Download In Search of the Magic Pill: Current and Developing Agents in

In Search of the Magic Pill:
Current and Developing Agents in
Weight Management
Donna Mojdami, PGY-4
Outline
• Current role for pharmacologic agents in obesity
management – Canadian Guidelines 2007
• Brief history of weight loss agents
• Review the major classes of anti-obesity drugs
• Currently approved agents for weight
management
– Orlistat
• Off-label use of known agents
• Drug therapy in development
CMAJ 2007;176(8 suppl):Online-1–117
The Role for Pharmacotherapy
• Realistic goals must be established
– Return to normal body weight is an unrealistic
expectation
– Drug therapy is not a cure to obesity
• Success must be measured not only by degree
of weight loss but also health benefits
– Weight loss of 5-10% reduces risk of DM and CVD
– Weight loss of 1 lbs per week, 5% below baseline
at 3-6 mo and maintained considered effective
History of Weight Loss Drugs
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Late 1800s - Thyroid extract was used as a remedy for obesity but resulted in
hyperthyroidism and other serious side effects.
1930s - Dinitrophenol reduced weight but sped up metabolism so much that it led to
nerve malfunction. It was sold legally before the FDA had the power to regulate drugs.
1940s - Amphetamine was used as an obesity drug, though it proved addictive.
1960s - Rainbow pills, a combination of amphetamine, digitalis and diuretics, were
linked to several deaths.
1971 - Aminorex, an appetite suppressant, was linked to cases of high blood pressure.
September 1997 - Fenfluramine, part of the "fen-phen" drug combination, was
withdrawn from the market because of heart valve problems. Redux, also contained a
related chemical dexfenfluramine and also was taken off the market in 1997.
November 2008 - Sanofi-Aventis pulled the plug on diet drug rimonabant, never won
U.S. approval after a panel of experts rejected it amid fears it may cause suicidal
thoughts.
May 2009 - Widely used Hydroxycut-brand diet supplements were pulled from store
shelves after reports of liver damage.
FACTBOX-A troubled history for weight-loss drugs. Reuters. February 1, 2011.
History of Weight Loss Drugs
• October 2010 - Abbott Laboratories Inc pulled sibutramine from
the U.S. market. Approved in November 1997, carried warnings
about high blood pressure and a risk of heart attack and stroke in
cardiovascular patients.
• October 2010 - Arena Pharmaceuticals Inc announced that the FDA
rejected its drug, lorcaserin, seeking an independent review of the
data and possibly more studies to assess cancer risk after tumors
were found in animals.
• October 2010 - The FDA rejected Qnexa, a diet pill made by Vivus
Inc and asked for more data on heart risks and other issues.
• January 2011 - Orexigen Therapeutics said the FDA rejected its diet
drug candidate, Contrave, and requested a clinical trial to resolve
concerns about heart risks.
FACTBOX-A troubled history for weight-loss drugs. Reuters. February 1, 2011.
The Fen Phen Story
• Fenfluramine first introduced in 1970’s
– Only modest effects on weight
• Fenfluramine combined with phentermine in 1990s
• Several cases of pulmonary hypertension known, but product
labelling only mentioned 4 cases
• NEJM case-control study in 1996 showed 23-fold increase in risk of
pulmonary hypertension
• FDA asked MDs to report valvular problems in their patients
receiving treatment
– 66 additional reports of valve disease received
• FDA requests company remove drug from market in 1997
• More than 50,000 liability suits filed against Wyeth, approximately
$14 billion
Major Classes of Anti-Obesity Drugs
• Sympathomimetic drugs
– Reduce food intake by inducing early satiety,
increase resting energy expenditure
– Stimulate release of NE or inhibit its reuptake e.g.
Phentermine
– Block serotonin reuptake e.g Sibutramine (now
discontinued)
Major Classes of Anti-Obesity Drugs
• Drugs altering fat digestion - Orlistat
– Inhibits pancreatic lipases therefore fats not
hydrolyzed and fecal fat excretion is increased
Major Classes of Anti-Obesity Drugs
• Antidepressants
– SSRIs e.g. Fluoxetine, sertraline
– Bupropion – believed to modulate action of NE
• Antiepileptic Drugs
– Topiramate
– Zonisamide – serotonergic and dopaminergic
activity
Major Classes of Anti-Obesity Drugs
• Diabetes Agents
– Metformin
– Pramlintide
– GLP-1 Receptor Agonists
• Exenatide, liraglutide
Major Classes of Anti-Obesity Drugs
• Cannabinoid-1 Receptor Antagonist
– E.g. Rimonabant – now discontinued
Approved Agents in Canada
• Orlistat (Xenical®)
• Sibutramine
• Withdrawn from market in October 2010
• SCOUT trial showed increased risk of cardiovascular
events
Orlistat
• Alters fat digestion by inhibiting pancreatic
lipases
• Primary site of action in the gut
– Only 1% of the drug is absorbed
• Dose-dependent effect that peaks when 30%
of dietary fat not absorbed
Orlistat – Side Effects
• GI side effects most common
– Cramps, flatus, fecal incontinence
– Improved by adhering to diet with <30% fat
• Absorption of fat-soluble vitamins slightly
reduced
– Vitamin D most frequently affected
– Vitamin supplementation advisable
• Rare but serious liver injury (13 reports over 10
years)
• Very little effect on absorption of other drugs
except for cyclosporine
Long-term Pharmacotherapy for
Obesity and Overweight
• 16 trials analyzed
• All studies showed greater weight loss than
placebo
Orlistat – Cochrane Review 2009
Weight Loss
Orlistat treated subjects lost 2.9kg more
weight than placebo (95% CI 2.5-3.2 kg)
Orlistat – Cochrane Review 2009
Change in Waist Circumference (cm)
Significant reduction in circumference 2.1 cm
(95% CI 1.3-2.9cm)
Orlistat – Cochrane Review 2009
Change in BMI (kg/m²)
Significant reduction in BMI 1.1 kg/m²
(95% CI 0.7 - 1.4 kg/m²)
Orlistat – Cochrane Review 2009
Change in SBP (mmHg)
Placebo-subtracted SBP reduction 1.5mmHg
(95% CI 0.9 – 2.2mmHg)
Orlistat – Cochrane Review 2009
Change in LDL
Reduction in LDL by 0.26mmol/L
(95% CI 0.22 – 0.3mmol/L)
Orlistat – Cochrane Review 2009
Change in HDL
Reduction in HDL by 0.03mmol/L
(95% CI 0.02-0.04mmol/L)
Orlistat – Cochrane Review 2009
Reduction in T2DM
• In the XENDOS trial, reduction in incidence of
T2DM from 9.0% to 6.2%
• Benefit seen primarily in those with impaired
glucose tolerance
Orlistat – Cochrane Review 2009
Change in Weight in Diabetics (kg)
Weight reduced by 2.3kg (95% CI 1.6 – 3kg)
Orlistat – Cochrane Review 2009
Change in FBG in Diabetics (mmol/L)
• In trials with both diabetics and nondiabetics, FBG reduced by 0.1 – 0.5mmol/L
• In patients with diabetes, FBG reduced by
1.0mmol/L (95% CI 0.6-1.5mmol/L)
Orlistat – Cochrane Review 2009
Change in HbA1c in Diabetics
Reduction in HbA1c of 0.4%
(95% CI 0.2 – 0.6%)
Orlistat – Cochrane Review 2009
Discontinuation Due to GI Side-Effects
Orlistat – Cochrane Review 2009
• Largest limitation in most studies is high attrition
rates
– 14 of 16 studies had attrition rates >20%
– Only two trials had true intention-to-treat analysis
– In the longest and largest trial, XENDOS, 60% of
patients dropped out over 4 year follow-up
• Most common reasons for drop out:
• Treatment refusal
• Loss to follow up
• Adverse effects
FDA Approved Agents
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Orlistat (Xenical®)
Diethylpropion (Tenuate®, Tenuate Dospan®)
Phentermine (Adipex®, Ionamin Slow
Release®)
Benzphetamine (Didrex®)
Phendimetrazine (Bontril®, Prelu-2®)
Sympathomimetic Drugs
• Stimulate release of norepinephrine or inhibit
its reuptake into nerve terminals
• Approved for short-term use
– Typically 12 weeks
• Phentermine and diethylpropion are Schedule
IV drugs – potential for abuse
Phentermine
• The better half of Fen-phen
• Most widely prescribed weight loss agent in
U.S.
– Use >12 weeks considered off-label
• Adverse effects
– Elevated BP, tachycardia, palpitations,
constipation, headache, insomnia
Phentermine
A mean placebo-subtracted weight loss of 7.5kg
Figure from UptoDate. Data from Munro, JF, MacCuish, AC, Wilson, EM, Duncan, LJ, BMJ 1968; 1:352.
Drugs Used Off-label in Obesity
• Anti-epileptics
– Zonisamide
– Topiramate
• Anti-depressants
– Bupropion
– Fluoxetine
– Sertraline
Li, Z. et al. Ann Intern Med 2005; 142:532-546.
New Drugs in Development for
Management of Obesity
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Gut hormones
Combination drugs
Tesofensine
Cetilistat
Lorcaserin
Melanocortin-4 receptor agonist
Gut Hormones
• Several gut hormones play a role in energy
metabolism regulation
– Glucagon-like peptide 1 (GLP-1)
– Cholecystikinin
– Amylin
– Pancreatic polypeptide
– Peptide YY
– Oxyntomodulin
– Ghrelin
Glucagon-like Peptide 1
Suppresses glucagon secretion GLP-1 secreted by L-cells of intestine
Enhances insulin secretion
in response to a meal
Decreases pancreatic beta cell apoptosis
Increases satiety in the
brain
Delays gastric emptying
Cobble, M. et al. The Journal of Family Practice Supp. 2008; 57: S1-S31
GLP-1 Receptor Agonists
• Originally developed for management of
T2DM
• Weight loss noticed in trials
• Liraglutide and exenatide are the most well
studied
• Similar weight loss on either drug - Liraglutide 3.24 kg and exenatide 2.87 kg
• Similar proportions lost weight – Liraglutide 78% and exenatide 76%
Buse, J. et al. Lancet 2009; 374: 39-47
• 60 overweight non-diabetic women with PCOS
• Randomized to metformin 1000mg bid,
exenatide 10µg bid or combination therapy
• Secondary outcomes included anthropometric
measures
Adverse Effects
• GI effects most common
– Constipation, diarrhea, dyspepsia, emesis, nausea
Pramlintide
• Synthetic analogue of human amylin
– Peptide hormone secreted from pancreatic β cells
in response to food stimuli
• Slows gastric emptying, improves postprandial
BG rise, modest improvement in HbA1c (<1%)
• Induces modest weight loss ~ 0.4 kg compared
to weight gain with placebo in T1DM Whitehouse, F.
et al. Diabetes Care 2002; 25: 724
Peptide YY
• Co-secreted with GLP-1 from intestinal L-cells
• Short-term administration in obese and lean
subjects shown to decrease appetite and intake
by 30% Batterham, R.L. et al. NEJM 2003; 349: 941
• 12 week randomized, placebo-controlled trial of
133 obese subjects showed no difference in
weight loss Gantz, I. et al. J Clin Endo Metab 2007; 92: 1754
– Weight loss not assessed in the subjects receiving
highest dose due to 60% drop-out (nausea, emesis)
Peptides – Leptin
• Primarily produced in adipose tissue
• Absence of leptin associated with massive obesity
in animal models and humans
– Administration of leptin induces weight loss
• Obese adults have leptin resistance associated
with high serum leptin levels
• Recombinant human leptin has modest dosedependent reduction in weight (-1.4 kg to -7.1kg)
in combination with caloric restriction
– Heymsfield, S.B. et al. JAMA 1999; 282: 1568
Peptides – Melanocortin-4 Receptor
Agonist
• Hypothalamic melanocortin system plays
important role in body weight
• MC4R gene has been the most strongly
associated and replicated in obesity
• Mutations in MC4R accounts for obesity in
1.8% of adults and 6.0% of children
Peptides – Melanocortin-4 Receptor
Agonist
• Intranasal administration of melanocortin
induced body fat loss of 1.7kg in healthy
subjects Fehm, H.L. et al. J Clin Endo Metab 2001; 86: 1144
• Same melanocortin compound in overweight
subjects did not induce significant changes in
body weight or fat Hallschmid, M. et al. J Clin Endo Metab
2006; 91:522
Combination Agents
• Benefit of targeting multiple pathways
involved in energy homeostasis
• Reduced doses of individual drugs decreases
risk of potential side-effects
Vetter, M. L. et al. Nat. Rev. Endocrinol. 6, 578–588 (2010)
Stimulates food intake
Inhibits food intake
Naltrexone and Bupropion (Contrave®)
• Bupropion – dopamine and NE reuptake
inhibitor
– increases firing of POMC neurons
• Naltrexone – opioid receptor antagonist
– inhibits β-endorphin-mediated autoinhibition of
POMC neurons
– Enhances activity of bupropion
• Currently in phase III clinical trials
Naltrexone & Bupropion
-5.2kg
-9.3kg
Wadden et al. Obesity. 2011; 19:110 -120.
Bupropion and Zonisamide (Empatic®)
• Zonisamide – enhances serotonergic and
dopaminergic activity
– Incidentally found to induce weight loss in
epilepsy trials
• Phase III trials currently in progress
Bupropion and Zonisamide (Empatic®)
• Drug efficacy and tolerability study combined
with hypocaloric diet Landbloom et al. Obesity. 2008; 16:S63S64
• Double-blind, placebo-controlled trial with
intention to treat analysis over 24 weeks
• Combination drug induced 8.6% weight loss
vs. 1.1% placebo
• Frequent side-effects: headache, nausea,
insomnia, dry mouth, anxiety
Pramlintide and Metreleptin
• Pramlintide – analogue of amylin
• Metreleptin – recombinant leptin
• 24 week, RCT, double-blind, active-drug-controlled
trial
• Enrolled 177 obese or overweight subjects, 25% drop
out
• Study design
Ravussin, E. et al. Obesity. 2009; 17: 1736-1743.
Ravussin, E. et al. Obesity. 2009; 17: 1736-1743.
• Trend towards
– Lower TGs (- 8%)
– Lower total cholesterol (-9%)
– Lower LDL (-8%)
– Lower insulin resistance
– Lower insulinemia (-22%)
Lorcaserin: Successor to
Dexfenfluramine?
• Selective serotonin agonist
• Activates 5-HT2C receptors in the
hypothalamus, thalamus, limbic system
• In theory avoids unwanted valvular effects (re:
fenfluramine) since receptors not found
peripherally
• FDA voted against approval in 2010
– Preclinical toxicology studies showing increased
risk mammary tumours & astrocytomas
• Double-blind, randomized, placebo-controlled
trial of 3182 obese or overweight subjects
• In year 1, randomization to lorcaserin or placebo
• In year 2, those on lorcaserin randomly
reassigned to placebo or lorcaserin
• Subjects received diet and exercise counselling
• 55.4% completed study (treatment)and 45.1%
completed study (placebo)
– 7.1% (treatment) and 6.7% (placebo) discontinued
because of adverse events
- 2.2kg
- 5.8kg
• Secondary end-points
• Valvulopathy
Tesofensine: Successor of
Sibutramine?
• Norepinephrine-, dopamine- and serotoninreuptake inhibitor
• Originally developed for treatment Parkinson’s
disease
• Induces weight loss by suppressing appetite
• Phase II, RCT, double-blind, placebo controlled
trial
• 203 obese subjects on calorie restriction
randomized to placebo or various doses
tesofensine
• Treatment for 24 weeks, 79% completed study
- 2.2 kg
- 6.7 kg
- 11.3 kg
- 12.8 kg
• Adverse Effects
– GI most common
• Dry mouth, nausea, abdo pain, constipation, diarrhea
– Insomnia, sleep disturbance, dizziness
– Increased SBP, DBP (1.0mg dose) - mean increase
6.8/5.8 mmHg
– Dose-related effect on HR
– Increased anger and hostility (1.0mg dose)
– Increased confusion
Limitations of Pharmacotherapy
• Studies investigate efficacy of agents as part of
intensive lifestyle and behavioural
interventions
• Safety concerns and tainted reputation limit
use of agents
• Most studies are short-term, long-term
outcomes unknown
• Weight loss is modest compared to patient
expectations
Limitations of Pharmacotherapy
• There is a maximum therapeutic effect after
which no further weight loss is achieved
• Weight is regained once drug stopped
– Most agents only approved for short-term use
• Effect of agents on hard outcomes e.g.
mortality, cardiovascular events not known
Summary
• Pharmacotherapy should be utilized as
adjunct to lifestyle modification only if patient
not able to lose 0.5kg/week by 3-6 mo
• Many classes of drugs available – central and
peripheral acting
• The only drug approved in Canada for weight
management is orlistat
– Expect 2.9kg weight loss in conjunction with
lifestyle modification
Summary
• While many new agents have shown promise
in phase II studies, safety concerns limit their
development