People living with HIV who take statins are less likely to experience cholesterol reductions and more likely to develop painful muscle damage as a side-effect if they have vitamin D deficiency, two studies show.
Statins are widely prescribed to reduce LDL cholesterol levels and so reduce the risk of cardiovascular disease. Raised levels of LDL cholesterol are common in people living with HIV, both as a consequence of some antiretroviral drug regimens and due to HIV infection itself.
People with HIV are at higher risk of a heart attack than others and statin treatment is not only highly effective in reducing LDL cholesterol, but has also been shown to halt or reverse the progression of cardiovascular disease in people living with HIV.
The SATURN-HIV study led by researchers at MetroHealth Medical Centre, Cleveland, Ohio tested the effect of rosuvastatin on immune activation and vascular disease in people with viral load below 1000 copies/ml on antiretroviral treatment. The impact of rosuvastatin on vitamin D levels was a secondary study endpoint, and in the light of their findings the investigators also carried out an analysis of the relationship between baseline vitamin D levels and cardiovascular risk markers.
The study randomised 147 adults to receive either 10mg of rosuvastatin a day or placebo for 96 weeks. The study population was 78% male, 68% African American and had a mean age of 45 years. Participants were at low risk for cardiovascular disease (mean Framingham score = 5) and would not ordinarily have been candidates for statin treatment. LDL and HDL cholesterol measurements were within the normal range (94.4 mg/dl and 48.6 mg/dl respectively).
53% were vitamin D deficient at baseline and 13% were severely deficient. 88% of all participants had suboptimal or deficient levels of vitamin D. Vitamin D deficiency is more common in black people because black skin permits less formation of vitamin D as a result of exposure to sunlight. Vitamin D deficiency is also common in people living with HIV.
The researchers found that throughout the study period, people in the rosuvastatin group without vitamin D deficiency (25[OH]D levels > 20 ng/ml) at baseline had greater reductions in LDL cholesterol than those who were deficient. However, vitamin D concentrations did not improve in those who received rosuvastatin. Adequate vitamin D levels were also associated with reductions in markers of immune activation and inflammation.
Vitamin D deficiency is common in people living with HIV; cohort studies have found that anywhere from 7 to 60% of people were deficient in vitamin D and that the majority of people who are not deficient nevertheless have levels that are considered insufficient (< 30 ng/ml / 75 nmol/l).
A separate study, led by researchers at the department of medical and surgical sciences, unit of infectious diseases and unit of microbiology, University of Bologna, S Orsola-Malpighi Hospital, Bologna, Italy was a retrospective analysis of myalgia (muscle pain) in people living with HIV who received either atorvastatin or rosuvastatin, found an association between vitamin D deficiency and myalgia.
Between 10% and 25% of people treated with statins report muscle pain (myalgia), although the frequency of muscle damage (myopathy) is much lower (< 1% in clinical trials). Muscle pain or myopathy tend to be more frequent at higher doses or where drug-drug interactions lead to higher statin levels. Although muscle pain and muscle damage are not life-threatening side-effects – except in very rare cases when rhabdomyolysis develops – they have a substantial effect on quality of life. A meta-analysis of cohort studies in the general population has found that muscle pain is associated with vitamin D deficiency or insufficiency, but this question has never been examined in people living with HIV.
The Italian investigators identified 545 people living with HIV treated with atorvastatin or rosuvastatin between 2011 and 2015. Of these, 100 (18%) had muscle toxicity, defined as patient report and/or creatine kinase (CK) elevation. 67 out of a hundred people with muscle toxicity reported muscle pain. Statin treatment was discontinued in 68 people, 44 of these discontinuations occurring in the first year of treatment. 48 out of 67 people reporting muscle pain discontinued treatment, and treatment was also discontinued in 20 people with CK elevations who did not have muscle pain. Statin treatment was dose-adjusted or changed in a further 16 people.
As in the general population, muscle toxicity occurred more frequently in older people (over 60, OR 1.61, 95% CI 1.22-2.18) and muscle pain occurred more frequently in those who had been on statins for at least two years (OR 1.78, 95% CI 1.19-2.31). The study also found that muscle pain occurred more frequently in those with vitamin D insufficiency or deficiency (OR 2.27, 95% CI 1.62-2.78). Muscle pain was not associated with concomitant treatment with a ritonavir-boosted protease inhibitor or any other medication with a potential for drug-drug interaction with a statin.
The investigators say that it is premature to recommend vitamin D supplementation to treat or prevent muscle pain or muscle damage during statin treatment – but that vitamin D supplementation should be considered for those with vitamin D deficiency and muscle pain. European AIDS Clinical Society 2016 guidelines recommend vitamin D screening at diagnosis for everyone with HIV, and supplementation in people with vitamin deficiency and osteoporosis, osteomalacia or parathyroid hormone elevation.
Abstract 1
Objective: Vitamin D deficiency is common in HIV. Statins may increase vitamin D and it is unknown whether vitamin D modifies the effect of statins on cardiovascular disease.
Design: SATURN-HIV was a 96-week, randomized, placebo-controlled trial designed to evaluate the effect of rosuvastatin on immune activation and subclinical vascular disease in HIV-infected adults on antiretroviral therapy. This analysis focuses on the pre-specified secondary endpoint 25-hydroxyvitamin D [25(OH)D] concentrations.
Methods: Mixed effects linear modeling and ANOVA were used to assess the rosuvastatin effect on plasma 25(OH)D concentrations over time and to determine whether baseline vitamin D modifies the rosuvastatin effect on changes in outcomes over the trial.
Results: 147 adults were randomized (72 to rosuvastatin, 75 to placebo); 78% were men, 68% African American, with mean age of 45 years. Baseline 25(OH)D concentrations were similar (overall mean 18 ng/ml) with 65% of participants below 20 ng/ml. Changes in 25(OH)D at 96 weeks were small and not significant within- or between-rosuvastatin and placebo groups. There were significant group by vitamin D status interactions for changes in LDL-cholesterol, proportion of patrolling monocytes expressing tissue factor (CD14dimCD16+TF+), lipoprotein-associated phospholipase A2 and common carotid artery intima media thickness at most time points. For each of these outcomes, the beneficial effects of rosuvastatin were either not apparent or attenuated in participants with 25(OH)D <20 ng/ml.
Conclusion: While 25(OH)D did not change with rosuvastatin, baseline vitamin D deficiency decreased the effectiveness of rosuvastatin. Vitamin D supplementation may be warranted for deficient patients initiating statin therapy.
Authors
Hileman CO, Tangpricha V, Sattar A, McComsey GA
Abstract 2
Background: Several studies have shown a significant association between vitamin D deficiency and an increased risk of statin-related symptomatic myalgia in the general population, but there are no data among HIV-infected persons.
Methods: A retrospective, cohort study was conducted to assess the incidence of symptomatic myalgia and elevation in serum creatine kinase (CK) level among HIV-positive adults on cART and treated with atorvastatin or rosuvastatin for at least 12 months between 2011 and 2015 in our Outpatient Unit.
Results: A total of 545 patients (mean age 53.4 years) were enrolled into the study. Atorvastatin was prescribed in 55.8% of patients and rosuvastatin in 44.2%. After a mean duration of statin therapy of 29 months, an isolated symptomatic myalgia was diagnosed in 42 patients (7.7%) and a myalgia associated with elevated CK level in 25 (4.6%). The mean concentration of 25-hydroxyvitamin D was significantly lower in patients with myalgia (19.4 ng/mL) and with CK elevation plus myalgia (22.8 ng/mL) than in those without muscle toxicity (32.1 ng/mL; p = 0.017 and 0.024, respectively). In stratified multivariable-adjusted logistic regression models, there was a statistically significant association between vitamin D deficiency and occurrence of symptomatic myalgia (p = 0.009) or CK elevation plus myalgia (p = 0.046). Other factors significantly associated with development of myalgia were duration of statin therapy >24 months, history of myalgia, and age older than 60 years.
Discussion: In our observational study, vitamin D deficiency was significantly associated with a statin-induced myalgia among HIV-infected patients on cART, in conformity with data of the general population.
Authors
Calza L, Magistrelli E, Colangeli V, Borderi M, Contadini I, Bon I, Re MC, Viale P
[link url="http://www.aidsmap.com/Vitamin-D-deficiency-reduces-statin-potency-increases-risk-of-muscle-pain-in-people-with-HIV/page/3111525/"]Aidsmap material[/link]
[link url="http://journals.lww.com/jaids/Abstract/publishahead/Baseline_vitamin_D_deficiency_decreases_the.97052.aspx"]Journal of Acquired Immune Deficiency Syndromes abstract[/link]
[link url="http://journals.lww.com/aidsonline/Abstract/publishahead/Significant_association_between_statin_associated.97590.aspx"]AIDS abstract[/link]