.

The observed mean MetS-Z was at inclusion 0.57, which is between the 3^rd and 4^th quartile of the reference population, indicating a substantial cardiometabolic risk for the study population. MetS-Z quartiles and their associated risks are presented in Fig. 1 of this study. At inclusion, the mean MetS-Z of female participants was placed within the 3^rd quartile of MetS-Z scores, while the mean for males was on the border of the 3^rd and 4^th quartiles. The distributions of scores between the groups were similar. The pattern of change in MetS-Z was generally similar between men and women between the three visits (see Additional file 1: Figs. S2 and S3 for observed MetS-Z for women and men separately). At inclusion, 62% of participants had hypertension, and 45% had pre-diabetes.

Observed MetS-Z before and after Low-calorie Diet and at Week 52 by Randomization Group. Observed MetS-Z of individual per-protocol participants (black dots) by randomization group at the three visits, before the low-calorie diet (week -8), after the low-calorie diet (week 0), and end of the trial (week 52), presented as box plots. Tops of the boxes indicate the upper quartile; bottom of the box is the lower quartile; white diamonds observed mean; black horizontal line medians; whiskers ± 1.5 times the interquartile range or highest or smallest observation. Box plots overlay MetS-Z quartiles associated with the risk of future diabetes [12] and coronary heart disease [13] compared to the first quartile and adjusted for individual MetS factors. For diabetes, unadjusted risks are also shown in parentheses. MetS-Z metabolic syndrome severity z-score. T2DM type 2 diabetes, CHD coronary heart disease

A total of 166 participants (85%) completed the study by attending final assessments at week 52. Thus, 15% were lost to follow-up (placebo: 9, exercise: 8, liraglutide: 8, combination: 4), Additional file 1: Fig. S1. Overall, there was an even pattern of loss to follow-up, and the most common cause of dropout was personal life conditions (e.g., job-related changes). The per-protocol population included 130 participants (placebo = 39; exercise = 26, liraglutide = 36; combination = 29).

Changes in body weight and total body fat percentage have previously been published [24]. In summary, results from the trial show that after the low-calorie diet, the participants had reduced body weight by 13.1 kg (~ 12%), Table 1. After one year, the placebo group had increased body weight. The exercise and liraglutide groups maintained body weight while lowering the total fat percentage. The combination group decreased body weight and fat percentage (Table 2) [24].

In the following Results section, we present the results from the participants who completed the trial according to the prescribed interventions (Table 2 and Additional file 1: Table S3 and Fig. 2). The intention-to-treat analysis, including all randomized participants, is presented in Additional file 1: Table S4.

Changes During Low-calorie Diet and From Randomization to Week 52. Per-protocol analysis of mixed model estimated changes in metabolic syndrome severity z-score (A), metabolic syndrome prevalence (B), android fat percentage (C), and high-sensitivity C-reactive protein (D) during a low-calorie diet (shaded area; weeks -8 to 0) and treatment (weeks 0 to 52). Changes are estimated mean differences with ± standard error of the mean. Changes in high-sensitivity C-reactive protein are presented as percentages via ratios from back-transformed log-data and shown with 95% confidence intervals. Between-group changes are estimated mean differences with 95% confidence intervals and p-values. Results are adjusted for age group (< / ≥ 40 years) and sex. Dashed line is the baseline for the low-calorie diet and randomized groups (at week 0)

Changes in metabolic syndrome

The MetS-Z decreased by 0.52 to 0.06, P < 0.001, during the low-calorie diet (Table 1 and Fig. 2A). This reduction shifted the Mets-Z means of all groups from the top 3^rd and bottom 4^th quartiles of the reference population, which indicates higher risk of diabetes and coronary heart disease, to average close to the limit of the 2^nd and 3^rd quartiles, which indicates a lower risk of diabetes and coronary heart disease after the low-calorie diet (Fig. 1). The diet-induced mean changes of individual MetS factors are shown in Table 1, which collectively translated into a decreased average prevalence of MetS from 55 to 29% after the low-calorie diet (Fig. 2B). Furthermore, the prevalence of participants with hypertension was halved (from 62 to 33%), while the prevalence of pre-diabetes was reduced by two-thirds (from 45 to 15%). Insulin resistance, measured by HOMA-IR, was 3.9 ± 2.4 before the low-calorie diet was reduced by 56% to 1.7 ± 1.0 after the diet (Table 1).

One year after the low-calorie diet, the MetS-Z was unchanged in the placebo and exercise groups (Table 2). Compared to placebo, MetS-Z decreased by 0.37, P < 0.001, in the liraglutide group and by 0.48, P < 0.001, in the combination group (Fig. 2A). Noticeably, the means of MetS-Z in the liraglutide and combination groups moved from the higher risk 3^rd to the lower risk 2^nd quartile, indicating a further risk reduction on top of the risk reduction by the low-calorie diet (Fig. 1). The prevalence of participants with MetS at week 52 was similar across active treatment groups, whereas the prevalence was higher within the placebo group (Fig. 2B). The prevalence of participants with hypertension or pre-diabetes was generally lower in the active treatment groups and notably lowered in the groups treated with liraglutide.

Adjusting for blood pressure or lipid-lowering medication, smoking, and alcohol consumption at inclusion did not affect the analysis results (Additional file 1: Table S5).

The reduced insulin resistance seen during low-calorie was maintained in the adherent exercise groups, while insulin resistance increased in the placebo and liraglutide groups (Table 2) after one year.

Changes in fat distribution

Android fat percentage was 44.3% ± 4.7 before the low-calorie diet and decreased by 2.9%-points, P < 0.001 to 41.4% ± 6.0 after the diet (Table 1). See Additional file 1: Table S6 for absolute masses. Men had a lower android fat percentage than women (41.3 vs. 46.0%, respectively) at inclusion and had larger reductions of android fat percentage than women during the low-calorie diet (− 4.6 vs. − 2.0%-points, respectively).

After one year, android and gynoid fat percentages were unchanged in the placebo group; however, android and gynoid fat masses increased (Table 2 and Additional file 1: Table S7). Generally, the active treatment groups seemed to lose relatively more android fat than gynoid fat. Compared to the placebo group, the exercise group decreased android fat percentage by 2.6%-points, P = 0.022, and the liraglutide group decreased android fat percentage by 2.8%-points, P = 0.006, Fig. 2C. Thus, participants in the exercise and liraglutide groups decreased android fat percentage by around 6%-points during the entire trial. The combination group decreased android fat percentage by 6.1%-points, P < 0.001, compared to placebo, around twice as much as exercise or liraglutide treatment alone. Furthermore, in men, android fat percentage was only significantly decreased in the combination group, whereas in women, android percentage was reduced in all the active treatment groups (Table 2).

Changes in high-sensitivity C-reactive protein

The median concentration of the inflammation marker hsCRP was 3.8 mg/L before the low-calorie diet and decreased by 32% to 2.4 mg/L after the diet, P < 0.001, Table 1.

After one year, the hsCRP concentrations did not change in the placebo and exercise groups (Table 2 and Fig. 2D). Within the liraglutide group, hsCRP decreased by 36%; however, this decrease was not different from the placebo group. The combination group reduced hsCRP by 43% compared to the placebo group, P = 0.030. In the intention-to-treat analysis, hsCRP decreased by 35% within the combination group, but this change was not different from the placebo group (Additional file 1: Table S4).

Adherence to interventions

In the per-protocol population, the exercise group performed 156 ± 54 min/week at an intensity of 78 ± 4% of maximum heart rate, and the combination group performed 144 ± 67 min/week at 78 ± 5% of maximum heart rate. The average dose of study medication was at least 2.6 mg/day in all groups. Details regarding exercise and study medication adherence in the intention-to-treat population have previously been published [24].

Safety

Gastrointestinal adverse events (e.g., one or more experiences of nausea, diarrhea, or vomiting during one year) were more commonly reported in the groups receiving liraglutide (placebo group: 45%, exercise group: 65%, liraglutide group: 86%, combination group: 71%). The frequency of serious adverse events was 4%, 8%, 12%, and 8% in the placebo, exercise, liraglutide, and combination groups, respectively. All safety outcomes have previously been reported [24].