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Update on off label use of metformin for obesity

Article  in  Primary Care Diabetes · March 2018

DOI: 10.1016/j.pcd.2018.02.004

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Amr Ahmed EL-Arabey

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 p r i m a r y c a r e d i a b e t e s 1 2 ( 2 0 1 8 ) 284–285
Contents lists available at ScienceDirect
Primary Care Diabetes
journal homepage: http://www.elsevier.com/locate/pcd
Letter to the Editor
Update on off label use of metformin for obesity
To the Editor:
Metformin, a biguanide, was approved by FDA in 1995
as an oral hypoglycemic agent and it has become one of
the most routinely prescribed drug therapies of type 2 dia-
betes mellitus. Several studies in recent years confirmed
additional potential efficacy for metformin as favorable drug
for treatment of cancer, aging, neurological diseases, cardio-
vascular diseases, metabolic syndrome and polycystic ovary
syndrome. Moreover, it is used off-label for weight reduc-
tion and prevent weight gain induced by antipsychotic drugs
[1]. Historically, the first clinical trial to follow the metabolic
effect of metformin was conducted in USA during 2005 on
10 non-insulin dependent diabetic patients; the outcome of
this study explained the primary metabolic effect of met-
formin in liver by inhibition of gluconeogenesis alongside
weight loss effect involving the adipose tissue [2]. Further,
randomized clinical trial linked to high quality of Diabetes
Prevention Program in 27 centers at high risk of diabetes in
2002 (http://www.bsc.gwu.edu/dpp) showed that metformin
significantly reduce weight in non-diabetic patients [3], this
action tolerated up to 8 years in case of adherence medica-
tion from patients [4]. In 2005, the first experimental study
deduced that metformin obviously improved the insulin resis-
tance resulting from high fat via activation of AMP-activated
protein kinase subunit ␣2 (AMPK␣2) in rats skeletal muscle
[5]. Importantly, study conducted from 2009 to 2013 to assess
the prescription patterns of metformin among adolescents
in United State showed its off-label use approximately 6.5%
diagnosed with obesity. However, in the previous study obe-
sity clarifies one of the most frequently diagnoses among
girl aged 10–14 years about (10.4–13.6%) and boy aged 15–19
years around (9.6–18.8%) [6]. In 2013, the first published study
demonstrated that metformin up to dosage 2500 mg per day
is an effective drug to reduce weight in a naturalistic non-
diabetic 154 consecutive outpatients with body mass index
more than 27 kg/m2 among 6 months setting in insulin sen-
sitive and insulin resistant overweight and obese patients [7].
After that, randomized clinical trial for six months concluded
that metformin 1000 mg twice daily useful for the manage-
ment of obesity through minimized the energy intake in
hyperinsulinemic obese children aged 6–12 years [8]. Diverse
scenarios have been manifested to illustrate the mechanism
of metformin action on obesity. However, the majority path-
way of metformin induces weight reduction through a loss
of adipose tissue beside energy expenditure regulation with
exercise [2]. Recent pioneer work by Lopez-Mejia et al. dis-
played that Cyclin Dependent Kinase 4 (CDK4), a protein that
is ordinarily implicated in the orchestrate of cell division, is
substantial organizer of cell energy equilibrium through direct
abrogation of activity of AMPK␣2 in mouse embryonic fibrob-
lasts. Furthermore, CDK4 suppresses fatty acid oxidation
through direct phosphorylation and inhibition of AMPK␣2 [9].
In addition, CDK4 is a major player of insulin signaling in white
adipose tissue which pools to obesity development related to
insulin resistance via raised shot of fatty acids [10]. Clinically,
AMPK␣2 is the critical regulator of cell consumption opera-
tions by triggering ATP output catabolic routes [11]. Hence, it
seems that AMPK␣2 one of the possible target of metformin
among its journey related insulin resistance and obesity treat-
ment. However, one question remains unanswered related to
the possibility of metformin to target CDK4 in normal obese
patients to produce its majority pathway through adipose tis-
sue. Moreover, further work on metformin actions for obesity
could change its status to on label use by FDA.
Conflict of interest
The author declares that he has no competing interests.
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Amr Ahmed EL-Arabey a,b,∗
a CAS-TWAS Fellowship at University of Science and Technology of
China (USTC), China
b Pharmacology and Toxicology Department, Faculty, of Pharmacy
Al-Azhar University, Egypt
∗ Correspondence
to: Pharmacology and Toxicology
Department, Faculty, of Pharmacy Al-Azhar University, Egypt.
E-mail addresses: ph.amrcapa@gmail.com,
amrel arabey@azhar.edu.eg
12 February 2018
1751-9918/© 2018 Primary Care Diabetes Europe.
Published by Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.pcd.2018.02.004
Available online 7 March 2018