SUMMARY

• The INVOKANA Prescribing Information,¹ United States (US) and international health authorities,^2-4 and the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE)⁵ have identified history of pancreatitis as one of several factors predisposing to sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated ketoacidosis.
• One patient with a subcutaneous abscess and chronic pancreatitis and a ketoacidosis event was discussed in a pooled analysis of clinical trial safety data conducted by Erondu et al (2015).⁶
• Ueda et al (2018)⁷ conducted a register-based cohort study in Sweden and Denmark. Results showed that new users of SGLT2i had an increased risk of acute pancreatitis compared to new users of glucagon-like peptide 1 receptor agonists (GLP-1 Ras) (hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.64-2.12).
• Frent et al (2021)⁸ conducted an observational retrospective study to characterize the acute pancreatitis reactions related to gliflozins in the World Health Organization (WHO) global database of individual case reports (ICSRs). INVOKANA was the SGLT2i that was most frequently involved in the cases (n=369, 59.7%).
• Zhang et al (2022)⁹ conducted a disproportionality analysis to characterize reports of acute pancreatitis related to SGLT2i, including INVOKANA, using the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2013 to the fourth quarter of 2021. INVOKANA had the strongest potential association with acute pancreatitis with information component (IC) of 2.41 (lower limit of the 95% CI of the IC [IC₀₂₅], 2.16), reporting odds ratio (ROR) of 5.37 (95% CI, 4.8-5.99), and empirical Bayesian geometric mean (EBGM) of 5.32 (lower limit of 90% CI of the EBGM [EBGM₀₅], 4.85).
• Patients with diabetes secondary to pancreatitis or pancreatectomy were excluded from phase 3 and phase 4 INVOKANA clinical studies.^10-23

PANCREATITIS AND SGLT2 INHIBITOR-ASSOCIATED KETOACIDOSIS

Reports of ketoacidosis have been identified in patients receiving SGLT2i, including INVOKANA. In some, but not all cases, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes [T1DM], history of pancreatitis, or pancreatic surgery) were identified as factors predisposing to ketoacidosis.¹

Advise patients to inform their healthcare professional if there are or have been problems with the pancreas, including pancreatitis or surgery on the pancreas.

Before initiating INVOKANA, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause. Consider monitoring for ketoacidosis and temporarily discontinuing in clinical situations known to predispose to ketoacidosis. For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKANA for at least 3 days prior to surgery. Ensure risk factors for ketoacidosis are resolved prior to restarting INVOKANA.¹

US and International Health Authorities

Pancreatic disorders suggesting insulin deficiency (e.g., T1DM, history of pancreatitis, or pancreatic surgery) were identified as factors that may predispose to ketoacidosis in an FDA Drug Safety Communication² and in a Health Canada Dear Healthcare Professional letter³.

European Medicines Agency cautions that patients with a history of pancreatitis may have low beta-cell function reserve, a known factor associated with diabetic ketoacidosis (DKA).⁴

Professional Organization

An AACE/ACE Position Statement on the Association of SGLT2 Inhibitors and Diabetic Ketoacidosis lists pancreatitis as one of several external factors that can precipitate ketoacidosis.⁵

CLINICAL DATA

Erondu et al (2015)⁶ performed a pooled analysis of safety data from 15 randomized controlled trials. Data from 17,596 patients were compiled to identify and assess serious adverse events (AEs) of DKA, ketoacidosis, metabolic acidosis, and acidosis with INVOKANA use. All trials excluded patients with a history of T1DM and/or DKA. Through May 11, 2015, there were 12 patients with 13 unblinded serious AEs of DKA, ketoacidosis, metabolic acidosis, and acidosis. Of the 12 patients with a DKA-related event, 10 were on INVOKANA therapy.

Among the 10 patients on INVOKANA therapy with a DKA-related event, 1 patient had a subcutaneous abscess and chronic pancreatitis. No history of pancreatic disorders was noted in the 2 non-INVOKANA patients.⁶

REAL WORLD EVIDENCE

Ueda et al (2018)⁷ conducted a register-based cohort study in Sweden and Denmark, utilizing a non-parsimonious propensity score model, which evaluated the association between new-users of SGLT2i or GLP-1 Ras use and AEs of concern, including acute pancreatitis. An additional analysis was conducted that excluded users of dipeptidyl peptidase 4 (DPP4) inhibitors.

• After propensity score matching, 34,426 patients (17,213 in each cohort) were included in the study. Of the SGLT2i, 1% used INVOKANA, 61% used dapagliflozin, and 38% used empagliflozin.
• New users of SGLT2i had an increased risk of acute pancreatitis compared to new users of GLP-1 Ras (HR, 1.16; 95% CI, 0.64-2.12). HR were not affected by exclusion of DPP4 users.

Frent et al (2021)⁸ conducted an observational retrospective study to characterize the acute pancreatitis reactions related to gliflozins reported in the VigiBase, the WHO global database of ICSRs. All pancreatitis reactions with INVOKANA, dapagliflozin, and empagliflozin as suspected or interacting drugs up until July 1, 2019, were analyzed.

• A total of 600 reports of 618 acute pancreatitis group (APG) reactions were included. INVOKANA was the SGLT2i that was most frequently involved in the cases (n=369, 59.7%), followed by empagliflozin (n=130, 21.0%), and dapagliflozin (n=119, 19.2%).
• Ketoacidosis was frequently associated with acute pancreatitis (21.3%), followed by renal injury (13.3%).
• In a disproportionality analysis, the proportional reporting ratio (PRR) for association of an APG reaction was 5.62 for INVOKANA, 3.67 for empagliflozin, and 3.16 for dapagliflozin. A positive association between INVOKANA use and pancreatitis, pancreatitis acute, and pancreatitis necrotizing was found.

Zhang et al (2022)⁹ conducted a disproportionality analysis to characterize reports of acute pancreatitis as AE related to SGLT2i (INVOKANA, dapagliflozin, empagliflozin, ertugliflozin) using the FAERS database from the first quarter of 2013 to the fourth quarter of 2021.

• Of a total of 76,872 reports of acute pancreatitis-related AEs, 757 were associated with SGLT2i. Most cases of acute pancreatitis were related to INVOKANA (n=317), followed by empagliflozin (n=287), dapagliflozin (n=150), and ertugliflozin (n=3).
• Overall, SGLT2i use was significantly associated with acute pancreatitis, with IC of 2.31 (IC₀₂₅, 2.15), ROR of 5.03 (95% CI, 4.68-5.41), and EBGM of 4.97 (EBGM₀₅, 4.68). Among SGLT2i, INVOKANA had the strongest potential association with acute pancreatitis with IC of 2.41 (IC₀₂₅, 2.16), ROR of 5.37 (95% CI, 4.8-5.99), and EBGM of 5.32 (EBGM₀₅, 4.85).
• The IC, ROR, and EBGM, respectively, for association of acute pancreatitis was 2.26 (IC₀₂₅, 1.92), 4.8 (95% CI, 4.09-5.64), and 4.77 (EBGM₀₅, 4.17) for dapagliflozin, 2.25 (IC₀₂₅, 2), 4.78 (95% CI, 4.25-5.37), and 4.74 (EBGM₀₅, 4.31) for empagliflozin, and 1.83 (IC₀₂₅, 0.59), 3.58 (95% CI, 1.15-11.12), and 3.57 (EBGM₀₅, 1.38) for ertugliflozin.

USE IN DIABETES SECONDARY TO PANCREATITIS OR PANCREATECTOMY

• Patients with diabetes secondary to pancreatitis or pancreatectomy were excluded from phase 3 and phase 4 INVOKANA clinical studies.^10-23

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 December 2024.