Reduction in the Risk of Peripheral Neuropathy and Preservation of Kidney Function with Metformin, Linagliptin, or Their FixedDose Combination, Compared with Placebo in Prediabetes-A Randomized Controlled Trial

Objective: To compare the effect of glucose-lowering drugs plus lifestyle modification with lifestyle alone on peripheral nerve and kidney function in people with prediabetes. Methods: Multicenter, randomized, placebo-controlled trial in 658 individuals aged 45-74 years with prediabetes (IFG or IGT), were randomized to either metformin monotherapy, linagliptin monotherapy, fixed-dose combination of linagliptin/metformin or masked placebo. Main outcomes: 1-year reduction in the risk of small fiber peripheral neuropathy (SFPN) estimated by foot electrochemical skin conductance <70 µSiemens, measured with the SUDOSCAN® and estimated glomerular filtration rate (eGFR). Results: The percentage of people at high-risk of SFPN increased by 29.6% in the placebo group, while the increase was significantly lower in the three active-drug groups:1.8% in the metformin group, 4.3% in the linagliptin group, and 3.9% in the combination linagliptin/metformin group (p<0.001 for all three comparisons). eGFR remained significantly higher with the fixed-dose combination linagliptin/metformin (3.3 mL/min; 95% CI: 0.38; 6.22, p = 0.03) than with placebo. FPG was significantly lower with metformin monotherapy (-0.3 mmol/L: 95%CI: -0.48; 0.12, p=0.0009), and with the fixed-dose combination metformin/linagliptin (-0,2 mmol/L; 95% CI: -0.37; -0.03, p = 0.0219) than with placebo. Reduction in body weight was significantly greater (-2.0 kg/year, 95% CI:-5.65; -1.65, p=0.0006) with metformin monotherapy, and with the combination metformin/linagliptin (-1.9 kg/year; 95% CI: -3.02; -0.97, p=0.0002) than with placebo. Conclusion: In people with prediabetes, 1-year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a better preservation of kidney function than with placebo. Disclosure R.Gabriel: None. J.Tuomilehto: Stock/Shareholder; Orion pharma. Funding European Commission (FP7EC-GA 279074); Boehringer Ingelheim Germany (1218.166); Merck Healthcare KGaA (EMR200084_621); Instituto de Salud Carlos III (PI11/01653)