This article was originally published in the 2020 Spring Issue, and can be read here.
Authors: Kestrel Brown, Ryan Clarke, Mekayla Forrest, Katherine Lord, Moyandi Udugama, Claire Gapare, Justin Matta
Globally, 1 in every 11 adults (463 million people) live with diabetes and the numbers are increasing at an alarming rate. While the majority of diabetes cases are type II, where patients become insulin resistant, approximately 5-10% of adults and the vast majority of youth with diabetes are affected by type I diabetes, an autoimmune disease where patients do not produce insulin at all. While type II diabetes can initially be treated with oral anti-hyperglycemic agents, insulin as an injection is the only medication that can be used to treat type I diabetes. Many patients with type II diabetes also eventually become dependent on insulin. In the U.S., three major pharmaceutical companies own patents for the manufacturing of biologic analogs of insulin. Without legislative regulation, these companies have been increasing the price of insulin substantially such that many people living with diabetes can no longer afford the required doses. In an attempt to provide a cheaper alternative, Walmart recently rolled out sales of human insulin under the brand ReliOn, which is manufactured by the same three pharma companies but marketed by Walmart at a lower cost of 25 USD per vial. This paper evaluates whether ReliOn can be considered a solution to the current insulin crisis. Although ReliOn successfully provides patients with diabetes an alternative, lower-cost insulin, the number of deaths and medical complications related to improper use continue to increase since its rollout. This effort was a failure for two reasons: firstly, ReliOn is human insulin (Regular, NPH, pre-mixed NPH/R) which is less adaptable compared to more modern analog insulins (specifically for patients with type I diabetes); secondly, there was a lack of education provided to patients switching medications causing an increase in acute complications. The results show that while there could be effective measures set in place to target the insulin crisis, Walmart’s rollout of ReliOn is merely a band-aid solution and does not solve the underlying issue of price-surging.
Background
Diabetes in the United States
30.3 million adults in the United States and 463 million adults globally are currently living with diabetes, numbers that have more than doubled over the last 20 years (1). Approximately 90% of diagnosed cases are classified as type II diabetes, a form of the disease where the body becomes resistant to insulin, making it difficult to maintain consistent blood sugar levels. Initially, anti-hyperglycemic oral agents are frequently used to treat this form of diabetes, but many patients eventually become insulin-dependent (2). While type II diabetes can typically be influenced by healthy lifestyle choices, it is also affected by genetic, social, economic and environmental determinants. In contrast, type I diabetes is a condition that requires a strict, life-long insulin regimen to control blood glucose levels (2). Caused by an autoimmune reaction where the body stops making insulin, blood sugar levels in patients suffering from type I diabetes can become dangerously elevated which, if left untreated, leads to diabetic coma (diabetic ketoacidosis) and death. Currently, there is no solution to prevent type I diabetes, which affects about 5-10% of adults
with diabetes, and 90-95% of children with diabetes (2). Gestational diabetes, a form of diabetes that occurs only during pregnancy, is similarly on the rise globally (2). If dietary control is insufficient, insulin treatment is required to prevent serious health complications from occurring, both during pregnancy and postpartum for the mother and child. In 2017, the crude death rate of diabetes was set at approximately 21.5 per 100,000 people in the U.S. and is listed as the seventh leading cause of death according to the latest U.S. mortality data (3).
Various Types of Insulin
Insulin is a hormone produced by the beta-cells of the pancreatic islets that helps maintain constant blood sugar levels, especially following meals. Insulin dysfunction or the dysregulation of beta-cells in the body can lead to insufficient insulin secretion resulting in elevated blood glucose levels, known as hyperglycemia (4). There is currently no cure for diabetes, but there are different techniques to manage and treat the disease, including the administration of insulin (5). Insulin is available in ultra- rapid-, rapid-, short-acting- (also known
as regular-), intermediate-, and long-acting types that can be used alone or in combination to effectively manage blood glucose levels relative to food intake and exercise (6). Insulin comes in different strengths, with the standard in the U.S. being U-100, or 100 units of insulin per milliliter of fluid (7). Although all insulins work to control blood glucose levels, there are various formulations of insulin that act with different strengths over different periods and there is therefore a clear need for precise and specific dosing.
Two main types of insulin are available
to patients with diabetes: human insulin, which is the same molecule produced by the human body and was the only option until the 1990s, and analog insulin, an altered, synthetic form of the hormone (8). According to a study published in the American Diabetes Association journal, analog insulins are a better alternative compared to human insulins and are now largely the standard of care in diabetes care delivery, especially in type I diabetes (9). According to the study, analog insulins have “been shown to improve treatment adherence and treatment satisfaction due to fewer injections, flexibility of timing of basal analogs, less fear of dose adjustments, mealtime administration of prandial analogs, as well as user-friendly injection devices” (9). Human insulin takes longer to enter the bloodstream and has pharmacokinetics that does not effectively match the physiologic insulin production, whereas analog insulin, which has improved pharmacokinetics, acts faster and maintains steady levels in the bloodstream throughout its course (10). Due to this difference, human insulin requires much more planning on the patients’ part by matching their dietary intake to ‘feed’ their pre-injected insulin. If meals, snacks, and exercise deviate from a rigid routine, they could risk reaching both hypoglycemic and hyperglycemic levels (11). Patients need to undergo a significant amount of education to learn how to self-manage their insulin regimen. Switching from one approach to another (e.g. from a ‘basal-bolus’ approach using analog insulins, to a human insulin that is premixed) requires a different dietary approach and must be carefully managed.
The Rise of Insulin Prices in the U.S.
Insulin as a treatment has been available since 1922, where successful human clinical trials at the Toronto General Hospital
made headlines around the world (12). To distribute the insulin to patients who needed it, the Canadian research team famously sold the patent to the University of Toronto for 1 USD (13). Due to strong demand, production was eventually transferred to pharmaceutical giants Eli Lilly and Novo Nordisk following initial rationing in 1923 (13). As production efficiency increased, 100 units of short-acting insulin prices dropped from 1 USD to less than 20 cents in the 1940s (13).
Currently, three companies represent 99% of the insulin market in the United States: Eli Lilly and Company, Novo Nordisk,
and Sanofi. They have quickly gained an oligopoly over the industry, driving prices up exponentially in the process (14). The average price of insulin increased by 300% between 2002 and 2013 (15). The main factors causing the rise of insulin prices in the U.S. are the negotiating power and market exclusivity of these pharmaceutical companies (16). In particular, the lack of specific legislation regarding insulin pricing allows pharmaceutical manufacturers to price their products however they see fit for the market, entitling them to raise the prices over time with no limit. Additionally, direct competition from cheaper or generic options is lacking, because the current analog insulin products are protected by patents that cover the insulin delivery method or formulation (13). Furthermore, because insulin is a biologic drug derived from various organisms using biotechnology rather than a small-molecule chemical drug, its synthesis is difficult and costly. This further limits other companies from attempting to create biosimilars. This combination of hurdles has contributed heavily to the constant rise of insulin prices in the United States.
In recent years, several attempts have been made to mitigate the insulin crisis. For example, the 2019 cost-sharing cap-appropriation act of Colorado, the “Emergency Access to Insulin Act of 2019,” and the “Affordable Drug Manufacturing Act” from 2018 were both introduced to decrease the burden of the insulin crisis (17-19). While these pieces of legislation present hope for the future of insulin access in the U.S., they have not produced any observable effects mostly because the legislation has simply been introduced and not yet passed.
Walmart’s Rollout of ReliOn
In 2012, Walmart partnered with Novo Nordisk and began selling an over-the-counter (OTC) human insulin known as ReliOn. Novo Nordisk was already selling their version of human insulin, Novolin, and they rebranded this identical drug for sale in Walmart pharmacies throughout the U.S. at a cheaper price as a part of their Patient Assistance Program to introduce affordable medication (20). Throughout this case study, the successes and failures of ReliOn insulin will be dissected and unpacked to understand why ReliOn is not a singular solution in addressing the insulin crisis that exists in the United States. This will be examined by discussing how this crisis came to be, the impacts ReliOn had or failed to have in the insulin crisis, and the future implications of the crisis.
Available in all states except Indiana, where OTC insulin is banned (21), ReliOn is considerably less expensive (approximately 25 USD per 10mL vial) than the OTC human insulins, Humulin (Lilly) and Novolin, bought at other pharmacies (approximately 155 USD per 10mL vial), and significantly cheaper than human insulin and analog products requiring a prescription (21). The apparent goal of the ReliOn rollout is to provide an alternative insulin product that is competitive with other pharmacies offering OTC insulin (11). This alternative may fill a gap in the healthcare system that gives patients with diabetes of a lower socioeconomic status an accessible insulin option (22).
As the world’s largest retail firm with an annual growth rate of 17.8%, Walmart is a for-profit entity (23). By choosing to sell low-cost human insulin, this intervention leads to the attraction of a vulnerable consumer base to profit off of.
The roll-out of Walmart’s insulin joined the retailer’s line of already implemented ReliOn brand insulin products, which includes cheaper access to other testing tools required daily by patients with diabetes including blood glucose meters, syringes, and blood sugar test strips. The ReliOn brand insulin administration and testing products were designed by Walmart to appeal to patients with diabetes who cannot fiscally access these products elsewhere (11). Often, these patients are uninsured or cannot afford the copayments required to acquire sufficient insulin and without access to affordable insulin, many of these patients can face life-threatening consequences (14, 22). To these financially strained populations, ReliOn is an appealing option. ReliOn insulin is accessible as it is cheap and does not need to be prescribed. While this is a key attraction of the program, a lack of necessary prescription allows for the purchase of Walmart’s insulin without any support or supervision from a medical professional (11). Due to the significant pharmacokinetic differences between human and analog insulin, a lack of medical supervision can seriously affect the efficacy and safety of the drug. Such a significant flaw in Walmart’s insulin roll-out puts in jeopardy the effectiveness of the entire program (24).
Finances
Based on our research, Walmart has not issued any information with regards to the financial cost of manufacturing ReliOn.
All documents related to financial investments, contributing stakeholders, and the amount invested by each stakeholder are kept private. As a result, the public does not know who is funding ReliOn, how much it costs to manufacture, or who the interested stakeholders are. Therefore, there is currently no data to carry out a cost-benefit analysis of the intervention. From the available data, a comparison between the cost of insulin for consumers versus production is available below in Tables 1 and 2.
A national telephone-based survey conducted in 2018 investigated the frequency of OTC insulin sales in Walmart and chain pharmacies in 49 states in the U.S. (21). The results provided evidence that OTC insulin was sold significantly more often in Walmarts compared to other chain pharmacies. OTC insulin was being sold weekly in 10.9% of Walmart pharmacies and only 1.4% in chain pharmacies (21). The reason for this difference among pharmacies is likely the price. As seen in Table 1, Walmart-brand insulin (ReliOn) is sold at 24.88 USD per 10mL whereas Novolin and Humulin sold OTC at chain pharmacies cost anywhere between 90-185 USD per 10mL. Overall, based on the 4,700 Walmart pharmacies interviewed in the 2018 survey, the authors concluded that Walmart pharmacies sell on average 18,000 vials per day across the U.S., with a single pharmacy selling between 1 and 50 vials daily (21).
Regarding the cost of insulin in diabetes care, as seen in Table 2, the estimated production cost for one vial of analog insulin is between 3.69 and 6.16 USD, while a vial of the human insulin costs between 2.28 and 3.42 USD (25). Based on these numbers, it should not cost more than 133 USD each year per person to get the best treatments such as ultra-rapid analog insulin (25). This cost of 133 USD includes expenses
for raw ingredients, production, and delivery. Therefore, despite ReliOn being the cheapest insulin option by far for American patients with diabetes, the price of 25 USD per vial still represents a significant markup. Considering the average adult with type I diabetes requires two to three vials per month, in addition to syringes, test strips and needles, this can add up to over 75 USD per month, or 900 USD per year for insulin alone. It is clear that although ReliOn is advertised as a cheap alternative to prescription insulins, a price tag this high still limits Americans of the lowest socioeconomic demographics from accessing consistent and affordable care.
A carton of insulin that costs 300 USD in the U.S. sells for 20 USD in Canada as Canadian laws prevent medication markups (26, 27). In the U.S., the lack of similar government legislation allows for substantial markups of insulin throughout the supply chain. Typically, the customers’ healthcare coverage, if any, does not cover these added costs, which increases overall out of pocket spending (14).
Impact
Walmart’s rollout of ReliOn did not have the impact on the insulin crisis that patients with diabetes in the U.S. had hoped for. As a human insulin, ReliOn has an inconvenient peak and duration of action times compared to the analog products
and does not offer the same coverage. According to Luo et al., ReliOn provides an effective switch for patients with type II diabetes who cannot afford analog insulins, yet it states this is not true for patients with type I diabetes (28). As human
insulin works differently than analogs, many patients who make the switch to this cheaper alternative face serious medical complications, or in some cases death, due to improper use (22). Furthermore, according to a systematic review and meta-analysis of results from twenty-two randomized clinical trials comparing short-acting insulin analogs versus regular human insulin for type I diabetes mellitus, short-acting insulin analogs are associated with a lower number of total hypoglycemic episodes per month (29). More specifically, the study found that the short-acting insulin analogs have a 45% lower risk rate of nocturnal hypoglycemia and a 32% lower risk rate of a severe hypoglycemic episode (29). Cheaper options, such as ReliOn and other OTC human insulins, do not offer the same clinical benefits that the more developed analog versions of insulin provide.
Evaluating the ease of use and reliability of insulin drugs is difficult due to the lack of data on their long-term benefits and clinical outcomes. The U.S. Food and Drug Administration (FDA) approves new diabetes drugs based solely on short-term glucose-lowering efficacy and safety (30). Furthermore, it is impossible to measure the direct effects of OTC insulin due to the unavailability of a tracking system for non-prescription medication. While ReliOn sales are successful, the issue with this insulin lies in the lack of medical follow up and education in patients who make abrupt switches from analog insulin, which can have severe impact on glycemic control leading to adverse health consequences.
Given the lack of data to measure the direct effects of Walmart’s ReliOn, a possible proxy measure to evaluate the effects of a new drug is to study changes at the population level. According to Peter and Lipska, findings from a nationally representative study revealed that between 2007 and 2010, about 8% more patients had excellent glycemic control than between 1999 and 2002. However, close to one-third of patients with diabetes between 2007 and 2010 had failed to achieve their individualized targets for glycemic control (30). Furthermore, the study also revealed that younger adults aged 18 to 44 years with diabetic complications, experienced no improvements in their glycemic control during this period (30). Therefore, although many new drugs are available for lowering blood glucose concentrations, only modest improvements in glycemic control are being observed at the population level. There was also a significant increase in
the rate of hospital admissions due to hypoglycemia during this period (30). Peter and Lipska also cite the U.S. Institute for Clinical and Economic Review and Drug Abacus, indicating that drugs with few benefits to patients are priced lower, and those with significant benefits are priced higher (30). As such, the convenience of a cheaper option of insulin, such as ReliOn,
is counteracted by its poorer quality and lower level of effectiveness in benefiting the patient. This also brings up the discussion of how offering a cheaper, less effective form of insulin disproportionately affects the poor and further exacerbates their unmet needs for quality insulin accessibility and affordability.
Evaluating the outcomes of patients who switched from analog to human insulin is difficult due to the lack of data; however, many news articles have surfaced shedding light on the numerous hospitalizations and deaths in people with diabetes after making the switch (31). These deaths and increased hospitalization rates are linked to the lack of education the patients had been given when switching to an OTC human insulin, which is essential to avoid adverse effects. Yet, if a patient is desperate for a cheaper alternative due to their current socioeconomic status, they may not seek professional opinion prior to switching, especially if they need to pay extra for a doctor’s advice.
Why ReliOn Falls Short
There is still a debate as to whether the rollout of ReliOn is an effective option for patients with diabetes (11). While OTC human insulin provides an affordable alternative to analog prescriptions, the pharmacokinetics of human insulin requires a significant understanding by the patient for proper and safe dosage. We argue that Walmart is failing to address the insulin crisis in the U.S. because the program is lacking the necessary educational tools to ensure proper insulin administration by patients. Additionally, Walmart’s intervention is profit-oriented, and ReliOn is simply a band-aid to the insulin crisis. ReliOn distracts consumers from the main issue that three major pharmaceutical companies have an oligopoly on insulin production, allowing them to quasi-fix insulin prices, with resulting soaring prices of an essential medicine that is now unaffordable for patients who need it to survive.
As ReliOn is available without a prescription, it is very hard to measure the effectiveness of the intervention and acquire accurate numbers on how many people have used this product. Additionally, if any information is available, Walmart and Novo Nordisk have not made this data public. There are not many studies available that have tracked the use of OTC insulin since the rollout, with the closest data available being the telephone survey mentioned above. Although the survey indicated
a high demand for cheaper insulin, no reports indicate if these consumers are regularly following up with physicians,
or if they have been properly educated on the use of ReliOn. Due to this lack of data, there is a clear knowledge gap in the actual impact of ReliOn and further studies following the purchases of OTC insulin are highly recommended.
The lack of education and follow up in patients with diabetes opting for OTC insulin remains the central concern regarding the sale of ReliOn. Since they can all access ReliOn without a prescription, patients with diabetes do not need to visit their doctors, meaning there are no regular check-ups to assess adherence to the drug regime, drug effectiveness, and overall health of the patient. Walmart pharmacists may provide basic education to patients with diabetes purchasing this product for the first time, but there is a clear lack of instruction for the proper use of human insulin. The pharmacokinetics of human versus analog insulins are different, and patients need to be re-educated when they switch from one to another. It is very difficult to receive the proper tools and information to manage diabetes when buying an OTC medication. When taking human insulin, one needs to match their diet accordingly. Yet, when taking prescribed analog insulin, it is prescribed by a doctor with considerations to the patient’s diet. The standard of care in type I diabetes management includes three to four injections per day (or more), which is known as a ‘basal-bolus’ approach (10). For patients switching from ultra-rapid-analog insulin to regular human insulin, an adjustment to their management method is necessary. An approach to selling human insulin would require significant education of both healthcare providers and patients with diabetes, which is not currently provided by Walmart (14). Although the rollout of ReliOn successfully provided patients with a cheaper alternative, the deaths and medical complications caused by improper or lack of insulin use are not decreasing (32). This intervention only succeeded in segregating poorer patient populations from the rich and provides them with a cheaper, less effective alternative, and therefore has not improved the state of the U.S. Insulin Crisis.
Discussion
With the price trajectory insulin has taken over the last few years, there is an evident need for cheaper and more effective insulin. The fate of such a program strongly depends on the change in accessibility and cost of high-grade analog insulin moving forward, with the possible legislature that may be involved for such a move to take place. To properly evaluate the effectiveness of an OTC insulin, Walmart, as well as other private pharmaceutical distributors, must release their data to the public. Although OTC human insulin may have once been deemed as a safe alternative; additive psychological and physical stressors become evident upon switching to a lower-grade medication, further emphasizing that this is not a long-term sustainable solution as it also further drives the inequities and inequalities within the U.S. healthcare system. The coexistence of both high-cost analog insulin and low-grade OTC insulin in the same market further raises questions over what the profitability manufacturers of analog insulin can get away with and the cost of individual lives that these companies are willing to put at stake. The different treatment options between analog and OTC human insulin strongly demonstrates many of the wide-ranging weaknesses and inequities in the domestic health care infrastructure that has allowed such a situation to occur. This would therefore require more attention to adequately solve this crisis.
Currently, the sales and usage data remain private among respective retailers and manufacturers which further hinders the process of new policymaking. Therefore, increased sales data transparency from these private companies is a crucial step moving forward. Due to the complexities of the U.S. healthcare system, finding an appropriate solution and direction to this crisis will require policy-making on a state and federal level. Moving forward, any effort to mitigate the insulin crisis must facilitate a transition to a model that incorporates patients with diabetes from both high and low socioeconomic statuses and will facilitate equitable treatment for all. To adequately provide such a system and reach a solution to the insulin crisis, pharmaceutical companies must end their dehumanizing and profit-centered actions by providing insulin at an affordable price.
Acknowledgments
We would like to thank Dr. Julia von Oettingen (MD, PhD, MMSc, FRCP) for taking the time to provide us with valuable information and advice during the writing process. All of her hard work was pivotal in the success of this project. We would also like to thank Sophie Huddart, Lena Faust, and Dr. Madhukar Pai (MD, PhD) for their feedback throughout the semester.
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