Dr. Ahmed Key points:
- The study challenges the old recommendation to always stop metformin in severe kidney disease (eGFR <30).
- Keeping patients on metformin in advanced kidney disease did not raise the risk of death or major heart problems.
- It used detailed health data from across Scotland, offering strong real-life proof.
- A solid method (target trial emulation) was used to reduce bias.
- The results suggest it might be time to rethink the current rules for using metformin in severe kidney disease.
Metformin is a key part of the treatment for millions of people around the world living with type 2 diabetes. It works well, is usually easy to tolerate, and is low-cost.
But when kidney function drops to advanced stages, doctors often question whether to keep patients on metformin.
This is because of fears about lactic acidosis, a rare but serious side effect, which has led many guidelines to recommend stopping the drug in those with advanced chronic kidney disease (CKD).
A recently published nationwide study from Scotland brings new insights that may change current thinking and help both doctors and patients make clearer decisions [ref].
The study used a creative method to imitate a randomized trial, relying on large sets of real-life patient data.
The goal was to weigh the risks and benefits of stopping versus continuing metformin in patients with advanced CKD (defined by an estimated glomerular filtration rate, or eGFR, below 30 mL/min/1.73 m²).
This is an important issue, as running high-quality clinical trials in this vulnerable group is very hard.
Methodology and analysis
The study used a method called target trial emulation. This approach helps researchers use real-world data in a way that closely copies a randomized controlled trial.
It reduces common biases found in observational studies by clearly setting the study group, treatment plans (either continuing or stopping metformin), and expected results, just like in a well-designed clinical trial.
Dr. Bell and team studied adults across Scotland with type 2 diabetes who were taking metformin and later developed stage 4 chronic kidney disease (eGFR <30 mL/min/1.73 m²) between January 2010 and April 2019.
The main focus was on death from any cause, with serious heart-related events (MACE) as a major secondary outcome.
To deal with changing factors over time, they used a method called clone-censor-weight, where they created copies of patients and applied weights to balance the differences between those who kept taking metformin and those who stopped.
To make sure their results were solid, they also ran extra tests using a method called marginal structural models, offering a clearer view of how continuing metformin affects this high-risk group in real life.
What did the study find?
While the full study details are best found in the published paper, this kind of research generally aims to see if the assumed risks of continuing metformin are actually true in a large group of people, and whether there are benefits to staying on the drug.
Dr. Bell found that stopping metformin was associated with a lower 3-year survival rate (63.7% vs. 70.5%) compared to continuing metformin, and the incidence of MACE was similar between the groups who stopped versus continued metformin.
Why is this important?
This Scottish study is particularly impactful for several reasons:
- Using data from across the country gives a clear and accurate view of how care is actually provided and what happens to patients, helping reduce bias in the results.
- A smart statistical method was used to understand cause-and-effect from real-world data, similar to what we’d get from a clinical trial.
- The results help doctors make better decisions when treating patients who have both diabetes and advanced kidney disease, which is often a tough situation to manage.
Implications for Practice
If this study shows that it is actually safe and maybe even helpful for some people with advanced kidney disease (CKD) to keep taking metformin, it could change how doctors treat these patients.
More people might be able to stay on metformin longer, which helps control blood sugar and may also protect the heart, instead of switching to other drugs that can be more complicated or costly.
But it is important to remember that any changes in treatment should be made with a doctor, because everyone’s situation is different.
Things like other health problems and the latest research need to be taken into account. Still, this study is an important step in learning more about how metformin could be useful for people with serious kidney issues.
What previous research has said about this:
In the past, the main reason metformin was not recommended for people with advanced chronic kidney disease (CKD) was the fear of lactic acidosis (MALA) [ref].
Since metformin is cleared from the body by the kidneys, poor kidney function could cause the drug to build up, possibly raising lactate levels [ref].
However, as time went by, the FDA revised its metformin labeling, moving from a serum creatinine-based contraindication to one based on eGFR, allowing for cautious use in patients with eGFR between 30 and 45 mL/min/1.73 m2 [ref].
However, the risk of Metformin-Associated Lactic Acidosis (MALA) is actually quite low, even in those with reduced kidney function, and is similar to the rate seen in diabetic patients not using metformin.
Although MALA is dangerous and can be deadly, research shows it’s very rare, with estimated rates between 0.03 and 0.06 cases per 1000 patient-years. [ref]
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