Wednesday, 10 July 2013

The Obesity Pandemic: What can be done?

The statistics on obesity are just frightening... according to the World Health Organisation (WHO) in 2010 the following is true regarding individuals over the age of 15:

Country
% Population that are Overweight (BMI>25)
% Population that are Obese (BMI>30)

Females
Males
Females
Males
Australia
66.5
75.7
29.1
28.4
Japan
16.2
29.8
1.1
2.3
South Africa
68.5
41.3
36.8
7.6
United Kingdom
63.8
67.8
26.3
23.7
United States
76.7
80.5
48.3
44.2

A healthy BMI is between 18.5 and 25. A person is usually called overweight if their BMI is >25. Usually a BMI of >30 is considered obese. However, I should probably state that this model does not take into consideration their tissue type, i.e. whether their weight is mostly due to adipose tissue (i.e. fat) or muscle.
If you would like to see more stats on the subject you can go to https://apps.who.int/infobase/Comparisons.aspx.

These statistics are worrying considering the detrimental health effects of obesity. Obese individuals are approximately 40% more likely to develop cardiovascular disease, and substantially more likely to develop a variety of cancers including oesophageal, pancreatic, colorectal, breast, endometrial, kidney, thyroid and gallbladder cancers and substantially more likely to develop type II diabetes mellitus.1-4 In one study men with a BMI of >35 had a 42 fold higher risk of developing type II diabetes mellitus.5 These risks are not all those that have come to light in recent years with dementia and multiple sclerosis, among other conditions, being more common among the obese.4,6,7

I personally see obesity as an addiction, an addiction to simple sugars like fructose, glucose, sucrose and to unhealthy fats like saturated and transunsaturated fats. Treatments for this addiction include drugs that suppress appetite (e.g. bupropion [ZYBAN], atomoxetine [STRATTERA], modafinil [PROVIGIL], naltrexone [REVIA], lorcaserin [BELVIQ], sibutramine [MERIDIA; withdrawn from the market due to safety concerns], amfepramone [BONTRIL], topiramate [TOPAMAX], phentermine [ADIPEX-P], rimonabant [ACOMPLIA; now withdrawn from the market due to safety concerns], fenfluramine [along with phentermine it formed the famous dieting medication FEN-PHEN which has now been withdrawn from the market due to safety concerns] etc.) and drugs that prevent the metabolism of dietary fats by the body (e.g. orlistat [ALLI]). Plus there is substituting unhealthy flavourings (e.g. simple sugars) with healthy flavourings like artificial sweeteners or natural sweeteners.

Of course there is the age-old technique of dieting and exercise, but in my opinion these methods are rather ineffective in the long-run due to the fact that obesity is an addiction and as with people telling an addict to change it just does not work regardless of how much knowledge of the consequences they have. I do believe that people can overcome addictions cold turkey (or via dieting and exercising in the case of obesity) if they are given real motivation to do so, perhaps by their habit threatening to harm those they care about and hence this might give them sufficient motivation for dieting and exercise to work. Since I like to talk about drugs, however, I am going to devote a great deal of this post to talking about the drugs used to combat obesity.

Bupropion, atomoxetine and modafinil are sometimes used off-label (i.e. the US FDA and the Australian TGA has not approved either drug for this use) to treat obesity, probably due to their stimulant effects. See drugs that serve as stimulants (i.e. drugs that promote wakefulness, alertness and generally stimulate brain activity. This includes illicit stimulants like methamphetamine, amphetamine, methylphenidate [RITALIN], etc) nearly always have additional appetite-supressing effects and the same is true with these three drugs. Bupropion is traditionally used to treat depression or help people quit smoking and it works by raising the levels of norepinephrine (or noradrenaline) and dopamine in the body, this includes the hypothalamus which is a part of the brain that, among other things, regulates feeding behaviour. Likewise atomoxetine is normally used to treat attention deficit hyperactivity disorder (ADHD) but it also elevates central nervous system (CNS; brain and spinal cord) levels of norepinephrine (while having minimal effects on dopamine concentrations in the CNS) including in the hypothalamus. Modafinil on the other hand is normally used to treat sleep disorders like narcolepsy and works primarily by increasing CNS concentrations of dopamine while also altering the actions of other neurotransmitters in the brain and spinal cord. These three drugs are reuptake inhibitors of these two neurotransmitters which means in effect they prevent the “leakage” of these neurotransmitters from the gap between neurons (electrically signalling brain, spinal cord and nerve cells) which is also known as the synaptic cleft, across which they are used as chemical messengers between neurons (the electrically signalling cells of the brain, spinal cord and nerves).  

Amfepramone (or diethylpropion) is also a stimulant drug but is different in that it is converted by the body into ethcathinone which is a releasing agent of norepinephrine (in contrast to reuptake inhibitors releasing agents just cause neurons to release more of the respective neurotransmitter [in this case norepinephrine] into the synaptic cleft) which is something the stimulant amphetamine does, but unlike amphetamine it has minimal effects on dopamine and serotonin release, hence limiting its potential for causing addiction (since dopamine is associated with the euphoria recreational drugs create and hence are implicated in how they cause addiction). Amfepramone is also unique compared to the aforementioned three stimulants in that it is actually FDA and TGA approved for weight loss.

Sibutramine is similar to atomoxetine in that it increases brain concentrations of norepinephrine by inhibiting its reuptake. It has been withdrawn from the market, however, amidst concerns it can cause cardiovascular disease in susceptible individuals.8

The mechanism via which topiramate manages to promote weight loss is not unclear, but it is known that it promotes satiety (i.e. not eating) by supressing appetite.9

Phentermine and fenfluramine also work via serving as stimulants hence promoting satiety.

Naltrexone on the other hand is a drug used to treat opioid dependence (i.e. addiction to opioids like heroin, oxycodone, etc.). Naltrexone is currently being investigated, when combined with bupropion that is, for its ability to reduce body weight in obese patients. Naltrexone when used by itself has inconsistently (i.e. some clinical trials have failed to demonstrate any benefit of it in the indication of weight loss) been found to cause some weight loss with some evidence indicating that the weight-loss it encourages is more prominent in females. It is believed its beneficial effects on weight are due to its ability to block the opioid receptors of the central nervous system which are involved in reward, perhaps including the rewarding effects of eating.10

Rimonabant, however, was quite a promising appetite-suppressant until it was withdrawn from the market in late 2008. It worked by blocking the first cannabinoid receptor, which is the receptor that cannabis, by stimulating, manages to elicit its appetite-stimulating effects. Unfortunately, however, by blocking this receptor it caused a number of patients to become depressed even to the point of suicide.11,12 It was promising in a number of ways, including that it managed to improve insulin sensitivity, and hence might afford protection against the metabolic consequences of obesity.

Lorcaserin is a member of a new class of weight loss medications with, hopefully, a more favourable side effect profile. It works, or so we believe, by activating the 5-HT2C receptor which, among other things, appears to regulate feeding behaviour. The 5-HT2C receptor may also be a promising as a target for drug abuse disorders like cocaine dependence. This is due to the fact that it reduces the concentrations of dopamine in the mesolimbic pathway which is also known as the “reward pathway”. Increases in dopamine in the mesolimbic pathway are directly associated with the rewarding effect of drugs of abuse like cocaine,13 and interestingly, even fructose.14 Unfortunately, however, in diabetic individuals lorcaserin has been linked to hypoglycaemia – low blood sugar, which can be fatal if not promptly treated.15 Since over-functioning of the mesolimbic pathway has also been associated with schizophrenia it was hoped that another 5-HT2C agonist (activator) vabicaserin might possess antipsychotic effects, which thing was confirmed by one clinical trial (the reason why it is no longer being pursued as a treatment for schizophrenia is a mystery to me).16

Orlistat on the other hand is a drug that inhibits pancreatic lipases which are enzymes that the body uses to metabolise dietary fats into things it can use. By inhibiting pancreatic lipases the body is left with no choice but to leave dietary fats in the stool which is why a well-known side effect of orlistat is that it causes loose, oily and foul-smelling stools. It is the only pharmaceutical weight loss drug that I am aware of that is over the counter in many countries. Orlistat also appears capable of reducing the incidence of diabetes in the obese.17

Some have also suggested that banning processed sugars from our food would reduce the incidence of obesity and while it sounds perfect on paper in practice it is less so seeing how prohibition of drugs that the public are already addicted to or accustomed to normally results in nothing of any benefit considering the fact that when America tried this in the 20s and 30s with the prohibition of alcohol and while the availability of alcohol was unchanged because alcohol production and distribution had fallen into the black market organised crime was profiting from the law and this saw the uprising of organised crime in America. Plus I personally do not see any sizeable benefit that would come from banning sugar since as is seen in countries with a high religious anti-drug presence, such as Saudi Arabia, when one (or in the case of Saudi several) substance of abuse is stamped out what remains that has a potential for abuse (in the case of Saudi this is unhealthy food, seeing how obesity is very common there) is abused more than prior to the prohibition.18 People with an addiction are born, often, with an predisposition towards addiction, sort of like a gap if you would that they feel the need to fill with something, be that drugs, be that unhealthy foods, be that alcohol, etc. and if you take away one substance of abuse they will substitute it with something else.

Reference List

  1. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation [Internet]. 1983 May 1 [cited 2013 Jul 9];67(5):968–77. Available from: http://circ.ahajournals.org/content/67/5/968
  2. Kruijsdijk RCM van, Wall E van der, Visseren FLJ. Obesity and Cancer: The Role of Dysfunctional Adipose Tissue. Cancer Epidemiol Biomarkers Prev [Internet]. 2009 Oct 1 [cited 2013 Jul 9];18(10):2569–78. Available from: http://cebp.aacrjournals.org/content/18/10/2569
  3. Mokdad AH FE. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA [Internet]. 2003 Jan 1 [cited 2013 Jul 9];289(1):76–9. Available from: http://dx.doi.org/10.1001/jama.289.1.76
  4. Haslam DW, James WPT. Obesity. The Lancet [Internet]. 1 [cited 2013 Jul 9];366(9492):1197–209. Available from: http://www.sciencedirect.com/science/article/pii/S0140673605674831
  5. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, Fat Distribution, and Weight Gain as Risk Factors for Clinical Diabetes in Men. Dia Care [Internet]. 1994 Sep 1 [cited 2013 Jul 9];17(9):961–9. Available from: http://care.diabetesjournals.org/content/17/9/961
  6. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology [Internet]. 2009 Nov 10 [cited 2013 Jul 9];73(19):1543–50. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777074/
  7. Beydoun MA, Beydoun HA, Wang Y. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obesity Reviews [Internet]. 2008 [cited 2013 Jul 9];9(3):204–18. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1467-789X.2008.00473.x/abstract
  8. Scheen AJ. Sibutramine on Cardiovascular Outcome. Diabetes Care [Internet]. 2011 Apr 27 [cited 2013 Jul 9];34(Supplement_2):S114–S119. Available from: http://care.diabetesjournals.org/content/34/Supplement_2/S114.full.pdf
  9. Verrotti A, Scaparrotta A, Agostinelli S, Di Pillo S, Chiarelli F, Grosso S. Topiramate-induced weight loss: A review. Epilepsy Research [Internet]. 2011 Aug [cited 2013 Jul 9];95(3):189–99. Available from: http://www.epires-journal.com/article/S0920-1211(11)00134-3/abstract
  10. Ornellas T, Chavez B. Naltrexone SR/Bupropion SR (Contrave). P T [Internet]. 2011 May [cited 2013 Jul 9];36(5):255–62. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138366/
  11. Stapleton JA. [Commentary] TRIAL COMES TOO LATE AS PSYCHIATRIC SIDE EFFECTS END HOPE FOR RIMONABANT. Addiction [Internet]. 2009 [cited 2013 Jul 9];104(2):277–8. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2008.02487.x/abstract
  12. Topol EJ, Bousser M-G, Fox KA, Creager MA, Despres J-P, Easton JD, et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. The Lancet [Internet]. 14 [cited 2013 Jul 9];376(9740):517–23. Available from: http://www.sciencedirect.com/science/article/pii/S014067361060935X
  13. Bubar M, Cunningham K. Serotonin 5-HT2A and 5-HT2C Receptors as Potential Targets for Modulation of Psychostimulant Use and Dependence. Current Topics in Medicinal Chemistry [Internet]. 2006 Sep 1 [cited 2013 Jul 9];6(18):1971–85. Available from: http://www.eurekaselect.com/77101/article
  14. Bernal SY, Dostova I, Kest A, Abayev Y, Kandova E, Touzani K, et al. Role of dopamine D1 and D2 receptors in the nucleus accumbens shell on the acquisition and expression of fructose-conditioned flavor–flavor preferences in rats. Behavioural Brain Research [Internet]. 2008 Jun 26 [cited 2013 Jul 9];190(1):59–66. Available from: http://www.sciencedirect.com/science/article/pii/S0166432808000788
  15. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Jul 10]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  16. Shen JHQ, Zhao Y, Rosenzweig-Lipson S, Popp D, Williams JBW, Giller E, Detke MJ, Kane J. A 6-week Randomized, Double-Blind, Placebo-Controlled, Comparator Referenced, Multicenter Trial of Vabicaserin in Subjects with Acute Exacerbation of Schizophrenia. Neuropsychopharmacology [Internet]. 2011 Dec 5 [cited 2013 Jul 10];36(60):S75–S197. Available from: http://www.nature.com/npp/journal/v36/n1s/full/npp2011291a.html
  17. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Dia Care [Internet]. 2004 Jan 1 [cited 2013 Jul 10];27(1):155–61. Available from: http://care.diabetesjournals.org/content/27/1/155.full.pdf
  18. Kim KH, Sobal J, Wethington E. Religion and body weight. Int J Obes Relat Metab Disord [Internet]. 2003 [cited 2013 Jul 9];27(4):469–77. Available from: http://www.nature.com/ijo/journal/v27/n4/full/0802220a.html

No comments:

Post a Comment