Incretin-based therapies in prediabetes: Current evidence and future perspectives

Table 1 Main clinical studies of dipeptidyl peptidase-4 inhibitors in a prediabetic state

Ref.	Study population	Study design	Main results
Utzschneider et al[50]	22 individuals with IFG	VILDA was administered in a dose of 100 mg daily for 6 wk. Two weeks of placebo treatment before (running period) and after (washout period) 6 wk was studied	FPG levels were not significantly reduced. AUC GLU and 2-h GLU decreased after a MTT. DI was increased by 69% and insulin sensitivity by 25% after an IVGTT These effects were not sustained in the washout period
Rosenstock et al[51]	179 individuals with IGT (80%: IFG + IGT)	Multicenter 12-wk double-blind study 90 participants received VILDA 50 mg/daily and 89 received placebo therapy	Improvements in β-cell function as estimated by insulin secretion relative to that of GLU. Improvements were also reported in α-cell function. These beneficial effects contributed to approximately 30% reduction in prandial GLU excursions
Werzowa et al[52]	48 IGT renal transplant recipients	3-mo, double-blind, placebo-controlled study. Participants were randomized to receive 50 mg of VILDA, 30 mg of PIO or placebo in a 1:1:1 ratio (n = 16 in each arm)	A1C reduction was statistically significant between treatment groups and placebo. VILDA and PIO reduced the 2 h plasma GLU at three months compared with baseline, while only PIO reduced FPG
Bock et al[57]	22 individuals with IFG	8-wk double blind placebo-controlled study Participants received SITA 100 mg daily (n = 11) or placebo (n = 11)	SITA increased postprandial intact GLP-1 concentrations. Both fasting and postprandial GLU values were unchanged with SITA therapy. A slightly increased DI was reported
Perreault et al[58]	23 individuals with either IFG (n = 10) or NGT (n = 13)	4-wk open-label, parallel group study. All participants received SITA 100 mg once daily	SITA resulted in a small, but significant decrease in FPG compared to baseline in both groups (P < 0.05) Administration of SITA did not altered insulin or GLU excursions in the post-intervention OGTT, but did increase AUC for active GLP-1 and C-peptide compared to baseline levels (P < 0.01 for both)

GLP-1: Glucagon-like peptide 1; IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance; NGT: Normal glucose tolerance; FPG: Fasting plasma glucose; AUC: Area under the curve; DI: Disposition index; IVGTT: Intravenous glucose tolerance test; MTT: Meal tolerance test; A1C: Glycated hemoglobulin; VILDA: Vildagliptin; SITA: Sitagliptin; PIO: Pioglitazone; GLU: Glucose; OGTT: Oral glucose tolerance test.

Table 2 Main clinical studies of glucagon-like peptide-1 receptor agonists in a prediabetic state

Ref.	Study population	Study design	Main results
Rosenstock et al[73]	152 obese individuals of whom 38 had IGT or IFG	Participants were randomized to receive either EXE (n = 73) (10 μg with a 4-wk 5 μg dose titration period) or placebo (n = 79) along with lifestyle modification for 24 wk	EXE-treated individuals lost 5.1 ± 0.5 kg from baseline vs 1.6 ± 0.5 kg in the placebo group (P < 0.001). An important percentage of individuals with prediabetes returned to NGT after the end period (77% compared to 56% in the placebo group)
Armato et al[74]	105 individuals with IGT and/or IFG. Mean follow-up period was 8.9, 6.9, and 5.5 mo in the three groups respectively	Participants were treated with: (1) Lifestyle modification only (n = 18); (2) PIO 15 mg daily and MET 850 mg daily (n = 40); and (3) PIO 15 mg daily, MET 850 mg daily and EXE 10 mcg twice daily (n = 47)	A robust 109% improvement in β-cell function and 52% increased in insulin sensitivity was observed in the EXE group, while 59% of individuals with IGT and 56% individuals with IFG reverted to NGT. No patient in both double and triple therapy groups developed T2D
Astrup et al[84]	564 obese individuals (31% had prediabetes)	20 wk double-blind prospective multicentre study. Participants were randomized to receive either one of four doses of LIRA (1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg, n: 95, 90, 93 and 93) or placebo (n = 98) or open label orlistat 120 mg three times a day (n = 95)	61% of the individuals in the LIRA groups lost at least 5% of body weight from the baseline, which was significantly more than in the placebo arm. The prevalence of prediabetes was decreased by 84%-96% with LIRA 1.8 mg, 2.4 mg and 3 mg. Mean FPG was decreased by 7%-8% only in the LIRA arm. Mean change in plasma GLU during OGTT were reduced in all LIRA groups compared with that of orlistat and placebo. Median β-cell function increased in the LIRA arm by 5%-24%
Kim et al[86]	68 overweight/obese individuals with IFG and/or IGT	14 wk double blind randomized placebo-controlled study. 24 individuals received LIRA 1.8 mg daily and 27 placebo therapy	Participants randomized to LIRA arm lost twice as much weight as those assigned to placebo (P < 0.001). Steady sate plasma GLU was reduced by 29% in the LIRA arm compared with no change in the placebo arm. 75% of the participants in the LIRA arm achieved normal FPG
Kim et al[87]	49 individual with isolated IFG, isolated IGT and combined IFG/IGT	14 wk double-blind, randomized, placebo-controlled, parallel-group study. Participants received LIRA 1.8 mg daily (n = 24) or placebo (n = 25)	Weight loss promoted a significant improvement in insulin resistance in the LIRA arm compared to the placebo arm (-7.7% vs -3.9%, P < 0.001). Insulin response, after intravenous GLU infusion, was decreased by 7% in the placebo arm whereas it increased by 34% in the LIRA arm. Despite weight loss and reduction of insulin resistance in the LIRA arm, the insulin secretion rate was significantly increased and there was no association between weight loss and changes in insulin secretion

IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance; NGT: Normal glucose tolerance; FPG: Fasting plasma glucose; EXE: Exenatide; LIRA: Liraglutide; PIO: Pioglitazone; MET: Metformin; T2D: Type 2 diabetes; GLU: Glucose; OGTT: Oral glucose tolerance test.