Anti-Obesity Drug Discovery and Development

Volume: 1

Pharmacological Approach for Obesity

Author(s): Mohannad Kusti, Forrest Olgers and Ehab Akkary

Pp: 67-81 (15)

DOI: 10.2174/978160805163211101010067

* (Excluding Mailing and Handling)

Abstract

Obesity has reached epidemic levels in the US and represents a major health and economic challenge. The weight loss process generally starts with behavioral modification and ends with surgical intervention in cases of severe or morbid obesity. Pharmacological therapies present a valid option for patients who are overweight or morbidly obese as an in addition to the role of behavioral modification, diet and exercise. This option should also be considered for post-operative patients with inadequate weight loss who are not candidates for revisional bariatric procedures. Weight loss medications (WLMs) can be divided into the following categories:

1. Noradrenergic Appetite Suppressants (NASs): more commonly used. Examples include phentermine, sibutramine, phendimetrazine, and diethylpropion.

2. Pancreatic Lipase Inhibitors (PLIs): examples include orlistat.

3. Fat Substitutes (FSs): examples include olestra which has been integrated into snack foods but not been studied as a formal weight loss medication.

4. Cannabinoid Receptor Antagonists (CRAs): examples include Rimonabant.

5. Thermogenics and Stimulators of Fat Mobilization.

There is multiple OTC and commercial brands, it is important to differentiate between the different types and their mechanism of action, for example Alli is the OTC version of orlistat with same mechanism and side effects.

Since the obesity “disease” is chronic, the medications have to be weighed carefully in terms of the risks and benefits for long term use.

Sibutramine, as a commonly used NAS, is a centrally acting serotonin/ noradrenaline reuptake inhibitor and increases thermogenesis. Studies showed weight reduction of 4.45 kg for sibutramine compared to placebo with overall improvement in the metabolic profile e.g. decreased triglycerides, increased HDL, and improved Hgb A1C. The main side effect is tachycardia; there is conflicting studies about the effect on blood pressure so overall NASs are not recommended in patients with uncontrolled hypertension, or in case of history of cardio- and cerebrovascular disease.

Orlistat, a PLI, blocks the lipolysis of dietary triglycerides. A recent meta-analysis showed mean weight loss of 2.89 kg with overall improvement of the metabolic profile especially diabetes parameters; however there was no effect on HDL and triglycerides. As mentioned, the side effects are mainly gastrointestinal but can cause considerable inconvenience for patients for example greasy diarrhea, incontinence, urgency and oily spotting. Overall it is not recommended for patients with malabsorption or cholestasis.

Rimonabant, as a CRA, inhibits the overactivation of the endocannabinoid system resulting in central anorexia. Rimonabant seems to have effects on the metabolism through the adipose tissue, liver, skeletal muscles and the pancreas. There are four published RIO trials (Rio-North America, RIO-Europe, RIO-Lipids, RIO-Diabetes), rimonabant decreased weight by 6.3-6.9 kg in the nondiabetic groups vs. placebo (-1.5-1.8 kg) (p <0.001), whereas in the diabetic subjects enrolled in RIO-Diabetes, weight loss was 5.3 vs. 1.4 kg in the placebo group with overall improvement in the metabolic profile in diabetic and non-diabetic patients. Rimonabant is contraindicated in patients with history of depression, suicidal ideation or uncontrolled psychiatric disorder.

In spite of the fact that serotonergic agents (fenfluramine, dexfenfluramine) were withdrawn from the US market in the late 1990’s secondary to their cardiovascular and pulmonary complications. At the present time, it is very important to assess the patient’s history regarding their intake as this might result in further cardiac or pulmonary evaluations.

In conclusion, WLMs have shown decrease in body weight and improved metabolic and cardiovascular risk factors. Since, the weight loss is modest, they should be considered in overweight (BMI 25 – 29.9kg/m2) or obese (BMI 30 – 34.9 kg/m2) patients and should not be considered as an alternative for surgical intervention in patients with higher BMIs. Diet, exercise and behavioral modification should always be implemented regardless of the weight loss means being applied.


Keywords: Obesity, medical weight loss, appetite suppressants, lipase inhibitors, fat substitutes, cannabinoid.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834620 and j.to_date >= 1739834620 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 539) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834620 and j.to_date >= 1739834620 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 539) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316440840 and j.to_ip >=316440840 )) and ((j.from_date <= 1739834620 and j.to_date >= 1739834620 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 539)
      920μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 829 and `b`.`banner_from_date` <= 1739834620 and `b`.`banner_to_date` >= 1739834620 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.49msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 829
      • 3: 1739834620
      • 4: 1739834620
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='fa563767813f58d9a0498b002687e8ad'
      310μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    6Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        oUVlSMCu7FppYWiprvlu9LOywDNRtQZh5WOsylGz
        uc_cart_id
        fa563767813f58d9a0498b002687e8ad
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/539" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/539
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
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        request_headers
        0 of 0
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        request_cookies
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        response_headers
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:23:40GET/chapter/539112198