Japan Trial Questions Metformin's Role in Protecting Diabetic Kidneys

A study from Japan is challenging one of the most deeply rooted assumptions in diabetes care: that metformin should always be the first medication prescribed for type 2 diabetes. Researchers at Shinshu University School of Medicine are running a head-to-head clinical trial comparing metformin to tofogliflozin — a newer SGLT2 inhibitor — to see which drug better protects the kidneys in people who already show signs of diabetic kidney disease (DKD).

Why an International Perspective Matters Here

Japan has one of the world's most rigorous diabetes research infrastructures and a high prevalence of diabetes-related kidney complications. Because Japanese researchers operate under different prescribing norms and healthcare systems, their willingness to directly challenge metformin's dominance offers a perspective that US researchers — shaped by decades of ADA guideline inertia — have been slower to test head-to-head. This kind of direct comparison trial is exactly what's been missing from the global evidence base.

What the Study Is Doing

The TRUTH-DKD trial is enrolling 120 adults with type 2 diabetes and diabetic kidney disease across multiple Japanese medical centers. Participants are randomly assigned to take either tofogliflozin or metformin for up to two years. The key measurement researchers are tracking is the urinary albumin-to-creatinine ratio (UACR) — a standard urine test that detects kidney leakage. A rising UACR signals worsening kidney damage.

To qualify, participants must have:

• A UACR between 30 and 2,000 mg/g (indicating mild-to-severe albuminuria)
• An estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m² — meaning moderate-to-normal kidney function, not yet dialysis-level

The primary goal is to measure UACR change at 52 weeks. Secondary outcomes include eGFR decline rate, A1C, body weight, and blood pressure changes at 26 and 104 weeks.

The Core Argument Against Metformin Alone

The researchers point out that while metformin has decades of use behind it, the cardiovascular evidence supporting it largely comes from a single older study (the UKPDS trial from the 1990s). More importantly, there is almost no direct clinical evidence that metformin protects the kidneys. SGLT2 inhibitors, by contrast, have repeatedly demonstrated kidney and heart protection in large modern trials — including CREDENCE, DAPA-CKD, and EMPA-KIDNEY.

US Measurement Equivalents

All measurements in this trial are already reported in units familiar to US patients. UACR is measured in mg/g — the same standard used by US labs. The eGFR cutoffs (30 and 60 mL/min/1.73 m²) align directly with the National Kidney Foundation's CKD staging system used throughout American nephrology practice.

How This Compares to US Guidelines

The American Diabetes Association (ADA) currently recommends metformin as a preferred first-line agent for most people with type 2 diabetes, but has increasingly moved SGLT2 inhibitors to the front of the line specifically when kidney disease or heart disease is present. The TRUTH-DKD trial could provide the direct comparative evidence needed to justify making SGLT2 inhibitors the default first choice for patients with DKD — not just an add-on.

Why This Matters for US Patients

Over 37 million Americans have diabetes, and approximately 1 in 3 will develop diabetic kidney disease. Kidney failure from diabetes remains a leading cause of dialysis in the US. If tofogliflozin — or SGLT2 inhibitors as a class — proves superior to metformin at slowing kidney damage, it could directly influence ADA guideline updates and change what your doctor prescribes at your next appointment. US patients with early kidney involvement should ask their provider whether an SGLT2 inhibitor may be appropriate as a primary therapy, not just an add-on medication. Results from TRUTH-DKD, expected over the next two years, will be important to watch.

Source: Kimura, Takagi, Harada. "Effect of Tofogliflozin on Urinary Albumin-to-Creatinine Ratio vs. Metformin in Diabetic Kidney Disease: Rationale and Study Protocol of the TRUTH-DKD Trial." Diabetes Therapy, 2026. PMID: 41252113. DOI: 10.1007/s13300-025-01822-8. ClinicalTrials.gov: NCT05469659.