Anti-Obesity Drugs and Lipids: What Do We Know? .Anti-Obesity Drugs and Lipids: What Do We Know?

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Transcript of Anti-Obesity Drugs and Lipids: What Do We Know? .Anti-Obesity Drugs and Lipids: What Do We Know?

  • Anti-Obesity Drugs and Lipids: What Do We Know?

    Pamela B. Morris, MDFACC, FACP, FACPM, FAHA, FNLA

    Director, Preventive CardiologyCo-Director, Womens Heart Care

    Medical University of South CarolinaCharleston, South Carolina

  • Disclosures

    Speakers Bureau

    Merck, Genzyme, Aegerion, Abbott, Liposcience

  • Objectives

    To briefly review the effects of diet and exercise on lipids and lipoproteins

    To understand the effects of currently approved anti-obesity agents on lipids and lipoproteins

    To review anti-obesity agents in development and effects on lipids and lipoproteins

  • Relationship of BMI to prevalence of metabolic diseases

    Journal of Clinical Lipidology 2013; 7:304-383

    NHANES 1999-2002

    Dyslipidemias are the most common comorbidities associated with increased body weight.

    (TC>240 mg/dl, LDL-C>160 mg/dl, HDL-C200 mg/dl)

  • BMI and lipid risk factors for men in FOS

    Journal of Clinical Lipidology 2013; 7:304-383

    LDL-C is positively but weakly related to LDL-C in men and womenat higher BMI correlation is no longer evident

    Strongest relationship is in lower BMI range

  • BMI and LDL composition in the MESA Study

    Journal of Clinical Lipidology 2013; 7:304-383

    Individuals with high LDL-P were significantly more obese.

    Increase BMI associated with fewer molecules of cholesterol per LDL particle (cholesterol-depleted).

  • LIPID AND LIPOPROTEIN EFFECTS OF ANTI-OBESITY MANAGEMENT STRATEGIES

    Diet Exercise Anti-obesity drugs Lorcaserin Phentermine Phentermine and topiramate extended-release Orlistat (Bupropion SR and naltrexone SR) (Liraglutide)

  • Lipids and Weight Loss: Diet

    NLA Consensus Statement

    Extent of weight loss: Varies considerably from 0->10 kg. Higher protein/lower carbohydrate diets often promote greater weight loss at

    6 months, at one year magnitude of weight loss is similar

    Extent of TG reduction: Most responsive lipid parameter to nutritional/exercise intervention Response depends on baseline TG level (higher, greater response) Greater weight loss, greater reduction Greater reduction with lower carbohydrate diet

    Journal of Clinical Lipidology 2013; 7:304-383

  • Lipids and Weight Loss: Diet

    NLA Consensus Statement

    Extent of LDL-C reduction:

    Higher protein/lower carb dietLDL-C may increase temporarily followed by eventual decrease as weight loss continues

    Lower protein/higher carb dietmore immediate reduction in LDL-C (and HDL-C) that stabilizes over time

    During weight maintenance phase when diet is more liberal (calories, SFA), LDL-C trends upward

    Journal of Clinical Lipidology 2013; 7:304-383

  • Lipids and Weight Loss: Diet NLA Consensus Statement

    Extent of HDL-C improvement:

    HDL-C response varies, affected by dietary intervention and amount of weight loss

    Higher protein/lower carb dietHDL-C may increase temporarily followed by eventual decrease as weight loss continues

    Lower protein/higher carb dietreduction or no change in HDL-C

    HDL-C may decrease during active weight loss phase but increase above baseline after weight loss maintained

    Journal of Clinical Lipidology 2013; 7:304-383

  • Lipids and Weight Loss: Diet Summary of effects of diet

    Weight loss of 4.5 kg (~10 lbs) would be expected to:

    Decrease TC by ~9 mg/dl Decrease LDL-C by ~4 mg/dl Increase HDL-C by 1.6 mg/dl during weight maintenance Decrease TG by 6 mg/dl

    Lipid changes with nutritional weight loss are modest and highly variable.

    Journal of Clinical Lipidology 2013; 7:304-383

  • Lipids and Weight Loss: Exercise

    Exercise and lipids/lipoproteins

    Wide variation in lipid responses to exercise training Some studies show 4-7% reduction in LDL-C, 4-25% increase in HDL-C,

    fasting TG reductions 4-37% (mean 24%) Reduction in LDL-P

    Fat weight reduction usually required for favorable lipid response

    Exercise volume is of primary importance (optimally 250-300 min/wk)

    Journal of Clinical Lipidology 2013; 7:304-383

  • History of Anti-Obesity Drugs

  • Drug Mechanism of Action Side Effects Comments

    Phentermine Increases the release of noradrenaline, dopamine and serotonin

    Cardiovascular: elevation in BP tachycardia

    CNS: insomnia, restlessness, alters sexual behavior, hormonal secretion and mood

    Approved by the FDA in 1959

    Recommended for short-term use (less than 3 months)

    Orlistat Gastrointestinal lipase inhibitor

    Steatorrhea, fecal incontinence, flatulence,and malabsorption of fat soluble vitamins

    Rare cases of severe liver injury

    Potential risk of kidney injury

    Approved by the FDA in 1999

    Lorcaserin 5-HT 2c receptor agonist that is more specific than previous compounds (eg, fenfluramine)

    Headache, dizziness, nausea, valvulopathy

    Approved by the FDA in June 2012

    Under evaluation by the EMA

    Post-marketing, long-term cardiovascular outcomes trial required

    Phentermine/topiramateextended-release

    Phentermine mechanism of action as above

    Topiramate: anticonvulsant, precise mechanism of action unknown

    Possible teratogeniceffects with topiramate

    Can increase heart rate

    Approved by the FDA in July 2012

    Post-marketing, long-term cardiovascular outcomes trial required

    Journal of Clinical Lipidology 2013; 7:304-383

  • Drugs withdrawn Mechanism of Action Side Effects Comments

    Fenfluramine Increases the release of serotonin

    Serotonin re-uptake inhibitor

    Hallucinations, valvulopathy, pulmonaryhypertension

    Approved by the FDA in 1973

    Withdrawn in 1997

    Sibutramine Noradrenalin and serotoninre-uptake inhibitor

    Increased risk of MI and CVA in patients with high risk of CVD

    Approved by the FDA in 1997

    Withdrawn in 2010

    Rimonabant Cannabinoid 1 receptor antagonist

    Risk of suicide Approved by the EMA in 2006

    Withdrawn in 2009

    Awaiting decision

    Bupropion SR/NaltrexoneSR

    Bupropion: inhibitor of dopamine and noradrenalin uptake

    Naltrexone: opioid receptor antagonist

    Nausea, constipation, vomiting, dry mouth

    Potential CVD risk

    FDA will not approve without CVD outcomesassessment, trial in progress

    Under investigation

    Liraglutide Human glucagon-like peptide-1 analog

    GI side effects (nausea,constipation, diarrhea, vomiting)

    Phase III trials completed and in progress

    Regulatory filings in EU and US expected in 2014

    Journal of Clinical Lipidology 2013; 7:304-383

  • LORCASERIN

  • LorcaserinLorcaserin

    Class of agent Approved for weight management in June 2012

    Mechanism(s) of action Serotonin 5-hydroxytryptamine 2c receptor agonist which may increase satiety

    (5-HT 2b implicated in valvulopathy)

    Little evidence to support increased energy expenditure

    Potential adverse effects Headache, dizziness, fatigue, nausea, dry mouth, constipation, cough, reduced heart rate, hyperprolactinemia

    JCL, 2013;7:304-383

  • Lorcaserin DOSAGE AND ADMINISTRATION

    One tablet of 10 mg twice daily Discontinue if 5% weight loss is not achieved by week 12

    DOSAGE FORMS AND STRENGTHS10 mg film-coated tablets

    CONTRAINDICATIONSPregnancy category X

  • Lorcaserin

    Avoided REMS program

    FDA is mandating a long-term cardiovascular outcomes trial that will finish in 2018 (begins mid-2013).

  • Lorcaserin Three sentinel phase 3 lorcaserin trials

    Behavior Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial

    Behavior Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) trial

    Behavior Modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus (BLOOM-DM) trial

  • BLOOM Study Multicenter, Placebo-controlled Trial of Lorcaserin for

    Weight Management

    3182 obese/overweight adults (83% female, 67% white, mean age 44 yr)

    Randomized to lorcaserin 10 mg BID vs placebo for 52 weeks (weight loss phase) with lifestyle counseling

    Lorcaserin group randomly reassigned at 1 year to continue lorcaserin or change to placebo (maintenance of weight loss phase)

    Smith SR et al. N Engl J Med 2010;363:245-256.

  • Baseline Characteristics of the Patients, According to Study Group

    Smith SR et al. N Engl J Med 2010;363:245-256.

  • Effects of Lorcaserin on Body Weight, According to Study Group

    Smith SR et al. N Engl J Med 2010;363:245-256.

    47.5%20.3%

    22.6%

    7.7%

    2.2 + 0.1 kg vs5.8 + 0.2 kg

    Net: 3.6 kg

  • Changes in Efficacy and Safety End Points between Baseline and 1 Year.

    Smith SR et al. N Engl J Med 2010;363:245-256.

    Improvements reduced in both groups by year 2

    %

  • BLOSSOM Trial

    A One-Year Randomized Trial of Lorcaserin for Weight Loss in Obese and Overweight Adults: The BLOSSOM Trial

    4008 patients, 18-65 yo, 79.8% female

    Excluded diabetics

    Randomized 2:1:2 to receive lorcaserin 10 mg BID, lorcaserin 10 mg QD, or placebo with lifestyle counseling

    J Clin Endocrinol Metab, 2011; 96:3067-3077

  • Body weight change from baseline to wk 52

    Fidler M C et al. JCEM 2011;96:3067-3077

    Net 2.9 kg weight loss

    with BID dosing

  • BLOSSOM TrialLorcaserin10 mg BID,

    n = 1561

    Lorcaserin 10 mg QD,

    n = 771

    Placebo, n = 1541

    P vs. placeboa

    BID QD

    Patients achie