# Metformin Extended Release

The World's Most Studied Longevity Compound: 60+ Years of Evidence for Metabolic Health, Cancer Protection & Healthspan Extension

Evidence-Based Scientific Guide | Updated December 2024

#### Key Takeaways

- 65+ years of clinical use with one of the best safety profiles of any medication
- TAME Trial - First FDA-approved trial specifically testing anti-aging effects
- Cancer protective - Meta-analyses show reduced cancer incidence and mortality
- Extended Release (XR) formulation offers better tolerability and steady-state levels
- AMPK activation - Mimics caloric restriction at the cellular level

## What is Metformin?

Metformin is a biguanide medication that has been used to treat type 2 diabetes since the 1950s. Originally derived from the French lilac plant (Galega officinalis), it has become one of the most prescribed medications worldwide, with over 150 million prescriptions annually in the United States alone.

What sets metformin apart from other diabetes medications is its remarkable safety profile and the growing body of evidence suggesting benefits far beyond glucose control - including potential anti-aging effects, cancer protection, and cardiovascular benefits.

65+
Years of Clinical Use
150M+
Annual Prescriptions (US)
40,000+
Published Studies
$4-20
Monthly Cost

## Extended Release vs. Immediate Release

Metformin Extended Release (Metformin XR, ER, or Glucophage XR) represents a significant advancement over the original immediate-release formulation.

### Why Extended Release is Preferred

- Superior GI Tolerability: The slow-release mechanism significantly reduces the gastrointestinal side effects (nausea, diarrhea, stomach upset) that cause many patients to discontinue immediate-release metformin
- Once-Daily Dosing: Extended release is typically taken once daily with the evening meal, improving adherence compared to multiple daily doses
- Steady Blood Levels: Provides more consistent drug concentrations throughout the day, potentially offering better metabolic effects
- Better Long-Term Compliance: Studies show significantly higher adherence rates with XR formulations

## Mechanisms of Action: How Metformin Works

Metformin operates through multiple interconnected pathways that explain both its glucose-lowering effects and its potential longevity benefits.

### Primary Mechanisms

#### 1. AMPK Activation

Metformin activates AMP-activated protein kinase (AMPK), often called the "master metabolic regulator." AMPK activation:

- Mimics the cellular effects of caloric restriction and exercise
- Enhances glucose uptake in muscles
- Inhibits hepatic gluconeogenesis (liver glucose production)
- Promotes fatty acid oxidation
- Activates autophagy - cellular cleaning and recycling

#### 2. Mitochondrial Complex I Inhibition

Metformin mildly inhibits mitochondrial Complex I, which:

- Reduces ATP production, triggering AMPK activation
- Decreases reactive oxygen species (ROS) production
- May contribute to hormetic stress response benefits

#### 3. Gut Microbiome Effects

Research has revealed that metformin significantly alters the gut microbiome:

- Increases beneficial Akkermansia muciniphila bacteria
- Promotes GLP-1 secretion from intestinal L-cells
- Enhances glucose sensing in the gut
- May account for up to 40% of its glucose-lowering effect

## The TAME Trial: Testing Metformin for Aging

The Targeting Aging with Metformin (TAME) trial represents a landmark moment in longevity research. Led by Dr. Nir Barzilai at the Albert Einstein College of Medicine, it is the first FDA-approved clinical trial specifically designed to test whether a drug can slow aging itself.

### TAME Trial Design

- Participants: 3,000 individuals aged 65-79
- Duration: 6 years
- Primary Endpoint: Time to first occurrence of any age-related chronic disease (cardiovascular disease, cancer, dementia) or death
- Significance: If successful, could establish "aging" as an indication treatable by drugs

#### Why This Trial Matters

The TAME trial could revolutionize medicine by proving that a single intervention can delay multiple age-related diseases simultaneously. Rather than treating each disease separately, targeting aging itself could prevent or delay heart disease, cancer, Alzheimer's, and other conditions all at once.

## Cancer: The Evidence for Protection, Not Risk

#### Addressing the Misinformation

Some individuals have been misled to believe that metformin causes cancer. This is factually incorrect. The scientific evidence overwhelmingly shows that metformin is associated with reduced cancer risk and improved cancer outcomes.

### What the Research Actually Shows

Meta-Analyses of Cancer Incidence:

- A 2014 meta-analysis of 65 studies found metformin users had a 31% reduction in overall cancer incidence
- A 2017 meta-analysis showed 33% reduced cancer mortality in diabetic patients on metformin
- Specific reductions have been observed for colorectal cancer (37%), liver cancer (78%), and pancreatic cancer (46%)

#### Mechanisms of Cancer Protection

Metformin's anti-cancer effects are mediated through multiple pathways:

- AMPK activation inhibits mTOR, a pathway that promotes cancer cell growth
- Reduces insulin and IGF-1 levels - both are growth factors that can promote tumor development
- Activates p53 - the "guardian of the genome" tumor suppressor
- Inhibits cancer stem cells that drive tumor recurrence
- Anti-inflammatory effects reduce the chronic inflammation that promotes cancer

### Major Studies Showing Cancer Protection

#### UKPDS Study (1998-2008)

Long-term follow-up showed 30% reduction in cancer mortality in patients randomized to metformin.

#### Libby et al., Diabetes Care (2009)

Scottish database study of 8,000+ patients: metformin associated with 37% lower cancer incidence.

#### Decensi et al., Cancer Prevention Research (2010)

Meta-analysis of 11 studies found 31% reduction in cancer risk with metformin use.

#### Gandini et al., Cancer Prevention Research (2014)

Comprehensive meta-analysis: 27% reduced cancer incidence, 33% reduced cancer mortality.

## Cardiovascular Benefits

Metformin has demonstrated significant cardiovascular protective effects, making it especially valuable given that heart disease remains the leading cause of death worldwide.

- UKPDS Trial: 39% reduction in heart attacks in overweight diabetic patients on metformin
- Reduced LDL Cholesterol: Average 5-10% reduction in LDL levels
- Anti-inflammatory: Reduces CRP and other inflammatory markers
- Endothelial Function: Improves blood vessel health and function
- Weight Neutral to Modest Loss: Does not cause weight gain like many diabetes medications

## Longevity and Healthspan Benefits

Beyond disease-specific benefits, metformin shows promise for extending overall healthspan - the years lived in good health.

### Evidence from Observational Studies

- Bannister et al. (2014): Diabetics on metformin had 15% lower all-cause mortality than matched non-diabetic controls - suggesting metformin users outlived even healthy non-diabetics
- UK Clinical Practice Research Datalink: 100,000+ patients showed consistent mortality benefits with metformin
- Veterans Affairs studies: Confirmed cardiovascular and mortality benefits in large populations

### Biological Hallmarks of Aging Addressed

Metformin has been shown to positively influence multiple hallmarks of aging:

- Genomic instability: Enhances DNA repair mechanisms
- Epigenetic alterations: Modulates age-related epigenetic changes
- Cellular senescence: Reduces accumulation of senescent cells
- Mitochondrial dysfunction: Improves mitochondrial biogenesis and function
- Chronic inflammation: Powerful anti-inflammatory effects

## Dosing for Longevity

While metformin dosing for diabetes typically ranges from 1500-2550mg daily, longevity-focused practitioners often use different protocols.

### Common Longevity Dosing Protocols

- Starting dose: 500mg Extended Release once daily with dinner
- Titration: Increase by 500mg every 1-2 weeks as tolerated
- Target dose: 1000-1500mg Extended Release daily for most longevity applications
- Timing: Evening dosing with food maximizes tolerability

#### The Exercise Consideration

Some research suggests metformin may blunt certain exercise adaptations, particularly muscle hypertrophy gains in older adults. Many longevity physicians recommend:

- Skipping metformin on days of intense resistance training
- Taking metformin later in the day, away from workouts
- Monitoring strength gains and adjusting protocol accordingly

The clinical significance of this interaction remains debated, and many experts believe metformin's benefits outweigh potential exercise blunting.

## Side Effects and Safety

Metformin has one of the best safety profiles of any medication, which is remarkable given its widespread use for over six decades.

### Common Side Effects

- GI symptoms: Nausea, diarrhea, stomach upset - usually resolve within 2-4 weeks and are minimized with XR formulation
- Metallic taste: Occasional, usually mild and temporary
- B12 deficiency: Long-term use can reduce B12 absorption - supplement B12 or monitor levels annually

### Rare but Serious Considerations

- Lactic acidosis: Extremely rare (1 in 30,000 patient-years), primarily in those with severe kidney impairment
- Contraindicated: In severe kidney disease (eGFR < 30), acute decompensated heart failure, severe liver disease
- Hold before contrast: Typically held 48 hours before and after IV contrast procedures

## Who May Benefit from Metformin

Beyond diabetics, metformin is being used off-label by many individuals interested in longevity optimization:

- Adults with prediabetes or metabolic syndrome
- Those with family history of type 2 diabetes or cancer
- Individuals with elevated fasting glucose or insulin
- People seeking evidence-based longevity interventions
- Those who cannot tolerate or don't respond to lifestyle interventions alone

#### Medical Supervision Required

Metformin is a prescription medication. While it has an excellent safety profile, it should only be used under medical supervision with appropriate monitoring of kidney function, B12 levels, and metabolic parameters. Never self-medicate or obtain metformin without a valid prescription.

## The Bottom Line

Metformin Extended Release represents one of the most well-studied, affordable, and promising compounds for metabolic health and longevity. With over 65 years of clinical use, extensive safety data, and growing evidence for benefits beyond glucose control, it has earned its place as a cornerstone of evidence-based longevity medicine.

The TAME trial will provide definitive answers about metformin's ability to delay aging. Until then, the preponderance of evidence supports its safety and potential benefits for those seeking to optimize their healthspan.

#### Summary of Evidence

- Cancer: Reduces risk, does NOT cause cancer
- Cardiovascular: Significant protection against heart disease
- Mortality: Associated with reduced all-cause death
- Safety: One of the safest medications in existence
- Cost: Extremely affordable ($4-20/month)
- Evidence Base: 40,000+ published studies

## References and Further Reading

- Barzilai N, et al. "Metformin as a Tool to Target Aging." Cell Metabolism, 2016
- UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998
- Bannister CA, et al. "Can people with type 2 diabetes live longer than those without?" Diabetes, Obesity and Metabolism, 2014
- Gandini S, et al. "Metformin and cancer risk and mortality." Cancer Prevention Research, 2014
- Valencia WM, et al. "Metformin and ageing: improving ageing outcomes beyond glycaemic control." Diabetologia, 2017
- TAME Trial: afar.org/tame-trial