Title
Effectiveness of Metformin in the management of Obesity among young adults – Randomized
Controlled Trial
Research Question
Whether 1000mg. sustained release Metformin daily along with life style intervention
for six months to young adult obese patients of age group 20 to 60 yrs. have better Body
Mass Index(BMI) reduction when compared to patients who were only on life style
intervention?
Introduction and Rationale
Obesity has reached epidemic proportions in India in the 21st century, with
morbid obesity affecting 5% of the country’s population. India is following a trend of
other developing countries that are steadily becoming more obese. Unhealthy processed
food has become much more accessible following India’s continued integration in global
food markets. Indians are genetically susceptible to weight accumulation especially
around the waist.
According to 2001 National Family Health Survey (NFHS), the position of Kerala
on prevalence of obesity among Indian states is 2nd rank, first is Punjab. In Kerala male
obesity is 24.3% and female obesity is 34%.
Over weight and obesity are defined as abnormal or excessive fat accumulation
that may impair health.
Body Mass Index (BMI) is a simple index of weight for height that is commonly
used in classifying over weight and obesity in adult populations and individuals. It is
defined as the weight in kilograms divided by the square of the height in meters (kg/m2).
The World Health Organization (WHO) defines over weight as a BMI equal to or
more than 25 and obesity as a BMI equal to or more than 30.
WHO’s latest projections indicate that globally in 2008,


Approximately 1.5 billion adult (age20+) were over weight.
Of these, more than 200 million men and 300 million women were obese.
WHO further projects that by 2015, approximately 2.3 billion adults will be over
weight and more than 700 million will be obese.
Nearly 43 million children under the age of 5 years were over weight globally in 2010
Once considered a problem only in high income countries. Over weight and
obesity are now dramatically on the rise in low and middle income countries,
particularly in urban settings.
What causes obesity and over weight


A global shift in diet towards increased intake of energy dense foods that are high
in fat and sugars but low in vitamins, minerals and other micronutrients.
A trend towards decreased physical activity due to the increasingly sedentary
nature of many forms of work, changing modes of transportation and increasing
urbanization.
Common Health consequences of over weight and obesity




Raised BMI is a major risk factor for chronic diseases such as,
Cardiovascular disease (mainly heart disease and stroke) – world’s number one
cause of death, killing 17 million people each year.
Diabetes – which has rapidly become a global epidemic. WHO projects that
diabetes deaths will increase by more than 50% world wide in the next 10 years.
Musculo skeletal disorders – especially osteo arthritis.
Some cancers – endometrial, breast, colon.
Commonly used medicines for obesity management are sibutramine and orlistat.
Both these drugs are costly and cannot afford by our poor patients. So the importance of
metformin arises, which is a cheap drug and its efficacy and safety in the management of
obesity was proven by many studies. In Trivandrum no study was conducted to check the
efficacy of metformin in the management of obesity, even though it was tried in few
patients with good results.. So I am trying to check the efficacy of metformin in
controlling obesity in patient attending obesity clinic, Trivandrum. If it works well in
controlling obesity many of our patients will be benefited.
There are studies available from many countries regarding the efficacy testing of
metformin in the management of obesity over life style intervention. Eg:- Min Hae Park
and Sanjay Kinra from London School of Hygiene and Tropical Medicine, United
Kingdom, conducted a similar study on adolescent obese ( The Journal of Pediatrics,
Vol.157, No.1). They selected two adolescent obese groups and gave life style
intervention to both groups and in addition gave 2gm sustained release metformin to
group 1 daily for 48 weeks. Result shows that BMI increased by 0.2 in the life style
intervention only group and BMI decreased by 0.9 in the metformin group. This study
clearly shows statistically significant decrease in BMI when metformin is added to
obesity management along with life style intervention.
Management of Obesity in the Obesity Clinic
Obesity Clinic is conducted by a team approach. The members of the team are



Physiatrist
Physician
Nutrition specialist
1. Life style management ( Life style intervention)
(a) Dietary habits
(b) Physical activity
(c) Behavior modification.
2. Pharmacotherapy
Suppression of appetite via centrally active medications that alter
monoamine neurotransmitters. Second strategy is to reduce the absorption
of selective macronutrients from the gastrointestinal tract.
Eg. Sibutramine, Orlistat, etc.
3. Surgery –
Bariatric surgery for grade 2 and grade 3 obesity.
Objectives
To assess the effectiveness of metformin 1000mg. sustained release daily for six
months in the management of Obesity along with the Life Style Intervention to patient
attending Obesity Clinic, Medical College, Trivandrum of the age group 20 to 60 yrs. and
BMI >25 compared to the Life Style Intervention alone.
Methodology
1.Hypothesis
Null Hypothesis (Ho) – 1 gram Metformin sustained release daily for six months has no
effect on reduction of obesity among young adults.
Alternate Hypothesis (H1) – 1 gram Metformin sustained release daily for six months
has effect on obesity reduction among young adults.
2.Study Design
Randomized Control Trial
3.Study Setting
Obesity Clinic in Department of Physical Medicine and Rehabilitation, Medical College ,
Trivandrum, a Tertiary Care Setting.
4. Study Population or participants
All young adults of age group 20 to 60 yrs. with obesity according to WHO guide line
attending Obesity Clinic of department of PMR, Medical College, Trivandrum who
satisfy inclusion and exclusion criteria.
(a) Inclusion Criteria
1. Patients with BMI >25
2. Age range 20 -60years
3. Those who are willing to comply with drug intake, exercise and diet management
and willing for regular follow up.
4. Those who are willing to give consent.
(b) Exclusion criteria
1.
2.
3.
4.
5.
6.
7.
Diabetes Mellitus on medications
Cardiovascular disease
Psychiatric illness
Hypertension
Mental retardation or cognitive impairment
Childhood Obesity
Drug allergy
5. Sample Size
Based on comparison of proportion.
P1(100-P1) + P2(100-P2)
n = ------------------------------- X (Zα + Zβ)2
(P2-P1)2
P1 = % of young adult obese who had BMI reduction on life style intervention.
P2 = % of young adult obese who had BMI reduction on metformin + life style
intervention.
Here P1 = 30%, P2 = 60%, Z α = 1.96, Zβ = 0.84
30X70 + 60X40
n = -------------------X (1.96+0.84)2 = 39.2
30X30
For drop out = 10% of n = 4
There fore n = 45
6.Recruitment of patient
The patients fulfilling the inclusion and exclusion criteria are randomly assigned to two
groups following block randomization.
0 – 4 = AB
5 – 9 = BA
1. Group I – Metformin 1000mg. sustained release tablet daily orally for six
months along with Life Style Intervention.
2. Group II – Life Style Intervention alone.
3. Life Style Intervention – It includes home programme of moderate aerobic
exercises, 30minutes brisk walking daily on all days and dietary modifications
advised to all patients by a qualified Dietician.
METFORMIN
Metformin hydrochloride is an oral antihyperglycemic drug used in the
management of type-2 diabetes mellitus. Metformin hydrochloride ( N1 N-dimethyl
imido dicarbonimidic diamide hydrochloride) is not chemically or pharmacologically
related to any other classes of oral antihyperglycemic agent.
Metformin hydrochloride is a white to off white crystalline compound with a
molecular formula of C4 H11 N5. HCL and a molecular weight of 165.63.
Metformin hydrochloride is freely soluble in water and partially insoluble in acetone,
ether and chloroform. The pKa of metformin is 12.4. The PH of 1% aqueous
solution of metformin hydrochloride is 6.68.
Metformin hydrochloride tablets available as 500mg, 850mg and 1000mg. Each
tablet contains the inactive ingredients povidone and magnesium stearate. Each tablet
is coated with hypromellose and polyethylene glycol.
Mechanism of action
1. Decreases hepatic glucose production.
2. Decreases intestinal absorption of glucose.
3. Improves insulin sensitivity by increasing peripheral glucose uptake and
utilization.
4. Does not produce hypoglycemia.
5. Does not cause hyperinsulinemia
Absorption and bioavailability
The absolute bioavailability of a metformin hydrochloride 500mg tablet given
under fasting condition is approximately 50 – 60%. Food decreases the extent of and
slightly delays the absorption. No dose proportion of absorption with increasing
dose.
Metformin is excreted unchanged in the urine and does not undergo hepatic
metabolism. Plasma elimination half life is approximately 6.2hrs.
Contra indications
1.
2.
3.
4.
Renal disease
Hypersensitivity to metformin hydrochloride
Acute or chronic metabolic acidosis
Congestive heart failure.
7. Data collection / Procedure
Data collected at first visit, then 1st, 3rd and 6th month of visit of patient in the
Obesity Clinic, Medical College, Trivandrum.
1. Body weight in Kgs – measured using Tanita Body fat monitor, TBF-611,
maximum weight measurable is 136Kgs. and d = 0.2 Kg.
2. Height – measured in meter, according to WHO criteria.
3. BMI – is calculated using the formula, BMI = Weight in Kg / Height in M2
4. Fat percentage - measured by Bio electrical impedance analysis technique using
Tanita Body fat monitor, TBF-611.
5. Waist circumference – measured in centimeter around the belly of maximum
measurement, with the measuring tape parallel to the ground and not tight to the
body or not too loose.
6. B.P.- Measured using mercury sphygmomanometer, Diamond Surex Gold. B.P.
cuff wind around arm 5cm proximal to the right elbow, patient in the sitting
position.
7. P.P.B.S – Advised to check blood sugar 11/2 hours after break fast, from the
biochemistry lab, Medical College Hospital, Trivandrum.
8. Metformin 500mg orally daily to the group A patient, which is available in the
hospital pharmacy.
8. Period of study
18 Months
9. Guide
Dr.V.K.Sreekala
Professor and HOD
Dept. of PMR
Medical College, Trivandrum.
Sl.No…….
Date……….
EFFECTIVENESS OF METFORMIN IN THE MANAGEMENT OF
OBESITY AMONG YOUNG ADULTS – RANDOMIZED
CONTROLLED TRIAL
PROFORMA
1.Name of Institution :
2.Name
:
3.Age
:
4.Education
1.Illiterate 2.Primary School
3.High School
4.Plus two or Predegree
5. Degree
6. Post graduation
7. Professional degree
5.Previous Employment
1.Unemployed 2.Unskilled Laborer 3.Skilled Laborer
4.Business/entrepreneur 5.Professional
6.Marital Status----- 1.married 2.unmarried
7.Spouse ……….1.alive 2.dead
8.Children No.…..
9. Medical History
a. DM ……1.Yes 2.No
b. HTN…..1.Yes 2.No
c. COPD /BA….1.Yes 2.No
d. CAD……1.Yes 2.No
e. Osteoporotic Fractures…. 1.Yes 2.No
f. Visual impairment…..1.Yes 2.No
g. Hearing impairment… 1.Yes 2.No
h. Vertigo….1.Yes 2.No
i. Claudication Pain……1.Yes 2.No
j. BPH……1.Yes 2.No 3.NA
10. Medications : No. of drugs/day –
11. Habits :
a. Smoking……….1.Yes 2.No
b. Alcoholism…….1.Yes 2.No
c. Tobacco chewing…1.Yes 2.No
12.Clinical Assessment :
a. Built …1.Well 2.Moderate 3.Poor
b. Ht --------cm
c.Wt -------kg
d. BMI………..
e.PR……/mt.
f. BP………mmHg.
g. RR………/mt.
h. Sleep…..1.Decreased 2.Increased
i.Urinary Incontinence….1.Yes 2.No
j.Bowel Incontinence…..1.Yes 2.No
13.Musculoskeletal system examination :
a.
b.
c.
d.
e.
Low back ache….1.Yes 2.No
Cervicobrachial neuralgia…1.Yes 2.No
Shoulder Pain….1.Yes 2.No
OA…..1.Yes 2.No
Polyarthralgia….1.Yes 2.N
First visit 1st Month 3rd Month 6th Month
Weight(Kg.)
Height(cm.)
Waist circ.
B.M.I.
Fat %
B.P.
P.P.B.S.
REFERENCES
1. Grundy SM. Dietary therapy in diabetes mellitus: Is their a single best diet? Diabetes Care 1991; 14: 796801
.
2. Pan X, Huy. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance.
Diabetes Care1997; 20(4):537-44
3. Labovitz HE. Non-Insulin dependent (type II ) diabetes mellitus, In: Krishna Berg RA(eds). Diabetes
Mellitus. La Jolla, Calif: Publishers National Health Laboratory 1992: 1625.
4. Marshall JA, Hamman RF, Baxter J. High fat low carbohydrate diet and etiology of non-insulin dependent
diabetes mellitus: The San Luis Valley Diabetes study. Am J Epidemiol 1991 ; 134: 590-603.
5. National Research Council : Diet and Health. Implications for reducing chronic disease risk. National
Academy Press, Washington DC1989.
6. Helmrich SP, Ragland DR, Leung RW, Paffenbarger RS. Physical activity and reduced occurrence of
Non-Insulin dependent diabetes mellitus. N Engl Med 1991; 325:147-5
7. Horton ES. Exercise and decreased risk of NIDDM. N Engl J Med 1991; 325: 196-8.
8. Pharmacology and Pharmacotherapeutics 13 th edn by Satoskar RS, Bhandorkar SD. Chapter 60. P. 806.
Insulin and Oral anti-diabetic drug.
9. Bailey CJ. Biguanides and NIDDM. Diabetes Care 1992; 15:755-72.
10. UK Prospective Diabetes Study group. Effect of intensive blood glucose control with metformin on
complications in overweight patients with type II diabetes. Lancet 1998; 352: 854-66.
11. Moses R, Slobodnuik R, Donnelly T. Additional treatment with repaglinide provides significant
improvement in glycemic control in NIDDM patients poorly controlled on metformin(abstr.) Diabetes 1997;
46(suppl.1) : 93A.
12. Harrison’s principles of internal medicine – 17th edition, page no. 470.
13. National Family Health Survey report 2007.
14.The Journal of Pediatrics, Vol.157, No.1, metformin treatment for adolescent obesity.
15. U.S. National Library of Medicine National Institute of Health, Rom J Interb Med. 2003; 41(3): 269-75,
metformin in the treatment of obesity in subjects with normal glucose tolerance.
16. U.S.National Library of Medicine National Institute of Health, Nutr. Metab. Cardiovasc. Dis. 2010 Feb.15.
17. U.S.National Library of Medicine National Institute of Health, Arch Pediatr Adolesc Med. 2010 Feb;
164(2): 116-23.
18. J Clin Endocrinol Metab. 2006 Jun; 91(6): 2074-80. Epub 2006 Apr.4.
CONSENT FORM
I am Dr.Selvan.P, MD PM&R Trainee, Medical College, Trivandrum, kerala is
doing a study titled “Effectiveness of Metformin in the management of Obesity among
young adults”. The purpose of the study is to find the effectiveness of metformin in the
management of obesity. If you participate in the study, you will be randomized to one
of the two groups. In either group, you will get the standard treatment for obesity. The
only difference is that the first group in addition get metformin 1000mg daily orally for
six months.
You are invited to participate in this study. You are free to ask any question you
have about this study with the investigator who will explain it to you. The decision to
participate or not is yours. Your participation in this study will be kept confidential and
in the event of any publication or presentation resulting from the research, no
personally identifiable information will be shared. If you decide to participate, please
sign at the end of this form.
I…………………………………………………………………… ……………………………….
Aged………….years have been informed about this study’s purpose, procedure, possible
benefits and risk and I have received a copy of this consent. I have been given the
opportunity to ask question before I sign, and I have been told that I can ask other
question at any time. I have been told that I have no financial burden. I voluntarily
agree & give consent to participate in this study. I understand that I am free to withdraw
from the study at any time without need to justify my decisions. This withdrawal will
not in any way affect my future treatment. I have been informed that if have any
difficulties or queries during the study I am free to contact Dr.Selvan.P (Ph.0471
2482999/9447303550). I agree to co-operate with the research staff and to inform
them immediately if I experience any unexpected or unusual symptoms.
Signature of patient
Name:
Date:
Place:
Signature of Investigator
Name: