obesity safety review emily m. armstrong, pharmd, bcacp assistant clinical professor auburn...

Obesity Safety Review

Emily M. Armstrong, PharmD, BCACPAssistant Clinical Professor

Auburn University Harrison School of PharmacyAnd

Adjunct Assistant ProfessorDepartment of Internal Medicine

University of South Alabama

Learning Objectives

Discuss the cardiovascular risk associated with obesity

Explain the mechanism by which anti-obesity medications are associated with cardiovascular risk

Evaluate the cardiovascular risk associated with current anti-obesity pharmacotherapy

Evaluate the risk of psychiatric risk with current anti-obesity pharmacotherapy

The Prevalence of Overweight and Obesity

Ogden CL et al. NCHS Data Brief 2012;82.

Obesity

Mortality

T2DM

CHD

HTN

DLDStroke

Asthma

Social Health

Mental Health

Sleep Apnea

Bray GA. J Clin Endocrinol Metab 2004;89:2583-2589.Irigaray P et al. Biomed Pharmacother 2007;61:665-678.

The Mortality Risk Overweight and Obesity

• Increase overall mortality• BMI ≥35 kg/m2 > BMI 30.0-34.9 kg/m2

• The J-curve• Men: BMI 23.5-24.9 kg/m2

• Women: BMI 22.0-23.4 kg/m2

The Obesity Paradox• J-curve: Elderly (50-80 years)

• Men: 28.2 kg/m2

• Women: 27.1 kg/m2

• Mortality increase with BMI ≥32 kg/m2

Dorner TE, Rieder A. Int J Cardiol 2012;155:56-65.Masters RK, et al. Am J Epidemiol 2013;177(5):431-332.

Obesity and Cardiovascular Disease Independent predictor of adverse CV outcome

• Women• BMI >23 kg/m2 but <25 kg/m2

• 50% increase risk CHD• Men

• BMI >25 kg/m2 but <29 kg/m2

• 72% increase risk CHD Abdominal obesity stronger predictor adverse CV outcome Obesity-associated CV risk

• Inflammation• Insulin resistance• Dyslipidemia• Hypertension• Myocardial function

Charakida M and Finer N. Am J Cardiovasc Drugs 2012;12(2):93-104.

Obesity and CVD: Pathophysiologic Link

Adipose Tissue

ProinflammatoryCytokines

MacrophageRecruitment

VLDL,LDL HDLBP

Glucose

Non-esterified

Fatty Acids

Liver

Myocytes

Ectopic Fat Heart

Insulin Resistance

Oxidative Stress

Inflammation

Platelet Aggregation

Atherosclerosis

CVD

Adapted from: Charakida M and Finer N. Am J Cardiovasc Drugs 2012;12(2):93-104.

Endothelial Dysfunction

Obesity and Inflammation Pro-inflammatory cytokines

• TNF-alpha• Interleukin 1 and 6• Monocyte chemoattractant protein-1• C-reactive protein (CRP)

Leptin• Elevated circulating levels• CV impact

• Reactive oxygen species• Vascular tone• Platelet aggregation• Arterial thrombosis

Adiponectin • Vasoprotective • Down-regulated


Obesity and Insulin Resistance

Altered insulin action Glucose impact

• ⇧production/ ⇩uptake and oxidation• ⇧lipolysis• Release of non-esterified fatty acids (NEPA)

NEPA• Liver metabolism• Myocardial contractility• Endothelial nitric oxide production• Reactive oxygen species


Obesity and Dyslipidemia

Overproduction VLDL

Impaired lipolysis• Decrease VLDL clearance

Altered LDL particles • Increase small, dense LDL particles

Down-regulated HDL cholesterol


Obesity and Hypertension

Increase prevalence

Overactivity• Sympathetic nervous system• Renin-angiotensin system

Renal dysfunction• Increase tubular sodium reabsorption


Obesity and Myocardial Function

Impaired systolic/diastolic function

Depressed myocardial contractility

Left ventricular hypertrophy

Lipid accumulation = cardiotoxicity• Cardiac conduction• Ventricular remodeling• Dilated cardiomyopathy


Non-pharmacologic Treatment of Obesity

Lifestyle• Weight loss at 2-3 years

• ⇩TC 1.3%/kg lost• ⇩TG 1.6%/kg lost

• Weight loss sustained >3 years not associated with benefit

Mancia G, et al. J Hypertens 2007;25(6):1105-1187.Straznicky N, et al. J Hypertens 2010;28(4):637-643.Aucott L, et al. Obesity Reviews 2011;12:e412-425.

Non-pharmacologic Treatment of Obesity Bariatric surgery

• Weight loss at 10 years• >10 kg

• SBP: -6.0 mmHg (95% CI -10.7, -1.4)• Pulse pressure: -3.9 mmHg (95% CI -7.6, -0.1)• Insulin: -3.8 mU/mL (95% CI -6.7, -1.0)

• 15 kg• HDL: +0.1 mmol/L (95% CI 0.01, 0.2)• Glucose: -0.8 mmol/L (95% CI -1.2, -0.3)

• 20 kg• Uric acid: -22.4 umol/L (95% CI -44.0, -0.8)

• 44 kg• DBP: -4.4 mmHg (95% CI -7.1, -1.7)• TG: -0.3 mmol/L (95% CI -0.6, -0.1)

Sjostrom CD, et al. Int J Obes (Lond) 2011;35:1413-1420.

Pharmacologic Treatment of Obesity

1930 1940 1950 1960 1970 1980 1990 2000 2010 2020

BenzphetaminePhendimetrazine

approved

Dinitrophenolwithdrawn

Phenylpropanolamineapproved

Phenylpropanolaminewithdrawn

Phentermine/Diethylpropion

approved

Phentermine/Diethylpropion

Withdrawn(Europe)

Fenfluramine approved(Europe)

Fenfluramine approved

(USA)

Fenfluramine/dexflenfluramine

withdrawn

Dexfenfluramine approved(Europe)

Dexfenfluramine approved

(USA)

Methamphetamine approved for

obesityOrlistat

approved

Lorcaserin,Phentermine/

topiramate approvedDinitrophenol

approved

Pharmacologic Treatment of Obesity

FDA Requirements for approval• Produce statistically significant weight loss

• >5% baseline at 1 year• >35% patients treated achieve >5% weight loss

• Must also be 2x weight loss achieved with placebo

• Improved obesity-related metabolic abnormalities• Blood pressure • Blood glucose• Lipid levels

Colman E. Circulation 2012;125(17):2156-2164.

Pharmacologic Treatment: Safety Concerns

Pulmonary artery hypertension Valvulopathy CV outcomes

• BP, lipids, glucose Psychiatric disturbances Addiction potential

Pulmonary Artery Hypertension (PAH)

Diffuse medial hypertrophy Endothelial/smooth-muscle cell hypoplasia of pulmonary arteries

• Right sided heart failure• Death

Classification• Idiopathic/primary (IPAH)• Familial (FPAH)• Anorexigen-induced (APAH)

Survival• 1 year: 50% APAH vs. 88% IPAH• 3 years: 17% APAH vs. 60% IPAH

Pietra GG, et al. J Am Coll Cardiol 2004;43:25S-32S.Rich S, et al. Chest 2000;117:870-874. Rubin LJ. N Engl J Med 1997;336:111-117.

Pulmonary Artery Hypertension

Fenfluramine/dexfenfluramine exposure• Increase risk PAH 7-23-fold

• >3 months therapy• 30 patients originally suspected

• 18 patients confirmed Mechanism

• 5HT role• Release 5HT from neurons/platelets• Extracellularly: 5HT1B, 5HT2B

• Intracellularly: 5HTT• Possible genetic role

• Bone morphogenetic protein receptor type 2 (BMPR2)• 5HT2BR Pietra GG, et al. J Am Coll Cardiol 2004;43:25S-32S.

Rich S, et al. Chest 2000;117:870-874. Rubin LJ. N Engl J Med 1997;336:111-117.

Valvulopathy

Plaques of proliferative myofibroblasts• Valve leaflets

Atypical plaque• Myxoid stroma• Proliferative myofibroblasts• Small vessels• Lymphocytic infiltrations

Connoly HM, et al. N Engl J Med 1997;337:581-588. Sachdev M, et al. Am Heart J 2002;144:1065-1073.

Valvulopathy

Fenfluramine/dexfenfluramine• 24 patients• 6%-30% patients with abnormal echocardiographic findings• 1/8 patients treated >90 days

Mechanism• 5HT role

• Agonist/activation of 5-hydroxytryptamine 2B receptor (5HT2BR)

• Increased circulation of 5HT No increase risk

• Agonists of 5HT2C/5HT2A

• Antagonists of 5HT2BRRothmann RB, et al. Circulation 2000;101:2836-2841. Rajamannan NM, et al. J Heart Valve Dis 2001;10:827-831.

Other CV Concerns

Sibutramine• Tachycardia, hypertension, arrhythmias, death

• 143 cardiac arrhythmias, 29 deaths• SCOUT

• CVD or DM + additional CV risk factor• Primary outcome

• 11.4% vs. 10% (HR 1.16, 95% CI 1.03-1.31, p=0.02)• Nonfatal MI (HR 1.28, 95% CI 1.04-1.57, p=0.02)• Nonfatal stroke (HR 1.36, 95% CI 1.04-1.77, p=0.02)

• All-cause mortality NS (HR 1.04, 95% CI 0.91-1.20, p=0.54)• ⇧HR (4 bpm) and BP (1-2 mmHg)

James WP, et al. N Engl J Med 2010;363(10):905-917. McNeely W, Goa KL. Drugs 1998;56(6):1093-1124.

Psychiatric Events

Rimonabant• FDA voted against approval 2007

• Depression • Suicidal ideation

Ling H, et al. Pharmacotherapy 2013; doi: 10.1002/phar.1277

Phentermine

No effect on heart valves CV impact• Increase BP• Tachycardia• Palpitations

Phentermine DCR• Improvement TC, LDL-c• NS difference BP

Use with caution• Risk hemodynamic/CV complications

Kaplan LM. Gasteroenterol Clin N Am 2010;39:69-79. Kang JG, Park CY. Diabetes Metab J 2012;36:13-25.

Diethylpropion

No effect on heart valves Cercato, et. al• CV impact

• NS difference BP, pulse rate, ECG• TGs significantly improved

• Psychiatric impact• NS difference observed

Common CV ADRs• Mild increase BP

Kang JG, Park CY. Diabetes Metab J 2012;36:13-25. Cercato C, et al. Int J Obes (Lond) 2009;33:857-865.

OrlistatXENDOS

Select CV Endpoints

PBO Orlistat P-value PBO Orlistat P-value

Year 1 Year 4SBP (mmHg) -5.2 -7.3 <0.01 -3.4 -4.9 <0.01

DBP (mmHg) -2.6 -3.6 <0.01 -1.9 -2.6 <0.01

TC (%) -1.3 -8.8 <0.01 -2.3 -7.9 <0.01LDL (%) -1.6 -11.4 <0.01 -5.1 -12.8 <0.01HDL (%) 8.5 3.4 <0.01 9.1 6.5 <0.01TG (%) -6.3 -6.2 <0.05 2.9 2.4 NSOther Significant Improvements

FPG, PPG, insulin, rate of new onset DM

Togerson JS, et al. Diabetes Care 2004;27:155-161.

Orlistat 1-year treatment

Select CV Endpoints

PBO Orlistat P-value

SBP (mmHg) -3.4 -4.9 <0.01

DBP (mmHg) -1.9 -2.6 <0.01

TC (mg/dL) 212±17 126±6 <0.05

LDL (mg/dL) 149±11 134±7 <0.05

HDL(mg/dL) 45±7 45±7 NS

TG (mg/dL) 88±32 76±27 NS

Other Significant Improvements

From baseline: HsCRP, HbA1c, FPG, PPG, HOMA-IR

Derosa G, et al. J Clin Pharm Ther 2012;37:187-195.

Current Anti-Obesity Medications: Orlistat

Liver injury• 1999-2008

• 32 reports serious liver injury• 6 cases liver failure

• FDA safety review• 1999-2009

• 40 million total patients• 13 cases severe liver injury

• Label revision

Kang JG, Park CY. Diabetes Metab J 2012;36:13-25.

LorcaserinSelect CV Endpoints BLOOM BLOSSOM BLOOM-DM

LORC PBO LORC PBO LORC PBO

SBP (mmHg) DBP (mmHg)

-1.4*-1.1*

-0.8-0.6

-1.9-1.9

-1.2-1.4

-0.8-1.1

-0.9-0.7

HR (bpm) -2.0* -1.6 -2.3 -1.6 -2.0* -0.4HbA1c (%) -0.04* 0.03 -0.19 -0.14 -0.93* -0.44TC (%) -0.90* 0.57 -0.7 0.0 -0.7 -0.1LDL (%) 2.87* 4.03 0.3 1.7 4.2 5.0HDL (%) 0.05 -0.21 3.7* 1.3 5.2* 1.6TG (%) -6.15* -0.14 -4.3* 0.9 -10.7* -4.8Hs-CRP -1.19* -0.17 NA NA -1.3 -0.6BDI-II -1.1 -0.9 NA NA -0.1 -0.3

*p<0.05 vs. placeboFidler MC, et al. Clin Endocrinol Metab 2011;96:3067-3077. O’Neil PM, et al. Obesity 2012;20(7):1426-1436.Smith S, et al. NEJM 2010;363:245-256.

LorcaserinPsychiatric Endpoints BLOOM BLOSSOM BLOOM-DM

LORC PBO LORC PBO LORC PBO

BDI-II score -1.1 -0.9 -0.8 -0.7 -0.1 -0.3Depression (%) NA NA 1.9 1.8 NA NADepressed Mood (%) NA NA 0.6 0.9 NA NASuicidal Thoughts/Ideation (%)

1.3 1.3 0.9 0.7 NA NA

Combination: (%)Depression, Depressed Mood, Depressive Symptoms

2.5 2.2 NA NA NA NA

Fidler MC, et al. Clin Endocrinol Metab 2011;96:3067-3077. O’Neil PM, et al. Obesity 2012;20(7):1426-1436.Smith S, et al. NEJM 2010;363:245-256.

Lorcaserin

Risk of valvulopathy• No activation of 5HT2B• Rates of valvulopathy vs. placebo

• BLOOM: 2.6% vs. 2.7%• BLOSSOM: 2.0% vs. 2.0%• BLOOM-DM:

• Baseline: 3.5% vs. 3.6%• 52 weeks: 2.9% vs. 0.5%• Not powered to detect difference• Rate of valvulopathy lower in the placebo group

Fidler MC, et al. Clin Endocrinol Metab 2011;96:3067-3077. O’Neil PM, et al. Obesity 2012;20(7):1426-1436.Smith S, et al. NEJM 2010;363:245-256.Ling H, et a. Pharmacotherapy 2013;doi:10.1002/phar.1277.

Phentermine/TopiramateStudy Group SBP

(mmHg)DBP (mmHg)

HR (bpm)

EQUIP

PBO 0.9 0.4 -0.2

3.75/23 -1.8* 0.1 -0.3

15/92 -2.9* 1.5* 1.2

CONQUERPBO -2.4 -2.7 -0.1

7.5/46 -4.7* -3.4 0.1

15/92 -5.6* -3.8* 1.7*

SEQUEL

PBO -3.2 -3.9 0.4

7.5/46 -4.7 -3.7 1.3

15/92 -4.2 -3.5 1.7

Allison DB, et al. Obesity 2011;20:330-342. Gadde KM, et al. Lancet 2011;377:1341-1352.Garvey TW, et al. Am J Clin Nutr 2012;95:297-308.P<0.05 vs. placebo

Phentermine/TopiramateStudy Group TC (%) LDL (%) HDL (%) TG (%) HS-CRP

(mg/L)

EQUIP

PBO -3.5 -5.5 0 9.1 NA

3.75/23 -5.4 -7.7 0.5 5.2 NA

15/92 -6.0* -8.4 3.5* -5.2* NA

CONQUERPBO -3.3 -4.1 1.2 4.7 -0.79

7.5/46 -4.9* -3.7 5.2* -8.6* -2.49*

15/92 -6.3* -6.9* 6.8* -10.6* -2.49*

SEQUEL

PBO NR -10.7 4.7 0.4 NR

7.5/46 NR -4.6* 7.3 -12.5* NR

15/92 NR -5.6* 11.9* -13.7* NR

P<0.05 vs. placeboAllison DB, et al. Obesity 2011;20:330-342. Gadde KM, et al. Lancet 2011;377:1341-1352.Garvey TW, et al. Am J Clin Nutr 2012;95:297-308.

Phentermine/TopiramateStudy Group Depression(%) Anxiety(%) Irritability (%)

EQUIP

PBO 1.2 1.2 0.6

3.75/23 3.3 2.9 1.7

15/92 4.7* 3.7* 4.5*

CONQUERPBO 3 2 <1

7.5/46 3 2 3*

15/92 3 4 3*

SEQUEL

PBO 7.9 3.1 NR

7.5/46 3.9 6.5 NR

15/92 8.1 9.5 NR

Allison DB, et al. Obesity 2011;20:330-342. Gadde KM, et al. Lancet 2011;377:1341-1352.Garvey TW, et al. Am J Clin Nutr 2012;95:297-308.P<0.05 vs. placebo

Summary

Obesity associated with increase CV risk

Patients taking current anti-obesity medications should be monitored for risk• CV endpoints• Psychiatric endpoints

No significant differences seen between medications vs. placebo for risk of depression/suicidality

Current Pharmacotherapy

SF has returned for a follow-up visit following recent initiation of lorcaserin for weight loss. While reading online regarding weight loss medications, she found reports of valvulopathy associated with multiple weight loss medications not currently on the market. She states that she is tolerating the lorcaserin, but she is now worried that she will develop valvulopathy. Additionally, SF is worried that continuing therapy will cause her depression to become uncontrolled.

What is the most appropriate response to SF regarding her risk of

valvulopathy? Test SF for genetic variations in bone morphogenetic protein receptor type 2

(BMPR2); if it returns positive, stop loracaserin as SF may be at increased risk for developing valvulopathy.

Stop lorcaserin; she is likely to develop valvulopathy due to since lorcaserin activates the 5HT2B receptor.

Continue lorcaserin; she is less likely to develop valvulopathy since lorcaserin activates the 5HT2C receptor.

Continue lorcaserin; she is less likely to develop valvulopathy since lorcaserin antagonizes the 5HT2C receptor.

A

B

C

D

What is the most appropriate response to SF regarding psychiatric

symptoms?Lorcaserin has not been found to worsen depressive

symptoms when compared to placebo.

Lorcaserin has been found to increase depressive symptoms compared to placebo.

Lorcaserin has been shown to cause increase risk of suicidality.

Lorcaserin has shown to cause increase risk of anxiety.

A

B

C

D

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biological link. Biomed Pharmacother 2007;61:665-678. 3. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009–2010. NCHS

data brief, no 82.Hyattsville, MD: NationalCenter for HealthStatistics. 2012.4. Dorner TE, Rieder A. Obesity paradox in elderly patients with cardiovascular disease. Int J Cardiol

2012;155:56-65.5. Masters RK, Powers DA, Link BG. Obesity and US Mortality Risk Over the Adult Life Course. Am J

Epidemiol 2013;177(5):431-332.6. Charakida M and Finer N. Drug Treatment of Obesity in Cardiovascular Disease. Am J Cardiovasc Drugs

2012;12(2):93-104.7. Mancia G, De BG, Dominiczak A, et al. Guidelines for the Management of Arterial Hypertension of the

European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25(6):1105-1187.

8. Straznicky N, Grassi G, Esler M, et al. European Society of Hypertension Working Group on Obesity antihypertensive effects on weight loss: myth or reality. J Hypertens 2010;28(4):637-643.

9. Aucott L, Gray D, Rothnie H, et al., for the PROGRESS group. Effects of lifestyle interventions and long-term weight loss on lipid outcomes: a systematic review. Obesity Reviews 2011;12:e412-425.

10. Sjostrom CD, Lystig T, Lindroos AK. Impact of weight change, secular trends, and ageing on cardiovascular risk factors. Int J Obes (Lond) 2011;35:1413-1420.

11. Colman E. Food and Drug Administration’s Obesity Drug Guidance Document: a short history. Circulation 2012;125(17):2156-2164.

References

12. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:25S-32S.

13. Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L. Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest 2000;117:870-874.

14. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111-117.15. Connoly HM, Crary JL, McGoon JL, et al. Valvular heart disease associated with

fenfluramine-phentermine. N Engl J Med 1997;337:581-588. 16. Sachdev M, Miller WC, Ryan T, Jollis JG. Effect of fenfluramine-derivative diet pills on cardiac

valves: a meta-analysis of observational studies. Am Heart J 2002;144:1065-1073. 17. Rothman RB, Michael H, Baumann MH, et al. Evidence for possible involvement of 5HT2B

receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 2000;101:2836-2841.

18. Rajamannan NM, Caplice N, Anthikad F, et al. Cell proliferation in carcinoid valve disease: a mechanism for serotonin effects. J Heart Valve Dis 2001;10:827-831.

19. James WP, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010;363(10):905-917.

20. McNeely W, Goa KL. Sibutramine. A review of its contribution to the management of obesity. Drugs 1998;56(6):1093-1124.

References 21. Ling H, Lenz TL, Burns TL, Hilleman DE. Reducing the Risk of Obesity: Defining the Role of Weight Loss Drugs.

Pharmacotherapy 2013; doi:10.1002/phar.1277. 22. Kaplan LM. Pharmacologic Therapies for Obesity. Gasteroenterol Clin N Am 2010;39:69-79. 23. Kang JG, Park CY. Anti-Obesity Drugs: A Review of Their Effects and Safety. Diabetes Metab J 2012;36:13-25. 24. Cercato C, Roizenblatt VA, Leanca CC, et al. A randomized double-blind placebo-controlled study of the long-term

efficacy and safety of diethylpropion in the treatment of obese subjects. Int J Obes (Lond) 2009;33:857-865.25. Torgerson JS, Boldrin MN, Hauptman J, Sjostrom L. XENical in the Prevention of Diabetes in Obese Subjects

(XENDOS). Diabetes Care 2004;27:155-161.26. Derosa G, Cicero FG, D’Angelo A, Fogari E, Maffioli P. Effects of 1-year orlistat treatment compared to placebo on

insulin resistance parameters in patients with type 2 diabetes. J Clin Pharm Ther 2012;37:187-195. 27. Fidler MC, Sanchez M, Raether B, et al. A One-Year Randomized Trial of Lorcaserin for Weight Loss in Obese and

Overweight Adults: The BLOSSOM Trial. Clin Endocrinol Metab 2011;96:3067-3077. 28. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized, Placebo-Controlled Clinical Trial of Lorcaserin for Weight

Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study. Obesity 2012;20(7):1426-1436.29. Smith S, Weissman NJ, Anderson CM et al. Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight

Management. NEJM 2010;363:245-256.30. Allison DB, Gadde KM, Garvey TW et al. Controlled-Release Phentermine/Topiramate in Severely Obese Adults: A

Randomized Controlled Trial (EQUIP). Obesity 2011;20:330-342. 31. Gadde KM, Allison DB, Ryan DH, et al. 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. Lancet 2011;377:1341-1352.

32. Garvey TW, Ryan DH, Look M, et al. 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. Am J Clin Nutr 2012;95:297-308.

obesity safety review emily m. armstrong, pharmd, bcacp assistant clinical professor auburn...

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