Long-term Metformin Use 'Has No Cognitive Impact'

Liam Davenport

May 19, 2017

The long-term use of metformin in individuals at risk of developing diabetes is not associated with worsening cognitive performance, say US investigators. The findings should reassure clinicians and patients alike that the drug is safe to use for diabetes prevention.

Previous studies have suggested that metformin use may be associated with worse cognitive performance and perhaps even the development of Alzheimer's disease, while other studies have conversely indicated it may even improve memory.

The current analysis of the Diabetes Prevention Program Outcomes Study (DPPOS), published online May 12 in Diabetes Care, shows that, in over 2000 adults, use of metformin for more than 8 years did not lead to cognitive impairment.

Lead author José A Luchsinger, associate professor in epidemiology and medicine at Columbia University Medical Center, New York, told Medscape Medical News that "of all studies that have looked at the relationship of metformin and cognition, I think that, arguably, this is the best, because of the design, because of the exposure to metformin in a randomized trial setting, and the follow-up."

He said that their finding that long-term exposure to metformin does not have a negative effect on cognition "should be incredibly reassuring to clinicians and patients who have read reports to the contrary."

Dr Luchsinger added: "I think that's enormously important because metformin is the most used diabetes medication in the world, and it's the one that most people who get diagnosed with type 2 diabetes get started on."

Higher HbA1c Linked to Lower Cognition, but No Link With Metformin Use

The Diabetes Prevention Program (DPP) was a randomized controlled trial involving 3234 individuals with prediabetes in which an intensive lifestyle intervention and metformin treatment was shown to reduce the incidence of type 2 diabetes by 58% and 31%, respectively, compared with placebo.

After a 13-month bridge period, participants continued in the DPPOS, an observational follow-up during which cognitive function was assessed using a battery of tests at years 8 and 10.

The current analysis focused on 2280 participants, including 749 from the original lifestyle-intervention arm, 776 from the metformin arm, and 755 from the placebo group, all of whom completed the cognitive assessments at year 8.

The mean age at randomization was 51.1 years, and the cognitive assessments were performed an average of 12.0 years after randomization. Of the participants, 67.7% were women, and 54.6% were white.

As expected, fasting glucose levels, the HbA1c area under the curve, and the prevalence and duration of type 2 diabetes at the year 8 assessment were lower in the metformin and lifestyle-intervention arms than in the placebo arm.

There was no significant difference in cognitive function between the three treatment groups at year 8, at composite z scores of -0.01 in the lifestyle group, -0.02 in the metformin arm, and 0.01 in participants given placebo (= .86).

The findings were unaffected by age group or APOE-ε4 carrier status (the latter was assessed because it is a strong risk factor for cognitive impairment). While 51.8% of the cohort developed type 2 diabetes by year 8, this had no impact on cognitive performance, and the association was not modified by age- group, sex, or APOE-ε4 carrier status.

The duration of exposure to metformin was, at 8.72 years, markedly longer in the metformin group than in the other study arms, at 0.96 years in the lifestyle arm and 1.43 years in the placebo group (P < .001). However, duration of metformin exposure was not related to cognitive performance, after adjustment age, sex, ethnic group, and treatment group, with a composite z score of -0.00 (= .76).

The team also notes that glycemia, measured using HbA1c as a continuous variable, revealed no association with cognitive performance.

Adjusting for age, sex, education, and randomization arm revealed significant associations, however, between higher HbA1c level and lower cognitive performance at year 8, at a composite z score of -0.05 (= .001).

Dr Luchsinger said that he and his colleagues "are not sure" what that finding means, adding that it nevertheless "raises some interesting questions" about the directional nature of the relationship.

He explained: "There's been a very vast literature suggesting that diabetes and higher glycemia are related to worse cognition, but the causality of that relationship — in other words, what's the chicken and what's the egg, or do they simply just go together — has not been clarified."

Future Research Plans Could Include Brain Imaging

To continue their research program, Dr Luchsinger and colleagues plan to conduct another round of quantitative measures on participants in the DPP, "so it's possible, and I underline the word possible, that we could see differences between the groups in the long term that we didn't see before."

He would also like to perform brain imaging to see whether — even though there has been no impact on cognition from long-term metformin use — there have been changes in the brain, "but that is something that we need to first get approved by the study and then get funding for, of course."

Outside of the DPP, Dr Luchsinger is carrying out a community-based study to examine brain correlates of diabetes and increased glycemia, including MRI and amyloid scans to determine whether there are any associations with Alzheimer's disease.

During the DPPOS, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the coordinating center. The Southwestern American Indian Centers were supported directly by the NIDDK. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the centers. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart, Lung, and Blood Institute, the Office of Research on Women's Health, the National Center for Minority Health and Human Disease, the Centers for Disease Control and Prevention, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP, Lipha (Merck-Sante) provided medication, and LifeScan donated materials during the DPP and DPPOS. LifeScan, Health O Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike Sports Marketing, Slim Fast Foods, and Quaker Oats donated materials, equipment, or medicines for concomitant conditions. The authors report no relevant financial relationships.

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Diabetes Care. Published online May 12, 2017. Abstract


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