SGLT2 Inhibitors: �The Good, The Bad, The Ugly

Robby Duke, PharmD

Surgery Pharmacist, Northside Hospital Atlanta

June 12, 2023

RJD

Financial Disclosure Statement

I have nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation. Brand names of all products in the presentation may be included for identification purposes only.

RJD

Learning Objectives

At the end of this presentation, participants should be better able to:

• Define the mechanism of action of sodium-glucose cotransporter 2 (SGLT2) inhibitors
• Identify the indications for SGLT2 inhibitors
• Understand potential side effects/adverse events associated with SGLT2 inhibitors
• Demonstrate an understanding of when and why SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) agonists should be held pre-operatively

​

RJD

Question 1

SGLT2 inhibitors work primarily in kidney.

A. True

B. False

​

RJD

Question 2

Which of the following is/are not an FDA approved indication(s) for SGLT2 inhibitors?

A. Diabetes mellitus, Type 1 (T1DM)

B. Heart failure w/ reduced ejection fraction (HFrEF)

C. Chronic kidney disease (CKD)

D. All of the above

E. None of the above

​

RJD

Question 3

Common side effects of SGLT2 inhibitors include which of the following:

A. Hyperglycemia

B. Fournier’s gangrene

C. Urinary tract infections

D. A and C only

E. None of the above

RJD

Question 4

SGLT2 inhibitors should be held pre-operatively a minimum of how many days?

A. 1-2

B. 3-4

C. 6-7

D. No requirement to be held pre-operatively

​

RJD

Question 5

GLP-1 agonists should be discontinued 2 weeks prior to any surgical procedure – regardless of their indication.

1. True
2. False

RJD

RJD

What are SGLT2 Inhibitors?�

• “…a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes.”
• Additional indications include:
• Heart failure with reduced ejection fraction (HFrEF)*
• Chronic kidney disease (CKD)*

​

*Not all SGLT2 inhibitors carry these additional indications

​

• Can be recognized by their ending “-flozin” or “-gliflozin”

​

​

Center for Drug Evaluation and Research. “Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors.” U.S. Food and Drug Administration, 20 Aug. 2018, www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/sodium-glucose-cotransporter-2-sglt2-inhibitors#:~:text=SGLT2%20inhibitors%20are%20a%20class,canagliflozin%2C%20dapagliflozin%2C%20and%20empagliflozin (Accessed 4/28/2023)

RJD

Product Names�

Lexi-Drugs/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Lexicomp app. UpToDate Inc. Version 7.7.2

RJD

Sotagliflozin

Zoler, PhD, Mitchel L. “FDA Approves New Drug, Sotagliflozin, for Heart Failure.” Medscape, 26 May 2023, www.medscape.com/viewarticle/992518#:~:text=Sotagliflozin%2C%20a%20novel%20agent%20that,failure%20visits%20in%20patients%20with.

​

RJD

Combination Product Names

Lexi-Drugs/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Lexicomp app. UpToDate Inc. Version 7.7.2

RJD

Role in Type 2 Diabetes Mellitus (T2DM)

• Most commonly used as an adjunctive therapy
• Can be used as a monotherapy
• Considerations for use include A1C, comorbidities, and cost

​

​

​

UpToDate. Uptodate.com. Accessed June 7, 2023. https://www.uptodate.com/contents/initial-management-of-hyperglycemia-in-adults-with-type-2-diabetes-mellitus

RJD

Pharmacokinetics

• Primarily metabolized hepatically
• Renal and/or hepatic impairment can affect dosing*
• Contraindicated in hemodialysis patients

​

Lexi-Drugs/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Lexicomp app. UpToDate Inc. Version 7.7.2

Inpefa. Package insert. Lexicon; 2023.

RJD

Mechanism of Action (MOA)

Lexi-Drugs/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Lexicomp app. UpToDate Inc. Version 7.7.2

RJD

MOA in T2DM

Hinnen D. Glucuretic effects and renal safety of dapagliflozin in patients with type 2 diabetes. Figure 1. Mechanism of action of SGLT2 inhibitors. Therapeutic Advances in Endocrinology and Metabolism. 2015;6(3):92-102. doi:10.1177/2042018815575273

​

RJD

MOA in T2DM

Hinnen D. Glucuretic effects and renal safety of dapagliflozin in patients with type 2 diabetes. Figure 1. Mechanism of action of SGLT2 inhibitors. Therapeutic Advances in Endocrinology and Metabolism. 2015;6(3):92-102. doi:10.1177/2042018815575273

​

RJD

MOA in HF and CKD

?

Diuretic effect

↓ Preload

↓ Afterload

Left ventricular remodeling

↓ Inflammation

↓ Oxidative stress

Osmotic diuresis

Tubuloglomerular feedback

↓ Inflammatory markers

↑ Oxygen availability

Pabel S, Hamdani N, Luedde M, Sossalla S. SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled? Current Heart Failure Reports. 2021;18(5):315-328. doi:https://doi.org/10.1007/s11897-021-00529-8

​

Bailey CJ, Day C, Bellary S. Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease. Current Diabetes Reports. Published online February 3, 2022. doi:https://doi.org/10.1007/s11892-021-01442-z

​

​

RJD

RJD

Side Effects/Adverse Events

• Urinary tract infections
• Increased urine output
• Genitourinary fungal infections
• Nasopharyngitis
• Hypovolemia

Lexi-Drugs/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Lexicomp app. UpToDate Inc. Version 7.7.2

Mascolo A, Di Napoli R, Balzano N, et al. Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary. Frontiers in Cardiovascular Medicine. 2022;9. doi:https://doi.org/10.3389/fcvm.2022.1010693

​

RJD

RJD

Rare Adverse Events

• Fournier’s Gangrene
• Lower limb amputation
• Bone fractures
• Diabetic ketoacidosis
• Euglycemic diabetic ketoacidosis

​

Mascolo A, Di Napoli R, Balzano N, et al. Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary. Frontiers in Cardiovascular Medicine. 2022;9. doi:https://doi.org/10.3389/fcvm.2022.1010693

​

Sodium-Glucose Cotransporter 2 Inhibitors: An Overview. Medscape. https://www.medscape.com/viewarticle/892957_6

​

Samuel, PharmD, BCPS, Essie, and Jiehyun Lee, PharmD, BCACP, CACP. “Sodium-Glucose Cotransporter 2 Inhibitors: An Overview.” Medscape, 21 Mar. 2018, www.medscape.com/viewarticle/892957_9.

​

​

RJD

Euglycemic DKA (EDKA)

“Simply put, EDKA is DKA in which normal glucose concentrations are present.”

Rawla, Prashanth, et al. “Euglycemic Diabetic Ketoacidosis: A Diagnostic and Therapeutic Dilemma.” EDM Case Reports, 4 Sept. 2017, edm.bioscientifica.com/view/journals/edm/2017/1/EDM17-0081.xml.

​

Daniya S. Mathew, PharmD Candidate 2022 St. John’s University College of Pharmacy and Health Sciences Queens, et al. “Management of Euglycemic Diabetic Ketoacidosis.” U.S. Pharmacist – The Leading Journal in Pharmacy, 19 Nov. 2021, www.uspharmacist.com/article/management-of-euglycemic-diabetic-ketoacidosis.

​

RJD

Euglycemic DKA (EDKA)

Rawla, Prashanth, et al. “Euglycemic Diabetic Ketoacidosis: A Diagnostic and Therapeutic Dilemma.” EDM Case Reports, 4 Sept. 2017, edm.bioscientifica.com/view/journals/edm/2017/1/EDM17-0081.xml.

​

Daniya S. Mathew, PharmD Candidate 2022 St. John’s University College of Pharmacy and Health Sciences Queens, et al. “Management of Euglycemic Diabetic Ketoacidosis.” U.S. Pharmacist – The Leading Journal in Pharmacy, 19 Nov. 2021, www.uspharmacist.com/article/management-of-euglycemic-diabetic-ketoacidosis.

​

Lexi-Drugs/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Lexicomp app. UpToDate Inc. Version 7.7.2

​

RJD

When/Why Held Preoperatively

Lucidoc > Search “anesthesia medication” > Anesthesia Medication Instructions for Day of Surgery

RJD

When/Why Held Preoperatively

% of drug

Lexi-Drugs/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor. Lexicomp app. UpToDate Inc. Version 7.7.2

Inpefa. Package insert. Lexicon; 2023.

RJD

Algorithm Example

Peri-procedure management of patients on sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Mdanderson.org. Accessed June 8, 2023. https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clin-management-mgmt-sglt2-web-algorithm.pdf

RJD

Unique Patient Case�

Presentation

• 53 y/o M
• Discharged 2 days s/p laprascopic appendectomy w/o complications
• SGLT2 inhibitor stopped 24 hrs preoperatively
• Returned to ER 2 hours after discharge
• CC: Generalized abdominal pain, SOB (non-exertional), fever

​

PMH

• T2DM
• Hypertension
• Hyperlipidemia

​

Medication History

• Metformin
• Canagliflozin

​

Aggarwal A, Jain A, Sachdeva S, Kulairi ZI. Prolonged Glucosuria With Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Case Report and Review of Literature. Cureus. Published online November 18, 2020. doi:https://doi.org/10.7759/cureus.11554

RJD

Unique Patient Case�

Labs

• Most WNL
• BG, Na, K, Cl, HCO3, BUN, SCr, Serum lactate
• Anion gap 20.8 mEq/L (3-11 mEq/L)
• Ph 7.21 (7.35-7.45)
• Serum ketones (+)
• Beta-hydroxybutyrate 2.69 mmol/L (<0.5mmol/L)
• Urinalysis
• Urine glucose >1500mg/dL (<100mg/dL)
• Ketonuria
• Infectious growth (-)

​

​

Vitals

• HR 114pm
• RR 30/min
• Temp 38.17°C
• SpO2 Sat 87%

​

Physical Exam

• Unremarkable

​

Aggarwal A, Jain A, Sachdeva S, Kulairi ZI. Prolonged Glucosuria With Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Case Report and Review of Literature. Cureus. Published online November 18, 2020. doi:https://doi.org/10.7759/cureus.11554

RJD

Unique Patient Case�

• Pt had restarted his normal diet and canaglifozin
• Subsequently diagnosed with EDKA and readmitted to ICU
• Canagliflozin D/C’d
• Treatment initiated
• Insulin drip w/ 10% dextrose
• Day 2: Symptomatic and lab improvement
• Anion gap 16.2 mEq/L
• Day 3: Drip changed to SQ insulin and SSI
• Anion gap 13.2 mEq/L and beta-hydroxybutyrate 0.81 mmol/L
• Transferred to floor
• Glucosuria still present (>1500mg/dL)

​

​

​

WHY?

Aggarwal A, Jain A, Sachdeva S, Kulairi ZI. Prolonged Glucosuria With Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Case Report and Review of Literature. Cureus. Published online November 18, 2020. doi:https://doi.org/10.7759/cureus.11554

RJD

Potential Mechanisms for Prolonged Glucosuria

​

• Potential plasma accumulation
• Remains plasma bound in an acidic environment; becomes unbound during acidotic resolution
• Slow off-rate = accumulation in proximal tubule despite low plasma levels of drug
• Polymorphisms in hepatic enzyme responsible for metabolism – uridine disphosphate glycosyltransferase (UGT1A9)

​

WHY IS THIS IMPORTANT?

Aggarwal A, Jain A, Sachdeva S, Kulairi ZI. Prolonged Glucosuria With Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Case Report and Review of Literature. Cureus. Published online November 18, 2020. doi:https://doi.org/10.7759/cureus.11554

RJD

GLP-1 Agonists

• Non-insulin injectable medications*
• Approved indications include T2DM and weight loss**
• Similar role as SGLT2 inhibitors
• Have ending of -glutide or –enatide
• Common side effects include: nausea, vomiting, diarrhea

*One oral formulation available

**Not all GLP-1 agonists carry weight loss indication

Lexi-Drugs/Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist. Lexicomp app. UpToDate Inc. Version 7.7.2

RJD

GLP-1 Agonists

*GLP-1 Agonist and Glucose-Dependent Insulinotropic Polypeptide (GIP)

Lexi-Drugs/Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist. Lexicomp app. UpToDate Inc. Version 7.7.2

Lexi-Drugs/Glucose-Dependent Insulinotropic Polypeptide (GIP)/Glucagon-Like Peptide (GLP-1) Receptor Agonist. Lexicomp app. UpToDate Inc. Version 7.7.2

RJD

GLP-1 Agonists MOA

Hinnen D. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes. Figure 1. Diabetes Spectrum. 2017;30(3):202-210. doi:https://doi.org/10.2337/ds16-0026

RJD

When/Why Held Preoperatively

Lucidoc > Search “anesthesia medication” > Anesthesia Medication Instructions for Day of Surgery

RJD

Additional Information

O’Mary L. FDA warns people to avoid compounded semaglutide medicines. Medscape. Published June 1, 2023. Accessed June 7, 2023. https://www.medscape.com/viewarticle/992632?ecd=WNL_trdalrt_pos1_230604&impID=5495439

RJD

Question 1

SGLT2 inhibitors work primarily in kidney.

A. True

B. False

​

RJD

Question 2

Which of the following is/are not an FDA approved indication(s) for SGLT2 inhibitors?

A. Diabetes mellitus, Type 1 (T1DM)

B. Heart failure w/ reduced ejection fraction (HFrEF)

C. Chronic kidney disease (CKD)

D. All of the above

E. None of the above

​

RJD

Question 3

Common side effects of SGLT2 inhibitors include which of the following:

A. Hyperglycemia

B. Fournier’s gangrene

C. Urinary tract infections

D. A and C only

E. None of the above

RJD

Question 4

SGLT2 inhibitors should be held pre-operatively a minimum of how many days?

A. 1-2

B. 3-4

C. 6-7

D. No requirement to be held pre-operatively

​

RJD

Question 5

GLP-1 agonists should be discontinued 2 weeks prior to any surgical procedure – regardless of their indication.

1. True

B. False

RJD

Key Take Aways

• SGLT2 inhibitors have multiple indications
• Important to recognize risk of EDKA associated with SGLT2 inhibitors and how to properly mitigate
• Use of GLP-1 agonists for weight loss is occurring more frequently
• Vital to obtain history of GLP-1 agonist use and source to appropriately manage preoperatively

​

​

RJD

SGLT2 Inhibitors: �The Good, The Bad, The Ugly

Robby Duke, PharmD

Surgery Pharmacist, Northside Hospital Atlanta

robby.duke@northside.com

June 12, 2023

RJD