Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

Peitao Wu; Jee-Young Moon; Iyas Daghlas; Giulianini Franco; Bianca C Porneala; Fariba Ahmadizar; Tom G Richardson; Jonas L Isaksen; Georgy Hindy; Jie Yao; Colleen M Sitlani; Laura M Raffield; Lisa R Yanek; Mary F Feitosa; Rafael R C Cuadrat; Qibin Qi; M Arfan Ikram; Christina Ellervik; Ulrika Ericson; Mark O Goodarzi; Jennifer A Brody; Leslie Lange; Josep M Mercader; Dhananjay Vaidya; Ping An; Matthias B Schulze; Lluis Masana; Mohsen Ghanbari; Morten S Olesen; Jianwen Cai; Xiuqing Guo; James S Floyd; Susanne Jäger; Michael A Province; Rita R Kalyani; Bruce M Psaty; Marju Orho-Melander; Paul M Ridker; Jørgen K Kanters; Andre Uitterlinden; George Davey Smith; Dipender Gill; Robert C Kaplan; Maryam Kavousi; Sridharan Raghavan; Daniel I Chasman; Jerome I Rotter; James B Meigs; Jose C Florez; Josée Dupuis; Ching-Ti Liu; Jordi Merino

doi:10.2337/dc21-1284

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

Peitao Wu
, Jee-Young Moon
, Iyas Daghlas
, Giulianini Franco
, Bianca C Porneala
, Fariba Ahmadizar
, Tom G Richardson
, Jonas L Isaksen
, Georgy Hindy
, Jie Yao
, Colleen M Sitlani
, Laura M Raffield
, Lisa R Yanek
, Mary F Feitosa
, Rafael R C Cuadrat
, Qibin Qi
, M Arfan Ikram
, Christina Ellervik
, Ulrika Ericson
, Mark O Goodarzi

Jennifer A Brody, Leslie Lange, Josep M Mercader, Dhananjay Vaidya, Ping An, Matthias B Schulze, Lluis Masana, Mohsen Ghanbari, Morten S Olesen, Jianwen Cai, Xiuqing Guo, James S Floyd, Susanne Jäger, Michael A Province, Rita R Kalyani, Bruce M Psaty, Marju Orho-Melander, Paul M Ridker, Jørgen K Kanters, Andre Uitterlinden, George Davey Smith, Dipender Gill, Robert C Kaplan, Maryam Kavousi, Sridharan Raghavan, Daniel I Chasman, Jerome I Rotter, James B Meigs, Jose C Florez, Josée Dupuis, Ching-Ti Liu, Jordi Merino^*

^*Corresponding author for this work

Data and Development Support

Research output: Contribution to journal › Article › Research › peer-review

Abstract

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.

RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.

RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).

CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Original language	English
Pages (from-to)	232-240
Number of pages	9
Journal	Diabetes Care
Volume	45
Issue number	1
Early online date	17 Nov 2021
DOIs	https://doi.org/10.2337/dc21-1284
Publication status	Published - 1 Jan 2022

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10.2337/dc21-1284

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Wu, P., Moon, J.-Y., Daghlas, I., Franco, G., Porneala, B. C., Ahmadizar, F., Richardson, T. G., Isaksen, J. L., Hindy, G., Yao, J., Sitlani, C. M., Raffield, L. M., Yanek, L. R., Feitosa, M. F., Cuadrat, R. R. C., Qi, Q., Arfan Ikram, M., Ellervik, C., Ericson, U., ... Merino, J. (2022). Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol. Diabetes Care, 45(1), 232-240. https://doi.org/10.2337/dc21-1284

@article{e64729c72e804c75a06d9e21ff181a51,

title = "Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol",

abstract = "OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95\% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95\% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95\% CI 1.01, 1.08]) with a proportion mediated of 38\% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8\% (P = 0.04).CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.",

author = "Peitao Wu and Jee-Young Moon and Iyas Daghlas and Giulianini Franco and Porneala, \{Bianca C\} and Fariba Ahmadizar and Richardson, \{Tom G\} and Isaksen, \{Jonas L\} and Georgy Hindy and Jie Yao and Sitlani, \{Colleen M\} and Raffield, \{Laura M\} and Yanek, \{Lisa R\} and Feitosa, \{Mary F\} and Cuadrat, \{Rafael R C\} and Qibin Qi and \{Arfan Ikram\}, M and Christina Ellervik and Ulrika Ericson and Goodarzi, \{Mark O\} and Brody, \{Jennifer A\} and Leslie Lange and Mercader, \{Josep M\} and Dhananjay Vaidya and Ping An and Schulze, \{Matthias B\} and Lluis Masana and Mohsen Ghanbari and Olesen, \{Morten S\} and Jianwen Cai and Xiuqing Guo and Floyd, \{James S\} and Susanne J{\"a}ger and Province, \{Michael A\} and Kalyani, \{Rita R\} and Psaty, \{Bruce M\} and Marju Orho-Melander and Ridker, \{Paul M\} and Kanters, \{J{\o}rgen K\} and Andre Uitterlinden and \{Davey Smith\}, George and Dipender Gill and Kaplan, \{Robert C\} and Maryam Kavousi and Sridharan Raghavan and Chasman, \{Daniel I\} and Rotter, \{Jerome I\} and Meigs, \{James B\} and Florez, \{Jose C\} and Jos{\'e}e Dupuis and Ching-Ti Liu and Jordi Merino",

note = "{\textcopyright} 2021 by the American Diabetes Association.",

year = "2022",

month = jan,

day = "1",

doi = "10.2337/dc21-1284",

language = "English",

volume = "45",

pages = "232--240",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "1",

}

Wu, P, Moon, J-Y, Daghlas, I, Franco, G, Porneala, BC, Ahmadizar, F, Richardson, TG, Isaksen, JL, Hindy, G, Yao, J, Sitlani, CM, Raffield, LM, Yanek, LR, Feitosa, MF, Cuadrat, RRC, Qi, Q, Arfan Ikram, M, Ellervik, C, Ericson, U, Goodarzi, MO, Brody, JA, Lange, L, Mercader, JM, Vaidya, D, An, P, Schulze, MB, Masana, L, Ghanbari, M, Olesen, MS, Cai, J, Guo, X, Floyd, JS, Jäger, S, Province, MA, Kalyani, RR, Psaty, BM, Orho-Melander, M, Ridker, PM, Kanters, JK, Uitterlinden, A, Davey Smith, G, Gill, D, Kaplan, RC, Kavousi, M, Raghavan, S, Chasman, DI, Rotter, JI, Meigs, JB, Florez, JC, Dupuis, J, Liu, C-T & Merino, J 2022, 'Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol', Diabetes Care, vol. 45, no. 1, pp. 232-240. https://doi.org/10.2337/dc21-1284

TY - JOUR

T1 - Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

AU - Wu, Peitao

AU - Moon, Jee-Young

AU - Daghlas, Iyas

AU - Franco, Giulianini

AU - Porneala, Bianca C

AU - Ahmadizar, Fariba

AU - Richardson, Tom G

AU - Isaksen, Jonas L

AU - Hindy, Georgy

AU - Yao, Jie

AU - Sitlani, Colleen M

AU - Raffield, Laura M

AU - Yanek, Lisa R

AU - Feitosa, Mary F

AU - Cuadrat, Rafael R C

AU - Qi, Qibin

AU - Arfan Ikram, M

AU - Ellervik, Christina

AU - Ericson, Ulrika

AU - Goodarzi, Mark O

AU - Brody, Jennifer A

AU - Lange, Leslie

AU - Mercader, Josep M

AU - Vaidya, Dhananjay

AU - An, Ping

AU - Schulze, Matthias B

AU - Masana, Lluis

AU - Ghanbari, Mohsen

AU - Olesen, Morten S

AU - Cai, Jianwen

AU - Guo, Xiuqing

AU - Floyd, James S

AU - Jäger, Susanne

AU - Province, Michael A

AU - Kalyani, Rita R

AU - Psaty, Bruce M

AU - Orho-Melander, Marju

AU - Ridker, Paul M

AU - Kanters, Jørgen K

AU - Uitterlinden, Andre

AU - Davey Smith, George

AU - Gill, Dipender

AU - Kaplan, Robert C

AU - Kavousi, Maryam

AU - Raghavan, Sridharan

AU - Chasman, Daniel I

AU - Rotter, Jerome I

AU - Meigs, James B

AU - Florez, Jose C

AU - Dupuis, Josée

AU - Liu, Ching-Ti

AU - Merino, Jordi

PY - 2022/1/1

Y1 - 2022/1/1

N2 - OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

AB - OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

U2 - 10.2337/dc21-1284

DO - 10.2337/dc21-1284

M3 - Article

C2 - 34789503

SN - 0149-5992

VL - 45

SP - 232

EP - 240

JO - Diabetes Care

JF - Diabetes Care

IS - 1

ER -

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

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