Review of NHANES data links metformin use to lower mortality and inflammatory markers in type 2 diabetesMetformin use linked to lower death risk and better inflammation markers in U.S. adults with diabetes

medRxiv Published May 1, 2026 Study authors: Chen, Y.; Guan, J.; Wang, Y.; Xu, Y.; Sun, H. DOI ↗ Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

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Key Takeaway

Consider that metformin's mortality benefits may involve anti-inflammatory pathways, but these are observational associations only.

This review analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2013-2018, including 2,116 U.S. adults with self-reported type 2 diabetes and valid mortality follow-up through 2019. The study examined associations between metformin use and inflammatory biomarkers (NLR, MLR, serum albumin, hs-CRP) as well as all-cause and cardiovascular mortality, using non-users and sulfonylurea monotherapy as comparators.

Metformin use was associated with lower NLR (beta = -0.35, 95% CI -0.57 to -0.14) and MLR (beta = -0.04, 95% CI -0.06 to -0.02), and higher serum albumin (beta = +0.11 g/dL, 95% CI 0.06 to 0.16). The association with hs-CRP was directionally consistent but not significant. For mortality, metformin was associated with lower all-cause mortality (HR 0.64, 95% CI 0.48 to 0.86) and cardiovascular mortality (HR 0.49, 95% CI 0.26 to 0.94). Notably, the highest tertile of NLR carried nearly twice the hazard of the lowest for all-cause mortality.

The authors note that population-level evidence connecting mortality benefits to inflammation-related pathways remains limited. The metformin-mortality association was modestly attenuated by inclusion of NLR or MLR, and the hs-CRP association was not significant. These are associations, not causation, though results were robust in active comparator and sensitivity analyses.

For clinicians, these findings support further investigation of non-glycemic pathways relevant to long-recognized clinical benefits of metformin. However, given the observational design, no causal conclusions can be drawn, and these results should not change current prescribing practices.

People with Type 2 diabetes often take metformin to manage their blood sugar. But doctors have long wondered if this common drug does more than just control glucose levels. A large review of data from U.S. adults found that those using metformin showed signs of lower inflammation and a reduced risk of dying from any cause or heart disease compared to non-users. This analysis looked at over 2,100 adults who reported having diabetes between 2013 and 2018. The researchers tracked these individuals through 2019 to see who survived and who did not. They also measured specific blood markers that signal how the body handles stress and infection. The results showed that metformin users had lower levels of neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio. These are numbers that help scientists understand how the immune system is working. Users also had higher levels of serum albumin, a protein that helps keep fluid in the blood vessels. The link to lower death risk was clear, but the connection to heart disease specifically was less certain in this group. The study did not report any safety issues or side effects for the people in this specific dataset. However, the researchers noted that this evidence comes from a broad survey of the population rather than a tightly controlled trial. This means the findings show a strong connection but do not prove that the drug directly causes these benefits. The data suggests that metformin might work through pathways that reduce inflammation, which could explain its long-known benefits. More research is needed to confirm these links and to understand exactly how the drug helps people live longer and healthier lives.

What this means for you:

Metformin use was linked to lower death risk and better inflammation markers in a large U.S. adult group.

Study Details

EvidenceLevel 5

PublishedApr 2026

View Original Abstract ↓

Metformin has been linked to mortality benefits in type 2 diabetes that may extend beyond glycemic control, but population-level evidence connecting these benefits to inflammation-related pathways remains limited. Using NHANES 2013-2018 data with mortality follow-up through 2019, we examined associations between metformin use and four inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), serum albumin, and high-sensitivity C-reactive protein (hs-CRP), and evaluated their relevance to all-cause and cardiovascular mortality. Among 2,122 adults with self-reported diabetes (60% metformin users; 2,116 with valid mortality follow-up), survey-weighted linear regression adjusted for demographic, socioeconomic, and metabolic covariates showed metformin use was associated with lower NLR ({beta} = -0.35; 95% CI -0.57, -0.14), lower MLR ({beta} = -0.04; 95% CI -0.06, -0.02), and higher serum albumin ({beta} = +0.11 g/dL; 95% CI 0.06, 0.16); the hs-CRP association was directionally consistent but not significant. Associations for NLR and MLR were essentially unchanged after BMI and HbA1c adjustment, remained robust in an active comparator analysis against sulfonylurea monotherapy, and were consistent across propensity score and overlap weighting sensitivity analyses. Survey-weighted Cox regression linked metformin to lower all-cause (HR 0.64; 95% CI 0.48, 0.86) and cardiovascular mortality (HR 0.49; 95% CI 0.26, 0.94). NLR was independently associated with all-cause mortality, with the highest tertile carrying nearly twice the hazard of the lowest, and inclusion of NLR or MLR modestly attenuated the metformin-mortality association. Metformin use is associated with a distinct cellular immune-inflammation profile in adults with type 2 diabetes, supporting further investigation of non-glycemic pathways relevant to its long-recognized clinical benefits.

Review of NHANES data links metformin use to lower mortality and inflammatory markers in type 2 diabetesMetformin use linked to lower death risk and better inflammation markers in U.S. adults with diabetes

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Review of NHANES data links metformin use to lower mortality and inflammatory markers in type 2 diabetesMetformin use linked to lower death risk and better inflammation markers in U.S. adults with diabetes

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