September 11, 2023 • 2hr 18min

Journal Club With Dr. Peter Attia | Metformin for Longevity & the Power of Belief Effects

Huberman Lab

In this journal club episode, Dr. Andrew Huberman and Dr. Peter Attia discuss two scientific papers and their implications. The first paper examines the effects of metformin on longevity in diabetics compared to non-diabetics. The second looks at how beliefs about nicotine dosage impact brain activation and cognitive performance. Through their discussion, they highlight how to critically analyze scientific studies and the potential real-world applications of the findings.

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Key Takeaways

Metformin, a common diabetes drug, may not provide the longevity benefits previously thought based on a large retrospective study of over 500,000 people
The study found that diabetics taking metformin still had higher mortality rates than non-diabetics, contradicting earlier research suggesting metformin could extend lifespan
Our beliefs about the dose and effects of a drug can significantly impact how our brain and body respond to it, even if the actual dose remains the same
In a study on nicotine, subjects who believed they received a higher dose showed greater activation in relevant brain areas, despite all receiving the same low dose
These "belief effects" appear to be dose-dependent and go beyond simple placebo effects, potentially having major implications for drug trials and treatments

Introduction

In this journal club episode, Dr. Andrew Huberman and Dr. Peter Attia discuss two scientific papers and their implications. The first paper examines the effects of metformin on longevity in diabetics compared to non-diabetics. The second looks at how beliefs about nicotine dosage impact brain activation and cognitive performance. Through their discussion, they highlight how to critically analyze scientific studies and the potential real-world applications of the findings.

Topics Discussed

Metformin and Longevity (12:36)

Dr. Attia presents a 2022 paper by Keyes et al. that reassesses the evidence for metformin providing a survival advantage in type 2 diabetics. This study was conducted in response to a influential 2014 paper by Bannister that had suggested metformin could extend lifespan.

The new study analyzed data from over 500,000 people in Danish health registries
It compared mortality rates between diabetics taking metformin and matched non-diabetic controls
The study also looked at discordant twins where one twin had diabetes and took metformin while the other did not

Key findings:

Diabetics taking metformin still had 32-48% higher mortality rates than non-diabetics
This contradicts the earlier Bannister study that had found a 15% reduction in mortality for metformin users
The twin analysis showed even larger mortality differences of 70-115%

"This makes much more sense to me than the Bannister paper, which never really made sense to me," notes Dr. Attia. He explains this aligns more with what would be expected given the health impacts of diabetes.

Limitations of Epidemiological Studies (44:27)

The doctors discuss some key limitations of this type of retrospective epidemiological study:

Cannot fully control for all variables and confounding factors
Medication use differed significantly between diabetic and non-diabetic groups
Cannot determine if metformin is actually helping diabetics live longer compared to no treatment

"No matter how slick you are, no matter how slick your model is, you can't control for everything," Dr. Attia emphasizes. This highlights the need for randomized controlled trials to definitively answer questions about metformin's effects on longevity.

Interpreting Hazard Ratios and Mortality Curves (51:28)

The doctors explain how to interpret key statistics and graphs from the paper:

Hazard ratios above 1 indicate increased risk - e.g. 1.48 means 48% higher risk
Kaplan-Meier survival curves show cumulative survival over time
Confidence intervals and p-values indicate statistical significance

They note the importance of looking at both statistical and clinical significance when evaluating results.

Implications for Metformin Use (1:09:00)

Dr. Attia shares his perspective on the implications:

He stopped taking metformin himself in 2018 after reconsidering the evidence
Still prescribes it for diabetics but not for longevity in healthy individuals
Awaiting results of the TAME trial testing metformin for anti-aging effects

"I think we just have to all walk around with an appropriate degree of humility around what we know and what we don't know," he concludes.

Belief Effects and Nicotine (1:38:10)

Dr. Huberman presents a pre-print paper by Pearl et al. examining how beliefs about nicotine dosage impact brain activation and cognitive performance. Key aspects of the study:

Smokers were given the same low dose of nicotine via vape pen but told they received low, medium or high doses
Brain activation was measured via fMRI while subjects performed a decision-making task
Subjective effects and task performance were also assessed

Key Findings on Belief Effects (1:51:07)

The study found several striking results:

Subjective feelings of nicotine effects matched what subjects were told about the dose
Brain activation in key areas like the thalamus scaled with believed dose, not actual dose
Connectivity between thalamus and prefrontal cortex showed dose-dependent increases with believed dose
Task performance improved in line with believed dose

"What we are told about the dose of a drug changes the way that our physiology responds to the dose of the drug," Dr. Huberman emphasizes. This goes beyond simple placebo effects by showing dose-dependent biological changes.

Implications of Belief Effects (2:00:07)

The doctors discuss potential implications of these findings:

Could impact how drugs are tested and prescribed
May allow for lower doses to be effective if patients believe they work
Highlights importance of patient education and framing of treatments
Raises questions about nocebo effects and side effects

"I think of the implications, for example, of blood pressure...How do we know that the belief system about it can't be changed?" Dr. Attia notes, highlighting potential clinical applications.

Limitations and Future Directions (2:05:14)

They also discuss some limitations of the study:

Relatively small sample size of smokers only
Did not test zero nicotine condition
Unclear if results would apply to non-smokers or other drugs

The doctors emphasize the need for further research to explore the full implications of belief effects across different contexts.

Conclusion

This journal club discussion highlights the complexities of interpreting scientific studies and their real-world implications. The metformin study demonstrates how new evidence can challenge previous assumptions about a drug's benefits. Meanwhile, the nicotine belief effects study reveals the powerful and nuanced ways our expectations can shape biological responses.

Both papers underscore the need for rigorous randomized controlled trials to definitively answer questions about drug effects. They also point to the importance of considering psychological factors alongside pharmacology when developing and prescribing treatments.

Ultimately, these discussions showcase how science is an ongoing process of discovery and refinement of knowledge. As Dr. Attia notes, maintaining humility about what we know and don't know is crucial as we continue to explore these complex topics.