The Promise of Oral Insulin: Improving Adherence and Impacting Diabetes Outcomes

It is no news to managed care experts that diabetes is a major chronic illness that places a substantial burden on the health of individuals and the cost to society. Worldwide, 1 in 11 adults (425 million people) has diabetes, with 1 in 2 adults (212 million) with undiagnosed diabetes. Additionally, the disease appears to be compounding in severity and it is currently projected that by 2045, it is expected that 693 million people will have diabetes.

In the United States, 30.3 million (9.4%) of people have diabetes with the majority having type 2 disease (90% to 95%). An additional 84.1 million (33.9%) of US adults aged 18 years and older have prediabetes, with nearly half of these (48.3%) in adults aged 65 years or older, according to the National Diabetes Statistical Report.

This latter estimate indicates the enormity of this disease going into the future. Many people with pre-diabetes will go on to develop type 2 diabetes within 5 years if not treated. 

“Even if we are able to prevent half of the pre-diabetes from developing diabetes, the amount of diabetes patients may double in the coming years,” Patty Taddei-Allen, PharmD, Director, Outcomes Research, College of Pharmacy, University of Florida, told First Report Managed Care in an interview. 

And the need for prevention is great. Not only is the cost significant to treat the disease itself, but also to treat the frequent complications that accompany the disease as well as the indirect costs associated with loss of productivity and wages. In addition, the need for prevention is heightened by the increasing number of youth who are developing this disease. National Diabetes Statistical Report found that from 2011-2012, 5300 youth were diagnosed with type 2 disease.

For people already diagnosed with type 2 diabetes, as well as the many people with prediabetes who will likely develop the disease, finding ways to improve treatment is essential to reduce complications and to improve quality of life as well as to reduce the cost burden on society.

One step in this direction is finding ways to improve what many providers identify as key to optimizing outcomes—treatment adherence. 

“Adherence to treatment is a problem in type 2 diabetes,” said Richard E Pratley, MD, adding that this is not unique to people with type 2 diabetes but shared by virtually all people with chronic diseases where persistence on medications is poor.

One way to improve adherence may be on the horizon for clinicians to employ in the near future—oral insulin. With evidence from clinical trials showing efficacy with oral insulin and the first clinical trial approved by the FDA to test such an agent recently initiated, patients may soon have a way to administer insulin that is more convenient and less costly. 

The High Cost of Diabetes 

Diabetes places a significant burden on the health of individuals, both by increasing mortality risk and the risk of incurring comorbid conditions caused by ineffective or insufficient treatment. 

In 2015, diabetes was the seventh leading cause of death in the United States. It is also the leading cause of kidney failure, lower-limb amputations not caused by injury, and new cases of blindness in adults, according to the CDC. Additionally, patients with diabetes are two to four times more likely to die from cardiovascular disease than people without diabetes, according to the American Heart Association. 

The human toll this takes is obvious. People struggling to effectively manage their disease and associated comorbidities face a number of challenges, among them the hight cost of insulin treatments. 

“Diabetes costs can be broken down into the costs of treating diabetes and the costs of the complications of diabetes—cardiovascular disease, strokes, heart failure, kidney failure, amputations, and blindness,” Dr Pratley said, emphasizing that the bulk of the cost is from the direct costs of treating the complications of diabetes as well as the indirect costs associated with those complications. 

Dr Taddei-Allen explained further that “treating type 2 diabetes not only includes direct health care costs, but also includes indirect financial costs such as being less productive at work and home, increased absenteeism and presentation at work, and decrease from participation in the labor force.”

By better managing adherence through increased access to effective treatments, it is likely that the individual cost burden would decrease.

The total estimated cost of diabetes in 2012 was $245 billion, which included direct medical costs ($176 billion) and decreased productivity ($69 million). Broken down by cost to individuals, it is estimated that the average medical expenditure for a person diagnosed with diabetes was about $13,700 per year of which $7,900 was the cost to treat the diabetes itself.

And these costs keep rising. “Costs have skyrocketed in recent years,” said Dr Pratley, citing the “inexorable increase in the prevalence” of the disease as driving part of this cost. “Every year, an additional 1 million patients are diagnosed with the disease in the US alone,” he added.

Dr Pratley emphasized, however, that the rise in prevalence is only half the picture. The other half is due to the significant increase in the cost of newer, more expensive drugs. From 2002 to 2013, the average price of insulin nearly tripled, according to the American Diabetes Association.

What emerges from all this data is the urgent need to curb the rise of diabetes and to better manage it. For people who already live with the disease, one key challenge to improving outcomes and reducing complications is improving treatment adherence. One step in this direction may be a more convenient way to administer insulin. Into this space is emerging clinical data showing the promise of oral insulin.

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Oral Insulin: A Game Changer?

What kind of impact an oral insulin agent may have on diabetes outcomes is unknown but recent clinical trials may provide an answer. In June, Novo Nordisk’s an oral GLP-1 analogue semaglutide demonstrated that it was non-inferior to both Victoza (liraglutide injection; Novo Nordisk) and Januvia (sitagliptin; Merck). Additionally, the oral insulin showed superior weight loss at 26 weeks compared with Victoza, and significant reductions in body weight in the comparative study with Januvia. Further, an older trial reported in May 2018, found that Novo’s oral insulin demonstrated superior improvement in HBA1C compared with Jardiance (Empagliflozin; Boehringer Ingelheim/ Lilly); however, there was no significant difference in weight loss demonstrated.

Additionally, under the direction of the FDA, Oramed Pharmaceuticals Inc. launched its largest clinical trial to date to assess the effectiveness of its oral insulin agent ORMD-0801. The multicenter trial includes 240 patients with type 2 diabetes, all of whom will receive the oral agent for 90 days. Patients will be divided into groups to receive different dosing regiments at varying times of the day. The main outcome of the newly launched study will assess the efficacy of this oral insulin agent at lowering glycated hemoglobin.

Previous data showed the agent to be both safe and effective, with sustained and significant education in glucose measures. In specific, results of a Phase 2b, placebo-controlled study comparing the addition of ORMD-0801 (16 mg insulin or 24 mg insulin) to metformin versus placebo for 28 days showed that the oral insulin was associated with a significant reduction in nighttime glucose compared to placebo. Secondary measures also showed significant improvements in fasting blood glucose, morning blood insulin, c-peptide, and triglycerides associated with the oral insulin regimen compared to placebo. 

Asked about the potential impact of an oral insulin agent on diabetes outcomes and cost, Dr Taddei-Allen was cautious. 

“While oral insulin may help some patients who are afraid of needles or do not like the burden of injecting themselves, it may not necessarily have a large enough impact to help improve outcomes as a whole,” she said.

Saying that there are already good oral diabetes drugs available, such as SGLT2 inhibitors, that have not led all patients to better adherence or disease control, she emphasized that patients may not necessarily do better because they are more apt to take oral versus injectable insulin.

“However, should an oral insulin product make it successfully through the FDA approval process, there will be patients who may benefit from the medication,” she said.

Dr Pratley was more succinct. “An oral insulin is not going to bend this curve,” he said, referring to the soaring treatment costs. As seen with novel agents in oncology, oral drugs tend to come to the market at a higher cost than intravenous drugs because of the lack of an administrative burden and the perceived added value of a less burdensome treatment option.

Both Drs Pratley and Taddei-Allen emphasized that the real change needed is more effective patient education and engagement to better understand the importance of treatment and adhering to it. 

“One of the biggest challenges that will need to be tackled to increase adherence to diabetes treatment is improving patient engagement,” Dr Taddei-Allen said. “Clinicians engaging the patients and providing patient-centered care allows the patient to take an active role in managing their diabetes, not just from taking their medications but also in improving their lifestyle choices.”

Dr Pratley also emphasized a need for lifestyle changes. “Cost is one factor,” he said, “but better education of patients on the benefits and risks of treatment is crucial.” This includes shared decision-making that offers the opportunity to better engage patients and improve adherence. “As with lifestyle interventions, promoting long-term behavioral changes should be the goal,” he concluded.  

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