Review of CV Effects of

Obesity Drugs in
Development and their
Potential Mechanisms
Boaz Mendzelevski, MD
Vice President Cardiology,
CoreLab Partners Inc.
5th DIA CV Safety Conference, 34 November 2011,
Barcelona, Spain

The Economist. Cover illustration. Dec 13, 03

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Defining Overweight and Obesity

Overweight and obesity are both labels for ranges of weight
that are greater than what is generally considered healthy for a
given height. The terms also identify ranges of weight that have
been shown to increase the likelihood of certain diseases and
other health problems.
Definitions for Adults
For adults, overweight and obesity ranges are determined by
using weight and height to calculate a number called the "body
mass index" (BMI). BMI is used because, for most people, it
correlates with their amount of body fat.
An adult who has a BMI between 25 and 29.9 is considered
overweight.
An adult who has a BMI of 30 or higher is considered obese.

Percent of Obese (BMI > 30) U.S. Adults

Past and projected prevalence of

overweight (BMI 25 kg/m2)

The Lancet 2011; 378:815-825 (DOI:10.1016/S0140-6736(11)60814-3)

Biologic Mechanisms Protecting Adipose Tissue Mass

NEJM 2008;358:1941-50

Clinical manifestations of obesity

Type 2 diabetes and

glycemic disorders

Glucotoxicity

FFAs

Lipotoxicity

Dyslipidemia

Adiponectin

Low HDL

Leptin

Small, dense LDL

Hypertriglyceridemia
Hypertension
Endothelial dysfunction/
inflammation (hsCRP)

Atherosclerosis

Insulin
resistance

Impaired thrombolysis
PAI-1
Courtesy of Selwyn AP, Weissman PN. 2006.

Intra-abdominal adiposity promotes

insulin resistance and increased CV risk
Secretion of
Hepatic FFA flux
metabolically active
(portal hypothesis)
substances (adipokines)
Intra-abdominal
adiposity
PAI-1
suppression of
lipolysis by insulin

FFA

Insulin resistance
Dyslipidaemia
Pro-atherogenic

Adiponectin
IL-6
TNF
Net result:
Insulin resistance
Inflammation

Heilbronn et al 2004; Coppack 2001; Skurk & Hauner 2004

The Metabolic Syndrome

The Metabolic Syndrome

Criteria for a diagnosis of Metabolic Syndrome

Why Treat Obesity?

Contributes to approximately 300,000 deaths a year,

making it 2nd only to smoking as a cause of death
Contributes or causes to many other health problems
including:
Type 2 Diabetes Mellitus
Coronary Artery Disease
Degenerative Joint Disease
Certain Types of Cancer
Nonalcoholic Steatohepatitis

Weight loss improves CV risk factors

N = 4047 with obesity
25
20
15
10
Change
from
baseline*
(%)

5
0
-5
-10
-15
-20
-25
Weight

SBP

Conventional treatment
(n = 1660)

DBP

HDL-C

FPG

Gastric surgery
(n = 1845)

*At 2 years

Sjstrm L et al. N Engl J Med. 2004;351:2683-93.

Costs of Obesity

Costs the US health-care system more than $99 billion

each year
Consumers also spend over $33 billion annually on
weight-reduction products and services
Annual health-care costs for patients with BMIs of 20 to
24.9 were 20% lower than costs for patients with BMIs
from 30 to 34.9 and almost 33% lower than for patients
who had BMIs of 35 or more.

IMS Report 2009

Potential Strategies for Anti-Obesity

Drug Action
Reducing food intake. Either amplify effects of
signals/factors that inhibit food intake or block signals/factors
that augment food intake
Blocking nutrient absorption (especially fat or
carbohydrates) in the intestine.
Increasing thermogenesis. Either increase metabolism and
dissipate food energy as heat or increase energy expenditure
through the enhancement of physical activity.
Modulating fat metabolism/storage. Regulate fat
synthesis/breakdown by making appropriate adjustments to
food intake or energy expenditure.
Modulating the central regulation of body weight. Either
alter the internal set point or modulate the signals presented
regarding fat stores.

Currently Available Agents

Indicated for Treatment of Obesity
Generic/Brand
Name

Usual Dose

Mechanism of
Action

Side Effects

Orlistat/Xenical

120 mg with each

meal

Peripheral: Blocks
absorption of about
30% of consumed
fat

GI symptoms (oily
spotting, flatus with
discharge, fecal
urgency, oily stools,
incontinence)

Sibutramine

5-15 mg/d

/Meridia
(withdrawn EU/US)

Central: Inhibits
synaptic reuptake of
norepinephrine and
serotonin

Dry mouth,
constipation,
headache, insomnia,
increased blood
pressure,
tachycardia

15-37.5 mg per day

Phentermine/
as a single or split
Adipex, Fastin,
Ionamin and others dose

Central: Stimulates
release of
norepinephrine

CNS stimulation,
tachycardia,
palpitations, dry
mouth, insomnia,

Agents sometimes used for Treatment of

Obesity NOT Indicated or FDA approved
Generic/Brand Name

Usual Dose

Mechanism of
Action

Side Effects

Ephedrine+/-caffeine
"Elsinore"pill

Varies: usually 75150 mg ephedrine

and 100-150 mg
caffeine

Central: Stimulates
adrenergic receptors

CNS stimulation,
tachycardia,
palpitations, dry
mouth, insomnia,

Bupropion/Wellbutrin
(constituent of
Contrave)

100-300 mg/d

Central: Inhibits
reuptake of dopamine
norepinephrine and
serotonin

CNS stimulation, dry

mouth, headache, GI
effects

Topiramate/Topamax
(constituent of
Qnexa)

96-192 mg/d

Uncertain: Central ?

CNS: paresthesia,
fatigue, dizziness,
memory difficulty,
concentration
difficulty, and
depression

Anti-obesity Drug Market

Datamonitor 2010

Obesity Regulatory Guidelines

Both FDA (2007) and EMA (2006) guidelines require
phase 3 studies to be designed as randomised, doubleblind, placebo-controlled trials including patients with a
BMI of 27 kg/m2 accompanied by co-morbidities and
with a BMI of 30 kg/m2, without co-morbidities.
The FDA recommends efficacy to be based on 12-month
data showing statistical differences in
the mean placebo subtracted weight loss 5%;
or the proportion of subjects who lose 5% of baseline body
weight in the active-product group is at least 35% and
approximately double the proportion in the placebo treated
group, with the difference between groups being statistically
significant.

Obesity Regulatory Guidelines

The FDA requires the safety database to include at least
3,000 subjects randomised to active doses of the
product and no fewer than 1,500 subjects randomised to
placebo for one year of treatment.
The EMA recommends efficacy to be based on a
significant weight loss at 12 months of 10% of the
baseline weight that is also significantly different from the
placebo change from baseline.

Sibutramine (Meridia)
Appetite suppressant that works by blocking reuptake of
serotonin and norepinephrine.
Maintaining weight loss has long been the major
downfall to most diet programs.
Removed from the market in EU and US in 2010
following the SCOUT study showing increased CV risk

Sibutramine effects on CV risk factors

Source: Am J Cardiovasc Drugs @ 2010 Adis Data Information BV

Mechanisms for sibutramine acute CV effects

Source: Am J Cardiovasc Drugs @ 2010 Adis Data Information BV

Sibutramine Cardiovascular outcomes and

regulatory actions

Abbott voluntary withdrawal

Source: Am J Cardiovasc Drugs @ 2010 Adis Data Information BV

Orlistat (Xenical)
Pancreatic lipase inhibitor that blocks the absorption of
up to one third of ingested fat.
In addition to helping reduce weight, orlistat has been
shown to also:
lower plasma low-density lipoprotein cholesterol
(LDL) cholesterol levels.
The decline in LDL cholesterol is greater than that
expected due to weight loss alone.
Lower HbA1C in diabetic patients

Orlistat- XENDOS

Orlistat- XENDOS

Weight Loss of Approved Medications

in Obese and Overweight Patients

Treatment
Duration
(Week)

Mean Weight-Change
in Treated Patients
Compared With
Placebo (95% CI)

Medication

Source of Data

Sibutramine

meta-analysis of
29 RCTs

52

-4.45 kg
(-5.29 to -3.62)

Orlistat

meta-analysis of
22 RCTs

52

-2.75 kg
(-3.31 to -2.20)

meta-analysis
of 9 RCTs

2 to 24

-3.6 kg
(-6.0 to -0.6)

Phentermine*

Li Z et al. Ann Intern Med. 2005;142:532-546.

BMI=body mass index; N/A=not available; RCT=randomized controlled trial.
* Approved for short-term use only.

Long-Term Weight-Loss Medications

Effects on Cardiometabolic Risk Factors

Medication

Waist
circum
(cm)

LDL-C
(mg/dL)

Sibutramine

- 3.99

N/A

+ 1.5

Orlistat

- 2.06

- 10.0

- 1.2

A1c
(%)

FPG
(mg/dL)

Systolic
BP
(mm Hg)

- 15.9

N/A

N/A

+ 1.7

- 2.7

- 0.38

- 18.6

- 1.5

HDL-C
TG
(mg/dL) (mg/dL)

N/A, not available

Values are weighted mean differences (active minus placebo).
LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol;
TG, triglycerides; A1c, hemoglobin A1c; FPG, fasting plasma glucose; BP, blood pressure.
Rucker D, et al. BMJ. 2007;335:1194-1199.

Average weight loss of subjects completing a minimum 1year weight-management intervention; based on review of
80 studies (N=26,455; 18,199 completers [69%]).

Advice alone

Weight Loss (kg)

Diet alone
Diet + exercise
Orlistat

Sibutramine

V. Low energy diet

6-mo

12-mo

24-mo

36-mo

48-mo

Exercise alone
Diet + exercise
Diet alone
Meal replacements
V. Low energy diet
Orlistat
Sibutramine
Advice alone

Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.

Percent Remaining on Therapy

Long-term Persistence with

Orlistat and Sibutramine in Canada

18%-O
26%-S

6%-O
8%-S

2%-Orlistat
2%-Sibutramine

Time (days)
Padwal R, et al. Int J Obes 2007;31(April)

Cannabinoids
Cannabinoids are a group of terpenophenolic
compounds present in Cannabis sativa
Cannabinoids are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors
Cannabinoids are exogenous and endogenous ligands
for these receptors
Autoprotection by the endocannabinoid system
Cannabinoid receptors
CB1 and CB2 receptors

Endocannabinoid system (ECS):

Overview
Endocannabinoid ligands

Produced on demand
Act locally
Inactivated rapidly
Bind to transmembrane G-protein receptors,
principally inhibiting neurotransmitter release

Cannabinoid receptor type 1

Cannabinoid receptor
type 1 (CB1)
(CB )
1

Most widespread CB receptor

(brain, spinal cord; peripheral nervous
system, organs, tissues)

Cannabinoid receptor type 2

(CB2)
Immune cells

J Am Coll Cardiol. 2006;47:1919-26.

Ann Med. 2005;37:270-5.

Implications of CB1 receptor

activation
Central nervous system

Peripheral tissue

Liver
Adipose tissue
Hypothalamus

Appetite

GI tract
Skeletal muscle

Limbic
system

Motivation
to eat/smoke

Lipogenesis
Altered glucose metabolism

CB1 receptors are present in the brain, adipose tissue, the GI tract and possibly
also in skeletal muscle and liver
J Am Coll Cardiol. 2006;47:1919-26.
Ann Med. 2005;37:270-5.

Sites of CB1 Receptor and Effects

of CB1 Blockade
Site of Action

Mechanism(s)

Hypothalamus/
Food intake
Nucleus accumbens

Clinical
Implications
Body weight
Abdominal obesity
Dyslipidemia
Insulin resistance

Adipose tissue

Adiponectin
ipogenesis

Muscle

Glucose uptake Insulin resistance

Liver

Lipogenesis
Fatty acid
synthesis

Dyslipidemia
Insulin resistance
Endocr Rev. 2006;27:73-100
Lancet. 2005;365:1389-1397.
Int J Obes. 2005;29:183-187
J Clin Invest. 2005;115:1298-1305

Rimonabant (CB1 Blocker):

A Multi-Impact Drug Mode Of Action
CB1

food intake

Brain

Central
effects

Body
weight

FA oxidation
FF
A

Rimonabant
Metabolic
peripheral effects

cle
ara
nc
e

Hyperinsulinemia
CB1

Adiponectin
Adipocyte

Insulin sensitivity
restored
TG
HDL-C

Changes in Weight & Waist Circumference

Weight
Weight (kg)
(kg)

Waist
Waist (cm)
(cm)

Completers

Weight change (kg)

-2
-3.6
-4.8

-4
-6

-8.6

-8
-10

12

16

20

24

28

32

36

40

Completers

44

48

52

Waist circumference change (cm)

-2

-6
-8.5

-8
-10

8 12 16 20 24 28 32 36 40 44 48 52

Weeks

Weeks
Placebo

-4.5
- 5.3

-4

Rimonabant 5mg

Rimonabant 20mg

Lancet 2005;365:138997

Rimonabant - The Epilogue

Due to safety concerns, primarily psychiatric in nature
(suicidalily), Rimonabant has not received approval in
the United States or Canada, either as an anti-obesity
treatment nor as a smoking-cessation drug.
Rimonabant was approved as an anti-obesity drug in the
European Union, subject to some restrictions. However,
in October 2008, the European Medicines Agency (EMA)
recommended that Acomplia no longer be available in
EU.
One month later, Sanofi-Aventis decided it would no
longer develop rimonabant for any further indication.

Topiramate
Topiramate is an antiepileptic drug approved by the FDA
as an anti-seizure medication in 1996.
When reports surfaced that patients enrolled in initial
trials of the drug and also in clinical practice were
experiencing unexpected weight loss, the effects of the
drug on weight began to be studied.
Mechanism for weight loss is still poorly understood

Topiramate
After 32 weeks, the changes in body weight were:
Placebo
-11.2%,
96-mg
-16.3% (P </= .001)
192-mg
-17.3% (P </= .001)
Visceral abdominal fat (VAF) measured by MRI after 32
wks:
Placebo
-27.1%,
96-mg
-36.7% (P </= .001)
192-mg
-34.7% (P </= .001)

Exenatide
Exenatide (Byetta) is a long-acting analogue of the
hormone GLP-1, which the intestines secrete in
response to the presence of food.
Among other effects, GLP-1 delays gastric emptying and
promotes a feeling of satiety.
Some obese people are deficient in GLP-1.
Byetta is currently available as a treatment for type 2
diabetes.
Some, but not all, patients find that they lose substantial
weight when taking Byetta.
Drawbacks of Byetta include that it must be injected
subcutaneously twice daily, and that it causes severe
nausea in some patients.
Byetta is recommended only for patients with Type 2
Diabetes.

Lorcaserin - Mechanism of action

Lorcaserin is a selective 5-HT2C receptor agonist
5-HT2C receptors are located almost exclusively in the
brain (choroid plexus, cortex, hippocampus, cerebellum,
amygdala, thalamus, and hypothalamus).
Activation of 5-HT2C receptors in the hypothalamus is
supposed to activate proopiomelanocortin (POMC)
production and consequently promote weight loss
through satiety.
While it is generally thought that 5-HT2C receptors help
to regulate appetite as well as mood, and endocrine
secretion, the exact mechanism of appetite regulation is
not yet known.

Lorcaserin Safety Profile

Lorcaserin produced side effects in clinical trials at rates
not significantly different than placebo and mostly with
mild and transient severity.
The most common side effect was headache,
experienced by about 18% of drug arm participants
compared to 11% of placebo participants.
Other reported side effects were: upper respiratory tract
infection (14.8% vs. 11.9%; L:P), nasopharyngitis (13.4%
vs. 12.0%), sinusitis (7.2% vs. 8.2%) and nausea (7.5%
vs. 5.4%).
Adverse events of depression, anxiety and suicidal
ideation were infrequent and were reported at a similar
rate in each treatment group.
On 15 September 2010 it was reported that lorcaserin
was associated with the development of cancer in
laboratory rats.

Lorcaserin Safety Profile

The manufacturer, Arena Pharmaceuticals, in agreement
with FDA, agreed to perform ECHO sub-study to rule out
an increase in the rate of valvulopathy, because a
number of other drugs in this class have been withdrawn
for these cardiovascular side-effects.
Multiple echocardiograms were performed during the
phase III studies, primarily at the BLOOM trial, and did
not show any significant increase in valvulopathy at 3, 6,
and 12-month intervals, compared with baseline
Rates of new FDA-defined valvulopathy in BLOOM were
as follows: lorcaserin 10 mg bid (2.7%) and placebo
(2.3%) at Week 52 and lorcaserin 10 mg bid (2.6%) and
placebo (2.7%) at Week 104.
For BLOSSOM, rates of new FDA-defined valvulopathy
at Week 52 were: lorcaserin 10 mg bid (2.0%), 10 mg
once daily (1.4%) and placebo (2.0%).

Lorcaserin State of affairs

However, late last year the FDA rejected an application
for lorcaserin, on the grounds that its benefits were
outweighed by safety concerns.
Part of the decision was related to carcinogenicity
studies in animals, however, a key issue involved CV
safety data from the randomized trials.
For lorcaserin to be considered safe, the trials had to
exclude the possibility that it raised the risk for cardiac
valvular disease by 50% or more, ie, the upper bound of
the 95% CI for RR had to be less than 1.5.
However, lorcaserin was associated with a nonsignificant
7% increase in the RR for valvular heart disease, with a
95% CI of 0.74-1.55. As a result, the trial missed its
target and the drug's safety could not be confirmed.
Key reason for this was that the lorcaserin event rate for
valvular disease was only 2% (out of about 2500 patients
in each group).

Contrave
Contrave (NB) is a combination of bupropion, a
relatively weak inhibitor of the neuronal uptake of
norepinephrine (NE) and dopamine (DA), combined with
naltrexone, a mu-opioid receptor antagonist.
Both naltrexone, an opioid antagonist, and bupropion, an
inhibitor of neuronal uptake of norepinephrine and
dopamine, are already FDA approved for other
indications;
naltrexone for opioid and alcohol addiction and
bupropion for depression, smoking cessation, and
seasonal affective disorder.

Contrave Mechanism of Action

Bupropion has been shown to stimulate hypothalamic
pro-opiomelanocortin (POMC) neurons that release
alpha-melanocyte stimulating hormone (-MSH) which,
in turn, binds to MC4 receptors.
The binding of -MSH to MC4 receptors initiates a
cascade of actions that results in reduced energy intake
and increased energy expenditure.
When -MSH is released, POMCs simultaneously
release -endorphin, that mediates a negative feedback
loop on POMC neurons leading to a decrease in the
release of -MSH.
Blocking this inhibitory feedback loop with naltrexone is
thought to facilitate a more potent and longer-lasting
activation of POMC neurons, thereby amplifying effects
on energy balance.

Contrave Mechanism of Action

As a result, co-administration of bupropion and
naltrexone produces a substantially greater effect on the
POMC firing rate than either compound administered
alone, suggesting that the drugs act synergistically.

Contrave Efficacy Data

The mean weight-loss difference between
contrave and placebo groups in the combined
registration trials was 4.2%.
This difference does not meet the 5% mean
weight loss at one year criterion set out by the
FDA in its 2007 guidance.
However, in three of the four studies, the
proportion of subjects taking contrave who lost
at least 5% of their initial weight was 35% or
more, double that seen in the placebo-treated
group - meeting the FDA's second criterion for
efficacy.

Contrave CV safety data

Contrave was associated with statistically significant
increases in both systolic and diastolic BP, compared
with placebo, as well as increased heart rate.
For other CV risk factors, compared with placebo
contrave was associated with slight increases in HDL,
more substantial decreases in triglycerides, minimal LDL
changes, improvements in glucose and insulin
parameters, and statistically significant decreases in
HbA1c.
One fatal MI, 1 nonfatal stroke, and 2 additional nonfatal
MIs were seen among contrave-treated subjects.
The FDA review concluded that: "Cardiovascular risk
with naltrexone /bupropion cannot be adequately
assessed due to the small number of ischemic CV
events in the database and the very limited number
of individuals with known CV disease at baseline in
the development program."

Qnexa
Qnexa is an investigational, once a day, proprietary, oral,
controlled-release formulation of low dose phentermine
and topiramate, which is believed to address both
appetite and satiety - the two main mechanisms that
impact eating behavior
Phentermine was approved in 1959 and is currently indicated as short
term treatment for weight reduction as an adjunct to exercise, behavior
modification and caloric restriction. Phentermine is currently the most
widely prescribed weight loss therapy in the U.S.
Topiramate was first approved in 1996 as a treatment for epilepsy and
more recently as a prophylactic for migraine.

Three pivotal phase 3 trials evaluating Qnexa in over

4,500 patients as a treatment for obesity were recently
completed under a Special Protocol Assessment by the
U.S. FDA. Qnexa is currently under review by the FDA
for the treatment of obesity and is not approved.

Qnexa: Phentermine
Originally approved as short-term adjunct treatment in
weight reduction by FDA in 1959
Anorectic activity mediated through hypothalamic
release of norepinephrine
Published clinical studies demonstrating modest weight
loss

Qnexa: Topiramate
Approved in the US for treatment of seizure disorders
(1996) and for prophylaxis of migraine headache (2004)
Works through a combination of inhibition of food intake,
increased energy expenditure and decreased energy
efficiency
Multiple mechanisms supporting positive effects on
hypertension, diabetes and lipids

Qnexa Weight Reduction

Vi-0521 (Qnexa) Advisory Committee Briefing Document

Change from baseline in Heart Rate (bpm)

Qnexa CV Effects - Heart Rate

Vi-0521 (Qnexa) Advisory Committee Briefing Document

Qnexa CV Effects Blood Pressure

Vi-0521 (Qnexa) Advisory Committee Briefing Document

Qnexa CV Effects Blood Pressure

Blood Pressure Change From Baseline at
Week 56 in Subjects With Hypertension

Vi-0521 (Qnexa) Advisory Committee Briefing Document

Qnexa CV safety summary

Thorough QT Study
- No QTc prolongation of clinical or regulatory concern
- Study validated using moxifloxacin positive control
No increase in cardiovascular SAEs with QNEXA
Mean decline in systolic and diastolic BP observed
consistently across studies.
Small dose-related increase in heart-rate associated with
baseline values
Echocardiographic assessment performed on 50 subjects
excluded the presence of any valvular heart abnormalities.

Qnexa - state of affairs

The FDA rejected Qnexa last October citing concerns
the medicine may cause birth defects and increased HR.
FDA asked Vivus to further characterize the CV profile
by providing two-year follow-up data as well as additional
information from the clinical program.
Vivus agreed to conduct an analysis to assess fetal
outcomes in offspring of women exposed to topiramate
during the first trimester of pregnancy. Initial results of
the study, titled "Fortress," are due for release in
December.
Vivus Inc. resubmitted Qnexa for FDA approval after
updating the drugs label to say it shouldnt be used by
women with childbearing potential.
In addition to the label warning, the resubmission
includes a risk evaluation and mitigation strategy.

The Myth of Anti-Obesity Drugs

Poor patient compliance

Large market, short sale half-life
High Cost of developing New Drug
Long approval time (especially USA)
Safety outweighs efficacy (so far)

Thanks You!