Yet Another Benefit for Metformin?

Metformin started for pre-diabetes also appeared to reduce patients' risk of developing gout, researchers found.

Among 1,154 people with elevated hemoglobin A1c (HbA1c) just short of the threshold for type 2 diabetes who began taking metformin, gout was subsequently diagnosed at a rate of 7.1 per 1,000 person-years (95% CI 5.1-10.0) during a median 4 years of follow-up, according to Javier Marrugo, MD, of Brigham and Women's Hospital in Boston, and colleagues.

Gout developed at a rate of 9.5 per 1,000 person-years (95% CI 8.8-10.2) among nearly 14,000 otherwise similar patients who did not initiate metformin, for a relative risk of 0.68 (95% CI 0.48-0.96) with metformin use, the researchers reported in Annals of the Rheumatic Diseases.

Interestingly, however, metformin seemed to have no impact on either serum urate or C-reactive protein (CRP) levels, complicating interpretation of the results.

It's not the first study to find an association between anti-diabetic medications and reduced gout risk. Such a relationship was previously noted for so-called gliflozin drugs that force urinary glucose excretion, although with these agents urate levels were reduced.

Metformin, of course, is the most common first-line treatment for type 2 diabetes, and its relative safety has made it a go-to drug for people with pre-diabetes (in the current study, defined as HbA1c of 5.7%-6.4%). Marrugo and colleagues observed that many studies on metformin have documented anti-inflammatory effects. "Therefore, beyond its established role in reducing the risk of [diabetes mellitus], metformin may also be associated with a lower risk of gout in individuals with pre-diabetes," they explained.

For the current study, Marrugo's group examined records for 50,588 patients treated in the Mass General Brigham health system from 2007 to 2022 for pre-diabetes. Half were excluded because they were quickly diagnosed with type 2 diabetes or gout, or because they had less than a year of baseline data. Of the approximately 25,000 remaining, the researchers identified 1,172 metformin users along with 23,892 others treated differently. Eighteen of the metformin users and 10,015 of the non-users couldn't be propensity-matched, leaving 1,154 and 13,877, respectively, for inclusion in the analysis.

About two-thirds were women and the average age was 57. Just over 60% were white. Mean body mass index was about 32; HbA1c averaged 6.0%. Participants not using metformin received no other glucose-lowering medications. In both groups, 10%-12% were taking aspirin and about the same number were on anti-hypertensives.

A Kaplan-Meier analysis covering 5 years of follow-up showed a gap between groups in gout incidence beginning after just a few months. After 5 years, 30 of the metformin users (2.6%) had developed gout, compared with 546 (3.9%) of the non-users (P=0.032 for trend). Most of those with gout onset were men.

Serum urate levels were slightly lower in the metformin group but not by enough to be statistically significant (P=0.73); levels declined somewhat with time in both groups and at the same rate. The same was true for CRP. As expected, metformin was effective in lowering HbA1c levels, with a decline of 0.14 percentage points after 1 year.

Marrugo and colleagues did not attempt to explain how metformin could decrease gout risk without a clear reduction in serum urate, but they did note that the drug cut HbA1c and appeared to induce some weight loss; these effects have previously been linked with reduced systemic inflammation (although, in the current study, no effect on CRP could be discerned). As well, the researchers pointed out that the earlier studies showing a urate-lowering effect from gliflozin drugs was conducted in people with full-blown diabetes, whereas the new study only involved people with less seriously elevated HbA1c.

Limitations to the study included the preponderance of women in the study sample, whereas gout primarily affects men. The retrospective, observational design, along with lack of data on lifestyle factors, also meant that unmeasured confounders could have influenced the results.

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