Realize the potential of adjunctive therapy in the treatment of type 1 diabetes
One approach to improve care and clinical outcomes for people with type 1 diabetes involves the use of adjunctive therapies along with insulin to improve glucose control or enable reductions in insulin doses.
Type 1 diabetes is an autoimmune disease that leads to the destruction of pancreatic insulin-secreting beta cells and subsequent loss of insulin production. It is a significant and growing health challenge. Today, more than 1.5 million people in the United States have been diagnosed with type 1 diabetes, and the prevalence is expected to increase to 2.27 million by 2026. Although the disease is primarily an endocrine disorder, it is complex and can cause long-term microvascular damage, including retinopathy and nephropathy, and neuropathy. Individuals with type 1 diabetes are also at increased risk for macrovascular complications, including cardiovascular disease, peripheral vascular disease and cerebrovascular disease.
Insulin essential, but suboptimal therapy
Insulin therapy is essential for survival of people with type 1 diabetes. If left untreated, insulin deficiency results in hyperglycemia, ketoacidosis and then coma and death. However, insulin management is challenging and complex and has significant limitations resulting from the need for careful titration to maintain blood glucose levels within a narrow physiologic range. Even with careful management, insulin therapy may lead to multiple adverse effects, including hypoglycemia, glycemic variability and weight gain.
The addition of noninsulin therapies may help mitigate these limitations. Improved glycemic control is proven to have long-term benefits, including delaying onset and slowing progression of retinopathy, nephropathy and neuropathy. Furthermore, reducing insulin doses may help to mitigate insulin-associated weight gain and episodes of hypoglycemia. Despite the potential benefits of adjunctive therapies, adverse effects, including hypoglycemia, ketoacidosis and gastrointestinal symptoms, have hindered their development to date.
Limitations of today’s adjunctive therapies
Pramlintide (Symlin, AstraZeneca), a synthetic amylin analogue, is currently the only FDA-approved adjunctive therapy for people with type 1 diabetes. Its use in real-world settings has been limited by the need for multiple daily injections and gastrointestinal adverse effects, and an increased risk for severe hypoglycemia led to a black box warning.
GLP-1 receptor agonists, which increase insulin secretion, decrease glucagon secretion, slow gastric emptying and promote satiety, are approved only for the treatment of type 2 diabetes. Despite high interest in the use of GLP-1 receptor agonists in the treatment of type 1 diabetes, none have yet been approved for use in this patient population, primarily due to the high incidence of gastrointestinal adverse events, including nausea, vomiting, diarrhea and constipation.
A large clinical study evaluating the GLP-1 receptor analogue liraglutide (Victoza, Novo Nordisk) as adjunctive therapy to insulin in people with type 1 diabetes showed benefits with respect to decreases in HbA1c, total insulin dose and body weight, but also found increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, which the study authors concluded would limit clinical use of liraglutide in this population. Similarly, a clinical study of the short-acting GLP-1 receptor agonist exenatide (Byetta/Bydureon, AstraZeneca) found that exenatide had no effect on HbA1c compared with placebo, but increased the number of self-reported gastrointestinal adverse events. Again, the study investigators concluded “short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes.”
SGLT2 inhibitors are an oral class of FDA-approved therapies for type 2 diabetes that have been evaluated in type 1 diabetes. Although multiple trials of the SGLT2 inhibitors empagliflozin (Jardiance, Boehringer Ingelheim), dapagliflozin (Farxiga, AstraZeneca) and the combination SGLT1/SGLT2 inhibitor sotagliflozin (Zynquista, Sanofi and Lexicon) have shown improvement in HbA1c, modest weight loss and slight reduction of insulin dose when used as adjuncts to insulin in people with type 1 diabetes, all of these studies showed increased risks for diabetic ketoacidosis. Based on this increased risk, the FDA recently rejected the application for empagliflozin as an adjunctive therapy for type 1 diabetes and has previously rejected applications for dapagliflozin and sotagliflozin.
Hepatoselective glucokinase activators hold promise
Glucokinase is the body’s glucose sensor and a key regulator of blood glucose levels. Hepatoselective glucokinase activators have several characteristics that make them a promising therapeutic target in diabetes and in type 1 diabetes specifically. First, glucokinase is primarily expressed in tissues that require glucose sensing — liver and pancreatic beta cells. Second, glucokinase senses changes in glucose levels and modulates hepatic and pancreatic function to maintain glucose within the physiologic range. Third, hepatic selectivity may overcome the adverse consequences of nonselective glucokinase activators observed in clinical trials in people with type 2 diabetes. Importantly, the mechanism of action of these agents does not require endogenous insulin secretion, rendering them ideal adjunct agents for the treatment of type 1 diabetes.
Results from a phase 2 study of TTP399, an investigational oral hepatoselective glucokinase activator (vTv Therapeutics), suggest that this novel approach may provide benefit in type 1 diabetes. The study, which was conducted in 85 adults with type 1 diabetes on optimized insulin therapy, demonstrated a statistically significant improvement in HbA1c (decrease of 0.32%; P < .01) compared with placebo at week 12. Daily time-in-range assessed with continuous glucose monitoring also improved by approximately 2 hours per day compared with placebo (P = .03), and there was a greater reduction in total daily bolus insulin requirement compared with placebo (P = .02). Importantly, these benefits were achieved with no diabetic ketoacidosis, no incidence of severe hypoglycemia and fewer symptomatic hypoglycemic episodes.
Although early, these data support a potential role for oral hepatoselective glucokinase activators as adjunctive therapy to insulin to address an unmet need in the treatment of type 1 diabetes. The ability to improve long-term glucose control while reducing daily insulin requirements without severe hypoglycemia or ketoacidosis and with fewer symptomatic hypoglycemic episodes in an oral therapy would be a substantial advancement over insulin monotherapy in type 1 diabetes.
Given the known benefits of improved long-term glucose control while mitigating the adverse consequences of insulin therapy, this study suggests that hepatoselective glucokinase activators could potentially improve near- and long-term outcomes for people living with type 1 diabetes. These initial data indicate that this investigational treatment has unique promise as an adjunct to insulin because it provides the benefits observed with other investigational adjunctive agents without the dangerous adverse effects of diabetic ketoacidosis or increased hypoglycemia.
- Evans M, et al. Diabetes Ther. 2020;doi:10.1007/s13300-019-00728-6.
- Johansen NJ, et al. Lancet Diabetes Endocrinol. 2020;doi:10.1016/S2213-8587(20)30030-9.
- Mathieu C, et al. Diabetes Care. 2016;doi:10.2337/dc16-0691.
For more information:
Wendy S. Lane, MD, is an endocrinologist at Mountain Diabetes and Endocrine Center in Asheville, North Carolina. She can be reached at firstname.lastname@example.org.