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NEWS & VIEWSNEWS AND VIEWSNEWS AND VIEWS– Focus on Obesity

this section...hlights from the latests and research

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Obesity surgery could save lives, in the right patients

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An extensive study carried out byresearchers in Sweden has foundthat surgery can reduce prematuredeath in those suffering fromsevere obesity.

Researchers from the Sahlg-renska Academy (Gothenburg,Sweden), looked at the 4047obese subjects who were part ofthe prospective, controlled Swed-ish Obese Subjects study. Ofthese, 2010 received bariatric

surgery (surgery group) and 2037 received con-ventional treatment (matched control group).Conventional treatment included advice aboutlifestyle changes that would lead to weight loss.Some also received drug therapy to help weightloss. In their study, published in the New EnglandJournal of Medicine, the researchers report theoverall mortality during an average of 10.9 yearsof follow-up. They found that in the controlgroup, average weight change was less than ±2%.By comparison, the weight loss results in the sur-gery group after 10 years were 25, 16 and 14%for gastric bypass, vertical-banded gastroplastyand banding, respectively. A total of 129 deathsoccurred in the control group, compared with101 in the surgery group, therefore it was con-cluded that mortality was significantly lower inthose patients who had received surgery.

“We show for the first time that surgery againstobesity not only leads to long-term loss of weight, italso significantly reduces mortality”, says LarsSjöström, Professor Emeritus at the SahlgrenskaAcademy. He continued: “The mechanisms behindthe lower mortality are not clear. It seems that thereduction in risk depends less upon the actual lossof weight itself than on the fact that the patientshave undergone surgery against obesity. This obser-vation opens new possibilities for discovering previ-ously unknown mechanisms behind the increase inrisk associated with obesity, and thus opens thepossibility of developing new treatments”.

Further research published in the same issue ofthe New England Journal of Medicine found thatobese patients who undergo gastric bypass surgeryare at a reduced risk of death from coronary heartdisease, diabetes and cancer.

This second, 14-year study was carried out byresearchers from the University of Utah School ofMedicine (UT, USA), and looked at 15,850 severelyobese patients. They found that mortality from cor-onary heart disease, cancer and diabetes was 56, 60and 92% lower, respectively, in the surgery groupcompared with the control group.

Lead author Ted D Adams commented: “Thisstudy helps to further define the effects of gastricbypass surgery on long-term mortality. Reduction indeath by any cause, and disease-specific deaths suchas coronary heart disease, diabetes and cancer weresignificantly reduced in surgery patients comparedto the nonsurgical control group. However, rates ofdeath not caused by disease were shown to be greaterin those who underwent the weight-loss surgerywhen compared to controls”.

These other deaths were due to reasons such asaccidents and suicides, which the authors suggestmay in part be due to unrecognized presurgicalmood disorders or post-traumatic stress. Theauthors state that these results emphasize theneed to carefully evaluation patients beforerecommending surgery.

Source: Sjöström L, Narbro K, Sjöström CD et al.: Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357(8), 741–752 (2007); Adams TD, Gress RE, Smith SC et al.: Long-term mortality after gastric bypass surgery. N. Engl. J. Med. 357(8), 753–761 (2007).

We show for the first time that surgery against

obesity not only leads to long-term loss of weight, it also

significantly reduces mortality

NEWS & VIEWS

Upper trunk fat may lead to insulin resistance

A study conducted by researchers from the San Francisco VA Medical Center(CA, USA), has found that deposits of fat on the chest and back (known asupper trunk fat) may be associated with an increased risk of insulin resistance,a known precursor of Type 2 diabetes. They also found that visceral fat(between and around internal organs) was independently linked to anincreased risk of insulin resistance.

The study is part of the Study of FatRedistribution and Metabolic Changein HIV Infection (FRAM). However,the association was found to be equallystrong in the HIV-infected subjectsand the negative controls that wereincluded in the study. The study con-sisted of 926 HIV-infected subjectsand 258 negative controls. Theylooked at visceral and subcutaneous fatin the legs, arms, upper trunk andlower trunk; each population was thendivided into thirds depending on theamount of fat that was found in eachlocation. In the groups that were in thehighest tertile for upper trunk fat, 57%

of the HIV-infected patients and 61%of the controls were found to be insu-lin resistant. However, of those, half ofthe HIV-infected patients lacked highvisceral fat, along with a third of thecontrol patients.

“We knew about the insulin resist-ance risk associated with visceral fat,which has been shown in previous stud-ies, but no one had ever looked at thecontribution of upper trunk fat”, sayslead author and FRAM principal inves-tigator Carl Grunfeld. “Strikingly, therewas very little difference between HIV-infected people and controls. If youhave fat up top, it’s bad for you”.

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Grunfeld went on to explain whythere was no difference in risk betweenthe HIV patients and the controls:“With the new, highly effective anti-retroviral medications, Americans withHIV now have the same weight prob-lems as everybody else”, he said. “Nomatter who you are, if you eat toomuch and you don’t exercise, you’regoing to be at risk for insulin resist-ance, cardiovascular disease, and everyother problem associated with beingoverweight”.

This research was funded by grantsfrom the National Institutes of Health,which were administered in part by theNorthern California Institute forResearch and Education.

Source: Grunfeld C, Rimland D, Gibert CL et al.: Association of upper trunk and visceral adipose tissue. J. Acquir. Immune Defic. Syndr. DOI: 10.1097/QAI.0b013e31814b94e2 (2007) (Epub ahead of print).

...If you have fat up top, it’s bad for you

Obesity vaccine a real possibility?

New research, conducted by scientists at the Pennington Biomedical Research Centre (PA, USA) has suggested that insome cases, obesity may be caused by a common virus. As such, a vaccine to cut the risk of obesity could be a possibilityfor the future. Although obesity is mainly caused by an imbalance between calorie intake and expenditure, it is possiblethat other factors may also have a role to play.

In research presented at theNational Meeting of the AmericanChemical Society, it has been shownthat infection with human adenovirus-36 (Ad-36) transformed stem cells,obtained from fatty tissue from lipo-suction patients, into fat cells. By con-trast, cells that were not exposed to thevirus remained unchanged. A viralgene was found that appeared to beinvolved in this effect, although theexact mechanism remains unknown.

The research was led by MagdalenaPasarica and was carried out in the labof Nikhil Dhurandhar, who said: “Not

all infected people will develop obesity.We’re not saying that a virus is the onlycause of obesity, but this study providesstronger evidence that some obesitycases may involve viral infections”.However, he emphasized that before

any work is carried out to develop a vac-cine, it first needs to be proven that Ad-36 is indeed involved in human obesity.

Dhurandhar said: “We would ulti-mately like to identify the underlyingfactors that predispose some obese peo-ple to develop obesity after infectionwith this virus and eventually find a wayto treat it”.

Previous research had also found alink to Ad-36, finding that 30% ofobese people were infected, comparedwith just 11% of non-obese individuals.Source: American Chemical Society www.acspresscenter.org/

...this study provides stronger evidence

that some obesity cases may involve viral

infections

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NEWS & VIEWS

UK scheme to help overweight children

A scheme based in Guilford (Surrey, UK) hasbeen established to help overweight children andtheir parents establish a healthier lifestyle.

Obesity in young people is a growing problemin the UK; it is estimated that by 2020, 20% ofall boys and 33% of all girls will be obese.

The program, run by MEND (Mind, Exer-cise, Nutrition and Diet) consists of 9 weeks of

Children of obese mothers may have an increased risk for

certain birth defects“The dramatic increase in the mechanisms underlying these

A recent study has indicated that increased maternal obesity is associated with a higher risk for chronic disease,

complications of pregnancy and adverse outcomes of pregnancy, including birth defects.

training related to a healthy lifestyle in general.Paul Sacher, research director of the program andan honorary specialist dietician at Great OrmondStreet Hospital (London, UK), said the focus ofthe program was not weight loss; “Weight is justone of the things we measure. It’s more about liv-ing healthily,” he said.

The program is a National Lottery-funded ini-tiative, and will target children aged between 7and 13 years.Source: MEND Programme www.mendprogramme.org

Food adverts reaching fewer children in the USA

An assessment commissioned by the Associationof National Advertisers and the Grocery Manu-facturers Association/Food Products Associationin the USA has found that there has been an8.5% reduction in the number of food-relatedadverts being viewed by children aged between 2and 11 years (between 2004 and 2006). Prior tothis, research had shown a 13.5% reductionbetween 1993 and 2004.

“The steady decline in food advertising tochildren on broadcast and cable, coupled withthe enormous changes in food advertising, signala remarkable transformation in the market-place,” said Robert Liodice, ANA President andCEO. “Everyone – government, educators andparents – must do their part to combat child-hood obesity in America. In that regard, themarketing industry has shown exceptional lead-ership by taking extremely strong, voluntarysteps”.Source: Association of National Advertisers http://www.ana.net/news/content/754

prevalence of overweight andobese women of childbearing ageis of great public health concernbecause they are at increased riskfor chronic disease, infertility,menstrual irregularities, preg-nancy complications, and adversepregnancy outcomes, includingbirth defects,” explains KimWaller from the University ofTexas (TX, USA).

The ongoing study from theNational Birth Defects PreventionStudy (NBDPS) looked at theindex of pregnancies in eight USstates, between October 1997 andDecember 2002. The body massindex (BMI) of each mother wascalculated from height and weightand recorded, and then comparedwith the birth outcomes of moth-ers with normal BMIs. The studyrevealed that there is a strong rela-tionship between the BMI of anexpectant mother and the likeli-hood of a birth defect occurring;particularly spina bifida andanencephaly.

Waller explained the impor-tance of the study: “To ourknowledge, this is the first popu-lation-based study of its scale toexamine pre-pregnancy obesityand a range of structural birthdefects. These results suggest aweak-to-moderate positive asso-ciation of maternal obesity withseven of 16 categories of birthdefects and a strong inverse asso-ciation with gastroschisis. The

associations are not yet under-stood but may be related toundiagnosed diabetes”.

In a further study, publishedin the British Journal of Nutri-tion, scientists warn against thedanger of pregnant and breast-feeding women increasing theirfat and sugar intake; so-called‘eating for two’. In a study con-ducted in rats it was found thatoffspring born to mothers fed ona junk food diet developed anexacerbated preference for fatty,sugary and salty foods at theexpense of protein-rich foodscompared with offspring fed abalanced diet.

Stephanie Bayol, from theRoyal Veterinary College in Lon-don, said: “Our study has shownthat eating large quantities ofjunk food when pregnant andbreastfeeding could impair thenormal control of appetite andpromote an exacerbated taste forjunk food in offspring. This couldsend offspring on the road toobesity and make the task ofteaching healthy eating habits inchildren even more challenging”.

Source: Waller K, Shaw GM, Sonja A: Prepregnancy obesity as a risk factor for structural birth defects. Arch. Pediatr. Adolesc. Med. 161, 745–750 (2007); Bayol SA, Farrington SJ, Stickland NC: A maternal ‘junk food’ diet in pregnancy and lactation promotes an exacerbated taste for ‘junk food’ and a greater propensity for obesity in rat offspring. Br. J. Nutr. 1–9 (2007).

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NEWS & VIEWS – Trial Watch

TRIAL WATCH

Good results for zonisamide SR/bupropion SR combination

Orexigen™ Therapeutics has announced positive top-lineresults at the 24-week primary end point of the Phase IIb trialof its anti-obesity drug Empatic™. Empatic (formerly knownas Excalia™), is a fixed-dose combination of zonisamide sus-tained release (SR) and bupropion SR, a combination that wasoriginally discovered by Kishore Gadde from Duke University(NC, USA). From initial studies in a screening model it wasfound that Empatic may act to enhance satiety and energyexpenditure. Zonisamide alone has been shown to cause weightloss in previous clinical trials.

The trial consists of six treatment arms, looking at differentratios of the two drugs in a total of 620 patients. Across all sixarms of the study treatment was found to result in statisticallysignificant weight loss (p < 0.001). It was also found that thedrug was safe and generally well-tolerated.

It was found that at the highest dose tested a weight loss of8.6% from baseline was achieved, compared with 1.1%weight loss for placebo in the intent-to-treat group; in thecompleter group 10.3% weight loss from baseline wasachieved compared to 1.2% for placebo. It was also found thatthe trajectory of weight loss for all treatment arms appeared tocontinue downward through 24 weeks.

“Thesetrial results illus-trate that we can delay theearly weight loss plateau often seen with diet-ing and many existing pharmaceutical approaches and alsoimprove tolerability with a sustained release formulation ofzonisamide,” said Orexigen President and Chief ExecutiveOfficer, Gary Tollefson. “If the magnitude of weight loss evi-dent in this trial continues to be seen, we believe that Empaticmay be particularly useful in severely obese individuals”.

Based on these results, development of the drug will con-tinue, with further safety and efficacy data due to be reportedfollowing completion of an ongoing 24-week trial extension.The primary trial results are scheduled to be presented at the2007 Meeting of the North American Association for the Study ofObesity (October 20–24, New Orleans, LA, USA).

“Despite epidemic rates of obesity, few people seek drug ther-apy. This may be because, as published reports indicate, cur-rently approved regimens typically achieve only modest weightloss that stalls at an early plateau”, said Orexigen Chief Scien-tific Officer Michael Cowley, also from Oregon Health & Sci-ence University (OR, USA). “By contrast, our approach isdesigned to achieve and sustain weight loss by enhancing sati-ety, diminishing appetite, improving energy expenditure andcounteracting the body’s efforts to compensate for weight loss”.

Orexigen also has another anti-obesity drug currently undertrial; Contrave™. This drug is a fixed dose combination of nal-trexone SR and bupropion SR, and a Phase III trial has recentlybeen initiated.

Source: Orexigen Therapeutics, Inc. www.orexigen.com

Company: Orexigen™ TherapeuticsDrug: Fixed-dose combination zonisamide sustained release and bupropion sustained release (Empatic™)Indication: ObesityTrial: Phase IIb

Interim Phase I data for trodusquemine announced

Genaera Corporation announced theirinterim Phase I data for their obesitydrug trodusquemine (MSI-1436) atthe IBC 12th Annual World Congress

on Drug Discovery & Development ofInnovative Therapeutics (August 6–8,Boston, MA, USA).

Trodusquemine acts by selectivelyinhibiting protein tyrosine phos-phatase 1B (PTP-1B); the drug actsboth centrally and peripherally, and isa candidate for the treatment of bothobesity and Type 2 diabetes. PTB-1B isinvolved in both the insulin and leptin

pathways, and is therefore expected todecrease appetite and normalize bloodsugar levels.

The trial is a single ascending dosePhase 1 study, and Anthony DelContereported the trial design being used (toevaluate drug safety and pharmacokinet-ics [PK]). Interim data was also providedfrom the initial cohorts in the double-blind, randomized, placebo-controlled

Company: Genera CorporationDrug: Trodusquemine (Empatic™)Indication: Obesity andType II diabetesTrial: Ascending dose Phase I

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Drug Watch – NEWS & VIEWS

trial which included safety and PK datafrom 20 treated subjects and eight vehi-cle controls in four sequential dosegroups. It was reported that the PK pro-files have a predictable pattern withminimal variability between subjects,and that no serious adverse events havebeen reported thus far.

“These initial findings validate thepreclinical safety and PK work doneby Genaera scientists. We are encour-aged by these findings and will con-tinue to further characterize the safetyprofile and provide proof of conceptfor trodusquemine in obesity andType 2 diabetes management”, com-

mented Jack Armstrong, Presidentand CEO of Genaera. “We anticipatea steady flow of clinical informationin the second half of 2007 as our clin-ical studies progress to broaderpopulations”.

Source: Genaera Corporation www.genaera.com

DRUG WATCH

Heart failure warning strengthened for somediabetes drugs

Based on an FDA recommendation, some manufacturershave been asked to strengthen their warning related to heartfailure risk for some drugs approved for the treatment ofType 2 (non-insulin-dependent) diabetes. The warning willcome in the form of a boxed warning, which is the FDA’sstrongest form of a warning.

Having reviewed postmarketing adverse event reports, theFDA recommended the changes to the labeling of all of thethiazolidinedione class of antidiabetic drugs. The adverseevent reports included incidences of weight gain and edema,which are warning signs for heart failure. In some cases, con-tinuing therapy has been associated with poor outcomes,including death. Drugs include: Avandia® (rosiglitazone),Actos® (pioglitazone) Avandaryl™ (rosiglitazone andglimepiride), Avandamet® (rosiglitazone and metformin),and Duetact™ (pioglitazone and glimepride). These drugsare used in conjunction with diet and exercise to improveblood sugar control in adults with Type 2 diabetes.

“Under FDA’s postmarketing surveillance program, wecarefully monitor new safety information for marketed drugsand take appropriate action when necessary to inform

patients andhealthcare providersof new information”,said Steven Galson, director of FDA’sCenter for Drug Evaluation and Research. “This new boxedwarning addresses FDA’s concerns that despite the warningsand information already listed in the drug labels, these drugs arestill being prescribed to patients without careful monitoring forsigns of heart failure”.

There is an ongoing FDA review related to Avandia andthe risk of heart attack; however, at the end of July the FDA’sEndocrine and Metabolic Advisory Committee and theDrug Safety and Risk Management Advisory Committeerecommended that Avandia continue to be marketed.

Source: FDA News www.fda.gov/bbs/topics/NEWS/2007/NEW01683.html

...despite the warnings and information already listed in the

drug labels, these drugs are still being prescribed to patients without careful

monitoring for signs of heart failure

Regulatory update for rimonabant

Sanofi Aventis have withdrawn theirNew Drug Application (NDA) for thedrug rimonabant in the USA. How-ever, they will work with the FDA tomake their application at a later date,and state that they remain committedto making the drug available in the

USA. Ongoing clinical trials involvingthe drug will continue.

Rimonabant is a member of a newclass of drugs that block the CB1receptors of the endocannabinoidsystem. The drug is currently approvedin 42 countries, and is used for the

treatment of overweight and obesity inpatients with associated cardiovascularrisk factors.

Source: Sanofi Aventis Press Release www.sanofi-aventis.us/live/us/medias/07B70509-ED2F-4FCE-9533-EDB7187D57AB.pdf

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