Controlling Diabetes: Advances & Adherence

Diabetes is a pervasive chronic condition that occurs when the pancreas does not produce enough insulin (type 1, often called childhood diabetes, which accounts for 5% to 10% of all diagnosed cases) or when the body cannot effectively process the insulin, it does produce (type 2, often called adult-onset diabetes, which accounts for 90% to 95% of all diagnosed cases). According to the World Health Organization (WHO), roughly 422 million people worldwide have diabetes. In the US, there are currently more than 37 million people living with diabetes (roughly one out of every 10 adults) and 96 million adults (more than one in three) have prediabetes, according to recent data from the Centers for Disease Control (CDC).¹ And that only counts those who have received a formal diagnosis.

Over the past 20 years, the number of diagnosed diabetes cases in the US has more than doubled. The most common risk factors, according to the CDC—being overweight, having a family history, being physically inactive, and 45 years of age or older—foreshadow ongoing growth in this public health crisis in years to come.

Successful management of diabetes requires the long-term control of hemoglobin A1c (HbA1c)—a measure of blood glucose levels over time determined with laboratory diagnostic testing. What is so vexing about diabetes is the fact that so many cases could be avoided with changes in lifestyle, and many more cases could be properly managed with diligent adherence to blood glucose monitoring and adherence to complex regimens of glucose-lowering medications and/or insulin. And yet, due to a constellation of reasons and despite increased morbidity and mortality, many patients routinely fail to keep their condition under control. “Diabetes is often paired with comorbidities and/or denial and depression, so it can become even more difficult for patients to manage daily medication regimens and control their diabetes and its progression,” says Vishal Khanna, vice president of marketing communications for HealthPrize Technologies.

The economic impact

Diabetes also imposes an enormous financial toll on healthcare systems worldwide. According to the CDC, the total direct and indirect cost of diagnosed diabetes in the US—medical costs coupled with absenteeism and lost wages—was estimated at $327 billion in 2017. Similarly, according to the agency, medical costs for people with diabetes are more than twice as high as they are for those without diabetes, thanks to the elevated risk of heart disease and stroke, chronic kidney disease, blindness, and limb loss associated with the disease.

With the drug spend in diabetes reaching nearly $170 billion by 2026, it is expected to be the third-largest therapy area globally (after oncology and immunology therapies), with growth estimated to be 6% to 9% a year over the next five years, according to IQVIA’s recent report The Global Use of Medicines 2022—Outlook to 2026. Current drug spending reflects both the consistent use of older (generic) therapies, such as metformin, and, as the patient’s type 2 diabetes progresses, the use of more costly therapies to lower blood glucose levels and eventually regular insulin use. Overall spending is expected to be buffered over time by exclusivity losses on many of today’s branded therapies and with the uptake of biosimilar versions of reference insulin products, the first of which have recently received regulatory approval.

What’s in your medicine cabinet?

Prescribed medications that are used to help patients manage diabetes can be segmented into therapeutic products (such as insulin, oral glucose-lowering agents, lipid-lowering drugs, and therapies to treat peripheral vascular diseases), and monitoring or testing devices (to track glucose, ketones and microalbumin/albumin in the patient’s blood), according to MarketResearch.com.² Insulin—administered via multiple daily injections or an insulin pump—is the primary treatment for patients with type 1 diabetes. However, patients with type 2 diabetes are typically treated with a range of glucose-lowering therapies earlier in their disease progression before starting regular insulin administration.

In addition to the widely used generic medication metformin to lower blood glucose, many other novel classes of glucose-lowering medications are available today. Such competing therapies target a variety of different pathological mechanisms implicated in type 2 diabetes, ranging from insulin secretion (i.e., sulfonylureas), peripheral glucose uptake (i.e., biguanides), and glucose reabsorption (i.e., SGLT2 inhibitors).³

Industry observers note that as a class, the SGLT2 inhibitors have produced a paradigm shift in the diabetes space. Examples include Invokana (canagliflozin) from Janssen, and Farxiga (dapagliflozin) from AstraZeneca and Bristol Myers Squibb (both approved in 2013); Jardiance (empagliflozin) from Boehringer Ingelheim and Eli Lilly (approved in 2014); and Steglatro (ertugliflozin) from Merck & Co. and Pfizer (approved in 2017). SGLT2 inhibitors are currently the second- largest group of antidiabetic agents in clinical trials (12%) after incretin therapies.

Today’s approved diabetes therapies include 36 new molecular entities (NMEs) as monotherapies—including first-in-class drugs for diabetes management and 23 unique drug combinations that use two or more (non-insulin) glucose-lowering agents. In fact, today, 40% of approved antidiabetic drugs are combination regimens. Meanwhile, there are more than 100 investigational therapies now in the diabetes pipeline (in 375 clinical trials),⁴ representing a broad mix of mechanisms of action, molecule types, and routes of administration (inhalation, oral, subcutaneous, IV).

The sheer number of approved therapies and combination therapies continues to grow, showing that drug innovators are trying to capitalize on different pathological pathways associated with this disease, notes Fran Gregory, vice president, payer and pharmaceutical operations for Cardinal Health’s outcomes business.

However, all of this complicates matters at the point of care. With so many competing therapy options and so much heterogeneity among patients calling for a personalized treatment approach, pharma brand teams must frame their positioning and their messaging to help delineate the options for prescribers and patients, and to stand out with payers and ensure strong formulary placement and coverage.

“The No. 1 question from payers is ‘Who’s the right patient?’ There is often rush in the diabetes sector for pharma innovators to say ‘anyone who is not controlled on metformin will benefit from our therapy,’ but that is often not the case from the payer perspective, which must balance providing access and managing costs,” says Aaron Davis, senior managing director, value and access consulting at Syneos Health.

“Not every therapy is right for every person, so determining which patient subset is going to benefit the most from any potential new intervention is the most important piece, because this impacts everything else,” he adds. “If you don’t define who your ideal patients are and how they benefit most from your therapy, the payer will then define it for you (based on evidence in literature and market trends), and it won’t likely be the same patients the brand should be targeting.”

Also, according to Davis, more robust planning early in development, especially in Phase II clinical trials and entering into Phase III, will benefit pharma companies the most. “It doesn’t mean you can’t grow from there, but the initial launch needs to have the strongest, data-driven value story, associated with the most well-defined patient cohort,” he says.

The so-called glucagon-like peptide-1 (GLP-1) class of diabetic therapies have also been making headlines. In May, Lilly received FDA approval for the Mounjaro (tirzepatide) injection, which acts on two receptors—glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. The drug’s approval represents the first new class of type 2 diabetes medications in almost a decade, according to Lilly. It is administered using the company’s auto-injector pen for the treatment of type 2 diabetes, and competes with existing injectable medications, including Lilly’s Trulicity (dulaglutide) and Ozempic (semaglutide) from Novo Nordisk.

Ozempic—a GLP-1 receptor protein treatment—was first approved in 2017, and in 2019, Rybelsus (semaglutide) was cleared as the first oral form in that drug class. “The GLP-1 category is one of the biggest drug-spend categories, and payers generally understand their value, but matching them better with specific patients helps to justify the spend,” explains Davis. “Payers have a limited budget, so how do we figure that out?”

He notes that there is an opportunity to address this unmet need by studying real-world data (RWD) from claims databases and other sources to identify uncontrolled patients earlier in the trial process and understand how much they are costing the system, and then designing the trial to demonstrate the benefit of the new intervention on them.

“If payers don’t understand the value—especially in a space with so many overlapping options—they can limit access by not covering it or requiring significant out-of-pocket (OOP) expenses for the patient,” says Davis.

“When it comes to formulary placement, it often comes down to the lowest price,” adds Christine Walton, senior director of Rx marketing for Dr. Reddy’s Laboratories. “The hope is that other competitive factors—such as convenience to patient—also play a role, and can be leveraged to improve access and adherence.”

Biosimilar insulin may reshape landscape

To date, the insulin market remains highly consolidated among the three top manufacturers—Lilly, Novo Nordisk, and Sanofi—keeping insulin costs artificially high from what industry observers contend is a lack of robust competition.⁵ A recent survey administered to patients with both type 1 and type 2 diabetes reported cost-related insulin underuse or rationing in 25.5% of patients, which leads to poor glycemic control.⁶

In July 2021, FDA approved the first interchangeable biosimilar insulin product, Semglee (insulin glargine-yfgn), by Biocon/Mylan Pharmaceuticals, which references Sanofi’s long-acting insulin Lantus (insulin glargine). This approval marked “a momentous day” in that this biosimilar “has the potential to greatly reduce healthcare costs,” said then-Acting FDA Commissioner Janet Woodcock, MD, at the time of the announcement (July 28, 2021). Biosimilars marketed in the US in other disease categories typically have launched with initial list prices 15% to 35% lower than the comparative prices of reference products, according to FDA.

“As an interchangeable long-acting biosimilar, Semglee is able to be automatically substituted by a pharmacist without prior approval from the patient’s prescriber, similar to how many generic medications are automatically interchanged today,” says Jeff Baldetti, director of biosimilars, Cardinal Health. “Semglee is available in both a branded and unbranded version, which represents a discount of between 5% and 65%, when compared to the list prices of its reference product Lantus.”

In December 2021, FDA approved the second insulin glargine biosimilar—Rezvoglar (insulin glargine-aglr) from Lilly, which references Sanofi’s insulin glargine. While initial uptake of insulin biosimilars has been slower than expected, payer coverage on formularies is beginning to increase, notes Syneos Health’s Davis. Some stakeholders note that potential misinformation or mistrust among patients may hinder the uptake of biosimilar insulins, so only time will tell.

“Perhaps more so than in other chronic conditions, within diabetes, the success of any biosimilar will be directly linked to the order of market entry—it’s not like the generics market of 20 to 30 years ago, where multiple generics can all be successful,” says Davis. “There may be room for maybe one or two, but not three or more biosimilar versions of any branded product—so it’s all about order of market entry.”

He continues: “At this time, payers are looking to find a few biosimilar partners for cost relief, but do not want to be making a lot of choices in any biosimilar category. If you can’t be first or second biosimilar to market in the disease category, you really should focus your investment and effort elsewhere.”

Meanwhile, the pursuit of insulin in capsule form has received a lot of attention in recent years. Oramed Pharmaceuticals’ investigational therapy ORMD-0801 is now in Phase III trials. If approved, this first-ever oral form of insulin could represent a paradigm shift by eliminating the need for patients to administer insulin via injection, while enabling improved adherence to therapy. The company is also developing an oral GLP-1 analog capsule (dubbed ORMD-0901). In a March survey involving 88 endocrinologists and 82 primary care physicians in the US and Europe (conducted with IQVIA), Oramed found that 76% of the respondents “definitely would” or “probably would” prescribe the oral form of insulin for type 2 diabetes patients.

Adherence matters

“With the recent uptick of patients taking their health journey into their own hands and becoming more healthy, the hope is that doctors and patients alike will focus more on preventative care and healthier lifestyles, reducing the need for prescription intervention,” says Walton of Dr. Reddy’s Laboratories. Despite this overall trend in health and wellness and technology options aimed at helping patients overcome their adherence barriers, “the adherence challenge remains a code that has not yet been cracked, and there is absolutely no silver bullet in diabetes or any other chronic condition,” adds Davis. The challenges are further compounded by social determinants, such as access to quality care, poor health literacy, and other factors.

“Some of the adherence challenges can also be addressed better by improving the conversation further upstream,” continues Davis. “Ideally, the brand team must make sure the prescriber has the tools to effectively communicate ‘the why’ to the patient, but typical physician visits continue to get shorter and shorter—so this undermines the likelihood of the patient actually understanding their condition, the role their medication plays, and the overall importance of sustained adherence.”

The coordination of care between a patient’s specialist and their general practitioner is particularly important in diabetes, Cardinal Health’s Gregory contends. Pharmacists can ensure that existing medications the patient may be taking do not interfere with any new drugs for diabetes management, and to provide other forms of support and access to resources.

“Often, overall care is not coordinated, specifically if the patient does not have access to quality healthcare facilities with integrated care,” says Gregory. Similarly, she notes that “pharmacy teams can help patients access the most cost-effective medications and provide access to financial resources that may be available for underinsured patients through a variety of sources, such as foundations or patient assistance programs.”

Within the realm of diabetes (and other chronic conditions), multiple innovative approaches are being used today to move the needle on adherence. For example, the HealthPrize digital engagement solution uses gamification, health education, and behavioral economics to engage and educate patients; the HealthPrize tool shares clinical information and educational messaging “in small doses, to simplify the complex and create an environment that makes them want to come back and check in every day,” says John Monahan, the company’s CEO. “When patients learn one little thing today, and another tomorrow, the collective information and understanding grows.”

HealthPrize’s Vishal Khanna adds: “Within diabetes, our branded offering gets patients to come back to the platform six or more times per week, spending two minutes or more every day, helping them to learn and ultimately be more adherent.” The HealthPrize platform’s gamification format provides rewards to further motivate users—patients earn points and can convert them to gift cards, health-related products, or charity donations.

HealthPrize recently carried out an analysis of transactional-level claims data with McKesson in a program in the diabetes space that had more than 40,000 users. The study examined what percentage of previously non-adherent users became adherent through HealthPrize—a metric that is particularly important in value-based care.

“The industry considers patients below 80% PDC (proportion of days covered—the gold-standard measure of medication adherence) as non-adherent, so the ability to move non-adherent patients to a state of adherence (reflected by PDC greater than 80%) provides a critical measure of success,” says Monahan.

“We looked at PDC among eligible patients before the HealthPrize intervention and then following utilization of our program and found that 83% of the previously nonadherent cohort—four out of five—became adherent through HealthPrize after 12 months,” adds Khanna. “From the pharma perspective, that translates to about two extra refills per year per patient—a substantial amount, especially given the scale of diabetes prevalence. This enables improved glycemic control, reduced medical interventions, and reduced healthcare expenditures.”

Another solution, from Sempre Health, comes from the cost perspective, in the form of a program that rewards patients every time they pick up and renew their prescriptions. In November 2020, UPMC Health Plan and Sempre Health extended their earlier drug-adherence collaboration to include diabetes medications. The program uses natural-language text reminders and messaging to provide discounts to reduce OOP treatment costs for patients. When participating members fill their eligible prescriptions on time, they receive discounts on their copayments to incentivize improved adherence. The savings realized on the Sempre program are significant—the offering is able to reduce a patient’s OOP costs on their eligible medications by up to 60%.⁸

Unlike traditional coupons, which operate without payer involvement and offer patients one-size-fits-all discounts, Sempre Health allows payers to turn on point-of-sale discounts for their members who have been prescribed specific chronic disease medications. This allows patients to share in the cost savings that their responsible health decisions are generating for insurers, care providers, and pharmaceutical companies.

Meanwhile, Sempre Health also has a collaboration with Sanofi, whereby eligible patients on Lantus (insulin glargine injection), Toujeo (insulin glargine injection), and Soliqua 100/33 (insulin glargine and lixisenatide injection) are able to use the Sempre platform to access discounts to support adherence to therapy. According to the company, a recent analysis of Sempre’s interventions led to an increase of 25% in PDC. On average, in their first year in the program, Sempre patients refilled three more prescriptions than patients in the comparable non-Sempre cohort.

Another company in the adherence space is EveryDose (formerly known as Groove Health). The organization combines its proprietary analytics platform with behavior-modification tactics, and partners with payers, hospital systems, self-insured employers, and Medicare/Medicaid plans. Through these partnerships, EveryDose identifies those patients who are at greatest risk of non-adherence to long-term, chronic medication regimens. The company’s mobile app supports patients in overcoming adherence barriers by combining predictive analytics and personalized engagement. For instance, EveryDose’s web-based app uses a conversational chatbot—dubbed Maxwell—that employs artificial intelligence to help identify the primary reasons for non-adherence, so that tailored follow-up can be provided via targeted content and resources, and through intervention by the patient’s care team.

Finally, Bigfoot Biomedical is using technology to support adherence objectives. In June 2021, the company launched Bigfoot Unity Diabetes Management System and Bigfoot Clinic Hub. The product features connected smart pen caps that recommend insulin doses for people managing multiple daily injections. The pen cap connects to a smart phone app and is integrated with Abbott’s FreeStyle Libre 2 CGM app, according to the company. The cap also works with insulin pens from Lilly, Novo Nordisk, and Sanofi. Bigfoot’s associated cloud-based platform automatically captures and presents insulin therapy data from the Bigfoot Unity System, so an initial number of diabetes clinics and endocrinology practices in select markets across the US can proactively support patients at a distance. Availability will expand to other markets through 2022, says the company.

References

1. https://www.cdc.gov/diabetes/data/index.html

2. Diabetes Market Research Reports & Industry Analysis

3. Chaudhury, A., et al., “Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus Management,” Front. Endocrinol. (Lausanne) 8, 6 (2017).

4. https://doi.org/10.3389/fphar.2021.807548

5. Pharmaceutical Care Management Association, “Insulins: managing costs with increasing manufacturer prices,” August 2020.

6. Herkert D, Vijayakumar P, Luo J, et al., “Cost-related insulin underuse among patients with diabetes.” JAMA Intern Med. 2019;179(1):112-14.

7. https://doi.org/10.1111/dme.14575

8. UPMC Health Plan Further Expands its Sempre Health Partnership to Better Serve Patients with Diabetes, globalnewswire.com, November 18, 2020.