Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://www.cardiologyres.org

Review

Volume 12, Number 4, August 2021, pages 210-218

Update on the Cardiovascular Benefits of Sodium-Glucose Co-Transporter-2 Inhibitors: Mechanism of Action, Available Agents and Comprehensive Review of Literature

**Table 1.** A Summary for SGLT2 Inhibitors Clinical Trials Including the Studied Drug, Primary Outcome, NNT for the Primary Outcome, and the Reported Adverse Events in Each Trial
Trial name	SGLT2 inhibitor	Primary outcome measure	NNT for the primary outcome	Adverse events
SGLT2: sodium-glucose co-transporter-2; NNT: number needed to treat; MI: myocardial infarction; UTI: urinary tract infection; ESRD: end-stage renal disease; DKA: diabetic ketoacidosis; MACE: major adverse cardiovascular event; HF: heart failure; MRI: magnetic resonance imaging; NT-proBNP: N-terminal pro-B-type natriuretic peptide; KCCQ: Kansas City Cardiomyopathy Questionnaire; LVESV: left ventricular end-systolic volume.
1. EMPA-REG OUTCOME	Empagliflozin 10 and 25 mg	A composite of cardiovascular death, nonfatal MI (excluding silent MI), or nonfatal strokes	NNT = 63/3.1 years or NNT = 195/1 year	Genital infections, and urosepsis without an increase in the overall rate of UTI, complicated UTI or pyelonephritis)
2. CANVAS	Canagliflozin 100 and 300 mg	A composite cardiovascular deaths, nonfatal MI, or nonfatal strokes	NNT = 220/1 year	Genital infections, increased rate of amputation, and increased bone fracture (statistically insignificant)
3. CREDENCE	Canagliflozin 100 mg	A composite of ESRD, serum creatinine baseline doubling, or renal and cardiovascular deaths	NNT = 22/2.5 years	DKA
4. DECLARE-TIMI 58	Dapagliflozin 10 mg	MACE for safety; MACE and cardiovascular death or HF hospitalization for efficacy	Not superior for safety, however, NNT = 112/4.2 years or NNT = 470/1 year for efficacy	Genital infections and DKA
5. VERTIS-CV	Ertugliflozin 5 and 15 mg	MACE	N/A as there was no difference in risk reduction	Genital infections and UTI (statistically significant), with more DKA and amputation events in the ertugliflozin arms
6. EMPA-HEART	Empagliflozin 10 mg	The delta in left ventricular mass index as noted on cardiac MRI	N/A	N/A
7. DEFINE-HF	Dapagliflozin 10 mg	Difference in mean NT-proBNP; improvement of ≥ 5 points in the KCCQ or a ≥ 20% decrease in NT-proBNP	N/A	N/A
8. PRESERVED-HF	Dapagliflozin 10 mg	Symptomatic and physical limitations as measured by the KCCQ	N/A	N/A
9. DAPA-HF	Dapagliflozin 10 mg	Deaths from cardiovascular causes, HF hospitalization, or urgent HF visit	NNT = 20.4/18 months	No statistically significant difference in adverse events
10. EMPEROR-REDUCED	Empagliflozin 10 mg	Cardiovascular death or HF hospitalization	NNT = 19/1.3 years	Uncomplicated genital tract infection
11. EMPEROR-PRESERVED	Empagliflozin 10 mg	Time-to-first-event analysis of the combined risk for cardiovascular death and HF hospitalization	Study is not completed yet	Study is not completed yet
12. EMBRACE-HF	Empagliflozin 10 mg	The delta change in pulmonary artery pressure from baseline to end of treatment	N/A	N/A
13. REFORM	Dapagliflozin 10 mg	The difference in LVESV using cardiac MRI	N/A	Decline in renal function, which was transient and resolved after reduction of loop diuretic dose without dapagliflozin dose change
14. EMPA	Empagliflozin 10 mg	Determining if empagliflozin would improve the loop diuretic’s natriuretic effect	N/A	Not reported
15. SOLOIST-WHF	Sotagliflozin 400 mg titrated from 200 mg if no side effects	Cardiovascular death, HF hospitalizations, and urgent HF visits	NNT = 7/9 months	Diarrhea, genital fungal infections, and severe hypoglycemia

Table 1. A Summary for SGLT2 Inhibitors Clinical Trials Including the Studied Drug, Primary Outcome, NNT for the Primary Outcome, and the Reported Adverse Events in Each Trial

Trial name

SGLT2 inhibitor

Primary outcome measure

NNT for the primary outcome

Adverse events

SGLT2: sodium-glucose co-transporter-2; NNT: number needed to treat; MI: myocardial infarction; UTI: urinary tract infection; ESRD: end-stage renal disease; DKA: diabetic ketoacidosis; MACE: major adverse cardiovascular event; HF: heart failure; MRI: magnetic resonance imaging; NT-proBNP: N-terminal pro-B-type natriuretic peptide; KCCQ: Kansas City Cardiomyopathy Questionnaire; LVESV: left ventricular end-systolic volume.

1. EMPA-REG OUTCOME

Empagliflozin 10 and 25 mg

A composite of cardiovascular death, nonfatal MI (excluding silent MI), or nonfatal strokes

NNT = 63/3.1 years or NNT = 195/1 year

Genital infections, and urosepsis without an increase in the overall rate of UTI, complicated UTI or pyelonephritis)

2. CANVAS

Canagliflozin 100 and 300 mg

A composite cardiovascular deaths, nonfatal MI, or nonfatal strokes

NNT = 220/1 year

Genital infections, increased rate of amputation, and increased bone fracture (statistically insignificant)

3. CREDENCE

Canagliflozin 100 mg

A composite of ESRD, serum creatinine baseline doubling, or renal and cardiovascular deaths

NNT = 22/2.5 years

DKA

4. DECLARE-TIMI 58

Dapagliflozin 10 mg

MACE for safety; MACE and cardiovascular death or HF hospitalization for efficacy

Not superior for safety, however, NNT = 112/4.2 years or NNT = 470/1 year for efficacy

Genital infections and DKA

5. VERTIS-CV

Ertugliflozin 5 and 15 mg

MACE

N/A as there was no difference in risk reduction

Genital infections and UTI (statistically significant), with more DKA and amputation events in the ertugliflozin arms

6. EMPA-HEART

Empagliflozin 10 mg

The delta in left ventricular mass index as noted on cardiac MRI

N/A

7. DEFINE-HF

Dapagliflozin 10 mg

Difference in mean NT-proBNP; improvement of ≥ 5 points in the KCCQ or a ≥ 20% decrease in NT-proBNP

N/A

8. PRESERVED-HF

Dapagliflozin 10 mg

Symptomatic and physical limitations as measured by the KCCQ

N/A

9. DAPA-HF

Dapagliflozin 10 mg

Deaths from cardiovascular causes, HF hospitalization, or urgent HF visit

NNT = 20.4/18 months

No statistically significant difference in adverse events

10. EMPEROR-REDUCED

Empagliflozin 10 mg

Cardiovascular death or HF hospitalization

NNT = 19/1.3 years

Uncomplicated genital tract infection

11. EMPEROR-PRESERVED

Empagliflozin 10 mg

Time-to-first-event analysis of the combined risk for cardiovascular death and HF hospitalization

Study is not completed yet

12. EMBRACE-HF

Empagliflozin 10 mg

The delta change in pulmonary artery pressure from baseline to end of treatment

N/A

13. REFORM

Dapagliflozin 10 mg

The difference in LVESV using cardiac MRI

N/A

Decline in renal function, which was transient and resolved after reduction of loop diuretic dose without dapagliflozin dose change

14. EMPA

Empagliflozin 10 mg

Determining if empagliflozin would improve the loop diuretic’s natriuretic effect

N/A

Not reported

15. SOLOIST-WHF

Sotagliflozin 400 mg titrated from 200 mg if no side effects

Cardiovascular death, HF hospitalizations, and urgent HF visits

NNT = 7/9 months

Diarrhea, genital fungal infections, and severe hypoglycemia