Structured lifestyle modification as an adjunct to obesity pharmacotherapy: there is much to learn.

We are at the start of an exciting new era of very effective pharmacotherapy for patients with obesity, with the latest generation of drugs approaching the efficacy of obesity surgery. Clinical trials of obesity drugs tend to emphasise the importance of participation in some form of structured lifestyle intervention for all trial participants. This usually consists of advice to reduce calorie intake and increase moderate to vigorous physical activity. There is strong evidence that structured lifestyle modification programmes improve health in patients with obesity and related disorders. However, there is no specific evidence that they improve the response to obesity medications. This is because of the way that drug trials for patients with obesity have traditionally been designed, with participants in the active drug treatment group being compared to participants on placebo drug treatment, but with both groups always receiving the same structured lifestyle intervention. While this approach is entirely reasonable, it makes it impossible to draw any inferences about the efficacy of structured lifestyle modification to augment the response to drug therapy. Given this genuine equipoise, a critical step in ensuring that our treatment of patients with obesity is robustly evidence-based is to determine whether "drug plus lifestyle" offer any advantage over "drug plus placebo" in large, well-designed and adequately powered clinical trials. We also need to determine the cost-effectiveness of these programmes.

Changes in the Leptin to Adiponectin Ratio Are Proportional to Weight Loss After Meal Replacement in Adults With Severe Obesity.

Hypocaloric diets are known to induce changes in adipokine secretion, but the influence of a low energy liquid diet (LELD) on the leptin: adiponectin ratio (LAR), a measure of insulin resistance and cardiovascular risk, has not previously been investigated in patients with severe obesity. We conducted a prospective, single-center cohort study of adults with severe obesity (defined as body mass index (BMI) ≥40 kgm-2, or ≥35 kgm-2 with co-morbidities) who completed a 24-week milk-based LELD. We measured leptin, adiponectin and LAR at the start and on completion of the programme. Of 120 patients who started, 52 (43.3 %) completed the programme. Their mean age was 50.3 ± 11.2 (range 18-74) years, 29 (55.8 %) were female and 20 (38.5 %) had type 2 diabetes mellitus (T2DM). Weight decreased from 148.2 ± 39.6 to 125.4 ± 34.8 kg and BMI decreased from 52.4 ± 11.1 to 44.3 ± 9.8 kgm-2, respectively (all p < 0.001). In patients with T2DM, HbA1c decreased from 60.0 ± 17.4 to 47.5 ± 15.5 mmol/mol (p < 0.001). Leptin decreased (from 87.2 [48.6, 132.7] to 39.1 [21.0, 76.4] ng/ml) and adiponectin increased (from 5.6 [4.5, 7.5] to 7.1 [5.5, 8.5] µg/ml), with a reduction in LAR from 15 [8.4, 22.4] to 5.7 [3.0, 9.1] ng/µg (all p < 0.001), indicating decreased insulin resistance. The percentage weight lost was associated with the percentage reduction in LAR (ß = 2.9 [1.7, 4.1], p < 0.001) and this association was stronger in patients with T2DM. Patients with severe obesity who completed a milk-based LELD had a substantial reduction in LAR, consistent with decreased insulin resistance and cardiovascular risk, proportional to weight loss.

Changes in alanine aminotransferase in adults with severe and complicated obesity during a milk-based meal replacement programme.

INTRODUCTION: Excess adiposity is associated with fat accumulation within the liver, and non-alcoholic steatohepatitis (NASH) is highly prevalent in bariatric patients. Elevated alanine aminotransferase (ALT) is associated with prevalent NASH. We sought to determine the influence of a milk-based meal replacement weight-loss programme on ALT levels in adults with severe and complicated obesity. METHODS: We conducted a retrospective cohort study of patients who completed a 24-week meal replacement programme, comprised of a weight loss phase followed by weight stabilisation and maintenance phases, each 8 weeks long. ALT was quantified using an enzymatic assay with spectrophotometric detection. We examined changes over time in ALT using the non-parametric Wilcoxon singed-rank test and the Friedman test. RESULTS: Of 105 patients, 56 were female, mean age was 51.2 ± 11.2 (range 18.0-71.6) years. There was an unanticipated but transient increase in ALT from 28.0 [20.0, 40.5] iu/L at baseline to 40.0 [26.0, 55.0] iu/L after 2 weeks (p < 0.0005), followed by a gradual reduction to 21.0 [17.0, 28.3] iu/L by 24 weeks (p < 0.0005). The overall reductions in ALT were more pronounced in patients who had elevated levels at baseline. Body weight decreased from 144.2 ± 28.0 kg at baseline to 121.6 ± 25.4 kg at 24 weeks (p < 0.0005) and body mass index (BMI) decreased from 50.7 ± 8.1 kg m-2 at baseline to 43.0 ± 7.6 kg m-2 by 24 weeks (p < 0.0005). CONCLUSION: In adults with severe and complicated obesity undergoing a milk-based meal replacement programme, there was an initial unanticipated rise in ALT in the first 2 weeks, followed by a gradual overall reduction by 24 weeks. These findings suggest that rapid weight loss secondary to significant caloric restriction might induce a transient deterioration in hepatic steatosis prior to an ultimate overall improvement.