PMID- 30153257
OWN - NLM
STAT- MEDLINE
DCOM- 20190409
LR  - 20220129
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 15
IP  - 8
DP  - 2018 Aug
TI  - Relationship between very low low-density lipoprotein cholesterol concentrations 
      not due to statin therapy and risk of type 2 diabetes: A US-based cross-sectional 
      observational study using electronic health records.
PG  - e1002642
LID - 10.1371/journal.pmed.1002642 [doi]
LID - e1002642
AB  - BACKGROUND: Observations from statin clinical trials and from Mendelian 
      randomization studies suggest that low low-density lipoprotein cholesterol 
      (LDL-C) concentrations may be associated with increased risk of type 2 diabetes 
      mellitus (T2DM). Despite the findings from statin clinical trials and genetic 
      studies, there is little direct evidence implicating low LDL-C concentrations in 
      increased risk of T2DM. METHODS AND FINDINGS: We used de-identified electronic 
      health records (EHRs) at Vanderbilt University Medical Center to compare the risk 
      of T2DM in a cross-sectional study among individuals with very low (</=60 mg/dl, N 
      = 8,943) and normal (90-130 mg/dl, N = 71,343) LDL-C levels calculated using the 
      Friedewald formula. LDL-C levels associated with statin use, hospitalization, or 
      a serum albumin level < 3 g/dl were excluded. We used a 2-phase approach: in 1/3 
      of the sample (discovery) we used T2DM phenome-wide association study codes 
      (phecodes) to identify cases and controls, and in the remaining 2/3 (validation) 
      we identified T2DM cases and controls using a validated algorithm. The analysis 
      plan for the validation phase was constructed at the time of the design of that 
      component of the study. The prevalence of T2DM in the very low and normal LDL-C 
      groups was compared using logistic regression with adjustment for age, race, sex, 
      body mass index (BMI), high-density lipoprotein cholesterol, triglycerides, and 
      duration of care. Secondary analyses included prespecified stratification by sex, 
      race, BMI, and LDL-C level. In the discovery cohort, phecodes related to T2DM 
      were significantly more frequent in the very low LDL-C group. In the validation 
      cohort (N = 33,039 after applying the T2DM algorithm to identify cases and 
      controls), the risk of T2DM was increased in the very low compared to normal 
      LDL-C group (odds ratio [OR] 2.06, 95% CI 1.80-2.37; P < 2 x 10-16). The findings 
      remained significant in sensitivity analyses. The association between low LDL-C 
      levels and T2DM was significant in males (OR 2.43, 95% CI 2.00-2.95; P < 2 x 
      10-16) and females (OR 1.74, 95% CI 1.42-2.12; P = 6.88 x 10-8); in normal weight 
      (OR 2.18, 95% CI 1.59-2.98; P = 1.1x 10-6), overweight (OR 2.17, 95% CI 
      1.65-2.83; P = 1.73x 10-8), and obese (OR 2.00, 95% CI 1.65-2.41; P = 8 x 10-13) 
      categories; and in individuals with LDL-C < 40 mg/dl (OR 2.31, 95% CI 1.71-3.10; 
      P = 3.01x 10-8) and LDL-C 40-60 mg/dl (OR 1.99, 95% CI 1.71-2.32; P < 2.0x 
      10-16). The association was significant in individuals of European ancestry (OR 
      2.67, 95% CI 2.25-3.17; P < 2 x 10-16) but not in those of African ancestry (OR 
      1.09, 95% CI 0.81-1.46; P = 0.56). A limitation was that we only compared groups 
      with very low and normal LDL-C levels; also, since this was not an inception 
      cohort, we cannot exclude the possibility of reverse causation. CONCLUSIONS: Very 
      low LDL-C concentrations occurring in the absence of statin treatment were 
      significantly associated with T2DM risk in a large EHR population; this increased 
      risk was present in both sexes and all BMI categories, and in individuals of 
      European ancestry but not of African ancestry. Longitudinal cohort studies to 
      assess the relationship between very low LDL-C levels not associated with 
      lipid-lowering therapy and risk of developing T2DM will be important.
FAU - Feng, QiPing
AU  - Feng Q
AUID- ORCID: 0000-0002-6213-793X
AD  - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, Tennessee, United States of America.
FAU - Wei, Wei-Qi
AU  - Wei WQ
AUID- ORCID: 0000-0003-4985-056X
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, Tennessee, United States of America.
FAU - Chung, Cecilia P
AU  - Chung CP
AUID- ORCID: 0000-0001-5908-9423
AD  - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, Tennessee, United States of America.
AD  - Division of Rheumatology, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
FAU - Levinson, Rebecca T
AU  - Levinson RT
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
FAU - Sundermann, Alexandra C
AU  - Sundermann AC
AUID- ORCID: 0000-0002-6790-5539
AD  - Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, 
      Vanderbilt University, Nashville, Tennessee, United States of America.
FAU - Mosley, Jonathan D
AU  - Mosley JD
AUID- ORCID: 0000-0001-6421-2887
AD  - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, Tennessee, United States of America.
FAU - Bastarache, Lisa
AU  - Bastarache L
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, Tennessee, United States of America.
FAU - Ferguson, Jane F
AU  - Ferguson JF
AUID- ORCID: 0000-0001-6896-1025
AD  - Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt 
      University Medical Center, Nashville, Tennessee, United States of America.
FAU - Cox, Nancy J
AU  - Cox NJ
AUID- ORCID: 0000-0001-9315-0830
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
FAU - Roden, Dan M
AU  - Roden DM
AD  - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, Tennessee, United States of America.
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, Tennessee, United States of America.
AD  - Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United 
      States of America.
FAU - Denny, Joshua C
AU  - Denny JC
AD  - Department of Biomedical Informatics, Vanderbilt University Medical Center, 
      Nashville, Tennessee, United States of America.
FAU - Linton, MacRae F
AU  - Linton MF
AD  - Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt 
      University Medical Center, Nashville, Tennessee, United States of America.
AD  - Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United 
      States of America.
FAU - Edwards, Digna R Velez
AU  - Edwards DRV
AD  - Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, 
      Tennessee, United States of America.
AD  - Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, 
      Vanderbilt University, Nashville, Tennessee, United States of America.
FAU - Stein, C Michael
AU  - Stein CM
AD  - Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University 
      Medical Center, Nashville, Tennessee, United States of America.
AD  - Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United 
      States of America.
LA  - eng
GR  - R01 GM120523/GM/NIGMS NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - 16FTF30130005/AHA/American Heart Association-American Stroke Association/United 
      States
GR  - R01 HL133786/HL/NHLBI NIH HHS/United States
GR  - T32 GM007347/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Observational Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180828
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
RN  - 0 (Cholesterol, LDL)
SB  - IM
MH  - Adult
MH  - Case-Control Studies
MH  - Cholesterol, LDL/*metabolism
MH  - Cohort Studies
MH  - Cross-Sectional Studies
MH  - Diabetes Mellitus, Type 2/*epidemiology/metabolism
MH  - Electronic Health Records
MH  - Female
MH  - Humans
MH  - Logistic Models
MH  - Male
MH  - Middle Aged
MH  - Odds Ratio
MH  - Risk Factors
MH  - United States/epidemiology
MH  - Young Adult
PMC - PMC6112635
COIS- The authors have declared that no competing interests exist.
EDAT- 2018/08/29 06:00
MHDA- 2019/04/10 06:00
PMCR- 2018/08/28
CRDT- 2018/08/29 06:00
PHST- 2017/09/19 00:00 [received]
PHST- 2018/07/25 00:00 [accepted]
PHST- 2018/08/29 06:00 [entrez]
PHST- 2018/08/29 06:00 [pubmed]
PHST- 2019/04/10 06:00 [medline]
PHST- 2018/08/28 00:00 [pmc-release]
AID - PMEDICINE-D-17-03325 [pii]
AID - 10.1371/journal.pmed.1002642 [doi]
PST - epublish
SO  - PLoS Med. 2018 Aug 28;15(8):e1002642. doi: 10.1371/journal.pmed.1002642. 
      eCollection 2018 Aug.