This article explores obesity as a condition characterized by excess dysfunctional adipose tissue, which contributes to chronic low-grade inflammation, insulin resistance, and obesity-related cardiometabolic syndrome. It examines the benefits of weight loss, the limitations of lifestyle interventions, and the emergence of anti-obesity medications as the new standard of care.
Obesity has become a global epidemic, with rates more than tripling between 1975 and 2022.1 According to the World Obesity Federation, nearly 3 billion people are now classified as overweight or obese – driving global increases in morbidity and mortality. To understand why treatment matters, it is important to look at the biology of obesity and its systemic effects.
The body contains two main fat depots: subcutaneous adipose tissue (SAT), which is the fat stored just beneath your skin, and visceral adipose tissue (VAT), which accumulates deeper in the abdomen, surrounding internal organs. With weight gain, it is primarily VAT that expands – through hypertrophy of its adipocytes – rather than SAT.
Because fat cannot be redistributed from VAT to SAT, once VAT reaches its storage limit, excess fat begins to accumulate in organs and tissues that are typically lean.
This process, known as ectopic fat deposition, affects the heart, liver, kidney, muscle, and pancreas and leads to lipotoxicity to these organs. The extent of ectopic fat correlates with the degree of visceral adiposity.2
Adipose tissue is an active gland with both endocrine and metabolic functions. Fat cells, or adipocytes, secrete at least 600 different adipokines – a group of hormones, bioactive peptides, and proteins.3
In the presence of normal adipose tissue levels, adipokines help maintain the balance between anti-inflammatory, insulin-sensitizing signals (e.g., adiponectin, omentin) and pro-inflammatory, insulin-resistant signals (e.g., leptin, TNF- alpha, IL-6). When obesity develops, particularly through the expansion of visceral adipocytes, this balance shifts. The result is chronic low-grade inflammation and insulin resistance, leading to endothelial dysfunction and obesity-related cardiometabolic syndrome.3
Beyond the damage caused by ectopic lipid accumulation (lipotoxicity), the ectopic fat deposits themselves secrete additional inflammatory adipokines, contributing to local organ injury and elevated cardiovascular risk.4 One instance is epicardial fat – located in the pericardial space and within the myocardium – which is both a marker for cardiovascular risk and a precursor of cardiac pathology. As an example, this can be an independent risk factor for the development of atrial fibrillation.5
Similarly, intrahepatic visceral fat, found in and around liver cells, can lead to metabolic dysfunction-associated steatotic liver disease (MASLD). This may progress to metabolic dysfunction-associated steatohepatitis (MASH) and ultimately to fibrosis (i.e., cirrhosis). MASLD is not only a known liver disease risk – it also acts as an independent risk factor for atherosclerotic heart disease.6
Obesity-related cardiometabolic syndrome (CMS), also referred to by the American Heart Association as cardiovascular-kidney-metabolic syndrome (CKM), is defined as “a systemic disorder characterized by pathophysiological interactions among metabolic risk factors, chronic kidney disease (CKD), and the cardiovascular system leading to multiorgan dysfunction and a high rate of adverse cardiovascular outcomes.”7
This condition is driven by the accumulation of excess dysfunctional adipose tissue, which causes inflammation, oxidative stress, and insulin resistance.
From an insurance perspective, the most significant impact of CMS is its strong association with cardiovascular morbidity and mortality.
The phrase “systemic disorder leading to multiorgan dysfunction” highlights the broad health consequences of CMS, including the development of hypertension, dyslipidemia, hyperuricemia, and prediabetes – a condition often accompanied by glucotoxicity and possible progression to type 2 diabetes mellitus (type 2DM).
In addition to these core metabolic effects, CMS contributes to a wide range of other conditions, including respiratory disease, dementia, obstructive sleep apnea, and increased incidence of obesity-related cancers.
Effective treatment of obesity-related CMS should ideally include two components:
Until recently, no widely available therapies effectively targeted obesity itself. As a result, the treatment focused on associated risk factors without reducing the visceral or ectopic fat driving the condition. This approach left individuals with persistently elevated mortality and morbidity risk.
Does weight loss reduce dysfunctional adipocytes in VAT and ectopic sites and improve a person’s cardiometabolic risk? The short answer is yes.
With weight loss, there is a preferential reduction of visceral fat. One study showed that weight losses of 5%, 11%, and 16% were associated with respective decreases in intra-abdominal fat of 9%, 23%, and 30% (measured in cm3). Even more significant were reductions in ectopic intrahepatic triglycerides of 13%, 52%, and 65%, respectively – measured by magnetic resonance imaging.8
Cardiometabolic risk factors begin to improve even with modest weight loss, with greater improvement seen as more weight is lost. A 5% reduction leads to a significant improvement in insulin sensitivity in both liver and adipose tissue, while a greater loss of 11%-16% is needed to significantly improve muscle insulin sensitivity. Inflammatory markers do not tend to improve with a 5% weight loss but do show meaningful reductions with a 11%-16% weight loss.8
These effects are seen clinically. A 2%-5% weight reduction improves fasting blood glucose and HbA1c in type 2DM. In those with impaired glucose tolerance, every kilogram lost reduces the risk of progression to type 2DM by 16%. A 2%-5% weight loss also improves triglycerides and systolic blood pressure, but a 5%-10% weight loss is required to improve HDL cholesterol and lower diastolic BP.
A 5%-10% loss is also associated with reduced pain and improved function in individuals with osteoarthritis, a reduction in liver fat in those with MASLD, and slower age-related mobility decline. These benefits have been observed in most lifestyle modification programs, which typically achieve weight losses of 3%-7% without medications.9
Greater weight loss of 10%-20% typically requires the use of newer anti-obesity medication, such as semaglutide (Wegovy, a GLP-1 RA – glucagon-like peptide 1 receptor agonist) or tirzepatide (Zepbound, a dual GLP-1 and GIP – glucose-dependent insulinotropic polypeptide). At this level of weight reduction, studies have shown improvement in MASH scores (based on liver biopsy) and in the apnea-hypopnea index (AHI) among individuals with obstructive sleep apnea.10
Weight loss greater than 20% has, until recently, been observed primarily in individuals undergoing bariatric surgery. One systematic review and meta-analysis found that, compared to controls, bariatric surgery was associated with:
A separate meta-analysis comparing bariatric surgery to controls reported similarly significant reductions:
These findings are based on non-randomized controlled studies and await confirmation in randomized clinical trials.
Weight loss greater than 20% has been observed in:
Weight loss greater than 25% has not been seen with semaglutide but occurs in:
Weight loss of more than 30% has been observed only in studies with retatrutide, affecting 26% of patients. This medication is currently in development, with an expected launch by Eli Lilly in 2027.13,14,15
The impact of these medications on population-level mortality and morbidity has been explored by RGA.
Oral forms of semaglutide (i.e., 50 mg/day) and a non-peptide GLP-1 receptor agonist (GLP-1RA) called orforglipron may reduce costs and improve access, once approved.
Another consideration is discontinuation. When GLP-1 medications are stopped, the weight lost is often regained. In contrast, continued use has shown sustained weight loss for up to four years.16
From a medical standpoint, it is not surprising that discontinuing GLP-1RAs often results in weight regain – just as stopping antihypertensive or antidiabetic medications can cause blood pressure or blood glucose to rise again.
In one- and two-year studies, discontinuation rates of GLP-1RAs were:
Lower discontinuation rates were associated with greater weight loss, higher income, and fewer gastrointestinal side effects. When weight was regained after stopping treatment, patients frequently reinitiated therapy. Reinitiation rates at one and two years were:
The optimal approach for long-term weight maintenance – whether through continuous dosing, microdosing, or intermittent use – remains uncertain and warrants future research.
The new GLP-1 anti-obesity medications represent a meaningful advance in treating the underlying cause of obesity-related cardiometabolic syndrome. By directly targeting adipose dysfunction, these therapies have the potential to reduce obesity-related morbidity and mortality.
For insurers, factors like access, adherence, and long-term outcomes will make the insurance impact more nuanced. In addition, the accurate risk assessment of individuals who are taking new GLP-1 therapies will require expert underwriting consideration.
RGA health insurance experts are actively engaging with insurers to help determine optimal paths forward with the GLP-1 impact and other emerging issues. Ready to join the conversation? Contact RGA.
