Objective: To compare the effect of glucose-lowering drugs on peripheral nerve and kidney function in prediabetes. Methods: Multicenter, randomized, placebo-controlled trial in 658 adults with prediabetes treated for 1 year with metformin, linagliptin, their combination or placebo. Endpoints are small fiber peripheral neuropathy (SFPN) risk estimated by foot electrochemical skin conductance (FESC < 70 μSiemens) and estimated glomerular filtration rate (eGFR). Results: Compared to the placebo, the proportion of SFPN was reduced by 25.1% (95% CI:16.3–33.9) with metformin alone, by 17.3% (95% CI 7.4–27.2) with linagliptin alone, and by 19.5% (95% CI 10.1–29.0) with the combination linagliptin/metformin (p < 0.0001 for all comparisons). eGFR remained +3.3 mL/min (95% CI: 0.38–6.22) higher with the combination linagliptin/metformin than with the placebo (p = 0.03). Fasting plasma glucose (FPG) decreased more with metformin monotherapy −0.3 mmol/L (95%CI: −0.48; 0.12, p = 0.0009) and with the combination metformin/linagliptin −0.2 mmol/L (95% CI: −0.37; −0.03) than with the placebo (p = 0.0219). Body weight (BW) decreased by −2.0 kg (95% CI: −5.65; −1.65, p = 0.0006) with metformin monotherapy, and by −1.9 kg (95% CI: −3.02; −0.97) with the combination metformin/linagliptin as compared to the placebo (p = 0.0002). Conclusions: in people with prediabetes, a 1 year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a lower decrease in eGFR, than treatment with placebo.