UNIVERSITY OF IOANNINA

FACULTY OF LIFE SCIENCES

DEPARTMENT OF MEDICINE

Conservative treatment of
obesity
in patients with Type 2 Diabetes Mellitus
Georgios Lavasidis
4th-year student

Obesity: Significant risk factor for T2DM

Mokdad AH et al, Diabetes Care, 2000;23:1278-83

Mokdad AH et al, JAMA, 1999;282:1519-22
Mokdad AH et al, JAMA, 2001;286:1195-200

BMI and T2DM

Obesity (BMI 30)

Increased adipose tissue

(endocrine-secretory organ)

Increased release of insulin

resistance-provoking
adipokines (e.g. TNF-a and
IL-6)

Decreased insulin sensitivity

Impaired glucose tolerance

Treating Diabetes and Prediabetes by Focusing on Obesity Management, Khaodhiar et al, Curr Diab Rep. 2009 Oct;9(5):348-54

Conservative treatment of obesity

Lifestyle modification

and COMPLEMENTARY

Drug treatment
The pharmacological and surgical management of adults with obesity, Ryan DH, J Fam Pract. 2014 Jul;63(7):S21-6
Randomized trial of lifestyle modification and pharmacotherapy for obesity, Wadden et al, N Engl J Med. 2005 Nov 17;353(20):2111-20

Lifestyle modification!
Reduced-calorie diet

Physical activity

Principles and Nonpharmacologic Management of Obesity in Adults, Kushner et al, J Fam Pract. 2014 Jul;63(7):S15-20

Without lifestyle modification the results are

mediocre
=224

Randomized trial of lifestyle modification and pharmacotherapy for obesity, Wadden et al, N Engl J Med. 2005 Nov 17;353(20):2111-20

Look AHEAD (RCT)

=5145
Follow-up:
10

Intensive lifestyle
intervention
vs.
diabetes support and
education (control)

No difference was
observed on
cardiovascular
events!

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes, Look AHEAD Research Group, N Engl J Med. 2013 Jul 11;369(2):145-54

Physicians contribution is vital

Assess

Advise

Agree

Assist

Arrange
Principles and Nonpharmacologic Management of Obesity in Adults, Kushner et al, J Fam Pract. 2014 Jul;63(7):S15-20

Drug treatment
As an adjunct to lifestyle interventions in patients with:
BMI 30 or
BMI 28 (27 for new medicines) with risk factors like:
T2DM
Hypertension
Dyslipidemia
Cardiovascular disease
Fatty liver disease

Obstructive sleep apnea

The pharmacological and surgical management of adults with obesity, Ryan DH, J Fam Pract. 2014 Jul;63(7):S21-6

Targets
Clinically-meaningful weight loss (5%) in one year
The results in the first 12 weeks are predictive for the final
outcome, thus the continuation or discontinuation of the
medicine is decided at this point

Long-term drug treatment for obesity: a systematic and clinical review, Yanovski SZ et al, JAMA. 2014 Jan 1;311(1):74-86

Medicines for obesity

In Greece (and in Europe) there is only:

Orlistat

FDA approval (new medicines):

Lorcaserin
Phentermine/extended release topiramate
The pharmacological and surgical management of adults with obesity, Ryan DH, J Fam Pract. 2014 Jul;63(7):S21-6

Orlistat
Gastric and pancreatic lipase inhibitor Reduces TG dissolve in the GI tract,
therefore reduces the dietary fat absorption as well

Pharmacology, Harvey RA, Champe PC, 3rd Edition, 2007

XENDOS Study
(RCT Orlistat+lifestyle vs. Placebo+lifestyle)

N=3305

Follow-up:
4 years

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, Torgeson et al, Diabetes Care. 2004 Jan;27(1):155-61

XENDOS Study
(RCT Orlistat+lifestyle vs. Placebo+lifestyle)

T2DM risk
reduction of 37%

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, Torgeson et al, Diabetes Care. 2004 Jan;27(1):155-61

Safety
Generally severe side effects are not common, however there
are reports of:
Gastrointestinal disorders (very common, usual reason for treatment
discontinuation)

Headache, infections (very common)

Possible nephrotoxicity (Coutinho et al, 2013)
Hepatotoxicity in rare cases

Case reports

The only anti-obesity drug indicated in adolescents

The pharmacological and surgical management of adults with obesity, Ryan DH, J Fam Pract. 2014 Jul;63(7):S21-6
Xenical 120mg hard capsules SPC

Lorcaserin
FDA approval: 2012

Selective (in therapeutic dose) agonist of 5-2C receptors

Hypothalamus,
satiety and
hunger center

Lorcaserin: A novel antiobesity drug, Brashier et al, J Pharmacol Pharmacother. 2014 Apr;5(2):175-8

Mechanism of action
Activation of 5-2C receptors on POMC neurons in arcuate nucleus of the
hypothalamus

a-MSH release

Activation of MC4R in paraventricular nucleus

Feeling of satiety and appetite reduction

Lorcaserin: A novel antiobesity drug, Brashier et al, J Pharmacol Pharmacother. 2014 Apr;5(2):175-8
Lorcaserin for the treatment of obesity, Redman et al, Drugs Today (Barc). 2010 Dec;46(12):901-10

BLOOM-DM Study
(RCT)

N=604
patients
with T2DM
Placebo
vs.
Lorcaserin

Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study, O'Neil et al, Obesity (Silver Spring). 2012 Jul;20(7):1426-36

BLOOM-DM Study
(RCT)

Secondary results: Lorcaserin and glycemic parameters (decrease is

attributed to weight loss)

Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study, O'Neil et al, Obesity (Silver Spring). 2012 Jul;20(7):1426-36

Safety
Well tolerated in general. Major side effects:

Headache (14-17%)
Hypoglycemia in diabetics taking metformin (13%)
Back pain (11%)
Nasopharyngitis (11%)

Valvulopathies (5-2B)
Psychiatric disorders
Carcinogenesis
Serotonin syndrome

Under investigation

Lorcaserin: A novel antiobesity drug, Brashier et al, J Pharmacol Pharmacother. 2014 Apr;5(2):175-8
Lorcaserin for the treatment of obesity, Redman et al, Drugs Today (Barc). 2010 Dec;46(12):901-10
Belviq, INN-Lorcaserin SPC (Procedure No. EMEA/H/C/002597)
QsymiaTM Prescribing information
Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study, O'Neil et al, Obesity (Silver Spring). 2012 Jul;20(7):1426-36

Phentermine/Extended release topiramate

FDA approval: 2012
Phentermine:
In the USA it is also used as monotherapy for short-term obesity
treatment
Centrally acting sympathomimetic medicine
Upregulation of dopamine, noradrenaline, and serotonin activity
appetite suppression

Increased energy expenditure

Management of obesity and cardiometabolic risk - role of phentermine/extended release topiramate, Sweeting et al, Diabetes Metab Syndr Obes. 2014 Feb 12;7:35-44

Phentermine/Extended release topiramate

Topiramate:
It is used as an antiepileptic and antimigraine medicine
GABA-agonist

Unclear mechanism of action

Increased energy expenditure, calorie intake reduction

Management of obesity and cardiometabolic risk - role of phentermine/extended release topiramate, Sweeting et al, Diabetes Metab Syndr Obes. 2014 Feb 12;7:35-44
Medical treatment of obesity: the past, the present and the future, Bray GA, Best Pract Res Clin Gastroenterol. 2014 Aug;28(4):665-84

EQUIP Study
(RCT)

N=1267

The following were compared:

1. Phentermine/Topiramate-ER (high dose)
2. Phentermine/Topiramate-ER (low dose)
3. Placebo
Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP), Allison et al, Obesity (Silver Spring). 2012 Feb;20(2):330-42

Safety
Major side effects:
Dry mouth

Constipation
Paresthesia
Dysgeusia

5%

The combination reduces the dose, and

thus the side effects, of each drug
separately

Insomnia
Dizziness

Contraindications: hyperthyroidism and glaucoma

Teratogenic (topiramate)
Management of obesity and cardiometabolic risk - role of phentermine/extended release topiramate, Sweeting et al, Diabetes Metab Syndr Obes. 2014 Feb 12;7:35-44
QsymiaTM Prescribing information

Comparison

Percentage of patients with 5% weight loss by medicine:

Orlistat: 35-73%
Lorcaserin: 37-47%

Phentermine/Topiramate-ER (high dose): 67-70%

Long-term drug treatment for obesity: a systematic and clinical review, Yanovski SZ et al, JAMA. 2014 Jan 1;311(1):74-86

Old medicines
Sibutramine
Serotonin-noradrenaline reuptake inhibitor

Withdrawn in 2010 because of cardiovascular events (nonfatal MI, nonfatal

stroke SCOUT study)

P<0,05

Rimonabant
Cannabinoid-1 receptor antagonist
Withdrawn in 2008 because of psychiatric dissorders (mainly depression,
incidents of suicides were reported)
Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects, James et al, N Engl J Med. 2010 Sep 2;363(10):905-17
Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials, Christensen et al, Lancet. 2007 Nov 17;370(9600):1706-13

Obesity treatment in patients with T2DM

The results are modest in comparison with the general

population:
Insulin and other antidiabetic drugs induce weight gain
Psychological reasons (long history of unsuccessful weight loss
intervention attempts)
Difficulties in exercise because of T2DM complications (arteriopathy,
neuropathy, heart disease)

Weight loss in type 2 diabetic patients, Pi-Sunyer FX, Diabetes Care. 2005 Jun;28(6):1526-7
Managing type 2 diabetes: balancing HbA1c and body weight, Mavian et al, Postgrad Med. 2010 May;122(3):106-17

Conclusions
Obesity is an important risk factor for T2DM
Conservative treatment of obesity includes lifestyle interventions and
medicines
The only available drug for obesity in Europe is orlistat

In the USA there are also lorcaserin and phentermine/topiramate-ER

The recent withdrawal of two drugs because of severe side effects
indicates the need for continuous safety check
The results of the treatment in diabetic patients are worse than in the
general population