Obesity is a major health problem in the United States. The Centers for Disease Control and Prevention (CDC) defines the problem as weight that is higher than what is healthy for a given height, with quantitative definitions of overweight and obesity as body mass indices (BMIs) of 25 to 29.9 kg/m2 and ≥ 30 kg/m2, respectively.1 The prevalence of obesity among adults in 2017 ̶ 2018 was reported by the CDC to be 42.4%.2 Among women, the reported prevalence of obesity was lowest among Asian individuals (17.2%) and greatest among non-Hispanic Black individuals (56.9%), with White (39.8%) and Hispanic individuals (43.7%) having rates in between.2 In a meta-analysis of prospective studies that included 4 million people who were never smokers and had no chronic disease at baseline, age- and sex-adjusted mortality rates were studied over a median of 14 years of follow-up.3 Compared with those with a BMI of 20 to 25 kg/m2, people with a BMI of 30 to 34.9 kg/m2 or a BMI of 35 to 39.9 kg/m2 had increased risks of death of 46% and 94%, respectively, demonstrating that obesity increases this risk.3
The increased risk of death associated with obesity is caused by obesity-related diseases that cause early mortality, including diabetes mellitus (DM), dyslipidemia, hypertension, coronary heart disease, heart failure, atrial fibrillation, stroke, and venous thromboembolic events.4 Obesity is also associated with an increased risk of many cancers, including cancer of the endometrium, kidney, esophagus, stomach, colon, rectum, gallbladder, pancreas, liver, and breast.5 With regard to gynecologic disease, obesity is associated with an increased risk of fibroids and heavy menstrual bleeding.6 For pregnant patients, obesity is associated with increased risks of7:
- miscarriage and stillbirth
- preeclampsia and gestational hypertension
- gestational diabetes
- severe maternal morbidity
- postterm pregnancy
- venous thromboembolism
- endometritis.
For obese patients, weight loss can normalize blood pressure, reduce the risk of cardiovascular events, decrease the risk of cancer, and cure type 2 DM.8
Bariatric surgery: The gold standard treatment for reliable and sustained weight loss
All patients with obesity should be counseled to reduce caloric intake and increase physical activity. Dietary counseling provided by a nutritionist may help reinforce advice given by a provider. However, lifestyle interventions are associated with modest weight loss (<5% of bodyweight; FIGURE).9 The gold standard treatment for reliable and sustained weight loss is bariatric surgery.
In the Swedish Obese Subjects study, involving 2,010 people, following bariatric surgery the mean decrease in bodyweight was 23% at 2 years, with a slow increase in weight thereafter, resulting in a sustained mean weight loss of 18% at 10 years.8 In this study, people in the diet and exercise control group had no change in bodyweight over 10 years of follow-up.8 Not all eligible obese patients want to undergo bariatric surgery because it is an arduous sequential process involving 6 months of intensive preoperative preparation, bariatric surgery, recovery, and intensive postoperative follow-up. The perioperative mortality rate is 0.03% to 0.2%.10 Following bariatric surgery, additional operations may be necessary for more than 10% of patients.10 With recent breakthroughs in the medication management of obesity, patients who do not want bariatric surgery can achieve reliable weight loss of greater than 10% of body weight with glucagon-like peptide -1 (GLP-1) agonists.
ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT
GLP-1 agonist analogues: Practice-changing breakthrough in medication treatment
GLP-1, a 30 amino acid peptide, is produced by intestinal enteroendocrine cells and neurons in the medulla and hypothalamus.11 GLP-1 reduces hunger cravings and causes satiety, reducing daily food intake.12 GLP-1 also enhances the secretion of insulin, making GLP-1 agonists an effective treatment for type 2 DM. In humans and experimental animals, the administration of exogenous GLP-1 agonists decreases hunger cravings and causes satiety, reducing food intake, resulting in weight loss.12 The synthetic GLP-1 agonists, liraglutide (Saxenda) and semaglutide (Wegovy) are approved by the US Food and Drug Administration (FDA) as anti-obesity medications.
Native GLP-1 has a short circulating half-life of approximately 2 minutes. The synthetic GLP-1 agonist medications liraglutide and semaglutide are modified to significantly increase their half-life. Liraglutide is a modified version of GLP-1 with a palmitic acid side chain and an amino acid spacer resulting in reduced degradation and a 15-hour half-life, necessitating daily administration. Semaglutide has a steric acid diacid at Lys26, a large synthetic spacer, a modification of amino acid 8 with the addition of α-aminobutyric acid and a 165-hour half-life, permitting weekly administration.13 For weight loss, liraglutide and semaglultide are administered by subcutaneous injection. Tirzepatide (Mounjaro) is a novel GLP-1 agonist. It is also a gastric inhibitory peptide, is FDA approved to treat type 2 DM, and is awaiting FDA approval as a weight loss medication.Tirzepatide causes substantial weight loss, similar to the effect of semaglutide.14
Semaglutide and weight loss
Semaglutide is approved by the FDA for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity in adults with a BMI ≥ 30 kg/m2 or ≥ 27 kg/m2 in the presence of a weight-related comorbidity. It is also FDA approved to treat type 2 DM.
In a weight loss trial, 1,961 overweight and obese patients with a mean BMI of 38 kg/m2, were randomly assigned to semaglutide or placebo treatment for 68 weeks. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity. The mean changes in body weight for the patients in the semaglutide and placebo treatment groups were -14.9% and -2.4%, respectively. The treatment difference was -12.4% (95% confidence interval [CI], -13.4% to -11.5%; P <.001). In this study, compared with placebo, semaglutide treatment resulted in a greater decrease in waist circumference, -5.3 in versus -1.6 in.15 A network meta-analysis of the efficacy of weight loss medicines indicates that semaglutide is the most effective medication currently FDA approved for weight loss, reliably producing substantial weight loss (FIGURE).9
In one randomized clinical trial, investigators directly compared the efficacy of semaglutide and liraglutide in achieving weight loss. In this trial, 338 patients were assigned randomly to treatment with semaglutide 2.4 mg weekly subcutaneous injection, liraglutide 3.0 mg daily subcutaneous injection, or placebo. All the participants were following a regimen that included a calorie-reduced diet and increased physical activity.16 After 68 weeks of treatment, the mean weight changes were -15.8%, -6.4%, and -1.9% in the semaglutide, liraglutide, and placebo groups, respectively. The difference between the semaglutide and liraglutide groups was -9.4% (95% CI, -12% to -6.8%; P <.001).16
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