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. Author manuscript; available in PMC: 2021 Sep 9.
Published in final edited form as: Expert Opin Drug Saf. 2020 Sep 9;19(9):1095–1104. doi: 10.1080/14740338.2020.1806234

The risk of cardiovascular complications with current obesity drugs

Ariana M Chao 1,2, Thomas A Wadden 2, Robert I Berkowitz 2,3, Kerry Quigley 2, Frank Silvestry 4
PMCID: PMC7554173  NIHMSID: NIHMS1621739  PMID: 32750250

Abstract

Introduction:

Obesity is associated with an increased risk of cardiovascular morbidity and mortality. Four medications are approved by the US Food and Drug Administration (FDA) for chronic weight management when used as an adjunct to a reduced-calorie diet and increased physical activity in adults. These medications result in clinically significant weight losses, as well as improvements in some cardiometabolic risk factors.

Areas covered:

We briefly review the history of anti-obesity medications (AOMs) as related to cardiovascular safety, and summarize weight loss efficacy and cardiovascular data from clinical trials of orlistat, phentermine/topiramate, naltrexone/bupropion, and liraglutide.

Expert opinion:

Current AOMs approved for chronic weight management have generally favorable effects on some cardiometabolic parameters. However, the long-term safety of orlistat, phentermine/topiramate, and naltrexone/bupropion on cardiovascular morbidity and mortality have not been established. The cardiovascular safety of liraglutide, at a dose of 1.8 mg/d, was demonstrated in a large randomized outcomes trial in participants with type 2 diabetes.

Keywords: cardiovascular, cardiovascular disease outcomes, obesity, pharmacotherapy, weight loss

1. Introduction

The prevalence of obesity, defined as a body mass index (BMI) ≥30 kg/m2, is 42.4% in US adults.1 Obesity is associated with an increased risk of hypertension, dyslipidemia, stroke, and type 2 diabetes.2-4 Compared to adults with normal weight, those with obesity have a 2- to 3-fold increased risk of cardiovascular disease.4

Guidelines for obesity treatment recommend a step-wise approach based on increasing BMI, as well as obesity-related comorbidities such as hypertension and type 2 diabetes.5,6 Individuals with a BMI ≥30 kg/m2 (or ≥27 kg/m2 with obesity-related comorbidities) who have not successfully achieved weight loss with lifestyle modification alone are candidates for adjunctive treatments, including anti-obesity medication (AOM). Four medications currently are approved by the US Food and Drug Administration (FDA) for chronic weight management, when used as an adjunct to a reduced calorie diet and increased physical activity. They are orlistat, phentermine/topiramate, naltrexone/bupropion, and liraglutide. The European Medicines Agency (EMA) has approved all of these except phentermine/topiramate. Placebo-subtracted weight losses for these medications range from 2.6 to 8.8 kg at 1 year.7,8 When combined with a program of structured lifestyle modification, all of these AOMs can help individuals obtain clinically significant weight losses of ≥5% of initial body weight.7,8 However, prescription of obesity medications should balance benefits and risks. This review provides a history of AOMs and cardiovascular safety, and summarizes cardiovascular data from clinical trials of FDA-approved weight loss medications. We conclude with our expert opinion on the cardiovascular safety of AOMs.

2. Historical Perspective on Obesity Medications and Cardiac Safety

Several weight loss medications have been withdrawn from the market due to adverse reactions. Cardiovascular toxicity has been a common reason for withdrawal after regulatory approval.9 As a class, medications that act on monoamine neurotransmitters (to suppress appetite) have been the most frequently withdrawn due to associated cardiovascular toxicity. These include aminorex (pulmonary hypertension), fenfluramine and dexfenfluramine (valvulopathy), phenylpropanolamine (stroke), and sibutramine (myocardial infarction and stroke).9,10

Sibutramine is a selective inhibitor of the reuptake of monoamines, primarily norepinephrine and serotonin. Sibutramine was approved by the FDA for weight reduction in 1997. At 1 year, the placebo-subtracted weight loss for sibutramine 10-15 mg/d was 4.5 kg, and the placebo-subtracted declines in fasting glucose and triglycerides were 3.6 mg/dL and 3.6 mg/dL, respectively.11 However, at 1 year, sibutramine-treated participants had an increase in heart rate of 3.8 beats per minute and increases in systolic and diastolic blood pressure of 4.4 mm Hg and 3.3 mm Hg, respectively.11 Additionally, there were concerns of cardiovascular issues in sibutramine-treated patients.12 The EMA reviewed sibutramine in 1999 and again in 2002 in response to these safety concerns. The EMA’s Committee for Proprietary Medicinal Products concluded at the time that the benefits of sibutramine for obesity outweighed the perceived risks, but it further ruled that use of sibutramine was contraindicated in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias.13 The Committee also recommended the initiation of a long-term study of cardiovascular outcomes for sibutramine.

The Sibutramine Cardiovascular Outcomes (SCOUT) trial was a 5-year, randomized, double blind, placebo-controlled study of over 10,000 patients with overweight or obesity and: preexisting cardiovascular disease; type 2 diabetes with at least one other cardiovascular risk factor; or both.14 The risk of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death) occurred in 11.4% of the sibutramine group which was significantly greater than the 10.0% in the placebo group (hazard ratio (HR)=1.16, 95% confidence interval (CI)=1.03-1.31). The rates of nonfatal myocardial infarction and nonfatal stroke were significantly different between groups, but those for cardiovascular and all-cause mortality were not. Based on these results, the EMA recommended suspension of marketing authorization for sibutramine across Europe. The FDA initially requested that healthcare professionals be notified that sibutramine should not be used in patients with known cardiovascular disease and required stronger product label warning. However, the FDA ultimately concluded that sibutramine posed undue cardiovascular risks and recommended withdrawal of the medication from the US market in 2010.

3. Obesity Medications and Cardiovascular Benefits and Risks

The FDA’s 2007 Draft Obesity Drug Guidance was designed to help facilitate the development and evaluation of the efficacy and safety of AOMs.15 The document contains information on therapeutic indications, target populations, clinical trial designs, and data analyses. Recommendations include that studies for obesity medications should assess adults with a BMI ≥30 kg/m2 or ≥27 kg/m2 with a weight-related comorbidity. Weight loss outcomes are specified such that the difference in mean weight loss between medication- and placebo-treated groups should be at least five percentage points and statistically significant. The proportion of participants who lose ≥5% of baseline body weight in the medication-treated group should be at least 35% and approximately double the proportion in the placebo-treated group, with the difference between groups statistically significant. Trials are to include at least 3000 participants randomized to active doses of the medication and 1500 participants to placebo for 1 year. This provides 80% power to rule out with 95% confidence, a 50% increase in the incidence of an adverse event that occurs at a rate of 3% in the placebo group. Cardiovascular benefits and safety are factored into benefit-risk assessments of the medications. Improvements in several cardiovascular disease risk factors are expected, proportionate to the degree of weight loss achieved. No stipulation is made in the 2007 Guidance concerning cardiovascular outcome trials, although recent FDA-approval of AOMs has included requirements for these trials.

3.1. Lorcaserin

Lorcaserin was approved by the FDA for chronic weight management in June 2012 but was ultimately withdrawn from the market in 2020 because of emergent health concerns. The drug is a selective serotonin 2C (5-HT2C) receptor agonist and was the first AOM to demonstrate safety for major adverse cardiovascular events in a cardiovascular outcomes trial. The placebo-subtracted weight loss of lorcaserin 10 mg twice daily was 3.2 kg.7 Pivotal trials of lorcaserin including the Behavioral Modification of Lorcaserin for Overweight and Obesity Management (BLOOM) Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM),17 and BLOOM DM studies,18 demonstrated that lorcaserin was generally well tolerated.

At the time of lorcaserin’s marketing approval, the FDA required a long-term trial to evaluate the medication’s potential cardiovascular effects, in the view of findings with sibutramine. In the Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients- Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61) trial, 12,000 patients with overweight or obesity, with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors, were randomly assigned to lorcaserin 10 mg twice daily or placebo.19 After a median follow-up of 3.3 years, the rate of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (HR=0.99; 95% CI, 0.85 to 1.14). However, in a post-hoc analysis of the broader study database, investigators observed an increase in the number of new cancers among lorcaserin-treated patients (7.7%) compared to the placebo group (7.1%). The FDA concluded that the potential risks of lorcaserin outweighed the benefits. The medication was voluntarily withdrawn from the US market in February 2020.

3.2. Orlistat

Orlistat is a gastric and pancreatic lipase inhibitor that decreases the absorption of dietary fat by 30%.20 In the US, orlistat was approved in 1999 as an adjunct to a reduced-calorie diet and increased physical activity.21 Orlistat is the only AOM that is FDA-approved for adolescents (12-17 years of age). It is available by prescription at 120 mg or over the counter at a 60 mg, both taken three times daily with meals containing fat.

3.2.1. Efficacy.

Over 17 randomized controlled trials have examined the effect of orlistat compared to placebo for ≥1 year.7,22 Orlistat, combined with lifestyle modification, produced a 2.6 kg placebo-subtracted weight loss at 1 year; 45% of participants achieved a ≥5% weight loss, which included 20% with a ≥10% loss.7 Data from a network meta-analysis demonstrated that at 1 year, orlistat, compared to placebo, was associated with a modest reduction in fasting blood glucose of −8.0 mg/dL and A1c of −0.4%.22 Orlistat also resulted in declines of 8.7 mg/dL in LDL-cholesterol, 1.7 mm Hg in systolic blood pressure (SBP), and 1.6 mm Hg in diastolic blood pressure (DBP). However, orlistat was associated with a placebo-subtracted reduction of 1.1 mg/dL in HDL cholesterol. One of the largest and longest trials of orlistat, referred to as XENical in the Prevention of Diabetes in Obese Subjects (XENDOS), was a 4-year, double-blind study in which 3,305 participants with obesity were randomly assigned to lifestyle change plus either 120 mg orlistat or placebo taken three times daily (Table 1). At 4 years, mean weight loss was significantly greater with orlistat than placebo (5.8 kg versus 3.0 kg).23 The cumulative incidence of diabetes was 6.2% in orlistat-treated participants, which was significantly less than the 9.0% in the placebo group.24 This corresponded to a risk reduction of 37.3%.

Table 1.

Effects of anti-obesity medications on cardiometabolic risk factors in randomized, placebo-controlled weight trials ≥1 year.

Length,
wk		 Treatment
arms (N)		 Change from Baseline
Weight SBP,
mm
Hg		 DBP,
mm
Hg		 HR,
BPM		 LDL-C Total
cholesterol		 HDL-C TG Glucose A1c
Orlistat
XENDOS23 208 Placebo (1637) −3.0 kg −3.4 −1.9 NR −5.1% −2.3% +9.1% +2.9 +0.2 mmol/L NR
Orlistat 120 mg (1640) −5.8 kg* −4.9* −2.6* NR −12.8%* −7.9%* +6.5%* +2.4 +0.1 mmol/L* NR
Phentermine/Topiramate CR (PHEN/TPM)
EQUIP31 56 Placebo (514) −1.6% +0.9 +0.4 −0.2 −5.5% −3.5% 0% +9.1% +1.9 mg/dL NR
PHEN 3.75 mg/TPM 23 mg (241) −5.1%* −1.8* −0.1 −0.3 −7.7% −5.4% +0.5% +5.2% +0.8 mg/dL NR
PHEN 15 mg/TPM 92 mg (512) −10.9%* −2.9* −1.5* +1.2 −8.4%* −6.0%* +3.5%* −5.2%* −0.6 mg/dL* NR
CONQUER32 56 Placebo (994) −1.2% −2.4 −2.7 −0.1 −4.1% −3.3% +1.2% +4.7% 0.13 mmol/L +0.1%
PHEN 7.5 mg/ TPM 46 mg (498) −7.8%* −4.7* −3.4 +0.1 −3.7% −4.9%* +5.2%* −8.6%* −0.01 mmol/L* 0%*
PHEN 15 mg/ TPM 92 mg (995) −9.8%* −5.6* −3.8* +1.7* −6.9%* −6.3%* +6.8%* −10.6%* −0.07 mmol/L* −0.1%*
SEQUEL (extension of CONQUER)33 108 Placebo (227) −1.8% −3.2 −3.9 +0.4 −10.7% NR +4.7% +0.4% +3.7 mg/dL +0.2
PHEN 7.5 mg/ TPM 46 mg (153) −9.3%* −4.7 −3.7 +1.3^ −4.6%* NR +7.3% −12.5%* +0.1 mg/dL +0.01*
PHEN 15 mg/ TPM 92 mg (295) −10.5%* −4.3 −3.5 +1.7^ −5.6%* NR +11.9%* −13.7%* −1.2 mg/dL* 0*
Naltrexone/Bupropion (Nal/Bup)
COR-I40 56 Placebo (511) −1.3% −2.1 −1.0 −0.1 −0.5% NR +0.8% −3.1% −0.7% NR
Nal 16 mg/bup 360 mg (471) −5.0%* +0.2* −0.0* +1.5* −1.5% +7.6%* −8.0%* −1.9%
Nal 32 mg/bup 360 mg (471) −6.1%* −0.4* −0.1* +1.0* −2.0% NR +8.0%* −12.7%* −2.6%* NR
COR-II41 56 Placebo (495) −1.2% −0.5 +0.3 NR −2.1 mg/dL NR −0.9 mg/dL −0.5% −1.3 mg/dL NR
Nal 32 mg/bup 360 mg (1001) −6.4%* +0.6* +0.4 NR −6.2 mg/dL* NR +3.6 mg/dL* −9.8%* −2.8 mg/dL NR
COR-BMOD42 56 Placebo + BMOD (202) −5.1% −3.9 −2.8 +0.2 +10.0% NR +2.8% −8.5% 0% NR
Nal 32 mg/bup 360 mg + BMOD (591) −9.3%* −1.3* −1.4* +1.1 +7.1% NR +9.4%* −16.6%* −1.5% NR
COR-Diabetes43 56 Placebo (170) −1.8% −1.1 −1.5 47.2% with a ≥5 bpm ↑ 0 NR −0.3 mg/dL −0.8% −4.0 mg/dL −0.1%
Nal 32 mg/bup 360 mg (335) −5.0%* 0 −1.1 50.2% with a ≥5 bpm ↑^ −1.4 mg/dL NR +3.0 mg/dL* −11.2%* −11.9 mg/dL −0.6%*
Liraglutide (Lira)
SCALE-Obesity and Pre-diabetes55 56 Placebo (1244) −2.6% −1.5 −1.9 0.1 −1.0% −1.0% −5.5% −5.5 +0.1 mg/dL −0.1%
Lira 3.0 mg (2487) −8.0%* −4.2* −2.6* 2.5* −3.0%* −3.1%* −13.1%* −13.3* −7.1 mg/dL* −0.3%*
SCALE-Diabetes56 56 Placebo (212) −2.0% −0.4 −0.5 −1.4 +5.0 +3.8 +1.9 +0.4% −0.2 mg/dL −0.3
Lira 1.8 mg (211) −4.7%* −3.5* −1.1 +2.1* −3.1 −2.2 +4.5 −9.5% −26.8 mg/dL* −1.1*
Lira 3.0 mg (423) −6.0%* −2.8* −0.9 +2.0* +0.6 −1.5* +4.7* −14.7%* −34.3 mg/dL* −1.3*
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Note. Table does not include trials designed to assess the maintenance of lose weight (e.g., SCALE Maintenance).

*

Statistical comparison with placebo is <0.05.

^

and NR = Not reported. SBP = systolic blood pressure. DBP = diastolic blood pressure. HR = heart rate. LDL-C = low-density lipoprotein cholesterol. HDL-C = high-density lipoprotein cholesterol. TG=triglycerides.

3.2.2. Cardiovascular safety.

Systemic exposure to orlistat is minimal. In therapeutic studies, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL) with no evidence of accumulation.25,26 No major cardiovascular side effects have been reported with this medication. Orlistat appears to have no reported cardiovascular risk and is considered safe for use by patients with cardiovascular disease. Insufficient data are available for use in patients with heart failure. It is the preferred medication for patients with existing hypertension, established coronary artery disease, or cardiac arrhythmias. However, a cardiovascular outcomes trial has not been conducted on this medication.

3.3. Phentermine/Topiramate Extended-Release (ER)

Phentermine and topiramate were both approved by the FDA as individual medications prior to the approval of the combined product for chronic weight management in 2012. Phentermine is a sympathomimetic amine anorectic that was approved in 1959 for short-term (<3 months) treatment of obesity.27 Topiramate is an anti-epileptic medication that modifies voltage-gate sodium and calcium channels and targets gamma-aminobutyric acid-mediated pathways.28 Topiramate is approved for the treatment of epilepsy and migraine prophylaxis. The exact mechanism of action for weight loss is not known. The fixed-dose combination medication is started at a dose of 3.75 mg of phentermine and 23 mg of topiramate ER, once daily in the morning, and titrated to a recommended dose of 7.5 mg/46 mg.29 The dose can be further increased to 15 mg/92 mg if 3% weight loss is not achieved after 12 weeks. The medication should be discontinued after 12 weeks if a 5% weight loss is not achieved after reaching 15 mg/92 mg.

3.3.1. Efficacy.

The weight loss efficacy of phentermine/topiramate ER has been demonstrated in four phase 3 trials, the EQUATE,30 EQUIP,31 CONQUER,32 and SEQUEL33 studies (Table 1). In a meta-analysis, at 1 year, the placebo-subtracted weight loss was 8.8 kg for phentermine/topiramate with 74% of participants achieving a ≥5% weight loss, which included 54% who attained a ≥10% weight loss.7 Compared to placebo, phentermine/topiramate was associated with a nonsignificant change in fasting blood glucose and A1c. The medication produced a placebo-subtracted decrease of 4.2 mg/dL in LDL and increase of 2.2 mg/dL in HDL cholesterol. The decline in SBP was 3.7 mm Hg and in DBP was 1.4 mm Hg relative to placebo.22

3.3.2. Cardiovascular safety.

Results at 1 year from pivotal trials showed an average increase in heart rate of 0.6 to 1.6 beats per minute more in participants taking phentermine/topiramate versus placebo.34 In studies of up to 1 year, 50.4% of those who took phentermine/topiramate 7.5 mg/46 mg, as well as 56.1% of those prescribed phentermine/topiramate 15 mg/92 mg, experienced an increase in heart rate greater than 10 beats per minute at some point during the trial, which was greater than the 42.1% of participants on placebo.29 Resting heart rate should be monitored regularly in all patients taking this medication, especially during treatment initiation and dose escalation. Those with a sustained increase may require a dose reduction or discontinuation of the medication.

The increases in heart rate prompted the FDA to mandate a randomized, post-marketing outcome study to demonstrate that phentermine-topiramate ER is not associated with an increase in major adverse cardiovascular events (MACE). The cardiovascular outcomes study, referred to as A Qysimia ™ cardiovascular morbidity and mortality study in subjects with documented cardiovascular disease (AQCLAIM), is currently ongoing.35 In a retrospective cohort study of medical claims databases, the incidence rate ratio of MACE did not differ among current and former users of fixed-dose phentermine/topiramate (incidence rate ratio=0.24, 95% CI=0.03, 1.70).36 However, there were too few MACE events to provide definitive conclusions. Phentermine/topiramate should be used with caution in patients with cardiovascular disease or elevated cardiovascular risk, pending results of the AQCLAIM trial which will provide further guidance.

3.4. Naltrexone HCl/Bupropion HCl ER

Naltrexone and bupropion were both approved by the FDA as individual drugs prior to the 2014 approval of the combined medication for chronic weight management. Naltrexone, an opioid antagonist, was originally approved to treat alcohol and opioid dependence.37 Bupropion, an aminoketone antidepressant and norepinephrine and dopamine reuptake inhibitor, was approved for depression, seasonal affective disorder, and for smoking cessation.38 The fixed-dose combination product is 8 mg of naltrexone and 90 mg of bupropion. Dosing begins with one tablet in the morning for 1 week. At week 2, a second tablet is added in the evening. The titration continues until reaching two tablets twice daily at week 4, for a total daily dose of 32 mg of naltrexone and 360 mg of bupropion.39 Response to treatment should be evaluated after 12 weeks at the maintenance dose and should be discontinued if a ≥5% weight loss has not been achieved. The combination is theorized to work synergistically in the hypothalamus and mesolimbic dopamine circuits to decrease food intake.40

3.4.1. Efficacy.

The efficacy of naltrexone/bupropion was tested in the Contrave Obesity Research (COR) program, which included four 56-week, multicenter, randomized, double-blind, placebo-controlled phase 3 trials (Table 1). COR-I,41 COR-II,42 and COR-behavioral modification (BMOD)43 focused on weight reduction in uncomplicated obesity or obesity with controlled hypertension and/or dyslipidemia. COR-Diabetes evaluated patients with overweight/obesity and type 2 diabetes.44 Across the four studies, placebo-subtracted weight loss was 5.0 kg, and 55% of participants achieved a ≥5% weight loss, which included 30% who lost ≥10% weight loss.7 In a meta-analysis, naltrexone/bupropion, compared to placebo, was not associated with a significant change in fasting blood glucose, A1c, LDL-cholesterol, SBP or DBP after 1 year of treatment.22 Naltrexone/bupropion was associated with an increase of 2.5 mg/dL in HDL cholesterol relative to placebo.

3.4.2. Cardiovascular safety.

Some of the pivotal trials of naltrexone/bupropion showed increases in heart rate and blood pressure. For example, in COR-I there was a transient increase in SBP of approximately 1.5 mm Hg during the first 8 weeks of treatment, which returned to baseline after week 12, before decreasing by approximately 1 mm Hg below baseline for the remainder of the study.41 A similar trend was reported for DBP. In COR-II there was a 0.2 mm Hg increase in SBP at 56 weeks compared to a 0.4 mm Hg decline in the placebo group.42 Heart rate increased by approximately 0.8 to 2 beats per minute higher than baseline values.41,42 Patients treated with naltrexone/bupropion should have their blood pressure and heart rate monitored regularly; these values may be greatest during titration and the initial 3 months of treatment. Use of the medication is contraindicated in patients with uncontrolled hypertension, and the drug should be used with caution in those with controlled hypertension, existing cardiac disease, or cerebrovascular disease.

Due to the increases in blood pressure and heart rate in the phase 3 trials, as well as concerns about cardiovascular safety, the FDA deferred approval of naltrexone/bupropion in 201145 and mandated that the medication be evaluated in a placebo-controlled, noninferiority cardiovascular outcomes trial. The LIGHT trial was designed to examine whether the combination of naltrexone (32 mg/d) and bupropion (360 mg/d) increased major adverse cardiovascular events (MACE), as defined by a composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction.46 The study enrolled 8910 patients with overweight or obesity who were at increased cardiovascular risk. Participants were randomized to placebo or naltrexone, 32 mg/d and bupropion, 360 mg/d. Both groups were provided an internet-based weight management program. To expedite approval, the FDA allowed a specified interim analysis after 25% of expected events had accrued, with the objective of ruling out an upper 95% confidence interval of the hazard ratio (HR) of 2.0 prior to approval, and a HR of 1.4 at study completion (potentially post approval). The sponsor and the FDA agreed not to disclose the 25% interim analysis until completion of the study. The data monitoring committee released the interim data to the sponsor in November 2013, and the FDA approved the medication in September 2014. However, due to a breach of confidentiality by the sponsor’s financial management team, the FDA stated that the trial could not be used to meet the post approval requirement to rule out a noninferiority margin of 1.4, but it recommended that the trial be continued. In March 2015, while the trial was ongoing, the sponsor publicly released the confidential 25% interim results via a patent publication.47 Consequently, the data monitoring committee recommended that the trial be terminated.46

At that time, results from the 50% interim data were the last prespecified analysis performed by the data monitoring committee. For the 25% interim analysis, MACE occurred in 0.8% of naltrexone-bupropion treated patients which was significantly less than the 1.3% in placebo-treated participants (HR=0.8%; 95% CI=0.39-0.90). After 50% of planned events, MACE occurred in 2.0% of the naltrexone-bupropion group compared to 2.3% among the placebo treatment group (HR=0.88; 99.7% CI=0.57-1.34). A second cardiovascular outcome trial, CONVENE, was initiated but terminated prematurely due to the sale of the medication to a different pharmaceutical company.48 Another adequately powered cardiovascular outcomes trial is still necessary to fully evaluate the cardiovascular safety of the medication. Thus, at this time, there are not sufficient data available to report on the cardiovascular safety of the combined use of naltrexone and bupropion.

3.5. Liraglutide

In 2014, liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, was approved at a dose of 3.0 mg daily (by subcutaneous injection) for chronic weight management. This followed its prior approval in 2010, at 1.2 and 1.8 mg/d, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. GLP-1 is a polypeptide incretin hormone secreted by the intestinal L-cells that has a half-life of 1-2 minutes due to proteolytic degradation.49 GLP-1 causes a glucose dependent stimulation of insulin secretion, delayed gastric emptying, and appetite suppression.50 Liraglutide shares 97% homology to native GLP-1 but extends the circulating half-life of GLP-1 to 11 to 15 hours.51 For the management of obesity, dosing begins at 0.6 mg/d and is titrated up to a maximum of 3.0 mg/d.52

3.5.1. Efficacy.

Liraglutide has been tested for chronic weight management in several studies including a 2-year, phase 2 dose-finding trial and four large scale, randomized, multicenter phase 3a trials named the Satiety and Clinically Adiposity- Liraglutide Evidence [SCALE] program (Table 1).53-58 SCALE Obesity and Prediabetes and Scale-Maintenance focused on the effects of individuals with obesity,55,56 SCALE-Diabetes included those with type 2 diabetes,57 and SCALE Sleep Apnea examined participants with moderate to severe obstructive sleep apnea.58 Across these studies, liraglutide produced a mean 5.2 kg placebo-subtracted weight loss at 1 year, with 63% of participants achieving a ≥5% weight loss, which included 34% achieving a ≥10% loss.7 Liraglutide, compared to placebo, was associated with reductions of 15.7 mg/dL in fasting blood glucose, 0.5% in hemoglobin A1c, and 2.8 mmHg in SBP.22 Some56 but not all 22,58 studies have also shown a reduction in fasting lipid levels. Reductions in DBP were not significantly different than the placebo.

3.5.2. Cardiovascular safety.

As with other GLP-1 agonists, liraglutide is associated with increases in heart rate of approximately 2 to 4 beats per minute.54,56,58,59 The underlying mechanism of this increase is not known. Heart rate should be monitored regularly and patients with sustained increases in heart rate should discontinue the medication. However, it does not appear to adversely affect cardiovascular outcomes, as revealed by results of the LEADER trial (i.e., The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results).60 In this large, multicenter, double-blind trial, cardiovascular outcomes study, 9340 patients with type 2 diabetes and high cardiovascular risk were randomized to receive liraglutide 1.8 mg daily or placebo and followed for a median of 3.8 years. The primary composite outcome -- death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke -- occurred in significantly fewer patients in the liraglutide group (13.0%) than in the placebo group (14.9%) (HR, 0.87; 95% CI, 0.78 to 0.97; p<0.001 for noninferiority; p=0.01 for superiority). There were significantly fewer deaths from any cause, as well as fewer cardiovascular deaths, in the liraglutide-treated group than with placebo.

Based on the favorable findings of the LEADER trial, the FDA did not request a separate CVD outcomes study of the effects of liraglutide 3.0 mg/d for obesity. However, post-hoc analyses of randomized, double- blinded, placebo-controlled studies of liraglutide 3.0 mg daily showed a hazard ratio of 0.42 (95% confidence interval=0.17, 1.08) for cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke as compared with placebo.61

4. AOMs in Development

Several novel AOMs currently are under investigation. One medication is semaglutide, a long-acting glucagon-like peptide-1 analogue, which has been approved by the FDA and EMA for the treatment of type 2 diabetes. Semaglutide is available as a subcutaneous injection taken once weekly or an oral administration given once daily.62 Two, large phase 3a pre-approval CVD outcome studies have been conducted to investigate the effects of subcutaneous and oral semaglutide on MACE in patients with type 2 diabetes and high cardiovascular risk. In the Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial, MACE occurred in 6.6% of the patients who received once-weekly subcutaneous injection of semaglutide (0.5 mg or 1.0 mg), which was significantly lower than the 8.9% of those in the placebo group (HR=0.74; 95% CI=0.58, 0.95; p<0.001 for non-inferiority; p=0.02 for superiority).63 The Peptide Innovation for Early Diabetes Treatment (PIONEER) 6 trial showed that MACE occurred in 3.8% of participants receiving once daily oral semaglutide (target dose 14 mg) compared to 4.8% for those in the placebo group (HR=0.79; 95% CI=0.57, 1.11; p<0.001 for noninferiority).64

A phase 2 trial of injectable semaglutide among patients with obesity has been completed. Participants on semaglutide 0.4 mg/d experienced a weight loss of −13.8% compared to −7.8% for liraglutide 3.0 mg/d and −2.3% for placebo.65 The phase 3 clinical studies evaluating semaglutide administered subcutaneously for patients with overweight or obesity, collectively called the Semaglutide Treatment Effect in People with Obesity (STEP) trials, are currently ongoing.62 A cardiovascular outcomes trial, the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, is also in progress.66 Tirzepatide, a gastric inhibitory polypeptide/GLP-1 agonist, is another example of an AOM that is currently being tested in phase 3 trials.67 A phase 3 CVD outcomes trial of tirzepatide in patients with type 2 diabetes and atherosclerotic cardiovascular disease is in progress.68 Other medications being evaluated for obesity in phase 3 clinical trials include setmelanotide (melanocortin-4 receptor agonist) and exenatide (GLP-1 analogue).69 But no CVD outcome data are available yet.

5. Conclusion

Four medications currently are approved by the US FDA for chronic weight management in adults with obesity. These medications have favorable effects on weight loss as well as some cardiometabolic parameters such as lipids and glucose. Phentermine/topiramate, naltrexone/bupropion and liraglutide are all associated with small increases in heart rate. Naltrexone/bupropion is also associated with modest increases in blood pressure. The clinical significance of these increases is uncertain. With the exception of liraglutide, for which a cardiovascular outcomes trial was conducted with a dose of 1.8 mg/d in patients with type 2 diabetes, cardiovascular outcome trials have not been completed for other AOMs. Thus, the effect on cardiovascular morbidity and mortality for AOMs aside from liraglutide has not been established. Additional medications such as semaglutide and tirzepatide are in the development pipeline, but their safety and efficacy as well as effect on cardiovascular outcomes have yet to be demonstrated.

6. Expert opinion

AOMs, used as an adjunct to a reduced calorie diet and increased physical activity, can help patients achieve clinically significant weight losses that can be maintained with continued use of the medication.16,55,70 Weight losses may be improved further when medications are combined with a structured program of intensive behavioral therapy.71-73 Weight losses of 5% to 10% of initial weight, as produced by current AOMs are associated with clinically meaningful improvements in cardiometabolic markers and risk factors. However, the adoption and utilization of these medications is low. Fewer than 2% of adults with obesity are offered and fill a prescription for one of these medications, creating a therapeutic gap in obesity treatment.74,75

Past experiences of AOMs being withdrawn from the market due to adverse cardiovascular outcomes have contributed to concerns among healthcare providers and patients about the safety of current weight loss medications. These experiences have also demonstrated that extrapolations from improvements in cardiovascular risk factors are not sufficient to establish cardiovascular outcome safety. Given the potential for cardiovascular risks of AOMs that occurred in phase 3 trials, the FDA has only recently approved medications with contingencies that cardiovascular outcomes trials be performed. Liraglutide is the only FDA-approved medication for chronic weight management that has a completed cardiovascular outcomes trial, albeit at a lower dose for type 2 diabetes.

Well-designed and adequately powered CVD outcome trials provide important information about the safety of these medications. Trials may be designed to exclude unacceptable cardiovascular risk, but some have also shown superiority after noninferiority was demonstrated (e.g., liraglutide). Evidence of cardiovascular benefits of particular medications could inform clinical guidelines for obesity treatment. This may be similar to the influence of results from CVD outcome trials on guidelines from the American Diabetes Association and European Association for the Study of Diabetes for care of patients with type 2 diabetes.76,77 For example, treatment choice for a diabetes medication now takes into account the individuals’ cardiovascular risk profile rather than being solely based on A1c or blood glucose.

The effects of these AOMs on cardiovascular morbidity and mortality need to be assessed throughout the various stages of medication development. The lessons learned from prior medications can help inform how these new AOMs are evaluated for cardiovascular safety. Upcoming trials must be designed to meet regulatory standards and also conducted in a manner that can help clinicians understand the cardiovascular risks and benefits. A careful analysis of the molecular properties, pharmacokinetics, preclinical data, and characteristics of the targeted populations should be considered.78 Early phase testing of medications could integrate assessments of possible cardiovascular risks or benefit signals such as sensitive, invasive or non-invasive surrogate endpoints and biomarkers that can identify cardiovascular signals.78,79 Example of surrogate endpoints include high-sensitivity CRP, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, interleukin-6, carotid artery intima-media thickness, and aortic pulse wave velocity.80-82 Conditional approvals of new medications should balance innovation and the urgent clinical needs for patients who may benefit with careful consideration of minimizing risks that may not be evident in efficacy trials. For example, patients who have not responded to an AOM after a few months should have their prescription discontinued. Studies are needed to investigate the behavioral mechanisms underlying AOMs, such as food cravings and emotional eating.83,84 In addition, studies are needed to identify phenotypes of patients who are most likely to receive benefit or harm from particular medications.

CVD outcome trials require substantial time and resources, and may delay regulatory approval. In 2018, a think tank with representatives from academia, industry, government, private payers, and regulatory agencies convened to review the effect of the FDA guidance on CVD outcome trials for medications to treat type 2 diabetes. Discussions included the burden, expense, and challenges of these trials. FDA advisors voted to continue requiring CVD outcome trials for diabetes medications, but the group made several recommendations for future regulatory guidance including: using a more simple, streamlined process to reduce costs and burden; increasing the diversity of patients enrolled; and considering head-to-head active comparator trials.85,86 Similar discussions need to occur about strategies that would optimize the efficiency, timeliness, and rigor of conducting CVD outcome trials for AOMs.

Current AOMs are demonstrated to have favorable effects on improving cardiometabolic markers such as cholesterol, and few adverse cardiovascular events have been reported. Future studies are needed to examine the long-term effects of these medications on cardiovascular safety. There is an urgent need for new AOMs which produce greater weight losses and improvements in obesity-related health complications, and which have favorable risk-benefit profiles.

Article highlights.

  • The current anti-obesity medications (AOMs) approved by the Food and Drug Administration for chronic weight management are orlistat, phentermine/topiramate, naltrexone/bupropion, and liraglutide.

  • AOMs generally have favorable effects on cardiometabolic parameters.

  • The long-term safety of orlistat, phentermine/topiramate, and naltrexone/bupropion on cardiovascular morbidity and mortality has not been established, and future studies are needed to examine the effects of these medications.

  • The cardiovascular safety of liraglutide was demonstrated in a large randomized cardiovascular outcomes trial in participants with type 2 diabetes.

  • New AOMs are needed which produce greater weight losses and have favorable risk-benefit profiles.

Acknowledgments

Funding

AM Chao was supported, in part, by the National Institute of Nursing Research of the National Institutes of Health under Award Number K23NR017209.

Footnotes

Declaration of interests

AM Chao reports grants and personal fees from WW International Co, outside the submitted work. TA Wadden reports serving on advisory boards for Novo Nordisk and WW International Co and receiving grants from both companies. RI Berkowitz reports serving on an advisory board for WW International Co and receiving a grant from Eisai Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

References

Papers of special note have been highlighted as:

* of interest

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