Miriam E Tucker
June 11, 2016
NEW ORLEANS — Metformin may exert a long-term protective effect against neurodegenerative diseases including Alzheimer's and Parkinson's, new research suggests.
Findings from a retrospective longitudinal study of data from Veterans' Affairs electronic medical records were presented June 11 here at the annual American Diabetes Association (ADA) 2016 Scientific Sessions by Qian Shi, a PhD candidate at Tulane University, New Orleans, Louisiana.
"For metformin exposure longer than 2 years, we found a significant reduction in neurodegenerative disease.…Metformin may be neuroprotective," Ms Shi told Medscape Medical News.
The results were consistent even after researchers controlled for kidney function, chronic renal disease, and other diabetes medications.
The mechanism is unclear, but metformin is known to cross the blood-brain barrier, she noted.
Asked to comment, session moderator Lawrence S Phillips, MD, professor of medicine at Emory University School of Medicine, Atlanta, Georgia, said: "Metformin has pleiotropic effects, and it is of great interest for a variety of reasons."
He added that there was an entire symposium here yesterday at the ADA meeting devoted to emerging findings regarding metformin, including its possible preventive roles in cancer and heart disease.
But at the same time, Dr Phillips cautioned that even though the investigators controlled for renal function and other potential confounders, "the hard question in all of these epidemiologic analyses is ruling out confounding by indication.…You wonder if the patients who didn't get metformin or stay on it were somehow sicker in ways other than what [estimated glomerular filtration rate] eGFR might have been picked up in the analysis. I think that's very hard to tell in an epidemiologic analysis of an administrative database."
Nonetheless, he told Medscape Medical News, "It absolutely deserves further study."
Effect Seen After 2 Years
Ms Shi said that prior data on metformin and neurodegenerative diseases have been conflicting. While two previous population studies have shown that long-term treatment with metformin may reduce the risk of cognitive decline, other data indicated that cognitive performance was worse among patients taking metformin, possibly due to vitamin B12 deficiency. And long-term use of the drug was associated with a slightly increased risk for Alzheimer's disease in another trial.
The current study population consisted of patients with type 2 diabetes older than 50 years from the Veterans Affairs electronic medical records database who were receiving insulin treatment. They were followed from the time of diagnosis until death or outcome.
Out of 150,435 who met those criteria, 41,696 were excluded for a variety of confounders, including neuropathy, vitamin B12 deficiency, prior neurodegenerative diseases, cognitive impairment, or late effects of cerebrovascular disease, cancer, or end-stage renal disease. Patients who took insulin for less than two-thirds of the study period were also excluded.
The final study sample was 6046 patients (over 90% male) with a mean age of 63 years. They were followed for a median of 5.25 years.
In addition to renal function and other diabetes medications, Ms Shi and colleagues also controlled for age, gender, race, tobacco use, obesity, and history of other complications and comorbidities at baseline.
During follow-up, 334 cases of dementia were diagnosed, as were 100 of Parkinson's, 71 Alzheimer's disease cases, and 19 with cognitive impairment.
The adjusted incidence of developing one or more neurodegenerative diseases per 100 person-years was 2.08 for those who never used metformin, 2.47 for those using metformin less than 1 year, 1.61 for less than 2 years, 1.30 for 2 to 4 years, and 0.49 for 4 or more years.
The protective relationship between metformin and neurodegenerative disease was statistically significant only after 2 years.
Compared with no metformin, the hazard ratios for 2 to 4 years of metformin therapy for all neurodegenerative diseases combined was 0.623 and for 4 or more years 0.216.
The findings were also significant for dementia specifically (0.567 at 2–4 years and 0.252 for 4+ years) and for Parkinson's and Alzheimer's diseases only beyond 4 years (0.038 and 0.229, respectively).
"Similar risk reductions occurred in dementia and Parkinson's but were not duplicated to other subtype diseases, most likely due to the limited numbers of events," Ms. Shi explained.
"A large-scale prospective cohort study may be needed to confirm the relationship and the causality between metformin exposure and the risk for neurodegenerative disease," she concluded.
Dr Shi has no relevant financial relationships. Dr Phillips has served on scientific advisory boards for Boehringer Ingelheim and Janssen and has or had research support from Merck, Amylin, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, Abbvie, Vascular Pharmaceuticals, and the Cystic Fibrosis Foundation.
American Diabetes Association 2016 Scientific Sessions; June 11, 2016; New Orleans, Louisiana. Abstract 72-OR/72
http://www.medscape.com/viewarticle/864681?src=wnl_edit_tpal&uac=140844CK
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