Hepatoselective glucokinase activator shows early promise in type 1 diabetes
medwireNews: Early findings suggest a novel molecule that selectively targets hepatic glucokinase may improve glucose control and reduce acute complication risk in people with type 1 diabetes.
Klara Klein (University of North Carolina School of Medicine, Chapel Hill, USA) and colleagues used an adaptive proof-of-concept design to test the molecule, known as TTP399, in a phase 1b/2 study – the SimpliciT1 trial.
The first part of the trial was a feasibility study conducted at four centers among 20 participants using insulin pumps plus continuous glucose monitoring (CGM). They undertook a 2-week single-blind placebo run-in period, followed by a 12-week double-blind phase, during which glycated hemoglobin (HbA1c) levels rose by 0.08 percentage points in participants randomly assigned to receive placebo and fell by 0.60 percentage points in those given TTP399 800 mg/day, giving a placebo-adjusted reduction of 0.69 percentage points.
The second part of the study involved 85 participants at 13 sites. People enrolled to this section could be using fingerstick testing or CGM with either daily injections or insulin pumps. HbA1c changes from baseline to week 12 in this phase of the trial were a 0.07 percentage point increase and a 0.14 percentage point decrease with placebo and TTP399, respectively, for a placebo-adjusted reduction of 0.21 percentage points.
The researchers note this reduction is “more modest” than that in the first phase, but stress that these were small studies, and the confidence intervals overlapped.
They add that the improvement with TTP399 versus placebo “was achieved despite a rigorous treat-to-target approach” for all study participants.
Moreover, the participants’ HbA1c was already close to the ADA target of 7.0% (53 mmol/mol), with the average baseline level ranging from 7.2% to 7.6% (55–60 mmol/mol).
“Small reductions in HbA1c therefore represent improvement in already good glycemic control,” the team writes in Diabetes Care. “It is unknown whether TTP399 would have a larger impact in participants with higher baseline HbA1c.”
In addition to reducing HbA1c, TTP399 treatment led to reductions in insulin use versus placebo, by 1.7% versus 0.1% in the first phase and 7.6% versus 1.6% in the second phase.
The researchers found that larger HbA1c reductions were associated with larger decreases in insulin use, suggesting “there is a subpopulation of people who respond particularly well to TTP399.”
The reductions in HbA1c and insulin use did not come at the expense of more hypoglycemia. Indeed, across both phases there were 12 incidences of symptomatic hypoglycemia in the TTP399 group versus 26 in the placebo group. The one case of severe hypoglycemia occurred in a placebo-treated participant.
“Tight glycemic control is often compromised by patient and provider fear of hypoglycemia,” say Klein et al.
“Given that hypoglycemia remains a leading cause of morbidity in the treatment of insulin-dependent diabetes, an adjunctive therapy that improves glycemia while reducing hypoglycemia would represent a significant advance.”
No participant developed diabetic ketoacidosis, but elevated serum ketone levels, measured at five study visits including three during active treatment, were identified at least once in five people taking TTP399, compared with 14 taking placebo.
“An adjunctive therapy that protects against [hypoglycemia and ketoacidosis] would be a substantial advance in the treatment of type 1 diabetes,” the researchers observe.
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