134-OR: Effects of PCSK9 Inhibitors on Glucose Metabolism and ß-Cell Function in Humans

PCSK9 inhibitors are monoclonal antibodies effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. Since PCSK9 is also expressed in other organs, including pancreas, studies on PCSK9 KO mice, have shown impaired insulin secretion. Other murine models in which PCSK9 was silenced only in the liver (mimicking the action of PCSK9i) had normal glucose metabolism. The aim of our study was to evaluate the effect of PCSK9 inhibitors on glucose metabolism and beta cell function in humans. 11 nondiabetic subjects candidate for PCSK9i therapy were enrolled in the study. All subjects underwent an OGTT at baseline and after 6 months of therapy, at which point surrogate insulin sensitivity indices were obtained (Matsuda; OGIS). During OGTT, insulin secretion parameters were derived from C-peptide levels by deconvolution; we evaluated basal insulin secretion rate, total insulin secretion rate and β-cell glucose sensitivity, for 6 of the 11 enrolled subjects. All patients showed a 53.3% reduction in LDL cholesterol after 6 months of therapy; the mean LDL-C baseline level (B) was 202.5 ± 45 mg/dl, while mean LDL-C post therapy (PT) value was 94.6 ± 27 mg/dl. Glycemic and insulinemic curves showed no significant differences between baseline and follow-up. Matsuda index (B 4.1 ± 1, PT 3.4 ± 0.7 mL min-1kg-1) and OGIS (B 396.9 ± 32, PT 386.2 ± 28 ml min-1m-2), showed no differences between baseline and post-therapy evaluation. There were no significant differences in insulin secretion parameters: basal insulin secretion rate (B 63.7 ± 34, PT 66.4 ± 23 pmol min-1m-2), total insulin secretion rate (B 48.7 ± 17, PT 46.9 ± 16, nmol m-2) and β-cell glucose sensitivity (B 117.5 ± 69, PT 141.2 ± 47 pmol min-1m-2mM-1) obtained from c-peptide deconvolution. Our study, although preliminary and in a small sample of patients, suggests that PCSK9is does not cause alterations in glucose metabolism and beta cell function. Further studies and a longer follow-up may provide us with further data to confirm our observations. Disclosure S. Moffa: None. T. Mezza: None. C. Cefalo: None. F. Cinti: None. G. Sorice: None. F. Impronta: None. U. Capece: None. A. Mari: Consultant; Self; Lilly Diabetes. Research Support; Self; Boehringer Ingelheim International GmbH. A. Giaccari: Speaker’s Bureau; Self; Amgen, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi-Aventis.