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The Skinny on Old and New Weight Loss Medications

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

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The Skinny on Old and New Weight Loss Medications

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  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

  6. Dietary supplements

  7. Dietary supplements

  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 • 200-500 strokes / year in 18-49 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 2009. 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 1965-1983 • 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 1975-1999 • 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 • 300-400mg/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

  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

  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 (kyoosimee’ 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

  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 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

  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 • www.qsymia.com for patient guides, provider guides, etc

  48. Ohio Regulations • Ohio Medical Board • Rule 4731-11-03 Schedule II controlled stimulants • May not use these for weight loss / management

  49. Ohio Regulations • Rule 4731-11-04 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 4731-11-04 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.

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