HMGCR and Rosuvastatin Regulates GLP-1 Secretion and Expression-A Translational Study.
Level 4 - case-series / case-control
Cross-sectional human observational cohort analysis combined with in vitro and animal mechanistic experiments
PubMed 41206007 · doi:10.1210/clinem/dgaf608
What was done
The authors investigated the effects of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibition and rosuvastatin on glucagon-like peptide 1 (GLP-1) dynamics across three models: a cross-sectional association study in the Malmö Diet and Cancer study cardiovascular cohort (MDCS-CC) reexamination cohort (n = 3734); in vitro assays in GLUTag cells evaluating GLP-1 secretion and Gcg mRNA following rosuvastatin exposure, Hmgcr knockdown, or PCSK9 inhibition; and acute versus chronic rosuvastatin administration in female, normoglycemic C57Bl/6j mice measuring glycemia and postprandial GLP-1 levels.
What was found
In the human cohort (n = 3734), statin usage in individuals without type 2 diabetes was associated with higher fasting glucose-dependent insulinotropic peptide (GIP), insulin, glucose, glucagon, and HOMA-IR, but not GLP-1. In patients with type 2 diabetes, statin use was associated with higher fasting GLP-1 levels. The abstract does not report specific numerical values, effect sizes, confidence intervals, or p-values for the human cohort. In GLUTag cells, rosuvastatin treatment or Hmgcr knockdown reduced GLP-1 secretion and increased Gcg mRNA, an effect mirrored by PCSK9 inhibition. In mice, acute rosuvastatin reduced postprandial GLP-1 secretion, whereas chronic treatment caused hyperglycemia and increased postprandial GLP-1 levels.
Why it matters
This study identifies HMGCR as a regulator of GLP-1 secretion, offering a biological mechanism for the clinically observed mild hyperglycemia and elevated diabetes risk linked to statin therapy.
Limits
The human data are cross-sectional and observational, precluding causal inference, and no quantitative estimates or confidence intervals are provided in the abstract. Preclinical mechanistic findings rely on cell lines and exclusively female mice, which may not fully reflect human in vivo physiology.
Cited by
- partial A study showed that statin medications reduce endogenous GLP-1 production by 50%.