The S-LiTE trial studied what should follow a diet that works. Adults with obesity completed an 8-week low-calorie diet of 800 kcal/day and were then randomized to 52 weeks of exercise, liraglutide, both, or placebo [2, 4]. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, a form of GLP-1-based obesity pharmacotherapy [1, 3]. Five reports published between 2022 and 2026 examine outcomes beyond body weight: eating and sedentary behavior, semen quality, physical fitness, glucose regulation, and vascular health and inflammation [1, 2, 3, 4, 5]. Read together, they suggest that exercise and the drug acted on different outcomes, but several are labeled exploratory or secondary, and the analyzed samples differ between reports [1, 2, 3, 4, 5].
One trial, not five
Four of the abstracts list the same registration numbers, EudraCT 2015-005585-32 and ClinicalTrials.gov NCT04122716 [1, 2, 3, 5]. The glucose-regulation abstract gives no registration number and does not name S-LiTE, but it describes an 8-week 800 kcal/day diet followed by randomization of adults with a body mass index of 32 to 43 kg/m2 without diabetes to 52 weeks of exercise, liraglutide 3.0 mg/day, the combination or placebo, matching the design reported in the other abstracts [2, 3, 4]. Agreement among these reports is therefore better read as consistency within one cohort than as independent replication [1, 2, 3, 4, 5]. The primary outcome, change in body weight, was published separately and is not among the sources reviewed here, so this review reports no weight-change figures for the randomized arms [1]. The eating-behavior report states that the placebo group regained weight, that the liraglutide and exercise groups maintained their weight loss, and that behavior changes in the combination group may have facilitated additional weight loss [1].
Design and populations
Participants were adults aged 18 to 65 years with a body mass index of 32 to 43 kg/m2 and without diabetes [3, 4]. The semen substudy reports that the trial ran at Hvidovre Hospital and the University of Copenhagen between August 2016 and November 2019, with participants from the Greater Copenhagen Area [2]. Randomization was 1:1:1:1, stratified by sex and by age group (under 40 and 40 or older) [1]. The trial is described as randomized, controlled and double-blind [1, 2]. Liraglutide and placebo pens were provided by Novo Nordisk, and liraglutide was given at 3 mg once daily [2, 3, 4].
The fitness report describes the exercise program in detail [3]. Group sessions of interval-based indoor cycling followed by circuit training were paired with individual sessions, all at moderate-to-vigorous intensity, designed to meet World Health Organization recommendations on physical activity for health [3]. Adherence was tracked with sports watches and heart rate monitors [3]. Participants randomized to exercise completed a median of 2.65 sessions per week, or 116 minutes per week at 79% of maximum heart rate, with no significant difference between those on placebo and those on liraglutide [3]. The glucose report describes its exercise arm as aerobic exercise [4].
The number of participants analyzed differs across the five reports [1, 2, 3, 4, 5].
- Glucose regulation: 195 participants randomized [4].
- Physical fitness: 193 adults [3].
- Eating and sedentary behavior: 130 participants who completed the trial according to protocol, split as 26 exercise, 36 liraglutide, 29 combination and 39 placebo [1].
- Vascular health and inflammation: 130 adults [5].
- Semen quality: 56 men [2].
Findings by outcome domain
Eating and sedentary behavior
One year after weight loss, the placebo group's postprandial appetite suppression score fell by 14% and its sedentary time rose by 31 minutes per day [1]. Liraglutide prevented the fall in appetite suppression relative to placebo (0% vs -14%; P = 0.023) [1]. Exercise did not raise appetite or sedentary behavior relative to placebo, even though exercise energy expenditure was higher [1]. The combination increased the cognitive restraint score, which reflects conscious restriction of food intake, by 13% versus -9% with placebo (P = 0.042) [1]. It also changed sedentary time by -10 versus +31 minutes per day, a reduction of 41 minutes per day (95% CI -82.3 to -0.2; P = 0.049) [1].
Physical fitness and strength
The three key secondary fitness endpoints, measured as change from randomization to week 52, were time to ascend and descend an 11-step stairway twice, peak oxygen consumption normalized to fat-free mass, and isometric knee extensor peak torque [3]. Compared with liraglutide alone, the combination shortened stair-climb time by 1.2 s (95% CI 0.6 to 1.9), or 8.6%, and raised peak oxygen consumption by 3.0 mL/min/kg fat-free mass (95% CI 0.5 to 5.5) [3]. Exercise alone produced similar benefits, whereas liraglutide alone did not improve physical fitness [3].
Relative muscle strength is strength normalized to body weight [3]. It changed by -7.8% with placebo, compared with -0.4% with exercise, +1.0% with liraglutide and +3.3% with the combination [3]. The authors attribute these differences to lower body weight with preserved absolute strength [3].
Glucose regulation
The glucose report used a 3-hour mixed meal test, and beta cell function was measured with the disposition index [4]. Compared with placebo, the combination produced three changes after 1 year of treatment [4].
- Postprandial glucose response fell by 9% (95% CI -14% to -3%; p = 0.002) [4].
- Beta cell function improved by 49% (95% CI 16% to 93%; p = 0.002) [4].
- Glucagon response fell by 18% (95% CI -34% to -3%; p = 0.024) [4].
Liraglutide alone lowered postprandial glucose response by 7% versus placebo (95% CI -12% to -1%; p = 0.018), but it did not change beta cell function or glucagon [4]. Exercise alone did not differ from placebo on any of the three measures [4].
Vascular health and inflammation
Exercise, alone or with liraglutide, reduced carotid intima-media thickness and the circulating pro-inflammatory cytokines interleukin-6 and interferon-γ [5]. The combination additionally improved three biomarkers of endothelial function: sICAM-1, sVCAM-1 and tPA [5]. Liraglutide alone showed none of these improvements [5]. The abstract does not report effect sizes or confidence intervals [5].
Semen quality
During the 8-week diet, the men lost on average 16.5 kg (95% CI 15.2 to 17.8) [2]. Over the same period, sperm concentration rose 1.49-fold (95% CI 1.18 to 1.88; P < 0.01) and sperm count rose 1.41-fold (95% CI 1.07 to 1.87; P < 0.01) [2]. At 52 weeks the improvements were still present among men who kept the weight off, and absent among men who regained weight [2]. Semen volume, sperm motility and motile sperm count did not change [2].
Where the reports agree
On fitness and vascular outcomes, the arms that included exercise improved fitness, carotid intima-media thickness and inflammatory cytokines, while liraglutide alone did not [3, 5]. The combination arm showed favorable results in every report that tested it: in eating and sedentary behavior against placebo [1], in fitness against liraglutide alone [3], in glucose regulation against placebo [4], and in endothelial biomarkers [5]. The finding that exercise did not raise appetite after weight loss fits with the report that the exercise group maintained its weight loss [1].
Where they diverge
Exercise alone improved fitness, carotid intima-media thickness and inflammatory markers, yet it matched placebo on glucose response, beta cell function and glucagon [3, 4, 5]. Liraglutide alone showed the reverse pattern: it preserved appetite suppression and lowered postprandial glucose, but it did not improve beta cell function, fitness or vascular markers [1, 3, 4, 5].
The authors' conclusions differ in emphasis as a result [1, 4, 5].
- The glucose report concludes that only the combination improved glucose tolerance, beta cell function and glucagon responses [4].
- The vascular report concludes that regular physical activity, with or without a GLP-1 receptor agonist, is essential for vascular health [5].
- The eating-behavior report proposes that targeting both eating and sedentary behavior may best prevent weight regain [1].
One apparent conflict comes from how an outcome was defined [3]. Liraglutide alone did not improve fitness, yet its relative muscle strength was higher than placebo's (+1.0% vs -7.8%) [3]. Because relative strength is divided by body weight, an arm can score better through lower weight with preserved absolute strength, which is the explanation the authors give [3].
The reports also use different comparators: the fitness report contrasts the combination with liraglutide alone, whereas the glucose report contrasts it with placebo, so their effect sizes cannot be set side by side [3, 4].
How strong the evidence is
For the randomized between-arm comparisons, the design supports direct statements about the interventions' effects in this population, but several features temper that strength [1, 2, 3, 4, 5].
- None of these outcomes was the primary endpoint: the eating-behavior outcomes were prespecified exploratory outcomes, the fitness endpoints were key secondary endpoints, and the vascular analysis was a prespecified secondary analysis [1, 3, 5].
- The eating-behavior report analyzed only the 130 participants who completed the trial according to protocol, against 195 randomized in the glucose report, so its comparisons may not fully preserve the balance that randomization creates [1, 4].
- Two eating-behavior results sit close to conventional significance thresholds: P = 0.042 for cognitive restraint, and P = 0.049 with a confidence interval bound of -0.2 for sedentary time [1].
- The semen gains occurred during the diet phase, before randomization, and the comparison of men who maintained versus regained weight groups them by weight trajectory rather than by assigned arm; the authors state that definite inferences cannot be made [2].
- The semen substudy reports funding from the Novo Nordisk Foundation, liraglutide and placebo pens supplied by Novo Nordisk, and author financial ties to Novo Nordisk and other companies [2].
What remains unknown
Several questions fall outside what these reports address [1, 2, 3, 4, 5].
- Duration: the randomized phase lasted 52 weeks, so durability beyond one year and the effects of stopping treatment are not addressed [1, 2, 3, 4, 5].
- Clinical events: the vascular and metabolic outcomes are biomarkers and imaging measures, not cardiovascular events or diabetes incidence [4, 5].
- Population: the trial enrolled adults aged 18 to 65 with a body mass index of 32 to 43 kg/m2 and without diabetes, so results may not extend to older adults or people with diabetes [3, 4].
- Setting: the semen substudy places participants in the Greater Copenhagen Area, and transfer to other settings is untested [2].
- Drug: only liraglutide 3 mg once daily was studied, so these reports say nothing directly about other GLP-1-based medicines [3, 4].
- Mechanism: the link between the combination arm's behavior changes and additional weight loss is offered as a possibility, not demonstrated [1].
Limitations
This review relies on published abstracts, not full texts, so interaction analyses, adverse events, sex-specific results and the vascular effect sizes could not be examined [1, 2, 3, 4, 5]. The trial's primary weight outcome was not among the sources, so the weight context comes only from the eating-behavior report [1]. The sources report on a single trial design, four of them by shared registration number, and only the semen substudy reports funding, so this synthesis cannot test whether the pattern holds in other cohorts or assess sponsorship across all five reports [1, 2, 3, 4, 5].
References
- Jensen SBK, Janus C, Lundgren JR, et al. Exploratory analysis of eating- and physical activity-related outcomes from a randomized controlled trial for weight loss maintenance with exercise and liraglutide single or combination treatment. Nat Commun. 2022;13(1):4770. doi:10.1038/s41467-022-32307-y. PMID: 35970829. https://pubmed.ncbi.nlm.nih.gov/35970829/
- Andersen E, Juhl CR, Kjøller ET, et al. Sperm count is increased by diet-induced weight loss and maintained by exercise or GLP-1 analogue treatment: a randomized controlled trial. Hum Reprod. 2022;37(7):1414-1422. doi:10.1093/humrep/deac096. PMID: 35580859. https://pubmed.ncbi.nlm.nih.gov/35580859/
- Jensen SBK, Fiorenza M, Juhl CR, et al. Physical Fitness with Exercise and GLP-1 Receptor Agonist Treatment Alone or Combined After Diet-Induced Weight Loss: A Secondary Analysis of a Randomized Controlled Trial in Adults with Obesity. Sports Med. 2026;56(7):1785-1800. doi:10.1007/s40279-025-02386-0. PMID: 41579235. https://pubmed.ncbi.nlm.nih.gov/41579235/
- Jensen SBK, Juhl CR, Janus C, et al. Weight loss maintenance with exercise and liraglutide improves glucose tolerance, glucagon response, and beta cell function. Obesity (Silver Spring). 2023;31(4):977-989. doi:10.1002/oby.23715. PMID: 36942420. https://pubmed.ncbi.nlm.nih.gov/36942420/
- Sandsdal RM, Holt J, Alkhefagie HGA, et al. Effects of exercise and liraglutide on vascular health and inflammation during weight loss maintenance: a prespecified secondary analysis of the S-LiTE trial. Nat Metab. 2026;8(7):1483-1488. doi:10.1038/s42255-026-01554-4. PMID: 42342869. https://pubmed.ncbi.nlm.nih.gov/42342869/