12. Pharmacotherapy in obesity management Flashcards
Healthy behaviour changes alone generally
achieve only a how many % weight loss, which is most often not sustained over the long term?
3-5%
what are the criteria that Health Canada has established for a pharmacotherapeutic agent to receive regulatory approval for long-term weight managemen?
- The agent must be studied in clinical trials of at least one year in duration.
- The agent must produce a placebo-adjusted mean weight loss of ≥ 5% or demonstrate a ≥ 5% weight loss in at least 35% of patients, with this proportion being more than double that in
placebo. - The agent should demonstrate an improvement in obesity-related comorbidities.
who is indicated for obesity drug treatment?
Pharmacotherapy is indicated for long-term weight management in Canada for individuals with a BMI ≥ 30 kg/m2 or ≥ 27 kg/m2
with comorbidities associated with excess body fat (e.g., T2DM, hypertension, dyslipidemia, obstructive sleep apnea).
what are 4 meds approved for obesity managment in Canada?
Orlistat 120mg tid
liraglutide 3mg SC daily
naltrexone/bupropion 16/180mg BID
semaglutide 2.4mg sc weekly
what is recommended to prevent obesity for anti-psychotic medication use weight gain?
metformin
what should be identified before initiating obesity pharmacotherapy?
goals of therapy;
targets of treatments
Obesity medications are intended as part of a long-term treatment strategy because..?
Clinical trials of pharmacotherapy for obesity management consistently demonstrate regain of weight when treatment is stopped.
The use of pharmacotherapy for obesity management is not recommended in ..?
pregnant or breastfeeding women, nor in women who are trying to conceive
how does orlistat work?
semisynthetic derivative of lipstatin - a potent and selective inhibitor of pancreatic lipase, thereby inhibiting the breakdown of dietary triglycerides into absorbable
free fatty acids - 30% ingested TGs are excreted, primarily in the feces;
orlistat does not target appetite or satiety mechanisms
what is the dose of orlistat?
120mg tid (during or up to 1 hour after meals)
what is the indication of orlistat?
weight reduction or reducing the risk of weight regain after prior weight loss in patients with a BMI >30 or 27 in the presence of comorbidities (e.g. hypertension, T2DM, dyslipidemia, excess visceral fat)
what is the effectiveness of orlistat?
2.9% weight loss at one year;
54% and 26% of patients achieved >5% and >10% weight loss;
what is the side effect of orslistat?
GI side effects - oily spotting and loose stools, flatus with discharge, fecal urgency and increased defecation;
interefere with the absorption of fat-soluble vitamins (ADEK) - need to take multivitamin at least 2 hours before or after taking orlistat
rare casese of severe liver injury or acute liver failure
some may develop increased levels of urinary oxalate on orlistat - oxalate nephropathy with renal failure have been reported;
long-term orlistat effect? at 6 months, 1 year, 2 year
18%, 6%, 2% persistence rates
contraindication of orlistat?
chronic malabsorption syndrome or cholestasis;
some may develop increased levels of urinary oxalate on orlistat - oxalate nephropathy with renal failure have been reported;
drug interaction with orlistat?
anti-coagulants - INR monitor - due to vit K absorption reduced;
levothyroxine or iodine salts - affect absorption - monitor thyroid function
reduction in plasma cyclosporine levels - monitor;
change in anti-convulsant medications - monitor seizures
what does GLP1 do?
act centrally on the pro-opiomelanocortin neurons to improve satiation and satiey and reduce hunger, with a transiet effect to decrease gastric emptying
what does liraglutide do?
increase insulin release and suppresses glucagon during times of glucose elevation
what is the dose of liraglutide?
start 0.6mg daily, titrate each week, upto 3.0mg daily for obesity
(1.2 or 1.8mg for diabetes)
what was the result of liraglutide?
8% weight loss at one year;
33% patients lost more than 10% of body weight
result of liraglutide at 3 years?
in addition to intensive behavioural therapy?
6% loss ;
7.5% loss
what is the side effect of liraglutide?
nausea - central and peripheral effect;
GI upset;
higher risk of gallstones;
small increased risk of pancreatitis;
contraindication of liraglutide?
personal or family hx of medullary thyroid cancer or a personal history of multiple endocrine neoplasia type 2 – increased risk of medullary thyroid cancer in rodent studies
what is naltrexone? how does it work for obesity?
opioid receptor antagonist;
Naltrexone disrupts the auto-inhibitory effect
of β-endorphin on the pro-opiomelanocortin cells by blocking the
μ-opioid receptors.
Naltrexone/bupropion also influences the mesolimbic reward system, resulting in a reduction in cravings
what is bupropion? how does it work for obesity?
antidepressant that inhibits the uptake of dopaine and norepinephrine;
Bupropion induces satiety centrally by enhancing production and
release of α-melanocyte stimulating hormone (α-MSH) and β-endorphin from the pro-opiomelanocortin cells in the arcuate nucleus
of the hypothalamus;
Naltrexone/bupropion also influences the mesolimbic reward system, resulting in a reduction in cravings
what is the dose of naltrexone/bupropion?
16/180MG BID;
one tablet (8/90mg) daily for the first week, increase by one tablet each week until the maintenance dose of two tablets twice daily (total daily dose 32 mg/360 m
what is the result of natre/bupro treatment?
Among patients with overweight or obesity without diabetes,
naltrexone/bupropion 16 mg/180 mg BID with a hypocaloric diet
(500 kcal/day deficit) and exercise was associated with weight loss
of -6.1% versus -1.3% in placebo. Weight loss of ≥ 5% was seen
in 48% of patients, and ≥ 10% weight loss was seen in 25% of
patients with naltrexone/bupropion, compared with 16% and 7%
in the placebo group, respectively.5
what is the predictive of greater weight loss by nalt/bup tx?
A combined analysis of three naltrexone/bupropion trials found that early
improvements in cravings were predictive of greater weight loss.45
how to measure reduction in cravings?
the Control Of Eating Questionnaire (COEQ)
The most common side effects of naltrexone/bupropion include?
nausea, constipation, headache, vomiting, insomnia, dry mouth,
dizziness and diarrhea.
Most nausea events occur during the
dose-escalation period and are transient.
Naltrexone/bupropion is contraindicated in patients with?
uncontrolled hypertension;
Any opioid use - Opioid therapy should be
discontinued for seven to 10 days prior to initiation of naltrexone/
bupropion to prevent the precipitation of opioid withdrawal;
seizure disorders, anorexia
nervosa, bulimia and patients undergoing abrupt discontinuation
of alcohol, benzodiazepines, barbiturates or anti-epileptic medications
Naltrexone/bupropion should be dosed with caution with which medication classes?
Naltrexone/bupropion should be dosed with caution with
any medications that lower seizure threshold
Monoamine inhibitors can increase the risk of XXX reactions, and naltrexone/
bupropion should therefore not be used within 14 days of taking monoamine inhibitors.
Monoamine inhibitors can increase the risk of hypertensive reactions, and naltrexone/
bupropion should therefore not be used within 14 days of taking monoamine inhibitors.
There are multiple potential medication interactions with naltrexone/bupropion, which stem from ?
There are multiple potential medication interactions with naltrexone/bupropion, which stem from the effect of bupropion and its
metabolites to inhibit the hepatic CYP2D6 enzyme system
Among patients already receiving naltrexone/bupropion, medications metabolized by CYP2D6 should be started at the
lower end of their recommended dosage range with cautious titration.
examples of medications are?
selective serotonin reuptake inhibitors, beta blockers, anti-psychotic agents, type 1C anti-arrhythmic agents and many tricyclic anti-depressants, such as citalopram, metoprolol, risperidone, propafenone and desipramine
Bupropion may result in reduced efficacy of xxx
and should therefore not be used in
combination with it.
tamoxifen
Bupropion is primarily metabolized by the CYP2B6 enzyme system. Therefore, naltrexone/bupropion dosing should not exceed
one tablet twice daily when used with CYP2B6 inhibitors. examples are?
ticlopidine, clopidogre
Naltrexone/bupropion should be avoided
in patients taking CYP2B6 inducers as these may …
reduce efficacy
of naltrexone/bupropion by reducing bupropion exposure (e.g.,
ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital,
phenytoin)
what can occur when
naltrexone/bupropion is used concomitantly with dopaminergic medicaitons? (levodopa, amantadine)
central nervous system toxicity
what is semaglutide? how does it work?
Semaglutide is a once-weekly, subcutaneously administered, human
GLP-1 analog that acts centrally on the POMC/CART neurons to improve satiation and satiety, reduce hunger and reduce cravings.43
what dose is near maximal therapeutic efficacy for A1C lowering for semaglutide?
1mg weekly
what is the dose of longterm obesity treatment of semaglutide?
2.4mg qweekly
what is the titrating dose of semaglutide?
start with 0.25mg weekly for 4 weeks, 0.5mg, 1mg, 1.7mg, 2.4mg
what was the result of semaglutide?
2.4 mg with health-behaviour modification resulted in -14.9% weight loss at 68 weeks.
86.4% of patients lost ≥ 5% body weight;
69.1% of patients lost ≥ 10% body weight;
50.5% of patients lost ≥ 15% body weight
In a study of semaglutide 2.4 mg weekly vs. liraglutide 3 mg daily amongst 338 people with overweight or obesity without diabetes, what was the mean weight loss at 68 weeks?
-15.8% with semaglutide
vs. -6.4% with liraglutide.
does liraglutide have effect in blood pressure and lipid profile?
yes - Among patients with obesity and prediabetes, liraglutide reduced systolic blood pressure by -2.8 mmHg compared with placebo over three years, with modest improvements in lipid parameters. A heart rate increase of two beats per minute (BPM) was observed,
in keeping with what is seen in the GLP-1 class.3
does semaglutide have effect in blood pressure and lipid profile?
Semaglutide reduced systolic blood pressure by -6.1 mmHg vs.
-1.1 mmHg with placebo at 68 weeks, with modest improvement
in lipid parameters, in a study of people with obesity without type
2 diabetes (see Table 2). A heart rate increase of +3.5 BPM was
noted vs. -0.7 BPM with placebo, in keeping with what is seen in
the GLP-1 class.1
The only obesity pharmacotherapy available in Canada which has been specifically studied amongst patients with obstructive sleep
apnea is ?
. Among patients with moderate or severe obstructive sleep apnea who were unable or unwilling to use a continuous positive airway pressure machine, liraglutide 3.0 mg combined with health-behaviour modification significantly reduced
the number of apnea-hypopnea index events by -12.2 events per
hour, compared with a reduction of -6.1 events per hour with
health-behaviour modification alone.13
which med is approved in US as dual GIP/GLP-1 agonist for treatment of diabetes?
tirzepatide
Weight loss with
tirzepatide 15 mg weekly ranged from..?
9.5 - 12.9%; superior to semaglutide
The proportion of patients achieving at least 5% weight loss were for tirzepatide 5 mg, 10 mg and 15 mg, respectively?
85%, 89% and 91%
The most
common adverse events of tirzepatide?
gastrointestinal side effects of mild
to moderate severity and transient, occurring primarily during dose
escalation.
Significant improvements were seen with systolic and diastolic blood pressure from tirzepatide. t/f?
t
