Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol
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Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol. / Wu, Peitao; Moon, Jee-Young; Daghlas, Iyas; Franco, Giulianini; Porneala, Bianca C; Ahmadizar, Fariba; Richardson, Tom G; Isaksen, Jonas L; Hindy, Georgy; Yao, Jie; Sitlani, Colleen M; Raffield, Laura M; Yanek, Lisa R; Feitosa, Mary F; Cuadrat, Rafael R C; Qi, Qibin; Arfan Ikram, M; Ellervik, Christina; Ericson, Ulrika; Goodarzi, Mark O; Brody, Jennifer A; Lange, Leslie; Mercader, Josep M; Vaidya, Dhananjay; An, Ping; Schulze, Matthias B; Masana, Lluis; Ghanbari, Mohsen; Olesen, Morten S; Cai, Jianwen; Guo, Xiuqing; Floyd, James S; Jäger, Susanne; Province, Michael A; Kalyani, Rita R; Psaty, Bruce M; Orho-Melander, Marju; Ridker, Paul M; Kanters, Jørgen K; Uitterlinden, Andre; Davey Smith, George; Gill, Dipender; Kaplan, Robert C; Kavousi, Maryam; Raghavan, Sridharan; Chasman, Daniel I; Rotter, Jerome I; Meigs, James B; Florez, Jose C; Dupuis, Josée.
In: Diabetes Care, Vol. 45, No. 1, 2021, p. 232–240.Research output: Contribution to journal › Journal article › Research › peer-review
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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
N1 - © 2022 by the American Diabetes Association.
PY - 2021
Y1 - 2021
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 - Journal article
C2 - 34789503
VL - 45
SP - 232
EP - 240
JO - Diabetes Care
JF - Diabetes Care
SN - 0149-5992
IS - 1
ER -
ID: 285238736