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

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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

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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.

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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)

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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

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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

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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

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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