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, Women’s 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-C<40 mg/dl, TG>200 mg/dl)

BMI and lipid risk factors for men in FOS


• LDL-C is positively but weakly related to LDL-C in men and women—at higher BMI correlation is no longer evident

• Strongest relationship is in lower BMI range

BMI and LDL composition in the MESA Study


• 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


Lipids and Weight Loss: Diet

NLA Consensus Statement

Extent of LDL-C reduction:

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

Lower protein/higher carb diet—more 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


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 diet—HDL-C may increase temporarily followed by eventual decrease as weight loss continues

Lower protein/higher carb diet—reduction or no change in HDL-C

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


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.


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)


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


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


Drugs withdrawn Mechanism of Action Side Effects Comments

Fenfluramine • Increases the release of serotonin

• Serotonin re-uptake inhibitor

• Hallucinations, valvulopathy, pulmonaryhypertension


• Withdrawn in 1997

Sibutramine • Noradrenalin and serotoninre-uptake inhibitor

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



Rimonabant • Cannabinoid 1 receptor antagonist

• Risk of suicide • Approved by the EMA in 2006


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


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


Effects of Lorcaserin on Body Weight, According to Study Group


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.


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 achieving ≥5% weight loss [n (%)] 737 (47.2) 310 (40.2)b 385 (25.0) <0.001 <0.001

Patients achieving ≥10% weight loss [n (%)]

353 (22.6) 134 (17.4)b 150 (9.7) <0.001 <0.001

Body weight

Baseline (kg) 100.3 (15.7) 100.1 (16.7) 100.8 (16.2)

Change (kg) −5.8 (6.4) −4.7 (6.4)b −2.9 (6.4) <0.001 <0.001

Change (%) −5.8 (6.3)* −4.7 (6.3)b −2.8 (6.3) <0.001 <0.001

J Clin Endocrinol Metab, 2011; 96:3067-3077*Identical to weight loss in BLOOM Study

BLOSSOM TrialTotal cholesterol (mg/dl) Lorcaserin

10 mg BIDLorcaserin10 mg QD Placebo P vs. placebo

BIDP vs. placebo

QD

Baseline 194.2 (37.5) 194.8 (37.8) 193.1 (36.8)

% change −0.7 (13.0) −1.3 (13.0) 0.0 (13.0) NS 0.03

LDL-C (mg/dl)

Baseline 116.3 (32.0) 116.7 (32.0) 114.8 (29.9)

% change 0.3 (19.7) −0.1 (19.7) 1.7 (19.7) NS NS

HDL-C (mg/dl)

Baseline 51.5 (12.9) 51.8 (13.6) 51.3 (13.2)

% change 3.7 (15.4) 3.5 (15.4) 1.3 (15.3) <0.001 <0.01

Triglycerides (mg/dl)

Baseline 133.3 (78.2) 133.3 (78.0) 135.9 (72.8)

% change −4.3 (36.9) −5.5 (36.9) −0.9 (36.9) 0.02 <0.01

ApoA1 (g/liter)

Baseline 1.47 (0.24) 1.49 (0.24) 1.47 (0.24)

% change −0.2 (11.2) 0.7 (11.2) −0.4 (11.2) NS NS

ApoB (g/liter)

Baseline 0.91 (0.22) 0.91 (0.20) 0.91 (0.20)

% change −2.9 (15.9) −0.5 (15.9) 1.4 (15.9) <0.001 NS

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

“The magnitude of changes in lipids and blood pressure are consistent with decreases secondary to the observed weight loss.”

“…increase in HDL and decrease in triglycerides among pts treated with lorcaserin 10 mg BID were associated with favorable changes in the use of

medications to treat dyslipidemia.”

BLOOM-DM Study Randomized, Placebo-controlled Clinical Trial of Lorcaserin for

Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study

604 obese or overweight patients with T2DM treated with metformin (91.7%), a SFU (50.2%), or both (41.9%) HgA1c 7-10% (mean 8%)

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

Approximately 54% women

Mean age 53 yr

Obesity, 2012;20:1426-1436

Randomized Placebo‐Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM‐DM Study

Obesity. 2012; 20:1426-1436

37.5%

44.7%

16.1%16.3%

18.1%

4.4%

4.5% (4.7 kg)

5.0% (5.0 kg)

1.5% (1.6 kg)

BLOOM-DM StudyChange in glycemic parameters by study week

Summary of Lorcaserin TrialsResults at 52 weeks

Study Design Subjects,N

Durationweeks

Primary outcomes Lorcaserin10 mg daily

Lorcaserin10 mg twice

daily

Placebo

BLOOM RC, DB 3182 104 Mean % weight loss 5.81(0.16) 2.16(0.14)*

Smith (2010) 5% weight loss (%) 47.5 20.3*

10% weight loss(%)

22.6 7.7*

% patients completing 52 weeks

55.4 45.1

BLOOM-DM RC, DB 604 52 Mean % weight loss 5.0(0.5) 4.5(0.4) 1.5(0.4)*

O’Neil (2012) 5% weight loss(%)

44.7 37.5 16.1*

10% weight loss(%)

18.1 16.3 4.4*


78.9 66.0 62.1

BLOSSOM RC, DB 4008 52 Mean % weight loss 4.7(6.3) 5.8(6.3) 2.8(6.3)*

Fidler (2011) 5% weight loss(%)

40.2 47.2 25.0*

10% weight loss(%)

17.4 22.6 9.7*


59.0 57.2 52.0

Ann Pharmacotherapy 2013;47:1007

Lorcaserin Summary: Lorcaserin

Non-diabetics Weight loss 5.8 kg vs 2.2 kg placebo (Net 3.6 kg)

Greater proportion of patients achieve >5% and >10% weight loss

Patients who did not lose at least 5% of baseline body weight by week 12 were unlikely to achieve this at one year

Modest reduction in triglycerides and apo B, increase in HDL-C which trends to baseline at 2 years

Most frequent AEs: headache, nausea, dizziness No increase in valvulopathy vs placebo

Summary: Lorcaserin

Diabetics Weight loss 4.7-5.0 kg vs 1.6 kg placebo (Net 3.1-3.4 kg)

Greater proportion of patients achieve >5% and >10% weight loss

Only HDL-C statistically significant change (Net 3.6%) Improved glycemic control Most frequent AEs: headache, nausea, dizziness No increased valvulopathy vs placebo

Lorcaserin

PHENTERMINE

Phentermine

Most widely prescribed anti-obesity drug

Regulatory environment at the time of its approval Generic status (reduced incentive for further

research) Lack of data on weight loss and metabolic effects

of monotherapy for >1 year

Phentermine

Phentermine

Class of agent • Short-term (12 week) weight-management agent

Mechanisms of action • Sympathomimetic amine related to amphetamine (not considered an amphetamine), but with minimal abuse potential, approved 1959

• Noradrenergic effects• Minimal dopaminergic, no serotonergic effects• Increase in satiety• No appreciable effect on energy expenditure

Potential adverse effects • Palpitations, tachycardia, increase in BP, tremor, diaphoresis, overstimulation of CNS (restlessness, dizziness, insomnia, euphoria, dysphoria, psychosis), headache, dry mouth, dysgeusia, constipation, urticaria, impotence and changes in libido

JCL, 2013;7:304-383

Phentermine

Effects on weight reduction and safety of short-term phentermine administration in Korean obese people

68 relatively healthy overweight and obese Korean adults with BMI>25 kg/m2

14-week placebo controlled trial (2-week run-in phase) Phentermine 37.5 mg vs placebo ITT analysis

7.2 kg weight loss vs 2 kg (p<.001) Completer analysis (36 patients)

7.5 kg weight loss vs 3 kg

Yonsei Med J. 2006;47:614-625

Phentermine

Effects on weight reduction and safety of short-term phentermine administration in Korean obese people

In “completers” phentermine expected to produce

4.5 kg (15%) weight loss 20 mg/dl (10%) reduction in total cholesterol 45 mg/dl (35%) reduction in triglycerides 15 mg/dl (15%) reduction in LDL-C Minimal change (2%) in HDL-C

Yonsei Med J. 2006;47:614-625

PHENTERMINE/TOPIRAMATEEXTENDED RELEASE

Phentermine/Topiramate ER

Topiramate CR

Class of agent • Antiepileptic drug• Migraine prophylaxis drug

Mechanisms of action • Unknown • Sulfamate-substituted monosaccharide

neurostabilizer via modification of excitatory voltage-activated sodium and calcium channels, antagonism of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid kainite receptors, and ehancement of gamma-aminobutyric acid receptor-mediated inhibitory currents

Potential adverse effects • Potentially teratogenic• Difficulty with concentration, memory,

cognition, psychomotor slowing, mood changes with nervousness, anxiety and depression

• Risk of suicidal ideation

JCL, 2013;7:304-383


Topiramate CRPotential adverse effects (continued) • Secondary angle glaucoma

• Laboratory abnormalities: bicarbonate, decreased phosphorous, increased alkaline phosphatase, decreased potassium, hyperammonemia with encephalopathy

REMS Program OverviewFDA has required a Risk Evaluation and Mitigation Strategy (REMS) so that healthcare providers can be informed about the increased risk of teratogenicityPurposeThe purpose of the REMS is to inform prescribers and females of reproductive potential (FRP) about the increased risk of congenital malformations, specifically orofacial clefts, in infants exposed to PHEN/TPM during the first trimester of pregnancy

JCL, 2013;7:304-383

Phentermine/Topiramate ERDosage and Administration

• Take once daily in morning. Avoid evening dose to prevent insomnia.• Recommended dose: PHEN/TPM 3.75 mg/23 mg daily for 14 days; then increase to 7.5 mg/46 mg

daily.• Discontinue or escalate dose (as described) if 3% weight loss is not achieved after 12 weeks on 7.5

mg/46 mg dose.• Discontinue PHEN/TPM if 5% weight loss is not achieved after 12 weeks on maximum daily dose of

15 mg/92 mg.• Discontinue 15 mg/92 mg dose gradually (as described) to prevent possible seizure.• Do not exceed 7.5 mg/46 mg dose for patients with moderate or severe renal impairment or patients

with moderate hepatic Impairment.

Supplied as capsules: (phentermine mg/topiramate mg extended-release)• 3.75 mg/23 mg (dose titration only)• 7.5 mg/46 mg• 11.25 mg/69 mg (dose titration only)• 15 mg/92 mg


Clinical Trials

EQUIP

CONQUER

SEQUEL (extension phase of CONQUER)

EQUIP TrialControlled-release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial (EQUIP)

56 week trial N=1267

BMI>35 kg/m2

TG<200 mg/dl BP<140/90 mmHg Fasting glucose <110 mg/dl

Randominzed 2:1:2 (placebo, PHEN/TPM ER 3.75/23 mg, PHEN/TPM ER 15/92 mg) with lifestyle counseling

Obesity. 2012;20:330-342

EQUIP TrialBaseline values

Variable Placebo PHEN/TPM ER3.75/23

PHEN/TPM ER15/92

LDL-C, mg/dlNMean (s.d.)

512121.3 (32.02)

240122.5 (32.96)

511119.8 (30.06)

HDL-C, mg/dlNMean (s.d.)

51349.5 (13.09)

24050.2 (11.20)

51149.8 (11.72)

TC, mg/dlNMean (s.d.)

513194.7 (36.36)

240196.1 (36.08)

511192.5 (33.77)

TG, mg/dlNMean (s.d.)

513118.8 (39.20)

240116.7 (40.12)

511114.0 (37.24)

Controlled‐Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial (EQUIP)

Obesity. 2012;20:330-342

• Significant weight loss occurred early

• Patients treated with 15/92 lost 8-10% of BW after 12 weeks of treatment

Controlled-release PHEN/TPM CR in severely obese adults: A randomized controlled trial (EQUIP)

Obesity. 2012;20:330-342

Variable Placebo PHEN/TPM CR 3.75/23 PHEN/TPM CR 15/92

N LS mean % change

N LS mean % change

P value vs. placebo

N LS mean % change

P value vs. placebo

P value vs. 3.75/23

TC (%) 479 -3.5(-4.7,-2.2)

230 -5.4(-7.1,-3.7)

0.0502 486 -6.0(-7.3,-4.8)

0.0014 0.5432

LDL-C (%) 478 -5.5(7.4,-3.7)

230 -7.7(-10.3,-5.2)

0.1338 486 -8.4(-10.2,-6.5)

0.0157 0.6584

HDL-C (%) 479 0(-1.6,+1.6)

230 0.5(-1.7,+2.7)

0.7057 486 3.5(1.9,5.1)

0.0005 0.0158

TG (%)

479 9.1(4.7,13.5)

230 5.2(-0.8,11.2)

0.2639 486 -5.2(-9.6,-0.8)

0.0001 0.0027

ITT LOCF

CONQUER Trial Effects of low-dose, controlled-release, phentermine plus topiramate

combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial

N=2487, 70% women, mean age 51 yr Mean BMI: ~36 kg/m2

Randomized 2:1:2 (placebo, PHEN/TPM CR 7.5/46 mg, PHEN/TPM CR 15/92 mg)

Baseline Lipids Total cholesterol: 205 mg/dl LDL-C: 124 mg/dl HDL-C: 50 mg/dl Triglycerides: 159 mg/dl

Effects of phentermine plus topiramate on bodyweight

Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial

Lancet.2011;377:1341-1352

Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial

Sequel Study Two-year sustained weight loss and metabolic benefits with controlled-

release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study

CONQUER extension study Patients continued with the original treatment to which they were randomized for

additional 52 weeks

866 eligible patients: 676 (78%) enrolled 85.5% on 15/92 79.4% on 7.5/46 69.4% on placebo

84% completed extension phase

Retained original endpoints

Am J Clin Nutr. 2012;95:297-308

SEQUEL Study: Mean (95% CI) percentage weight loss from baseline to week 108.

Garvey W T et al. Am J Clin Nutr 2011;95:297-308

Percentages (and 95% CIs) of subjects achieving ≥5%, ≥10%, ≥15%, or ≥20% weight loss from baseline to week 108 (ITT-LOCF).


Effects of PHEN/TPM CR on cardiometabolic variables


SEQUEL Study Summary

Beneficial therapeutic effects of PHEN/TPM CR were sustained during a 2-year period.

Improvement in cardiometabolic variables

Statistically significant improvements in triglycerides and HDL-C on active therapy 7.5/46 and 15/92 mg.

Placebo-treated patients (net 17.2% increase LLT) 20.3% increased #LLT 31.5% decreased #LLT

PHEN/TPM CR (net 5.2% and 4.7% increase LLT) Increase in #LLT: 11.1% (7.5/46) and 10.5% (15/92) Reductions in #LLT: 5.9% (7.5/46) and 5.9% (15/92)


SEQUEL Study Summary

Beneficial therapeutic effects of PHEN/TPM CR were sustained during a 2-year period.

Improvement in cardiometabolic variables

Statistically significant improvements in triglycerides and HDL-C on active therapy 7.5/46 and 15/92 mg.

Treatment effects on lipids may be confounding results from changes in medications.

Placebo-treated patients more likely to require increase in lipid lowering therapy (net 17.2% increase LLT) vs. active therapy patients (net 5.2% and 4.7% increase LLT)


ORLISTAT

OrlistatOrlistatClass of agent • Weight management agent approved in 1999

• Not a controlled substance

Mechanism of action • Reversible inhibitor of gastrointestinal lipases (lumen of stomach and small intestine)

• Forms covalent bond with active serine residue site of lipases

• TG not hydrolyzed into absorbable FFA and are excreted undigested

Potential adverse effects • Oily discharge from the rectum• Flatus with discharge• Fecal urgency, fatty/oily stool, oily anal evacuation• Increased defecation• Fecal incontinence• May increase risk of cholelithiasis, esp. if substantial

weight loss• May increase risk of oxalate nephropathy• Rare reports of severe liver injury with hepatocellular

necrosis or acute hepatic failure resulting in Tx or death

JCL, 2013;7:304-383

OrlistatPotential drug interactions • May decrease cyclosporine levels

• May decrease fat-soluble vitamins (patients should take daily MVT with A, D, E, K, and beta-carotene)

• May reduce levothyroxine levels• May enhance warfarin effect if vitamin K

absorption is diminished

Administration • One 120 mg capsule three times a day with each main meal containing fat (during or up to 1 hour after the meal)

• Vitamin supplement should be taken at least 2 hours before or after the administration of orlistat, such as at bedtime

• Cyclosporine should be administered 3 hours after orlistat

• Levothyroxine and orlistat should be taken at least 4 hours apart

JCL, 2013;7:304-383

Am J Clin Nutr 2004;80:1461-1468

Orlistat Changes in body weight and serum lipid profile in obese

patients treat with orlistat in addition to a hypocaloricdiet: a systematic review of randomized clinical trials

283 citations, 28 eligible RCTs Obese individuals with

Low CVD risk, n=15 Type 2 DM, n=5 High CVD risk with additional risk factors, n=8

17 studies reported data for one-year comparison orlistat vs. placebo (10,041 patients)

Clinically significant weight loss in 1-y studies.n, number of events; N, total sample size; RCT, randomized controlled trial; RR, relative risk

Am J Clin Nutr 2004;80:1461-1468

Mean weight loss in 1-y studies

Am J Clin Nutr 2004;80:1461-1468

Variable Obese, low-risk patients

Diabetes patients Obese, high-risk patients

No. studies(# pts.)

WMD, OL-PL(95% CI)

No. studies(# pts.)

WMD, OL-PL(95% CI)

No. studies(# pts.)

WMD OL-PL(95% CI)

Totalcholesterol(mmol/L){mg/dl}

5(2679) -.32(-0.39,-0.25)

{-12}*

4(1729) -0.37(-0.47,-0.26)

{-14}*

2(908) -0.24(-0.41,-0.07)

{-9.3}*

LDL-C(mmol/L){mg/dl}

5(2679) -0.25(-0.31,-0.19)

{-9.7}*

4(1729) -0.25(-0.35,-0.15)

{-9.7}*

2(908) -0.19(-0.30,-0.09)

{-7.3}*

HDL-C(mmol/L){mg/dl}

4(1799) -0.03(-0.06,-0.01)

{-1.2}

4(1729) -0.03(-0.05,-0.01)

{-1.2}*

1(376) -0.02(-0.06.-0.02)

{-0.78}

TG(mmol/L){mg/dl}

3(1581) 0.00(-0.17,-0.16)

4(1729) -0.20(-0.35,-0.05)

{-18}*

1(376) 0.11(-0.1,0.32)

{9.7}

Changes in body weight and serum lipid profile in obese patients treated with orlistat in addition to hypocaloric diet: a systematic review of randomized clinical trials

Am J Clin Nutr 2004;80:1461-1468

Risk Factor Orlistat120 mg TID

Placebo

Total cholesterol -7.02% -2.03

LDL-cholesterol -11.66% -3.85%

HDL-cholesterol +5.92% +7.01%

Triglycerides +3.64% +1.30%

Pooled data from 5 clinical trials: Mean change in risk factors at 4-year treatment for population as a whole

XENICAL, Prescribing Information

Orlistat Conclusions

Orlistat produces a more robust reduction in LDL-C and less reduction in TGs relative to other weight loss agents

Similar lipid effects of orlistat in XENDOS trial for prevention of new onset diabetes (-37.3%, p=0.0032) in obese subjects with IGT observed out to 4 years

Individual clinical trials may report greater lipid improvements than the modest changes often seen in meta-analyses

JCL 2013;7:304-383Diabetes Care 2004;27;155-161

ANTI-OBESITY DRUGS IN DEVELOPMENT

BUPROPION SR/NALTREXONE SR

Bupropion BupropionClass of agent • Indicated for treatment of major

depressive disorder, smoking cessation, seasonal affective disorder

Mechanisms of action • Closely resembles the structure of diethylpropion, an appetite suppressant with minimal CNS effects

• Relatively weak dopamine and norepinephrine reuptake inhibitor that increases activation of the POMC neurons in the brain to decrease food intake and increase energy expenditure

• Does not inhibit MAO or re-uptake of serotonin

Contraindications and cautionary use • Seizure disorder• Current or previous dx of anorexia or

bulimia• Abrupt discontinuation of alcohol or

sedatives• Concurrent administration of MAO

JCL, 2013;7:304-383

NaltrexoneClass of agent • Competitively binds to opioid receptors in the CNS

• Opioid antagonist used for treatment of alcohol dependence and for the blockade of the effects of IV administered opioids, reducing the physical dependence to morphine, heroin and other opioids,as well as alcohol

Mechanisms of action • Blocks the negative feedback mechanism or self-down-regulation of POMC neurons (via neuropeptides Y and agouti-related protein which increase energy balance by increasing food intake and decreasing energy expenditure)

• Allows bupropion to yield a longer activation of POMC neurons

Potential adverse effects • Nausea• Hepatocellular injury with excessive doses• In alcoholic patients may cause withdrawal

symptoms (tearfulness, mild nausea, abdominal cramps, restlessness, bone or joint pain, myalgia, nasal symptoms, headache, dizziness, nervousness, fatigue, insomnia, vomiting, anxiety, somnolence, depression, suicidal ideations, suicide attempts)

JCL, 2013;7:304-383

Naltrexone SR/bupropion SR

Combination of sustained-release forms of both naltrexone and bupropion

Proposed mechanism is to affect CNS regulation of appetite and energy expenditure Bupropion is weak inhibitor of dopamine uptake and is thought to

reduce food intake and increase energy expenditure via the POMC system

Naltrexone complements bupropion by blocking the feedback loop that inhibits these specific neurons, amplifying the effects of bupropion

Naltrexone SR/bupropion SR Sentinel phase 3 clinical trials

Contrave Obesity Research program COR-I COR-II COR-Diabetes COR-BMOD

Naltrexone SR/bupropion SR

COR-I 58-week safety and efficacy study Randomized, double-blind, placebo controlled 1742 obese patients without T2DM NB16/360 mg, NB32/360 mg, placebo (1:1:1)

Change in bodyweight Observed least squares mean (SE) percentage change from baseline in bodyweight and number of participants at each visit during 56 weeks. *p<0·0001 compared with placebo.

Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

The Lancet Volume 376, Issue 9741 2010 595 - 605

-6.1%-6.1 KGNet: -4.7 kg

-5.0%

-1.3%-1.4 kg

• Weight loss in active therapy patients began early (week 4)

• Maximum weight loss achieved between 28-36 weeks

COR-IPlacebo NB16 NB32 p value for comparison with

placeboTriglyceridesmg/dl

Baseline 113.4 117.8 115.1

% change -3.1% -8.0% -12.7% 0.0461 <0.0001

HDL-Cmg/dl

Baseline 52.2 52.2 51.8

Change 0.00 -3.5 -3.5 <0.0001 <0.0001

% change 0.8% 7.6% 8.0%

LDL-Cmg/dl

Baseline 119.9 124.9 119.1

Change -3.1 -3.9 -4.3 0.8112 0.4838

% change -0.5% -1.5% -2.0%


COR-II

A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II)

1496 patients without T2DM Randomized 2:1 to NB32:placebo 56 weeks

Obesity 2013;21:935-943

A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity‐related risk factors (COR‐II)

Obesity 2013;21:935-943

COR-IIMeasure Week 28 Week 56

PlaceboN=456

NB32N=825

P value Placebo n=456

NB32N=702

P value

Triglycerides

Baseline 113.4+1.6 119.0+1.6 112.8+1.6 118.9+1.6

% change -1.4% -7.3% 0.007 -0.5% -9.8% <0.001

HDL-C

Baseline 51.4+13.1 51.4+13.3 51.6+12.9 51.8+13.6

change -1.4+0.4 +1.2+0.3 <0.001 -0.9+0.5 +3.6+0.4 <0.001

LDL-C

Baseline 117.1+32.6 119.8+30.2 116.8+32.9 120.5+30.2

change 0.00+1.3 -4.4+0.9 0.004 -2.1+1.3 -6.2+0.9 0.008

Obesity 2013;21:935-943

COR-BMOD

Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: The COR-BMOD Trial

56-week, randomized, placebo-controlled trial Efficacy and safety of NB32 as an adjunct to intensive behavior modification 793 patients without T2DM randomized 1:3 (placebo:NM32)

Obesity.2011;19:110-120

Weight Loss With Naltrexone SR/Bupropion SR Combination Therapy as an Adjunct to BehaviorModification: The COR‐BMOD Trial

Obesity2010;19:110-120

COR-BMODVariable Placebo+BMOD NB32+BMOD P value

Triglycerides(mg/dl)

Baseline 104.6+1.6 111.6+1.6

End point 95.6+1.6 91.4+1.6

% change (95% CI)

-8.5%(-1.37%,-3.0%)

-16.6%(-19.7%,-13.5%)

0.004

HDL-C(mg/dl)

Baseline 55.3+12.9 53.6+13.5

End point 56.9+13.4 58.5+14.1

Change(95% CI)

+0.9(-0.7,+2.4)

+4.1(+3.1,+5.1)

<0.001

% change (95%)

+2.8%(-0.3%,+6.0%)

+9.4%(+7.4%,+11.4%)

<0.001

LDL-C(mg/dl)

Baseline 109.2+27.3 109.5+27.5

End point 117.3+33.2 115.0+30.9

Change (95% CI)

+8.1(+4.0,+12.3)

+5.4(+2.8,+8.1)

0.245

% change (95% CI) +10.0(+5.7%,+14.3%)

+7.1(+4.3%,+9.8%)

0.219

Obesity2010;19:110-120

Naltrexone SR/bupropion SR A multicenter, randomized, double-blind, placebo-controlled study

assessing the occurrence of major adverse cardiovascular events (MACE) in overweight and obese subjects with cardiovascular risk factors receiving naltrexone SR/bupropion SR 32/360 mg (The Light Study)

Primary Outcome Measure Time from treatment period randomization to the first confirmed occurrence of MACE Follow-up 4 years

Secondary Outcome Measures Time to CVD death, nonfatal MI, nonfatal stroke, nonfatal unstable angina requiring hospitalization Time to occurrence of CVD death (fatal MI, fatal stroke) Time to occurrence of MI (fatal or nonfatal) Time to occurrence of stroke (fatal or nonfatal)

Estimated enrollment: 10,400

Study start: June 2012 Estimated completion: July 2017

LIRAGLUTIDE

Liraglutide Analog of the incretin hormone glucagon-like peptide-1 (GLP-1)

Effects of liraglutide in the treatment of obesity: a randomized, double-blind, placebo-controlled study

20-week trial in 564 obese, non-diabetic patients Randomized to one of 4 doses of liraglutide (1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg),

placebo, or orlistat 120 mg TID 84% completed the trial

Baseline lipids (after run-in) Total cholesterol: 188-195 mg/dl LDL-C: 131-137 mg/dl HDL-C: 49-52 Triglycerides: 115-138 mg/dl

Lancet 2009;374:1606-1616Int J of Obesity 2012;36:843-854

Change in bodyweight Data are mean (95% CI) (ANCOVA estimate) for the intention-to-treat population with the last observation carried forward.

Effects of liraglutide in the treatment of obesity: A randomized, double-blind, placebo-controlled study


Percentage of individuals who lost more than 5% and more than 10% of baseline weight at week 20 (intention-to-treat population) *p=0·002 vs placebo. †p<0·0001 vs placebo. ‡p≤0·0001 vs placebo or orlistat.

Effects of liraglutide in the treatment of obesity:A randomized, double-blind, placebo-controlled study


Liraglutide Safety, tolerability and sustained weight loss over 2 years with the

once-daily human GLP-1 analog, liraglutide

Int J Obesity 2012;36:843-854

◦ 2-year extension study◦ 564 adults enrolled, 398 entered the extension

study and 268 completed the 2-year trial

Int J Obesity. 2012;843-854

Int J Obesity. 2012;843-854

Results: no effects on fasting lipid concentrations at year 1. Modest increase in HDL-C in open-label extension study at year 2 (p=0.03)

Liraglutide

No effects of liraglutide vs placebo on fasting lipids apparent after year 1

At year 2 HDL-C significantly increased with liraglutide 2.4/3.0 mg vs orlistat (p=0.03)

Trend toward reduction in TGs vs orlistat (p=0.053)

Int J Obesity 2012;36:843-854

Liraglutide Weight maintenance and additional weight loss with

liraglutide after low-calorie-diet-induced weight loss: The Scale Maintenance randomized study

551 non-diabetics entered low calorie diet run-in, 422 participants lost >5% of initial body weight during variable-length run-in period (4-12 weeks) with low-calorie diet 1200-1400 kcal/day

Recommended 150 minute/week of aerobic exercise

Met every other week with RD

Randomized to placebo vs liraglutide 3.o mg daily

Int J Obesity 2013;1-9

Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The Scale Maintenance randomized study


Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The Scale Maintenance randomized study


Variable Liraglutide3.0 mgN=207

PlaceboN=206

Est. treatment differences(95% CI), p

Total cholesterolmmol/L{mg/dl}

0.2(0.7) 0.3(0.7) -0.1(-0.2,0.03)

P=0.11{-3.87}

LDL-Cmmol/L

{mg/dl}

0.2(0.6) 0.3(0.6) -0.09(-0.2,0.02)

P=0.11{-3.48}

HDL-Cmmol/L

0.2(0.2) 0.1(0.2) 0.0(-0.03,0.04)

P=0.82

Triglyceridesmmol/L

{mg/dl}

0.0(0.5) 0.1(0.5) -0.11(-0.20,-0.01)

P=0.03{-9.74}

Change from randomization to week 56

SUMMARY: OBESITY DRUGS AND LIPIDS/LIPOPROTEINS

Net weight

loss (kg)

Observed changes (mg/dl) Predicted changes based on weight loss alone (mg/dl)

TC p

LDL-Cp

HDL-Cp

TGp

TC LDL-C HDL-C TG

BLOOM(lorcaserin)

-3.6 -6.4

0.001

+3.2

0.049

NS

0.72

-8.26

<0.001

-7.2 -3.2 -1.28 -4.8

BLOSSOM(lorcaserin)

-2.9 NS NS +1.2<0.001

-4.50.02

-5.76 -2.56 -1.02 -3.84

BLOOM-DM -3.4 NS NS -1.630.005

-10.20.054

-6.84 -3.04 +1.22 -4.56

PHENMONO RX

-4.5 -20 -15 +2 -45 -9 -4 +1.6 -6

EQUIPPHEN/TPM

-10.8 -4.80.0014

-3.50.0157

+1.70.0005

-13.30.0001

-21.6 -9.6 -3.84 -14.4

CONQUERPHEN/TPM

-8.8 -5.90.005

NS +3.950.0002

-26.70.0002

-17.64 -7.84 +1.34 -11.76

Net weight

loss (kg)


TC p

LDL-Cp

HDL-Cp

TGp

TC LDL-C HDL-C TG

OrlistatLow-riskpatients

-3.86 -12 -9.7 NS NS -7.74 -3.44 +1.38 -5.16

OrlistatT2DM

-2.50 -14 -9.7 -1.2 -18 -5.04 -2.24 +0.90 -3.36

OrlistatHigh-risk patients

-2.04 -9.3 -7.3 NS NS -4.05 -1.80 0.72 -2.7

COR-INB32

-4.7 NA -1.2NS

-3.78<0.0001

-11.0<0.0001

-9.36 -4.12 +1.66 -6.24

COR-IINB32

-4.9 NA -4.10.008

+4.5<0.001

-11.0<0.001

NA -4.7 +4.91 -11.99

COR-BMOS -4.21 NA NS +1.70<0.001

-9.040.004

-8.46 -3.76 +1.50 -10.49

Net weight

loss (kg)


TC p

LDL-Cp

HDL-Cp

TGp

TC LDL-C HDL-C TG

Liraglutide1 year

-5.8 NS NS +2.71 NS -11.61 -5.16 +2.06 -7.74

LiraglutideSCALE

Maintenance

-5.9 NS NS NS -9.740.03

-11.79 -5.24 +2.10 -7.86

Anti-obesity drugs and lipids/lipoproteins

Difficult to define consistent benefit beyond that achieved by weight loss/exercise alone

Variable effects on lipids/lipoproteins Orlistat: reduction in LDL-C All others: greatest benefit on TG, HDL-C Greater TG reduction with higher baseline levels Greater weight loss required for LDL-C benefit Studies do not always describe changes in lipid

modification drugs

Obesity, adiposity, and dyslipidemia: A consensus statement from the National Lipid Association

Harold E. Bays, MD, FNLA, Peter P. Toth, MD, PhD, FNLA, Penny M. Kris-Etherton, PhD, RD, FNLA, Nicola Abate, MD, Louis J. Aronne, MD, W. Virgil Brown, MD, FNLA, J. Michael Gonzalez-Campoy,

MD, PhD, Steven R. Jones, MD, FNLA, Rekha Kumar, MD, Ralph La Forge, MSc, FNLA and VarmanT. Samuel, MD, PhD

Journal of Clinical LipidologyVolume 7, Issue 4, Pages 304-383 (July 2013)

DOI: 10.1016/j.jacl.2013.04.001

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

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