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 Jager; 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. GoodarziJennifer 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 Jager, 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

School of Medicine

Research output: Contribution to journal › Article › 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 (b 5 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 5 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 5 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 (US)
Pages (from-to)	232-240
Number of pages	9
Journal	Diabetes care
Volume	45
Issue number	1
DOIs	https://doi.org/10.2337/dc21-1284
State	Published - Jan 2022

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Advanced and Specialized Nursing

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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., Ikram, M. A., 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

Wu, P, Moon, JY, 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, Ikram, MA, 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, Jager, S, Province, MA, Kalyani, RR, Psaty, BM, Orho-Melander, M, Ridker, PM, Kanters, JK, Uitterlinden, A, Smith, GD, Gill, D, Kaplan, RC, Kavousi, M, Raghavan, S, Chasman, DI, Rotter, JI, Meigs, JB, Florez, JC, Dupuis, J, Liu, CT & 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

@article{edf0a903114c491da27386473b6f6589,

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 (b 5 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 5 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 5 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 Moon, {Jee Young} 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 Ikram, {M. Arfan} 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 Jager 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 Smith, {George Davey} 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 Liu, {Ching Ti} and Jordi Merino",

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

year = "2022",

month = jan,

doi = "10.2337/dc21-1284",

language = "English (US)",

volume = "45",

pages = "232--240",

journal = "Diabetes care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

number = "1",

}

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 - Ikram, M. Arfan

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 - Jager, 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 - Smith, George Davey

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

Y1 - 2022/1

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 (b 5 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 5 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 5 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 (b 5 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 5 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 5 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.

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DO - 10.2337/dc21-1284

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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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