Despite Advancements in the Treatment Landscape for Type 1 Diabetes, There Is a Significant Need for Innovation

Endocrine Society member Tina Gupta, MD, spent many years managing her patients’ type 1 diabetes when she was in a clinical setting. Now that she’s associate medical director on the Type 1 Diabetes Medical Affairs team at Vertex Pharmaceuticals, she’s even more determined to help find solutions to help these patients.

As an endocrinologist, my goal is to help people living with type 1 diabetes maintain glycemic control, to avoid dangerous hypoglycemia, as well as reduce hyperglycemia which can lead to serious complications and to do so with minimal compromise to their quality of life.

There have been many advancements in type 1 diabetes over recent years such as ultra rapid-acting insulins, continuous glucose monitors (CGMs), and automated insulin delivery (AID) systems, yet many patients still struggle to meet glycemic targets and continue to experience severe hypoglycemic events (SHEs) and impaired awareness of hypoglycemia (IAH).

In a retrospective, observational study by Jennifer Sherr, MD, PhD, et al., survey data from over 2,000 adults with type 1 diabetes in the U.S. were used to assess the impact of advanced diabetes technologies, including CGMs and AID, on glycemic metrics and prevalence of SHEs and IAH.

In a population with high utilization of diabetes technologies, with over 90% of participants on CGMs and roughly half using AID, the study authors found that only about 57% of participants reported a hemoglobin A1c <7%, the generally recommended glycemic target for nonpregnant adults according to American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) guidelines. Furthermore, irrespective of technology use, ∼20% of respondents reported experiencing at least one SHE within the prior 12 months, and approximately one-third reported IAH as assessed by questionnaire at the time of the survey.

These data illustrate that even with use of the most recent available therapies, reaching glycemic targets and avoiding dangerous hypoglycemia remains a significant struggle for some people with type 1 diabetes. In addition, demonstration of these findings within this cohort of highly engaged and well-resourced T1D Exchange community suggest that unmet need may be even greater among a population with more limited access to care.

As a former provider, I know that the clinical picture I would have assembled during an appointment is often incomplete, and, in my experience, this particularly applies to the incidence of severe hypoglycemia. Just like each patient is different, there are innumerable reasons for why hypoglycemic events are often not reported to clinicians. – Tina Gupta, MD, associate medical director on the Type 1 Diabetes Medical Affairs team, Vertex Pharmaceuticals

According to Sherr et al., these findings further support the call to action for research and development of additional therapeutic options and strategies, such as bi-hormonal AID systems and β-cell replacement, to help enable more people living with type 1 diabetes to meet their clinical goals.

Hypoglycemic Events: Underreported and Undetected

As a former provider, I know that the clinical picture I would have assembled during an appointment is often incomplete, and, in my experience, this particularly applies to the incidence of severe hypoglycemia. Just like each patient is different, there are innumerable reasons for why hypoglycemic events are often not reported to clinicians. Many people with type 1 diabetes live with IAH and are likely experiencing more hypoglycemia than they recognize, a problem that we know persists despite CGM use as evidenced by the Sherr, et al. data previously mentioned.

Furthermore, patients may have differing perceptions of what constitutes a “severe” event and may not consider all hypoglycemia occurrences as worthy of reporting. This can be especially common if they have a long-standing history with type 1 diabetes and have resigned themselves to hypoglycemia being a burdensome, yet inevitable, part of the disease. Similarly, they may feel as if their provider is not interested in hearing about their lows unless a threshold of care, such as hospitalization, is reached.

Even worse, they may fear that they will be judged or even penalized (for example, license suspension, work restrictions) after reporting hypoglycemia. In a disease that relies so heavily on the patient for relentless and ever-shifting decision making, any perturbations from “optimal control” can be perceived as a failure.

Patients are Waiting for Additional Treatment Options

The discovery of insulin has been life changing for people living with type 1 diabetes. However, insulin has a narrow therapeutic range with potentially dangerous consequences if levels are insufficient or excessive in relation to glucose levels. Keeping blood sugars in target range requires a delicate balancing act that can be impacted by just about every aspect of daily life — diet, exercise, sleep, stress, menstrual cycles, illness, and more. People living with type 1 diabetes must manage their disease 24 hours a day, seven days a week, for their entire lives. From a clinical perspective, we appreciate the importance of achieving and maintaining target glycemic metrics; however, acknowledging and addressing the monumental disease burden and decision-making responsibilities for a person with type 1 diabetes must also be prioritized.

Keeping these different aspects of care in mind can help us form more complete clinical pictures of our patients. In my former practice, I used to care for a young woman living with type 1 diabetes who was an experienced healthcare professional. As a result of her education, training, and personality, she was incredibly health literate, up to date on the latest therapeutic advances in type 1 diabetes, and rigorous with her insulin dosing, diet, and overall management of her disease. Regardless, whenever she deviated from her very limited rotation of meals, she experienced significant hyperglycemia, and even minimal adjustments to her insulin regimen to preempt the next episode resulted in severe hypoglycemia.

After much discussion of glycemic targets and risk reduction, and weighing this against her personal priorities, she made a conscious decision to accept these glycemic excursions without modifying her insulin regimen to avoid the more disruptive hypoglycemia while allowing herself a break from the misery of her monotonous diet. This was what made sense to her based on her individualized risk-benefit assessment.

A Complex and Burdensome Issue

The progress made in developing new management tools for type 1 diabetes are numerous and for many have led to improvements in glycemic control and reduced risk of hypoglycemia. However, the gap between these solutions and physiology remains, and living with type 1 diabetes can still be complex and burdensome.

The discovery of insulin has been life changing for people living with type 1 diabetes. However, insulin has a narrow therapeutic range with potentially dangerous consequences if levels are insufficient or excessive in relation to glucose levels. – Tina Gupta, MD, associate medical director on the Type 1 Diabetes Medical Affairs team, Vertex Pharmaceuticals

When discussing the findings of their observational study, Sherr et al. described some of the limitations of current available treatments that may account for the SHE and IAH outcomes reported. Despite advances in drug formulations, exogenous insulin is limited by different pharmacodynamic properties from endogenous insulin with protracted time of action from administration. Subcutaneously injected insulin also bypasses the portal circulation, precluding the insulin gradient created with pancreatic insulin secretion responsible for regulating hepatic glucose production.

These factors all can contribute to the occurrence of hypoglycemia, a risk further compounded by the loss of one’s glucagon “buffer” due to the progressive alpha-cell dysfunction seen in type 1 diabetes. Diabetes technologies aim to mitigate, but do not eliminate, this problem. CGMs are still subject to a glucose-sensing lag compared to physiologic mechanisms of native beta cells, and, while AID systems continue to advance, many users resort to manual management in pursuit of tighter glucose control than they believe the device algorithm permits. These overrides can potentially result in insulin stacking, and, consequently, hypoglycemia.

Vertex Hopes to Transform the Treatment Landscape for Type 1 Diabetes

The underlying pathophysiology of type 1 diabetes is well described and understood — there is autoimmune destruction of pancreatic beta cells leading to insulin deficiency. Currently, the standard of care for treating type 1 diabetes is lifelong administration of exogenous insulin therapy. At Vertex, we have ongoing clinical trials investigating cell therapies aimed at replacing the destroyed beta cells with functional islets to potentially restore insulin production to people living with type 1 diabetes.

As research in this field continues to progress, I have hope that we are approaching a time when the daily struggles, burden, and fear affecting the lives of people with type 1 diabetes can be significantly reduced or even eliminated.

Gupta is an associate medical director on the Type 1 Diabetes Medical Affairs team at Vertex Pharmaceuticals. She received her Bachelor of Arts (BA) and Doctor of Medicine (MD) degrees from the University of Tennessee. Her medical education continued at Boston Medical Center where she completed her internal medicine residency, followed by a fellowship for endocrinology, diabetes, and metabolism at Brigham and Women’s Hospital. Prior to joining Vertex, she worked as a clinical endocrinologist at Massachusetts General Hospital, specializing in diabetes, bone metabolism, and adrenal disorders.