Metformin reduces dementia risk and mortality in obese people

A new large-scale study published in the journal Diabetes, Obesity and Metabolism has found that taking metformin is associated with a significant reduction in the long-term risk of dementia and overall mortality among overweight and obese patients. Scientists analyzed data from 1.2 million obese patients from four global medical databases (USA, Europe, Latin America, Asia-Pacific region) and found that regular metformin use is associated with:

• 20% reduction in the risk of primary dementia;
• 15% reduction in overall mortality.

Compared with patients not taking metformin or using other antidiabetic drugs.

How was the study conducted?

• Federated analysis: Data was stored locally and results were aggregated through a common OHDSI platform, allowing for the inclusion of over a million patient records without sharing personal data.
• Inclusion criteria: adults with BMI ≥30 who started metformin or alternative hypoglycemic therapy.
• Control for covariates: age, gender, comorbidities, comparable baseline glycemia levels.

Key Results

1. Risk of dementia

   • Metformin gave HR = 0.80 (95% CI 0.76–0.84; p < 0.001), i.e. 20% fewer cases of dementia.

2. Overall mortality

   • Metformin use was associated with HR = 0.85 (95% CI 0.83–0.88; p < 0.001), or 15% fewer deaths.

3. Duration of therapy

   • The greatest benefit was seen with metformin treatment for ≥2 years: the risk of dementia fell to 25%, mortality to 18%.

Why is this important?

• Neuroprotection: In addition to glycemic control, metformin may have direct protective effects on the brain, possibly through AMPK activation, reduced inflammation, and improved mitochondrial function.
• Prevention in a cardiometabolic context: obesity itself is a risk factor for dementia and early mortality; metformin provides a double “punch” by combating both metabolic and neurodegenerative risk.
• **The 'doxy' perspective: Metformin may be a cheap and safe addition to current dementia prevention strategies in obese patients, even without diabetes.

"Our results demonstrate that metformin is not just a 'sugar pill' but also an effective treatment for protecting the brain and prolonging life in overweight people," said Dr. Juan Lopez, co-author of the study.

The authors highlight the following key points:

1. Neuroprotective properties of metformin
   “We observe that in addition to glucose control, metformin activates the AMPK signaling pathway and reduces systemic inflammation, which may directly protect neurons from degeneration,” notes Dr. Juan Lopez.

2. Duration of therapy matters
   “The greatest benefit is seen in patients treated with metformin for at least two years, highlighting the importance of early initiation and long-term adherence,” adds co-author Prof Maria Silva.

3. Potential for prevention
   “Our results open the possibility of using metformin not only in diabetics but also in obese people without diabetes to reduce the risks of dementia and premature death,” Dr. Lopez concludes.

Next steps

• Randomized clinical trials to test the direct neuroprotective effect of metformin in obese but non-diabetic patients.
• Mechanistic studies in neuronal cultures and animal models to determine how metformin protects against amyloid plaque accumulation and inflammation in the brain.
• Recommendations for physicians: consider metformin as part of combination therapy for obese patients at high risk of dementia.

This is the largest observational study to date, confirming the promising additional benefits of metformin and opening the door to new strategies for combating dementia in a growing population of obese patients.