VIENNA, Austria — Long-term use of the diabetes medication metformin may increase the risk for neurodegenerative disease in patients with type 2 diabetes mellitus (T2DM), new research suggests.

In a cohort study that followed about 9300 patients with T2DM in Taiwan for up to 12 years, the risk for Parkinson's disease (PD) or Alzheimer's dementia was more than double during a 12-year period for those who took metformin vs those who did not — even after adjusting for multiple confounders.

In addition, outcome risks increased progressively with higher dosage and longer duration of treatment.

The results were presented here at AD/PD 2017: The 13th International Conference on Alzheimer's and Parkinson's Diseases by Yi-Chun Kuan, MD, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

Dr Yi-Chun Kuan

Interestingly, recent research has suggested that use of metformin may protect against neurodegenerative diseases. When asked about that, Dr Kuan told Medscape Medical News that "some studies have actually found positive [outcomes] but some have been negative." So the researchers wanted to look into this using their own data.

"We'd heard about a possible protective effect from metformin. However, we found the reverse," she said, but stressed that large-scale, prospective studies in other countries are needed to clarify the results.

Higher Cumulative Incidences

The investigators note that past research has shown a link between T2DM and increased risk for neurodegenerative diseases, but there's been "some question" about the association with specific diabetes medications.

They examined records for patients with T2DM from the National Health Insurance research database of Taiwan, including 4651 who had metformin prescriptions and 4651 matched controls who were not using the medication.

After adjustment for factors such as age, sex, and diabetes severity, "the cumulative incidences of Parkinson's and dementia were significantly higher for our metformin cohort" at 12 years (P < .001), reported Dr Kuan.

Table 1. Outcomes in Metformin Users vs Nonusers

Outcome Event Rate (%) Adjusted Hazard Ratio (95% Confidence Interval) PD 6.85 vs 2.78 2.27 (1.66 - 3.07) All-cause dementia 11.5 vs 6.7 1.66 (1.35 - 2.04) Alzheimer's dementia 1.64 vs 0.83 2.13 (1.20 - 3.79) Vascular dementia 1.64 vs 0.69 2.30 (1.25 - 4.22)

In addition, the outcomes mostly increased as the use duration and dosage of metformin increased, especially with use for more than 300 days and doses greater than 240 g.

Table 2. Comparison of Metformin Use Duration vs Nonuse

Risk Event Rate (%) Adjusted Hazard Ratio (95% Confidence Interval) For PD <180 d 5.90 1.77 (1.17 - 2.68) 180 - 300 d 4.30 1.46 (0.90 - 2.37) 300 - 400 d 6.05 2.20 (1.47 - 3.28) ≥400 d 14.3 4.49 (3.06 - 6.58) For all-cause dementia <180 d 7.99 1.02 (0.74 - 1.41) 180 - 300 d 11.4 1.79 (1.32 - 2.43) 300 - 400 d 10.4 1.61 (1.21 - 2.16) ≥400 d 20.6 2.84 (2.12 - 3.82)

Table 3. Comparison of Metformin Dosage vs Nonuse

Risk Event Rate (%) Adjusted Hazard Ratio (95% Confidence Interval) For PD <130 g 5.36 1.58 (1.02 - 2.44) 130 - 240 g 6.80 2.21 (1.45 - 3.35) 240 - 385 g 6.19 2.14 (1.41 - 3.25) >385 g 9.38 3.54 (2.41 - 5.20) For all-cause dementia <130 g 9.97 1.22 (0.90 - 1.67) 130 - 240 g 12.0 1.61 (1.19 - 2.17) 240 - 385 g 12.3 2.06 (1.54 - 2.75) >385 g 11.9 1.97 (1.45 - 2.68)

Dr Kuan said that the investigators would like to eventually look into possible associations with other antidiabetic medications, such as insulin or sulfonylureas.

"I'm a neurologist so I want to know which kinds of medication is best for the patient," she said. "Because there are some limitations with our study, I can't say the risk effects we found are real," but clinicians should keep them in mind, she concluded.

Surprised and Skeptical

When asked for comment, Larry Ereshefsky, PharmD, with Follow the Molecule consulting group, Los Angeles, California, told Medscape Medical News that he was "very surprised" and skeptical about the results.

He noted that the poster didn't explain how the investigators controlled for the confounders and didn't mention anything about alternative treatments for T2DM or hemoglobin A1c levels between the groups, which would affect the analyses.

"It's interesting and I would like to know more but I don't believe the findings based on what's up there," said Dr Ereshefsky, who was formerly a psychiatry and pharmacology professor at the University of Texas, San Antonio.

Dr Kuan and Dr Ereshefsky have disclosed no relevant financial relationships.

AD/PD 2017: International Conference on Alzheimer's and Parkinson's Diseases. Abstract 312. Presented March 29, 2017.

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