Triglycerides Contribute to Higher HIV+ Heart Attack

Higher triglycerides were marginally associated with increased risk of myocardial infarction in the large D:A:D trial, but the effect was small after taking into account cholesterol and other cardiovascular disease risk factors.

Several observational studies have shown that people with HIV have an elevated risk for cardiovascular events such as heart attacks, but there has been conflicting information about the magnitude of the association and relevant risk factors.

One of the first studies to show such a link was the large D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) trial, a prospective observational study consisting of 11 cohorts of HIV positive people at 212 clinics in Europe, Australia, and the U.S. In 2006 D:A:D investigators reported that HIV positive people taking protease inhibitors were at increased risk for myocardial infarction (MI), or heart attack, which they attributed in part to blood fat abnormalities.

Studies of the general population have shown that elevated levels of total cholesterol and low-density lipoprotein (LDL or "bad") cholesterol, low levels of high-density lipoprotein (HDL or "good") cholesterol, and increased triglyceride levels are associated with development of atherosclerosis ("hardening of the arteries"). This can lead to heart attacks and strokes as arteries become inflamed and clogged with fat, cell debris, and blood clots, thereby restricting the flow of oxygenated blood to the heart muscle or brain.

HIV positive people on antiretroviral therapy (ART) commonly have abnormal blood fat levels. Some changes are associated with specific antiretroviral drugs -- protease inhibitors are most often blamed -- but metabolic syndrome, chronic HIV infection, lifestyle characteristics such as smoking, and other known and unknown factors likely also play a role.

As described in the May 30, 2011, online edition of AIDS, Signe Worm from the University of Copenhagen and fellow D:A:D investigators explored the relationship between elevated triglyceride levels and the risk of MI in HIV positive individuals, after adjusting for other lipids and non-lipid-related risk factors.

The analysis included more than 33,000 participants in the D:A:D cohort during 1999-2008. Nearly 75% were men, just over half were white, about one-third were smokers, and 19% were coinfected with chronic hepatitis C. The median CD4 cell count was about 400 cells/mm3 but only 32% had undetectable HIV viral load.

The researchers stratified incidence of MI during follow-up according to the latest triglyceride measurement. They then used multivariate regression models to estimate the independent association between the latest triglyceride level and MI risk after adjusting for total and HDL cholesterol, non-lipid cardiovascular disease (CVD) risk factors, HIV diseases status, and treatment-related factors.

Results

• 33,038 participants experienced a total of 580 MIs during 178,835 person-years (PY) of follow-up.
• The incidence of MI rose as triglyceride levels increased, from 1.1 events per 1000 PY among people with triglycerides < 1.00 mmol/L to 6.1 events per 1000 PY among those with triglycerides > 3.00 mmol/L.
• The unadjusted risk of MI increased by 67% per doubling of triglyceride level (relative risk 1.67).
• After adjusting for the latest total and HDL cholesterol levels, the risk increase dropped to 33% (relative risk 1.33).
• The risk increase was further attenuated, to 17%, when other cardiovascular disease risk factors were considered (relative risk 1.17).
• Adding in HIV disease and treatment-related factors further diminished the triglyceride risk increase to 11%, though it did remain statistically significant (relative risk 1.11).

Based on these findings, the study authors concluded, "Higher [triglyceride] 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 [total cholesterol], latest [HDL cholesterol] and other confounders suggests that any independent effect is small."

"In the present study, we found that higher [triglyceride] levels were independently associated with an increased risk of MI," they elaborated in their discussion. "However, the residual effect of elevated [triglycerides], [total cholesterol], [HDL cholesterol], and non-lipid risk factors was very small (11% per doubling in [triglycerides]) 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 [triglycerides]," they recommended.

"The importance of understanding whether high levels of [triglycerides] preceded or followed the presence of cardiovascular risk factors is not yet clear," they explained. "As elevated [triglycerides] are often seen in many conditions associated with inflammation (e.g. CVD, fatty liver disease), elevated [triglycerides] 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."

Investigator affiliations: Copenhagen HIV Programme (CHIP), University of Copenhagen, Denmark; Research Department of Infection and Population Health, UCL, London, UK; HIV Monitoring Foundation, Academic Medical Center, Amsterdam, Netherlands; Columbia University/Harlem Hospital, NY; University Clinic for Infectious Diseases and University of Bern, Switzerland; CHU Nice Hopital de l'Archet, Nice, France; Hospital San Paolo, University of Milan, Italy; CHU Saint-Pierre Hospital, Department of Infectious Diseases, Bruxelles, Belgium; National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia; ISPED, Université Victor Segalen, Bordeaux, France.

6/17/11

Reference
SW Worm, DA Kamara, P Reiss, et al. Elevated triglycerides and risk of MI in HIV-positive persons, the D:A:D study. AIDS (abstract). May 30, 2011 (Epub ahead of print).