To treat obese persons usually the drug is given which act as pancreatic lipase inhibitor like orlistat.Such inhibitors, as they block the action of lipase, decrease the absorption of fat into body.

I will provide below a critical summary and assessment of the major reasonably effective pharmacological interventions for obesity reduction and treatment, with limitations noted. I also briefly discuss the much cited recent results from the University of Louisville team under Kira Taylor and locate their role and impact more modestly than as hailed in the uncritical popular medical literature. Finally, I conclude with a look forward and suggest that to date our progress is insufficient to halt the worst of the adverse impact on mortality and morbidity that is indisputably projected to be the wages of obesity across the globe from the furiously accelerating diabesity pandemic.

GASTRIC/PANCREATIC LIPASE INHIBITOR CLASS:

- Orlistat (Xenical/Alli) which blocks fat absorption from the gut, and remains the only drug currently approved by the FDA for long-term management of obesity. use in the clinical practice is limited by gastrointestinal side effects, mainly steatorrhea. Recently, however, even the safety of orlistat has come under scrutiny, following reports of serious events in obese patients, and in 2010, the FDA revised the label for orlistat to include safety information about severe liver injury, while orlistat has now even been associated with kidney and pancreas injuries [1].

- Cetilistat (Cametor) [In Phase III]: highly lipophilic benzoxazinone inhibitor of gastrointestinal (GI) and pancreatic lipases with plausible evidence of efficacy and non-inferior to orlistat [1,2].

NA-DA CLASS: these are noradrenaline (NA) + dopamine (DA) releasing agents

- Phentermine (Ionamin/Duromine)

- Methamphetamine (Desoxyn)

- DCR-Phentermine, a new experimental diffuse-controlled release formulation of phentermine (DCR-phentermine)

Efficacy and safety were shown in a small 12-week RCT [4] [ ], and decreased obesity was accompanied by reductions in waist circumference, LDL and total cholesterol; and although adverse effects were typical of the sympathomimetics no drug-related increases in systolic or diastolic blood pressure were observed. These preliminary results suggest that DCR-phentermine offers greater efficacy than many new experimental candidates awaiting approval. And although the issue of drug dependence could be raised, recent data found that abrupt cessation of phentermine in obese subjects on long-term phentermine therapy did not provoke either withdrawal or drug craving [5].

SYMPATHOMIMETIC CLASS:

These primarily target energy expenditure via the basal metabolic rate (BMR), with modest efficacy but not widespread use.

- Phendimetrazine (Tepanil/Bontril)

- Diethylpropion (Tenuate/Apisate)

- Benzphetamine (Didrex)

NA + 5-HT REUPTAKE INHIBITOR CLASS

Act centrally to enhance satiety

- Sibutramine (Reductil, Meridia) [Withdrawn 2010, due to increased heart attacks and strokes, based on controversial data from the SCOUT (Sibutramine Cardiovascular OUTcome) study [6]. Note: this author (C. Kaniklidis) has critically appraised the SCOUT study and found it fatally flawed methodologically, being performed in a subject population expressly contraindicated from sibutramine treatment both in the European Summary of Product Characteristics (SPC) and the US (FDA) Product Label, and thus represents an illicit off-label clinical trial in an inappropriate patient population. Bizarrely, despite the fact that the final results of the SCOUT trial did not show any increased cardiovascular mortality, sibutramine was withdrawn from the US market by FDA in October 2010. Based on best evidence-based review, critical appraisal, and assessment of methodological quality (I use the Heyland MQS metric), this author would conclude that the withdrawal was premature, in error and against the evidence.

CANNABINOID CB1 ANTAGONIST CLASS

- Rimonabant (Accomplia) [US: not approved but under development/EU. Efficacy and safety shown in the RIO-Europe, the RIO-North America, the RIO-Diabetes, and the RIO-Lipids RCTs. It has been withdrawn due to increased anxiety and depressive symptoms and suicidal ideation, and I would further argue its efficacy has now been challenged by the CARDIO-REDUSE RCT.

SSA/NA-DA CLASS: (Sugar Sulfamate Anticonvulsant) + NA-DA releasing agent)

- Topiramate (Topamax)/phentermine (Qnexa/Qsymia)

With efficacy and safety demonstrated in a number of clinical trials, especially the two, large, one-year Phase III pivotal trials OB-302 and OB-303, and the CONQUER RCT. It appears to be the most effective new generation antiobesity agent, and highly probably also superior to orlistat, rimonabant and sibutramine. To date, it manifestly satisfies the European regulatory requirements for anti-obesity drug approval; yet despite this, it has been withdrawn from the European market by the EMA in October 2012, due to adverse effects on heart rate, adverse psychiatric events, as well as concerns about fetal toxicity, and the birth defect issue is as yet resolved. It continues to be available in the US, with appropriate safety warnings.

DA REUPTAKE INHIBITOR/OPIOID ANTAGONIST CLASS

- Bupropion/naltrexone (Contrave)

The efficacy and safety of Contrave has been determined in four pivotal, 56-week, multicenter RCTs (NB-301, NB-302, NB-303 and NB-304 [7], and in the COR- and COR-2 trials. The efficacy approximates that of sibutramine or rimonabant, and appears to ranks below Qnexa in terms of weight loss efficacy, but above lorcaserin (Lorqess/Belviq) [8]. After resubmission of its NDA to the FDA in Dec 2013, the FDA is now expected to render a decision on Contrave by Jun 10, 2014, awaiting completion of the FDA sponsored Light Study RCT, with completion due in 2017. Based in interim reported findings, this author expects FDA approval.

SEEROTONIN 2C AGONIST CLASS

- Lorcaserin (Lorqess/Belviq), with safety and activity demonstrated in three RCTs: BLOOM, BLOSSOM and BLOOM-DM. Monotherapy yields very modest benefit, 3–4% more body weight loss compared to placebo after 1 year of treatment [BLOOM-DM].

SA-DA CLASS: Sulfonamide Anticonvulsant (SA)+DA Reuptake Inhibitor

- Zonisamide (Zonegran)+bupropion (Empatic)

In phase III awaiting FDA approval. However, Orexigen recently placed a hold on its clinical development, so the arrival of the Phase III trial results is uncertain. Nonetheless, Empatic appears to show more promise in delivering weight loss than bupropion+naltrexone (Contrave), but the lingering unanswered question is whether the anticonvulsant component (zonisamide) has any potential for fetal toxicity.

NA-DA-SSRI CLASS: (Reuptake inhibitor of noradrenaline, dopamine and serotonin)

- Tesofensine now in Phase III is a " triple monoamine reuptake inhibitor", of dopamine, norepinephrine, and serotonin, structurally similar to the dopamine reuptake inhibitor cocaine, and originally developed as an anti-parkinsonian agent, and with anti-obesity mode of action similar to that of sibutramine. Efficacy established in Phase I and II trials, but with cardiovascular safety as yet not satisfactorily demonstrated.

GLP1 AGONIST CLASS: Glucagon-like peptide-1 agonist

GLP-1 is released post-prandially, retards gastric emptying, and mediates satiety, and in general it appears that long-acting GLP-1 agonists like exenatide and liraglutide enhance insulin release, with accompanying body weight loss. The major entry is:

- Liraglutide (Victoza) with safety and efficacy established in the DURATION-6 trial [9, and with emerging GLP-1 agonists albiglutide, a GLP-1 receptor agonist, and taspoglutide, a GLP-1 analogue being explored although not yet in regulatory pipeline.

EMERGING STRATGEIES

Given the fact that plasma ghrelin levels correlate with hunger scores, with ghrelin release increasing following dieting, ghrelin may be a critical contributor to relapse to increased food intake and weight gain after dieting, so ghrelin receptor antagonists appear biologically and molecularly attractive, especially in the form of what's called GOAT (ghrelin-O-acyl transferase) antagonists. These are awaiting clinical testing. Another avenue of pursuit appeared to be the satiety hormone PYY (processed into PYY3–36), and although infusion of PYY3–36 in humans decreases 24-h caloric intake, the magnitude of effects have been so far disappointing. A third avenue centers around amylin released, along with insulin, from pancreatic β cells; amylin increases satiation via neuronal receptors, thus influencing part of the neural circuit that mediates satiation. Pramlintide (Symlin) is an approved anti-diabetic agent drug and also a novel human amylin peptide derivative, and I note that in a recent meta-analysis [10] of pramlintide treatment in diabetic and in obese subjects, it demonstrated modest weight loss after treatment for at least 16 weeks. Also being explored is a heterogeneous group of compounds targeting reduction of fat mass by increasing energy expenditure (especially modulating the basal metabolic rate (BMR)) or by redistributing adipose tissue, and these include angiogenesis inhibitors, beta-3 receptor agonists, sirtuin-I activators, and diazoxide among others like oxyntomodulin (OXM), pramlintide, obinepitide, leptin-based candidates, and dozens of others in various stages of clinical trial and investigation.

THE UNIVESITY OF LOUISVILLE ADIPOSITY-GENE STUDY

A genomic approach has recently been suggested by the University of Louisville collaboration with NHLBI’s CARe Project (Candidate Gene Association Resource) [13] via the identification of five genes - culled from a meta-analysis of ~2100 cardiovascular-related genes in individuals of European descent (n=50,00) from 22 cohorts - associated with increased WHR (waist-to-hip ratio) independent of overall obesity, two specific to women, and three shared across males and females, with special focus on the SHC1 gene strongly associated with abdominal fat through insulin receptor activation. This is intriguing research but it remains preliminary and not yet achieving even proof-of-concept stage let only human clinical trial stage, since the potential biological significance of these newly discovered loci are suggested and extrapolated only at the in vivo preclinical level, through the observation that mice lacking the SHC1 protein live longer and are leaner than their wild-type counterparts. It remains for clinical demonstration whether SHC1 is indeed effectively druggable and targetable at clinically relevant levels, and no pharmacological candidates for modulation (whether activation of inhibition) are yet available or even researched. Furthermore, without a two-stage study design which the investigators admit not conducting, the effect estimates themselves may be inflated.

Finally, the investigators admit that not all of these discovered genes have clear rationale in adiposity, so we still require the mature ex vivo and clinical demonstration that modulation of any of these genes can actually significantly disrupt the biological pathways that affect adiposity development.

MORE STILL NEEDED

Yet despite an increasingly more sophisticated understanding of the pathophysiology of obesity, accompanied by a broad spectrum of candidate interventions, I would conclude that we are still poorly in control of both (1) underlying etiological and molecular pathways, and (2) of the fundamental patho-behavioral drivers of human obesity and its demonstrable high degree of resistance to durable and clinical relevant weight loss gains: to date, we barely break 10% gains and the grim epidemiology of the diabesity (obesity + diabetes) pandemic (which I have elsewhere discussed [11,12] shows that we are effectively losing the battle with gains insufficient to stem the tide which unrelentingly is assured to bring the foremost and highest levels of morality and morbidity than that from even the leading cancers combined. We need new approaches to obesity that will deliver more than just modest incremental gains, and we concomitantly need to focus additional resources on prevention and not just therapeutics if we hope to avoid a global catastrophe that, regrettably as always, will disproportionately hit hardest the less developed and underserved regions (as I document in my "Cancer, Culture and Cooperation in the Middle East" paper). This will require international cross-cultural cooperative collaborations with governments and businesses under a collective umbrella of academia and leading research institutes, something that is still relatively unfocused and unintegrated to this day. But all of us medical and public health researchers have a stake and a role to play in fostering this sooner rather than later.

REFERENCES

1. M.A. Weir, M.M. Beyea, T. Gomes, D.N. Juurlink, M. Mamdani, P.G. Blake, R. Wald, A.X. Garg, Orlistat and acute kidney injury: an analysis of 953 patients. Arch Intern Med 2011; 171, 703–704.

2. Kopelman P, Bryson A, Hickling R et al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes (Lond) 2007;31:494–499.

3. Kopelman P, de Groot HG, Rissanen A., et al. Weight Loss, HbA1c Reduction, and Tolerability of Cetilistat in a Randomized, Placebo-controlled Phase 2 Trial in Obese Diabetics: Comparison With Orlistat (Xenical). Obesity 2010; 18:108–115.

4. Kang JG, Park CY, Kang JH, Park YW, Park SW. Randomized controlled trial to investigate the effects of a newly developed formulation of phentermine diffuse-controlled release for obesity. Diabetes Obes Metab 2010; 12: 876–882.

5. Hendricks EJ, Greenway FL, Westman EC, Gupta AK. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring) 2011; 19: 2351–2360.

6. James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al., SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010; 363: 905–917.

7. Contrave FDA Briefing Document. NDA 200063. December 7, 2010. At:

http://www.fda.gov/downloads/advisorycommittees/

committeesmeetingmaterials/drugs/endocrinologica

ndmetabolicdrugsadvisorycommittee/ucm235671.pdf.

8. Heal DJ, Gosden J, Smith SL. A review of late-stage CNS drug candidates for the treatment of obesity. Int J Obes (Lond) 2013; 37(1):107-17.

9. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013; 381, 117–124.

10. Singh-Franco, D., et al. (2011). The effect of pramlintide acetate on glycemic control and weight in patients with type 2 diabetes mellitus and in obese patients without diabetes: a systematic review and meta-analysis. Diabetes Obes. Metab. 13, 169–180.

11. Kaniklidis C. Diabetes Prevention - Promise and Limitations: A Review. [publication pending]. Available on ResearchGate at: https://www.researchgate.net/publication/236235056_Diabetes_Prevention_-_Promise_and_Limitations_A_Review.

12. Kaniklidis C. The Obesity Paradox - and commentary on the Flegal JAMA Study. [publication pending]. Available on ResearchGate at: https://www.researchgate.net/publication/236165156_The_Obesity_Paradox_-_and_commentary_on_the_Flegal_JAMA_Study.

13. Yoneyama S, Guo Y, Lanktree MB, et al. Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. Hum Mol Genet 2014 Jan 6.

Article Diabetes Prevention - Promise and Limitations: A Review

Article The Obesity Paradox - and commentary on the Flegal JAMA Study

Presently, body mass index (BMI), waist circumference, and waist-to-hip ratio are employed for classifying obesity and the risks of abdominal fat accumulation. For exercise professionals, the important question is, in addition to the body composition technique (skinfolds, bioelectrical impedence, hydrostatic weighing) they use to track body fat and muscle change, which anthropometric assessment is most suitable to use with their clients for detecting cardiovascular and metabolic risk?

http://www.unm.edu/~lkravitz/Article%20folder/waisttohipUNM.html

Restorative Yoga Better Than Stretching for Trimming Subcutaneous Fat in Overweight Women.http://www.ajmc.com/publications/evidence-based-diabetes-management/2013/2013-1-Vol19-sp7/Restorative-Yoga-Better-Than-Stretching-for-Trimming-Subcutaneous-Fat-in-Overweight-Women

In my experience Phentermine is still a fairly effective medication if used properly. It works best if combined with a low dose SSRI like Celexa or Lexapro. The drug should also be combined with a proper diet. In my experience the best diet is a low carbohydrate, moderate protein, relatively high fat diet (healthy fats). Phentermine is a very safe drug and can be used long term for the treatment of obesity.

Although there is provisional evidence of safety for phentermine-based obesity regimens, but only assuring within its current limits, we lack robust FDA-required long-term studies of safety at least out to 5 years, three of which are required, although only one of which has yet been registered and launched. Eisai Pharmaceuticals, which markets lorcaserin (which along with phentermine constitutes Belviq) is conducting its required postmarketing trial for cardiovascular safety and valvulopathy (CAMELLIA-TIMI 61) [1] due to complete no earlier than October of 2018, reporting sometime in 2019. The other two FDA-mandated trials are of the long-term safety of phentermine-topiramate (Qysmia) via two randomized clinical trials to evaluate the drug’s cardiovascular risk, including heart valve damage, and both are seriously overdue to commence. Note also that the FDA approvals were based on 1-year trials, that in addition all participants had to comply with rigorous diet and lifestyle requirements (where in the real-world many patients will be non-compliant), and with the US FDA approval letters acknowledging that:

"There have been signals of a serious risk of major adverse cardiovascular events with some medications developed for the treatment of obesity, and available data have not definitively excluded the potential for this serious risk with [lorcaserin hydrochloride or phentermine and topiramate extended release".

Note also that the European Medicines Agency (EMA) explicitly rejected phentermine-topiramate twice - first in 2012 and again upon reconsideration in 2013 - precisely because of unresolved concerns about the medicine's long-term effects. And I should also add that

concerns expressed by the medical editors of publications like Consumer Reports and fears of side effects has in the U.S. led to extremely poor sales of Qsymia, and to date that consumer watchdog group and dozens of others strongly recommend against its use in the current environment of long-term safety questions. In addition, Steven Woloshin and Lisa Schwartz of from the Dartmouth Institute for Health Policy & Clinical Practice [2] have indicated in JAMA Internal Medicine there are many unanswered questions regarding the risk/benefit profiles of these 2 drugs, and along with others (including myself) have called for a change in the FDA prescribing information for both lorcaserin and phentermine-topiramate, to be reframed as a clear warning (they suggest: "Because of concerns that this drug might increase cardiovascular morbidity or mortality, the FDA has required randomized trials to be completed by 2018", an amendment currently under consideration).

So given the absence of demonstrable long-term safety in high-methodological-quality trials, until the Postmarketing Surveillance Studies (PMSS) completed and report results, patients who do not lose at least 5% of their body weight within 12 weeks of starting to take either drug should stop taking it, as stated and required in the prescribing information.

Other "durable-efficacy" concerns have also been raised: weight loss recurred when the phentermine was restarted indicating that the drug is really only effective during the time that it is being taken.[3-7].

Finally, The Korean Postmarketing Surveillance Study of the Efficacy and Safety of Phentermine in Patients with Obesity [8], the largest to date, has found that "there are several problems with prescribing phentermine continuously. The most troublesome aspect is the possibility of abuse or misuse of these kinds of psychotropic appetite suppressants", noting that "Some patients who experienced desirable results demanded that their physicians extend the application of the medication to > 3 months or repeat the same treatment protocol" with many visiting "many hospitals in order to receive duplicate prescriptions". And although the PMS found general safety, it should be remembered that it observed the participants for only three months.

Given that obesity is a lifelong chronic disease requiring prolonged therapy, current limited clinical experience must be combined with protracted clinical trials to assess longer-term efficacy and safeties, and comparatively evaluate strategies that employ all treatment options to sustain weight loss over decades, not just a few (

The result is that we tend to weigh slightly more on Sunday and Monday, but then slightly less again by Friday, reports the Smithsonian. And enough of us do this that scientists say they've observed the general weight trend in a small study published in the journal Obesity Facts, FoxNews reports.

http://med.news.am/eng/news/4184/why-we-weigh-slightly-less-on-fridays.html

According to a latest research findings, avoiding foods that contain nickel significantly decreased body fat and body-mass index in overweight women allergic to the metal, especially those in early menopause. The study found an unusually high prevalence of nickel allergy in women and men who were overweight. Nickel, a trace element found in water, soil and food, is the most common cause of metal allergies. Foods that contain high levels of nickel include whole grains, legumes, cocoa and some vegetables, the study said.

http://www.newindianexpress.com/lifestyle/health/Food-High-in-Nickel-Linked-to-Obesity/2015/05/02/article2791054.ece

n rich countries, obesity is more common among the lower educated, whilst in poor countries, obesity is more common among the higher educated, confirms new research. Previous studies have shown that the number of people with obesity increases with the gross domestic product (GDP) of a country. Previous research has also indicated that education can be an important factor in this context. The aim of this new study was to explore the assumption from previous studies that obesity is linked to GDP and education, and to include new data from several different countries.

http://www.sciencedaily.com/releases/2015/09/150930074433.htm