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

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.