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Cardiovascular implications of newer obesity medications
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Obesity affects more than 30% of adults in the United States and directly contributes to increased risk for cardiovascular disease. Lifestyle interventions are the mainstay of treatment, but pharmacotherapy may be considered as an adjunct for adults with a BMI of at least 30 kg/m2 or a BMI of at least 27 kg/m2 with one or more obesity-related comorbidities.
Withdrawal of antiobesity medications from the U.S. market (eg, fenfluramine, dexfenfluramine, sibutramine) has been primarily associated with drug-related adverse CV events. Until recently, the only medications approved for weight management include sympathomimetic amines (eg, phentermine) and orlistat (Alli, GlaxoSmithKline; Xenical, Hoffmann-La Roche), a lipase inhibitor. We review the CV implications of four newer agents approved for chronic weight management since 2012.
A look at lorcaserin
The FDA approved lorcaserin (Belviq, Eisai) for the treatment of obesity based on three phase 3 clinical trials (BLOOM, BLOSSOM, BLOOM-DM) in 2012. Lorcaserin positively affected cardiometabolic parameters (see Table 1 on page 7), and the average weight reduction from baseline at week 52 was 5.8% for lorcaserin 10 mg twice daily vs. 2.2% for placebo.
Lorcaserin promotes satiety through selective activation of serotonin 5-HT2C hypothalamic receptors. Despite this drug’s selectivity for 5-HT2C, there is concern for development of asymptomatic valvulopathy as seen with fenfluramine, which is attributed to nonselective activation of 5-HT2B receptors in cardiac valves. In clinical trials, the incidence of valvular regurgitation was 2.4% for lorcaserin vs. 2% for placebo, but studies were underpowered and lorcaserin was not evaluated in patients with valvular heart disease, heart failure or pulmonary hypertension. No signal of adverse cardiac events was seen during the reported trials.
An ongoing long-term study (median follow-up, 3-4 years), CAMELLIA-TIMI 61, will evaluate the effects of lorcaserin vs. placebo on major adverse CV events in patients with established CVD or type 2 diabetes plus multiple risk factors for CVD. Results are anticipated in 2018.
Although the 2015 Endocrine Society guideline on the pharmacologic management of obesity recommends lorcaserin (and orlistat) over sympathomimetic amines in patients with CVD, until more long-term safety data are available, patients presenting with potential signs of valvular heart disease should be evaluated and the drug potentially discontinued. Because of its mechanism of action, lorcaserin should not be given to individuals taking selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. Headache is the most common adverse effect. Lorcaserin is not recommended in patients with severe renal disease and has no dose adjustment for patients with mild to moderate renal or hepatic disease (see Table 2).
A look at phentermine/topiramate
Phentermine/topiramate (Qsymia, Vivus) was approved by the FDA in 2012 for chronic weight management. Phentermine is a sympathomimetic amine that stimulates the release of norepinephrine from the hypothalamus; topiramate is an anticonvulsant that is thought to promote weight loss by augmenting gamma-aminobutyrate, modulating voltage-gated ion channels, inhibiting AMPA/kainate excitatory glutamate receptors and inhibiting carbonic anhydrase, although the actual mechanism for weight loss is unclear.
The clinical efficacy of phentermine 15 mg/topiramate 92 mg once daily is supported by two 56-week phase 3 studies (CONQUER, EQUIP) and one 52-week extension study (SEQUEL) that demonstrated sustained weight loss of approximately 9% to 10% vs. 1.8% with placebo, improved cardiometabolic markers and reductions in antihypertensive medications after 2 years of treatment. Of note, patients receiving the drug experienced a dose-dependent increase in heart rate of 1.2 bpm to 1.7 bpm (average). Palpitations and tachycardia also occurred more frequently, but the rate pressure product was not statistically significant vs. placebo. Additionally, there was no difference in major adverse CV events between phentermine/topiramate and placebo, but given the low number of events, a definitive association cannot be made.
While awaiting the results of a long-term CV outcome study in patients at intermediate and high risk (AQCLAIM), heart rate should be monitored in all patients taking phentermine/topiramate, and phentermine-containing products should be avoided in patients with known CVD and uncontrolled hypertension.
Insomnia, paresthesia, dry mouth and constipation are the most common adverse effects. The medication should not be used in patients with severe renal disease, and a dose reduction is required in patients with moderate renal and moderate hepatic disease. Phentermine/topiramate is a teratogen, and contraception and monthly pregnancy testing under a Risk Evaluation and Mitigation Strategy (REMS) program are mandated for women with reproductive potential. Periodic renal function monitoring is required. Increases in area under the curve and additive effects on hypokalemia are observed when phentermine/topiramate is combined with a thiazide diuretic, and therefore, more careful monitoring of serum potassium is required when used with nonpotassium-sparing diuretics.
A look at naltrexone/bupropion
Naltrexone SR/bupropion SR (Contrave, Orexigen Therapeutics) was approved by the FDA for weight management in 2014. Bupropion is a dopamine and norepinephrine reuptake-inhibitor that stimulates release of alpha-melanocyte-stimulating hormone from hypothalamic pro-opiomelanocortin (POMC) neurons to reduce appetite and increase energy expenditure. Naltrexone, a pure opioid receptor antagonist, blocks opioid receptor-mediated POMC autoinhibition, augmenting the effects of POMC. Through regulation of the hypothalamic melanocortin and mesolimbic reward systems, these synergistic agents promote weight loss.
Naltrexone 32 mg/bupropion 360 mg daily positively affected weight loss, glycemic control and lipid parameters in four phase 3 clinical trials (COR-I, COR-II, COR-BMOD, COR-DIABETES). After 56 weeks of treatment, increases in systolic BP (average, 1.1 mm Hg- 1.8 mm Hg) and heart rate (average, 1 bpm-2.5 bpm) were noted in patients taking the drug vs. placebo.
LIGHT was a long-term CV outcomes trial evaluating the drug in adults with overweight and obesity with confirmed or at high risk for CVD. The primary endpoint was time to first occurrence of major adverse CV events. This study was terminated prematurely after release of confidential 25% interim analysis data, which revealed that major adverse CV events occurred in 35 (0.8%) patients in the naltrexone/bupropion group vs. 59 (1.3%) patients in the placebo group (HR = 0.59; 95% CI, 0.39-0.9). The less favorable 50% interim analysis showed that major adverse CV events occurred in 90 (2%) and 102 (2.3%) of naltrexone/bupropion- and placebo-treated patients, respectively (HR = 0.88, adjusted 99.7% CI, 0.57-1.34). As a result of study termination, noninferiority could not be assessed, and thus, the overall CV benefits and safety remain unclear.
A second study evaluating CV outcomes for naltrexone/bupropion is to be completed in early 2022. Until additional information is known, the drug should be avoided as first-line in patients with high CV risk.
Common adverse effects include nausea, constipation and headache. The use of the medication is contraindicated in patients with uncontrolled hypertension, seizure disorder, eating disorders or chronic opioid use. Bupropion carries a black box warning for suicidal thinking/behavior and neuropsychiatric effects; proportions of patients reporting psychiatric and sleep adverse effects were higher with naltrexone/bupropion vs. placebo in clinical trials. The maximum daily dose should be reduced in patients with hepatic or renal impairment.
A look at liraglutide
Liraglutide (Saxenda, Novo Nordisk) is the latest FDA-approved agent for chronic weight management. Liraglutide is a glucagon-like peptide-1 receptor agonist administered as a once-daily injection. Liraglutide also is approved for diabetes treatment at lower doses.
The efficacy of liraglutide 3 mg once daily has been established in three phase 3 studies (the SCALE clinical trials), but average increases in heart rate of 4.3 bpm to 8.1 bpm were noted in patients receiving the drug. The LEADER trial was a long-term CV outcomes study evaluating the effects of liraglutide 1.8 mg daily in adults with diabetes aged 50 years and older with at least one CV comorbidity or adults aged 60 years and older with at least one CV risk factor. After a median follow-up of 3.8 years, the primary composite outcome of major adverse CV events occurred in 608 (13%) vs. 694 (14.9%) of patients in the liraglutide and placebo arms, respectively (HR = 0.87; 95% CI, 0.78-0.97; P < .001 for noninferiority, P = .01 for superiority). These findings are favorable, but may not be applicable to the higher 3-mg dose used for weight management. Although liraglutide appears to have a favorable CV profile compared with other agents, HR should be monitored in patients prescribed liraglutide 3 mg daily.
Liraglutide should not be administered with other GLP-1 agonists. Common adverse effects are nausea, vomiting, diarrhea, constipation and dyspepsia. Hypoglycemia is potentiated in patients with type 2 diabetes. Liraglutide has a black box warning on the risk for thyroid C-cell tumors and should not be used in patients with medullary thyroid carcinoma or a family history of medullary thyroid carcinoma.
Current and future use
Newer antiobesity medications have demonstrated clinically significant weight loss and improvements in surrogate cardiometabolic parameters (see Table 1). All contemporary trials are conducted against a background of behavior therapy modification counseling, physical activity averaging about 30 minutes of moderate activity per day and a 500 kcal per day to 600 kcal per day deficit diet.
However, overall long-term CV risks and benefits are unknown for these agents in patients being treated for obesity. Based on available literature, liraglutide currently may offer a safer CV profile, whereas other approved agents should be used cautiously in patients with known CV history (see Table 2).
Individualized pharmacotherapy for this chronic condition requires careful CV assessment and consideration for comorbid conditions. Appropriate CV monitoring for adverse events should follow drug initiation to promote the safe and effective use of these agents.
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- Anne M. Kome, PharmD, is an ambulatory care PGY2 resident at The Ohio State University. Debra J. Barnette, PharmD, is an assistant professor at The Ohio State University. Sarah A. Spinler, PharmD, FCCP, FAHA, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at the University of the Sciences in Philadelphia. Spinler is the Pharmacology Consult column editor. She can be reached at s.spinle@usciences.edu.
Disclosure: The authors report no relevant financial disclosures.