Does empagliflozin (Empagliflozin) and glimepiride (Glimepiride) cause transaminitis (elevated liver enzymes)?

Empagliflozin and Glimepiride: Transaminitis Risk

Empagliflozin does not cause transaminitis, while glimepiride is not specifically associated with elevated liver enzymes as a class effect. However, when considering combination therapy with statins and fibrates (which may be relevant in diabetic patients), transaminitis becomes a significant concern.

Empagliflozin and Liver Safety

Empagliflozin has demonstrated a favorable hepatic safety profile and may actually improve liver enzyme levels in patients with metabolic liver disease.

• SGLT2 inhibitors like empagliflozin have shown moderate reductions in ALT levels in clinical trials involving patients with type 2 diabetes 1
• In the EMPA-REG H2H-SU trial comparing empagliflozin 25 mg to glimepiride over 208 weeks, there was no signal for hepatotoxicity or transaminase elevations with empagliflozin 2, 3
• A recent safety study in patients with advanced chronic liver disease (including decompensated cirrhosis) found empagliflozin 10 mg daily for 4 weeks was safe and well-tolerated, with adverse event frequency similar to phase 3 trials in non-cirrhotic populations 4
• In patients with MASLD/MASH without cirrhosis (F0-F3), SGLT2 inhibitors like empagliflozin can produce moderate reductions in liver fat content and improve ALT levels 1

Glimepiride and Liver Safety

Glimepiride, as a sulfonylurea, does not have a well-established association with transaminitis in clinical practice.

• In the head-to-head comparison trial, glimepiride 1-4 mg daily showed no specific hepatotoxicity signal over 208 weeks of treatment 2, 3
• The primary safety concerns with glimepiride are hypoglycemia (occurring in 24-28% of patients), weight gain, and poor durability of glycemic control—not hepatotoxicity 2, 3

Context: Transaminitis in Diabetic Patients on Combination Therapy

The real concern for transaminitis in diabetic patients arises from statin-fibrate combination therapy, not from empagliflozin or glimepiride.

• Combination therapy with statins and fibrates is associated with increased risk for abnormal transaminase levels, myositis, and rhabdomyolysis 1
• The risk is particularly elevated when statins are combined with gemfibrozil compared to fenofibrate 1
• Statin-fibrate combination therapy has not shown improvement in cardiovascular outcomes and is generally not recommended 1

Specific Hepatotoxicity Concerns in Diabetes Medications

Other diabetes medications have more established hepatotoxicity profiles than empagliflozin or glimepiride:

• Certain tyrosine kinase inhibitors (bosutinib, nilotinib) may cause hepatotoxicity with transaminase elevations, though these are used for different indications 1
• Lomitapide carries a black box warning for liver transaminase elevations and hepatic steatosis, requiring regular monitoring of ALT, AST, alkaline phosphatase, and total bilirubin 1

Clinical Monitoring Recommendations

Routine liver enzyme monitoring is not required for empagliflozin or glimepiride monotherapy, but should be considered in specific clinical contexts:

• Monitor liver enzymes if patients are on concomitant medications known to cause hepatotoxicity 1
• In patients with pre-existing liver disease, empagliflozin appears safe even in advanced cirrhosis, though baseline and periodic monitoring is prudent 4
• For patients with MASLD/MASH, empagliflozin may actually improve liver enzymes and is recommended for treating coexistent type 2 diabetes 1

Common Pitfalls to Avoid

• Do not withhold empagliflozin due to concerns about hepatotoxicity—it has a favorable liver safety profile and may improve liver parameters 1, 4
• Do not confuse the hepatotoxicity risk of statin-fibrate combinations with the safety profile of empagliflozin or glimepiride 1
• Do not assume all diabetes medications carry similar hepatotoxicity risks—empagliflozin and glimepiride are not associated with clinically significant transaminitis 2, 3