Glucose-Lowering Drugs for Neuropathy

Today's post from natap.org (see link below) looks at the results of a study into the possibility of non-insulin based, glucose reducing drugs being used to reduce the progression of neuropathy. These were brought to light at the recent Conference on Retroviruses and Opportunistic Infections (CROI). These drugs are widely given for the treatment of diabetes (itself a major cause of sensory neuropathy) but it seems they may well have a positive effect on the progression of HIV-related neuropathies. The article is not particularly easy to understand but then it was never meant to be - this sort of research paper isn't really designed to be light reading over the cornflakes. Hopefully, the research will lead to speedy implementation and widespread access to the drugs but as with all of these things...it may be some years yet!

Glucose-Lowering Drugs May Limit Progression to Symptomatic Peripheral Neuropathy
19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle: Mark Mascolini

Noninsulin glucose-lowering drugs may stall progression from mild peripheral neuropathy to symptomatic peripheral neuropathy, according to results of a study involving AIDS Clinical Trials Group (ACTG) A5001 participants [1]. The investigators confirmed that stavudine and didanosine heightened the risk of progression to symptomatic neuropathy--but protease inhibitors did not.

Sensory neuropathies remain the most frequent neurologic disorder associated with HIV infection and antiretroviral therapy (ART), noted Scott Evans (Harvard School of Public Health) and colleagues at other centers. Pain is the most common symptom of sensory neuropathy with HIV; other symptoms include numbness, paresthesia (tingling or pricking), and burning. There are no FDA-licensed agents for HIV-associated sensory neuropathies.

This study involved almost 1600 people in the ACTG Longitudinal Linked Randomized Trials (ALLRT), a meta-study of people enrolled in ACTG clinical trials. All these people were naive to antiretrovirals when they signed up for an ACTG trial, and all had neuropathy data recorded, including the Brief Peripheral Neuropathy Screen [2,3] administered as part of ALLRT every 48 weeks by trained personnel. Evans and coworkers defined peripheral neuropathy as "at least mild loss of vibration sensation in both great toes or absent or hypoactive ankle reflexes bilaterally relative to knees." They defined symptomatic peripheral neuropathy as peripheral neuropathy plus any bilateral symptoms.

The investigators devised two models to explore associations between peripheral neuropathy and progression to symptomatic peripheral neuropathy. The first model considered 1592 antiretroviral-naive ACTG trial participants, 80% men, 45% white, 32% black, 42% between 30 and 39 years old at first neurologic assessment, and 30% between 40 and 49. Median pretreatment viral load and CD4 count were 80,000 copies and 213. The second model considered 374 antiretroviral-naive people, 80% men, 43% white, 36% black, 30% between 30 and 39 at first neurologic assessment, and 39% between 40 and 49. Median pretreatment viral load and CD4 count were 100,000 copies and 166. Only about 10% of people in either model group had a history of injection drug use.

In the first model, people with peripheral neuropathy had a 58% higher risk of progressing to symptomatic peripheral neuropathy than did people without peripheral neuropathy (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.08 to 2.29, P= 0.027). In the second model, people taking ART including didanosine or stavudine had a doubled risk of progression to symptomatic peripheral neuropathy (OR 2.16, 95% CI 1.21 to 3.85, P = 0.009). In this model using a noninsulin glucose-lowering drug cut the risk of progression to symptomatic peripheral neuropathy almost 90% (OR 0.12, 95% CI 0.02 to 0.83, P = 0.031).

Protease inhibitor use did not correlate with progression from peripheral neuropathy to symptomatic neuropathy. Neither did age, race, gender, pretreatment CD4 count or viral load, HCV positivity, or injection drug use. There was a nonsignificant trend toward an association with diabetes and neuropathy progression.

The investigators suggested that the association between glucose-lowering drugs and lack of neuropathy progression "could potentially have considerable clinical prevention effect." They cautioned that, because of the study's observational nature, the associations they identified may not be causal.

References

1. Evans S, Lee A, Ellis R, Chen H, Wu K, Bosch R, Clifford D. Progression to symptoms of peripheral neuropathy in HIV: suggested protection with use of glucose-lowering drugs. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 478. http://www.retroconference.org/2012b/PDFs/478.pdf.

2. Ellis RJ, Evans SR, Clifford DB, et al. Clinical validation of the NeuroScreen. J Neurovirol. 2005;11:503-511. http://informahealthcare.com/doi/abs/10.1080/13550280500384966.

3. Simpson DM, Kitch D, Evans SR, et al. HIV Neuropathy Natural History Cohort Study: Assessment measures and risk factors. Neurology 2006;66:1679-1687. http://www.neurology.org/content/66/11/1679.abstract.

http://www.natap.org/2012/CROI/croi_81.htm