In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo. (Funded by Arena Pharmaceuticals; ClinicalTrials.gov number, NCT00395135.)

The evolution of the human mitochondrial genome is characterized by the emergence of ethnically distinct lineages or haplogroups. Nine European, seven Asian (including Native American), and three African mitochondrial DNA (mtDNA) haplogroups have been identified previously on the basis of the presence or absence of a relatively small number of restriction-enzyme recognition sites or on the basis of nucleotide sequences of the D-loop region. We have used reduced-median-network approaches to analyze 560 complete European, Asian, and African mtDNA coding-region sequences from unrelated individuals to develop a more complete understanding of sequence diversity both within and between haplogroups. A total of 497 haplogroup-associated polymorphisms were identified, 323 (65%) of which were associated with one haplogroup and 174 (35%) of which were associated with two or more haplogroups. Approximately one-half of these polymorphisms are reported for the first time here. Our results confirm and substantially extend the phylogenetic relationships among mitochondrial genomes described elsewhere from the major human ethnic groups. Another important result is that there were numerous instances both of parallel mutations at the same site and of reversion (i.e., homoplasy). It is likely that homoplasy in the coding region will confound evolutionary analysis of small sequence sets. By a linkage-disequilibrium approach, additional evidence for the absence of human mtDNA recombination is presented here.

Mellitus) study evaluated efficacy and safety of lorcaserin for weight loss in patients with type 2 diabetes. Secondary objectives included evaluations of glycemic control, lipids, blood pressure, and quality of life. This 1-year, randomized, placebo-controlled trial enrolled 604 patients 1:1:1 to placebo, lorcaserin 10 mg once daily (QD) or lorcaserin 10 mg twice daily (BID). Patients were treated with metformin, a sulfonylurea (SFU) or both; had glycated hemoglobin (HbA 1c ) 7-10%; were 18-65 years old; and had BMI 27-45 kg/m 2 . Patients received diet and exercise counseling. Safety monitoring included serial echocardiograms. Mean (± SD) age was 52.7 ± 8.7; 54.2% were women; 60.5% were white, 20.9% were African American, and 13.8% were Hispanic. Mean (± SD) weight was 103.6 ± 17.8 kg; BMI was 36.0 ± 4.5 kg/m 2 . Most patients (91.7%) took metformin; 50.2% took a SFU. More patients lost ≥5% body weight with lorcaserin BID (37.5%; P < 0.001) or lorcaserin QD (44.7%; P < 0.001) vs. placebo (16.1%; modified intent to treat (MITT)/last observation carried forward (LOCF)). Least square mean (± SEM) weight change was −4.5 ± 0.35% with lorcaserin BID and −5.0 ± 0.5% with lorcaserin QD vs. −1.5 ± 0.36% with placebo (P < 0.001 for each). HbA 1c decreased 0.9 ± 0.06 with lorcaserin BID, 1.0 ± 0.09 with lorcaserin QD, and 0.4 ± 0.06 with placebo (P < 0.001 for each); fasting glucose decreased 27.4 ± 2.5 mg/dl, −28.4 ± 3.8 mg/dl, and 11.9 ± 2.5 mg/dl, respectively (P < 0.001 for each). Symptomatic hypoglycemia occurred in 7.4% of patients on lorcaserin BID, 10.5% on lorcaserin QD, and 6.3% on placebo. Common adverse events were headache, back pain, nasopharyngitis, and nausea. Lorcaserin was associated with significant weight loss and improvement in glycemic control in patients with type 2 diabetes.Obesity ( articles intervention and PreventionThe BLOOM-DM (Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus) study had as its main objective the evaluation of the efficacy and safety of lorcaserin for weight loss in adults with type 2 diabetes treated with metformin and/or a sulfonylurea (SFU). Secondarily, the impact of lorcaserin on glycemic control was evaluated. Methods and Procedures study designThe study was conducted at 58 academic and private research sites in the United States between 27 December 2007 and 9 August 2010 under the guidelines of the Declaration of Helsinki. Institutional review boards reviewed and approved the protocol for each research site. All patients provided written informed consent before participation in the trial.The overall objective of the 1-year, randomized, double-blind, placebo-controlled trial was to evaluate the safety and efficacy of lorcaserin for weight loss in patients with type 2 diabetes when administered in conjunction with a lifestyle modification program. The prespecified coprimary endpoints were: (i) the proportion of patients achieving ≥5% reduction in baseline body weight at the end of 1 year, (ii) change in weight, and (iii) t...

Lorcaserin administered in conjunction with a lifestyle modification program was associated with dose-dependent weight loss that was significantly greater than with placebo.

Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.pramlintide ͉ metreleptin ͉ adiposity ͉ synergy ͉ leptin resistance T he discovery of leptin in 1994 (1) revolutionized our understanding of the biological basis of body-weight regulation and raised hopes that this adipokine could be a breakthrough treatment for obesity. Although leptin plays a pivotal role in regulating energy homeostasis in rodents and humans, its pharmaceutical development as a stand-alone antiobesity agent has proven unsuccessful (2). Although leptin replacement elicits profound weight loss in leptindeficient (Lep ob /Lep ob ) mice and humans (3, 4), even high pharmacological doses elicit only marginal weight loss in non-leptindeficient, diet-induced obese (DIO) rodents and humans (2, 5). The obese state is thus thought to be associated with ''leptin resistance,'' wherein overweight/obese individuals become insensitive to high circulating leptin concentrations (6). The mechanistic basis for leptin resistance is poorly understood, but rodent data implicate leptin transport saturation (7), leptin receptor down-regulation (8), and reduced hypothalamic postreceptor signaling (9, 10).Amylin, a 37-aa peptide hormone cosecreted with insulin from pancreatic ␤-cells (11), binds specific receptors in the hindbrain area postrema (AP) that activate multiple central nervous system (CNS) regions to regulate both glucose and energy homeostasis (12). In obese humans, the amylin analog pramlintide elicited sustained reductions in food intake and body weight (13,14). Amylin-induced weight loss in DIO rats that was observed to be fat-specific with relative...