Role of Gut Microbiota in Statin-Associated New-Onset Diabetes-A Cross-Sectional and Prospective Analysis of the FINRISK 2002 Cohort

Kari Koponen; Oleg Kambur; Bijoy Joseph; Matti O Ruuskanen; Pekka Jousilahti; Rodolfo Salido; Caitriona Brennan; Mohit Jain; Guillaume Meric; Michael Inouye; Leo Lahti; Teemu Niiranen; Aki S Havulinna; Rob Knight; Veikko Salomaa

doi:10.1161/ATVBAHA.123.319458

Role of Gut Microbiota in Statin-Associated New-Onset Diabetes-A Cross-Sectional and Prospective Analysis of the FINRISK 2002 Cohort

Arterioscler Thromb Vasc Biol. 2024 Feb;44(2):477-487. doi: 10.1161/ATVBAHA.123.319458. Epub 2023 Nov 16.

Authors

Kari Koponen¹, Oleg Kambur¹, Bijoy Joseph¹, Matti O Ruuskanen², Pekka Jousilahti¹, Rodolfo Salido^{3

4}, Caitriona Brennan³, Mohit Jain⁵, Guillaume Meric^{6

7}, Michael Inouye^{6

8}, Leo Lahti², Teemu Niiranen^{1

9}, Aki S Havulinna^{1

10}, Rob Knight^{3

4

11

12}, Veikko Salomaa¹

Affiliations

¹ Finnish Institute for Health and Welfare (THL), Helsinki, Finland (K.K., O.K., B.J., P.J., T.N., A.S.H., V.S.).
² Department of Computing, University of Turku, Finland (M.O.R., L.L.).
³ Department of Pediatrics (R.S., C.B., R.K.), University of California San Diego, La Jolla.
⁴ Department of Bioengineering (R.S., R.K.), University of California San Diego, La Jolla.
⁵ Department of Medicine and Pharmacology (M.J.), University of California San Diego, La Jolla.
⁶ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Australia (G.M., M.I.).
⁷ Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Australia (G.M.).
⁸ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, United Kingdom (M.I.).
⁹ Department of Medicine, Turku University Hospital and University of Turku, Finland (T.N.).
¹⁰ Institute for Molecular Medicine Finland, FiMM-HiLIFE, Helsinki, Finland (A.S.H.).
¹¹ Department of Computer Science and Engineering (R.K.), University of California San Diego, La Jolla.
¹² Center for Microbiome Innovation (R.K.), University of California San Diego, La Jolla.

Abstract

Background: Dyslipidemia is treated effectively with statins, but treatment has the potential to induce new-onset type-2 diabetes. Gut microbiota may contribute to this outcome variability. We assessed the associations of gut microbiota diversity and composition with statins. Bacterial associations with statin-associated new-onset type-2 diabetes (T2D) risk were also prospectively evaluated.

Methods: We examined shallow-shotgun-sequenced fecal samples from 5755 individuals in the FINRISK-2002 population cohort with a 17+-year-long register-based follow-up. Alpha-diversity was quantified using Shannon index and beta-diversity with Aitchison distance. Species-specific differential abundances were analyzed using general multivariate regression. Prospective associations were assessed with Cox regression. Applicable results were validated using gradient boosting.

Results: Statin use associated with differing taxonomic composition (R², 0.02%; q=0.02) and 13 differentially abundant species in fully adjusted models (MaAsLin; q<0.05). The strongest positive association was with Clostridium sartagoforme (β=0.37; SE=0.13; q=0.02) and the strongest negative association with Bacteroides cellulosilyticus (β=-0.31; SE=0.11; q=0.02). Twenty-five microbial features had significant associations with incident T2D in statin users, of which only Bacteroides vulgatus (HR, 1.286 [1.136-1.457]; q=0.03) was consistent regardless of model adjustment. Finally, higher statin-associated T2D risk was seen with [Ruminococcus] torques (ΔHR_statins, +0.11; q=0.03), Blautia obeum (ΔHR_statins, +0.06; q=0.01), Blautia sp. KLE 1732 (ΔHR_statins, +0.05; q=0.01), and beta-diversity principal component 1 (ΔHR_statin, +0.07; q=0.03) but only when adjusting for demographic covariates.

Conclusions: Statin users have compositionally differing microbiotas from nonusers. The human gut microbiota is associated with incident T2D risk in statin users and possibly has additive effects on statin-associated new-onset T2D risk.

Keywords: diabetes mellitus, type 2; metagenome; microbiota; prospective studies; statins.

Publication types

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

MeSH terms

Cross-Sectional Studies
Diabetes Mellitus, Type 2* / diagnosis
Diabetes Mellitus, Type 2* / epidemiology
Dyslipidemias* / diagnosis
Dyslipidemias* / drug therapy
Dyslipidemias* / epidemiology
Gastrointestinal Microbiome*
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / adverse effects

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors