Recent research has brought to light notable differences in weight loss outcomes between women and men using Wegovy (semaglutide), a drug developed by Novo Nordisk. This article delves into these findings, exploring the nuances of how Wegovy impacts weight loss and cardiovascular health in both sexes, particularly among individuals with obesity-related heart failure.
Introduction
Obesity is a growing global health concern, with significant implications for cardiovascular health. Heart failure with preserved ejection fraction (HFpEF) is a condition where the heart pumps normally but is too stiff to function correctly, and it is often associated with obesity. Wegovy, known generically as semaglutide, has emerged as a promising treatment for weight management and has shown potential in improving cardiovascular outcomes. Recent studies, however, indicate that the effects of Wegovy may vary between men and women.
Wegovy and Heart Failure: A Gender-Based Analysis
Research presented at the American Diabetes Association’s 2024 Scientific Sessions and published in the Journal of the American College of Cardiology has revealed that Wegovy induces more significant weight loss in women than men with HFpEF. The data stems from Novo Nordisk’s STEP-HFpEF program, encompassing 1,145 patients across two clinical trials. These studies aimed to evaluate the impact of a 2.4-mg dose of semaglutide on health status, particularly via the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), and weight loss outcomes. Approximately half of the participants were women, who initially exhibited higher body mass index (BMI) and C-reactive protein levels, alongside a greater left ventricular ejection fraction. At the beginning of the study, women also reported more severe heart failure symptoms compared to men.
Weight Loss Disparities
After a 52-week treatment period with semaglutide, both male and female participants saw significant weight reductions. On average, men experienced a 10.2% decrease in body weight, while women achieved a 12.6% reduction. When adjusted for placebo effects, the weight-loss benefits of semaglutide remained more pronounced in women, with an average body weight reduction of 9.6%, compared to 7.2% in men. This gender-specific effect was statistically significant, evidenced by a p-value of 0.006 for the interaction.
Cardiovascular Outcomes
Regarding cardiovascular outcomes, the efficacy of semaglutide was comparable between sexes. Improvements in KCCQ-CSS were 7.6 points for women and 7.5 points for men. Additionally, semaglutide significantly enhanced the six-minute walk distance, with no notable differences between genders.
Read also: Sustainable weight loss using Wegovy
Expert Insights
Senior author Mikhail Kosiborod highlighted the importance of recognizing sex-based differences in obesity and related HFpEF. According to Kosiborod, these findings underscore the consistent benefits of semaglutide for both men and women. He noted that obesity and visceral adiposity significantly contribute to HFpEF development and progression, especially in women who constitute the majority of HFpEF patients and experience more severe symptoms and physical restrictions.
Semaglutide: Mechanism and Applications
Semaglutide is a GLP-1 receptor agonist that triggers insulin secretion from the pancreas in response to blood sugar levels. It is marketed as Ozempic for type 2 diabetes treatment and as Wegovy for chronic weight management. Novo Nordisk recently expanded Wegovy’s label to include reducing the risk of cardiovascular death, heart attack, and stroke in adults with obesity and cardiovascular disease. Additionally, Novo Nordisk is exploring semaglutide's potential as a kidney treatment. Results from the Phase III FLOW trial showed a 20% reduction in death from any cause among type 2 diabetes patients with chronic kidney disease, emphasizing the drug's versatility and potential in treating various conditions.
Factors Influencing Weight Loss Differences
Several factors may explain the observed differences in weight loss between men and women using Wegovy.
Metabolic and Hormonal Differences
Dr. John Lowe, a Physician at Restore Care, commented on the study, saying that this difference between the sexes could be explained by metabolism as well as hormonal profiles. Females generally have more body fat, distributed differently, which may respond better to the mechanisms of action of Wegovy.
Social and Behavioral Factors
Females often react differently in weight loss trials due to diverse prompting factors and social pressures. These factors could increase adherence to treatment protocols and lifestyle changes, enhancing the drug's effectiveness.
Read also: Weekly Wegovy Progress
Genetic Variations
Pharmacogenomics studies show that genetic variations can affect how individuals react to a medication, potentially accounting for the differences in weight loss outcomes.
Exposure and Dosage
One factor is presumably related to exposure difference due to women having a lower average body weight. A number of studies have shown the weight loss increased with greater exposure to glucagon-like peptide 1 receptor agonist (GLP-1 RA) and appeared to level off at the highest exposure in most women.
Sex Hormones and Feeding Behavior
Recent evidence suggests that women and men may regulate feeding behavior differently due to the impact of sex hormones. In preclinical models, conjugated GLP-1 RA and estrogen reduced body weight, food intake and food reward more than either of these agents applied separately.
Gastric Emptying
Gender is significantly associated with the rate of gastric emptying (GE). GE of solids in pre-menopausal women has been found to be slower than that in men, irrespective of the phase of the menstrual cycle.
Adverse Event Profiles
There are also a number of minor differences between men and women in terms of adverse event profiles that might also lead to some differences in the efficacy of semaglutide. Knowing the positive correlation between frequency and severity of gastro-intestinal adverse events (GI-AEs) and weight reduction, sex-related differences in the occurrence of GI-AEs may also be associated with observed increased GLP-1 RA efficacy among women.
Read also: Duration of Wegovy Treatment
Implications for Cardiovascular Health
Dr. Michael O. McKinney, a physician and nutritionist with Healthy Outlook, commented on the study, saying that obesity is a major risk factor for developing cardiovascular disease. Additionally, heart disease is the leading cause of death for males and females. Wegovy could play a central role in mitigating this risk through weight reduction for women suffering from obesity. Losing weight helps to mitigate several cardiovascular risk factors such as decreased blood pressure levels, cholesterol and inflammation.Weight loss in females living with obesity and heart disease can improve the management of their condition as well as reverse some of the consequences of carrying excess pounds. If it works better in women than men, then Wegovy could be an amazing strategy for such patients toward effective control of their body weight, thereby reducing the chances of them having heart problems in the future. McKinnney further described the findings of the study as “promising,” especially for females in at-risk groups. This means that targeting efficient strategies toward achieving what would optimize female physiological functions will highly contribute to a better health system by reducing mortality rates due to heart disease among women.
Broader Context: Semaglutide and Obesity Treatment
The Semaglutide Treatment Effect in People with Obesity (STEP) Phase 3a clinical development program evaluated the safety and efficacy of semaglutide for weight management in adults with obesity or overweight with at least one weight-related comorbidity. Subgroup analyses of trials on adults conducted to evaluate the change in efficacy response of semaglutide by sex found a greater mean weight reduction in women than in men in STEP 1, 2 and 4.
Dosage and Titration
Finding the optimal dose titration scheme helps to reduce AEs, and improve tolerability and adherence. A phase 2 dose-finding study for semaglutide in which 65% of the study population were men reported that slow dose escalation of semaglutide using 4-week dose escalation steps starting from an initial dose of 0.25 mg/week ameliorated AEs without compromising efficacy. Based on differences in exposure-response analysis between men and women, established MTSD and our clinical experience, we propose that a higher initial dose of semaglutide of 0.5 mg/week should be considered for men, especially those with BMI > 35 kg/m2. In the event of good tolerability, a rapid titration scheme in general may then be used in men. Since the response on weight reduction in men seems to be delayed in comparison to that in women, we also advise to delay the efficacy assessment in men to later than 3 months after treatment initiation.
Male Obesity and Hypogonadism
Obesity contributes significantly to male hypogonadism and infertility. The potential benefit of weight loss induced by GLP-1 RA on male sexual function and fertility remains significantly understudied, and the impact of GLP-1 RA on the gonadal axis and on obesity-related hypogonadism in men has been evaluated only in one study. This study demonstrated that treatment with GLP-1 RA had a modest effect on testosterone levels and a significant potential to improve sexual symptoms irrespective of modest increase in total testosterone.
SELECT Trial: Semaglutide Effects on Heart Disease
The SELECT trial studied patients with established CVD and overweight or obesity but without diabetes. In SELECT, semaglutide was associated with a 20% reduction in major adverse CV events. Data derived from the SELECT trial offer the opportunity to evaluate the weight loss efficacy, in a geographically and racially diverse population, of semaglutide compared with placebo over 208 weeks when both are given in addition to standard-of-care recommendations for secondary CVD prevention (but without a focus on targeting weight loss). Furthermore, the data allow examination of changes in anthropometric measures such as BMI, waist circumference (WC) and waist-to-height ratio (WHtR) as surrogates for body fat amount and location.
Weight and Anthropometric Outcomes in SELECT
At week 208, semaglutide was associated with mean reduction in weight (−10.2%), waist circumference (−7.7 cm) and waist-to-height ratio (−6.9%) versus placebo (−1.5%, −1.3 cm and −1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m−2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide. Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased.
Subgroup Analysis in SELECT
Women had a greater difference in mean weight loss with semaglutide versus placebo (−11.1% versus −7.5% in men; P < 0.0001). There was a linear relationship between age category and degree of mean weight loss, with younger age being associated with progressively greater mean weight loss, but the actual mean difference by age group is small. Patients from Asia and of Asian race experienced slightly lower mean weight loss. There was no difference in weight loss with semaglutide associated with ethnicity, glycemic status or renal function.
Clinical Implications and Future Directions
The observed differences in weight loss between men and women using Wegovy have significant clinical implications. It is crucial to consider these sex-based differences when prescribing and monitoring Wegovy treatment. Tailoring treatment strategies to optimize outcomes for both sexes may involve adjusting dosages, considering hormonal and metabolic factors, and addressing social and behavioral influences on adherence to treatment.Future research should focus on elucidating the underlying mechanisms driving these sex-based differences. Further studies are needed to explore the impact of semaglutide on male sexual function and fertility, as well as to evaluate the long-term effects of Wegovy on cardiovascular outcomes in both men and women.
Paradigm Shift in HFpEF Treatment
Kosiborod said, is a paradigm shift in how the medical community is thinking about HFpEF-ie, that it is a cardiometabolic disease. I think this opens up an entirely new avenue of clinical research with various anti-obesity strategies in this patient population, which is super exciting.