Effects of PCSK9 inhibition on glucose metabolism and β-cell function in humans: a pilot study

Simona Moffa; Teresa Mezza; Pietro Manuel Ferraro; Gianfranco Di Giuseppe; Chiara M A Cefalo; Francesca Cinti; Flavia Impronta; Umberto Capece; Gea Ciccarelli; Andrea Mari; Alfredo Pontecorvi; Andrea Giaccari

doi:10.3389/fendo.2023.1124116

Effects of PCSK9 inhibition on glucose metabolism and β-cell function in humans: a pilot study

Front Endocrinol (Lausanne). 2023 May 31:14:1124116. doi: 10.3389/fendo.2023.1124116. eCollection 2023.

Affiliations

¹ Centro Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
² Pancreas Unit - Digestive Disease Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
³ Unità Operativa Semplice Terapia Conservativa della Malattia Renale Cronica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
⁴ Institute of Neuroscience, National Research Council, Padova, Italy.

Abstract

Background: Anti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans.

Methods: Fifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda).

Results: Glucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min^-1m^-2mM^-1; p<0.05). Using linear regression, we found a significant correlation between βCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m²) and found that those with higher BMI had a greater increase in βCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min^-1m^-2mM^-1; p=0.007). There was also a significant correlation between βCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below the median (3.8). This subgroup analysis showed a slight though not significant improvement in βCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min^-1m^-2mM^-1; p=0.066).

Conclusions: Our pilot study demonstrates that six-month treatment with anti-PCSK9 mAb improves β-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI.

Keywords: BMI; Dyslipidaemia; PCSK 9 inhibition; diabetes; precision medicine; statins; β-cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Glucose* / metabolism
C-Peptide
Glucose
Glucose Tolerance Test
Humans
Insulin* / metabolism
Mice
Pilot Projects

Substances

Blood Glucose
C-Peptide
Insulin
Glucose

Grants and funding

This study was supported by grants from the Università Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2, Fondi Ateneo Linea D.1, anno 2019 and Fondi Ateneo Linea D.1, anno 2020 and from “Ministero della Salute – Ricerca Corrente 2022”.