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, 3. Educate a patient on the expected success / known risks of weight loss medications Weight Loss Medicines Dietary supplements (herbal) OTC Prescription 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 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 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 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) Other weight loss ideas Sensa, Aroma Patch, SlimScents: Alter taste / appetite by sense of smell Ear Stapling: Principles of accupuncture 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 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 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 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 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. 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. 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. 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. What do we have today Orlistat – previously discussed Diethylpropion Phentermine Lorcaserin Phentermine / Topiramate 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 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 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 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 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 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 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 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 Lorcaserin: BLOSSOM End point Days on drug L 10mg BID 1561 pts 257 L 10mg /day 771 pts 265 Placebo 1541 pts 242 5% weight loss 737 (47.2%) Sig vs placebo Sig vs L10/day 310 (42%) Sig vs placebo 385 (25%) 10% weight loss 353 (22.6%) Sig vs placebo 134 (17.4%) Sig vs placebo 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 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 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 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% P < 0.001 7.7% Weight change -5.8 kg P < 0.001 -2.2 kg 2% 0.8% 0.8% 0.1% Withdrawal due to - Headache - Dizziness 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 Lorcarserin: BLOOM Year 2 continuation 67.9% of locaserin patients vs 50.3% of placebo patients maintained their weight loss.(p<0.001) 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. 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 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. 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 gammaamiobutyrate, modulates voltage-gated ion channels, inhibits AMPA/kainite excitatory glutamate receptors, inhibits carbonic anhydrase 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 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 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 P + T: CONQUER End points 5% weight loss 10% weight loss Avg weight loss Placebo 979 pts P7.5 / T46 488 pts P15 / T92 981 pts 204 (21%) 303 (62%) P<0.0001 687 (70%) P<0.0001 72 (7%) 182 (37%) P<0.0001 467 (48%) P<0.0001 1.4 kg 8.1 kg 10.2 kg 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. 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 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 P + T: EQUIP End points Placebo 514 pts P3.75 / T23 241 pts P15 / T92 512 pts % 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. 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 P + T: SEQUEL End point Placebo 227 pts P7.5/T46 154 pts P15/T92 295 pts % 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% 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. QsymiaR Available via certified mail order pharmacies: CVS Walgreens Prescriptions faxed www.qsymia.com for patient guides, provider guides, etc Ohio Regulations Ohio Medical Board Rule 4731-11-03 Schedule II controlled stimulants May not use these for weight loss / management 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 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. 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 / lifestyle modification for both short term and long term success. If diabetes, knowledge of symptoms of hypoglycemia and how to respond to them. 35 yo, wt 110kg, BMI 44.4, Read about the new diet pills. Old pills didn’t work. A. Phentermine / Topiramate B. Locaserin C. Orlistat D. Life-style 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. A. Phentermine / topiramate B. Locaserin C. Orlistat D. None are safe for her 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. A. Phentermine / topiramate B. Locaserin C. Orlistat D. Get a new girlfriend 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) ?