Efficacy of combination therapy with GABA, a DPP-4i and a PPI as an adjunct to insulin therapy in patients with type 1 diabetes

Abstract

Introduction: The purpose of this retrospective clinic chart review study was to determine the potential of a combination therapy (CT) consisting of γ-aminobutyric acid (GABA), a dipeptidyl peptidase-4 inhibitor (DPP-4i), and a proton pump inhibitor (PPI) to improve glycemic control as an adjunct to insulin therapy in patients with type 1 diabetes (T1D).

Research design and methods: Nineteen patients with T1D on insulin therapy were treated with additional CT in oral form. Fasting blood glucose (FBG), HbA1c, insulin dose-adjusted HbA1c (IDA-A1c), daily insulin dose, insulin/weight ratio (IWR), and fasting plasma C-peptide were measured after 26-42 weeks of treatments.

Results: FBG, HbA1c, IDA-A1c, insulin dose and IWR were all significantly decreased while plasma C-peptide was significantly increased by the CT. Treatment outcomes were further analyzed by separation of the 19 patients into two groups. One group started on the CT within 12 months of insulin treatment (early therapy, 10 patients) and another group started on this therapy only after 12 months of insulin treatment (late therapy, 9 patients). FBG, IDA-A1c, insulin dose, and IWR decreased significantly in both the early and late CT groups, however to a better extent in the early therapy group. Moreover, plasma C-peptide increased significantly only in the early therapy group, and 7 of the 10 patients in this group were able to discontinue insulin treatment while maintaining good glycemic control to study end compared with none of the 9 patients in the late therapy group.

Conclusion: These results support the concept that the combination of GABA, a DPP-4i and a PPI as an adjunct to insulin therapy improves glycemic control in patients with T1D, and that the insulin dose required for glycemic control can be reduced or even eliminated in some patients receiving this novel therapy.

Keywords: DPP-4i; GABA; PPI; insulin; type 1 diabetes.

Figure 1

Fasting blood glucose (A), HbA1c (B), insulin dose-adjusted HbA1c (C), daily insulin dose (D), insulin/weight ratio (E) and fasting plasma C-peptide (F) values are shown before (white bars) and after (black bars) treatment with the combination of GABA, a DPP-4i, and a PPI within 12 months of insulin treatment in 10 patients (early therapy) and more than 12 months after the start of insulin treatment in 9 patients (late therapy). Data are means ± SD if the distribution of values was close to normal, or medians with interquartile width if the distribution of values differed from normal. P-values are levels of significant paired differences between values before and after therapy for the numbers of patients indicated above, except for C-peptide values in 8 of the 10 patients in the early therapy group.

Figure 2

Ten patients were treated early (within 12 months) after diabetes onset and the start of insulin therapy by the addition of a three-drug combination of GABA, a DPP4i and a PPI. HbA1c (A), daily insulin doses (B) and plasma C-peptide levels (C) are shown for each patient before and after 27-42 weeks of the three-drug combination therapy. Insulin treatment was discontinued in 7 of the 10 patients who had HbA1c levels ≤6.8% after therapy (solid circles) but not in the remaining 3 of the 10 patients (white circles) who continued to require insulin to maintain HbA1c levels <7.0%.

Figure 3

Nine patients were treated late (more than 12 months) after diabetes onset and the start of insulin therapy by the addition of a three-drug combination of GABA, a DPP-4i and a PPI. HbA1c (A), daily insulin doses (B) and plasma C-peptide levels (C) are shown for each patient before and after therapy with the three-drug combination therapy for a mean of 29 weeks (range 26-41 weeks).

Figure 4

The plasma C-peptide response (delta C-peptide, y-axis) to the combination of GABA, a DPP-4i and a PPI is shown as a function of the time interval from the start of insulin treatment to the start of the combination therapy (A), and as a function of patient age at the start of combination therapy (B). Patients treated with the drug combination within 12 months after the start of insulin treatments were subsequently able to stop insulin treatments (Early therapy, off insulin) or not (Early therapy, on insulin). Other patients treated with the drug combination more than 12 months after the start of insulin treatments were not able to stop insulin treatments (Late therapy, on insulin).