Lorcaserin treatment decreases body weight and reduces cardiometabolic risk factors in obese adults: A six-month, randomized, placebo-controlled, double-blind clinical trial.

Lorcaserin is a serotonin 2c receptor agonist that promotes weight loss while contributing to the prevention and improvement of type 2 diabetes and improvement of atherogenic lipid profiles, without higher rates of major cardiovascular events. The full spectrum of possible lorcaserin-induced improvements in cardiometabolic health remains to be clarified. Thus, we investigated the way in which lorcaserin treatment may alter cardiovascular disease risk, either independently or through changes in body weight. We measured, for the first time, lipid particle quantification, lipid peroxidation, appetite-regulating hormones and mRNA expression of the 5-hydroxytryptamine 2c receptor (5-HT2c receptor). A total of 48 obese participants were enrolled in this six-month, randomized (1:1), placebo-controlled, double-blinded clinical trial. Lorcaserin treatment reduced fat mass (P < 0.001), the fatty liver index (P < 0.0001) and energy intake (P < 0.03) without affecting energy expenditure or lean mass. Total low-density lipoprotein (LDL) (P < 0.04) and small LDL particles (P < 0.03) decreased, while total high-density lipoprotein (HDL) P < 0.02) increased and heart rate significantly decreased with lorcaserin treatment. No mRNA expression of the 5-HT2c receptor was observed in peripheral organs. These data suggest that lorcaserin treatment for six months improves cardiometabolic health in obese individuals, acting mainly through the brain.

Leptin in human physiology and pathophysiology.

Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.

Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

Lorcaserin is a serotonin 5-hydroxytryptamine 2c receptor agonist effective in treating obesity. Studies in rodents have shown that lorcaserin acts in the brain to exert its weight-reducing effects, but this has not yet been studied in humans. We performed a randomized, placebo-controlled, double-blind trial with 48 obese participants and used functional MRI to study the effects of lorcaserin on the brain. Subjects taking lorcaserin had decreased brain activations in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state. Decreases in emotion- and salience-related limbic activity, including the insula and amygdala, were attenuated at 4 weeks. Decreases in caloric intake, weight, and BMI correlated with activations in the amygdala, parietal, and visual cortices at baseline. These data suggest that lorcaserin exerts its weight-reducing effects by decreasing attention-related brain activations to food cues (parietal and visual cortices) and emotional and limbic activity (insula, amygdala). Results indicating that baseline activation of the amygdala relates to increased efficacy suggest that lorcaserin would be of particular benefit to emotional eaters.

Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women.

Strenuously exercising young women with hypothalamic amenorrhea are hypoleptinemic and have low bone mineral density (BMD) and content (BMC), which predispose them to increased fracture risk. Short-term leptin replacement in these women corrects many neuroendocrine abnormalities and increases circulating levels of bone formation markers. Whether treatment with recombinant methionyl human leptin (metreleptin) for a long period improves BMD and BMC remains unknown. We studied 20 strenuously exercising young women with hypoleptinemia (leptin concentration <5 ng/mL) and hypothalamic amenorrhea of at least 6 months' duration. Eleven were randomized to metreleptin (initial dose, 0.08 mg/[kg·d] for 3 months; altered thereafter to 0.12 mg/kg for lack of efficacy or 0.04 mg/[kg d] for more than 5% weight loss) and 9 were randomized to placebo for 9 months. After a 3-month washout period, subjects were reexamined at the 1-year time point. Six subjects elected to continue on open-label metreleptin treatment for another 12 months. Two subjects dropped out after 18 months, and 4 completed the entire 2-year study. The BMD and BMC of the total body, lumbar spine (L1-L4), hip, and radius were assessed by using dual-energy x-ray absorptiometry at baseline and at 3, 6, 9, 12, 18, and 24 months of treatment. Metabolic and hormonal parameters and bone markers were measured in blood and urine. Metreleptin significantly increased BMC (P = .034) and tended to increase BMD (P = .069) at the lumbar spine at 9 months in the entire study group (intention-to-treat analysis). In subjects who completed the entire 2-year study (n = 4), metreleptin significantly increased BMD (P = .024) and BMC (P = .049) at the lumbar spine by 4% to 6%. Changes were not significant at the whole body, hip, and radius. Changes in hormonal and metabolic parameters and bone markers were moderate during the first year of treatment, but metreleptin further increased insulin-like growth factor 1 and decreased cortisol and cross-linked C-terminal telopeptide of type 1 collagen concentrations in serum during the second year of treatment (P < .05). The incremental area under the estradiol concentration curve over the 2-year course of the study correlated positively with the corresponding increase in lumbar spine BMD (ρ = 0.42, P = .039). Long-term metreleptin administration in strenuously exercising young women with hypothalamic amenorrhea and hypoleptinemia increases lumbar spine BMD and BMC and alters bone remodeling milieu to favor bone accretion. Results from this pilot study should be confirmed by future, larger clinical trials and need to be extended by studying bone microarchitecture and fracture risk.