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Journal Article

HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials

Authors

  1. Daniel I. Swerdlow
  2. David Preiss
  3. Karoline B. Kuchenbaecker
  4. Michael V. Holmes
  5. Jorgen E. L. Engmann
  6. Tina Shah
  7. Reecha Sofat
  8. Stefan Stender
  9. Paul C. D. Johnson
  10. Robert A. Scott
  11. Maarten Leusink
  12. Niek Verweij
  13. Stephen J. Sharp
  14. Yiran Guo
  15. Claudia Giambartolomei
  16. Christina Chung
  17. Anne Peasey
  18. Antoinette Amuzu
  19. KaWah Li
  20. Jutta Palmen
  21. Philip Howard
  22. Jackie A. Cooper
  23. Fotios Drenos
  24. Yun R. Li
  25. Gordon Lowe
  26. John Gallacher
  27. Marlene C. W. Stewart
  28. Ioanna Tzoulaki
  29. Sarah G. Buxbaum
  30. Daphne L. van der A
  31. Nita G. Forouhi
  32. N. Charlotte Onland-Moret
  33. Yvonne T. van der Schouw
  34. Renate B. Schnabel
  35. Jaroslav A. Hubacek
  36. Ruzena Kubinova
  37. Migle Baceviciene
  38. Abdonas Tamosiunas
  39. Andrzej Pajak
  40. Romanvan Topor-Madry
  41. Urszula Stepaniak
  42. Sofia Malyutina
  43. Damiano Baldassarre
  44. Bengt Sennblad
  45. Elena Tremoli
  46. Ulf de Faire
  47. Fabrizio Veglia
  48. Ian Ford
  49. J. Wouter Jukema
  50. Rudi G. J. Westendorp
  51. Gert Jan de Borst
  52. Pim A. de Jong
  53. Ale Algra
  54. Wilko Spiering
  55. Anke H. Maitland-van der Zee
  56. Olaf H. Klungel
  57. Anthonius de Boer
  58. Pieter A. Doevendans
  59. Charles B. Eaton
  60. Jennifer G. Robinson
  61. David Duggan
  62. John Kjekshus
  63. John R. Downs
  64. Antonio M. Gotto
  65. Anthony C. Keech
  66. Roberto Marchioli
  67. Gianni Tognoni
  68. Peter S. Sever
  69. Neil R. Poulter
  70. David D. Waters
  71. Terje R. Pedersen
  72. Pierre Amarenco
  73. Haruo Nakamura
  74. John J. V. McMurray
  75. James D. Lewsey
  76. Daniel I. Chasman
  77. Paul M. Ridker
  78. Aldo P. Maggioni
  79. Luigi Tavazzi
  80. Kausik K. Ray
  81. Sreenivasa Rao Kondapally Seshasai
  82. JoAnn E. Manson
  83. Jackie F. Price
  84. Peter H. Whincup
  85. Richard W. Morris
  86. Debbie A. Lawlor
  87. George Davey Smith
  88. Yoav Ben-Shlomo
  89. Pamela J. Schreiner
  90. Myriam Fornage
  91. David S. Siscovick
  92. Mary Cushman
  93. Meena Kumari
  94. Nick J. Wareham
  95. W. M. Monique Verschuren
  96. Susan Redline
  97. Sanjay R. Patel
  98. John C. Whittaker
  99. Anders Hamsten
  100. Joseph A. Delaney
  101. Caroline Dale
  102. Tom R. Gaunt
  103. Andrew Wong
  104. Diana Kuh
  105. Rebecca Hardy
  106. Sekar Kathiresan
  107. Berta A. Castillo
  108. Pim van der Harst
  109. Eric J. Brunner
  110. Anne Tybjaerg-Hansen
  111. Michael G. Marmot
  112. Ronald M. Krauss
  113. Michael Tsai
  114. Josef Coresh
  115. Ronald C. Hoogeveen
  116. Bruce M. Psaty
  117. Leslie A. Lange
  118. Hakon Hakonarson
  119. Frank Dudbridge
  120. Steve E. Humphries
  121. Philippa J. Talmud
  122. Mika Kivimäki
  123. Nicholas J. Timpson
  124. Claudia Langenberg
  125. Folkert W. Asselbergs
  126. Mikhail Voevoda
  127. Martin Bobak
  128. Hynek Pikhart
  129. James G. Wilson
  130. Alex P. Reiner
  131. Brendan J. Keating
  132. Aroon D. Hingorani
  133. Naveed Sattar

Publication date

24 Jan 2015

Summary

Background
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
Funding
The funding sources are cited at the end of the paper.

Published in

The Lancet

Volume and page numbers

385 , 351 -361

DOI

http://dx.doi.org/10.1016/S0140-6736(14)61183-1

ISSN

16

Subjects

Medicine, Health, and Biology

Notes

Open Access article; Open Access funded by Medical Research Council

#522790


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