Is Synjardy (empagliflozin and metformin) associated with an increased risk of diarrhea?

Synjardy and Diarrhea Risk

Yes, Synjardy is strongly associated with diarrhea, primarily due to its metformin component, which causes gastrointestinal adverse effects in a substantial proportion of patients. The empagliflozin component does not typically cause diarrhea, making metformin the culprit in this combination product.

Metformin's Gastrointestinal Effects

Diarrhea is one of the most common adverse effects of metformin, occurring in approximately 53% of patients in clinical trials compared to 12% with placebo 1. The FDA drug label for metformin explicitly lists diarrhea as the most frequent adverse reaction, leading to discontinuation in 6% of patients 1.

• Metformin causes gastrointestinal intolerance through multiple mechanisms including bloating, abdominal discomfort, and diarrhea 2
• These effects can occur both at treatment initiation and surprisingly, even after years of stable therapy 3
• The American Diabetes Association recognizes gastrointestinal side effects as the principal adverse effects of metformin 2

Clinical Presentation and Timing

Metformin-induced diarrhea can present in two distinct patterns:

• Early-onset diarrhea: Occurs during initial titration and is widely recognized 4
• Late-onset chronic diarrhea: Can develop after several years of stable therapy and is frequently misdiagnosed as irritable bowel syndrome 5, 3

One case report documented a patient who experienced chronic diarrhea with 6 kg weight loss over six years after metformin initiation, which completely resolved upon discontinuation 5.

Risk Factors for Metformin-Induced Diarrhea

Six specific risk factors increase the likelihood of diarrhea 6:

• Initial dose of 750 mg (higher doses carry greater risk)
• Female sex
• Age ≤65 years
• Body mass index ≥25 kg/m²
• Aspartate aminotransferase ≥30 IU/L
• Alkaline phosphatase ≥270 IU/L

The incidence of diarrhea increases linearly with the number of risk factors present 6.

Does Synjardy Worsen Pre-existing Diarrhea?

Yes, Synjardy would likely worsen pre-existing diarrhea due to the metformin component. Evidence shows that metformin causes more gastrointestinal adverse effects compared to other diabetes medications including thiazolidinediones, sulfonylureas, and DPP-4 inhibitors 2.

• Combination therapy with metformin plus sulfonylurea shows more diarrhea than thiazolidinedione plus sulfonylurea 2
• The metformin component is responsible for the gastrointestinal effects, not the empagliflozin 2

Management Strategies

If diarrhea occurs with Synjardy, implement these specific interventions 7, 4:

1. Gradual dose titration: Start with low doses and increase slowly to minimize GI effects 2, 7
2. Take with meals: This significantly reduces gastrointestinal side effects 1, 7
3. Consider extended-release formulation: Switch to extended-release metformin if available in combination products 7, 4
4. Add probiotics: Meta-analysis demonstrates that probiotics reduce the risk of diarrhea, bloating, and constipation when combined with metformin 8
5. Trial discontinuation: If diarrhea persists despite these measures, a drug-free interval should be attempted before pursuing expensive diagnostic workup 3

Critical Clinical Pitfall

Do not assume chronic diarrhea in diabetic patients on Synjardy is due to diabetic diarrhea or other causes without first considering metformin as the culprit 3. Diabetic diarrhea is actually rare in type 2 diabetes, whereas metformin-induced diarrhea is common 3. Patients deserve a trial off metformin before undergoing extensive gastrointestinal investigations 3.

When to Discontinue

Temporary or permanent discontinuation is warranted if 7:

• Diarrhea causes dehydration (which increases lactic acidosis risk) 1
• GI symptoms persist despite dose reduction and supportive measures 7
• Symptoms significantly impact quality of life or lead to weight loss 5
• Patient develops severe illness with vomiting or diarrhea 1