In the United States, more than 1.5 million people are diagnosed with type 1 diabetes (T1D), a prevalence expected to increase to 2.27 million by 2026. A key challenge in effectively managing patients with T1D for optimal outcomes is that it is a complex disease with long-term negative microvascular effects, including retinopathy, nephropathy, and neuropathy.

Replacement Insulin Therapy

Unlike type 2 diabetes, in which diet and exercise may control or even reverse the disease and for which multiple therapies are available, patients with T1D are entirely reliant on replacement insulin therapy. While replacement insulin is essential for T1D, it remains a less-than-optimal treatment due to significant differences between the trafficking and activity of replacement and physiologic insulin.

Physiologic insulin is trafficked directly to the liver via the portal circulation, whereas replacement insulin is administered systemically and interacts with non-physiologic tissues. Consequently, it is nearly impossible to couple the action of replacement insulin with changing glucose levels as occurs in normal, non-diabetic physiology. In fact, nearly 80% of people with T1D fail to achieve the American Diabetes Association’s target A1C levels. Given the negative microvascular effects of T1D, replacement insulin therapy presents a perilous balancing act for patients to obtain the life-preserving benefits while avoiding the life-threatening side-effects.

A primary challenge in replacement insulin therapy is the critical need to carefully titrate insulin use in order to maintain blood glucose levels within a narrow physiologic range. Fluctuations in glucose levels are unpleasant but nearly impossible to avoid, and failure to maintain glucose levels within a physiologic range may lead to multiple adverse effects, including vascular complications, hypoglycemia, glycemic variability, and weight gain. One study found that 6% of people with T1D reported a seizure or loss of consciousness and 3% reported at least one event of diabetic ketoacidosis during the previous 3 months. Additionally, failure to maintain glucose levels within a physiologic range may leave patients feeling unwell, even in the absence of serious adverse events.

Adjuvant Therapies

To address the limitations of replacement insulin therapy, some newer insulin pump technologies have incorporated algorithms that sense decreasing glucose levels and shut off the pump in order to reduce insulin utilization and avoid hypoglycemic events. Unfortunately, despite these advances, physiologic insulin replacement is still both the “holy grail” and an unachieved long-term goal of diabetes therapy.

Adjunctive therapies that could improve glucose control and/or enable reductions in insulin doses are essential for improving care and outcomes for patients with T1D. Improved glycemic control is shown to have long-term benefits in patients with T1D, and insulin dose reductions may help decrease or prevent insulin-associated weight gain and episodes of hypoglycemia. To date, the development of adjunctive therapies has been hindered by side effects like hypoglycemia and ketoacidosis. Failed approaches include a variety of agents approved for use in patients with T2D, as well as other agents initially developed for use in patients with T1D. There are no approved oral adjunctive therapies for T1D in the United States.

Hope on the Horizon

However, a growing body of preclinical and clinical data suggest that there may be hope on the horizon. Liver-specific glucokinase (GK) activators hold promise in adjunctive therapy for T1D. GK is the body’s glucose sensor and a key regulator of blood glucose levels. Primarily expressed in tissues that require glucose sensing (liver and beta cells of the pancreas), GK senses glucose level changes and modulates liver and pancreatic function to maintain glucose within a physiologic range. Liver-selective activation may overcome the failures of non-liver-selective GK agonists observed in clinical trials in patients with type 2 diabetes. As a result, compared with failed approaches, liver-specific GK activators are more glucose-dependent and can harness the body’s normal physiologic process to regulate glucose levels. Rather than impacting the activity of cells and tissues throughout the body, GK activators leverage normal physiology to make key target cells function more efficiently, somewhat akin to using a hearing aid to correct hearing loss.

Promising results have been reported from a placebo-controlled Phase II trial of a liver-specific GK activator, including a statistically significant improvement in A1C compared with placebo at week 12 (both in primary and placebo-subtracted analyses). Daily time in range improved by approximately 2 hours per day compared with placebo, and there was a greater reduction in total daily mealtime insulin bolus compared with placebo. Importantly, these benefits were achieved with no diabetic ketoacidosis, no incidence of severe hypoglycemia, and fewer symptomatic hypoglycemic episodes than placebo.

Looking Ahead

Although additional clinical trials are needed to fully assess its safety and efficacy as an oral adjunctive therapy for the treatment of T1D, a growing body of clinical evidence in patients with T1D suggests that this novel GK activator may achieve the goals of adjunctive therapy—improved long-term glucose control and reduction in daily insulin—without severe hypoglycemia or ketoacidosis and with fewer symptomatic hypoglycemic episodes. A pivotal trial anticipated to begin by the end of 2020 will provide further insight into the role it may play in advancing care and outcomes for this large and growing patient population.