What can cause pancreatitis with SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors or DPP-4 (Dipeptidyl Peptidase-4) inhibitors?

Pancreatitis Risk with SGLT2 Inhibitors and DPP-4 Inhibitors

DPP-4 inhibitors carry a documented risk of acute pancreatitis and should be used with caution, while SGLT2 inhibitors have minimal established association with pancreatitis based on current evidence.

DPP-4 Inhibitors and Pancreatitis

Established Risk Profile

• DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin, linagliptin) have been associated with acute pancreatitis in post-marketing surveillance and case reports 1, 2.

• A 2024 FDA Adverse Event Reporting System analysis found DPP-4 inhibitors had the highest signal for pancreatitis risk (ROR: 13.2,95% CI 11.84-14.70) compared to other diabetes medications, with the information component highest at 3.61 3.

• The incidence remains low overall, with one medical center study reporting only 4 cases of suspected DPP-4 inhibitor-induced pancreatitis among 2,305 adverse drug reaction reports 2.

Clinical Presentation

• Patients typically present with abdominal pain, nausea, vomiting, and elevated pancreatic enzymes (lipase >90 IU/L, amylase >150 IU/L) 4, 2.

• The temporal relationship varies, but symptoms generally occur within weeks to months of drug initiation 2.

Management Approach

• Discontinue the DPP-4 inhibitor immediately if acute pancreatitis is suspected 2.

• Exclude other common causes: gallstones, alcohol use, hypertriglyceridemia (>1000 mg/dL), hypercalcemia, and recent procedures 5, 6.

• Monitor pancreatic enzymes and provide supportive care with bowel rest, IV fluids, and pain management 2, 6.

SGLT2 Inhibitors and Pancreatitis

Limited Evidence of Association

• SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) have minimal established association with pancreatitis, with only scattered case reports in the literature 5, 6.

• A 2024 FAERS database analysis found SGLT2 inhibitors accounted for only 14.7% of pancreatitis reports among diabetes medications, compared to 70.2% for GLP-1 agonists and 15% for DPP-4 inhibitors 3.

• The reporting odds ratio for SGLT2 inhibitors was not significantly elevated in disproportionality analyses, unlike DPP-4 inhibitors 3.

Case Report Evidence

• Isolated case reports describe pancreatitis occurring 2 weeks after empagliflozin initiation and shortly after dapagliflozin initiation, but causality remains uncertain 5, 6.

• In these cases, patients presented with severe abdominal pain, peripancreatic fat stranding on CT imaging, and resolution after drug discontinuation 5, 6.

Primary SGLT2 Inhibitor Risks (Not Pancreatitis)

• The FDA issued warnings about euglycemic diabetic ketoacidosis with SGLT2 inhibitors, presenting with dyspnea, nausea, vomiting, and abdominal pain—symptoms that can mimic pancreatitis 1, 7.

• Patients should stop SGLT2 inhibitors and seek immediate medical attention if ketoacidosis symptoms develop 1.

• Canagliflozin carries an FDA black box warning for lower limb amputation risk (6.3 vs 3.4 per 1,000 patient-years), particularly in patients with peripheral arterial disease or prior amputation 1, 7.

Clinical Decision Algorithm

When Pancreatitis Occurs on DPP-4 Inhibitor:

1. Discontinue the DPP-4 inhibitor permanently 2.
2. Rule out alternative causes with lipid panel, calcium level, alcohol history, and abdominal imaging 5, 6.
3. Switch to alternative diabetes therapy such as SGLT2 inhibitor, GLP-1 agonist (noting their own pancreatitis risk), or insulin 1.
4. Do not rechallenge with any DPP-4 inhibitor 2.

When Pancreatitis Occurs on SGLT2 Inhibitor:

1. First exclude euglycemic diabetic ketoacidosis by checking beta-hydroxybutyrate or urine ketones, as symptoms overlap significantly 1, 7.
2. Thoroughly investigate other pancreatitis causes before attributing to SGLT2 inhibitor, given weak association 5, 6.
3. If drug-induced pancreatitis is suspected after excluding other causes, discontinue SGLT2 inhibitor 5, 6.
4. Consider alternative agents including DPP-4 inhibitors (if no contraindication), GLP-1 agonists, or insulin 1.

Important Caveats

• GLP-1 receptor agonists have stronger pancreatitis signals than either SGLT2 or DPP-4 inhibitors, with liraglutide showing the highest association (ROR: 6.83) 3.

• Saxagliptin and alogliptin carry additional FDA warnings for heart failure risk, especially in patients with preexisting heart failure or renal impairment 1.

• The absolute risk of drug-induced pancreatitis remains low (<5% of all pancreatitis cases), but vigilance is warranted given the serious morbidity 3.

• Patients over 50 years old and females appear to have higher reporting rates of pancreatitis with these agents 3.