Does Methotrexate Affect Blood Sugar?

Methotrexate appears to have a modest blood-sugar-lowering effect, at least in people with inflammatory conditions like rheumatoid arthritis. Multiple studies have found small but consistent reductions in HbA1c (the marker of average blood sugar over roughly three months) in patients taking methotrexate, and laboratory research points to a plausible biological mechanism behind the effect. The picture is more nuanced than a simple yes-or-no, though, because the size of the effect varies across diseases, populations, and what other medications are in the mix.

What the Clinical Evidence Actually Shows

Several studies have directly measured what happens to HbA1c when people start taking methotrexate. In one study of patients with newly diagnosed rheumatoid arthritis or psoriatic arthritis who were not diabetic, HbA1c dropped in a time-dependent fashion from about 5.80% at baseline to 5.55% after six months. The effect was especially pronounced in patients who had normal insulin sensitivity at the start, where HbA1c fell from 5.82% to 5.42%, with reductions seen in 12 out of 14 people in that group.¹ A separate study confirmed a similar pattern, with HbA1c concentration falling from 5.80% to 5.51% at six months.²

A larger trial looked at multiple treatment arms and found that methotrexate alone reduced HbA1c by about 0.08% after three months. That is a small shift, but it was statistically significant. When researchers measured the intracellular levels of methotrexate’s active metabolites (called polyglutamates) in red blood cells, higher levels tracked consistently with greater HbA1c reductions.³ In other words, the more the drug accumulated in tissue, the bigger the drop in blood sugar markers. That dose-response relationship is one of the stronger pieces of evidence that the effect is real rather than a statistical fluke.

To put these numbers in perspective, a 0.08% to 0.29% drop in HbA1c is not going to replace diabetes medication for anyone. For context, metformin typically lowers HbA1c by about 1% to 1.5%. But for someone whose blood sugar is borderline or whose inflammatory disease itself is pushing their metabolic markers in the wrong direction, even a modest shift can be clinically meaningful.

Why Methotrexate Might Lower Blood Sugar

The leading explanation centers on a cellular energy sensor called AMPK. When AMPK gets switched on, cells ramp up their glucose uptake and start burning fat for fuel. Methotrexate, through its interference with purine metabolism, causes a buildup of a molecule called AICAR inside cells. AICAR is a natural activator of AMPK, and methotrexate can boost AICAR levels dramatically. One study in cell lines found roughly a 30-fold increase in intracellular AICAR after methotrexate treatment.⁴

What does that mean in practical terms? In skeletal muscle, which is the body’s biggest glucose sink, methotrexate lowered the threshold for AMPK activation and boosted both glucose uptake and fat burning.⁵ In animal models of type 2 diabetes, chronic low-dose methotrexate increased the expression of GLUT4, a glucose transporter protein in muscle tissue, and improved overall metabolic control.⁶ Think of GLUT4 as the doorway that lets glucose move from the bloodstream into muscle cells; more doorways means glucose gets cleared from the blood more efficiently.

There is also an anti-inflammatory pathway at work. Chronic inflammation, the kind that characterizes rheumatoid arthritis and other autoimmune conditions, interferes with insulin signaling. By tamping down inflammation, methotrexate may remove some of that interference. Research in obese mice showed that methotrexate treatment reduced circulating levels of TNF-alpha (a key inflammatory molecule), lowered both insulin and glucose levels, and improved insulin sensitivity. Fat tissue from treated mice produced fewer inflammatory signals and more anti-inflammatory ones.⁷ A separate study found that methotrexate improved insulin sensitivity in fat tissue and liver through an adenosine-dependent signaling cascade.⁸

So the blood sugar effect likely comes from two overlapping routes: a direct metabolic boost via AMPK, and an indirect benefit from reducing the chronic inflammation that makes insulin work less effectively. Which one matters more in a given patient probably depends on how inflamed they are to begin with.

Does Methotrexate Reduce the Risk of Developing Diabetes?

If methotrexate nudges blood sugar markers downward, you might wonder whether long-term use actually prevents type 2 diabetes. A systematic review and meta-analysis found that methotrexate use was associated with a lower risk of developing type 2 diabetes in rheumatoid arthritis patients, with a relative risk of about 0.48, meaning roughly half the risk. That sounds impressive, but the confidence interval was wide and crossed 1.0, so the result did not reach statistical significance.⁹ The trend is suggestive rather than proven.

A narrative review of psoriasis and psoriatic arthritis patients found similar signals. In one large retrospective study of nearly 85,000 patients with psoriasis or psoriatic arthritis, those treated with methotrexate had a substantially lower hazard ratio for developing diabetes (0.35) compared to untreated patients. Another study of over 121,000 patients with rheumatoid arthritis or psoriasis showed a lower, though not statistically significant, adjusted hazard ratio for new-onset diabetes with methotrexate (0.77).¹⁰ The general pattern is consistent: methotrexate users seem less likely to develop diabetes, but the evidence is not yet strong enough to call it definitive.

It is worth noting that people with autoimmune inflammatory conditions already have an elevated diabetes risk because chronic inflammation and corticosteroid use both push metabolic health in the wrong direction. Methotrexate may be partly correcting that elevated baseline rather than providing protection that would also apply to someone without an inflammatory condition.

How Methotrexate Compares to Other Rheumatic Disease Drugs

If you have an inflammatory condition and diabetes or prediabetes, the choice of disease-modifying drug may matter for blood sugar. Not all of these medications are equal on the metabolic front.

Hydroxychloroquine, often used alongside methotrexate in rheumatoid arthritis, appears to have a stronger blood-sugar-lowering effect. In a study of diabetic patients with rheumatic diseases, those starting hydroxychloroquine saw an average HbA1c reduction of 0.66%, compared with just 0.11% for those starting methotrexate. After adjusting for other factors, the hydroxychloroquine group’s reduction was 0.54% greater than methotrexate’s.¹¹ That is a meaningful gap, especially for someone whose diabetes management is a priority.

TNF inhibitors, the biologic drugs often prescribed when conventional medications are not enough, also show blood sugar benefits. One study found that the median HbA1c drop was 0.40% after starting methotrexate, compared with 0.35% after starting a TNF inhibitor. Interestingly, methotrexate actually outperformed the TNF inhibitors in that comparison, though both were considerably less effective than metformin, which showed a median drop of 0.80%.¹²

A study looking specifically at whether adding a TNF inhibitor to methotrexate improved glycemic outcomes found that the combination group had a slightly greater HbA1c reduction than methotrexate alone, though the difference was small and the analysis had limitations.¹³ A broader analysis found that methotrexate combination therapy and biologic drugs were associated with lower diabetes risk compared to methotrexate monotherapy, with hazard ratios around 0.50 and 0.51 respectively.¹⁴ This suggests that combining therapies may provide a greater metabolic benefit, though it is hard to disentangle whether the benefit comes from better inflammation control or the direct metabolic effects of the added drugs.

The Psoriatic Arthritis Question

The evidence in psoriatic arthritis specifically is less encouraging than in rheumatoid arthritis. A pilot study of psoriatic arthritis patients, including those with metabolic syndrome, found no significant change in HbA1c after methotrexate treatment in any subgroup, whether men, women, those with metabolic syndrome, or those without it.¹⁵ HbA1c levels hovered around 5.6% to 5.9% before and after therapy, with the small shifts in each direction falling well within the range of random noise.

The reassuring takeaway from that study is also worth stating plainly: methotrexate did not make blood sugar worse. For anyone with psoriatic arthritis and metabolic syndrome who needs methotrexate for joint disease, the fear that it might destabilize blood sugar appears unfounded in the short term.¹⁰ Why the signal is clearer in rheumatoid arthritis than in psoriatic arthritis remains unclear. One possibility is that the systemic inflammatory burden differs between the two diseases, and methotrexate’s indirect metabolic benefit is proportional to how much inflammation it is controlling.

The Corticosteroid-Sparing Angle

There is another, often-overlooked way methotrexate can affect blood sugar: by reducing the need for corticosteroids. Prednisone and similar drugs are notorious for raising blood glucose, sometimes dramatically. Anyone who has been put on a course of steroids for a disease flare knows the roller coaster. In conditions where methotrexate serves as a steroid-sparing agent, its introduction can allow corticosteroid doses to be tapered. One study in patients with corticosteroid-dependent asthma found that methotrexate use allowed roughly 37% less prednisone to be used compared to placebo, without loss of lung function.¹⁶

For someone whose blood sugar is being pushed up by chronic steroid use, that reduction in prednisone dose can translate into meaningful glycemic improvement that would not show up in a study measuring methotrexate’s direct effect alone. In clinical practice, rheumatologists often consider this when choosing a treatment plan for patients with both active inflammatory disease and diabetes or prediabetes. In the HbA1c data from the larger methotrexate trial mentioned earlier, the treatment arms that combined methotrexate with glucocorticoids actually showed bigger HbA1c drops (0.34% to 0.50%) than methotrexate alone (0.08%), partly because the combination regimens allowed better disease control and lower subsequent steroid exposure.³

What Happens in the Liver

Methotrexate is well known for its potential liver toxicity, and the liver is central to blood sugar regulation. Research in animal models has found that methotrexate depletes hepatic glucose, lactate, and glycogen stores, likely because the drug disrupts oxidative phosphorylation and forces the liver to burn through stored fuel faster.¹⁷ That could contribute to lower circulating glucose in the short term, but over the long term, a liver under metabolic stress is not doing anyone’s diabetes management any favors.

This matters especially for people who already have diabetes, because methotrexate carries a higher risk of liver fibrosis in diabetic patients than in those without diabetes.¹⁰ The practical implication is straightforward: if you are taking methotrexate and have diabetes, liver monitoring is not optional. Regular blood work to check liver enzymes is standard for anyone on methotrexate, but the threshold for concern should arguably be lower in people with metabolic disease.

Methotrexate Alongside Metformin

Given that methotrexate and metformin both activate AMPK through different mechanisms, you might wonder whether they interact. A study of psoriasis patients with metabolic syndrome examined the combination of metformin and methotrexate and found significant reductions in blood glucose in the group receiving both drugs, though the authors attributed the glucose-lowering primarily to metformin’s known hypoglycemic action.¹⁸ No dangerous hypoglycemia was reported, which is reassuring for the large number of patients who take both medications simultaneously. Still, the shared metabolic pathway is worth being aware of, and anyone starting methotrexate who is already on diabetes medications should have their blood sugar monitored a bit more closely in the early weeks.

Why the Effect Size Varies So Much

If you read across these studies, the HbA1c reductions range from essentially zero (in some psoriatic arthritis cohorts) to around 0.3% to 0.4% (in rheumatoid arthritis patients with high baseline inflammation). Several factors likely explain the spread. First, baseline inflammation matters: the more inflamed you are, the more metabolic dysfunction is being driven by that inflammation, and the more room there is for an anti-inflammatory drug to improve things. Second, baseline blood sugar matters. Studies consistently find that the largest drops occur in patients whose HbA1c was higher to begin with, or whose insulin sensitivity was already relatively normal. People with frank insulin resistance may not respond as readily because the metabolic problem has moved beyond what inflammation alone is driving.

Third, the dose of methotrexate and how well the body converts it to active polyglutamate forms varies between individuals. The finding that higher intracellular polyglutamate levels predicted bigger HbA1c drops suggests that two people on the same weekly dose could have very different metabolic responses depending on their individual pharmacokinetics.³ And fourth, study duration matters. Some trials measured changes at three months, others at six, and the six-month results generally showed larger effects, consistent with a gradual metabolic shift rather than an acute one.²

One thing the data does not support is the fear some patients have that methotrexate will raise their blood sugar. Across every study in the literature, methotrexate either lowered HbA1c modestly or left it unchanged. No study has found a hyperglycemic effect, which is an important reassurance for people who need the drug for their inflammatory disease and are worried about metabolic side effects stacking up.