Received: 29 December 2020 Revised: 27 January 2021 Accepted: 1 February 2021

DOI: 10.1111/obr.13224

OBESITY PHARMACOTHERAPY

Cardiovascular safety of naltrexone and bupropion therapy:

Systematic review and meta-analyses

Andrei C. Sposito1,2 | Isabella Bonilha1 | Beatriz Luchiari1 |

Alexander Benchimol3 | Alexandre Hohl4 | Fabio Moura5 | Cíntia Cercato6 |
Bruno Geloneze2 | Wilson Nadruz1 | Carlos Aguilar-Salinas7 |
Luiz Sergio F. Carvalho1,8

1
Department of Cardiology, State University
of Campinas, Campinas, Brazil Summary
2
Obesity and Comorbidities Research Center, Despite being approved for clinical use, evidence of cardiovascular safety (CV) is
State University of Campinas, Campinas, Brazil
lacking for treatment with bupropion, naltrexone, or their combination (B-N).
3
Obesity and Eating Disorders Group, State
Institute of Diabetes and Endocrinology, Rio The purpose of the study is to determine the relationship between these treatments
de Janeiro, Brazil and the risk of major cardiovascular adverse events (MACE). Phase 3 randomized
4
Department of Clinical Medicine, Federal
clinical trials (RCT) evaluating bupropion, naltrexone, or B-N versus control with
University of Santa Catarina, Florianópolis,
Brazil reported incidence of MACE. The meta-analysis included 12 RCTs, 69% for weight
5
Endocrinology and Metabolism Department, loss and 29% for smoking cessation, with 19,176 patients and 7354 patient-years
University of Pernambuco, Recife, Brazil
6
who were randomized to an active treatment (bupropion [n = 2965] or B-N
Obesity and Metabolic Syndrome Group,
Division of Endocrinology and Metabolism, [n = 6980] or naltrexone [n = 249]) versus control (placebo [n = 6968] or nicotine
Clinical Hospital, School of Medicine, patch [n = 2014]). The mean age was 54 ± 8 years (55% female), and the baseline
University of S~ao Paulo, S~ao Paulo, Brazil
7 BMI was 32 ± 5 kg/m2. The additive network meta-analysis model for random effects
Department of Endocrinology and
Metabolism, National Institute of Medical showed no association between bupropion, B-N, or naltrexone and MACE (odds ratio
Sciences and Nutrition, Mexico City, Mexico
[OR] = 0.90 [95%CI 0.65–1.25], p = 0.52; OR = 0.97 [95%CI 0.75–1.24], p = 0.79;
8
Directory of Clinical Research and Innovation,
Institute for Strategic Management in OR = 1.08 [95%CI 0.71–1.63], p = 0.73, respectively; I2 = 0%, p = 0.86). Meta-
Healthcare, Brasília, Brazil regression analyses showed no significant association between MACE and potential
Correspondence confounders from RCT demographic disparities (p = 0.58). The statistical power (post
Andrei C. Sposito, Department of Cardiology, hoc two-tailed) for non-inferiority was 91%, giving a strong probability of validity.
State University of Campinas, Campinas,
Brazil. Naltrexone, bupropion, or B-N is not associated with the incidence of MACE as
Email: sposito@unicamp.br compared with placebo.

Funding information
KEYWORDS
Research Career Awards from the Brazilian
National Research Council (CNPq), Grant/ bupropion, cardiovascular risk, meta-analysis, naltrexone
Award Number: 301465/2017-7

1 | I N T RO DU CT I O N heart failure, cancer, and coronary or cerebrovascular atheroscle-

rotic disease.5
A set of genetic, epigenetic, behavioral, and inflammatory factors Although lifestyle change represents a logical way to counter
has triggered a disruption in the fine regulation of body energy obesity, this strategy alone proved to be insufficient for significant
balance, paving the worldwide obesity epidemic.1–3 In fact, and sustained weight loss.6 Hence, pharmacological and surgical
4
1.9 billion adults worldwide are overweight. This excess weight therapies have become essential tools in clinical practice.
has shortened life expectancy, mostly due to early manifestation of Unexpectedly, cardiovascular (CV) damage was directly related to

Obesity Reviews. 2021;1–9. wileyonlinelibrary.com/journal/obr © 2021 World Obesity Federation 1

2 SPOSITO ET AL.
some therapies for obesity,7,8 raising concern and complexity in
the therapeutic decision. Randomized placebo-controlled trials
(RCTs) have been conducted to rule out excess CV risk for several
therapies, but evidence of CV safety is still lacking for some of the
drugs that are in clinical use.
Combination therapy with naltrexone, an opioid antagonist, and
bupropion, a norepinephrine and dopamine reuptake inhibitor, has
been approved and used for the treatment of obesity in Europe and
the United States since 2014. Together, these drugs act on the
hypothalamus and the mesolimbic dopamine circuit, promoting
9
satiety and reducing food intake. The LIGHT clinical trial was
conducted to test the CV safety of the naltrexone–bupropion (N-B)
combination, but it was stopped prematurely with about 50% of the
originally planned endpoints, suggesting a modest 12% reduction in
10
favor of the combined therapy (p = ns). Due to the unplanned
early interruption, the study did not generate statistical power to
support CV safety with the therapy. Another clinical trial was
started but also stopped early due to sponsor issues.11 Despite this,
N-B therapy remains in clinical use, and no comprehensive
examination of its CV safety has been reported so far. Hence, we
used a combination of conventional and additive effects network
meta-analyses to investigate whether there is any sign of increasing
CV risk with these therapies using a wide spectrum of RCTs that
tested naltrexone, bupropion, or the combination to treat obesity,
smoking, and other clinical conditions. In addition, we used meta-
regression analyses to investigate potential sources of heterogeneity
between trials based on patients' characteristics
indications for the RCTs.
2 | METHODS
2.1 | Search strategy and study eligibility
This systematic review was planned and conducted according to
the Preferred Reporting Items for Systematic Reviews
Meta-Analyses (PRISMA).12 A detailed description of all the
procedures is included in the Supplementary Data. In short,
the review was performed by searching queries of literature using
the MEDLINE (PubMed), ClinicalTrials.gov, Cochrane
Register of Controlled Trials, Embase, European Union Clinical
Trials Register, and World Health Organization (WHO) International
Clinical Trials Registry Platform electronic database entries until
August 2020 in order to identify all RCTs that assessed the use of
bupropion, naltrexone, or the combined therapy. Studies were
included in the meta-analysis if they met all of the following
criteria: (1) randomized double-blinded controlled study design;
(2) study participants in the treatment group used bupropion,
naltrexone, or B-N therapy; and (3) the study should have
reported CV event incidence in both control and intervention
groups. The meta-analysis is registered in PROSPERO
(international prospective register of systematic
CRD42020197709).
2.2 | Data extraction and quality assessment
Data were extracted by two authors (IB and BL) and any inconsistencies
were resolved after debate with a third researcher (ACS). Extracted data
concerning patient characteristics and study results included year of
publication, authors, journal published, study design, characteristics of
patients, sample size, duration of intervention, drug dose, clinical out-
comes, mean weight loss, mean systolic and diastolic blood pressure,
mean fasting blood glucose, mean body mass index (BMI), and waist cir-
cumference as well as mean plasma levels of high-density lipoprotein
cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).
2.3 | Data synthesis and statistical analyses
The primary endpoint was defined as major adverse cardiovascular
events (MACEs) composed of CV death, nonfatal myocardial infarc-
tion (MI) and nonfatal stroke. Secondary endpoints were initially
defined as individual MACE endpoints, hospitalization due to heart
failure (HHF), and all-cause death. Because we found a small number
of studies reporting stroke (n = 4) and HHF (n = 3) and a small number
of both clinical events, as described below, we were not able to pro-
ceed with the analyses of these individual endpoints. In order to cover
the overall CV risk, we expanded MACE by adding HHF to the above-
described MACE. We chose to use additive component network
meta-analysis (CNMA) as the most appropriate approach for indirect
or clinical comparison between the interventions. This model assumes that the
effect of a treatment combination is the sum of the effects of its com-
ponents, which implies that common components cancel out in com-
parisons. We used the discomb function in R because our network
was not fully connected. This function implements the additive model
in a frequentist way.13
Dichotomous variables are reported as percentages, whereas con-
tinuous variables are reported as mean ± SD or median (interquartile
range). Baseline data were obtained by weighted calculation. To iden-
and tify the potential effects of bupropion and/or naltrexone on outcomes
(MACE, nonfatal MI, and all-cause death), we calculated an overall
odds ratio (OR) with random-effects model for additive CNMA or rela-
tive risk (RR) with random-effects model meta-analysis. OR and RR
Central were universally identical during data analysis. We assessed statistical
heterogeneity between trials with I2 statistic (with 95%CIs), which is
derived from Cochran's Q [100 × (Q – df  Q)] and provides a mea-
sure of the proportion of overall variation that is attributable to
between-trial heterogeneity. We used meta-regression analyses to
investigate potential sources of heterogeneity between trials. The fac-
tors that we investigated were sample size, duration of intervention,
indication for therapy, and mean weight loss during trials, and these
factors were determined before the meta-analysis was undertaken.
To test for publication bias, we formed funnel plots and undertook
the Egger test. For the summary treatment effect estimate, a two-
tailed p-value less than 0.05 was considered statistically significant.
reviews; The extracted data were analyzed using the R v4.0.1 (2020, Auckland,
New Zealand) and discomb, metaviz, and metafor packages.
SPOSITO ET AL.
3 | RESULTS
We identified 1228 citations using the search terms and platforms
(Supplementary Data), which included 461 articles on bupropion,
543 on naltrexone, and 224 articles on B-N. We excluded 146 dupli-
cates and 977 articles that were unsuitable based on abstract. We fur-
ther excluded 93 studies based on full-text evaluation, mostly due to
the lack of CV outcome reports (details on Supplementary Data). We
ended this extraction with 12 trials to be included for qualitative syn-
thesis and meta-analysis. The flow diagram of this selection process is
shown in Figure 1 and the network profile in Figure S1. Details of the
baseline characteristics of the trials are shown in Table 1.
All studies presented a low risk of bias as assessed by the
Cochrane Collaboration tool for assessing risk of bias24 (see Table S1)
25
and were deemed high quality by the GRADE system. One study
was not conducted at multiple centers. As shown in Figure S2a–c and
Table S2, there was no significant publication bias in funnel plots as
well as no significant small study bias by the Egger tests.
The mean age was 54 ± 8 years (55% female), and 69% were
included in trials aiming at weight loss and 29% designed for smoking
cessation. The mean baseline BMI was 32 ± 5 kg/m2, waist
FIGURE 1 Flow diagram of the trials' selection process
3
circumference was 112 ± 13 cm, systolic blood pressure (SBP) was
123 ± 12 mmHg, diastolic blood pressure (DBP) was 77 ± 9 mmHg,
HDL-C was 49 ± 12 mg/dL, and LDL-C was 110 ± 31 mg/dL.
3.1 | Primary outcome
Figure S3a depicts a conventional random-effects model revealing a
very low heterogeneity between the trials (I2 = 0% [95%CI 0%–33%];
p for heterogeneity = 0.93) and no association between the treat-
ments and the incidence of MACE. The RR of MACE by the pool of
the therapeutic regimens was 0.92 (95%CI 0.78–1.09; p = 0.35).
Consistently, as seen in Figure 2a, in an additive model network
meta-analysis for random effects, bupropion, B-N, or naltrexone did
not significantly increase the risk of MACE compared with placebo or
nicotine patch. Neither component nor B-N was associated with the
risk of MACE. The retrospective power to detect the B-N (random)
effect on MACE given 12 studies is 0.91, two-tailed, based on
non-inferiority equation (Supplementary Data).
3.2 | Secondary outcomes
For the incidence of nonfatal MI, data from seven trials were available,
and no results were reported for naltrexone alone. As shown in
Figure S3b, by conventional meta-analysis using random-effects
model, no heterogeneity was found between the trials (I2 = 0% [95%
CI 0%–7%]; p for heterogeneity = 0.96). The pooled effect of
bupropion and B-N on the RR for nonfatal MI was 0.93 (95%CI
0.74–1.16; p = 0.51). As shown in Figure 2b, in an additive model for
random effects, bupropion and B-N did not increase the risk of non-
fatal MI as compared with placebo.
Data from all-cause death were available in five trials. The
random-effects conventional meta-analysis model (Figure S3c)
showed no heterogeneity between these five trials (I2 = 0% [95%CI
0%–26%]; p for heterogeneity = 0.99). The RR of all-cause death was
not changed by the pool of the therapeutic regimes (0.92 [95%CI
0.63–1.28]; p = 0.43). In the additive effects network meta-analysis
model (Figure 2c), no significant association was found between the
therapies and all-cause death.
Expanded MACE according to the random-effects conventional
meta-analysis model (Figure S3d) had no heterogeneity between the
12 trials (I2 = 0% [95%CI 0%–45%]; p for heterogeneity = 0.71). The
pooled effect of the three therapies on the RR for expanded MACE
was 0.97 (95%CI 0.82–1.11; p = 0.45). In the additive effects network
meta-analysis model (Figure 2d), no significant association was found
between the therapies and the OR for expanded MACE.
3.3 | Sensitivity analyses
As shown in Tables S3–S5, after removing the LIGHT trial,10
there was no change in results regarding MACE, nonfatal MI, or
 4

TABLE 1 Baseline characteristics of participants within RCTs

Study Sample size Dose of naltrexone mg/day Dose of bupropion mg/day Comparator Clinical condition Duration (weeks) Age (years) Female (%)
14
Hollander et al. (2013) 505 32 360 Placebo Obesity 56 54 ± 9 56
Nissen et al. (2016)10 8905 32 360 Placebo Obesity 16 61 ± 7 55
15
Apovian et al. (2013) 1496 32 360 Placebo Obesity 28 44 ± 11 85
Greenway et al. (2010)16 1742 24 360 Placebo Obesity 56 44 ± 11 78
11
NCT02638129 (2017) 58 8 90 Placebo Obesity 13 63 ± 9 26
Rigotti et al. (2006)17 248 - 300 Placebo Smoking 12 56 ± 19 31
18
Eisenberg et al. (2013) 392 - 300 Placebo Smoking 12 54 ± 10 32
Planer et al. (2011)19 149 - 300 Placebo Smoking 8 52 ± 11 20
20
Tonstad et al. (2003) 626 - 300 Placebo Smoking 7 53 ± 9 24
Smith et al. (2015)21 538 - 300 Placebo Smoking 12 44 ± 12 56
Benowitz et al. (2018)22 4020 - 300 Nicotine patch Smoking 12 46 ± 13 56
Webster et al. (2018)23 248 12 - Placebo Constipation 7 57 ± 13 53
23
Webster et al. (2018) 249 24 - Placebo Constipation 7 56 ± 13 54

Note: Data are presented as mean ± SD or median (interquartile range).

SPOSITO ET AL.
 SPOSITO ET AL.

TABLE 1 Continued

Study BMI (kg/m2) Waist circumference (cm) SBP (mmHg) DBP (mmHg) FPG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Proportional weights by study
Hollander et al. (2013)14 36 ± 5 115 ± 13 125 ± 11 77 ± 8 162 ± 41 46 ± 10 101 ± 34 0.026
10
Nissen et al. (2016) 37 ± 5 118 ± 18 126 ± 13 74 ± 9 45 (38–53) 82 (65–106) 0.464
Apovian et al. (2013)15 36 ± 4 109 ± 12 118 ± 10 77 ± 7 95 ± 11 51 ± 13 118, ±30 0.078
16
Greenway et al. (2010) 36 ± 4 110 ± 12 119 ± 10 77 ± 7 94 ± 11 52 ± 14 121 ± 32 0.091
NCT02638129 (2017)11 0.003
Rigotti et al. (2006)17 29 ± 6 0.013
Eisenberg et al. (2013)18 0.020
19
Planer et al. (2011) 28 ± 5 123 ± 17 74 ± 11 0.008
Tonstad et al. (2003)20 0.033
21
Smith et al. (2015) 0.028
Benowitz et al. (2018)22 28 ± 6 0.210
Webster et al. (2018)23 0.013
Webster et al. (2018)23 0.013

Note: Data are presented as mean ± SD or median (interquartile range).

5
6 SPOSITO ET AL.

FIGURE 2 Additive model network meta-analysis with random effects for MACE (a), nonfatal MI (b), all-cause death (c), and expanded
MACE (d)
SPOSITO ET AL.
all-cause death. We then removed another RCT,21 and once
again, B-N remained not associated with death (OR:0.90 [95%CI
2
0.64–1.26]; p = 0.55; I = 0% [95%CI 0%–64%];
heterogeneity = 0.65) as compared with placebo (Table S6). We
were not able to perform sensitivity analysis for expanded MACE
due to the small number of trials reporting HHF (n = 3).
3.4 | Meta-regression analyses
Meta-regression analyses were performed to investigate potential
confounders among trials that could not be solved by the additive
network approach. As shown in Table S7, no significant association
was found between the risk of MACE and mean weight
loss (p = 0.66), indication for therapy (smoking cessation or obesity;
p = 0.58), duration of intervention (p = 0.45), or sample size
(p = 0.92). We did not conduct meta-regression for all-cause death,
HHF, or nonfatal MI due to the small number of studies presenting
these outcomes.
4 | DISCUSSION
The present study used a combination of meta-analysis techniques
and meta-regression to investigate the CV risk during treatment
with naltrexone, bupropion, or N-B. To achieve statistical power,
the study's strategy was to include RCTs with these drugs in
different clinical settings, which was successful, as there was no
heterogeneity between clinical indications for RCTs or between
therapeutic regimens with regard to primary or
outcomes. Consistently, we found no association between the
characteristics of patients enrolled in these RCTs and the
outcomes. In addition to that, the paucity of RCTs for CV safety
with the direct comparison of the N-B association against placebo
was circumvented in the present study by the use of meta-analysis
of the network of additive components. In this model, it is
possible to carry out an indirect comparison between the
interventions assuming that the effect of a treatment combination
is the sum of the effects of its components, which implies that
the common components cancel each other out
comparisons. The main result of the study was that MACE was
not associated with the use of naltrexone, bupropion, or N-B. In
addition, no association was detected between these medications
and the incidence of nonfatal MI, expanded MACE, or all-cause
death.
Previous meta-analyses26,27 evaluated a large set of therapies
14–16,28
for weight loss including four RCTs that tested N-B.
found no heterogeneity among the studies and no increased risk of
death or cardiac events.27 As the definition of cardiac events in
these RCTs has been broad and unspecific, including arrhythmias
and palpitations, the need for further investigation remains. The
therapies for obesity were associated with an elevated discontinua-
tion rate due to adverse effects, but CV disease was not mentioned
7
among the adverse events.26 In fact, among 2510 patients allocated
for treatment with N-B in the four RCTs, only two MACE (both MI)
p for were reported.14–16,28 Consistently, since 2014, when B-N was
approved for clinical use in Europe and the United States, three MI
episodes, four HF, and eight cerebrovascular accidents have been
reported in thousands of users of this medication.29,30 More
recently, a different approach to verify CV safety of B-N was based
on a meta-analysis of raw, unpublished reports originating from four
clinical studies for weight reduction that were submitted to
regulatory agencies.31 The meta-analysis revealed a high rate of
missing data in the case report forms, mainly of CV outcomes, and
a great heterogeneity between the RCTs.31 In this context, the
present study should be considered the first step forward as it was
able to achieve statistical power, with the inclusion of RCTs with
different clinical indications, allowing testing of the risk of MACE
with N-B.
As mentioned above, pharmacological treatment is an essential
complementary tool in the management of excess weight. Considering
the set of studies with B-N, it is expected that a reduction in waist
circumference (−3.14 cm [−3.69 to −2.59]),31 a loss of 5.0 kg (95%CI
4.4–5.5 kg), and an OR of 3.96 (95%CI 3.03–5.11) to achieve 5% of
weight loss,26 a target considered as a minimum trigger for clinical
benefit.32 It is possible, therefore, that long-term control of obesity
with B-N may result in a reduction in CV risk, particularly in
individuals who achieve significant reduction in body weight with this
therapy.
4.1 | Limitations
secondary
This study has limitations that need to be considered. The main issue
is the scarcity of long-term studies that properly assess the CV safety
of B-N. The two RCTs designed for this purpose were stopped early
due to sponsors' issues and thus did not reach statistical power to
investigate CV safety of B-N.10,11 Longer follow-ups are necessary to
estimate whether there is an effect of B-N on CV risk, either
beneficial or harmful. In fact, in obesity RCTs, the reduction in MACE
incidence was only observed after long follow-up.33 Nonfatal MI and
death from all causes were not specified in some of the selected
in the RCTs; hence, the analyses did not reach adequate statistical power for
these two outcomes.
5 | CONC LU SIONS
Naltrexone, bupropion, or the combination of both was not
They associated with the incidence of MACE as compared with
placebo. In addition, no evident imbalance was found between B-N
and placebo in the incidence of nonfatal MI or all-cause death.
As long as an RCT to investigate the CV safety of B-N is
not properly done, this is the best evidence available and supports
the clinical use of this combination of drugs to control excess
weight.
8 SPOSITO ET AL.
ACKNOWLEDGMENTS
Prof. Sposito is recipient of a Research Career Awards from the
Brazilian National Research Council (CNPq) (grant number
301465/2017-7).
CONF LICT OF IN TE RE ST
The authors declare no conflict of interest.
AUTHOR CONTRIBUTION
Professor Sposito had full access to all of the data in the study
and takes responsibility for the integrity of the data and the
accuracy of the data analysis. The following roles considered for
authorship: Concept and design: Carvalho and Sposito. Acquisition,
analysis, or interpretation of data: Bonilha, Luchiari, Carvalho, and
Sposito. Drafting of the manuscript: Sposito. Critical revision of the
manuscript for important intellectual content: All authors. Statistical
analysis: Carvalho. Supervision: Carvalho and Sposito.
ORCID
Andrei C. Sposito https://orcid.org/0000-0001-7127-2052
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