1. The Skinny on Old and New Weight Loss Medications
Steven R Smith, MS, RPh, BCACP
TASHP
September 27, 2012

2. Objectives
1. State the rules that control the prescribing of weight loss medicines in Ohio,
2. Given patient characteristics, select the best weight loss medication,
3. Educate a patient on the expected success / known risks of weight loss medications

3. Weight Loss Medicines
Dietary supplements (herbal)
OTC
Prescription

4. Dietary supplements Dr. Oz
Uncontrolled claims on TV, in magazines, and on the web
Claims fall under FDA and FTC
Not removed from the market until substantial harm is proved
Endless list of ingredients / Proprietary blends

5. Dietary supplements Supplement How it works
Conjugated linoleic acid (CLA)
Feeling of fullness
Chromium
Trace element needed for insulin action
Green tea extracts
Decreased appetite, fat burner
Guar gum
Dietary fiber
Senna
Laxative
Ephedra (ma huang)
Stimulant (off the market in US)
Hydroxycitric acid (Garcinia combogia extract)
Promotes fat oxidation by inhibiting ATP-citrate lyase
Gymnemia sylvestre
Decrease blood sugar

6. Dietary supplements Supplement How it works Ginger root Reduce nausea
Raspberry ketones
Fat burner
Ginseng
Adaptogenic
Coconut oil
MCT not stored in adipose tissue but high in calories / fat
Apple cider vinegar
Drink before eating to decrease appetite
Bitter orange
Contains stimulants (synephrine, octopamine)
Caffeine (guarana)
Short acting stimulant, diuretic
Lipovarin
Contains synephrine

7. Dietary supplements Supplement How it works Hoodia
Appetite suppressant (P57), FDA warnings for false claims
Glucomannan (LipozeneR)
Dietary fiber to increase “fullness”
Chitosan
Sugar from the hard outer layers of lobsters, crabs, shrimps. Blocks absorption of fat
Licorice root
Adaptogenic
Cayenne powder
Fat burner
Magnolia bark extract
Cortisol blocker
(CortiSlim –FTC-false claims)

8. Other weight loss ideas
Sensa, Aroma Patch, SlimScents:
Alter taste / appetite by sense of smell
Ear Stapling:
Principles of accupuncture

9. OTC Historical: Phenylpropanolamine 75mg once daily
Increased strokes and other CV events
11/2000 – FDA advises to not make it
Officially off the market in 2005 due to concern over its use to make amphetamines
strokes / year in yo users

10. OTC
Orlistat (AlliR) 60mg up to three times daily with meals became available in 2007
Blocks 25% of dietary fat absorption
The “Antabuse” of dieting
No more than 15gm of fat with the meal
Expected weight loss: 3 to 5 pounds / year

11. Prescription
Orlistat (XenicalR) 120mg up to 3 times a day with meals approved in 1999
Blocks at least 25% of dietary fat absorption
Expected weight loss: 5 to 7 pounds / year
Drug interactions: cyclosporine, warfarin, T4
Take a multivitamin daily at bedtime

12. Orlistat
A meta-analysis of 29 studies where enrolled patients had an average BMI of 36.7
Average weight loss compared to placebo
2.89kg (-3.51 to -2.27)
RR for diarrhea: 3.4, for flatulence: 3.1, for bloating-abdominal pain-dyspepsia: 1.48
In a second year extension study:
1/3 on orlistat regained weight lost in 1st year
2/3 on placebo regained weight lost in 1st year

13. Orlistat Patient Education
Take it 60 minutes prior or with a meal or up to 60 minutes after.
Reduce the fat in your diet for 3 days prior to starting orlistat.
Teach symptoms of liver disease: itching, yellow eyes or skin, loss of appetite
Go to myalli.com for lots of good information about fat in the diet and other tips to be successful.

14. Prescription Historical:
Amphetamine, dextroamphetamine, methamphetamine, phenmetrazine were C-II drugs no longer indicated for weight loss
Fenfluramine (PondominR), dexfenfluramine (ReduxR) worked through serotonin and were taken off the market in 1997 due to pulmonary hypertension and heart valve disease.

15. Prescription Historical:
Sibutramine (MeridiaR) works on serotonin at lower doses, norepinephrine at higher dose. Questionable efficacy / increased risk of CV event so the FDA pressured Abbott to remove it from the market in Oct, 2010
Rimonobant, a cannabinoid CB1 antagonist was on the market in 56 other countries. FDA said it was approvable in 2006, an advisory committee said not to approve in 2007, Europe took it off the market in Sanofi-Aventis dropped pursuing it.

16. Prescription
Benzphetamine (DidrexR) – CIII is converted to methamphetamine and amphetamine. Dose is 25 to 50mg up to 3 times daily.
Phendimetrazine (BontrilR) – CIII is a prodrug to phenmetrazine (PreludinR – CII). Phenmetrazine gained notoriety when the Beatles were found to favor it. Phendimetrazine dose is 105mg sustained release capsule daily or 17.5 to 35mg tablets 2 or 3 times daily one hour AC.

17. What do we have today Orlistat – previously discussed Diethylpropion
Phentermine
Lorcaserin
Phentermine / Topiramate

18. Diethylproprion C-IV 25mg immediate release 2 or 3 times a day
75mg sustained release once daily
Meta-analysis of 13 studies, 6 to 52 weeks, from
Weight loss compared to placebo
3kg (-1.6 to 11.5kg)
Side effects as expected from a stimulant

19. Phentermine C-IV Sustained release resin (ionamin): 15, 30, 37.5mg
Tablet: 37.5mg; Oral disintegrating: 15, 30mg
Meta-analysis of 9 studies, 2 to 24 weeks, from
Doses of 15 to 30mg daily
Weight loss compared to placebo: 3.6kg (0.6 to 6kg)
Side effects as expected from a stimulant

20. Fluoxetine
Meta-analysis of 9 studies using 60mg/day in patients with baseline BMI of 35.5
6 month results: 0.9 to 9.1kg weight loss
12 month results: -0.4 to 14.5 kg
Side effects:
Nervous, sweating, tremor: RR 6.37
Nausea & vomiting: RR 2.68
Insomnia: RR 2.06

21. Other Antidepressants
Sertraline: only one study with negative results
Bupropion:
3 studies, avg baseline weight: 94.3kg
mg/day
2.77 (1.1 to 4.5) kg weight loss
Side effect: dry mouth RR 2.99

22. So what’s new? Two new drugs recently approved
Lorcaserin (BelviqR): a 5HT-2c agonist
Phentermine / Topiramate (QsymiaR)
Results now presented as (%) of body weight lost with proportion losing 5% and losing 10%
Studies tending to be longer duration
BelviqR studies evaluated echocardiographic signs of valvulopathy
QsymiaR studies evaluated depression/suicides

23. Lorcaserin BLOSSOM Study design:
52 weeks on 10mg daily (1/5) vs. 10mg twice daily(2/5) vs. placebo (2/5)
18 to 65 year olds
BMI =>30 or BMI =>27 with HTN, dyslipidemia, CV disease, glucose intolerance, sleep apnea
Excluded if on on SSRI, recent use of other weight loss medications, unable to participate in moderate-intensity exercise, recent CV event, major surgery, recent low calorie diet, 5kg change in weight, bariatric surgery

24. Lorcaserin: BLOSSOM Follow-up at 2 and 4 weeks then monthly
Reduce daily caloric intake to 600 kcal below WHO equations for estimating daily energy requirements using 1.3 for the activity factor (1.4 if patient already exercised => 1 hour/day)
Encouraged to exercise moderately for 30 minutes daily
Also Beck Depression Inventory-II, echocardiograms, DEXA, and other testing

25. Lorcaserin: BLOSSOM Primary endpoints:
Proportion achieving 5% weight loss
Mean weight change from baseline
Proportion achieving 10% weight loss
Assumed 15% of placebo would lose 5%, 40% dropout at week 52: need 720 patients per group
Primary echocardiographic endpoint at week 52 using FDA criteria of aortic or mitral regurgitation

26. Lorcaserin: BLOSSOM End point L 10mg BID 1561 pts L 10mg /day 771 pts
Placebo
1541 pts
Days on drug
257
265
242
5% weight loss
737 (47.2%)
Sig vs placebo
Sig vs L10/day
310 (42%)
385 (25%)
10% weight loss
353 (22.6%)
134 (17.4%)
150 (9.7%)
Base weight
100.3 kg
100.1 kg
100.8 kg
Change in wt
-5.8 kg
-4.7 kg
-2.9 kg
Base BMI
36.1
35.9 36
Change in BMI
-2.1
-1.7 -1

27. Lorcaserin: BLOSSOM No effect on:
LDL cholesterol
Total cholesterol (sig diff, not clinically diff)
Triglycerides (sig diff, not clinically diff)
HgbA1c
Blood pressure
Heart rate
Echocardiographic valvulopathy
Different: Slight increase in HDL, Quality of Life

28. Lorcaserin: BLOOM Same inclusion and exclusion as BLOSSOM
L: 10mg twice daily vs placebo
Primary endpoints same as BLOSSOM
2nd year extension study for those who achieved 5% or more body weight reduction
Stay on placebo if on it year one
If on L: randomized to continue L or get placebo

29. Lorcaserin: BLOOM End points -1st L 10mg BID 1538 pts Placebo 1499 pts
5% weight loss
47.5%
P < 0.001
20.3%
10% weight loss
22.6%
7.7%
Weight change
-5.8 kg
-2.2 kg
Withdrawal due to
Headache
Dizziness 2%
0.8%
0.1%

30. Lorcaserin: BLOOM Secondary endpoints – year 1:
Total and LDL cholesterol (sig diff, not clinically)
Triglycerides reduced approximately 6%
Fasting glucose and insulin (sig diff, not clinically)
HgbA1c (sig diff, not clinically)
Quality of Life (sig diff, questionable clinical sig)
Beck Depression Inventory-II (not diff)
FDA-defined valvulopathy: no difference over the two years

31. Lorcarserin: BLOOM Year 2 continuation
67.9% of locaserin patients vs 50.3% of placebo patients maintained their weight loss.(p<0.001)

32. Lorcaserin: BLOOM-DM
This trial was the first to enroll patients diagnosed with diabetes mellitus type 2.
The design was the same as BLOSSOM.
37.5% of lorcaserin patients lost 5% or more of their body weight compared to 16.1% of placebo patients.
HgbA1c was reduced 0.9% in lorcaserin patients compared to 0.4% in placebo patients.

33. Lorcaserin Summary
Modest weight loss. In fact, if the 5% mark is not achieved by 12 weeks, stop the drug.
Daily exercise and 600 less kcal /day
Cost of a “venti latte” or $3.57
If per day, then $107 per month
If per tablet, then $214 per month
Side effects: headache, dizziness, fatigue, dry mouth, and all the usual GI side effects
Pregnancy: X / C-IV

34. Lorcaserin Summary Low abuse potential
Unknown what to expect if on SSRI’s also.
Inhibits CYP-2D6 but specifics are unexplored.
May take with or without food.
If DM patient with good control, watch for hypoglycemia, adjust doses of DM meds.

35. Phentermine / Topiramate
QsymiaR (kyoo sim ee’ uh) is a combination of immediate release phentermine HCl and extended release topiramate
Phentermine, a stimulant and appetite suppressant
Topiramate augments the activity of gamma- amiobutyrate, modulates voltage-gated ion channels, inhibits AMPA/kainite excitatory glutamate receptors, inhibits carbonic anhydrase

36. P + T: CONQUER Patients 18 to 70 years for 56 weeks BMI 27 to 45
Two or more comorbidities (HTN, hypertriglyceridemia, diabetes) and waist circumference (=>102cm for men, =>88cm for women)
Excluded uncontrolled HTN, uncontrolled hypertriglyceridemia, DM-1, use of DM medications other than metformin, hx of nephrolithiasis, recurrent major depression / suicidal behavior, TCA’s, MAOI’s

37. P + T: CONQUER Assigned in 2:1:2 ratio
Placebo
P 7.5mg + T 46mg
P 15mg + T 92mg
Titration starting at P 3.75mg + T 23mg with weekly increases in the 3.75 / 23 increments until the assigned dose was achieved

38. P + T: CONQUER All patients given:
A LEARN manual by Kelly D. Brownell, PhD
Lifestyle, Exercise, Attitude, Relationships, Nutrition
Advised to implement lifestyle changes
Instructed to reduce calories by 500 kcal/day
Monthly visits

39. P + T: CONQUER End points Placebo 979 pts P7.5 / T46 488 pts P15 / T92
5% weight loss
204 (21%)
303 (62%)
P<0.0001
687 (70%)
10% weight loss
72 (7%)
182 (37%)
467 (48%)
Avg weight loss
1.4 kg
8.1 kg
10.2 kg

40. P + T: CONQUER
Waist circumference: reduced 5.1 to 6.8 cm more than placebo
Systolic but not diastolic BP reduced by 2 to 3 mm Hg
Total cholesterol reduced 1.6 to 3%, Triglycerides reduced 12 to 15%, HDL raised 4 to 5%
HgbA1c reduced (sig diff, but not clinically)
Side effects: dry mouth, dysgeusia, paraesthesia, insomnia, dizziness, anxiety, irritability, disturbance in attention, tachycardia.

41. P + T: EQUIP Assigned in 2:1:2 ratio
Placebo
P 3.75mg + T 23mg
P 15mg + T 92mg
Titration starting at P 3.75mg + T 23mg with weekly increases in the 3.75 / 23 increments until the assigned dose was achieved

42. P + T: EQUIP
Enrolled 18 to 70 year olds with BMI =>35 and controlled hypertriglyceridemia, controlled hypertension, and fasting blood sugar =<110.
Same titration as CONQUER study
Study design same as CONQUER study

43. P + T: EQUIP End points Placebo 514 pts P3.75 / T23 241 pts P15 / T92
% weight loss
1.6%
5.1%
10.9%
5% weight loss
17.3%
44.9%
66.7%
10% weight loss
7.4%
18.8%
47.2%
15% weight loss
3.4%
7.3%
32.3%
Side effects: Paraesthesia, dry mouth, constipation, dysgeusia, insomnia, depression, disturbance in attention, anxiety, irritability.

44. P + T: SEQUEL
Patients who finished the CONQUER trial were eligible to participate in an additional 52 week continuation trial.
866 eligible / 676 participated
Results are calculated from baseline of the CONQUER trial to 108 weeks

45. P + T: SEQUEL End point Placebo 227 pts P7.5/T46 154 pts P15/T92
% weight loss
1.8%
9.3%
10.5%
5% weight loss
30%
75.2%
79.3%
10% weight loss
11.5%
50.3%
53.9%
15% weight loss
6.6%
24.2%
31.9%
20% weight loss
2.2%
9.2%
15.3%

46. Qsymia titration Take daily in the morning.
P 3.75mg / T 23mg for 14 days, then
P 7.5mg / T 46mg daily.
If do not lose 3% of body weight on this dose at 12 weeks, discontinue or escalate dose
To escalate: P 11.25mg / T 69mg daily for 14 days, then
P 15mg / T 92mg for 12 weeks then re-evaluate.

47. QsymiaR Available via certified mail order pharmacies:
CVS
Walgreens
Prescriptions faxed
for patient guides, provider guides, etc

48. Ohio Regulations Ohio Medical Board
Rule Schedule II controlled stimulants
May not use these for weight loss / management

49. Ohio Regulations
Rule Controlled substances for weight reduction
May only use a C-III or C-IV for weight reduction if it is FDA approved for that use
Patient must have made a good faith effort to lose weight via other means
Physician does good exam
BMI =>30 or =>27 with comorbidities
Meets with the patient every 30 days face-to-face to assess success

50. Ohio Regulations
Rule Controlled substances for weight reduction
Duration of use matches how it was FDA approved, ie “a few weeks” = 12 weeks
May use for maintenance of weight loss if FDA approved for that manner of use
Must discontinue the medication if the patient is not losing weight over a 30 day period.

51. Patient Education
Side effects / adverse effects specific to the prescribed medication.
Treatment agreement on monthly appointments and 30 day prescriptions
Importance of exercise / calorie restriction / life- style modification for both short term and long term success.
If diabetes, knowledge of symptoms of hypoglycemia and how to respond to them.

52. 35 yo, wt 110kg, BMI 44. 4, Read about the new diet pills
35 yo, wt 110kg, BMI 44.4, Read about the new diet pills. Old pills didn’t work.
Phentermine / Topiramate
Locaserin
Orlistat
Life-style

53. Phentermine / topiramate Locaserin Orlistat None are safe for her
55 yo, wt 150kg, BMI 55, Read about the new diet pills. Old pills didn’t work. DM-2 (A1c=9.8%) on metformin and sitagliptin. Controlled HTN on metoprolol, Lipids ok on simvastain.
Phentermine / topiramate
Locaserin
Orlistat
None are safe for her

54. 42yo, lost his job, BMI=28. 5, girlfriend says lose some weight
42yo, lost his job, BMI=28.5, girlfriend says lose some weight. Serious exercises 4 days/week, still not losing weight. Ex-wife suing for custody of 2 kids. Nothing is going right in life. On citalopram 40mg daily. BP good on lisinopril / amlodipine.
Phentermine / topiramate
Locaserin
Orlistat
Get a new girlfriend

55. Conclusion
Medications for weight loss, both old and new, produce modest benefit.
Life-style change, exercise, calorie restriction are required.
How much are we willing to spend to lose 5 to 15 kg and what are the other health benefits (mortality, strokes, MI’s, etc) ?