Drug therapy is indicated in

–   Patients with BMI >30
–   Patients with BMI >28 with additional risk factors.

Withdrawn drugs:

•      Amphetamine  Methamphetamine
•      Phenmetrazine
•      Fenfluramine
•      D-fenfluramine
•      Mazindol
•      Dinitrophenol
•      Rainbow pills
•      Aminorex
•      Phenylpropanolamine

Tried or testing!

•      Phenteramine
•      Diethylpropion
•      Phendimetrazine
•      Benzphetamine

Probably promising?

•      Ephedrine
•      Caffeine
•      Fluoxetine / Paroxetine/ Venlafaxine
•      Topiramate
•      Bupropion

Fat substitutes

•      Sitostanol (Benecol)
•      Olestra (Olean)
•      Tagatose

Future Options

Drugs Modulating neurotransmitters:
Rimonabant:
Cannabinoid receptor antagonist
Blocks CB-1 receptor
Phase III trials in >6000 patients
 Lancet. 2005 Apr 16-22;365(9468):1389-97.

          Bupropion
          Smoking cessation drug
          Inhibitor of neuronal uptake of serotonin, dopamine, nor-epinephrine
          Variable weight loss in studies
          Clin Ther. 2002 Apr;24(4):662-72.

  Topiramate
  Derivative of d-fructose
  Blocks glutamate receptors
  Controlled release formulation in development
  > 1 year trial to date
  Cognitive impairment and paraesthesias noted as adverse effects in significant proportion of patients
 Am J Cardiol. 2005 Jul 15;96(2):243-51.

 Zonisamide:
 Anti-epileptic medication
 serotoninergic and dopaminergic activity
 weight loss demonstrated in 16 week trial
JAMA. 2003 Apr 9;289(14):1820-5.

Qnexa (from Vivius)
Combination of Phenteramine and topiramate

Contrave (from Orexigen)
Combination of Bupropion and Naltrexone

Peptide YY (from Nastech)
Nasal preparation
In Phase II studies
also pegylated PYY from Pfizer in development
TM30338 is a synthetic analog of PYY and pancreatic polypeptide (from 7TM pharma)

 

Anti-Diabetic Drugs:

Adiponectin derivatives
PTP-1 B gene antisense inhibitors
PPAR-gamma antagonists?

 

Drugs acting on Leptin pathway:

Leptin analogues / agonists
Leptin sensitizers
Leptin promoters
Leptin like effects- Ciliary Neurotrophic factor (Axokine)

 

Drugs acting on NPY-AgRP pathway:

NPY antagonists
AgRP antagonists
POMC promoters
alpha MSH analogues
MC4r agonists

CB1 receptor agonists:

Rimonabant
7TM Pharma and Pfizer (CP-946,598) are  also working on CB1 targeting

 

Drugs that increase Metabolic Rate:

Selective Beta 3 agonists
UCP (uncoupling protein) analogues
Adipose tissue specific Thyroid hormone analogues
 

Miscellaneous

P57: African Cactus Extract
Phytosterol analogues
DHEAS analogue (fluasterone)
11BetaHSD antagonist
CRH agonists
Carboxypeptidase inhibitors
Fatty acid synthase inhibitors

Currently Used Drugs:

        Sibutramine

        Orlistat

        Rimonabant

Sibutramine (Reductil)

•      Selective serotoninergic nor-epinephrine neurotransmitter reuptake inhibitor

•      Depresses central appetite through effects on serotonin

•      Small peripheral thermogenic effect

•      Raises HDL cholesterol.

•      Can raise blood pressure and cause tachycardia

•      Currently licensed in the UK for one year treatment.

•      Discontinue if weight loss<5% of initial weight in three months

•      Contraindication:

        Renal and hepatic disease, hypertension, IHD,

        Cerebrovascular disease, BPH, glaucoma, alcohol abuse.

•      Drug interaction :antidepressants

Nice Guidelines on Sibutramine use

 Lorcaserin  from Arena
A selective 5HT2c agonist
In phase III trials

Orlistat (Xenical) from Roche

•      Tetrahydrolipostatin

•      Peripherally acting

•      Gastrointestinal lipase inhibitor.

•      Prevents absorption of 30% of ingested fat.

•      No drug interaction

•      70% wt loss over placebo

•      Beneficial aversive conditioning

•      FDA-approved for weight loss and weight loss maintenance since 1999

•      NICE approved in march 2001

•      120 mg tds with meals

•      Reduces LDL cholesterol and triglycerides.

•      Reduces Glycated Hb levels

•      Can be continued for 2 years ( evidence for 4 yrs following the XENDOS study- vide infra)

       Alli : (from glaxo)
       60 mg Orlistat preparation available over the counter

Nice Guidelines on Orlistat use

 

 

Orlistat vs. Placebo
German study

•      383 type 2 diabetes

•      Sulfonylureas 66%      No sulphonylureas 34% .

•      Baseline BMI  34.1 kg/m2

•      waist circumference was 110 cm

•      Fasting glucose 10.1 mmol/L,

•      HbA1c 8.3%.    

    1 year outcome measures

•      Weight loss: 5.4% vs 3.6%

•      Waist circumference reduction: 4 cm vs 1 cm

•      Decrease in FBS: 1.6 vs 0.7 mmol/L

•      Decrease in HbA1c: 0.9% vs 0.4%

XENDOS STUDY:

Orlistat plus lifestyle intervention is significantly better than lifestyle intervention alone in preventing or delaying the development of type 2 diabetes

The risk of developing type 2 diabetes was 37% lower in people treated with Orlistat plus lifestyle intervention compared with lifestyle intervention alone

Orlistat vs. Placebo in XENDOS:

Weight loss at 1 year:             -11.4  vs.    -7.5 kg

Weight loss at four years:        -6.9   vs.     -4.1kg

Number of patients with 5% weight loss at four years:       53%    vs.    37%

Number of patients with 10% weight loss at four years:     26%    vs.   16%

Orlistat-treated patients had significant, sustained, long-term improvements in cardiovascular risk factors such as blood pressure and lipid profiles compared with lifestyle intervention alone

Treatment with Orlistat for 4 years was safe and well-tolerated. Orlistat is now the only weight loss medication available whose safety has been studied for this length of time

Further reading: Diabetes Obes Metab. 2003 Sep;5(5):356.

Orlistat contraindication

•      Fat Malabsorption

•      Vitamin deficiency  

•      Cholestasis

•      Interaction with Acarbose, anticoagulants

•      Discontinue if weight loss <5% of body weight after 3 months

The mean additional weight loss of 3 kg with orlistat is maintained for at least 4 years and reduces the incidence of diabetes by >30%

Orlistat (Tetrahydrolipostat) does not produce diarrhoea as long as daily fat consumption is <90 gm/day.

Cetilistat (Alizyme) or ATL 962 has efficiency similar to orlistat and is in phase III trials as of 2007

AOD9604 hGH:
Failed Phase II b trials
Lipid metabolism modulator
inhibits acetyl Coa carboxylase and prevents glucose incorporation into lipids while enhancing breakdown of stored fats

Meta analysis of the effect of pharmacological treatment of obesity (2005)
(Tabulated Overview of Meta analysis results )

GASTRIC PACING

Electrical pacing of the stomach is being investigated as a possible non-drug treatment of morbid obesity.  Chirurg. 2002 Jul;73(7):700-3. An Implantable Gastric Stimulator (IGS) is placed on the abdominal wall with two leads being positioned on the stomach wall, under gastroscopic guidance to ensure that perforation does not happen. Obes Surg. 2002 Apr;12 Suppl 1:17S-20S.  Gastric pacing for 6 months seems to be associated with a mean weight loss of 10 kgs and changes in gut hormones although the mechanism and implications remain to be elucidated. Obes Res. 2003 Dec;11(12):1456-62.

Read on SIGN guidelines on Treatment of Childhood Obesity

Guidelines for treating adult obesity in primary care (National Obesity forum)

Guidelines for treating adult obesity (NHLBI)

  .

    This page was last updated on: 07/03/2007

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