Statin Reduced Risk of Heart Disease in People With HIV

BRISBANE, Australia — The cholesterol-lowering agent pitavastatin (Livalo) as primary prevention reduced the risk of major adverse cardiovascular events (MACE) among people living with HIV, the randomized REPRIEVE trial showed.

Over a median follow-up of about 5 years, incidence of any MACE was 35% lower in the pitavastatin group compared with a placebo group, at 4.81 versus 7.32 per 1,000 person-years, respectively (HR 0.65, 95% CI 0.48-0.90, P=0.002), reported Steven Grinspoon, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, during his oral presentation at the International AIDS Society Conference on HIV Science.

Results of the phase III trial, which was stopped prematurely for efficacy and included over 7,700 HIV patients at low-to-moderate risk of cardiovascular disease, were simultaneously published in the New England Journal of Medicine.

The reduction in MACE — defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause — was not at the expense of serious adverse events, Grinspoon said.

Muscle-related symptoms occurred in 2.3% of the pitavastatin group and 1.4% of the placebo group, while diabetes occurred in 5.3% and 4.0%, respectively. “There was an increased number of cases of diabetes in the pitavastatin patients versus placebo, which has been shown in virtually all statin studies, but it was a relatively low percentage,” Grinspoon noted.

“Cardiovascular disease is significantly increased in people living with HIV,” Grinspoon explained. “Although antiretroviral therapy has been very, very successful, and the mortality gap between people living with HIV and HIV-negative people has shrunk somewhat, the comorbidity gap remains increased.”

“Many large epidemiological studies have suggested that it’s not simply a matter of traditional risks that are increased, but there’s something beyond the traditional risk,” he added. “Our thinking was that statin therapy would both reduce traditional risks and the non-traditional inflammatory risk in people living with HIV. And we know that statins, as well as lowering LDL, lower that excess inflammation in patients.”

The median age of the participants in the study was 50 years, and their median Atherosclerotic Cardiovascular Disease risk score was 4.5%, which Grinspoon suggested was low.

“Our results may be generalizable to the large global population of persons with HIV infection between the ages of 40 and 75 years who are receiving antiretroviral therapy and who are at low-to-moderate risk for atherosclerotic cardiovascular disease,” the researchers wrote.

“Our trial population was 65.2% non-white and 31.1% female and was thus representative of these important groups,” they added. “Although persons with HIV infection who have known cardiovascular disease or who are at higher risk should be receiving statin therapy on the basis of revised existing guidelines, further evidence has been needed to support recommendations for the prescribing of statins in those at low or moderate risk. Our identification of benefit in the groups at lower or moderate risk now establishes the need to expand this recommendation.”

In addition to medications that reduce low-density lipoprotein (LDL) cholesterol and other cardiovascular risk factors, physicians should also be advising patients to optimize lifestyle factors beyond lipids, including smoking, Grinspoon and team noted.

In an accompanying editorial, Matthew Freiberg, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, noted that “[a]lthough pitavastatin targets one and perhaps two important risk factors for atherosclerotic cardiovascular disease (i.e., LDL cholesterol and systemic inflammation), other risk factors merit attention for this preventive approach to be transformative.”

“Hypertension and diabetes are often routinely addressed in clinical care, although behavioral risk factors such as cigarette smoking, unhealthy alcohol consumption, drug use, obesity, and mental health conditions are often underassessed, underaddressed, or both, in part because these risk factors can be challenging to modify,” he wrote. “Moreover, alcohol consumption at lower doses can result in a higher risk of physiological injury among persons with HIV infection. Thus, targeting of these less traditional risk factors in this population could result in beneficial effects, either directly on the cardiovascular system or indirectly by reducing systemic inflammation.”

For this study, Grinspoon and colleagues randomized 7,769 patients with HIV and a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy 1:1 to daily pitavastatin calcium 4 mg or placebo. Most participants were men and cisgender; 41.3% were Black, 34.8% were white, and 17.8% were Hispanic or Latino.

The median CD4 count was 621 cells/mm³, and the HIV RNA value was below quantification in 87.5% of participants with available data.

“Although our results are specific to pitavastatin, other statins may have similar protective effects,” Grinspoon and colleagues wrote. “For persons who are living in areas where pitavastatin is not available, the use of other statins that do not interact with antiretroviral therapy may be a reasonable choice. Other strategies that lower LDL cholesterol may also be useful and will need to be tested in large trials and compared with results achieved with statin therapy alone, including with respect to cost, efficacy, and safety.”