New Weight Loss Medications
The FDA recently approved two new medications for weight loss. They are:
1) lorcaserin, BelviqR, a serotonin-2c agonist
2) phentermine/topiramate, QsymiaR, a combination of a well-known weight loss
stimulant and well known neurologic medication with the side effect of weight
loss
Both are approved but not yet available. As such, prices have not been set.
Please see the Product Information for full prescribing details.
Steve’s Bottom Line: QsymiaR is way too complicated to prescribe, will have
limited pharmacy distribution, and has too many adverse effects and monitoring
parameters.
BelviqR will be much easier to use and appears to be better tolerated by patients.
A key limitation is the exclusion of patients on antidepressants in the studies.
While it is not contraindicated in patients on antidepressants and this mechanism
of action is unique, educate patients to stop taking BelviqR if signs of serotonin
syndrome occur. The half-life is 11 hours, which gives a modest reassurance that
side effects will dissipate in 48 hours or so.
Lorcaserin, BelviqR, is FDA approved for weight loss in patients with a BMI
of 30 or more and patients with a BMI of 27 or higher with one or more
comorbidities such as diabetes, hypertension, or hyperlipidemia. Despite one
study finding low abuse potential (significant levels of “dislike” in supratherapeutic
doses compared to other drugs of abuse), the DEA determined it would be a
schedule IV controlled substance.
SAFETY
Given the small number of patients who were exposed to lorcaserin during
development, it is important to report adverse events in the early post-marketing
period. Because lorcaserin works on serotonin receptors, serotonin syndrome
and neuroleptic malignant syndrome are listed in the package information as
possible adverse reactions.
Because obesity and other weight loss medications are associated with
pulmonary hypertension and valvular heart disease, lorcaserin also lists these as
possible adverse effects. Patients in the studies were followed for up to 2 years
and the incidences of these events were not different from placebo.
Other safety issues are cognitive impairment (1.9% compared to 0.5% in placebo
subjects) and euphoria with supratherapeutic doses (0.2% compared to <0.1% in
placebo subjects).
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Patients with reasonably well-controlled diabetes mellitus who lost weight were
more likely to experience hypoglycemia. These patients will need close
monitoring and possible adjustments to their hypoglycemia medications.
Lorcaserin subjects experience an increase in prolactin levels greater than two
times the upper limit of normal (6.7% compared to 4.8% in placebo subjects).
Lorcaserin is a category X in pregnancy due to weight loss.
TOLERABILITY
Side effects occurring more commonly than placebo (% incidence – incidence in
placebo) includes nausea (3%), diarrhea (0.9%), constipation (1.9%), dry mouth
(3%), vomiting (1.2%), fatigue (3.6%), headache (6.7%), and dizziness (3.3%).
EFFICACY
The trials reviewed exclude patients on SSRI in the past year, recent use of other
weight loss medications, recent cardiovascular events, uncontrolled
hypertension, uncontrolled hypertriglyceridemia, previous bariatric surgery, very
low calorie diet, or weight loss greater than 5kg within 3 months. Patients with
diabetes were excluded from the BLOSSOM and BLOOM trials and were studied
specifically in the BLOOM-DM trial.
The BLOSSOM trial was 52 weeks long in 18 to 65 year olds, 80% female, in
which 2/5 of subjects received lorcaserin 10mg twice daily, 1/5 received
lorcaserin 10mg once daily, and 2/5 received placebo. Patients received nutrition
guidance to reduce their calories to 600 kcal below a WHO based estimate of
their daily energy requirements. Guidance on 30 minutes of daily exercise was
also provided. Patients with known valvulopathy were excluded.
Intention to treat with last observation carried forward analysis: 47.2% of
lorcaserin10mg twice daily, 40.2% of lorcaserin10mg once daily, and 25% of
placebo patients lost 5% or more of baseline body weight. The proportion of
patients who lost 10% or more was 22.6%, 17.4%, and 9.7%, respectively.
Various physiologic factors were monitored and while the reduction in
triglycerides and the rise in HDL were statistically significant, they were not
clinically significant. Approximately 45% of patients had dropped out prior to the
end of the study.
The BLOOM trial compared lorcaserin 10mg twice daily to placebo for weight
loss over 52 weeks and for weight loss maintenance over another 52 weeks in
patients who lost 5% or more of body weight in the first year. Diet and exercise
was the same as the BLOSSOM study and these patients also received monthly
individual counseling.
Intention to treat with last observation carried forward analysis: 47.5% of
lorcaserin 10mg twice daily and 20.3% of placebo patients lost 5% or more of
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their baseline body weight. This was an average of 5.8kg in the lorcaserin group
and 2.2kg in the placebo group.
Patients who achieved a 5% or more weight loss were continued in the second
year. Placebo patients were continued on placebo while lorcaserin patients were
randomized 2:1 to continue lorcaserin or switch to placebo. Among patients who
lost weight on lorcaserin and were randomized for year two, 67.9% of lorcaserin
and 50.3% of placebo patients maintained the 5% or more weight loss.
The BLOOM-DM enrolled patients with diabetes mellitus and was designed like
the BLOSSOM trial. The proportion of patients losing 5% or more from baseline
was 37.5% in the lorcaserin 10mg twice daily group and 16.1% in the placebo
group. Patients on lorcaserin had a 0.9% reduction in HgbA1c compared to 0.4%
reduction in the placebo patients.
PRICE
Unknown at this time. Will be updated when the information becomes available.
SIMPLICITY of USE
Lorcaserin dose is 10mg twice daily and can be taken with or without food.
If a 5% weight loss is not achieved by 12 weeks, lorcaserin should be
discontinued.
Lorcaserin inhibits CYP-2D6. Other medications that are substrates of this
enzyme system may need monitoring or dose adjustment. Specific drug
interactions with lorcaserin have not been evaluated.
Because BelviqR is a scheduled IV controlled substance, the Ohio Medical Board
Rule 4731-11-04 “Controlled substances: utilization for weight loss” applies to its
use.
Phentermine / Topiramate extended-release, QsymiaR
Is a combination of the sympathomimetic amine, phentermine, and the antiseizure drug, topiramate. QsymiaR is FDA approved for weight loss in
combination with a reduced-caloric diet and increased physical activity in adults
with a BMI of 30 or more or a BMI of 27 or more in the presence of comorbidity
such as hypertension, type 2 diabetes mellitus, or hyperlipidemia.
SAFETY
Pregnancy category X: Topiramate use in pregnancy is associated with cleft lip /
cleft palate. Because of the teratogenic risk, QsymiaR will only be available from
certified mail order pharmacies. A “Healthcare Provider Training Program” is
available at www.qsymiaREMS.com.
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Because obesity and other weight loss medications are associated with
pulmonary hypertension and valvular heart disease, phentermine/topiramate also
lists these as possible adverse effects. Patients in the studies were followed for
up to 2 years and the incidences of these events were not different from placebo.
Elevation in heart rate of more than 5bpm (70-78% vs. 65.4% placebo), 10bpm
(50-56% vs. 42.1% placebo), 15bpm (33-37% vs. 26% placebo), and 20bpm (1520% vs. 12% placebo) and is most common with the 15mg/92mg dose.
Suicidal behavior and ideation is reported with most antiepileptic drugs including
topiramate. The risk is one case for every 530 patients treated with an
antiepileptic medication. It is observed as early as the first week of treatment.
Acute myopia and secondary angle closure glaucoma is reported with
topiramate. Typically, this occurs within the first month of treatment but can
happen at any time.
Mood disorders including depression, anxiety and insomnia are associated with
QsymiaR. Patients with a history of depression are at increased risk.
Cognitive impairment including impaired concentration, memory difficulties, and
problems with speech are reported with topiramate. Too rapid dose titration
increases the risk. Follow the dose titration steps carefully.
Topiramate is associated with hyperchloremic, non-anion gap metabolic acidosis.
Renal disease, severe respiratory disease, status epilepticus, diarrhea, surgery,
and ketogenic diet increase the risk. Carbonic anhydrase inhibitors (zonisamide,
acetazolamide, and dichlorphenamide) also increase the risk. The peak reduction
in serum bicarbonate occurred by week 4 and most subjects were able to selfcorrect by 56 weeks. Discontinue the drug if persistent metabolic acidosis
develops.
QsymiaR can cause an increase in serum creatinine with the peak effect within 4
to 8 weeks of treatment. The serum creatinine tends to decline over time but
likely remains elevated over the baseline value.
Patients with reasonably well-controlled diabetes mellitus may experience
hypoglycemia with weight loss. Monitor blood sugars and adjust hypoglycemic
medication doses as needed.
Patients with hypertension may experience hypotension with weight loss. Monitor
blood pressure and adjust antihypertensive medication doses as needed.
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Abrupt withdrawal of QsymiaR in patients without a history of seizures or epilepsy
has caused seizures. Patients on the highest dose, 15mg/92mg, should take a
dose every other day for at least one week before discontinuing.
QsymiaR requires dose reduction in renal impairment (Clcr less than 50ml/min).
QsymiaR requires dose reduction in mild to moderate hepatic impairment, ChildPugh score 5 to 9. It has not been studied in severe hepatic impairment, ChildPugh score 10 or higher.
Topiramate is associated with kidney stone formation due to inhibition of carbonic
anhydrase activity. Avoid other drugs that inhibit carbonic anhydrase and other
therapies that increase the risk of kidney stones.
Topiramate is known to cause oligohidrosis and hyperthermia leading to
hospitalization.
Topiramate may lower serum potassium levels via its inhibition of carbonic
anhydrase.
TOLERABILITY
Common side effects QsymiaR are: paraesthesia (dose related up to 20% on
15mg/92mg), dizziness, dysgeusia (dose related metallic taste up to 9% on
15mg/92mg), constipation, and dry mouth. Insomnia (up to 11%), anxiety (up to
8%, and depression (up to 7%) are also dose related and occur 2 to 3 times
more than placebo.
Problems with attention, concentration, memory, and “word finding” are dose
related up to 7.6% compared to 1.5% on placebo.
EFFICACY
The CONQUER trial evaluated 7.5mg/46mg and 15mg/92mg respectively
phentermine/topiramate and placebo in a 56 week trial of adults (18 to 70 years)
with a BMI 27 to 45 and 2 or more comorbidities. Patients were excluded if they
had uncontrolled hypertension, uncontrolled diabetes mellitus type 2, diabetes
medicines other than metformin, history of nephrolithiasis, recurrent major
depression, history of suicidal behavior or ideation. Antidepressants other than
tricyclic antidepressants or MAOI were permitted if the dose was stable for 3 or
more months.
Patients were randomized in a 2:1:2 ratio of placebo,7.5mg/46mg dose
and15mg/92mg dose, respectively. All doses were controlled release and
administered once daily in the morning. All analysis is intention to treat with last
observation carried forward. The primary endpoint was proportion achieving 5%
or greater weight loss from baseline. All patients followed a dose titration of one
week of 3.75mg/23mg, followed by dose increases to 7.5mg/46mg, then
15mg/92mg at weekly intervals until the assigned dose was reached. Each
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patient was given the “LEARN” manual, advised to implement lifestyle changes,
and were given instruction to reduce daily caloric intake by 500 kcal/day. Patients
visited study staff monthly.
Both active drug doses were superior to placebo. The 7.5mg/46mg dose resulted
in 5% or more weight loss in 62% of patients whereas the 15mg/92mg dose and
placebo resulted in a 5% or more weight loss in 70% and 21% of patients,
respectively. For 10% or greater weight loss, the proportions were 37%, 48%,
and 7% respectively.
The most common side effects were dry mouth, constipation, dysgeusia,
paraesthesia, insomnia, dizziness, anxiety, irritability, and disturbance in
attention. Drop out rates were 12%, 19%, and 9% for 7.5mg/46mg, 15mg/92mg,
and placebo.
The SEQUL trial is an extension of the CONQUER trial. Subjects who wished to
continue stayed in the same assigned group for 52 additional weeks. 676 of 866
eligible subjects from 36 of the original 93 study sites continued. Patients were
excluded if their BMI was 22 or less at the conclusion of the CONQUER trial.
Blinding of investigators and subjects was continued. Analysis was intention to
treat with last observation carried forward and analysis was done from baseline
(total of 108 weeks).
The least squares mean percentage weight loss over the 108 weeks was 1.8%,
9.3%, and 10.5% for placebo, 7.5mg/46mg dose, and 15mg/92mg dose
respectively. The proportion of patients in each group who lost 5% or more and
10% or more of baseline weight was greater in the two phentermine/topiramate
doses compared to placebo (5% or more: 75.2%, 79.3%, 30%; 10% or more:
50.3%, 53.9%, 11.5% for low dose, high dose, placebo respectively).
The EQUIP study was a 56 week for patients who BMI was 35 or higher. All
patients underwent a 4 week titration starting at 3.75mg/23mg and increasing by
3.75mg/23mg weekly until the assigned dose was achieved. Patients were
randomized in a 2:1:2 ratio of placebo, 3.75mg/23mg, and 15mg/92mg groups.
All patients received life-style counseling based on the “LEARN” manual, a diet
reduced by 500 kcal/day, instruction to increase water consumption, and
instruction to increase physical activity. The primary end-point was percent
weight loss and proportion achieving 5%, 10%, and 15% weight loss. Analysis
was intention to treat with last observation carried forward.
The dropout rate was 40% and reasons for drop out were lost to follow-up,
withdrawal of consent, or adverse effects. Average weight loss for each group
was 10.9%, 5.1%, and 1.6% for high dose, low dose, and placebo. The
respective proportions losing 5% or more of baseline weight were 66.7%, 47.2%,
and 32.2%. The respective proportions losing 10% or more of baseline weight
were 44.9%, 18.8%, and 7.3%.
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PRICE
QsymiaR is available only from certified mail order pharmacies (CVS &
Walgreens). Prescriptions must be faxed. Go to www.qsymia.com for the
information and fax numbers. The price will be updated when known.
SIMPLICITY of USE
QsymiaR should be taken in the morning with or without food.
Start: 3.75mg/23mg daily for 14 days. Then increase to 7.5mg/46mg.
Evaluate: weight loss after 12 weeks of 7.5mg/46mg.
If the patient has not lost at least 3% of baseline body weight, discontinue
QsymiaR or escalate the dose to 11.25mg/69mg daily for 14 days followed by
15mg/92mg daily.
Evaluate: weight loss after 12 weeks of 15mg/92mg.
If the patient has not lost at least 5% of baseline body weight, discontinue.
DO NOT stop the 15mg/92mg dose abruptly. Take a dose every other day for at
least one week and then discontinue.
Renal dosing: If the patient’s Clcr is < 50ml/min, the maximum dose is
7.5mg/46mg.
Hepatic dosing: If the Child Pugh score is 7 or more, the maximum dose is
7.5mg/46mg.
Because QsymiaR is a scheduled IV controlled substance, the Ohio Medical
Board Rule 4731-11-04 “Controlled substances: utilization for weight loss”
applies to its use.
QsymiaR will only be available from “certified mail order pharmacies”. The list of
pharmacies will be available at www.QsymiaREMS.com
It is not clear if healthcare providers must be “trained” before prescribing
QsymiaR. A healthcare provider training program is available at
www.QsymiaREMS.com
References:
Fidler MC, Sanchez M, Raether B, et.al. “A one-year randomized trial of
lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial” J
Clin Endocrinol Metab 2011;96(10):3067-77.
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Smith SR, Weissman NJ, Anderson CM, et.al. “Multicenter, placebo-controlled
trial of lorcaserin for weight management” NEJM 2010;363:245-56.
O’Neil PM, Smith SR, Weissman NJ, et.al. “Randomized placebo-controlled trial
of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study”
Obesity 2012:20(7):1426-36.
Shram MJ, Schoedel KA, Barlett C, et.al. “Evaluation of the abuse potential of
lorcaserin, a serotonin 2c (5-HT2c) receptor agonist, in recreational polydrug
users” Clinical Pharmacology & Therapeutics 2011;89(5):683-692.
BelviqR Prescribing Information, Arena Pharmaceuticals, 6/2012.
Gadde KM, Allison DB, Peterson CA, et.al. “Effects of low-dose, controlled
release, phentermine plus topiramate combination on weight and associated
comorbidities in overweight and obese adults (CONQUER): a reandomised,
placebo-controlled, phase 3 trial”, Lancet 2011;377:1341-52.
Garvey WT, Ryan DH, Look M, et.al. “Two-year sustained weight loss and
metabolic benefits with controlled-release phentermine/topiramate in obese and
overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3
extension study” Am J Clin Nutr 2012;95:297-308.
Allison DB, Gadde KM, Garvey WT, et.al. “Controlled-release phentermine /
topiramate in severely obese adults: A randomized controlled trial (EQUIP)”
Obesity 2011;20:330-42.
QsymiaR Prescribing Information. Vivus 7/2012
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