Barbara McGowan

The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity

There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity.

Adjustable gastric banding and sleeve gastrectomy in Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with an estimated incidence of 1 in 125,000 in Europe [1, 2]. It is characterised by obesity, polydactyly, retinal dystrophy, congenital defects and renal dysfunction [3]. BBS is genetically heterogeneous, and to date, 16 BBS genes on multiple loci have been identified [4]. Obesity is a major concern in BBS. Data from a large cohort from our centre and others suggest that between 72 and 96 % of post-pubertal individuals are obese [1, 5]. Whilst birth weight is usually normal in these patients, significant weight gain is seen in childhood and throughout adult life. The pathophysiology of obesity in BBS has not been fully determined. Surgical treatment may lead to sustainable weight loss in the general population [6], but currently, there are few data on surgery in syndromic obesity. One patient with BBS has been reported to undergo Roux-en-Y gastric bypass surgery and achieved a successful outcome [7]. However, gastric bypass surgery is not ideal for all and other procedures may be appropriate. We report two cases of alternative bariatric surgical procedures in BBS patients, one with adjustable gastric banding and the second with sleeve gastrectomy. identified at birth due to polydactyly. He had a history of speech delay, educational needs, hypogonadism and retinitis pigmentosa. He fulfilled five out of the six major diagnostic criteria [8] required for the diagnosis of BBS and had a confirmed genetic diagnosis of BBS. Two younger siblings had also been diagnosed with BBS. He was obese from early childhood. Bullying at school contributed to depression and he had a propensity to comfort eating. Weight management consisted of exercise and dietary measures, but with limited success. Orlistat was trialed but gastrointestinal side effects led to discontinuation. At presentation to the BBS clinic, he had type 2 diabetes (T2DM) of 10 years in duration, hypertension and dyslipidaemia. Glycaemic control was poor with glycated haemoglobin (HbA1c) of 10.3 % (89 mmol/mol) despite maximal doses with gliclazide and metformin. Exenatide, a glucagon-like-peptide 1 (GLP-1) analogue, was initiated for 6 months but had little effect on weight or glycaemic control. In view of his metabolic complications and psychosocial co-morbidities, surgery was considered. Pre-operative body mass index (BMI) was 53.1 kg/m and body weight 149.8 kg. Laparoscopic adjustable gastric banding was chosen in conjunction with patient choice, and the patient underwent a standard very low calorie diet prior to surgery. The post-operative course was uneventful. He underwent regular band adjustments and adhered to an appropriate postsurgical diet. Six months post-procedure, his weight was 131.4 kg with a BMI of 46.6 kg/m representing a total weight loss of 18.6 kg (12.4 % of pre-operative total body weight) (Fig. 1). Glycaemic control initially improved with HbA1c at 6 months of 8.2 % (66.1 mmol/mol). Gliclazide and exenatide were discontinued and the diabetes was managed on metformin alone. At 26 months post-procedure, there was moderate weight regain (136.5 kg) but glycaemic control had deteriorated with HbA1c of 10.3 % despite gliclazide, exenatide (once weekly) OBES SURG (2014) 24:1746–1748 DOI 10.1007/s11695-014-1379-7

Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial

BACKGROUND Obesity is a major public health issue, and new pharmaceuticals for weight management are needed. Therefore, we evaluated the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss. METHODS We did a randomised, double-blind, placebo and active controlled, multicentre, dose-ranging, phase 2 trial. The study was done in eight countries involving 71 clinical sites. Eligible participants were adults (≥18 years) without diabetes and with a body-mass index (BMI) of 30 kg/m2 or more. We randomly assigned participants (6:1) to each active treatment group (ie, semaglutide [0·05 mg, 0·1 mg, 0·2 mg, 0·3 mg, or 0·4 mg; initiated at 0·05 mg per day and incrementally escalated every 4 weeks] or liraglutide [3·0 mg; initiated at 0·6 mg per day and escalated by 0·6 mg per week]) or matching placebo group (equal injection volume and escalation schedule to active treatment group) using a block size of 56. All treatment doses were delivered once-daily via subcutaneous injections. Participants and investigators were masked to the assigned study treatment but not the target dose. The primary endpoint was percentage weight loss at week 52. The primary analysis was done using intention-to-treat ANCOVA estimation with missing data derived from the placebo pool. This study is registered with ClinicalTrials.gov, number NCT02453711. FINDINGS Between Oct 1, 2015, and Feb 11, 2016, 957 individuals were randomly assigned (102-103 participants per active treatment group and 136 in the pooled placebo group). Mean baseline characteristics included age 47 years, bodyweight 111·5 kg, and BMI 39·3 kg/m2. Bodyweight data were available for 891 (93%) of 957 participants at week 52. Estimated mean weight loss was -2·3% for the placebo group versus -6·0% (0·05 mg), -8·6% (0·1 mg), -11·6% (0·2 mg), -11·2% (0·3 mg), and -13·8% (0·4 mg) for the semaglutide groups. All semaglutide groups versus placebo were significant (unadjusted p≤0·0010), and remained significant after adjustment for multiple testing (p≤0·0055). Mean bodyweight reductions for 0·2 mg or more of semaglutide versus liraglutide were all significant (-13·8% to -11·2% vs -7·8%). Estimated weight loss of 10% or more occurred in 10% of participants receiving placebo compared with 37-65% receiving 0·1 mg or more of semaglutide (p<0·0001 vs placebo). All semaglutide doses were generally well tolerated, with no new safety concerns. The most common adverse events were dose-related gastrointestinal symptoms, primarily nausea, as seen previously with GLP-1 receptor agonists. INTERPRETATION In combination with dietary and physical activity counselling, semaglutide was well tolerated over 52 weeks and showed clinically relevant weight loss compared with placebo at all doses. FUNDING Novo Nordisk A/S.

The Endocrine and Metabolic Characteristics of a Large Bardet-Biedl Syndrome Clinic Population.

Context Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder in which previous reports have described obesity and a metabolic syndrome. Objective We describe the endocrine and metabolic characteristics of a large BBS population compared with matched control subjects. Design We performed a case-control study. Setting This study was performed at a hospital clinic. Patients Study patients had a clinical or genetic diagnosis of BBS. Main Outcome Measurements Our study determined the prevalence of a metabolic syndrome in our cohort. Results A total of 152 subjects were studied. Eighty-four (55.3%) were male. Mean (± standard deviation) age was 33.2 ± 1.0 years. Compared with age-, sex-, and body mass index-matched control subjects, fasting glucose and insulin levels were significantly higher in subjects with BBS (glucose: BBS, 5.2 ± 1.2 mmol/L vs control, 4.9 ± 0.9 mmol/L, P = 0.04; insulin: BBS, 24.2 ± 17.0 pmol/L vs control, 14.2 ± 14.8 pmol/L, P < 0.001). Serum triglycerides were significantly higher in subjects with BBS (2.0 ± 1.2 mmol/L) compared with control subjects (1.3 ± 0.8 mmol/L; P < 0.001), but total cholesterol, high-density lipoprotein, and low-density lipoprotein were similar in both groups. Systolic blood pressure was higher in the BBS group (BBS, 135 ± 18 mm Hg vs control subjects, 129 ± 16 mm Hg; P = 0.02). Alanine transaminase was raised in 34 (26.8%) subjects with BBS, compared with five (8.9%) control subjects (P = 0.01). The rate of metabolic syndrome, determined using International Diabetes Federation criteria, was significantly higher in the BBS group (54.3%) compared with control subjects (26% P < 0.001). Twenty-six (19.5%) of male subjects with BBS were hypogonadal (serum testosterone, 9.9 ± 5.3 mmol/L), but significant pituitary abnormalities were uncommon. Subclinical hypothyroidism was present in 24 of 125 (19.4%) patients with BBS, compared with 3 of 65 (4.6%) control subjects (P = 0.01). Conclusions Insulin resistance and the metabolic syndrome are increased in adult patients with BBS compared with matched control subjects. Increased subclinical hypothyroidism in the BBS cohort needs further investigation.

Early post-operative aldosterone concentration can be used to assess outcome from adrenalectomy in aldosterone producing adenoma

Immediately post surgery: 19 (83%) were normokalaemic, 3 (13%) hypokalaemic and 1 (4%) hyperkalaemic 20 (87%) had normal ARR After 3/12 post surgery: 21 (91%) were normokalaemic and 2 (9%) were hyperkalaemic 23 (100%) had normal ARR Early post-operative aldosterone concentration can be used to assess outcome from adrenalectomy in aldosterone producing adenoma Irfan Baig, Jake Powrie, Barbara McGowan, Jonathan Hubbard, Paul V Carroll Guy’s & St. Thomas NHS Foundation Trust, London

Erratum to: Adjustable Gastric Banding and Sleeve Gastrectomy in Bardet-Biedl Syndrome

1. Beales PL. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. Journal of Medical Genetics. 36:437–446. 1999 Jun 1. 2. Klein D. The syndrome of Laurence-Moon-BardetBiedl and allied diseases in Switzerland: clinical, genetic and epidemiological studies. Journal of the Neurological Sciences 1969;9(3):479–513 3. Bardet-Biedl Syndrome. 2003 Jul 14 [Updated 2014 Feb 20]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1363/ 4. Stoetzel C, Muller J, Laurier V, et al. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet. 2007;80(1):1–11. DOI:10.1086/510256 5. Green JS. The cardinal manifestations of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. New England Journal of Medicine 1989 Oct 12;321(15):1002–9. 6. Sjostrom CD. Effects of bariatric surgery on mortality in Swedish obese subjects. New England Journal of Medicine 2007 Aug 23;357(8):741–52 7. Daskalakis M. Roux-en-Y gastric bypass in an adolescent patient with Bardet-Biedl syndrome, a monogenic obesity disorder. Obesity Surgery 2010 Jan;20(1):121–5. 8. Beales PL, Elcioglu N, Woolf AS, et al. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36(6):437–46. 9. Iannello S. A review of the literature of Bardet-Biedl disease and report of three cases associated with metabolic syndrome and diagnosed after the age of fifty. Obesity Reviews 2002 May;3(2):123–35 10. Imhoff O. Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. Clinical Journal of the American Society of Nephrology 2011 Jan;6(1):22–9 11. Moore SJ, Green JS, Fan Y, et al. Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study. Am J Med Genet. 2005;132A(4):352–60. DOI:10.1002/ajmg.a.30406 The online version of the original article can be found at http://dx.doi.org/ 10.1007/s11695-014-1379-7. S. Mujahid :M. S. B. Huda (*) : P. V. Carroll : B. M. McGowan Department of Diabetes and Endocrinology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK e-mail: bobby.huda@bartshealth.nhs.uk