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THE PRESENT AND FUTURE

REVIEW TOPIC OF THE WEEK

Cardiovascular Effects of theNew Weight Loss Agents

Matthew H. Vorsanger, MD,a Pritha Subramanyam, MD,b Howard S. Weintraub, MD,a Steven H. Lamm, MD,c

James A. Underberg, MD,c Eugenia Gianos, MD,a Ira J. Goldberg, MD,d Arthur Z. Schwartzbard, MDa

ABSTRACT

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The global obesity epidemic and its impact on cardiovascular outcomes is a topic of ongoing debate and investigation in

the cardiology community. It is well known that obesity is associated with multiple cardiovascular risk factors. Although

life-style changes are the first line of therapy, they are often insufficient in achieving weight loss goals. Liraglutide,

naltrexone/bupropion, and phentermine/topiramate are new agents that have been recently approved to treat obesity,

but their effects on cardiovascular risk factors and outcomes are not well described. This review summarizes data

currently available for these novel agents regarding drug safety, effects on major cardiovascular risk factors, impact on

cardiovascular outcomes, outcomes research that is currently in progress, and areas of uncertainty. Given the impact of

obesity on cardiovascular health, there is a pressing clinical need to understand the effects of these agents beyond

weight loss alone. (J Am Coll Cardiol 2016;68:849–59) © 2016 by the American College of Cardiology Foundation.

W ith the designation of obesity as a dis-ease by the American Medical Associa-tion in 2013, 35% of adults in the United

States became bearers of a chronic illness associatedwith adverse cardiovascular outcomes—and one thatis mandated by consensus guidelines to require treat-ment (1,2). Obesity, through either associations withother disease states (e.g., dyslipidemia, diabetes, hy-pertension, obstructive sleep apnea) or direct endo-crinologic, inflammatory, and prothrombotic effects,is an important contributor to the global burden ofcardiovascular disease (3–8).

Despite advice on caloric restriction and increasedphysical activity, the majority of obese patients either

m the aDivision of Cardiology, Department of Medicine, New York Unive

ivision of General Internal Medicine, Department of Medicine, The Moun

neral Internal Medicine, Department of Medicine, New York University La

epartment of Medicine, Division of Endocrinology, New York Universit

. Weintraub has received research funding from Amarin and Sanofi; has serv

s been a speaker for Gilead, Amgen, and AstraZeneca. Dr. Lamm has rec

bvie, and Endo; and has served on the Speakers Bureau for Eisai. Dr. Und

traZeneca, Regeneron, Amgen, Sanofi, Genzyme, Merck, Synageva, Alexion

n, AstraZeneca, Eli Lilly, Sanofi, Alexion, Synageva, Amgen, Recombine, and

gen, Sanofi, Eli Lilly, Genzyme, Regeneron, Astra Zeneca, and Aegerion;

nzyme, and Aegerion. Dr. Goldberg has consulted for Amgen, Sanofi, and M

d ISIS Pharmaceuticals. Dr. Schwartzbard has received research support to

other authors have reported that they have no relationships relevant to th

nuscript received May 11, 2016; accepted June 13, 2016.

fail to lose weight or regain weight that is lost. Asan adjunct to life-style modification, medicationsapproved by the Food and Drug Administration (FDA)for the treatment of obesity include orlistat, lorcaserin,phentermine/topiramate, liraglutide, and naltrexone/bupropion (9–13). However, the effect of these agentson cardiovascular risk factors and outcomes has notbeen well described. As nonpharmacological weightloss is known to have beneficial effects on cardiovas-cular risk factors, the effects of pharmacologicalweight loss agents on these parameters is important todistinguish from the effects produced fromweight lossalone. Previously approved weight loss agents, suchas sibutramine and fenfluramine, despite showing

rsity Langone Medical Center, New York, New York;

t Sinai Hospital, New York, New York; cDivision of

ngone Medical Center, New York, New York; and the

y Langone Medical Center, New York, New York.

ed as a consultant for Amgen, Sanofi, and Gilead; and

eived consulting fees from Eisai, Alkermes, Takeda,

erberg has received Speakers Bureau honoraria from

, and Aegerion; has served as a consultant for Aege-

Amarin; has served on the advisory boards for Akcea,

and has been involved in clinical research for Pfizer,

erck; and has received research support from Janssen

New York University from Merck, Pfizer, and Sanofi.

e contents of this paper to disclose.

ABBR EV I A T I ON S

AND ACRONYMS

BMI = body mass index

FDA = Food and Drug

Administration

GLP = glucagon-like peptide

HbA1c = glycosylated

hemoglobin

HDL-C = high-density

lipoprotein cholesterol

HR = hazard ratio

hsCRP = high-sensitivity

C-reactive protein

LDL-C = low-density

lipoprotein cholesterol

POMC = pro-opiomelanocortin

SBP = systolic blood pressure

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efficacy for weight loss, were withdrawn fromthe market due to adverse cardiovascular ef-fects (increased myocardial infarction andstroke with sibutramine, valvular heart dis-ease and pulmonary hypertension with fen-fluramine) (14–16).

The recent approval of 2 new weight lossmedications, a naltrexone/bupropion combi-nation and liraglutide, raises an importantquestion as to the true impact of these agentson cardiovascular risk factors and outcomes.Using the available evidence, this review fo-cuses on the known effects of these medica-tions on cardiovascular risk factors as well asclinical cardiovascular outcomes, reviewsimportant safety data, and highlights areaswhere a knowledge gap exists.

LIRAGLUTIDE

WEIGHT LOSS EFFECTS. Liraglutide (Saxenda, NovoNordisk, Bagsværd, Denmark) is a glucagon-likepeptide (GLP)-1 receptor agonist, a modified form ofhuman GLP-1 with enhanced albumin binding, self-oligomerization, and resistance to breakdown bydipeptidyl peptidase 4 (17). Liraglutide exerts its ac-tion through binding the GLP-1 receptor on pancre-atic beta cells, increasing their sensitivity to glucose.It also suppresses glucagon production by pancreaticalpha cells, diminishing hepatic gluconeogenesis,inhibiting gastric emptying, and promoting satietyand weight loss (18). Liraglutide also binds to GLP-1receptors located in the arcuate nucleus of the hy-pothalamus, as well as mesolimbic neurons, acting onknown central pathways of hunger and satiety(Central Illustration) (19,20). Originally approved forthe treatment of type 2 diabetes mellitus on the basisof the LEAD (Liraglutide Effect and Action in Dia-betes) series of trials, liraglutide was noted to pro-mote significant weight loss at a dose of 1.8 mg daily(21). A phase II weight loss trial evaluating liraglutideat doses up to 3 mg daily also showed favorable re-sults compared with orlistat and placebo, promptingthe phase III SCALE (Satiety and Clinical Adiposity -Liraglutide Evidence in Nondiabetic and Diabetic In-dividuals) trials (12). The SCALE Maintenance, SCALEObesity and Prediabetes, and SCALE Diabetes trialsshowed placebo-adjusted weight loss ranging from4.0% to 6.1% of initial body weight (22–24). Liraglu-tide was approved by the FDA in 2014 for the treat-ment of obesity in patients with a body mass index(BMI) >30 kg/m2 or >27 kg/m2 with an obesity-relatedcomorbidity and can be used in patients with known

cardiovascular disease (25). The dose of liraglutideapproved for weight loss is 3 mg injected once daily,compared with 0.6 to 1.8 mg daily for the treatmentof diabetes.

CARDIOMETABOLIC VARIABLES. Glycemic ef fects .The beneficial effects of liraglutide on blood sugar arewell documented, and the phase III LEAD studiesshowed its efficacy in treating type 2 diabetes melli-tus, with reductions in glycosylated hemoglobin(HbA1c) ranging from 0.33% to 1.85%, dependingon the comparator (26–32). Additionally, the SCALEtrials showed a reduction in HbA1c of 0.2% to 0.9%with liraglutide compared with placebo (22–24). Anatural concern with the use of a diabetic agent is theincidence of hypoglycemia, particularly in nondiabeticpatients. This is of particular concern, as hypoglycemiais known to be a risk factor for cardiovascular events(33). Although the incidence of symptomatic hypo-glycemia was not significantly different betweengroups in the SCALE Obesity and Prediabetes trial(1.3%with liraglutide vs. 1.0%with placebo), there wasan increased incidence with liraglutide in the SCALEMaintenance trial (5.2% vs. 2.4%) (22,23). The risk ofhypoglycemia was also increased by liraglutide indiabetic patients in the SCALE Diabetes trial (87 per100 patient-years vs. 31 per 100 patient-years) (24).L ip id effects . The effects of liraglutide on the lipidprofile have also been examined. A network meta-analysis of 35 trials showed a mean decrease inhigh-density lipoprotein cholesterol (HDL-C) of 0.4mg/dl, a decrease in low-density lipoprotein choles-terol (LDL-C) of 4.6 mg/dl, a decrease in totalcholesterol of 6.2 mg/dl, and a decrease in tri-glycerides of 23 mg/dl (34). The SCALE trials showed areduction in triglycerides (�10 to �25 mg/dl), aswould be expected from an agent improving glycemiccontrol, and more neutral effects on HDL-C (neutralto þ3 mg/dl) and LDL-C (�4 to þ3 mg/dl) (22–24).Blood pressure and heart rate effects . Regardingliraglutide’s effects on blood pressure, a patient-levelmeta-analysis of the LEAD trials showed that lir-aglutide treatment resulted in a systolic blood pres-sure (SBP) reduction of approximately 2.8 mm Hg, asopposed to 0.5 mm Hg with placebo. Treatment wasalso associated with an increase in heart rate of3 beats/min (35,36). In the SCALE trials, a minorimprovement was seen in blood pressure with lir-aglutide over placebo, with decreases in SBP of be-tween 2.6 and 3.1 mm Hg (22–24). Of potentialconcern, heart rate in the SCALE trials generallyincreased with liraglutide when compared with pla-cebo (þ0.6 to þ3.5 beats/min). Increases in heart ratehave been previously noted with sympathomimetic

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weight loss agents, which were associated withadverse cardiovascular effects (37).Inflammatory markers . The effects of liraglutide oninflammatory markers and hormones associated withobesity have also been evaluated. In a study of obesediabetic patients treated with liraglutide for 2 weeks,there were no significant changes in leptin, adipo-nectin, tumor necrosis factor-alpha, or interleukin-6.However, plasma levels of the insulin-mimetic hor-mone visfatin and the insulin desensitizer resistinwere both significantly higher following treatment(38). Another study of 6 months of liraglutide treat-ment showed that liraglutide decreased levels of theinsulin sensitizer adiponectin and increased levels ofthe inflammatory protein pentraxin-3 (39). Obesewomen with polycystic ovarian syndrome showed asignificant decrease in levels of high-sensitivityC-reactive protein (hsCRP), urinary isoprostanes,platelet P-selectin, and serum endothelial adhesionmarkers with liraglutide treatment (40). Liraglutidealso improves markers of oxidative stress byincreasing glutathione and decreasing lipid hydro-peroxides and heme oxygenase-1 (41). Additionally,the SCALE Diabetes study showed significant de-creases in hsCRP, increases in fibrinogen, and nochange in adiponectin (24).

SAFETY AND CARDIOVASCULAR OUTCOMES.

Regarding clinical cardiovascular outcomes, a reviewpublished in Circulation discusses in depth the role ofGLP-1 receptor agonists in the treatment of cardio-vascular disease (42). In the SCALE trials of liraglutidefor weight loss, which followed a combined 4,999patients for an average of 56 weeks, serious cardiacevents (such as acute coronary syndrome and cardiacdeath) were rare and occurred less frequently in theliraglutide than in the placebo groups. In the SCALEMaintenance trial, there was 1 death due to heartfailure in the placebo group and no serious cardiacevents in the liraglutide group (22). In the SCALEDiabetes trial, an acute coronary syndrome occurredin 1 patient in the liraglutide 3-mg group, 2 patients inthe liraglutide 1.8-mg group, and 2 patients in theplacebo group; the single death in the trial occurredin a patient in the liraglutide 1.8-mg group, due topulmonary embolism and embolic stroke (24). In theSCALE Obesity and Prediabetes trial, the rate of acomposite of cardiovascular events was 8.7% in theliraglutide group and 9.9% in the placebo group—thisincluded 2 nonfatal myocardial infarctions and 1 car-diovascular death in the liraglutide group, comparedwith 1 nonfatal myocardial infarction and 1 cardio-vascular death in the placebo group (23). Designed onthe premises that GLP-1 receptors are present in

cardiomyocytes and that small short-term studieswith GLP-1 receptor agonists have shown improve-ment in cardiac function and hemodynamics, therecently completed LIONESS (Liraglutide to ImproveCoronary Haemodynamics During Exercise Stress)study will describe the effect of liraglutide comparedto placebo on exercise stress test parameters in pa-tients with chronic stable angina. Additionally, asmall study assessing the effects of short-term lir-aglutide administration during acute non–ST-segment elevation myocardial infarction showedsmall but significant benefits in ejection fraction at 3months (43). Current clinical evidence, drawn frompooled data from the LEAD liraglutide trials fordiabetes (at a target dose of 1.8 mg daily) includes6,638 patients, and shows a nonsignificant trendtoward a decrease in cardiovascular events (inci-dence ratio: 0.73; 95% confidence interval: 0.38 to1.41) (44). The FIGHT (Functional Impact of GLP-1for Heart Failure Treatment) trial evaluated the useof liraglutide (at a target dose of 1.8 mg daily)compared to placebo in high-risk heart failurepatients with reduced ejection fraction. There wasno significant difference in time to death or heartfailure hospitalization between groups, with pointvalues favoring the placebo group (hazard ratio[HR]: 1.296 for liraglutide; p ¼ 0.142) (45).

To provide further insight into the effect of lir-aglutide on cardiovascular outcomes, the LEADER(Liraglutide Effect and Action in Diabetes: Evaluationof Cardiovascular Outcome Results) trial examinedapproximately 9,300 diabetic patients at high risk forcardiovascular disease. The patients were random-ized to usual care plus either liraglutide (at a targetdose of 1.8 mg daily) or placebo, and followedfor 5 years for a primary composite endpoint of car-diovascular death, nonfatal myocardial infarction, ornonfatal stroke (46). The results of this trial wererecently published, showing superiority for liraglu-tide for the primary endpoint (HR: 0.87 for liraglu-tide; p ¼ 0.01 for superiority) (47). Additionally, therates of death from cardiovascular causes and deathfrom any cause were significantly lower in the lir-aglutide group (HR: 0.78 and 0.85, respectively). It isimportant to note that 81.3% of patients included hadestablished cardiovascular disease at baseline andderived a significantly greater benefit from liraglutidein subgroup analysis. However, patients with anacute coronary or cerebrovascular event in the pre-vious 14 days were excluded from the study. Thereare currently neither outcomes data available for the3-mg dose of liraglutide approved for weight loss norongoing studies examining cardiovascular outcomeswith this dose.

CENTRAL ILLUSTRATION Central Effects of the New Weight Loss Agents

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NALTREXONE/BUPROPION

WEIGHT LOSS EFFECTS. The naltrexone/bupropioncombination (Contrave, Orexigen Therapeutics, LaJolla, California) is comprised of a m-opioid receptorantagonist and a dopamine and norepinephrine re-uptake inhibitor. Naltrexone is approved as mono-therapy for opioid addiction and alcohol dependence,whereas bupropion is approved as monotherapy fordepression, smoking cessation, and seasonal affectivedisorder (48). The mechanism of action of the com-bination relates to complex central pathways ofreward and satiety. Pro-opiomelanocortin (POMC)cells in the arcuate nucleus of the hypothalamusplay an important role in increasing energy expendi-ture, and reducing food intake and body weightvia production of a-melanocyte-stimulating hor-mone (49,50). However, the endogenous opioid,b-endorphin, is also released by POMC cells andmediates an autoinhibitory feedback loop via them-opioid receptor, mitigating POMC-induced weightloss (51). Bupropion increases the activity of POMCcells, whereas naltrexone blocks the opioid-drivenautoinhibitory feedback loop (Central Illustration)(52,53). Although both agents had been previouslystudied as monotherapy for weight loss, results weredisappointing: naltrexone monotherapy studies hadgenerally shown no benefit as compared to placebo,whereas bupropion studies had shown modest weightloss only (on the order of 2% to 4%), with a relativelyearly plateau in improvement (53–60). Pilot studies ofthe naltrexone/bupropion combination showed a sig-nificant weight reduction as compared with placebo(approximately 4% to 5%) (53,56). This, in turn, ledto the phase III COR (Contrave Obesity Research)trials: COR-I, COR-II, COR-Diabetes, and COR-BMOD(Contrave Obesity Research Behavior Modification),which demonstrated placebo-adjusted weight lossesat 56 weeks, ranging between 2.5% and 5.2% of initialbody weight, at the currently approved target dose ofnaltrexone/bupropion (13,61–63). These studies led toFDA approval of naltrexone/bupropion in 2014 for thetreatment of obesity with a BMI >30 kg/m2 or >27kg/m2 with an obesity-related comorbidity, at a target

CENTRAL ILLUSTRATION Continued

Liraglutide acts on glucagon-like peptide-1 receptors in the arcuate nuc

opiomelanocortin cells, whereas naltrexone blocks the autoinhibitory fe

norepinephrine uptake in several areas of the hypothalamus, including

multiple channels, including voltage-gated sodium (Naþ) and calcium (C

kainate receptors, and gamma-aminobutyric acid (GABAA) receptors. MC

Figure adapted in part from Christou GA, Kiortsis DN. The efficacy and

update. Hormones (Athens). 2015;14:371.

dose of 16 mg naltrexone and 180 mg bupropion orallytwice daily (64). Of note, naltrexone/bupropion iscontraindicated in patients with uncontrolled hyper-tension but can otherwise be prescribed to patientswith known cardiovascular disease.

CARDIOMETABOLIC VARIABLES. The effects ofnaltrexone/bupropion on cardiovascular risk factorshave been evaluated through analysis of bloodglucose, lipid profile, blood pressure, and heart rate.Glycemic effects . The effect of naltrexone/bupro-pion on glucose metabolism has ranged from neutralto slightly favorable in the COR trials, although to alesser degree than liraglutide (change in HbA1c

neutral to �0.5%) (13,61–63).L ip id effects . The effects on the lipid profile ofnaltrexone/bupropion have also been characterizedand are overall favorable, with placebo-adjustedincreases in HDL-C (þ3 to þ5 m/dl) and decreases inboth LDL-C (�1 to �4 mg/dl) and triglycerides (�11 to�15 mg/dl) (13,61–63).

Blood pressure and heart rate effects . Incontrast, the effects of naltrexone/bupropion onblood pressure and heart rate appear to be relativelyunfavorable. In the COR trials, when compared toplacebo, there was an increase in SBP (þ1.1 to þ2.6mm Hg). Heart rate also increased with naltrexone/bupropion (þ0.8 to þ1.1 beats/min) (13,61–63). Thesefindings are consistent with previously documentedeffects of bupropion monotherapy on blood pressureand heart rate, thought to be mediated by its effectson dopamine and norepinephrine (65).

Inflammatory markers . Data on the effects ofnaltrexone/bupropion or its individual componentson inflammatory markers and obesity-related hor-mones are inconsistent. There were significantplacebo-adjusted reductions in hsCRP of 12.3% and20.5% with naltrexone/bupropion in COR-I and COR-II, respectively, but no significant change in COR-BMOD or COR-Diabetes (13,61–63). A trial to evaluatethe effect of naltrexone on antipsychotic-inducedweight gain is currently in the recruitment phase andalso plans to evaluate naltrexone’s effects on markerssuch as leptin, ghrelin, peptide YY, adiponectin,

leus of the hypothalamus. Bupropion also acts in the arcuate nucleus on pro-

edback loop mediated by the m-opioid receptor (MOP-R). Phentermine blocks

the arcuate nucleus and the ventromedial nucleus. Topiramate has effects on

a2þ) channels, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/

4R ¼ melanocortin-4 receptor; MSH ¼ melanocyte-stimulating hormone.

safety of the naltrexone/bupropion combination for the treatment of obesity: an

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interleukin-6, interleukin-1B, interleukin-18, andtumor necrosis factor-a (66). Several case reports sug-gest a potential role for bupropion in lowering tumornecrosis factor-a (67,68).

ADDICTION-REWARD PATHWAYS. Naltrexone/bupropionmay have unique benefits related to its effects onaddiction-reward pathways, and the indications of itscomponents in the treatment of alcohol dependenceand smoking cessation (48). In 2 open-label studies ofcigarette smokers, naltrexone/bupropion resulted incomplete tobacco abstinence in 30% to 40% of par-ticipants during the study period, with minimizationof the weight gain that typically accompanies tobaccocessation (69,70). Because tobacco is a major riskfactor for cardiovascular disease, naltrexone/bupro-pion may impact cardiovascular outcomes exclusiveof other beneficial cardiometabolic effects. Addition-ally, alcohol consumption has been linked to weightgain and obesity (71). Naltrexone treatment of alcoholdependence might provide additional benefit forthose attempting to abstain from alcohol as part of aweight loss strategy (72). Finally, consistent withbupropion’s effects in treating depression,naltrexone/bupropion alleviates depressive symp-toms and facilitates weight loss in patients withobesity and depression, an important considerationgiven the association of depression with adversecardiovascular outcomes (73–75).

SAFETY AND CARDIOVASCULAR OUTCOMES. TheCOR trials enrolled a total of 4,536 patients, followedfor an average of 56 weeks, and generally reportedvery low rates of cardiovascular events in both groups(13,61–63). The COR trials were not powered to assessthese outcomes and did not reveal any statisticallysignificant trends either in favor of or against theactive treatment. In May 2012, Orexigen Therapeuticsinitiated the LIGHT study to specifically determinethe impact of naltrexone/bupropion on clinical car-diovascular outcomes in high-risk obese patients,originally scheduled for completion in 2017 (76).However, in March 2015, as part of a patent filing withthe Securities and Exchange Commission, Orexigendisclosed portions of the 50% interim analysis of theLIGHT study in a manner that was deemed to beinappropriate by the FDA (77). Instead of the initialFDA-mandated target of excluding a doubling ofcardiovascular risk with naltrexone/bupropion, theinitial 25% data suggested a 41% reduction in death,stroke, and heart attack, whereas the next 25% datasuggested neutral results (78). The FDA publiclyrebuked Orexigen for this, stating that the disclosurewas broader than required, with potentiallymisleading data that could compromise the ability to

successfully complete the LIGHT trial (79). Followingthis, in May 2015, Orexigen Therapeutics announcedthe early termination of the LIGHT trial. The results ofthe trial were recently published and used data ob-tained after accrual of 50% of the originally plannedevents for the primary analysis (80). The in-vestigators were unable to meet their pre-designatedcriteria for noninferiority, the exclusion of a hazardratio of 1.4 for major adverse cardiovascular events,with an event rate of 2.3% in the placebo group versus2.0% in the naltrexone/bupropion group (HR: 0.88).Individual components of the primary endpoint werealso not significantly different between the 2 groups.It was noted that SBP and heart rate were both higherin the naltrexone/bupropion group compared withthe placebo group, with differences of 0.46 mm Hgand 0.45 beats/min, respectively. Also of note, only64% of the treatment group remained on the studydrug by 16 weeks, leading to a between-group differ-ence in body weight of only 2.5%. As such, physiciansare left without clear answers as to the question ofcardiovascular outcomes with naltrexone/bupropion.The authors acknowledge that another trial will berequired to meet the FDA’s regulatory mandate butwould not be available for at least 3 years.

PHENTERMINE/TOPIRAMATE

WEIGHT LOSS EFFECTS. The phentermine/topiramatecombination (Qsymia, VIVUS, Mountain View, Cali-fornia) was the first drug approved for the long-termmanagement of obesity (81). Of its components, thesympathomimetic amine phentermine acts to blockreuptake of norepinephrine to suppress appetite andincrease energy expenditure (82). Although limitedby adrenergic side effects, phentermine monotherapyresulted in placebo-adjusted weight loss of w7 kg,and was approved in 1959 by the FDA for the short-term treatment of obesity (83,84). The sulfamate-substituted monosaccharide topiramate is tradition-ally viewed as an antiepileptic agent (CentralIllustration). It has several postulated mechanisms ofweight loss, including appetite reduction from alteredneuropeptide Y levels and decreased adipose fat massassociated with reduction in lipoprotein lipase activ-ity (85,86). Although topiramate monotherapy cancause weight loss of 2.2% to 5.3% of initial bodyweight, the dose used is greater than that containedin the maximum dose of phentermine/topiramate(87–93). With the theory that lower doses of theagents in combination would show both improvedweight loss and tolerability, phentermine/topiramatewas tested in 4 phase III clinical trials: EQUIP,EQUATE, CONQUER, and the CONQUER extension

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study, SEQUEL. Placebo-adjusted weight loss rangedbetween 7.5% and 9.3% at the target dose of the drugcombination (94–97). These studies led to theapproval of the phentermine/topiramate combinationin 2012 for the treatment of obesity with a BMI >30kg/m2 or >27 kg/m2 with an obesity-related comor-bidity, at a maximum dose of 15 mg phentermine and92 mg topiramate orally once daily (98). It is impor-tant to note that the labeling information for phen-termine/topiramate states that its use is notrecommended in patients with recent or unstablecardiac syndromes.

CARDIOMETABOLIC VARIABLES. The randomizedtrials involving phentermine/topiramate also providevaluable information regarding its impact on media-tors of cardiometabolic risk.Glycemic effects . Measures of glycemic controlmodestly improved, with a decrease in HbA1c of 0.1%to 0.2% (94–97). In diabetic patients, phentermine/topiramate showed a significant placebo-adjusted0.4% decrease in HbA1c, as well as a significantlydecreased need for other diabetic agents (99). Afurther analysis of patients in the SEQUEL trial withpre-diabetes or metabolic syndrome showed areduction of 78.7% in the annualized incidence rate ofdeveloping diabetes (100).

L ip id effects . Similar to the other weight loss agentsdescribed, phentermine/topiramate has a beneficialeffect on HDL-C (þ2 to þ4 mg/dl) and triglycerides(�17 to �24 mg/dl), with a neutral effect on LDL-C(�4 to þ6 mg/dl) (94–97).

Blood pressure and heart rate effects . AlthoughSBP generally decreased with phentermine/top-iramate (�1.1 to �3.8 mm Hg), the effect on diastolicblood pressure was neutral (�1.9 to þ0.4 mm Hg)(94–97). As with the other agents described in thisreview, heart rates were increased in the phenter-mine/topiramate group compared with placebo (þ0.3to þ1.8 beats/min) (94–97). Increased heart rates areconsistent with the known sympathomimetic effectsof phentermine, and have led to specific cautionregarding tachycardia in the prescribing informationfor phentermine/topiramate (98).

Inflammatory markers . The effect of phentermine/topiramate on inflammatory markers has also beenstudied. The CONQUER trial showed a reduction inhsCRP of 1.7 mg/l, as well as an increase in adipo-nectin of 1.75 mg/ml, whereas the SEQUEL trialconfirmed a similar increase in adiponectin, but nosignificant change in hsCRP (95,97). A study specif-ically looking at the effects of phentermine/topiramate on obstructive sleep apnea showed a sig-nificant placebo-adjusted decrease of 14.9 in the

apnea-hypopnea index, which was correlated withthe weight loss achieved (101).

SAFETY AND CARDIOVASCULAR OUTCOMES. Clin-ical trials on phentermine/topiramate have included atotal of 5,186 patients who were followed for 28 to 108weeks, depending on the individual study. As withthe other weight loss agents, the rate of cardiovas-cular events was low, with no major cardiovascularevents reported in the phentermine/topiramate groupin any study (94–97). Overall, these trials were notpowered for the assessment of cardiovascular end-points, and, as of yet, no pooled analysis or pro-spective study exists addressing this question.

CONCLUSIONS

Obesity remains a highly prevalent disease and amajor modifiable risk factor for adverse cardiovascu-lar outcomes. In the past few years, the FDA hasapproved several antiobesity agents with diversemechanisms of action for weight loss. Because pre-viously approved pharmaceutical agents had beenshown to cause adverse cardiovascular outcomes,despite being effective for weight loss, the FDA hasset a higher bar for current agents, requiring morestringent assessment of safety, as well as post-approval outcomes studies. Given the pressing needfor effective and safe pharmacological agents to treatobesity, as well as the difficulties and delaysdemonstrated thus far with cardiovascular outcomesstudies, it is of crucial importance to understand theeffects of the new weight loss agents on the car-diometabolic risk profile (Table 1).

Although therapeutic life-style changes remain thepreferred initial strategy for weight loss, a significantproportion of obese patients fail to lose weight withthese measures alone, or regain the weight that islost, and it is for these patients that pharmacologicalweight loss agents are indicated. The agents dis-cussed in this review show generally favorable effectson cardiometabolic risk factors, including glycemicand lipid parameters. However, it is important tocompare findings seen with these weight loss agentswith those seen in patients achieving a similar degreeof weight loss through nonpharmacological means(102–104). For the most part, the changes in car-diometabolic parameters seen with the weight lossmedications are less impressive than those thatwould be achieved with similar degrees of non-pharmacological weight loss. In terms of glycemicmeasures, only liraglutide, as might be expected froma proven diabetic agent, potentially produces animprovement in HbA1c over a similar degree of non-pharmacological weight loss. Beneficial changes to

TABLE 1 Summary of Characteristics of Weight Loss Agents

Drug Target Dosing ContraindicationsWeightLoss (%)

Cardiometabolic Effects(Placebo Adjusted) Common Adverse Reactions

Liraglutide 3 mg injected daily Personal or family historyof medullary thyroid canceror multiple endocrineneoplasiasyndrome type 2

Pregnancy

�6.0 to �8.0 HbA1c Y

(�0.2% to �0.9%)Triglycerides Y

(�10 to �25 mg/dl)Nausea, hypoglycemia,

diarrhea, constipation,vomiting, headache,decreased appetite,dyspepsia, fatigue,dizziness, abdominalpain, increased lipase

HDL-C [

(þ0 to þ3 mg/dl)LDL-C 4

(�4 to þ3 mg/dl)

SBP Y

(�2.6 to �3.1 mm Hg)Heart rate [

(þ0.6 to þ3.6 beats/min)

Naltrexone/bupropion

16 mg naltrexone/180 mg bupropionorally twice daily

Uncontrolled hypertension �3.6 to �9.3 HbA1c Y

(�0% to �0.5%)Triglycerides Y

(�11 to �15 mg/dl)Nausea, constipation,

headache, vomiting,dizziness, insomnia,dry mouth, diarrhea

Seizure disorder

Anorexia nervosa orbulimia

HDL-C [

(þ3 to þ5 mg/dl)SBP [

(þ1.1 to þ2.6 mm Hg)

Abrupt discontinuation ofalcohol, benzodiazepines,barbiturates, antiepilepticagents

Chronic opioid use LDL-C Y

(�1 to �4 mg/dl)Heart rate [

(þ0.9 to þ1.1 beats/min)Current or recent monoamineoxidase inhibitor use

Pregnancy

Phentermine/topiramate

15 mg phentermine/92 mg topiramateorally daily

HyperthyroidismGlaucomaCurrent or recent monoamine

oxidase inhibitor usePregnancy

�10.9 HbA1c Y

(�0.1% to �0.2%)Triglycerides Y

(�17 to �24 mg/dl)Paresthesia, dizziness,

dysgeusia, insomnia,constipation,dry mouth

HDL-C [

(þ2 to þ4 mg/dl)SBP Y

(�1.1 to �3.8 mm Hg)

LDL-C 4

(�4 to þ6 mg/dl)Heart Rate [

(þ0.3 to þ1.8 beats/min)

HbA1c ¼ glycosylated hemoglobin; HDL-C ¼ high-density lipoprotein cholesterol; LDL-C ¼ low-density lipoprotein cholesterol; SBP ¼ systolic blood pressure.

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the lipid profile are generally less than might be ex-pected with nonpharmacological weight loss as well,although both liraglutide and naltrexone/bupropionconfer an additional slight increase in HDL-C.For all agents studied, a greater degree of bloodpressure reduction would be expected with non-pharmacological weight loss. Of particular concern isthe paradoxical increase in heart rate also seen withall pharmacological agents. The magnitude of changein heart rate expected with nonpharmacologicalweight loss is not well described, but smaller seriesshow that nonpharmacological weight loss typicallyresults in lower heart rates from baseline (105,106).These comparisons highlight the multifaceted bene-fits of therapeutic life-style changes, while stressingthe important role of pharmacological weight lossfor the large group of patients for whom life-stylechanges are inadequate or not sustained.

Of additional concern, current data are limited tothe short-term effect of these agents on weight lossalone, with their major weight loss trials beingapproximately 1 year in duration. Long-term effects onweight loss are unfortunately unavailable, and clinicalcardiovascular outcomes have been adequately eval-uated only with liraglutide, but at a different dosethan that approved for weight loss. No trial has spe-cifically studied the effects of these agents at theapproved doses for weight loss on outcomes such as

atherosclerosis, heart failure, coronary artery disease,or diabetes. As such, physicians prescribing theseagents should inform patients of the full side effectprofile and highlight the absence of long-term out-comes data.

Questions that remain to be answered include thedirect comparison of weight loss agents, as well aslonger duration outcome trials. The FDA hasapproved these agents to meet an urgent clinicalneed, and it is important that prescribing physiciansare well versed in all aspects of their safety toeffectively incorporate them into practice. The careof the obese patient must be individualized, andshould always begin with therapeutic life-stylechanges. We believe that the balance of the evidence(both in terms of changes in cardiometabolic riskfactors and clinical cardiovascular outcomes,including the recent LEADER trial showing benefit incardiovascular outcomes in diabetic patients treatedwith liraglutide) favors the use of liraglutide over theother agents currently available, particularly in dia-betic patients. Due to its unique effects on addiction-reward pathways, naltrexone/bupropion may have aparticular niche in treating the obese patient withalcohol or nicotine dependence. For practitionerstreating patients with established cardiovasculardisease, it should be again noted that naltrexone/bupropion should not be used in patients with

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uncontrolled hypertension, and phentermine/topiramate should not be used in patients with recentor unstable cardiac syndromes. It remains importantfor prescribing physicians to be aware of contraindi-cations and adverse drug reactions and to strictlyadhere to the indications and dosing approved foreach drug.

REPRINT REQUESTS AND CORRESPONDENCE:

Dr. Arthur Schwartzbard, Clinical Lipid Research,NYU Center for Prevention of Cardiovascular Disease,Department of Medicine (Cardiology), 530 FirstAvenue, Suite 4F, New York, New York 10016. E-mail:arthur.schwartzbard@nyumc.org.

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KEY WORDS cardiovascular disease,obesity, pharmacology, prevention,risk factors