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Elevated triglycerides and risk of
MI in HIV-positive persons, the D:A:D study - pdf attached
 
 
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AIDS:
POST ACCEPTANCE, 30 May 2011
 
Despite the fact the elevated TG is a frequent side effect of antiretroviral therapy, the association between elevated TG and the risk of MI has never yet been assessed in a study with clinical end-points. In the present study, we found that higher TG levels were independently associated with an increased risk of MI. However, the residual effect of elevated TG levels after adjustment for TC, HDL-C and non-lipid risk factors was very small (11% per doubling in TG) compared with the original unadjusted effect size of 67%. Overall these findings suggests that MI risk stratification in HIV-positive subjects should focus more on other modifiable risk factors than elevated TG.
 
The duration of elevated TG might have been too short to translate into a clinical end- point such as MI, so we cannot exclude the possibility that elevated TG for more than 7 - 10 years is associated with a greater risk of MI. Finally, as this is an observational study, we cannot capture information on other changes to patient management and/or lifestyles that may have had an impact on MI risk.
 
Although our findings are based on observational cohort data, a risk of 11% of MI associated with a doubling in TG levels would question if the use of drugs to lower TG levels (e.g. fibrates, nicotinic acid) would have a major impact on the incidence of MI in HIV-positive patients, particularly if these drugs have no other independent effects on MI risk. Two randomized controlled trials have demonstrated the effectiveness of fibrates in terms of lipid parameters in HIV-positive persons [23,24]. However no randomized controlled trial of the effect of these drugs on the risk of MI have been conducted in HIV-positive persons. Recent guidelines from the European AIDS Clinical Society (EACS) does not recommend the use of niacin and fibrates to treat elevated TG [25]
 
Elevated triglyceride (TG) levels are common in HIV- positive persons for several reasons. Firstly, conditions that traditionally result in elevated TG, such as insulin resistance, diabetes mellitus (DM) and fatty liver are prevalent in the HIV-positive population [1-4]. Secondly, the physiological distress that results from untreated HIV infection may cause lipid perturbations, in particular elevated TG [5,6]. Indeed, it has been suggested that HIV-positive patients may experience increased post- prandial TG levels [7], this being one potential explanation for the increased risk of myocardial infarction (MI) that is seen in HIV-positive persons. The presence of increased levels of atherogenic remnant lipoproteins (chylomicron remnants and very low-density lipoprotein remnants) might be associated with increased levels of nonfasting triglycerides. These smaller triglyceride-rich lipoproteins may penetrate the endothelial cell layer where they can contribute to the formation of foam cells, involved in early stages of atherosclerosis [8].

 
Worm, Signe W; Kamara, David Alim; Reiss, Peter; Kirk, Ole; El-Sadr, Wafaa; Fux, Christoph; Fontas, Eric; Phillips, Andrew; Monforte, Antonella D'Arminio; De Wit, Stephane; Petoumenos, Kathy; Friis-Moller, Nina; Mercie, Patrick; Lundgren, Jens; Sabin, Caroline aFrom the Copenhagen HIV Programme (CHIP), University of Copenhagen, Denmark, bResearch Department of Infection and Population Health, UCL, London, UK, cHIV Monitoring Foundation, Academic Medical Center, Amsterdam, The Netherlands, dColumbia University/Harlem Hospital, NY, USA, eUniversity Clinic for Infectious Diseases and University of Bern, Switzerland, fCHU Nice Hopital de l'Archet, Nice, France, gHospital San Paolo, University of Milan, Italy, hCHU Saint-Pierre Hospital, Department of Infectious Diseases, Bruxelles, Belgium, iNational Centre in HIV Epidemiology and Clinical Research, Sydney, Australia, and jISPED, Universite Victor Segalen, Bordeaux, France.
 
Abstract
 
Objectives: The purpose of this analysis was to explore the relationship between elevated TG levels and the risk of MI in HIV-positive persons, after adjustment for total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C) and non-lipid risk factors
 
Background: Although elevated triglyceride (TG) levels are commonly noted in HIV-positive individuals, it is unclear whether they represent an independent risk factor for myocardial infarction (MI).
 
Methods: The incidence of MI during follow-up was stratified according to the latest TG level. Multivariable Poisson regression models were used to describe the independent association between the latest TG level and MI risk after adjusting for TC and HDL-C, non-lipids cardiovascular disease (CVD) risk factors, HIV and treatment related factors.
 
Results: The 33,308 persons included in the study from 1999-2008 experienced 580 MIs over 178,835 person-years. Unadjusted, the risk of MI increased by 67% (relative risk [RR] 1.67 [95% confidence interval 1.54-1.80]) per doubling in TG level. After adjustment for the latest TC and HDL-C level, the RR dropped to 1.33 [1.21, 1.45]; this effect was further attenuated by other CVD risk factors, the RR was reduced to 1.17 [1.06-1.29]. In models that additionally adjusted for HIV and treatment factors, the risk was further diminished, although remained significant (1.11 [1.01-1.23]).
 
Conclusions: Higher TG levels were marginally independently associated with an increased risk of MI in HIV-positive persons, although the extent of the reduction in relative risk after taking account of latest TC, latest HDL-C and other confounders, suggests that any independent effect is small.
 
Introduction:

 
Elevated triglyceride (TG) levels are common in HIV- positive persons for several reasons. Firstly, conditions that traditionally result in elevated TG, such as insulin resistance, diabetes mellitus (DM) and fatty liver are prevalent in the HIV-positive population [1-4]. Secondly, the physiological distress that results from untreated HIV infection may cause lipid perturbations, in particular elevated TG [5,6]. Indeed, it has been suggested that HIV-positive patients may experience increased post- prandial TG levels [7], this being one potential explanation for the increased risk of myocardial infarction (MI) that is seen in HIV-positive persons. The presence of increased levels of atherogenic remnant lipoproteins (chylomicron remnants and very low-density lipoprotein remnants) might be associated with increased levels of nonfasting triglycerides. These smaller triglyceride-rich lipoproteins may penetrate the endothelial cell layer where they can contribute to the formation of foam cells, involved in early stages of atherosclerosis [8].
 
Finally, elevated TG is a frequent side-effect of antiretroviral therapy [9 - 11]. Different antiretroviral drugs have different propensities to cause elevated TG, with drugs from the protease inhibitor (PI) class, but also the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz and some nucleoside reverse transcriptase inhibitor (NRTI) drugs [9-11] all being reported to cause elevated TG. Some of these drugs have been associated with an increased risk of MI in HIV- positive patients [12,13].
 
The extent to which elevated TG is a cause of or even an independent risk factor for CVD in the general population remains controversial. Some recent papers have identified elevated TG as an independent risk factor for CVD after adjusting for high density- lipoprotein (HDL-C) and total cholesterol (TC) [14,15]. However a recent meta-analysis concluded that there was no independent effect of elevated TG on the risk of MI [16]. In HIV-positive persons, where the causes and clinical implications of elevated TG may differ, it is particularly unclear whether TG levels provide additional prognostic information regarding MI risk once TC and HDL-C are taken into account. The purpose of this analysis is therefore to explore the independent relationship between elevated TG levels and the risk of MI in HIV-positive persons, after adjustment for cardiovascular risk factors (including TC and HDL-C), HIV and treatment related factors.
 
Results

 
The 33,308 patients included in the D:A:D Study were followed for a total of 178,835 person-years (PY, median 5.8 [IQR 3.9, 7.5] per person) over which time 580 incident MIs occurred (event rate 3.2/1000 PY, 95% confidence interval [3.0, 3.5]). Overall 30703 (92.2%) patients had a least one TG measurement available; these patients contributed 435,658 TG measurements to the analysis (median 13, interquartile range [7,18] per person). Of these, 25.7% were known to be measured in a fasting state and 12.1% in a non-fasting state; information on fasting state was not available for the remaining 62.2% of TG measures. Overall, the median (interquartile range) TG measurement was 1.70 (1.10, 2.80) mmol/L (n = 435,658), the median TC measurement was 5.00 (4.20, 5.90) mmol/L (n = 425,677) and the median HDL-C measurement was 1.18 (0.94, 1.45) mmol/L (n = 303,075).
 
Most of the patients included in the analysis were male (74.1%), white (53.6%) and likely mode of HIV acquisition was through sex between men (43.2%). Around a third (34.7%) of patients were current smokers, 2.9% had DM, and 18.8% were co-infected with hepatitis C (Table 1). A total of 3.1% had a BMI < 18 kg/m2, 4.5% had a BMI >30 kg/m2, and 4.1% were on a lipid lowering drug. Their median latest CD4 count was 408 (IQR 249 - 600) cells/mm3 and 32% of patients were virologically suppressed (<50 copies/ml), of which 97.8% were antiretroviral therapy (ART) experienced.
 
Risk of MI associated with elevated TG levels
 
The incidence of MI increased as TG levels increased, from 1.1/1000 PY in those with TG<1.00 mmol/L to 6.1/1000 PY in those with TG>3.00 mmol/L (Table 2). Similarly, the incidence of MI increased as TC increased, from 1.8/1000 PY in those with TC<4.0 mmol/L to 6.7/1000 PY in those with TC>6.1mmol/L. In contrast, the incidence of MI decreased as HDL-C levels increased, from 4.4/1000 PY in those with HDL- C<0.90 mmol/L to 1.9/1000 PY in those with HDL- C>1.60 mmol/L.
 
RR associated with a doubling of TG level did not change appreciably (RR 1.63 [1.50, 1.77]), but adjustment for the latest TC measurement (model 4) did lead to a reduction in the RR associated with an elevated TG (RR 1.43 [1.32, 1.56]). Adjustment for both the latest TC and HDL-C measurement (model 7) reduced the association further (1.33 [1.21, 1.45]). Of note, the latest TC and HDL-C measurements remained strongly associated with MI risk in all models (Table 3).
 
Figure 1 shows the association between the latest TG level and MI risk after adjusting for the latest TC and HDL-C levels as well as the results from additional adjusted analyses. Further adjustment for other CVD risk factors, as well as for HIV and treatment related factors, reduced the association between a doubling of TG and MI risk further, from 1.33 to 1.17 and 1.11 respectively. At this point, further adjustment for DM and the use of lipid- lowering drugs, as well as for blood glucose levels, had no additional impact on the RR associated with elevated TG, although confidence intervals were widened slightly.
 
In models that used multiple imputation methods to impute lipid data, the association between a doubling of TG and MI risk (after adjustment for other lipids as well as CVD risk factors) changed from 1.17 [1.05, 1.30] to 1.18 [1.07, 1.30]. To exclude the possibility that the apparent residual association between a doubling of TG and an increased risk of MI was being driven by a small number of patients with very high levels of TG, we repeated the analyses after subdividing the highest TG strata further. The results were unchanged, and continued to support a gradual increase in MI risk as the TG level increased (data not shown). Although sensitivity analyses suggested that the association between raised TG levels and MI risk might be slightly stronger in women (1.14 [0.79, 1.64]) than in men (1.10 [0.99, 1.23]), a formal interaction test was non-significant (p = 0.20). Whilst the test of interaction between older age (0 years) and raised TG levels was significant (p = 0.01), estimates in the two age groups did not differ greatly (<40 years: 1.15 [0.86, 1.52]; (<40 years: 1.11 [1.00, 1.24]). Finally, we explored if the 'residual effect' of TG of 11% was explained by ART-induced TG changes. But there was no such evidence or modification by exploring an interaction with drugs and TG.
 
Discussion
 
Despite the fact the elevated TG is a frequent side effect of antiretroviral therapy, the association between elevated TG and the risk of MI has never yet been assessed in a study with clinical end-points. In the present study, we found that higher TG levels were independently associated with an increased risk of MI. However, the residual effect of elevated TG levels after adjustment for TC, HDL-C and non-lipid risk factors was very small (11% per doubling in TG) compared with the original unadjusted effect size of 67%. Overall these findings suggests that MI risk stratification in HIV-positive subjects should focus more on other modifiable risk factors than elevated TG.
 
Our findings are in accordance with two recent meta- analyses based on studies conducted in the general population [16,17], where adjustment for HDL-C led to a reduction in the RR associated with TG levels from 1.37 [1.31 - 1.42] to 0.99 [0.94 - 1.05] [15], but are less concordant with findings from other studies [14,15,18- 21]. One explanation for the differences between the studies may be the different CVD risk profile of the included patients: not only were patients in the D:A:D Study 10 - 15 years younger, on average, than subjects in most studies from the general population, but the average BMI at baseline is also much lower (median 23kg/m2, with 4.5% of patients having a BMI of >30 kg/m2).
 
Of interest, neither the association between TC and MI risk, nor that between HDL-C and MI risk changed dramatically after adjustment for other CVD or HIV- related risk factors, and both remained significant after adjustment in multivariable models. The strong and independent association between elevated TC and MI risk has also been shown in the general population [16,17,22].
 
It may be anticipated that drug-induced TG changes might have a different impact on MI risk than 'lifestyle'- induced TG changes. However, a sensitivity analysis in which we explored the interaction between TG levels and use of lopinavir/r and/or ritonavir (PI drugs that are both known to lead to a rapid increase in TG levels after initiation) did not indicate that this was the case.
 
Although our findings are based on observational cohort data, a risk of 11% of MI associated with a doubling in TG levels would question if the use of drugs to lower TG levels (e.g. fibrates, nicotinic acid) would have a major impact on the incidence of MI in HIV-positive patients, particularly if these drugs have no other independent effects on MI risk. Two randomized controlled trials have demonstrated the effectiveness of fibrates in terms of lipid parameters in HIV-positive persons [23,24]. However no randomized controlled trial of the effect of these drugs on the risk of MI have been conducted in HIV-positive persons. Recent guidelines from the European AIDS Clinical Society (EACS) does not recommend the use of niacin and fibrates to treat elevated TG [25]
 
Limitations
 
Several limitations of our study should be noted. Firstly, information on fasting conditions was not available for all lipid measurements. Previous analysis from our study suggest that whilst the absolute level of TG measurements differed according to whether the measurement was taken in a fasting or non-fasting condition, the association between elevated TG and MI risk did not differ (D Kamara, manuscript in press). Secondly, the lack of repeated sampling and the within-person variability of TG levels may introduce bias when assessing the association with CVD, a phenomena known as regression dilution bias [26]. Whilst this is unlikely to have a major impact on our findings, it may mean that we have underestimated the effects of TC and HDL-C and, hence, the extent to which they attenuate the association between TG and MI risk. In addition, our study does not include data on LDL-cholesterol, nor on insulin resistance, lipoproteins or particle size, all factors that have an impact on TG [13]. The duration of elevated TG might have been too short to translate into a clinical end- point such as MI, so we cannot exclude the possibility that elevated TG for more than 7 - 10 years is associated with a greater risk of MI. Finally, as this is an observational study, we cannot capture information on other changes to patient management and/or lifestyles that may have had an impact on MI risk.
 
The large reduction in RR from 1.67 to 1.11 suggests that a large proportion (if not all) of the effect seen in univariable analyses is due to confounding. Additional adjustments for DM and fasting glucose levels did not modify the RR further, but did result in wider confidence intervals and non-significant associations. Furthermore a causal link between TG level and MI cannot be established due to the observational nature of our study.
 
The importance of understanding whether high levels of TG preceded or followed the presence of cardiovascular risk factors is not yet clear. As elevated TG are often seen in many conditions associated with inflammation (e.g. CVD, fatty liver disease), elevated TG might be a non- specific biomarker rather than an independent risk factor for MI or CVD and therefore likely more affected in HIV-positive subjects, in whom ongoing inflammation is not infrequent, compared to the general population.
 
 
 
 
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