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CROI 2012: Metformin, Statins, and ACE Inhibitors May Reduce Cardiovascular Risk of People with HIV

The diabetes drug metformin can help stall progression of calcium build-up in the arteries of HIV positive people with metabolic abnormalities, potentially reducing their risk of cardiovascular events, researchers reported this month at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) in Seattle. Other studies found that statin drugs showed a trend toward lowering the risk of non-AIDS events and death, and an ACE inhibitor reduced blood pressure and certain inflammation biomarkers.

Observational studies have shown that people with HIV have higher rates of cardiovascular disease and metabolic problems compared with the general population. While the underlying cause is not yet fully understood, long-term viral infection, persistent inflammation, antiretroviral drugs, and traditional risk factors such as smoking and sedentary lifestyle may all play a role. HIV positive people and their clinicians are eager to find interventions that can help reduce this risk.

Metformin

Kathleen Fitch from Massachusetts General Hospital in Boston (abstract 119) presented findings from a randomized study looking at the effect of lifestyle modification and metformin on coronary artery calcification, or CAC, in HIV positive people with metabolic syndrome.

Metabolic syndrome is characterized by insulin resistance, dyslipidemia (abnormal blood fat levels), high blood pressure, and abdominal obesity. These factors are associated with atherosclerosis, a process in which dead cells, clotted blood, cholesterol, calcium, and other material builds up on inflamed artery walls. Over time this plaque can block arteries supplying the heart, causing a heart attack, or pieces may break off and lodge in small blood vessels in the brain, causing a stroke.

Increased coronary artery calcification has been linked to cardiovascular disease in large general population studies. CT scans can non-invasively measure calcium in plaques. CAC cores range from 0 to more than 400, with a score greater than 100 indicating elevated risk for heart disease.

The researchers randomly assigned 50 HIV positive participants to receive metformin (500 mg twice-daily for 3 months, then 850 mg twice-daily for the rest of the study), participate in a lifestyle modification program, or both for 12 months. The lifestyle program involved 60 minutes of cardiovascular exercise and strength training 3-times-weekly, as well as weekly nutrition counseling.

A majority of participants (about 75%) were men, the average age was 47 years, nearly half were white, 30% were black, and 18% were Hispanic. They had HIV for approximately 15 years on average, but CD4 T-cell counts were relatively high (400-700 cells/mm³). They met U.S. National Cholesterol Education Program (NCEP) criteria for metabolic syndrome, meaning they had any 3 of the following: elevated fasting glucose, low HDL "good" cholesterol, high triglycerides, high blood pressure, or large waist circumference (>88 cm for women or >102 cm for men).

People with history of angina, uncontrolled hypertension, or current use of insulin or diabetes medications were excluded. Most participants (64%-87% across study arms) were on lipid-lowering drugs and about half were taking blood pressure medication. Smoking rates ranged from 23% to 55%. More than half had baseline CAC scores greater than 0.

Results

• Overall, 72% of participant completed the study.
• Adherence was good for both metformin pills and the exercise and nutrition sessions (88% ad 84%, respectively).
• After 1 year, participants who received metformin -- with or without lifestyle modification -- showed significantly less progression of coronary artery calcification:
  • Metformin/lifestyle: CAC score decrease of 4 points;
  • Metformin-only: increase of 1;
  • Lifestyle-only: increase of 19;
  • No intervention: increase of 43.
• People taking metformin also had significantly smaller increases in calcified plaque volume and significantly improved HOMA-IR insulin resistance scores.
• Participants assigned to the lifestyle modification program alone showed:
  • Significant improvement in HDL levels;
  • Decrease in intramyocellular lipid levels;
  • Decrease in high-sensitivity CRP (an inflammation biomarker);
  • Better cardio-respiratory fitness;
  • No significant effect on coronary artery calcification.

"Metformin had a significant effect to prevent progression of [coronary artery calcification] and calcified plaque volume," the researchers concluded.

It is unclear whether this attributable to metformin's insulin-sensitizing effects, its anti-inflammatory effect, or some other mechanism.

Fitch noted that the no-intervention group had a 56% increase in CAC during the course of a year, about twice the rate seen in general population studies. However, no coronary disease events occurred during the year of follow-up.

"Metformin may be a useful drug to modify [cardiovascular disease] risk," the investigators stated. "Larger, longer-term studies using metformin in HIV-infected patients with metabolic syndrome and insulin resistance will be useful to determine whether this strategy will prevent [cardiovascular disease] events."

Statins

In the second study, Turner Overton from the Universityof Alabama at Birmingham and colleagues (abstract 124) looked at statin use and its association with major clinical events and non-accidental death among participants in the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort.

Statins, also known as HMG-CoA reductase inhibitors, are usually used to lower elevated LDL "bad" cholesterol, but they also have anti-inflammatory effects. Large general population studies have shown that they reduce the risk of cardiovascular events even among people without elevated cholesterol.

This study included 3601 participants who had started combination ART in an ACTG study and remained in long-term follow-up. They were not taking statins at baseline. This was an observational study looking at what type of treatment patients happened to receive; they were not randomly assigned to receive or not receive statins.

About 80% of participants were men, about half were white, 30% were black, and the median age was 39 years. The median current CD4 count was about 350 cells/mm³, but the median nadir (lowest-ever) level was 180 cells/mm³. Looking at cardiovascular risk factors, just under 40% were current smokers, the median systolic blood pressure was 120 (normal), 73% had normal LDL (<130 mg/dL), and 10% had a Framingham score indicating high cardiovascular risk.

The researchers looked at how many participants started statins during the study and time to development of non-AIDS-defining end-organ disease or non-accidental death.

Results

• Over the course of follow-up (total 15,135 person-years), 481 participants (13%) started taking statins and 616 events of interest occurred:
  • 144 new cases of diabetes;
  • 124 severe bacterial infections;
  • 115 cases of kidney disease;
  • 81 non-AIDS cancers;
  • 42 cardiovascular events;
  • 17 cases of thrombosis or pulmonary embolism;
  • 9 cases of liver disease;
  • 8 non-traumatic fractures;
  • 76 non-accidental deaths.
• In an unadjusted analysis, more people who started statins experienced non-AIDS events or death than those not on statins (4.4 vs 4.0 per 100 person-years), but this reflected in part that people who needed to start statins had poorer health.
• After controlling for baseline factors, the adjusted hazard ratio (HR) was 0.81, reflecting a 19% risk reduction, which did not reach statistical significance.
• When early events were excluded (those occurring soon after starting statins, before they had time to have much effect), risk reduction was 12%.
• The beneficial effect of statins was greatest for older patients and those with low nadir CD4 cell counts.
• Separating out event types, the adjusted risk of cardiovascular events was 11% lower among statin recipients (HR 0.89), while non-cardiovascular events decreased by 15% (HR 0.85), both non-significant.
• The only significant decline was in cancer rates, which fell by 57% among statin recipients (HR 0.43).
• Looking at non-accidental death alone, the reduction was 18% (HR 0.82).

Based on these findings, the researchers concluded, "Statin therapy was associated with a non-significant reduction in time to first non-AIDS events or death. Although not statistically significant, the observed effect increased with age and was influenced by nadir CD4 count."

Responding to a question about the reduction in cancer risk, Overton suggested that statins might influence immune surveillance of malignancies.

Lisinopril + Pravastatin

In a related poster presentation, Jason Baker and colleagues (abstract 825)presented findings from a small pilot study of the ACE inhibitor lisinopril (Prinivil, Zestril) and pravastatin (Pravachol) for HIV positive people with modest cardiovascular risk.

Like statins, ACE inhibitors also have anti-inflammatory effects in addition to their usual use for lowering blood pressure. Prior studies have shown that pravastatin is well-tolerated and less likely than other statins to interact with antiretroviral drugs.

This study included 37 participants on ART (65% using a protease inhibitor) with undetectable HIV viral load. Almost all (97%) were men, 46% were black, 43% were white, the median age was 48 years, and the median CD4 count was 495 cells/mm³. About one-third had hepatitis B or C coinfection and none had a history of injection drug use. None had clinical evidence of existing cardiovascular disease, but all had at least modest risk, with Framingham 10-year risk scores of 3% or higher (but below 20%); 68% were current smokers.

Participants were randomly assigned to receive 10 mg daily lisinopril (10 mg daily) or lisinopril placebo (L-placebo), plus 20 mg daily pravastatin or pravastatin placebo (P-placebo), for 4 months. One-quarter received both active drugs, half got 1 active drug and 1 placebo, and the remainder received both placebos. The researchers evaluated tolerability, adherence, and changes in blood pressure, cholesterol levels, and inflammatory biomarkers at months 1 and 4.

Results

• Pravastatin and P-placebo recipients showed no significant differences in reduction of total cholesterol or LDL levels.
• There was no treatment effect for pravastatin on any of the inflammatory biomarkersstudied.
• Lisinopril recipients, compared with L-placebo recipients, experienced a significantly larger decrease in diastolic blood pressure.
• Lisinopril recipients also showed significantly greater declines in high-sensitivity CRP and TNF-alfa levels, but there was no difference in IL-6.
• 18% of lisinopril recipients reported side effects compared with 6% in the L-placebo arm, but the difference was not significant.
• Participants taking lisinopril were more likely than L-placebo recipients to report missed doses (62% vs 29%) and < 90% adherence (42% vs 0%).
• Similar numbers reported side effects in the pravastatin and P-placebo arms (11% vs 12%), and adherence was the same (20% with < 90% adherence).

"Lisinopril and pravastatin were safe at doses given [though] adherence to lisinopril was less," the researchers concluded. "These data support the hypothesis that [ACE inhibitor] therapy may have anti-inflammatory benefits, beyond traditional risk factor modification, for ART-treated persons with HIV infection."

3/22/12

References

K Fitch, S Abbara, H Lee, et al. Effects of Life-Style Modification and Metformin on Coronary Calcium in HIV+ Patients with the Metabolic Syndrome. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 119.

E Overton, D Kitch, P Tebas, et al. Effect of Statin Therapy on Reducing the Risk of Serious Non-Aids-Defining Events and Non-Accidental Death: ACTG ALLRT Cohort. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 124.

J Baker, K Huppler Hullsiek, R Prosser, et al. ACEi or HMG-CoA Reductase Inhibitor (Statin) Treatment as Adjunct Therapy for Persons with HIV infection: A Pilot Study. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, March 5-8, 2012. Abstract 825.