CV Effects of the New Weight Loss Agents

Vorsanger MH, Subramanyam P, Weintraub HS, et al.
Cardiovascular Effects of the New Weight Loss Agents. J Am Coll Cardiol 2016;68:849-859.

The following are 10 points to remember about the cardiovascular (CV) effects of the new weight loss agents:

  1. Excess weight is associated with CV risk factors including dyslipidemia, diabetes, hypertension, and obstructive sleep apnea. In addition to prior Food and Drug Administration (FDA)-approved medications for the treatment of obesity (orlistat, lorcaserin, phentermine/topiramate), the two recently approved weight loss medications are liraglutide and the combination of naltrexone/bupropion. In addition, the CV profile of phentermine/topiramate was reviewed. These recently approved medications are likely to be used by patients with CV disease (CVD) or at risk for CVD; therefore, it is important for clinicians to understand the effects of these drugs.
  2. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, which increases pancreatic beta cells’ sensitivity to glucose and suppresses glucagon production by pancreatic alpha cells. This results in hepatic gluconeogenesis, which inhibits gastric emptying and promotes satiety and weight loss.
  3. Liraglutide (injected once per day) was approved for weight loss in patients with a body mass index (BMI) >30 kg/m2 or >27 kg/m2 with an obesity-related comorbidity, including those with known CVD.
  4. Liraglutide reduces glycated hemoglobin (HbA1c), along with minimal reductions in high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. Mild reductions in blood pressure as well as improvements in inflammatory biomarkers have also been observed. However, increases in heart rate have been observed in liraglutide trials. Among the clinical trials, liraglutide has not been associated with increased risk for CVD outcomes; however, the authors note, there are currently neither outcome data available for the 3 mg dose of liraglutide approved for weight loss, nor ongoing studies examining CV outcomes with this dose.
  5. The second drug recently approved for weight loss is a combination of naltrexone/bupropion, which is comprised of a μ-opioid receptor antagonist and a dopamine and norepinephrine reuptake inhibitor. Pro-opiomelanocortin (POMC) cells in the arcuate nucleus of the hypothalamus play an important role in increasing energy expenditure, and reducing food intake and body weight. Bupropion increases the activity of POMC cells, whereas naltrexone blocks the opioid-driven autoinhibitory feedback loop. Pilot studies of the naltrexone/bupropion combination showed a significant weight reduction as compared with placebo, which was greater than either agent alone.
  6. The FDA has approved naltrexone/bupropion for the treatment of obesity for patients with a BMI >30 kg/m2 or >27 kg/m2 with an obesity-related comorbidity, at a target dose of 16 mg naltrexone and 180 mg bupropion orally twice daily.
  7. Naltrexone/bupropion’s effect on HbA1c is neutral to slightly favorable. Lipid effects appear favorable, with an increase in HDL and reduction in LDL cholesterol. However, both blood pressure and heart rate appear to increase with naltrexone/bupropion.
  8. Data on CV outcomes related to naltrexone/bupropion are not clear. In the LIGHT study, CV outcomes were specifically collected; however, parts of the results were disclosed early, which the FDA deemed inappropriate. Following this, the pharmaceutical company, Orexigen, announced an early termination of the study, and the investigators were unable to meet the predefined criteria for noninferiority regarding CV events. The investigators acknowledged a second trial is needed for determination of the CV events related to naltrexone/bupropion.
  9. The combination of phentermine/topiramate includes the sympathomimetic amine phentermine, which blocks reuptake of norepinephrine to suppress appetite and increase energy expenditure, while topiramate is thought to reduce appetite and lipoprotein lipase activity. The combination was approved for the treatment of obesity for patients with a BMI >30 kg/m2 or >27 kg/m2 with an obesity-related comorbidity, at a maximum dose of 15 mg phentermine and 92 mg topiramate orally once daily.
  10. Measures of glycemic control modestly improved, with a decrease in HbA1c. Lipid profiles appear to improve as well, with an increase in HDL and reduction in triglycerides. Systolic blood pressure has been observed to decrease as well with phentermine/topiramate, while increases in heart rate have been observed. So far, CV events in clinical trials have been low; however, these trials were not powered to examine CV events as a primary outcome.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Hypertension

Keywords: Anti-Obesity Agents, Appetite Depressants, Benzazepines, Blood Pressure, Body Mass Index, Bupropion, Cholesterol, LDL, Diabetes Mellitus, Dopamine, Dyslipidemias, Energy Metabolism, Glucagon-Like Peptide 1, Hemoglobin A, Glycosylated, Hypertension, Insulin-Secreting Cells, Lipoproteins, HDL, Naltrexone, Narcotic Antagonists, Obesity, Phentermine, Primary Prevention, Risk Factors, Triglycerides, Weight Loss

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