1. GOING WITH THE ‘FLO’-ZINS:
TOP CONSIDERATIONS WITH SGLT2 INHIBITORS
By: Emily Cowley, PharmD ACPR | Saturday, April 22nd, 2023
Canadian Cardiovascular Pharmacists Network 26th Annual CCPN Contemporary Therapeutic Issues Conference

2. DISCLOSURES
Presenter Name: Emily Cowley
I have no current or past relationships with commercial entities
I have received honoraria in-kind from CCPN for this learning activity

3. LEARNING OBJECTIVES
1. Evaluate and identify patients who would benefit from
SGLT2i therapy in your hospital or outpatient practice
2. Implement safety and monitoring parameters associated
with SGLT2i therapy in patients
3. Describe the proposed mechanism of action and the
management SGLT2i-mediated euglycemic DKA
Image from: Medical Museion, University of Copenhagen

4. PATIENT CASE: MEET MRS. AS
77F presents to the ED with SOBOE and dizzy spells. She has known history of moderate aortic stenosis post-AVR(t)
PMHx & Medications:
Admitted for TAVI workup and management of heart failure -> undergoes uncomplicated TAVI several days later
TTE post-TAVI demonstrates a dilated LV with EF ~20%, normal prosthetic valve function
AVR(t) in 2014 ASA 81mg daily
HTN & HFrEF Irbesartan 37.5mg daily
Rheumatoid Arthritis Azathioprine 100mg dailyEtanercept 50mg
subcut once weekly
Dyslipidemia Rosuvastatin 10mg daily
Diabetes (A1C 7.1%) Metformin 1000mg BID
GERD Pantoprazole 40mg daily
Physical Exam JVP 3-4cm ASA, no edema
Vitals / Weight SBP: 90-108, DBP: 65-74, HR 92-102Wt:
60.8kg
Labs SCr: 50-60sBNP: 6254 ng/L
ECG Normal sinus rhythm
Echo Severe aortic stenosis, EF 21%, RV normal
CXR Possible signs of pulmonary edema

5. THE SGLT2I’S
Revolutionized the treatment of diabetes, heart failure and chronic kidney disease
Enhances excretion and blocks reabsorption of glucose in the proximal tubules
Demonstrated an impressive significant benefit to reduce morbidity and mortality
Hypotheses regarding role in acute decompensated HF (ADHF)
Image from: https://www.medscape.com/viewarticle/810787

6. YEAR OF THE SGLT2I
Can J Diabetes. 2020;44(7):575-591. Kidney Int. 2022;102(5):990-999. Can J Cardiol. 2021;37(4):531-546.

7. WHY THE RUSH?
Early optimization is safe and can improve outcomes
Significant benefit regardless of background therapy
Opportunity for close monitoring in-hospital
Lancet. 2022;400(10367):1938-52.
Image from: Dixit NM, et al. 2022; US Cardiology Review.
Image from: Vaduganathan M, et al. 2022; JAMA Cardiol.
JAMA Cardiol. 2022;7(12):1259-1263
JAMA Cardiol. 2021;6(5):499-507.

8. TRIAL OVERVIEW - EMPULSE
EMPULSE (n= 530)
P
Patients admitted to hospital with AHF with SBP > 100 mmHg, no recent IV
diuretics or inotropes and elevated cardiac enzymes
I Empagliflozin 10mg daily
C Placebo
O
Composite of death, # of HF events, time to first HF event and change in
KCCQ at 90 days
Regardless of
DM status or EF!
Nat Med. 2022;28:568-580.

9. EMPULSE TRIAL - RESULTS
Majority of patients NYHA II or III and
median LVEF: 31%
Randomized at a median of 3 days after
admission
Used a ‘win ratio’ to analyze composite
endpoints
No safety concerns identified
Image from: https://pro.boehringer-ingelheim.com/us/products/jardiance/in-hospital-initiation
Nat Med. 2022;28:568-580.

10. FUTURE DIRECTIONS
DICTATE AHF (n=240*)
P
>18 years old newly admitted for acute HF
with T2DM, planned IV loop diuretic therapy
and eGFR > 25mL/min
I
Dapagliflozin 10mg daily + Protocolized
diuretic therapy
C Protocolized diuretic therapy
O Cumulative change in weight (kg) by Day 5
DAPA-ACT HF-TIMI 68 (n=2400*)
P
>18 years old admitted with HF requiring
diuresis, with elevated cardiac enzymes
I Dapagliflozin 10mg daily
C Placebo
O CV death or worsening HF at 60 days
Regardless of
DM status or EF!
ClinicalTrials.gov Identifiers: NCT04363697, NCT04298229

11. BLOOD PRESSURE
Minimal effect on BP (SBP reduction: ~2-6 mmHg and DBP ~1-2mmHg)
Derived benefit regardless of baseline SBP
Hold if SBP < 90-95 or significant symptomatic hypotension
Image: Mazidi et al. 2017; J Am Heart Assoc.
Circulation. 2022;145:1581-91.
Circulation. 2021;143:1750-53.
J Am Heart Assoc. 2017;6(6):e004007.

12. FLUID BALANCE
Potential for intravascular volume depletion
Non-significant adverse outcome reported across landmark trials (5-8%)
Majority (~80-90%) on diuretics in HF trials vs. ~40% usage in non-HF trials
Similar loop diuretic use - potential for reductions
Consider 30-50% dose reduction in loop diuretics if volume deletion occurs
Image: Jackson et al. 2020; Circulation
Circulation. 2022;146(4):289-98.
Circulation. 2020;142(18):1713-24.
J. Heart Lung Transplant. 2022;41(4):S340.

13. KIDNEY FUNCTION
Initiation of an SGLT2i can acutely result in a ‘dip’ in eGFR within first weeks
Studies in CKD show ↓ in progression of ESRD, sustained decline in eGFR and/or death from renal cause
Reasonable to continue therapy until dialysis/renal transplant or sustained eGFR < 15 mL/min
Withholding SGLT2is and risk of AKI debated
Image: Bailey et al. 2022; Curr Diab Rep.
Kidney Int. 2022;102(5):990-999.
Diabetes. 2021;70(1):1-16.
ClinTrials.gov Identifier: NCT05468203
Curr Diab Rep. 2022;22(1):39-52.
Circulation. 2022;146:463-65.

14. BOTTOM LINE
AHA/ACC and CCS guidelines do not provide recommendations on use of SGLT2i in ADHF
Available studies on initiation of SGLT2is during ADHF are pending
Likely potential for safe initiation during hospital admissions including ADHF
Consider: BP, fluid balance and kidney function!
J Am Heart Assoc. 2017;6(6):e004007.
Can J Cardiol. 2021;37(4):531-546.
Circulation. 2022;145:e895-1032.

15. WHAT HAPPENED TO: MRS. AS
Initiated on dapagliflozin 10mg daily (2 days after TAVI)
Other HFrEF therapies: initiated on spironolactone 25mg daily, metoprolol 12.5mg BID
Up-titration limited by BP (SBP ~95-110)
Referral to Heart Function Clinic
Image from: https://roalddahl.fandom.com/wiki/Grandma_(George%E2%80%99s_Marvellous_Medicine)

16. EUGLYCEMIC
DIABETIC
KETOACIDOSIS

17. PATIENT CASE: MEET MR. BOH
67M with occasional dizziness and SOB worked up as outpatient and revealed to have critical AS. Now admitted to CVICU
following his AVR(t) and CABG x 1
PMHx: dyslipidemia, diabetes (A1C 6.5%), active smoker (0.5 pad x 30 yrs), COPD
Pre-op TTE: LVEF 59%, normal RV
Angiogram: 70% LAD lesion

18. POD#1 BLOOD GAS

19. HOME MEDICATION LIST

20. EUGLYCEMIC DIABETIC KETOACIDOSIS
Clinical syndrome in T1DM or T2DM characterized by:
Euglycemia (<14 mmol/L)
Metabolic acidosis (pH < 7.3, serum bicarbonate < 18 mEq/L)
Presence of ketones in blood/urine
Signs & symptoms include: N/V, fatigue, SOB, hemodynamic instability
Beta-hydroxybutyrate typically > 3 mmol/L (normal: <0.5 mmol/L)
Image from: https://www.renalfellow.org/2020/09/08/sglt2-inhibitor-induced-euglycemic-diabetic-ketoacidosis/
Clin Ther. 2016;38(12):2654-64.
Diabetes Care. 2015;38(9):1638-42.

21. INCIDENCE
Incidence reported as 0.1% in T2DM, up to 5-12% in T1DM
Likely under-reported or misdiagnosed
Risk increases with infection, low carb diets, alcohol use, NPO, acute illness
Clin Ther. 2016;38(12):2654-64.
Diabetes Care. 2015;38(9):1680-86.

23. TREATMENT
Continuous insulin infusion to stop ketone production (= correct the metabolic acidosis)
D5W required to avoid hypoglycemia, can switch to D10W
Only stop insulin/dextrose once AG closes, bicarbonate and pH (pH >7.3) normalizes
Replace K and correct fluid deficit as needed
Repeat BOH and/or urine ketones may help guide treatment
Half-lives:
Dapagliflozin: 13h
Empagliflozin: 12.5h
Canagliflozin: 10-13h
Diabetes Care. 2015;38(9):1638-42.
Br Med J. 1973;2(5866):578-80.

24. WHAT HAPPENED TO: MR. BOH
BOH comes back at 3.9 mmol/L !!
Insulin 1 unit/hour initiated along with D10W if needed
24h after initiating insulin infusion -> eating well and transitioned to BBIT on ward transfer
Discharged home with medication teaching

25. A PERI-OPERATIVE APPROACH
Pre-operative Phase:
• PAC patient teaching
• Review BPMH
• Instructions to hold at least 3 days prior to surgery
Post-operative Phase:
• Recognize at risk patients of euDKA
• Monitor for signs/sx
• Prompt initiation of insulin +/- dextrose
Discharge Home:
• Sick Day Management Teaching
• When / if it is safe to restart SGLT2i

26. A REMINDER
TO STAFF
Image: AHS memo, internal data ONLY

27. REFERENCES
1. Lipscombe L, et al. Pharmacologic Glycemic Management of Type 2 Diabetes in Adults: 2020 Update. 2020; 44(7):575-591.
2. Rossing P, et al. Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly
emerging new evidence. Kidney Int. 2022;102(5):990-999.
3. McDonald M, et al. CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction. Can J
Cardiol. 2021;37(4):531-46.
4. Mebazaa A, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-
label, randomised, trial. Lancet. 2022;400(10367):1938-52.
5. Berg DD, et al. Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection
Fraction. JAMA Cardiol. 2021;6(5):499-507.
6. Vaduganathan M, et al. Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified
Secondary Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. 2022;7(12):1259-1263.
7. Voors AA, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-74.
8. Cox ZL. Efficacy and Safety of Dapagliflozin in Acute Heart Failure (DICTATE-AHF) [unpublished]. Vanderbilt University Medical Center.

28. REFERENCES
9. The TIMI Study Group. Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure -Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68) [unpublished].
10. Furtado RHM, et al. Efficacy and Safety of Dapagliflozin in Type 2 Diabetes According to Baseline Blood Pressure: Observations From DECLARE-TIMI 58 Trial. Circulation.
2022;145:1581-91.
11. Kario et al. Are SGLT2 Inhibitors New Hypertension Drugs?. Circulation. 2021;143:1750-53.
12. Mazidi M. Effect of Sodium-Glucose Cotransport-2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of 43 Randomized
Control Trials With 22 528 Patients. J Am Heart Assoc. 2017;6(6):e004007.
13. Wildemann R, et al. Change in Diuretic Dose After Initiation of a SGLT2 Inhibitor in Patients with Heart Failure with Reduced Ejection Fraction. J. Heart Lung Transplant.
2022;41(4):S340.
14. Mordi NA, et al. Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure. Circulation.
2020;142(8):1713-24.
15. Schulze PC, et al. Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF). Circulation.
2022;146(4):289-98.
16. Umanath K, et al. “Dip” in eGFR: Stay the Course With SGLT-2 Inhibition. Circulation. 2022;146:463-65.
17. Bailey CJ, et al. Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease. Curr Diab Rep. 2022;22(1):39-52.

29. REFERENCES
18. Tuttle KR, et al. SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.
Diabetes. 2021;70(1):1-16.
19. Gallagher MP. PREVENTion With Sglt-2 Inhibition of Acute Kidney Injury in Intensive Care (PREVENTS-AKI) [unpublished]. The George Institute.
20. Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association
Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e895-1032.
21. Rosenstock J, et al. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015;38(9):1638-42.
22. Goldenberg RM, et al. SGLT2 Inhibitor-associated Diabetic Ketoacidosis: Clinical Review and Recommendations for Prevention and Diagnosis. Clin Ther. 2016;38(12):2654-64.
23. Erondu N, et al. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care. 2015;38(9):1680-86.
24. FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. 2018. Available from: https://www.fda.gov/drugs/postmarket-
drug-safety-information-patients-and-providers/sodium-glucose-cotransporter-2-sglt2-inhibitors.
25. Munro JF, et al. Euglycaemic Diabetic Ketoacidosis. Br Med J. 1973;2(5866):578-580.

30. THANK YOU!
emily.cowley@albertahealthservices.ca

31. SUPPLEMENTAL MATERIAL

32. TRIALS ACROSS THE SPECTRUM
https://www.sciencedirect.com/science/article/abs/pii/S0002870320303574

33. PRACTICAL APPROACH TO SGLT2I

34. SGLT2I COVERAGE
R= restricted
R
L= listed
L
R
*Empa
only
R
EDS
SA
Form
R
EDS
R
R
R
R
R
L
L
*NIHB
*NIHB
Derived from: https://www.diabetes.ca/DiabetesCanadaWebsite/media/Advocacy-and-Policy/Provincial%20and%20Territorial%20Formulary%20Chart/PT-formulary-listings_July-2021.pdf