An adverse lipoprotein phenotype-hypertriglyceridaemic hyperapolipoprotein B-and the long-term risk of type 2 diabetes: a prospective ...
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Articles
An adverse lipoprotein phenotype—hypertriglyceridaemic
hyperapolipoprotein B—and the long-term risk of type 2
diabetes: a prospective, longitudinal, observational cohort
study
Karol M Pencina, Michael J Pencina, Line Dufresne, Michael Holmes, George Thanassoulis, Allan D Sniderman
Summary
Background This study examines the risk of new-onset diabetes in patients with hypertriglyceridaemic Lancet Healthy Longev 2022;
hyperapolipoprotein B (high triglycerides, high apolipoprotein B [apoB], low LDL cholesterol to apoB ratio, and low 3: e339–46
HDL cholesterol). The aim was to establish whether this lipoprotein phenotype identified a substantial group at high See Comment page e312
risk of developing diabetes over the next 20 years. Section on Men’s Health, Aging
and Metabolism, Brigham and
Women’s Hospital, Harvard
Methods In this prospective, longitudinal, observational cohort study, we used data from the Framingham Medical School, Boston, MA,
Offspring cohort (recruited in Framingham, MA, USA). Participants were aged 40–69 years and free of diabetes and USA (K M Pencina PhD); Duke
cardiovascular disease at a baseline examination done between April, 1987, and November, 1991, and were followed University School of Medicine,
Biostatistics and
up until March, 2014. Cox proportional hazards regression with hierarchical adjustment for age and sex, waist
Bioinformatics, Duke Clinical
circumference, and fasting blood glucose were used to model the relationship between each lipid marker and Research Institute, Durham,
incident diabetes, as well as the relationship between hypertriglyceridaemic hyperapoB (defined as values greater NC, USA (M J Pencina PhD);
than sample medians of triglycerides and apoB, and less than medians of HDL cholesterol and LDL cholesterol to Mike and Valeria Rosenbloom
Centre for Cardiovascular
apoB ratio) and incident diabetes.
Prevention, Department of
Medicine, McGill University
Findings Of 3446 individuals aged 40–69 years who completed baseline examination, 2515 participants were eligible Health Centre, Montreal, QC,
and included in all analyses. During median 21·1 years (IQR 11·1–23·1) of follow-up, 402 (16·0%) individuals Canada (L Dufresne MSc,
G Thanassoulis MD,
developed diabetes. Age (p=0·032), waist circumference (pArticles
Research in context
Evidence before this study hyperapoB identified a group of people with an extraordinarily
We searched PubMed from inception to Dec 31, 2021, for high risk of diabetes over the next 20 years. The known risk
papers published in English using terms “apoB” AND factors for diabetes, such as obesity, are continuous markers
“lipoproteins” AND (“incident diabetes risk”) AND “prediction” (eg, the risk increases as body-mass index increases).
NOT (“cardiovascular” OR “stroke” OR “myocardial infarction” Hypertriglycerideamic hyperapoB is a categorical marker (ie, a
OR “coronary artery disease”), which yielded 31 results. yes or no marker). Categorical markers can be more useful to
Previous studies have examined the relation of individual physicians than continuous markers. The predictive effect of
markers, such as apolipoprotein B (apoB), triglycerides, or HDL hypertriglycerideamic hyperapoB for diabetes incidence
cholesterol (and ratios such as apoB to apoA1), or created a includes, in part, the predictive effect of obesity or glucose, but
panel of markers specifically chosen to be associated with even after these are accounted for, hypertriglycerideamic
insulin resistance. hyperapoB remains a substantial marker of increased risk.
We also suggest a pathophysiological mechanism that might
Added value of this study
account for the relationship between hypertriglycerideamic
By contrast, this study tests within the Framingham Heart Study
hyperapoB and diabetes risk, but further work is required to test
a hypothesis, generated from a previous Mendelian
its validity.
randomisation analysis, that a specific lipoprotein phenotype—
hypertriglyceridaemic hyperapoB—which is characterised by Implications of all the available evidence
increased plasma triglycerides, elevated atherogenic apoB Diagnosis of hypertriglycerideamic hyperapoB should alert
particle number, and low HDL cholesterol, is associated with an physicians to a high risk of diabetes in a patient so that
increased risk of diabetes. Thus, the hypothesis from the preventive measures can be emphasised and instituted.
previous Mendelian randomisation analysis was tested explicitly These results suggest new lines of research to understand the
within a well characterised, long-term, prospective pathophysiology of diabetes and the mechanisms by which
observational study. This study extended the power of lipid statins, for example, might increase the risk of diabetes.
factors, such as high triglycerides and low HDL cholesterol, to Our findings also add to the evidence suggesting that apoB
indicate an increased risk of diabetes by adding an index of should be measured along with the conventional lipid panel for
particle number to demonstrate that hypertriglyceridaemic routine assessment of lipoprotein status.
triglycerides. By measuring apoB as well as the Accordingly, the objectives of this study were to
conventional lipoprotein lipids, the different apoB determine whether apoB, LDL cholesterol to apoB ratio,
dyslipoproteinaemias can be identified.6 Hypertrigly and HDL cholesterol are independently associated with
ceridaemic hyperapoB is characterised by elevated new-onset diabetes in a model that accounts for age, sex,
triglycerides, elevated VLDL, and elevated LDL particle waist circumference, fasting blood glucose, and
number, and therefore by elevated apoB, lower triglycerides. We also aimed to assess whether hypertri
LDL cholesterol to apoB ratio, and lower HDL cholesterol.6 glyceridaemic hyperapoB precedes and predicts new-
The elevated triglyceride and apoB are due to increased onset diabetes in a long-term prospective follow-up.
secretion of VLDL particles by the liver with increased
production of LDL particles from VLDL particles. The Methods
lower LDL cholesterol to apoB ratio and lower HDL Study design and participants
cholesterol reflect increased core lipid exchange.7 Hyper In this prospective, longitudinal, observational cohort
tri
gly
ceridaemic hyperapoB is the most common study, we used data from the Framingham Offspring
atherogenic lipoprotein phenotype in patients with cohort (recruited in Framingham, MA, USA), which
type 2 diabetes,9 but its temporal relation to diabetes has offers high-quality data and a prolonged follow-up of
never been determined. participants. Framingham Offspring cohort participants
A recent multivariable-adjusted Mendelian random who attended examination 4 (an in-person examination
isation of multiple health outcomes in first-degree by a physician) between April, 1987, and November, 1991,
relatives of participants from the UK Biobank were eligible for this study if they were aged 40–69 years,
demonstrated that higher apoB concentrations led to with no diabetes or cardiovascular disease diagnosis.11 In
decreased longevity and increased cardiovascular this analysis, participants were followed up at subsequent
disease.10 Further analysis demonstrated that when examination cycles 5 to 9 conducted every 4 years, unless
evaluated together, higher concentrations of apoB, but they had no follow-up assessment for diabetes incidence,
lower concentrations of LDL cholesterol, were associated had triglyceride concentration of 400 mg/dL or greater
with an increased risk of diabetes, consistent with risk (excluded to facilitate the use of the Friedewald
increasing with increasing numbers of cholesterol- approximation for LDL cholesterol), or did not have
depleted LDL particles but decreasing with increasing records for baseline lipids, fasting blood glucose, or
numbers of cholesterol-enriched LDL particles. waist circumference. Follow-up extended until
e340 www.thelancet.com/respiratory Vol 10 May 2022Articles
examination 9 (April, 2011, to March, 2014), with diabetes parameters (triglycerides, apoB, LDL cholesterol to
status confirmed at examinations 5 to 8 based on apoB ratio, and HDL cholesterol), adjusted for age, sex,
measurement of fasting glucose or reported diabetes waist circumference, fasting blood glucose, and the
treatment. Censoring occurred at the last examination incidence of diabetes. We chose to use the
with available data at or before examination 9. LDL cholesterol to apoB ratio to reduce the impact of
Diabetes status was defined as fasting blood glucose the correlation between these two markers and as a
concentrations of 126 mg/dL or more or as receiving a surrogate for cholesterol-depleted LDL particles.
glucose-lowering agent. Prevalent cardiovascular disease Linearity of association between lipids markers and
was defined as myocardial infarction, angina, coronary diabetes incidence was graphically inspected, and
insufficiency, stroke, transient ischaemic attack, proportionality of hazards’ assumption was examined.
intermittent claudication, or congestive heart failure. We first considered a baseline model (model 1) with
All participants in the Framingham Heart Study gave standard risk factors for incident diabetes, which
written informed consent and the study protocol was included age, sex, waist circumference (standardised
approved by the McGill University Health Center within sex), fasting blood glucose, and the natural
Institutional Review Board. logarithm of triglycerides. To this model, we added
apoB, LDL cholesterol to apoB ratio, and HDL
Procedures cholesterol to create model 2. To investigate the extent
Collection and adjudication of cardiovascular disease to which the observed effects can be explained by
status in the Framingham Heart Study have been bodyweight change during follow-up, we re-ran the last
described previously.12 Lipid markers and other model with waist circumference as a time-dependent
characteristics were measured at baseline (examination 4). covariate, forming model 3. We calculated hazard ratio
Plasma cholesterol and triglyceride concentrations were (HR) estimates and the corresponding 95% CIs for all
measured by enzymatic methods and HDL cholesterol continuous measurements (lipids, waist circumference,
after precipitation of apoB lipoproteins with dextran- and fasting glucose) per 1 SD change.
sulphate magnesium reagent. LDL cholesterol concen To assess the association of hypertriglyceridaemic
trations were calculated using the Friedewald formula hyperapoB with diabetes risk, we created three groups,
and non-HDL cholesterol was calculated as total which were defined as follows: an optimal phenotype
cholesterol minus HDL cholesterol. ApoB was measured group, in which participants had apoB less than the
by enzyme-linked immunosorbent assay (developed in- sample median (98 mg/dL), HDL cholesterol greater than
house at Tufts University, Boston, MA, USA). Blood or equal to the median (49 mg/dL), LDL cholesterol to
glucose concentrations were measured after at least 8 h of apoB ratio greater than or equal to the median (ratio 1·35),
fasting. Waist circumference was measured at the level of and triglycerides less than the median (96 mg/dL); a
the umbilicus when the patient was standing. Body-mass hypertriglyceridaemic hyperapoB phenotype group, in
index was calculated as bodyweight (kg) divided by the which participants had apoB greater than or equal to the
square of height (m). Seated systolic and diastolic blood median, HDL cholesterol less than the median,
pressures were measured on site at the Framingham LDL cholesterol to apoB ratio less than the median, and
Heart Study clinic using a mercury column sphygmo triglycerides greater than or equal to median; and a mixed
manometer and were calculated as an average of phenotype group, which consisted of all remaining
two physicians’ measurements. Current smoking status participants. This grouping was chosen to achieve an
and lipid and blood pressure lowering medications were adequate sample size in each subgroup. Similar to
obtained through physician interview at baseline analyses of continuous lipid measurements, we employed
(examination 4). Cox proportional hazards models adjusted for age, sex,
waist circumference, and fasting blood glucose to
Statistical analysis compare relative risk of hypertriglyceridaemic hyperapoB
Baseline characteristics are shown for all participants by versus optimal and mixed versus optimal lipid phenotype
diabetes incidence status, and for individuals with groups. Model 1 included age, sex, waist circumference
missing records for covariates. Values are expressed as (standardised within sex), and fasting blood glucose. To
mean (SD) or median (IQR) for continuous variables, create model 2, we added a factor for the lipid phenotype
and as numbers and percentages for categorical data. and compared relative risk of the hypertriglyceridaemic
Pearson correlation coefficients were calculated to assess hyperapoB versus optimal and mixed versus optimal lipid
the magnitude of the associations between continuous phenotype group. The last analysis included all variables
variables (apoB, LDL cholesterol, LDL cholesterol to from model 2; however, waist circumference was added
apoB ratio, natural logarithm-transformed triglycerides, as a time-dependent covariate, forming model 3. Baseline
HDL cholesterol, waist circumference, and fasting blood characteristics of the study partici pants were also
glucose). evaluated by lipoprotein phenotype. The 20-year incidence
Cox proportional hazards models were applied to of diabetes (adjusted Kaplan–Meier estimates) calculated
investigate the associations between continuous lipids in optimal, hypertriglyceridaemic hyperapoB, and mixed
www.thelancet.com/respiratory Vol 10 May 2022 e341Articles
lipid phenotype groups was estimated using direct We also did several sensitivity analyses. To mitigate the
standardisation methods based on a stratified Cox impact of early-onset diabetes we re-ran the analyses
proportional hazard model, which was fully adjusted for excluding individuals with diabetes events occurring in
age, sex, waist circumference, and fasting blood the first 4 years after baseline examination. Although the
glucose.13,14 Sensitivity of hypertriglyceridaemic hyperapoB LDL cholesterol to apoB ratio is a better approximation of
and optimal lipid phenotype cohorts are presented as a particle size with low correlation with apoB, we re-ran
ratio of the expected numbers of events in the group the analyses including LDL cholesterol instead of
divided by the expected number of events in the entire LDL cholesterol to apoB ratio in the model. Furthermore,
sample. Similarly, specificity is shown as one minus a to account for different distributions of some of the lipid
ratio of the expected numbers of non-events in the group markers in women versus men, we re-ran the analyses
divided by the expected number of non-events in the with the lipid phenotype defined using sex-specific
entire sample. Expected numbers of events and non- medians.
events were calculated as a product of group size and the All hypotheses were tested at the two-sided α level
corresponding Kaplan–Meier estimate. of 0·05. Analyses were done using SAS (version 9.4).
Role of the funding source
No diabetes Diabetes Total sample
incidence incidence (n=2515) The funder of the study had no role in study design, data
(n=2113) (n=402) collection, data analysis, data interpretation, or writing of
Age at baseline, years 52·1 (7·9) 53·0 (7·7) 52·3 (7·9) the report.
Sex
Female 1162 (55·0%) 180 (44·8%) 1342 (53·4%)
Results
Male 951 (45·0%) 222 (55·2%) 1173 (46·6%)
Of 3446 individuals aged 40–69 years who completed
Median follow-up, years 21·8 (15·2–23·2) 11·5 (8·0–17·9) 21·1 (11·1–23·1)
examination 4, 2515 (73·0%) participants were included in
Current smoker 477 (22·6%) 107 (26·6%) 584 (23·2%)
all analyses. 215 individuals (6·2%) were excluded due to
diabetes status at baseline, 253 (7·3%) had prevalent
Body-mass index, kg/m² 26·0 (4·2) 30·0 (5·4) 26·6 (4·6)
cardiovascular disease at baseline, 46 (1·3%) had
Waist circumference, inch 34·3 (5·4) 38·9 (5·0) 35·0 (5·6)
triglyceride concentration of 400 mg/dL or greater, and
Fasting blood glucose, mg/dL 89·9 (7·9) 99·3 (10·4) 91·4 (9·1)
417 (12·1%) did not have records for baseline lipids, fasting
Treatment for blood pressure 270 (12·8%) 98 (24·4%) 368 (14·6%)
blood glucose, waist circumference, or follow-up records
Treatment for hypercholesterolaemia 55 (2·6%) 17 (4·2%) 72 (2·9%)
for diabetes incidence.
Systolic blood pressure, mm Hg 125·3 (17·2) 133·1 (17·0) 126·5 (17·4)
The baseline characteristics of the 2515 participants
Diastolic blood pressure, mm Hg 78·7 (9·5) 83·4 (9·9) 79·5 (9·8)
included in our study, both overall and stratified by
Apolipoprotein B, mg/dL 97·7 (23·6) 109·8 (24·6) 99·6 (24·1)
diabetes incidence, are shown in table 1. The median
Total cholesterol, mg/dL 206·2 (36·7) 214·2 (39·8) 207·5 (37·3)
follow-up was 21·1 years (IQR 11·1–23·1; maximum
HDL cholesterol, mg/dL 52·2 (14·8) 44·1 (12·7) 50·9 (14·8)
26 years), during which time 402 (16·0%) participants
Non-HDL cholesterol, mg/dL 154·0 (39·0) 170·1 (39·2) 156·5 (39·5) developed diabetes. Mean baseline lipids and fasting
LDL cholesterol, mg/dL 132·5 (34·1) 140·2 (36·1) 133·7 (34·5) blood glucose concentrations differed between those
LDL cholesterol to apolipoprotein B ratio 1·37 (0·25) 1·28 (0·23) 1·35 (0·25) participants who developed diabetes and those who did
Triglycerides, mg/dL 107·4 (61·9) 149·5 (70·9) 114·1 (65·3) not develop diabetes (table 1). The mean waist
Data are mean (SD), n (%), or median (IQR). circumference of women who developed diabetes was
37·1 inches (SD 5·6) versus 31·2 inches (4·4) for women
Table 1: Baseline characteristics of study participants by incidence diabetes status and overall
who did not develop diabetes. In men, the mean waist
LDL cholesterol LDL cholesterol Natural logarithm- HDL cholesterol Waist Fasting blood
to apoB ratio transformed circumference glucose
triglycerides
ApoB 0·821; pArticles
Model 1 Model 2 Model 3*
HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value
Age, years 1·02 (1·00–1·03) 0·032 1·02 (1·01–1·03) 0·0087 1·02 (1·01–1·04) 0·0050
Female, yes or no 0·95 (0·77–1·17) 0·64 1·10 (0·88–1·38) 0·38 1·28 (1·03–1·61) 0·028
Waist circumference* 1·67 (1·52–1·84)Articles
Model 1 Model 2 Model 3*
HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value
Age, years 1·02 (1·00–1·04) 0·0025 1·02 (1·00–1·03) 0·010 1·02 (1·01–1·04) 0·0047
Female, yes or no 0·88 (0·72–1·08) 0·23 0·98 (0·80–1·21) 0·87 1·11 (0·90–1·37) 0·31
Waist circumference* 1·81 (1·66–1·97)Articles
documented that pancreatic islet cells can be injured by adverse lipid phenotype.29,30 Genetic data suggest similar
increased uptake of LDL particles by the LDL pathway or effects in the case of variants that decrease PCSK9 activity
by decreased efflux of cholesterol.17–22 or concentration and therefore increase activity of the
If injury to islet cells, which leads to reduced insulin LDL receptor pathway.31 Whether other drugs, such as
secretion, is related to increased uptake of LDL particles, ANGPTL4 inhibitors, might preserve pancreatic function
this might explain the observed finding that triglycerides, by avoiding receptor-mediated clearance of apoB particles,
which are principally in VLDL particles but are not taken thereby reducing the risk of diabetes, warrants further
up by these cells, lose their significance as a risk factor consideration.
when apoB and LDL cholesterol to apoB ratio are Our study has important limitations. The Framingham
accounted for. However, increased VLDL apoB secretion Heart Study recruited principally White people from
produces hypertriglyceridaemia as well as increased the USA. Therefore, our findings cannot necessarily be
production and clearance of LDL apoB. Thus, hypertri extrapolated to other groups of people. Moreover, the
glyceridaemia would be associated with, but not directly total number of participants in the Framingham Heart
related to, increased uptake of LDL particles by pancreatic Study and the total number of individuals who developed
islet cells. The hypothesis that islet cell injury is due to diabetes is relatively small. On the other hand, the
excessive uptake of LDL particles and the cholesterol they Framingham Heart Study has almost unique strengths
contain is also consistent with previous observations that for this type of investigation in terms of the length, detail,
the risk of diabetes is reduced in patients with familial and quality of the follow-up, almost all of which was in
hypercholesterolaemia in whom the defining abnormality the pre-statin era.
is reduced clearance of LDL particles by the LDL pathway.23 In summary, these data demonstrate that patients
We recognise that our present observations establish aged 40–69 years who are normoglycaemic with
only a temporal sequence, not a causal relationship. hypertriglyceridaemic hyperapoB are at a high risk of
However, our findings are consistent with the results of a new-onset type 2 diabetes over the next 20 years, and
recent Mendelian randomisation analysis10 and with the that this relation remains potent even when waist
results of the ATTICA study, which demonstrated that circumference, fasting blood glucose, and other
the risk of diabetes was directly related to the diabetes risk factors are accounted for. Our observations
LDL cholesterol to apoB ratio, indirectly related to apoA-1, do not establish a causal relation, but identification of
the major apolipoprotein in HDL, and directly related to this specific dyslipoproteinaemic phenotype—hypertri
the triglyceride to apoA-1 ratio.24 Our findings are also glyceridaemic hyperapoB—should alert the patient and
consistent with previous work implicating smaller the physician so that aggressive preventive measures
cholesterol-depleted LDL particles in increased risk of can be undertaken. Further studies are necessary to test
diabetes.4,5 Accordingly, we believe the pathophysiological the hypothesis that injury to pancreatic islet cells from
hypothesis that hypertriglyceridaemic hyperapoB might excess uptake of LDL particles might underlie the
injure pancreatic islet cells and thereby increase the association. We hypothesise that a similar mechanism
likelihood of diabetes merits further investigation. might explain the increased risk of type 2 diabetes
Our findings might have additional clinical associated with statin use. If so, therapies that reduce
implications. Statin therapy has been shown to be apoB lipoproteins by LDL-receptor independent
modestly associated with an increased risk of type 2 mechanisms might avoid the pro-diabetic effect and
diabetes.25 Statins decrease apoB by increasing the activity lower the risk of type 2 diabetes.
of the LDL pathway, which increases LDL clearance,26 Contributors
which might then injure islet cells. Genetic variants that KMP was the primary statistical analyst and contributed to the design
are associated with lower hydroxy-3-methylglutaryl- and analysis of this study. MJP and GT contributed to the design,
analysis, and writing of the study. LD contributed to the statistical
coenzyme A reductase activity are also associated with analysis of the study. MH contributed to the writing of the manuscript.
lower levels of LDL cholesterol due, presumably, to ADS contributed to the design, analysis, and writing of the manuscript.
increased activity of the LDL-receptor pathway. These KMP and MJP have accessed and verified the data. All authors had
genetic variants have also been linked to a greater risk of access to the data reported in this study. All authors had full access to all
of the data and the final responsibility to submit for publication.
diabetes, supporting the hypothesis that the excess risk of
these variants might be related to injury to pancreatic islet Declaration of interests
KMP reports funding from the non-profit Doggone Foundation.
cells due to excess uptake of LDL particles.27 Moreover, the MJP reports funding from the non-profit Doggone Foundation, past
risk of type 2 diabetes following statin use has been grants to Duke from Regeneron/Sanofi and Amgen, and has participated
related to the decrease in LDL cholesterol: the greater the in the past in an advisory board for Boehringer Ingelheim. GT has
decrease in LDL cholesterol, the greater the number of participated in advisory boards and speaker bureaus for Amgen,
Regeneron/Sanofi, HLS Therapeutics, Ionis, Servier, and Novartis and
LDL particles removed per day by the LDL pathway and, has received grant funding from Servier and Ionis. All other authors
thereby, the greater the risk of diabetes.28 Finally, the risk declare no competing interests.
of diabetes is greater in individuals with obesity and high Data sharing
triglycerides and low HDL cholesterol receiving statin All participant data for the analyses included in this paper were obtained
therapy—that is, individuals who are likely to have an from the Framingham Heart Study. As secondary users of the data we do
www.thelancet.com/respiratory Vol 10 May 2022 e345Articles
not have the permission to share. Interested prospective users should 15 Vergès B. Abnormal hepatic apolipoprotein B metabolism in type 2
contact the Framingham Heart Study. diabetes. Atherosclerosis 2010; 211: 353–60.
16 Dietschy JM, Spady DK, Stange EF. Quantitative importance of
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