Cardiovascular Effects of Novel Weight Loss Therapies

Usman MS, Davies M, Hall ME, et al.
The Cardiovascular Effects of Novel Weight Loss Therapies. Eur Heart J 2023;Nov 15:[Epub ahead of print].

The following are key points to remember from a state-of-the-art review on the current evidence regarding cardiovascular (CV) effects of novel weight loss therapies:

  1. The prevalence of overweight and obesity has increased dramatically, such that >50% of adults in the European Union are overweight (body mass index [BMI] >25 to <30 kg/m2) and 17% meet criteria for obesity (BMI ≥30 kg/m2).
  2. Adults with obesity carry an increased risk for type 2 diabetes (T2D), CV risk factors including hyperlipidemia and hypertension, and incident CV disease (CVD; i.e., coronary artery disease, heart failure, and stroke).
  3. Lifestyle modification has been the cornerstone of treatment for obesity. Lifestyle intervention is recommended by the U.S. Preventive Services Task Force, Centers for Medicare & Medicaid Services, and the Guidelines for Managing Overweight and Obesity in Adults. Guidelines recommend an intervention duration of ≥6 months with an extension of ≥1 year for maintenance.
  4. The diet goal should be 1200-1500 kcal/day for women and 1500-1800 kcal/day for men with an individualized macronutrient composition. The recommended exercise target is ≥150 minutes/week or 30 minutes of walking 5 days per week, and recommended behavioral changes include goal setting, stimulus control, daily monitoring of food intake and physical activity, and weekly record of weight.
  5. Several medications have demonstrated improvements in weight loss and associated CV risk factors. Trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated weight loss among patients with T2D, but with heterogeneity across the GLP-1 agonist class; liraglutide and semaglutide have the greatest efficacy. GLP-1 RAs increase glucose-dependent insulin secretion, reduce glucagon secretion, slow gastric emptying, and increase satiety.
  6. Both the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) have approved liraglutide (3.0 mg SQ once-daily) and semaglutide (2.4 mg SQ once-weekly) for chronic weight management in patients with overweight or obesity and at least one weight-related condition (such as hypertension, T2D, or hypercholesterolemia). Semaglutide 2.4 mg once weekly is the only weight loss medication that has shown improvement in CV outcomes and should be considered in all patients with overweight or obesity, and especially in patients with established CVD.
  7. Tirzepatide is a combined glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA, and is the first licensed dual GLP-1 and GIP RA for glucose lowering in T2D. Tirzepatide was recently approved by both the EMA and FDA for the treatment of T2D as an addition to diet and exercise, but is not yet approved for weight management. Furthermore, the long-term safety and CV effects of this agent remain uncertain. Ongoing trials including SURMOUNT-MMC and SURPASS-CVOT in T2D will provide data on weight loss and CV outcomes associated with tirzepatide.
  8. Naltrexone/bupropion is a combination medication that acts centrally to promote satiety and increase energy expenditure, resulting in weight loss. The combination is approved by the EMA and FDA for chronic weight management; however, data on CV outcomes are limited. Because these drugs tend to cause a mild increase in blood pressure, naltrexone/bupropion should be avoided in patients with hypertension, especially if severe or uncontrolled.
  9. Orlistat lowers dietary fat absorption by approximately 30%, inhibiting gastrointestinal (GI) lipase. The effect of orlistat on weight and cardiometabolic parameters has been assessed in >150 trials, either on its own or in combination with other obesity pharmacotherapy, glucose-lowering, or lipid-lowering medications. In a network meta-analysis, orlistat was found to reduce weight by 3.2% more compared with usual care. Trials of orlistat have demonstrated reductions in blood pressure, low-density lipoprotein (LDL) cholesterol, and triglycerides. Among adults with pre-diabetes, orlistat is associated with a reduced risk for developing T2D and improved glycemic control among T2D patients. The EMA and FDA have approved over-the-counter sale of orlistat for weight loss. It is also the only medication approved for weight loss in adolescents. Although no CV outcome trials have been conducted, improvements in CV risk factors and risk markers have been demonstrated. It should be noted GI side effects are common and can limit patient tolerance for taking orlistat.
  10. Bariatric surgery is also associated with significant weight loss. The two most frequently performed bariatric surgeries are Roux-en-Y gastric bypass and sleeve gastrectomy. Numerous clinical trials have shown that bariatric surgery results in a weight loss of 15%-20% in excess of medical weight management or lifestyle alone. This weight loss is achieved by year of follow-up and has been shown to be sustained up to 5 years. Bariatric surgery also improves CV risk factors, including reductions in systolic and diastolic blood pressure, LDL, and triglycerides. Bariatric surgery is currently recommended for: a) patients with a BMI ≥40 kg/m2; b) those with a BMI ≥35 kg/m2 and obesity-related complications such as T2D, CVD, or sleep apnea; and c) patients with BMI ≥30 kg/m2 and T2D that is difficult to control with medical treatments and lifestyle modification.
  11. Weight loss pharmacotherapy should be continued on a chronic basis to maintain the weight loss. Bariatric surgery should be considered in patients with refractory or complicated morbid obesity.

Clinical Topics: Prevention

Keywords: Glucagon-Like Peptide-1 Receptor, Obesity, Weight Loss

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