Diabetes Drugs Reduce MS Biomarkers in Cohort Study

Patients with multiple sclerosis and metabolic syndrome saw improvements

         by Parker Brown
Staff Writer, MedPage Today                                   

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Action Points

• The diabetes drug pioglitazone (Actos) benefited multiple sclerosis patients with metabolic syndrome in a small trial.
• Note that the study suggests that metformin and pioglitazone treatment regulate immune and inflammatory responses in MS patients that should be studied further.

The diabetes drug pioglitazone (Actos) benefited multiple sclerosis patients with metabolic syndrome in a small trial.
Researchers followed 50 MS patients with obesity who were taking metformin or pioglitazone, or who were not treated with either agent; those receiving the active drugs showed reductions in several biomarker measures including MRI lesion burden compared with the untreated controls, according   report published on Monday in JAMA Neurology.
Those in the metformin (n=20) and pioglitazone (n=10) groups showed a significant decrease in the number of T2 lesions: from 2.5 at baseline to 0.5 after 2 years in the metformin group and 2.3 to 0.6 in the pioglitazone group. Both groups also had fewer gadolinium-enhancing lesions by the study's end (1.8 to 0.1 and 2.2 to 0.3, respectively).
"Collectively, these observations provide both in vitro and in vivo evidence that metformin and pioglitazone treatment regulate immune and inflammatory responses and support recommendation of weight reduction in obese patients with MS," wrote lead author Laura Negrotto, MD, at the Institute for Neurological Research in Buenos Aires. "Although these findings need to be interpreted with caution, it is nevertheless a study based on initial exploratory assessments. Further investigation in the field is warranted to improve the management of MS and treatment results."
Compared with the 20 controls, treatment was associated with a decrease in mean leptin levels (metformin 5.5 [SD 2.4] versus 10.5 [3.4] ng/mL, P<0.001 and pioglitazone 4.1 [0.8] versus 11.0 [2.6] ng/mL, P<0.001), found the authors.
Further findings included:

• Active drug treatment was associated with an increase in mean (SD) adiponectin serum levels (metformin 15.4 [5.5] versus 4.5 [2.4] μg/mL, P<0.001; pioglitazone 12.6 [3.6] versus 4.8 [0.6] μg/mL, P<0.001).
• The mean number of myelin basic protein peptide–specific cells secreting interferon γ and interleukin (IL)–17 were significantly lower in the metformin group than in the control group (interferon γ, 30.3 [11.5] versus 82.8 [18.8], P<0.001; IL-17, 212.4 [85.5] versus 553.8 [125.9], P<0.001).
• Compared with controls, treatment with pioglitazone was associated with a decrease in the mean number of myelin basic protein peptide specific cells secreting IL-6 and tumor necrosis factor compared with controls (IL-6, 361.6 [80.5] versus 1130.7 [149.21], P<0.001; tumor necrosis factor, 189.9 [53.4] versus 341.0 [106.0], P<0.001).
• And compared with controls, both metformin and pioglitazone appeared to significantly increase the number and regulatory functions of CD4+CD25+FoxP3+ regulatory T cells (metformin, 6.7 [1.5] versus 2.1 [1.0], P=0.001; pioglitazone, 6.9 [0.8] versus 3.0 [0.8], P=0.001).

Pioglitazone was found in a recent study to be useless for treating Parkinson's. The FDA has reviewed the safety of pioglitazone after some evidence pointed to a link with heightened cancer risk -- the drug even got a label update in 2011 to reflect that risk -- but ultimately left it on the market.

There are several questions raised by the study, according to an accompanying editorial by Ralf Gold, MD, and Aiden Haghikia, MD, at the St. Josef-Hospital Bochum in Germany. The study authors didn't use a placebo in the control group, so it's unclear how the beneficial effects may have interacted with existing MS-specific therapy. The patients weren't stratified according to the MS treatment they were receiving, and no data was given on how the patients' metabolic syndrome changed over the duration of the study.
"Despite these unsolved questions, the merits of this study are that it lines up with other promising approaches that address dietary measures as adjuvant treatment to established and safe MS therapies," the authors of the editorial concluded. "This combination may increase their overall efficacy at an acceptable cost and risk profile."
The study was done from 2012 to 2014. Patients in the metformin group received 850-1,500 mg/d, and the pioglitazone group received 15 to 30 mg/d. The 20 patients used as the control group chose not to receive treatment for their metabolic syndrome. All patients underwent a neurologic exam every 3 months, and brain magnetic resonance imaging was used every 6 months. Immune system examinations were done only in the last 6 months of the study.
Patients were followed an average of 26.7 months from baseline, and there were no significant between group differences among the groups. Despite the advantages in some measures, there were no significant differences in MS annualized relapse rate or disability between the groups after 24 months, though the study wasn't powered to detect treatment effects on those outcomes.
At 12 months, the authors found that fasting glucose levels, insulin levels, insulin resistance, hemoglobin levels, cholesterol levels, triglyceride levels, and systolic blood pressure all declined significantly in both treatment groups. Adherence was 85% or greater in the two treatment groups.
Limitations of the study include its small size and nonrandom, open label design.

Haghikia and Gold reported relationships with Biogen Idec, Genzyme, Teva Pharmaceutical INdustries, Bayer Schering, Novartis, and Merck Serono.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner