Impact of the hepatoselective glucokinase activator TTP399 on ketoacidosis during insulin withdrawal in people with type 1 diabetes

Abstract

Aims: To determine the effect of TTP399, a hepatoselective glucokinase activator, on the risk of ketoacidosis during insulin withdrawal in individuals with type 1 diabetes (T1D).Materials and methods: Twenty-three participants with T1D using insulin pump therapy were randomized to 800 mg TTP399 (n = 12) or placebo (n = 11) for 7 to 10 days. After the treatment period, an insulin withdrawal test (IWT) was performed, during which insulin pumps were removed to induce ketogenesis. The IWT was stopped after 10 hours or if blood glucose reached >399 mg/dL [22.1 mmol/L], if beta-hydroxybutyrate (BHB) was >3.0 mmol/L, or for patient discomfort. The primary endpoint was the proportion of participants who reached BHB concentrations of 1 mmol/L or greater.Results: During the 7-to 10-day treatment period, mean fasting plasma glucose was significantly reduced ( À27.6 vs. À4.4 mg/dL [À1.5 vs. À0.2 mmol/L]; P = 0.03) and there were fewer adverse events, including hypoglycaemia, in the TTP399-treated arm. During the IWT, no differences were observed between TTP399 and placebo in mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was numerically higher and urine acetoacetate was quantitatively lower in the TTP399-treated participants. As a result of higher bicarbonate values, none of the TTP399-treated participants met the prespecified criteria for diabetic ketoacidosis (DKA), defined as BHB >3 mmol/L and serum bicarbonate <18 mEq/L, compared to 42% of placebo-treated participants.Conclusions: When used as an adjunctive therapy to insulin, TTP399 improves glycaemia without increasing hypoglycaemia in individuals with T1D. During acute insulin withdrawal, TTP399 did not increase BHB concentrations and decreased the incidence of DKA.

Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes

“…The indication for TTP399 in clinical development has changed to type 1 diabetes (T1D) beginning in 2019. A phase 1b/2 adaptive study with a 12‐week treatment duration demonstrated that hepatic GK activation could simultaneously decrease HbA1c, plasma β‐hydroxybutyrate, urinary ketones, and the frequency of severe or symptomatic hypoglycemia relative to placebo 51,52 …”

New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment

“…A clinical study investigated the effect of TTP399 on the risk of ketoacidosis during insulin withdrawal in T1DM patients [ 68 ]. Participants with T1DM using insulin pump therapy were randomized to receive either 800 mg TTP399 or a placebo for 7 to 10 days.…”

“…The primary endpoint was the proportion of patients who reached beta-hydroxybutyrate (BHB) concentrations of 1 mmol/L or greater. During the treatment period, TTP399 significantly reduced mean FPG levels and resulted in fewer AEs compared to placebo treatment [ 68 ]. During the IWT, there were no differences between the TTP399 and placebo groups in the mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT.…”

“…During the IWT, there were no differences between the TTP399 and placebo groups in the mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was statistically higher and urine acetoacetate was quantitatively lower in the TTP399-treated patients [ 68 ]. Importantly, none of the TTP399-treated participants met the criteria for DKA, as compared to 42% of the placebo-treated individuals.…”

“…Additionally, TTP399 does not increase BHB concentrations and reduces the incidence of DKA during acute insulin withdrawal. These findings suggest that TTP399 may be a promising adjunctive therapy for T1DM [ 68 ].…”