For decades, scientists have puzzled over how metformin, the world’s most prescribed diabetes drug, works beyond lowering blood sugar.
Now, a study from Kobe University reports that metformin users have lower blood copper and iron levels and higher zinc levels compared with non-users.
The findings, published in BMJ Open Diabetes Research & Care, suggest that the drug’s ability to bind metals may play a role in its wide-ranging benefits.
Metformin’s mechanism of action remains unclear
Metformin has been prescribed for more than 60 years and remains the first-line treatment for type 2 diabetes. Its glucose-lowering effect is thought to arise mainly from reduced glucose production in the liver, but the exact mechanisms remain only partly defined.
Beyond glycemic control, metformin is associated with a range of additional benefits, including anti-inflammatory, anti-tumor, anti-atherosclerotic and anti-obesity effects. These broader actions are well documented but poorly explained.
One hypothesis is that some of these effects relate to metformin’s ability to bind metals. Laboratory studies have shown that the drug can form complexes with transition metals, particularly copper. This binding has been suggested to influence mitochondrial function and cell signaling. However, it has not been clear whether such interactions occur in patients, and earlier small studies measuring copper levels in people taking metformin produced inconsistent results.
Altered levels of metals such as copper, iron and zinc are themselves linked to diabetes and its complications. Higher copper and iron levels are often associated with poorer glucose control and increased risk of cardiovascular disease. Zinc, in contrast, is generally thought to play a protective role in glucose metabolism and in limiting complications.
“It is known that diabetes patients experience changes in the blood levels of metals such as copper, iron and zinc. In addition, chemical studies found that metformin has the ability to bind certain metals, such as copper, and recent studies showed that it is this binding ability that might be responsible for some of the drug’s beneficial effects,” said corresponding author Dr. Wataru Ogawa, a professor at Kobe University.
“We wanted to know whether metformin actually affects blood metal levels in humans, which had not been clarified,” he added.
Metformin’s effect on blood metals
The cross-sectional analysis involved a total of 189 adults with type 2 diabetes. Of these, 93 participants had been taking metformin for at least 6 months, while the remaining 96 had not used the drug during the same period. Blood samples from all participants were analyzed for copper, iron, zinc, vitamin B12 and other related biochemical markers. The researchers identified serum copper concentration as the primary outcome, with secondary outcomes including iron and zinc levels, vitamin B12, homocysteine and parameters linked to copper and iron metabolism.
Patients taking metformin had lower serum copper levels than non-users (16.0 vs 17.8 µmol/L). Iron levels were also reduced in the metformin group (16.3 vs 17.3 µmol/L), along with ferritin and other markers that pointed to latent iron deficiency.
By contrast, zinc levels were higher in metformin users (13.3 vs 12.5 µmol/L). Vitamin B12 was significantly lower in those on metformin, consistent with earlier reports, and was accompanied by higher homocysteine levels.
Cobalt measurements showed no difference, although analysis was limited by detection sensitivity.
The associations remained after accounting for age, sex, body mass index, kidney function and medications that might affect metal metabolism. Multiple regression analysis identified metformin use as an independent predictor of reduced copper and iron and increased zinc levels.
Subgroup analyses by sex and medication use produced similar results, strengthening confidence in the findings.
What changes in copper, iron and zinc mean for metformin’s role
The findings suggest that metformin’s long-recognized ability to bind metals is not just a laboratory observation but has measurable effects in patients. The lower copper and iron levels, together with higher zinc, may contribute to the drug’s glucose-lowering activity and its protective effects against complications. This aligns with preclinical studies showing that reducing copper availability can influence mitochondrial function, dampen inflammation and even slow tumor growth.
“It is significant that we could show this in humans. Furthermore, since decreases in copper and iron concentrations and an increase in zinc concentration are all considered to be associated with improved glucose tolerance and prevention of complications, these changes may indeed be related to metformin’s action,” said Ogawa.
The results also raise questions about how different antidiabetic drugs might work. Imeglimin, a recently approved derivative of metformin in Japan, does not share the same metal-binding properties. Direct comparisons between the two could help clarify which effects depend on metal interactions.
“Imeglimin is thought to have a different method of action and we are already conducting studies to compare the effects the two drugs have,” Ogawa added.
“We need both clinical trials and animal experiments to pinpoint the causal relationship between the drug’s action and its effects. If such studies progress further, they may lead to the development of new drugs for diabetes and its complications by properly adjusting the metal concentrations in the body,” said Ogawa.
Reference: Otowa-Suematsu N, Sakaguchi K, Yamada T, et al. Association of metformin treatment with changes in metal dynamics in individuals with type 2 diabetes. BMJ Open Diabetes Res Care. 2025. doi: 10.1136/bmjdrc-2025-005255
This article is a rework of a press release issued by Kobe University. Material has been edited for length and content.