Researchers discovered that a popular diabetes medication called thiazolidinediones helps control blood sugar but causes uncomfortable water retention and bloating. In mouse studies, scientists found that adding a second drug called an SGLT2 inhibitor prevented this side effect by protecting blood vessel walls in fat tissue. The combination worked by stopping a protein called VEGF from damaging the structures that hold blood vessels together. This finding suggests doctors might be able to prescribe these two drugs together to get the benefits of thiazolidinediones without the bloating problem.

The Quick Take

  • What they studied: Whether adding a second diabetes drug (SGLT2 inhibitor) could prevent water retention caused by thiazolidinediones, a common diabetes medication
  • Who participated: Obese mice fed a high-fat diet were divided into three groups: one receiving thiazolidinedione alone, one receiving both drugs together, and a control group receiving no treatment
  • Key finding: Mice receiving both drugs together had significantly less water retention and better blood vessel health in fat tissue compared to mice receiving thiazolidinedione alone
  • What it means for you: This research suggests that people with diabetes taking thiazolidinediones might be able to avoid bloating by also taking an SGLT2 inhibitor, but human studies are needed to confirm this works in people

The Research Details

Scientists used obese mice to test whether combining two diabetes drugs could prevent water retention. The mice were divided into three groups: one received thiazolidinedione (a drug that helps cells use insulin better), another received both thiazolidinedione and empagliflozin (an SGLT2 inhibitor), and the control group received only water. After six weeks, researchers measured how much water was stored in different body tissues and examined the health of blood vessels in fat tissue.

The researchers also conducted laboratory experiments using human blood vessel cells to understand exactly how the drugs work. They tested whether blocking a protein called VEGF could explain why the combination prevented water retention. This two-pronged approach—testing in living mice and in isolated cells—helps confirm that the findings are real and not just coincidence.

Understanding why thiazolidinediones cause water retention is important because these drugs are very effective at helping people with diabetes control their blood sugar. However, many patients stop taking them because of bloating and weight gain. If scientists can find a way to prevent this side effect, more people could benefit from this medication without suffering uncomfortable symptoms.

This is a laboratory study using animal models and cell cultures, which means the results are preliminary. Animal studies don’t always translate directly to humans, so human clinical trials would be needed to confirm these findings work in people. The research was published in a peer-reviewed journal, which means other experts reviewed the work for quality. The study design was thorough, including both whole-animal experiments and detailed cellular studies to understand the mechanism.

What the Results Show

Mice treated with thiazolidinedione alone developed significant water retention in fat tissue and showed damaged blood vessel walls. The researchers found that a protein called VE-cadherin, which acts like glue holding blood vessel cells together, was reduced in these mice, allowing fluid to leak out.

When mice received both thiazolidinedione and empagliflozin together, the water retention problem was prevented. The combination therapy restored VE-cadherin levels and kept blood vessel walls intact. The researchers discovered that empagliflozin worked by blocking a signaling pathway involving a protein called VEGF-A, which was responsible for breaking down the VE-cadherin glue.

Laboratory experiments with human blood vessel cells confirmed these findings. When researchers blocked VEGF signaling, they could prevent the damage to blood vessel integrity that normally occurs with thiazolidinedione treatment. This suggests the same protective mechanism would likely work in humans.

The study also examined how the drugs affected kidney function and water channels in the kidneys. The combination therapy appeared to normalize kidney function compared to thiazolidinedione alone. Additionally, researchers found that the protective effects were specific to fat tissue, suggesting the drugs work through a targeted mechanism rather than a general body-wide effect.

Previous research had identified that thiazolidinediones increase vascular permeability (leakiness) in fat tissue, but the exact mechanism wasn’t clear. This study builds on that knowledge by identifying the specific protein pathway involved and demonstrating that SGLT2 inhibitors can counteract this effect. The findings align with growing evidence that SGLT2 inhibitors have protective effects on blood vessel health beyond their blood sugar-lowering abilities.

This research was conducted entirely in mice and laboratory cell cultures, not in humans. Mouse biology doesn’t always match human biology, so results may not translate directly. The study didn’t examine long-term effects or potential side effects of the combination therapy. Additionally, the specific doses used in mice may not correspond to typical human doses. Human clinical trials would be necessary to confirm these findings are safe and effective in people with diabetes.

The Bottom Line

Based on this research, there is moderate evidence suggesting that combining SGLT2 inhibitors with thiazolidinediones may prevent water retention. However, this is preliminary research in animals. Anyone taking thiazolidinediones who experiences water retention should discuss combination therapy options with their doctor—do not start or stop medications without medical guidance. Human studies are needed before this can be recommended as standard practice.

This research is most relevant to people with type 2 diabetes who take thiazolidinediones and experience water retention or bloating as a side effect. It may also interest healthcare providers looking for ways to improve medication tolerability. This research does not currently apply to people without diabetes or those not taking thiazolidinediones.

In the mouse studies, the protective effects appeared within six weeks of treatment. If similar effects occur in humans, benefits might be expected within weeks to months, but this timeline is speculative until human studies are conducted. Individual responses may vary significantly.

Want to Apply This Research?

  • Track daily weight and waist circumference measurements at the same time each morning. Note any changes in bloating, swelling in legs or feet, or how clothes fit. Record these weekly to identify patterns over time.
  • If prescribed a combination of thiazolidinedione and SGLT2 inhibitor, set daily reminders to take both medications at the same time. Track adherence to ensure consistent dosing, as the protective effect depends on regular use of both drugs.
  • Maintain a simple log of water retention symptoms (bloating, swelling, weight changes) and medication adherence. Share this data with your healthcare provider at regular check-ups to assess whether the combination therapy is working for you personally. Monitor for any new side effects and report them promptly.

This research is preliminary and based on animal studies and laboratory experiments. It has not been tested in humans. Do not change, start, or stop any diabetes medications based on this information. Always consult with your healthcare provider before making any changes to your medication regimen. This article is for educational purposes only and should not be considered medical advice. Individual responses to medications vary, and your doctor can best determine the appropriate treatment for your specific situation.