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CROI 2013: Statins for People with HIV -- How Sweet Is It?

Statins may help reduce co-morbid conditions such as cardiovascular disease and lower mortality for some people with HIV, but with a possible trade-off of higher diabetes risk, according to a series of studies presented and discussed at 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) this month in Atlanta.

Use of statins for control of elevated cholesterol, and ultimately of cardiovascular disease, in HIV negative people is well documented. Some research has seen a slight increase in the risk of type 2 diabetes among statin-users in the general population, but the association is controversial.

Studies increasingly show that -- independent of cholesterol reduction -- statins also have immune modulatory, anti-inflammatory, and antiviral effects that may have utility for managing HIV-related inflammation and resulting complications. The use of statins in this sense harkens back to the days of prophylaxis for opportunistic infections, and may be a welcome preventive intervention for the looming number of heart disease cases as people with HIV age.

But the studies discussed in a lively session entitled "Statin Use in HIV: How Sweet Is It?" (led by Priscilla Hsue from the University of California at San Francisco and Steven Grinspoon from Massachusetts Hospital) leave more questions than answers for HIV positive people and their doctors. 

All-cause Mortality

The first study, presented by Line Rasmussen from Odense University Hospital in Denmark, sought to determine the impact of statin therapy on all-cause mortality among people with HIV before or after diagnosis of cardiovascular disease or diabetes.

The researchers looked at a large retrospective Danish cohort of 1738 HIV positive people who started combination antiretroviral therapy (ART) after January 1, 1998. Data were obtained from the Danish National Prescription Registry.

They found that among people who reached undetectable viral load within 6 months after starting ART, there may be an effect on all-cause mortality for patients who received a cardiovascular disease or diabetes diagnosis, yet the impact for those without diagnosed co-morbidity was "small or absent."

Cumulative Statin Exposure

A second study led by Henning Drechsler from the VA North Texas Health Care System showed similar findings in an analysis of the effect of cumulative statin exposure on non-AIDS conditions in the combination ART era.

One-third of the 25,884 study patients were using statins. During a median follow-up period of 6.6 years, a total of 6435 deaths, 2199 incident acute myocardial infarctions and strokes, 5011 malignancies, 3196 cases of chronic kidney disease, and 610 osteoporotic fractures were observed.

The researchers analyzed associations with statins among all participants and only among virologically suppressed individuals, controlling for other factors such as hypertension, smoking, and low-density lipoprotein (LDL) levels.

In the first model, the researchers observed reduced hazard ratios associated with statin use for all 4 outcomes -- death, cardiovascular disease, malignancies, and fragility fractures -- but only malignancies reached statistical significance.

In the second analysis, with more statistical power, the model showed a significant reduction in death associated with statins, which was even more pronounced with atorvastatin (Lipitor) and rosuvastatin (Crestor).

The researchers concluded that statins may reduce mortality due to certain non-AIDS complications, but not necessarily reduce their incidence.

Statins and Diabetes

The next 2 presentations highlighted the risk of incident diabetes in HIV positive people using statins.

Vincenzo Spagnuolo from the San Raffaele Science Institute in Milan reported findings from a retrospective analysis of the association between statin use and occurrence of diabetes. The researchers analyzed 5380 patients with no diagnosis of diabetes and no previous use of statins at the time of ART initiation. During a median 9.8 years of follow-up 726 people (14%) used statins (about 80% rosuvastatin and just under 20% pravastatin [Pravachol]). Statin users were older and had longer ART exposure, more obesity, and higher total cholesterol, LDL, fasting glucose, and triglyceride levels.

A total of 162 participants developed diabetes, an unadjusted incidence rate of 2.82 per 1000 person-years. The analysis showed that 1.7% of people on statins developed diabetes compared with 3.2% of non-users. Incidence rates were 1.3 per 1000 person-yearsfor statin users compared with 3.4 for non-users.

Overall, there was a 77% reduction in the risk of developing diabetes among ART-treated participants using statins. A multivariate analysis showed that higher nadir (lowest-ever) CD4 cell count and use of statins were independently associated with reduced diabetes risk.

Turning to the U.S., Kenneth Lichtenstein from National Jewish Health in Denver presented a prospective analysis of statin use and risk of diabetes from the HIV Outpatient Study.

During 2002-2011 the HOPS researchers analyzed 4962 participants at 9 sites with no prior statin use or diabetes diagnosis. During 4 years of follow-up, 590 were prescribed statins and 355 eventually developed diabetes. They used a Cox proportional hazard model to assess associations between cumulative years of statin use and incident diabetes, controlling for age, sex, race/ethnicity, body mass index (BMI), and use of antiretroviral drugs, specifically HIV protease inhibitors.

The researchers found a moderately increased risk of diabetes associated with statin use, with a hazard ratio of 1.1. Incidence rates were 3.1 per 100 person-years for people prescribed statins versus 1.7 for those not on statins. Older people, Hispanics, and people with higher BMI were at increased risk. There was no association with antiretroviral or protease inhibitor use.

"What this tells us is that we need to be monitoring glucose intolerance in all patients anyway, and we don't think that these results would alter our use of statins following guidelines for management of hyperlipidemia," Lichtenstein concluded.

Implications

This session really highlighted the risks versus benefits of adding statins in the age of increasing non-AIDS co-morbidities, and clearly more research needs to be done, especially if statins are to be used for prevention of heart disease.

In a closing wrap-up, Hsue highlighted the continued challenge of statin use in HIV management. "Clearly there are tons of unanswered questions," she said. Is there a group of individuals at risk for development of diabetes who take statins, and are there HIV-specific features that increase this risk? The mechanism underlying the development of diabetes with statins is also unclear.

At the end of the session, Jens Lundgren the University of Copenhagen thanked the panel and stated that it's about time we had this discussion. But he regretted that there were 2 different discussions happening. The first is whether prescribers use statins where it is clinically indicated, and the second is whether there is a benefit where it is not indicated. He said he is concerned that a lot of people use statins where it is not indicated, and that should be a separate discussion.

Grinspoon responded that it is "critically important to separate the discussion" about when statins should be prescribed. We are relying on data from the HIV negative population, he said, but it is probably not wrong to give statins to HIV positive people for the standard indication of lowering LDL cholesterol. The bigger point is that non-indicated use needs more study. There is a lot of evidence that statins may have some pleotropic effects that are favorable in terms of cardiovascular disease, but there are also some warning signs of co-morbidities.

"We shouldn’t be giving these things until we have more data one way or another -- they may be spectacularly important or may be associated with risk," Grinspoon concluded.

Unfortunately, the studies presented in this session were unable to answer these questions because they were largely retrospective trials. But at least the organizers were thoughtful in starting the discussion.

3/26/13

References

L Rasmussen, G Kronborg, C Larsen,et al. Statin Therapy and Mortality in HIV+ Individuals: A Danish Nationwide Population-based Cohort Study. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 764.

H Drechsler, S Zhang, N Maalouf, et al. Impact of Statin Exposure on Mortality and Non-AIDS Complications in HIV Patients on HAART. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 765.

V Spagnuolo, L Galli, A Poli, et al. Association between Statin Use and Type-2 Diabetes Mellitus Occurrence among HIV-1+ Patients Receiving ART. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 766.

K Lichtenstein, R Debes, K Wood, et al. Statin Use Is Associated with Incident Diabetes Mellitus among Patients in the HIV Outpatient Study. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 767.