Hepatoselective glucokinase activator exhibits early promise in sort 1 diabetes


medwireNews: Early results suggest that a novel molecule that selectively targets glucokinase in the liver may improve glucose control and reduce the risk of acute complications in people with type 1 diabetes.

Klara Klein (University of North Carolina Medical School, Chapel Hill, USA) and colleagues used an adaptive proof-of-concept design to identify the molecule known as TTP399 in a Phase 1b / 2 study – the SimpliciT1 study – to test.

The first part of the study was a feasibility study conducted in four centers among 20 participants using insulin pumps plus continuous glucose monitoring (CGM). They performed a 2-week, single-blind, placebo break-in period, followed by a 12-week, double-blind period in which the glycated hemoglobin (HbA1c) levels in the participants who were randomly given placebo increased by 0.08 percentage points and by 0.60 percentage points fell in those who were administered TTP399 800 mg / day, giving a placebo-controlled reduction of 0.69 percentage points.

The second part of the study included 85 participants at 13 locations. Individuals enrolled in this section can use fingerstick tests or CGM with daily injections or insulin pumps. The HbA1c changes from baseline to week 12 at this phase of the study were an increase of 0.07 percentage points and a decrease of 0.14 percentage points with placebo and TTP399, respectively, a placebo-adjusted decrease of 0.21 percentage points.

The researchers note that this reduction is “more modest” than in the first phase, but emphasize that the studies are small and that the confidence intervals overlap.

They add that the improvement with TTP399 over placebo “despite a rigorous approach to treating the target” was achieved for all study participants.

In addition, the participants’ HbA1c was already close to the ADA target of 7.0% (53 mmol / mol), with the average starting value between 7.2% and 7.6% (55–60 mmol / mol).

“Small reductions in HbA1c therefore mean an improvement in the already good blood sugar control,” writes the team in Diabetes Care. “It is not known whether TTP399 would have a greater impact in participants with higher HbA1c levels.”

In addition to reducing HbA1c, TTP399 treatment resulted in a 1.7% reduction in insulin use versus placebo versus 0.1% in the first phase and 7.6% versus 1.6% in the second phase.

The researchers found that greater HbA1c reductions were associated with greater decreases in insulin use, suggesting that there is a subpopulation of people who respond particularly well to TTP399.

The reduction in HbA1c and insulin consumption was not at the expense of increased hypoglycemia. In fact, there were 12 cases of symptomatic hypoglycemia in both phases in the TTP399 group versus 26 in the placebo group. One case of severe hypoglycaemia occurred in a placebo-treated participant.

“Tight blood sugar control is often compromised by patient and provider fear of hypoglycemia,” say Klein et al.

“Given that hypoglycemia remains a major cause of morbidity in the treatment of insulin-dependent diabetes, add-on therapy that improves glycemia while reducing hypoglycemia would be a significant advance.”

Neither participant developed diabetic ketoacidosis, but elevated serum ketone levels, measured in five study visits, including three while on active treatment, were seen at least once in five people who took TTP399 compared with 14 who took placebo.

“An additional therapy that protects against it [hypoglycemia and ketoacidosis] This would be a major advance in the treatment of type 1 diabetes, ”the researchers note.

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Diabetes Care 2021; doi: 10.2337 / dc20-2684