July 2014

Studies explore statin use for lower limb indications

statin-mainA growing body of research suggests that statins may help improve not just cardiovascular outcomes but also those associated with lower extremity conditions such as peripheral arterial disease and knee osteoarthritis. Risks of adverse events, however, may warrant caution.

By Larry Hand

Statins entered the prescription drug market as agents to lower cholesterol, but increasingly, researchers and clinicians are looking at statins as a pharmaceutical tool to improve lower extremity outcomes, including limb salvage and knee osteoarthritis.

As is usually the case in medical research, however, studies have produced results that have triggered confusion about whether statins are good (for example, improving outcomes in some cases) or bad (perhaps creating risks for new-onset disease) for the lower extremity. As more research emerges, the “good” seems to be winning.

Potential benefits

In an article published online February 28 by the European Heart Journal,1 Dharam J. Kumbhani, MD, assistant professor of interventional cardiology at the University of Texas Southwestern Medical Center in Dallas, and colleagues assessed the impact of statin use on lower limb outcomes in patients with peripheral arterial disease (PAD) who were enrolled in the international Reduction of Atherosclerosis for Continued Health (REACH) registry.2

Of the 5861 participants with symptomatic PAD, just over 62% were taking statins at baseline; during the four-year study period, those patients had a statistically significant 18% lower risk of primary adverse limb outcomes compared with patients not taking statins. Adverse outcomes included worsening symptoms, peripheral revascularization, and ischemic amputations.

How this apparent protective effect occurs is still under investigation.

“The exact mechanism is not well understood and is the subject of current studies under way,” Kumbhani told LER by email. “Both [low-density lipoprotein] LDL-dependent [reduction in atheroma volume and plaque stabilization] and LDL-independent [improved vasodilation, anti-inflammatory, enhanced angiogenesis] mechanisms are postulated. Ongoing studies will provide better insight into this.”

In summary, Kumbhani wrote, “Overall, our study indicates that all patients with PAD should be treated with a statin to improve limb outcomes, such as repeat procedures and amputations. If a given statin causes muscle aches, an alternative statin should be considered.”

He added, “Muscle aches can interfere with the ability to walk, which is one of the main problems in this patient population to begin with. Moreover, many patients will self discontinue statins due to this. Given the importance of statin use, it is best to switch to another statin since myalgias are usually not a class effect with statins.”

University of Colorado and US Department of Veterans Affairs researchers found similar results when administering statins in combination with aspirin and angiotensin-converting enzyme (ACE) inhibitors, as recommended by American College of Cardiology, along with stopping smoking, in its guidelines for treatment of patients with PAD. In an study published online April 10 in the Journal of the American Heart Association,3 patients taking all three treatments and who stopped smoking (237 of 739 patients overall) had almost half the risk (55% hazard ratio) of developing a major adverse limb event such as major amputation, thrombolysis, or surgical bypass, compared with other patients.

The new studies follow previous studies documenting benefits of statin use in either limb salvage or diabetic foot ulcer.4-6

In a study of foot ulcers,6 researchers in Norway conducted a six-month pilot trial involving 13 diabetic patients with neuropathic foot ulcers. The participants were randomized to receive either 10 mg or 80 mg of atorvastatin in addition to conventional care. The high dose showed enough of a benefit to warrant further study, the researchers wrote.

Knee osteoarthritis

Studies into the effect of statins on knee or generalized osteoarthritis (OA) provide more debatable evidence on whether they are beneficial or cause adverse side effects. Most of the differences have been attributed to differences in research methods, according to sources interviewed for this article.

In an article published in 2012 in Annals of the Rheumatic Diseases,7 researchers in the Netherlands reported that older patients who took statins were significantly less likely to experience knee OA progression after an average of 6.5 years than patients who did not.

The prospective population-based cohort study included 2921 patients aged 55 years or older living in Rotterdam between 1990 and 1999. Of those, 677 had some degree of knee OA and 355 had hip OA at baseline. Overall, knee OA progression occurred in 6.9% of the participants and hip OA progression in 4.7%.

The researchers found that 15 statin users had progression of knee OA compared with 288 nonusers, and they calculated that statin users were 57% less likely to progress (odds ratio = .43), while statin use was not associated with hip OA progression. The difference, they wrote, may be attributable to the fact that knee OA is more susceptible than hip OA to metabolic factors, including vascular pathology or lipid effects on joint tissue.

A study published last year in the Journal of General Internal Medicine also found that statins were associated with a reduced risk of long-term occurrence of OA (generalized) in another population-specific group.8 Umesh T. Kadam, PhD, of the Health Services Research Unit at Keele University in Staffordshire, UK, and colleagues analyzed results for a 10-year period through 2006 for 16,609 adults aged 40 years or older who had records in the UK General Practice Research Database.

In their dose-response study, the researchers found that individuals who took the highest doses of statins (20 mg daily) had an estimated 18% lower incidence of clinically defined OA at two years than nonstatin users, and a 40% lower incidence at four years.

“There are two hypotheses that have been postulated for the mechanisms for statins,” Kadam told LER by email. “The first, which our paper was based on, is that by modifying lipid metabolism and lowering cholesterol, statins reduce the intra-articular changes that occur in OA. The second postulates that statins have anti-inflammatory properties, [a view supported by] in vitro studies.”

In one recent in vitro and in vivo study, for example, Japanese researchers found that statins “may have the potential to prevent the catabolic stress-induced chondrocyte disability and aging observed in articular cartilage,” and that statins “are potential therapeutic agents for protection of articular cartilage against the progression of OA.”9

Orthopedic surgeon Joseph F. Baker, MCh, from the Department of Trauma and Orthopaedic Surgery at Connolly Memorial Hospital in Dublin, Ireland, who coauthored a review of statins in management of OA,10 offers another potential mechanism: the effect of statins on matrix malloproteinases (MMPs), which play a role in articular cartilage degeneration. He led a study into how MMPs might affect chondrocytes, which can repair cartilage.11

“The use of statins is based on their ability to suppress MMP activity,” he told LER in an email. “MMPs seem to be key modulators in the pathophysiology of OA and a handful of in vitro studies have shown statins can suppress MMPs.”

He continued, “This is almost certainly the mechanism by which statins would be of benefit. Suppressing MMP-13, in particular, would be of benefit as MMP-13 is nonspecific and can potentially degrade all articular cartilage constituents. Having said that, some MMPs appear to be more upregulated than others in response to a stimulus. I do not know which MMP is the most aggressively up­regulated.”

Potential risks

Then there’s the other side of the coin.

Late last year, in a study published in the British Medical Journal, researchers found that, in high-risk patients with impaired glucose tolerance and cardiac risk factors, use of statins and diuretics increased the risk of new-onset diabetes by about 23%.12

In a study published last year in Annals of the Rheumatic Diseases,13 researchers from Virginia Commonwealth University in Richmond found not only that statin use was not associated with improvements in knee pain, function, or structural progression in 2207 patients with knee OA, it was associated with statistically significant worsening in Western Ontario and McMaster Universities (WOMAC) Arthritis Index scores over a four-year period.

In a 2011 study published in Neuroendocrinology Letters, researchers found that statin use for more than two years by patients undergoing neurophysiological examinations led to “clinically silent but definite damage” to lower limb peripheral peroneal and tibial nerves.14

In another study, Australian researchers found that statin use was associated with decreased peripheral sensory perception, which may result from peripheral sensory neuropathy.15 And then there’s the 2005 study in which statin use by elderly women was associated with a significantly higher incidence of summary grade 3 or higher radiographic hip OA than in nonstatin users, but not with progression of established disease.16

The search to determine how statins affect lower extremity outcomes continues.

Researchers at the Centers for Disease Control and Prevention (CDC), in a study published in the Journal of Diabetes last year,17 found an association between statin use and prevalence of peripheral neuropathy in US women aged 40 years or older, but they cautioned about drawing a straight line between the two conditions.

They found the prevalence of peripheral neuropathy was significantly higher among women who used statins than in nonusers (23.5% vs 13.5%), based on data from the National Health and Nutrition Examination Survey 1994-2004.

However, “we could think of no plausible biological mechanism to explain why statins would cause peripheral neuropathy,” primary author Edward F. Tierney, MPH, of the CDC’s Division of Diabetes Translation in Atlanta, told LER in an email. “Like most associations with a chronic condition, the magnitude is modest. As such, uncontrolled confounding—something associated with both the outcome and the exposure of interest—may explain the association. The other issue is that our study was a cross-sectional one, and as in all cross-sectional studies, association does not equate with causation.”

He continued, “From our study, I’m not convinced that the association between statin use and peripheral neuropathy is a public health issue. I think for some people it is a problem: namely, those who develop peripheral neuropathy after initiation of a statin drug and in whom the neuropathy goes away after stopping the drug. Further evaluation is needed for those people.”

His results and those of others, as described above, create confusion that calls for further studies to sort out questions of benefit versus risk.

“This is the reason people get confused with epidemiology,” Tierney wrote. “Because in different studies on the same thing, something can show an elevated association, a reduced association, or no association. Differences in populations studied, study design, and exclusions may also contribute to getting different results.”

Reflection of the clinic today

In a broad sense, the more positive data that emerge may reflect what is actually happening, according to David Armstrong, DPM, PhD, MD, a professor of surgery and codirector of the Southern Arizona Limb Salvage Alliance (SALSA) at the University of Arizona College of Medicine in Tucson.

“From our standpoint, these findings are not only plausible, they support experiences and other data that have been emerging over the last decade or more,” Armstrong said. “In the broad context of this, I don’t think the data are really conflicting. I think if someone can tolerate a statin, it’s becoming a standard of care for many of our high-risk patients. Data continue to suggest that statins, and to some extent fibrates, may collectively improve vascular patency and reduce amputation.”

He continued, “This is, in a lot of ways, our generation’s penicillin. The only difference is our generation is not dealing as much with infectious disease as we’re dealing with disease of decay. So this is not something that is taken for a short spell. This is something that is taken over the long term to try to reduce this decay.

“Nowhere does this seem more appropriate than in a blood vessel, and in reducing the development of atheroma, whether that’s in the heart or, just as plausibly, in peripheral blood vessels. We believe that good quality cholesterol and lipid control is important, and likely just as important, if not more important, than glucose control in our patients with diabetes.”

What now?

So what needs to be done to get a clearer picture? Kumbhani of UT Southwestern in Dallas would like to see more dose-response clinical trials, as well as a deeper look into potential mechanisms.

Kadam, who led the dose-response study8 noted above, agreed.

“Whilst our study provides the initial evidence of the potential impact of statin-dose relationship on clinical OA outcomes, research is testing further this hypothesis,” he said. “There have been studies that have investigated the use of statins [but not dose] on radiographic outcomes for the knee and hip.13,16 The results are mixed and there needs either to be a meta-analysis of specifically statin dose and radiographic outcomes, or a large cohort [study].”

He added that osteoarthritis is a “unique condition” in which there appear to be systemic effects, such as generalized OA, as well as localized OA, with lower extremity outcomes influenced by environmental and pathologic processes. Osteoarthritis treatment, he said, “requires innovation in thinking—that there are potential drug solutions but also that environmental influences such as obesity and occupation remain as part of a package of solutions.”

Baker, in Dublin, suggested that further work should be done on an in vivo basis, perhaps using an ovine model, with intra-articular statins.

“This would allow, hopefully, a supraphysiologic dose of the statin to be administered locally and not have systemic effects,” he said.

Tierney recommends follow-up or cohort studies to confirm an association between statins and peripheral neuropathy and to establish causation, though he noted this may be increasingly more difficult to do since so many people are taking statins.

Several things are needed to establish causation, he added, including demonstrating biologic plausibility; the strength of the association, the consistency of association (reproduced in several studies, the temporal relationship (outcome follows exposure, not precedes it), and dose response (higher dose, stronger association).

“All these points are weak or missing with statin use and peripheral neuropathy,” he wrote.

Here to stay?

Benefit or risk, statins appear to be here to stay.

“All patients with peripheral vascular disease (but not necessarily arthritis) should be on a statin,” Kumbhani wrote. “The reduction in amputations (although in an observational study) is very important, and should be emphasized given the high mortality and morbidity associated with this life-changing surgery.”

More lower extremity clinicians should be aware of this benefit, he added.

“Increased awareness among all practitioners that interact with these patients is critical,” he said.

Armstrong agreed.

“If someone is not on a statin, we advise them to talk to their primary care doctor or cardiologist about getting onto a statin if they have any diseases of decay like cerebrovascular disease or diabetes,” he said.

Problems, Armstrong added, can be accentuated in the periphery.

“Clinicians who are dealing with the lower extremity should really be focusing on medical therapy as well as surgical therapies and mechanical therapies,” he said. “This is just part and parcel. The extremity is a magnifier for what’s happening centrally.”

Larry Hand is a writer in Massachusetts.

REFERENCES

1. Kumbhani DJ, Steg PG, Cannon CP, et al. Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry. Eur Heart J 2014 Feb 28. [Epub ahead of print]

2. Wilson AT, D’Agostino R Sr, Bhatt DL, et al. An international model to predict recurrent cardiovascular disease. Am J Med 2012;125(7):695-703.

3. Armstrong EJ, Chen DC, Westin GG, et al. Adherence to guideline-recommended therapy is associated with decreased major adverse cardiovascular events and major adverse limb events among patients with peripheral arterial disease. J Am Heart Assoc 2014;3(2):e000697.

4. Vogel TR, Dombrovskiy VY, Caliñanes EL, Kruse RL. Preoperative statins and limb salvage after lower extremity revascularization in the Medicare population. 2013;6(6):694-700.

5. Sohn MW, Meadows JL, Oh EH, et al. Statin use and lower extremity amputation risk in nonelderly diabetic patients. J Vasc Surg 2013;58(6):1578-1585.

6. Johansen OE, Birkeland KI, Jørensen AP, et al. Diabetic foot ulcer burden may be modified by high-dose atorvastatin: a 6-month randomized controlled pilot trial. J Diabetes 2009;1(3):182-187.

7. Clockaerts S, Van Osch GJ, Bastiaansen-Jenniskens YM, et al. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann Rheum Dis 2012;71(7):642-647.

8. Kadam UT, Blagovevic M, Belcher J. Statin use and clinical osteoarthritis in the general population: a longitudinal study. J Gen Intern Med 2013;28(7):943-949.

9. Yudoh K, Karasawa R. Statin Prevents chondrocyte aging and degeneration of articular cartilage in osteoarthritis. Aging 2010;2(12):990-998.

10. Baker JF, Walsh P, Mulhall KJ. Statins: a potential role in the management of osteoarthritis. Joint Bone Spine 2011;78(1):31-34.

11. Baker JF, Walsh PM, Byrne DP, Mulhall KJ. Pravastatin suppresses matrix metalloproteinase expression and activity in human articular chondrocytes stimulated by interleukin-1ß. J Orthopaed Traumatol 2012;13(3):119-123.

12. Shen L, Shah BR, Reyes EM, et al. Role of diuretics, ß blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. BMJ 2013;347:f6745.

13. Riddle DL, Moxley G, Dumenci L. Associations between statin use and changes in pain, function and structural progression: a longitudinal study of persons with knee osteoarthritis. Ann Rheum Dis 2013;72(2):196-203.

14. Otruba P, Kanovsy P, Hlustik P. Treatment with statins and peripheral neuropathy: results of a 36-month prospective clinical and neurophysiological follow-up. Neuro Endocrinol Lett 2011;32(5):688-690.

15. West B, Williams CM, Jilbert E, et al. Statin use and peripheral sensory perception: a pilot study. Somatosens Mot Res 2014;31(2):57-61.

16. Beattie MS, Lane NE, Hung YY, Nevitt MC. Association of statin use and development and progression of hip osteoarthritis in elderly women. J Rheumatol 2005;32(1):106-110.

17. Tierney EF, Thurman DJ, Beckles GL, Cadwell BL. Association of statin use with peripheral neuropathy in the US population 40 years of age or older. J Diabetes 2013;5(2):207-215.

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