Managing Hypertension and Obesity through Therapeutics and Lifestyle Modifications 

 

 

 

 

December 4, 2013 

Baltimore, Maryland  

 

 

 

 

Educational Partner: 

The American Society for Preventive Cardiology  

 

 

 

 

Session 2

Session 2: Managing Hypertension and Obesity Through Therapeutics and Lifestyle Modifications Learning Objectives: 1. Outline current guidelines on the diagnosis, management, and treatment of patients who are obese. 2. Identify the constellation of cardiovascular risk markers in diabetic, insulin-resistant, metabolic syndrome and/or

obese patients. 3. Understand the comprehensive approach to the treatment of obesity and hypertension. Faculty

James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA Diplomate, American Board of Clinical Lipidology Clinical Assistant Professor of Medicine New York University (NYU) Medical School NYU Center for Cardiovascular Disease Prevention Director Bellevue Hospital Lipid Clinic New York, New York

Dr Underberg is a clinical assistant professor of medicine in the division of general internal medicine at New York University (NYU) Medical School and the NYU Center for Cardiovascular Disease Prevention. He is the director of the Bellevue Hospital Primary Care Lipid Management Clinic and is also a member of the executive committee of the division of general internal medicine. His clinical focus is preventive cardiovascular medicine. He is an American Society of Hypertension (ASH)-certified specialist in clinical hypertension and a diplomate of the American Board of Clinical Lipidology. Dr Underberg is the founder and president of the New York Preventive Cardiovascular Society and a founding member of the board of directors of the Northeast Chapter of the National Lipid Association (NLA). He serves on the editorial board of the Journal of Clinical Lipidology, co-chairs the communication committee of the NLA, and is the co-editor of the NLA quarterly newsletter Lipid Spin. He currently serves on the CME committee of the ASH. He graduated from Yale University with a BS and MS and from the University of Pennsylvania Medical School. His internship and residency were completed at NYU-Bellevue Hospital Medical Center. He has been elected a fellow of the American College of Preventive Medicine, the Society of Vascular Medicine, the NLA, the American College of Physicians, and the ASH. He is currently involved in several clinical trials in the areas of hypertension, lipids, diabetes, and cardiovascular disease prevention. He sees patients both in a university-based referral practice and in the Bellevue Hospital Lipid Clinic.

Robert K. Gleeson, MD, FACP, FNLADiplomate, American Board of Clinical Lipidology Assistant Professor, Medicine Froedtert and The Medical College of Wisconsin Milwaukee, Wisconsin

Dr Gleeson is an assistant professor in the department of general medicine at the Medical College of Wisconsin. He is director of the preventive cardiology and lipid management program, which is part of the college’s Heart and Vascular Center, and director of the executive physical program, which is part of the college's Clinical Ventures Group.

Session 2

He is a diplomate of the American Board of Clinical Lipidology and along with Michael Davidson, the co-author of Lipidology, a Primer: The What, Why, and How of Better Lipid Management. Their second book, Conversations with a Preventive Cardiologist, was published in the late fall of 2012. He authored What Healthy People Know: And the 7 Things They Do To Stay Healthy and Live Long (2006), a book promoting a heart-healthy lifestyle. His professional interests are promoting a heart-healthful lifestyle and the use of easily understood lipid treatment protocols to improve compliance. Faculty Financial Disclosure Statements The presenting faculty reports the following: Dr Underberg serves on a speaker bureau for Abbott Laboratories, Aegerion Pharmaceuticals, Amarin Pharma Inc., AstraZeneca, Daiichi Sankyo, Inc., GlaxoSmithKline, Kowa Pharmaceuticals, LipoScience, Merck & Co., Inc., and Sanofi. Dr Gleeson has no financial relationships to disclose. Education Partner Financial Disclosure Statement The content collaborators at the American Society for Preventive Cardiology have no financial relationships to disclose. Suggested Reading List Sica D, Toth P. Clinical Challenges in Hypertension II. Oxford, UK: Clinical Publishing; 2010. Tonkin A. Therapeutic Strategies in Lipid Disorders. Oxford, UK: Clinical Publishing; 2009. Toth P, Sica D. Clinical Challenges in Lipid Disorders. Oxford, UK: Clinical Publishing; 2008.

1

Managing Hypertension and Obesity through Therapeutics and Lifestyle Modifications

SPEAKERsJames A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA

Robert K. Gleeson, MD, FACP, FNLA

SESSION 29:15–10:45am

Presenter Disclosure Information

►Dr Underberg serves on a speaker bureau for Abbott Laboratories, Aegerion Pharmaceuticals, Amarin Pharma Inc., AstraZeneca, Daiichi Sankyo, Inc., GlaxoSmithKline, KowaPharmaceuticals, LipoScience, Merck & Co., Inc., and Sanofi.

►Dr Gleeson has no financial relationships to disclose.

The following relationships exist related to this presentation:

Off-Label/Investigational Discussion

► In accordance with pmiCME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

New Strategies for Obesity Management & Cardiometabolic Risk Reduction:

Proven Strategies in Different Patient Populations

James A. Underberg MD, MS, FACPM, FACP, FASH, FNLA

Clinical Assistant Professor , NYU School of Medicine

NYU Center for Cardiovascular Disease Prevention

Director, Bellevue Hospital Lipid Clinic, New York, NY

Cardiometabolic Risk

Gives a comprehensive picture of a patient’s health and potential risk for future disease and complications

Is inclusive of all risks related to metabolic changes associated with CVD

Accommodates emerging risk factors as useful predictive tools

Refocuses clinical attention to the value of systematic evaluation, education, disease prevention and treatment

Supports an integrated approach to care

Kahn, et al. The Metabolic Syndrome: Time for a Critical Appraisal: Joint Statement From the AmericanDiabetes Association and the European Association for the Study of Diabetes Diabetes Care. 28 (9)22892304, 2005

Abnormal Lipid Metabolism

LDL ApoB HDL Trigly.

Cardiometabolic Risk

Global Diabetes / CVD Risk

Overweight / Obesity

Inflammation Hypercoagulation

Elevated Blood Pressure

Smoking

Age, Race, Sex,

Family History

GlucoseBP Lipids

Age Genetics

Insulin Resistance?

Insulin Resistance SyndromeInsulin Resistance Syndrome

Physical Activity

Relationship Between BMI and Risk of Type 2 Diabetes

Chan J et al. Diabetes Care 1994;17:961.Colditz G et al. Ann Intern Med 1995;122:481.

Age-

Adju

sted

Rel

ativ

e Ri

sk

Body Mass index (kg/m2)

Men

Women

<22 <23 23-

23.9

24-

24.9

25-

26.9

27-

28.9

29-

30.9

31-

32.9

33-

34.9

35+

1.0

2.91.0

4.31.0

5.01.5

8.12.2

15.8

4.4

27.6

40.3

54.0

93.2

6.711.6

21.3

42.1

2

NHANES – Prevalence of Obesity1961-2010

NCHS Data Brief ■ No. 82 ■ January 2012 

Non-modifiable Modifiable

Age

Race/ethnicity

Gender

Family history

Overweight/obesity

Smoking

Physical inactivity

Abnormal lipid metabolism

Hypertension

Insulin resistance

Inflammation

Cardiometabolic Risk Factors

NCEP Metabolic Syndrome Definition(Any three of the five criteria)

• Blood pressure

• Fasting plasma glucose

• Triglycerides

• Waist circumference

• HDL-C

• >130 / >85 mmHg

• >110 mg/dL

• >150 mg/dL

• Women >35”

• Men >40”

• Women <50 mg/dL

• Men <40 mg/dL

Grundy, Circulation. Definition of the Metabolic Syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference of Scientific Issues Related to Definitions. 2004;109:433-438.

Components of the Metabolic Syndrome and Incidence of CHD Events

12

10

8

6

4

2

0

0 1 2 3 4 5

Years

Wit

h C

HD

eve

nt

(%)

0

1

2

3

4/5Components:TG 150 mg/dLHDL-C <40 mg/dLFG 100 mg/dLBP 130 or / 85 mm HgBMI >28.8 kg/m2

Sattar N et al. Circulation. 2003;108:414‐419.

Number of components

Metabolic Syndrome as a Predictor of CHD and Diabetes in WOSCOPS

Sattar N, et al. Circulation. 2003;108:414‐419.

14

12

10

6

01

% with event

0 32 64Years

1 32 65

12

6

4

2

00

Years

4

2

5 4

% with event

CHD death/nonfatal MI Onset of new DM

8

10

RR RR

24.40

7.26

4.50

2.36

1.00

3.65

3.19

2.25

1.79

1.00

4/5 factors

3 factors

2 factors

1 factor

0 factors

4/5 factors

3 factors

2 factors

1 factor

0 factors

Treatment Options by BMI and Co-morbidity Status

Lifestyle Modification

Healthy Diet Physical Activity

Pharmacotherapy

Surgery

BMI > 30(25 w/ co-morbidities)

BMI > 30(27 w/ co-morbidities)

BMI > 40(35 w/ co-morbidities)

NHLBI, Obes Res 6.suppl 2 (1998): 51S-209S

3

(1) A low‐calorie diet (LCD; 800–1,200 kcal/day) can reduce total body weight by an average of 8% over 6 months and can help reduce abdominal fat.

(2) A very‐low‐calorie diet (VLCD; 250–800 kcal/day) produces greater initial weight loss than a LCD, but long‐term weight loss at > 1 year is similar with both diets.

(3) Aerobic exercises result in modest weight loss and may reduce abdominal fat in overweight and obese adults. It may also improve cardiorespiratory fitness.

(4) Reduced calorie intake and increased physical activity, when used in combination, produce greater weight loss than the use of either modality alone.

(5) When behavior therapy is used in combination with other weight loss approaches, it provides additional short‐term benefits.

NIH Obesity clinical guidelines‐ Key Points

Jindal et al.: Obesity and the Cardiorenal Metabolic Syndrome: Therapeutic Modalitiesand Their Efficacy in Improving Cardiovascular and Renal Risk Factors Cardiorenal Med 2012;2:314–327

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults – The EvidenceReport. National Institutes of Health. Obes Res 1998; 6(suppl 2):51S–209S.

(6) Pharmacological therapy for obesity should only be used as part of a comprehensive weight loss program (including diet and physical activity) for patients with a BMI of >30 with no concomitant obesity‐related risk factors, or for patients with a BMI of >27 with concomitant obesity‐related risk factors or diseases.

(7) Bariatric surgery is an option for severely obese patients (BMI > 40 or > 35 with comorbid conditions) who are at high risk of obesity‐related morbidity and who have failed a trial of less invasive interventions.

(8) The initial goal of weight loss therapy should be to reduce body weight by approximately 10% from baseline weight.

(9) Target weight loss should be approximately 1–2 pounds/week for a period of 6 months.

(10) Initially, moderate levels of physical activity for 30–45 min at least 3–5 days per week should be encouraged.

NIH Obesity clinical guidelines‐ Key Points

Jindal et al.: Obesity and the Cardiorenal Metabolic Syndrome: Therapeutic Modalitiesand Their Efficacy in Improving Cardiovascular and Renal Risk Factors Cardiorenal Med 2012;2:314–327

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults – The EvidenceReport. National Institutes of Health. Obes Res 1998; 6(suppl 2):51S–209S.

Key Elements Of Lifestyle Change

Increased Activity

Dietary Changes

Dietary Considerations

• Calorie level 

•Macronutrient content

•Meal replacement products

Benefits of the Mediterranean Diet?

• Weight loss:• Meta analysis of 16 RCT’s with 3,436 patients examining diet for weight loss

demonstrated a significant effect on weight (-1.75 kg), BMI (-0.57 kg/m2), with greater reductions in the setting of energy restriction and increased physical activity

• CHD risk:• One systematic review of cohort and 43 RCT’s found a RR 0.34 for CHD and strong

causality association between Mediterranean Diet “pattern” (vegetables, legumes, nuts, fruits, whole grains, MUFA>SFA) and improved CHD risk among 146 cohort studies

• Dementia/Alzheimer’s Disease:• Prospective study of 1,180 elderly, NYC population followed for 5 years found that higher

adherence to Mediterranean style diet was independently associated with a lower HR of 0.60 for Alzheimer’s, equivalent to physical activity (HR 0.67)

Bays et. al. Journal of Clinical Lipidology (2013) 7, 304–383

Mediterranean Diet and Cardiovascular Disease:Historical Perspective and Latest Evidence Curr Atheroscler Rep (2013) 15:370

Mediterranean Diet and Risk for Alzheimer’s Disease Ann Neurol. 2006 June  ,59(6) 912‐921

Diet and Reinfarction Trial: Methods

• Randomized, controlled, prospective

• Factorial design

• 2,033 men, <70 yo

• Allocated to receive (or not) advice to decrease fat intake to <30% energy, or

increase intake of fatty fish (200-400 g/wk), or

increase intake of dietary fiber to 18 g/d

• Followed for all-cause mortality for 2 yr

Lancet. 1989 Sep 30;2(8666):757‐61. Effects of changes in fat, fish,and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).

4

1.0

0.9

0.8

0 1 2 yrs

Control

Fish Advice

Diet and Reinfarction TrialTotal Mortality

Per

cent

Sur

vivi

ng

Lancet. 1989 Sep 30;2(8666):757‐61. Effects of changes in fat, fish,and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).

Lyon Heart Study (1999)

• Secondary prevention of CHD in male survivors of MI

• Randomized, single blinded trial comparing Med diet (enriched with ALA) with “prudent” diet

• N = 605

• Median age 53 years

• Baseline LDL-C 175mg/dL

• Stopped after 27 months (planned for five years) due to excess M&M in control group

• Benefits for MedDiet group persisted over 4 years of followup

• No statin use – aspirin & beta blockers given to ~60% of patients

de Lorgeril M, Salen P, Martin JL, et al. final reportof the Lyon Diet Heart Study. Circulation. 1999;99:779–785.

Endpoint

Mediterranean Diet, EVOO

(n=2453)

Mediterranean Diet, Nuts(n=2454)

Mediterranean Diet Better

Control Diet Better

p-Value† for Mediterranean

Diets Combined vs

Control(Reference

Value = 1.00)Hazard Ratio for Mediterranean Diets

Combined vs Control (95% CI)

Primary endpoint‡

Unadjusted 0.70 (0.55, 0.89) .003

Multivariable-adjusted 1§ 0.71 (056, 0.90) .004

Multivariable-adjusted 2¶ 0.71 (0.56, 0.90) .005

Secondary Endpointsǁ

Stroke 0.61 (0.44, 0.86) .005

Myocardial Infarction 0.77 (0.44, 1.15) .200

CV Mortality 0.83 (0.54, 1.29) .410

All-cause Mortality 0.89 (0.71, 1.12) .320

Primary Prevention of Cardiovascular (CV) Disease with a Mediterranean Diet

Outcomes According to Study Group

Adapted from: Estruch R, et al. N Engl J Med. 2013;DOI: 10.1056/NEJMoa1200303.

Trial stopped early (median f/u 4.8 years) due to interim analysis showing benefit for primary endpoint with Med Diet

Med diet, EVOO: hazard ratio (HR), 0.70

(95% CI, 0.53, 0.91); p= .009

Med diet, nuts: HR, 0.70(95% CI, 0.53, 0.94); p= .02

Incidence of Outcome Events in the Total Study Population

Primary Endpoint*

Adapted from:Estruch R, et al. N Engl J Med. 2013; DOI: 10.1056/NEJMoa1200303.

Number at Risk

Control Diet 2450 2268 2020 1583 1268 946

Med Diet EVOO 2543 2486 2320 1987 1687 1310

Med Diet, nuts 2454 2343 2093 1657 1389 1031

* Myocardial infarction, stroke, or death from cardiovascular causesEVOO=extra virgin olive oil

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

Inc

ide

nc

e o

f C

om

po

sit

e

Car

dio

vasc

ula

r E

nd

po

int

Years

Control Diet

Med diet, nuts

Med diet, EVOO

Anti Obesity Medications

D‐Fenfluramine

Mazindol

Sibutramine(Meridia)

Phenylpropanolamine 

Phendimetrazine

Benzphetamine

Heart DiseaseStrokeValvular Disease

Withdrawn from US Market

Drugs@FDA. http://www.acccessdata.fda/gov

Anti Obesity Medications: Currently FDA approved

Orlistat

Lorcaserin

Phentermine

Currently available as of 2013

Phentermine/Topiramate

5

Orlistat

• Brand name: Xenical

• Prescription orlistat 120 mg TID approved for long-term weight management in 1999; OTC orlistat (60 mg TID) approved in 2007

• Mechanism: Gastrointestinal lipase inhibitor; decreases intestinal energy absorption

• Most common AEs: Oily rectal discharge, fecal urgency, fatty/oily stool

• Rare postmarketing reports of severe liver injury

• Notes• May decrease cyclosporine and levothyroxine levels

• May decrease fat-soluble vitamin absorption; users should take daily multivitamin containing vitamins A, D, E, K, beta carotene

• May enhance warfarin effect if vitamin K absorption is diminished

• Pregnancy category X

AE = adverse events.Xenical [prescribing information]. South San Francisco, CA: Genentech USA, Inc; 2012.

Bays et. al. Journal of Clinical Lipidology (2013) 7, 304–383

Early Weight Loss Predicts Later Weight Loss

2-year Orlistat Trial

% weight lossat 2 years

Weight loss at 12 weeksData from Rissanen et al,Int J Obesity (2003) 27, 103 – 109

Phentermine• Phentermine resin (15-30 mg/d) approved in 1959 for short-term (12 wk)

weight management

• Phentermine HCl developed in 1970s with doses of 8-37.5 mg (generally equivalent to 6.4-30 mg of phentermine resin)

• Mechanism: Noradrenergic, sympathomimetic amine–decreases appetite

• Most common AEs: Tachycardia, increase in BP, tremor, overstimulation of CNS, dry mouth, constipation

• Notes

• Generic; most commonly prescribed/least expensive option

• Phentermine HCl salt easily dissociates in GI tract, resulting in immediate-release of phentermine drug; absorbed ~3× faster than resin

• DEA Schedule IV drug

• Pregnancy category X

DEA = Drug Enforcement Agency; GI = gastrointestinal; IV = intravenous.Bays HE. Expert Rev Cardiovasc Ther. 2010 8;12:1777-1801.

Bays et. al. Journal of Clinical Lipidology (2013) 7, 304–383

Lorcaserin

• Brand name: Belviq

• Approved in 2012 (10 mg BID) for long-term weight management

• Mechanism: Selective 5-HT2C receptor agonist–increases satiety

• Most common AEs: Headache, nausea, dizziness, fatigue, dry mouth, constipation

• Notes

• Discontinue if 5% weight loss is not achieved by week 12

• Discontinue for evaluation if signs or symptoms of valvularheart disease

• DEA Schedule not complete

• Pregnancy category X

Bays HE. Expert Rev Cardiovasc Ther. 2009;7:1429-1445; Belviq [prescribing information]. Woodcliff Lake, NJ: Eisai; Inc. 2012.

BLOOM Study Body Weight Over Years 1 and 2

Study Week

BLOOM = Behavioral Modification and Lorcaserin for Obesity. Smith SR, et al. N Engl J Med. 2010;363:245‐256.

Bo

dy

We

igh

t (k

g)

Year 1

Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1, placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

Year 2

0

102

100

98

96

94

92

90

10472 806448 564024 32160 8 88 96

Fasting Plasma Glucose

-40

-30

-20

-10

0

0 2 24 52

BLOOM-DMChange in Glycemic Parameters

HbA1C

*P <.001; †P <.05; least square mean change ± standard error of the mean.HbA1C = glycosylated hemoglobin.

O’Neil PM, et al. Obesity. 2012;20:1426-1436.

Ch

ang

e F

rom

Bas

elin

e (m

g/d

L)

Ch

ang

e F

rom

Bas

elin

e (%

)

Study WeekStudy Week

PlaceboLorcaserin 10 mg twice a day

* * **

*†

*

6

Phentermine/Topiramate

• Brand name: Qsymia

• IR phentermine HCl/CR topiramate approved for weight management in 2012 (titrated in AM up to 7.5/46 mg/d; max 15/92 mg/d)

• Mechanism: Phentermine–decreases short-term appetite. Topiramate–decreases longer-term appetite and may have glycemic effects

• Most common AEs: Paresthesia, dizziness, cognitive dysfunction, dysgeusia, insomnia, constipation, dry mouth, metabolic acidosis, elevated creatinine

• Notes• Discontinue if 5% weight loss is not achieved after 12 weeks on full (maximum) daily dose

of 15 mg/92 mg

• Schedule IV drug

• May contribute to secondary angle-closure glaucoma

• If full/max dose discontinued, it should be done gradually to prevent seizures

• Pregnancy category X (cleft palate)

CR = controlled release; IR = immediate‐release. 

Bays HE, Gadde KM. Drugs Today. 2011;47:903‐914; Bays HE. Expert Rev Cardiovasc Ther. 2010 8;12:1777‐1801;Qsymia [prescribing Information]. Mountain View, CA: Vivus, Inc.; 2012.

EQUIP & CONQUER: Study Entry Criteria

• One year

• Adults ≤70 years of age

• BMI ≥35 kg/m2

• Blood pressure ≤140/90 mmHg using 0-2 antihypertensive medications

• Fasting blood glucose ≤110 mg/dL

• Triglycerides ≤200mg/dL using 0 or 1 lipid lowering medications

• One year

• Adults ≤70 years of age

• BMI ≥27 and ≤45 kg/m2

(no lower BMI limit in T2DM)

• Have two or more of the following obesity-related co-morbid conditions:

• SBP 140-160 mmHg and/or DBP 90-100 mmHg or taking ≥2 meds for HTN

• Triglyceride level between 200-400 mg/dL or taking ≥2 meds for dyslipidemia

• Fasting blood glucose >100 mg/dL and /or >140 mg/dL 2 hours post 75 gm glucose load (OGTT) and/or diagnosis of type 2 diabetes

• Waist circumference ≥102cm (40 in) for men or ≥88 cm (35 in) for women

EQUIP CONQUER

Allison DB, et.al.  Obesity 2012;20:330‐42Gadde KM, et. al.  Lancet 2011;377:1341‐52

*

*****

*

* ****

* ***

0 8 16 24 32 40 48 56 LOCF MI

CONQUER: Weight Loss Over Time

52

*

*

Ch

an

ge

Fro

m B

as

elin

e (

%)

0

-2

-4

-6

-8

-10

-12

-14

Week

PlaceboPhentermine 7.5 mg/topiramate 46.0 mg*Phentermine 15.0 mg/topiramate 92.0 mg*

Patients Placebo Mid Full

Completers (% of randomized) 557 (57%) 338 (69%) 625 (64%)

*Weight change for either dose vs placebo, P <.0001.LOCF = last observation carried forward; MI = multiple imputation.Gadde M, et al. Lancet. 2011;377:1341‐1352. 

Naltrexone/Bupropion Proposed brand name: Contrave

Investigational agent undergoing CV outcomes trial (Light Study)

Mechanism: Naltrexone–opioid antagonist for treatment of alcohol dependence and blockade of effects of exogenous opioids; may reduce appetite and addictive behavior; bupropion–antidepressant of the aminoketone class chemically unrelated to tricyclic, tetracyclic, SSRI, or other antidepressant agents that may reduce appetite

Most common AEs: Nausea, constipation, dizziness, dry mouth, tremor, upper abdominal pain, tinnitus

Notes• Light Study enrolling obese patients (N ≈10,000) with estimated background rate

of 1.0%-1.5% annual risk of major CV event with upper bound of 95% CI excluding hazard ratio of 2.0 at interim analysis (87 events), 1.4 at final analysis

• The combination agent doses being studied include naltrexone SR 32 mg/d combined with bupropion SR 360 mg/d

CV = cardiovascular; SR = sustained release; SSRI = selective serotonin reuptake inhibitor.Orexigen Therapeutics. http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1608571. Accessed August 20, 2012; Wadden TA, et al. Obesity. 2011;19:110-120.

*****

Percent Change in Body Weight With Naltrexone/Bupropion: COR/BMOD Trial

• BMI 36.5 ± 4.2 kg/m2

• Placebo + BMOD, n = 193 NB32 + BMOD, n = 482

• Completer population: placebo + BMOD, n = 106 NB32 + BMOD, n = 301 

*P <.001, for NB32 + BMOD vs placebo + BMOD. COR/BMOD = Contrave Obesity Research/Behavioral Modification; ITT – LOCF = intent to treat, last observation carried forward; NB32 = naltrexone 32 mg/bupropion 360.

Wadden TA, et al. Obesity. 2011;19:110-120.

Ch

an

ge

in B

od

y W

eig

ht

(%)

Completers

NB32 + BMOD

Placebo + BMOD

56Week

Modified-ITT-LOCF

*

-7.3%

-11.5%

-5.1%

-9.3%

*

*****

**

*

Liraglutide for Weight Loss in Patients With Type 2 Diabetes

• Brand name: TBD

• GLP-1 analog approved for type 2 diabetes mellitus

• Mechanism: Anorectic effect possibly mediated by activation of GLP-1 receptor expressed on vagal afferents and by GLP-1 receptor activation in CNS, which may affect visceral fat adiposity, appetite, food preference, and CV biomarkers in patients with type 2 diabetes

• Most common AEs: Dose-dependent nausea, vomiting, diarrhea

• Not approved as a stand-alone weight management agent

Inoue K, et al. Cardiovasc Diabetol. 2011;10:109.

7

Effect of Obesity Drugs on LipidsAverage Changes from Baseline

Total Cholesterol LDL-C Triglycerides HDL-C

Orlistat ↓ 2% ↓ 4% ↑ 1% ↑ 9%

Lorcaserin ↓ 1% ↑ 2% ↓ 5% ↑ 2%

Phentermine/ Topiramate

↓ 6% ↓ 8% ↓ 5% ↑ 4%

Xenical Package Insert. Genentech USA, Inc., South San Francisco, CA: January 2012.Belviq Package Insert. Arena Pharmaceuticals, Woodcliff Lake, NJ: June 2012.

Qsymia Package Insert. VIVUS Inc., Mountain View, CA: July 2012. 58

Summary

• Obesity /Overweight continues to be a problem worldwide associated with Cardiometabolic Risk

• Theraputic interventions include lifestyle, bariatric surgery and pharmacologic therapies

• Weight loss vs. Preventing Weight Gain may be important issues

• Dietary Interventions can cause short term weight loss, and some long term CV benefits

• Pharmacologic intervention for weight loss should be used with an understanding of potential cardiometabolic benefits.

Hypertension and Obesity

Still Waters Run Deep

Robert Gleeson, MD, FACP, FNLA

Medical College of Wisconsin

Preventive Cardiology and Lipid Management

Does Preventive Cardiology Make a Difference?

Why does preventive cardiology matter?

1. Since 1960, has worked to identify the major causes of atherosclerosis and CAD

2. Identified treatments that lowered the risk factor and CAD

3. Wrote guidelines for best treatment

But cardiovascular disease remains the leading cause of premature

morbidity and mortality

The American Society for Preventive Cardiology is proud to continue the fight to prevent cardiovascular disease.

Please join us in our journey.

Together we can work to prevent atherosclerosis.

aspconline.org

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Key Points about Obesity

1. Obesity increases risk of all CVD risk factors, events, and mortality

2. Obesity increases hypertension, which is largely untreated

3. Treating hypertension in the obese patient lowers risk of CVD events

4. Treating obesity lowers hypertension and improves other CV risk factors

Measuring BP in the Obese

• A standard BP cuff over-estimates BP in obese

• For every 5 cm increase in arm circumference, the BP increases 3/2 mm

• Standard cuff fits 9 to 13 inches circumference

• Large cuff fits 13 to 17 inches circumference

Regardless of etiology,hypertension increases

• CV deaths

• Coronary artery disease

• Stroke

• Peripheral artery disease

• Heart failure

• Valvular heart disease

Hypertension and CVD

• BP has a continuous, graded, and linear effect on CVD with a nadir of 115/75

• Above that, CVD events and mortality double for every

• 20 mm increase in systolic

• 10 mm increase in diastolic

• 66% of CHD deaths occur in men with systolic BP between 130 and 159

Stamler et al Lancet 2002

Obesity and Hypertension

• 75% of hypertension is related to obesity1

1. Krus et al e Circ 1998

BMI Prevalence of HBP %NHANES 2005 to 2008

< 25 15.3

25‐30 27.8

30 42.5

Hypertension in obesity

• Only 30% of hypertension in obese is treated adequately

Kurukulasuriya LR et al. Med Clin North Am 2011 Sep;95(5):903‐17

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Obesity and CVD

1. Obesity is the leading public health crisis of our time

• The obesity pandemic may be flattening century + gain in life

2. Obesity is epidemic in children and adolescents

• CVD disease burden likely increases with duration of obesity

Hazard ratios for CV death by BMIin subjects who had never smoked

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

15 20 25 30 35 40 45 50

Hazard Ratio

BMI

de Gonzalez, AB et al. N Engl J Med 2010;363:2211‐9.

About sameas smoking 

Obesity increases CVD by increasing

• Hypertension

• Atherogenic dyslipidemia

• Insulin resistance and diabetes

• Inflammation

• Thrombosis

• Endothelial dysfunction

• Sleep apnea

Obesity increases hypertension

• Multiple inter-related causative factors

• Activation of the RAAS, SNS, insulin resistance, leptin, adiponectin, dysfunctional fat, FFA, resistin, 11 Beta dehydrogenase, renal structural and hemodynamic changes, and OSA

• Obesity has a central role in development of CVD and risk is linear with weight gain

• AHA defines obesity as an independent risk factor for CHD

• Obesity is a Class II risk factor

• Intervention is likely to lower incidence of CHD events

• But relatively little outcomes data

27th Bethesda Conference.  Matching intensity of risk factor management with hazard for coronary mortality  J Am Coll Card 1996;27 

Metabolic Syndrome increases CVD risk more than the sum of its parts

Relative risk

Cardiovascular mortality 2.40

Cardiovascular disease 2.35

MI 1.99

Stroke 227

Mottillo S et al, J Am Coll Cardiol. 2010 Sep 28;56(14):1113‐32

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Is overweight with normal risk factors still a risk?

• Yes.

• They still had impaired vaso-reactivity, increased LV mass, impaired clotting1

• No

• 22.000 hypertensive patients with CHD2

1.  Lind  ATVB 2011;312.  Uretsky Obesity Paradox Am J Med 2007;120

BMI HR

20-25 1.0

25 - 30 0.77

30 - 35 0.68

Overweight versus waist measurement

• At every BMI and in both men and women, the risk of cardiovascular disease is increased by increasing abdominal fat

• WHR is better predictor of CVD than BMI

Waist measurement

• Increased risk for HBP, diabetes, dyslipidemia if

• Caucasian and Blacks M > 40 F > 35

• S. Asian and Japanese M > 35 F > 31

• Most useful if BMI 25 to 35

• If BMI > 35, waist measurement adds little predictive value

Waist to hip ratio WHR fromNurses Health Study

• Normal

• Men: WHR < 0 .9

• Women < 0.8

• A larger WHR is always worse

• Females:

• WHR > 0.88 compared to WHR < 0.72 has HR of CHD = 3.2

• Even if BMI normal (20 to 25), a WHR > 0.76 compared to WHR < 0.76 has a HR of CHD = 2

Rexrode JAMA 1988;280

Treating obesity to lower blood pressure

1. Lose weight

2. Lose weight and exercise more

3. Treat BP and CV risk factors

4. Lose weight, exercise more, and treat the BP

5. Major social campaigns like the no smoking campaigns

6. All of the above

Weight-loss and BP mixed results

• Weight-loss diets lower BP best

• Diet weight loss of 4 kg lowers BP 6/3 mm Hg

• Some weight-loss meds lower BP, some raise

• Orlistat lowers BP but not as much as diet

• Sibutramine no effect

• Roux-en-Y gastric bypass lowers BP, but not as much as anticipated

• Liposuction no effect on BP

Horvath Arch Med 2008 commentary

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Benefits of Weight Loss

• 5% weight loss is associated with reduction of

• angiotensinogen levels by 27%

• renin by 43%

• aldosterone by 31%

• angiotensin-converting enzyme activity by 12%

• angiotensinogen expression by 20% in adipose tissue

Engeli S et al.  Hypertension. 2005 Mar;45(3):356‐62.

Weight loss options

• Commercial weight-loss programs

• Work quite well, may be sustainable

• Diet and exercise

• Necessary to do both, but sustaining is hard

• Pharmaceuticals

• All short-term and with side effects

• Surgery, esp. bariatric surgery

• Long-term benefit, but need compliant patient

National Weight Control Registry predictors of successful long-term weight control

1. Self-monitoring of weight

2. Consumption of a low-fat diet

• Different macronutrient components of diet are less important than over-all calorie restriction

3. Daily physical activity of approximately 60 minutes

4. Minimal sedentary “screen time”

5. Eating most meals at home

National Weight Control Registry

Major difficulty of weight loss

• “Body weight and body fat are tenaciously regulated.” emedicine on obesity options

• When patients lose weight by dieting, their total and resting energy expenditure also drop in an effort to conserve energy.

• The only way to counteract this drop is to increase activity levels

Treating hypertension in the obese

Anti-hypertensives in the obese

It’s the lower BP, not the drugs that matter

Treat high-risk obese when BP > 130/80

Landsberg et al J Clin Hyperten Jan 213

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Anti-hypertensives in the obese

Most of the anti-hypertensive benefit comes from the lowest dose of the drug

Treating hypertension in obese according toJan 2013 statement of ASH and Obesity Society

• Target < 140/90 unless DM, CKD and then aim for < 130/80

• RAAS inhibition

• ACE or ARB

• CCB

• Diuretics

• Low-dose thiazide or thiazide like agents

• Loop diuretics if required

• Potassium sparing agents

• Avoid beta-blockers except for specific cardiac indication

• All agents are potentiated by weight loss

Treating hypertension in obese patients cont’d

• Beta-blockers and thiazides both increase insulin resistance and diabetes

• Thiazide diuretics increase dyslipidemia associated with obesity

• If use thiazides, use low dose like 12.5 to 25 mg of HCTZ or chlorthalidone

• Beta blockers cause insulin resistance and weight gain

• Limit beta blockers to post MI or HF

Summary

1. Obesity increases risk of hypertension

2. The combination substantially increases the risk of CVD

3. Treating hypertension in the obese requires treating the obesity as part of the therapeutic plan

1. Lifestyle management is required for every case

4. Lower HBP in the obese is essential to reduce risk of CVD

Question & Answer