A new angle for glp-1 receptor agonist: the medical economics argument

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are relatively new medications for diabetes that offer a weight-loss profile that can be considered desirable for patients with both type 2 diabetes (T2D) and obesity. GLP-1 RA are effective in combination with insulin, and even slightly superior or at least equal to short-acting insulin in T2D; however, since they work in the incretin system, they may not be effective in long-standing disease. Additionally, only recently have publications reported their cardiovascular safety, and there is limited evidence for long-term effectiveness. The work presented by Huetson et al. offers a much needed perspective through a medical economic model for the long term cost-effectiveness of GLP-1 RA. The authors found benefits in quality-adjusted life years and reduced lifetime healthcare costs. While there are a few limitations, this study contributes to the understanding of these agents and their impact on the epidemics of obesity in T2D, where weight management is no longer an option, but an essential component of the diabetes plan of care.

Key words: :

• Type 2 diabetes
• Obesity
• Economic model
• Glucagon-like peptide-1 receptor agonists

The most relevant guidelines for diabetes management (American Diabetes Association, American Association of Clinical Endocrinologist, and the European Association for the Study of Diabetes) foster individualized goals and treatment approaches, according to disease duration, comorbidities, established vascular complications, risk of hypoglycaemia, and adverse events, resources, and support systems1–3. This requires proper medication selection, close monitoring and timely titration, dose maximization, and addition of other agents, in order to avoid clinical inertia and accomplish glucose control. However, the disproportionate number of individuals with type 2 diabetes (T2D) is not consistent with available specialized providers. Thus, management is carried out mostly by providers in the community, where challenges include clinical inertia, limited pharmacologic interventions, psychological barriers, poor adherence and concern with side-effects, fear of hypoglycaemia, and weight gain4. Obesity is already a major associated problem, with the US data showing a 62.4% prevalence of obesity in T2D patients5. Furthermore, several effective anti-diabetes agents commonly used in primary care (insulin, sulfonylureas, thiazolidinediones) are associated with weight gain6.

Since the dipeptidyl peptidase-4 inhibitors (DPP-4i) and the glucagon-like peptide-1 receptor agonists (GLP-1 RA) have weight-neutral or weight-loss profiles, respectively, they can be considered desirable better options. GLP-1 RA are effective in combination with insulin, and even slightly superior or at least equal to short-acting insulin in T2D2^,7^,8. However, since they work in the incretin system, they may not be effective in long-standing disease. Additionally, only recently publications have reported their cardiovascular (CV) safety, meaning no harm from these agents, unlike metformin which does offer CV benefit. There is limited evidence in long-term efficacy and safety, and proper informed discussion must always precede starting these agents, especially in older adults9.

Thus, the work presented by Huetson et al.10 offers a much needed perspective through a medical economic model for the long-term cost-effectiveness of GLP-1 RA. The authors report a comparison between short-acting insulin vs long-acting GLP-1 RA, both combined with basal insulin. The study used the framework of the GetGoal-L trial11, where patients were uncontrolled, despite treatment with metformin (79% of them) plus basal insulin (glargine 50% or human neutral protamine Hagedorn 40%), and then treated with Lixisenatide vs placebo for 24-weeks. Based on these data, the authors built a model to compare GLP-1 RA combined with basal insulin for 3-years, vs basal-bolus regimen. They accounted weight loss only for the 3 years on GLP-1 RA use, as patients were then switched to the basal-bolus regimen. They found benefits in quality-adjusted life years (QALYs) and reduced lifetime healthcare costs in the group treated with the GLP-1 RA.

This study is quite relevant because it provides data that otherwise would not be available for many years to come, with an anti-diabetes agent that can provide additional benefits in terms of weight control. The authors conservatively modeled 3-years of intervention, but this time could be longer in some patients, who would then experience further weight loss. There may be differences among the safety, efficacy and costs among agents within the GLP-1 RA class, and it would be interesting to see similar studies using Exenatide and Liraglutide. Furthermore, the study opens additional questions, and contrasts with other studies where bolus insulin added to basal insulin is reported to be cost-effective, and actually the insulin-related hypoglycemia and weight gain may offset clinical and economic benefits12, which is also true for Huetson’s model.

There are, however, a few limitations to consider. The scenario may no longer be compatible with current guidelines, in which using basal insulin is suggested to follow, not precede, the use of newer agents such as GLP-1 RA, Sodium Glucose Co-transporter 2 inhibitor (SGLT-2i) and DPP-4i3. Moreover, our current understanding of obesity in T2D would promote active pharmacologic management of obesity6. In that their proposed sample had an average age of 57.2 ± 9.6 years, we may not have enough information about what could happen in older patients who may be good candidates for GLP-1 agonists, but behave as a different population, where cardiovascular complications may have already occurred, and the targets for weight reduction are different than in younger adults13. The reported improvement of 0.066 QALY and the cost-savings (NOK 6,869 are equivalent to $883.96 USD or €810.43 euros) could be confusing. The National Institute for Health and Care Excellence (NICE) suggests that treatments are cost-effective if their cost per quality-adjusted life year (QALY) gained is less than US$30, 412–45,619 or €27,833–41,749¹4. Lastly, some investigators propose less emphasis on 40-year or lifetime costs and consequences of the therapies, with a greater focus on short-term (5-year) and intermediate-term (10-year) outcomes15.

Nevertheless, such economic models are important, as they help evaluate the long-term impact of diabetes treatment. They do, however, need to be updated to include decisions to be made before many of those data will be contemporary, with important clinical trial data assessing hard clinical outcomes in patients with diabetes15. The pharmacologic management of T2D certainly increases costs, and it is our duty to understand the factors that impact cost-effectiveness. Those with diabetes and obesity may enter into a vicious cycle, leading to worse diabetes control that requires additional medications, and then greater costs. Proper selection of pharmacologic agents is paramount. Barriers due to economic burden to the patient ought to be considered and actively explored, as they may also lead to non-adherence16. Each single person with diabetes may double or triple the costs in healthcare resources compared to people without diabetes. Diabetes imposes a large economic burden that will continue to increase in the next two decades, especially in older adults, because of a higher prevalence of diabetes and higher rates of diabetes-related complications in older age-groups17. Obesity also imposes higher costs in adults, negatively impacting income and quality-of-life18. Compared with metformin and sulfonylureas, newer agents have substantially higher drug acquisition costs, with DPP-4 inhibitors being less expensive than GLP-1 receptor agonists. However, it might be that preventing weight gain or fostering weight loss in the setting of T2D and obesity could be beneficial and worth initially higher medications costs as an investment for the future. The financial impact of new treatment modalities needs to be addressed at the individual level, local society, and globally19.

We continue to increase our understanding of the factors that are common to T2D and obesity and affect their chronic nature. Therefore, more economic model studies are needed, and we recommend they incorporate the use of anti-diabetes and anti-obesity agents. The authors conservatively conclude that their results may assist the decision-makers in their home country, yet we argue that such studies may have a greater impact worldwide, where weight management in obesity is no longer an option, but an essential component of the plan of care for T2D. Only time will teach us more about the long-term safety of newer agents like the GLP-1 RA, which cannot be ascertained by models. However, we know that these agents have the potential to be cost-effective now.

Transparency

Declaration of funding

No funders are reported for this manuscript.

Declaration of financial/other relationships

WMV and HJF have no conflicts of interest to disclose.

Acknowledgment

The authors would like to thank Dr. Guy Howard for his review of this manuscript.