Inequalities in the provision of GLP-1 receptor agonists for the treatment of obesity

Abstract

GLP-1 receptor agonists are effective treatments for obesity but are less accessible worldwide than pharmacological treatments for diabetes, reflecting biases and lack of education, and perpetuating health inequalities.

Obesity, defined as excess adiposity, is the most prevalent chronic disease, affecting more than 800 million people worldwide^1,2. Although lifestyle interventions and behavioral modifications are the foundation of obesity management, most patients can also benefit from pharmacotherapy and/or metabolic and bariatric surgery to assist with weight loss or maintenance and to improve overall health (Table 1)^2,3. Unfortunately, only 1–2% of eligible patients in the USA are prescribed medication or offered surgery to assist with obesity treatment⁴.

Table 1 |.

Causes of and treatments for obesity

Factor	Examples
Pathophysiology	Genetics Epigenetics Reduced insulin sensitivity Medication induced, including by steroids, psychotropics, antihistamines, antidepressants and sleep agents Glucotoxicity Lipotoxicity Inflammation
Contributory social determinants of health	Toxic stress Bias and discrimination Food insecurity Income insecurity and inequality Environmental health hazards such as tobacco smoke, air pollution, chemical pollutants and lack of green space
Pharmacological treatments	Phentermine Phentermine–topiramate (Qsymia) Bupropion–naltrexone (Contrave) Orlistat (Xenical, Alli) Liraglutide (Saxenda) Semaglutide (Wegovy)
Issues that reduce treatment accessibility	Lack of insurance coverage Variations in insurance coverage Prescribing barriers such as bias, lack of provider education and requirement for prior authorizations

Metabolic and bariatric surgery is the most effective way to manage severe obesity with a body mass index (BMI) of ≥35 kg/m². This surgery leads to an average weight loss of 20–35%, depending on the surgical procedure, which in turn leads to substantial improvement in metabolic markers and decreased morbidity and mortality. First-generation anti-obesity medications, including phentermine, phentermine–topiramate and bupropion–naltrexone, promote ~5–10% weight loss, which enables favorable changes in blood pressure, fasting glucose and cholesterol.

Second-generation medications mimic the gastric hormone glucagon-like peptide-1 (GLP-1) to promote gastric fullness and control hunger and appetite. Liraglutide and semaglutide are long-acting GLP-1 receptor agonists that can result in an average of ~5–15% weight loss and favorable metabolic changes, making them more suitable alternatives to first-generation medications for long-term weight loss. Current inequities in access, however, limit the use of GLP-1 receptor agonists as an obesity pharmacotherapy option.

Treatments for overweight and obesity

In 1987, GLP-1 was discovered as an incretin released from the gut. Modifying the native GLP-1 molecule to increase its half-life from 1–2 min to hours led to the development of exenatide, the first GLP-1 receptor agonist approved for type 2 diabetes (T2D) treatment by the US Food and Drug Administration (FDA) and European Medical Agency (EMA), in 2005 and 2006, respectively. Subsequently, liraglutide 1.8 mg, dulaglutide 3.0 mg and semaglutide 1.0 mg were also approved for T2D management.

Outside the pancreas, there are GLP-1 receptors in the brain, stomach and gut, and adipose tissue⁵. Within the brain, GLP-1 decreases appetite and food intake while increasing satiety. GLP-1 slows gastric and intestinal motility in the stomach and gut, and GLP-1 receptors within adipose tissue can promote browning, leading to increased thermogenesis. The multiple roles of GLP-1 in the central nervous system, gastrointestinal tract and adipose tissue make GLP-1 receptor agonists viable weight management options. Thus, in 2014, liraglutide 3.0 mg, administered subcutaneously daily, was approved by the FDA for weight management, and approval of semaglutide 2.4 mg followed in 2021.

Semaglutide is the most effective GLP-1 receptor agonist approved thus far for concurrent treatment of T2D and management of overweight and obesity, with a half-life of around 7 days. The biochemical modifications to the native GLP-1 molecule in semaglutide increase permeability across the blood–brain barrier, augmenting the effect of GLP-1 receptor agonists on the central nervous system: hunger control and reducing food cravings⁶.

Access for diabetes

Obesity is a risk factor for over 200 diseases, including T2D. The term ‘diabesity’ was coined in the 1970s to describe the pathophysiological connection between diabetes and excess adipose tissue¹. Diabesity is marked by the development of insulin resistance, which affects biochemical and cellular pathways in insulin-sensitive organs such as the liver, skeletal muscle and adipose tissue, leading to chronic inflammation¹. Although it is difficult to estimate the prevalence of diabesity worldwide, the probability of T2D increases with higher body mass indexes⁷.

Diabesity is managed through dietary change, increased physical activity and other lifestyle modifications. However, like overweight and obesity, diabesity can also be treated with medications and/or surgical procedures¹. In patients with diabesity, expert opinion supports using pharmacotherapy agents that minimize weight gain or promote weight loss, such as the GLP-1 receptor agonists (with semaglutide preferable to liraglutide)⁸. Recent clinical practice guidelines from the American Gastroenterology Association prioritize using semaglutide 2.4 mg weekly in managing overweight and obesity in adults⁹. Despite these recommendations and overlapping contributory factors, patients with diabetes (including diabesity and T2D) have greater access to GLP-1 receptor agonist therapy than those with overweight and obesity without diabetes².

Lack of approval

Worldwide disparities in access to and provision of anti-obesity pharmacotherapy for weight management exist³, particularly for GLP-1 receptor agonists. For over 15 years, increased prescribing of GLP-1 receptor agonists for weight management has lagged their use for T2D, leading to the inequitable treatment of obesity as a chronic condition. Variability in obesity management standards and governing body regulations, direct consumer costs and insurance coverage, lack of robust long-term effectiveness data, short- and long-term safety concerns, and provider and patient expectations and reticence about treatment, as well as societal bias, are all barriers to access (Table 2).

Table 2 |.

Barriers and solutions to widening access to GLP-1 agonists for the treatment of obesity

Actor	Barriers	Solutions
Healthcare professionals	Lack of education Safety concerns Anti-obesity stigma and weight bias	Improved training within medical school and residency Knowledge acquisition via continuing medical education (CME) requirements Cultural competency training Training in implicit bias, weight bias and the effects of weight stigmatization Use of people-first language and neutral weight terminology
Patients	Safety concerns Long-term use required High cost	Enable patient understanding of obesity as a chronic disease requiring long-term therapy Improve healthcare provider efficacy in educating patients on the risks and benefits of starting and continuing anti-obesity pharmacotherapy Improve access, regardless of ability to pay, through better insurance coverage and third-party payer discounts
Insurance companies	Long-term use required High cost	Facilitate greater access to improve cost sharing Remove anti-obesity pharmacotherapy with less efficacy and undesirable side effects (such as orlistat)
Governmental regulatory agencies	Anti-obesity stigma and bias Safety concerns	Follow medical society and drug manufacturer guidelines Evaluate more clinical data on safety and efficacy endpoints to support long-term use
Drug manufacturers	Safety concerns Long-term use required	Conduct more studies specifically analyzing long-term use, thereby acquiring clinical data on long-term safety and efficacy endpoints.

Obesity management standards and coverage of obesity medications vary by state and country, with some countries not acknowledging the utility of anti-obesity medication for weight regulation¹⁰. Of 23 European countries participating in a survey to assess the status of obesity management, in only nine was obesity pharmacotherapy made available. Nineteen provided access to bariatric surgery for those with severe obesity; however, in only seven was there a focus on health promotion (such as nutrition, physical activity or mental health). The study concluded that universal, effective and appropriate obesity management is lacking. A long-term, multidisciplinary, patient-centered approach that includes effective anti-obesity pharmacotherapy is needed in many nations¹⁰.

Stringent regulations

In 2022, the UK National Institute for Health and Care Excellence (NICE) found semaglutide 2.4 mg cost-effective for weight management when combined with diet and exercise. NICE only recommends use of semaglutide, however, for people with a BMI ≥35 kg/m² or with ≥30 kg/m² and an obesity-related co-morbidity. In addition, treatment is for a maximum of 2 years, with prescribing generally limited to weight management specialists within the National Health Service (NHS)¹¹. These recommendations are stringently based upon the clinical trial and efficacy modeling data on which the drug manufacturer’s analysis, drug outcomes and cost-effectiveness ratios are based, which only extend out to 2 years. Despite the realization by NICE that discontinuation of effective therapy after a 2-year period is less than ideal and will result in weight regain by some, NICE allows consideration of re-starting treatment only for those experiencing weight regain after a re-referral through NHS weight management services¹¹.

Similarly, despite the lower annual and out-of-pocket cost in the Netherlands, stringent indications (BMI ≥35 kg/m², combined with trial and failure of lifestyle measures) are required for liraglutide reimbursement¹². In effect, a disconnect between the indications for use supported by the drug manufacturer’s clinical trial data and marketing authorization indications and anti-obesity pharmacotherapy clinical guidelines, which are based upon clinical scientific expert opinion, may have hindered regulatory body approval for use in populations other than those included in the randomized trials. Such stringent regulations likely contribute to hesitance from providers regarding the relative benefit of these medications for weight management in those not meeting the clinical trial criteria (that is, otherwise healthy individuals with a BMI >30 kg/m² or those with a BMI >25 kg/m² and an obesity co-morbidity), but for whom treatment with these medications could still be beneficial.

Varied costs and coverage

Aside from regulatory concerns, list cost price and insurance coverage are common financial barriers to access. In the USA, the average annual cost for GLP-1 receptor agonists for obesity treatment ranges from ~$16,000 to $17,000, compared to ~$3,000 annually in some countries in Europe¹². Public and private insurance coverage for these medications for obesity in the USA varies between and within states depending on the managed care plan offered.

Medicare, which covers people over 65 years in the USA, explicitly prohibits coverage of anti-obesity pharmacotherapy. Seventeen states include anti-obesity medications under Medicaid, which provides healthcare for people with low incomes, but only nine of these have preferred drug plans that cover the newer agents (such as the GLP-1 receptor agonists) for obesity, unlike the broader coverage for newer antidiabetic therapies to treat T2D¹³. In some states, anti-obesity pharmacotherapy may be covered through state employee health plans but is not covered for populations receiving Medicaid¹⁴. Wider provision of these newer anti-obesity medications via Medicaid would greatly increase access; the Affordable Care Act (ACA) in the USA, for example, resulted in an approximate 5- to 8-fold increase in GLP-1 receptor agonist reimbursement and prescribing for T2D¹⁵.

Lack of understanding

The disparate utilization of GLP-1 receptor agonists for weight management as compared to T2D could have many causes, including inadequate provider training and poor prescriptive attitude, which may reflect larger societal biases against the conceptualization of obesity as a disease; inequitable insurance coverage and cost concerns; and uncertainty about long-term effects¹³. Compared to their understanding of the pathophysiology of diabetes and the need for chronic pharmacologic therapy, healthcare providers, the general public, health insurers, and government and private sector policy developers may have less understanding of the physiology of optimal body weight regulation, which also requires long-term management with effective medications^3,10 such as GLP-1 receptor agonists for those with obesity.

Concerns regarding the removal from the market of prior anti-obesity therapies, such as fenfluramine, sibutramine and lorcaserin, because of safety problems also likely contribute to provider reluctance to adopt anti-obesity pharmacotherapy, in addition to the increased cost in time and labor required to ensure insurance coverage of these medications due to prior authorization requirements. Lastly, providers may also be influenced by their own negative perceptions and stereotypes of people with obesity (weight bias) or have insufficient knowledge about the safety, efficacy and side effects of GLP-1 receptor agonists and their management.

From the patient perspective, concerns about drug safety, the need for long-term use, self-internalization of weight stigma and biases experienced in society all impair the acceptance of these therapies. Society all too often conceptualizes obesity as a problem of individual willpower, which could reduce the demand for pharmacological treatments among those who are most affected and who have the potential for greatest benefit.

GLP-1 receptor agonists can potentially improve health outcomes for people with obesity and obesity co-morbidities. Governmental regulatory bodies as well as medical societies are increasingly recommending access^2,11, and coverage by insurers has been followed by increases in utilization¹⁵. High list prices, variable insurance coverage and bias in prescribing, however, are all barriers to the equitable distribution of these medications. Health is a social good, and thus society has an obligation to provide health services that address the needs of all. GLP-1 agonists are effective treatments for weight management, and although regulatory bodies and medical providers are on the right path, we have a long way to go.