SGLT2 Inhibitors in Patients with Chronic Kidney Disease and Heart Disease: A Literature Review

Abhishek Kansara; Faiza Mubeen; Jawairia Shakil

doi:10.14797/mdcvj.1120

SGLT2 Inhibitors in Patients with Chronic Kidney Disease and Heart Disease: A Literature Review

Methodist DeBakey Cardiovascular Journal

Volume 18 (2022): Issue 4

By: Abhishek Kansara , Faiza Mubeen and Jawairia Shakil

Open Access

|Sep 2022

Figures & Tables

Table 1

SGLT2i approved by the United States Food and Drug Administration. CV: cardiovascular; DKA: diabetic ketoacidosis; eGFR: estimated glomerular filtration rate; NYHA: New York Heart Association; CKD: chronic kidney disease.

SGLT2i	TRADE NAME	FDA APPROVAL	LIMITATIONS OF USE
Canagliflozin Initial US approval: 2013	Invokana	As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease	Not for treatment of type1 diabetes mellitus or DKA
Dapagliflozin Initial US approval: 2014	Farxiga	To reduce the risk of sustained eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple CV risk factors As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus	Not for treatment of type 1 diabetes mellitus; may increase the risk of DKA Not for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m² Not for the treatment of CKD with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease
Empagliflozin Initial US approval: 2014	Jardiance	To reduce the risk of cardiovascular death and hospitalizationfor heart failure in adults with heart failure To reducethe risk of cardiovascular death in adults with type 2diabetes mellitus and established cardiovascular disease As an adjunct todiet and exercise to improve glycemic control in adults withtype 2 diabetes mellitus	Not for treatment of type 1diabetes mellitus; may increase the risk of DKA
Ertugliflozin Initial US approval: 2017	Steglatro	As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus	Not for treatment of type 1diabetes mellitus; may increase the risk of DKA

Table 2

Summary of renal outcomes trials of SGLT2 inhibitors. CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; RRR: relative risk reduction.

TRIAL	DRUG	NO. OF PARTICIPANTS	PERCENTAGE OF PARTICIPANTS WITH CKD, eGFR <60 ml/min/1.73m²	PRIMARY OUTCOME^#	PROGRESSION OF ALBUMINURIA	COMPOSITE OF 40% REDUCTION IN eGFR, RENAL REPLACEMENT THERAPY OR RENAL DEATH	DOUBLING OF SERUM CREATININE	ESRD: eGFR <15, CHRONIC DIALYSIS, KIDNEY TRANSPLANTATION	DECLINE IN eGFR OF ≥50%	ABSOLUTE DIFFERENCE IN eGFR, (STUDY DRUG-PLACEBO, ml/min/1.73m²)	INCIDENT OR WORSENING NEPHROPATHY
EMPA-REG OUTCOME 06/2016	Empagliflozin	7,020	25.9	Table 3	38% RRR		44% RRR	46% RRR			39% RRR
CANVAS 06/2017	Canagliflozin	10,142	20.1	Table 3	27% RRR	40% RRR
CREDENCE 04/2019	Canagliflozin	4,401	59.9	30% RRR			40% RRR	32% RRR
EMPEROR-REDUCED 08/2020	Empagliflozin	3,730	48.2	Table 4		50% RRR				1.73 (1.1–2.37)
VERTIS-CV 09/2020	Ertugliflozin	8,246	21.9	Table 3	21% RRR	34% RRR	NS			2.55 (1.5–3.61)
DAPA-CKD 09/2020	Dapagliflozin	4,304	89.5	39% RRR				36% RRR	47% RRR
SCORED 11/2020	Sotagliflozin	10,584	100	Table 3				NS*

[i] ^# Primary outcomes varied between different studies. CREDENCE: Composite of end-stage kidney disease (dialysis, transplantation, eGFR < 15 ml/min/1.73m²), doubling of serum creatinine or death from renal or cardiovascular causes); DAPA-CKD: composite of first occurrence of any of decline of at least 50% in eGFR, onset of end-stage kidney disease (dialysis, kidney transplantation or eGFR < 15 ml/min/1.73m²), or death from renal or cardiovascular causes.

^* NS not significant for first occurrence of a sustained decrease of ≥50% in eGFR from baseline for ≥30 days, long-term dialysis, renal transplantation, or sustained eGFR of ≤15 ml/min/1.73m² for ≥30 days.

Table 3

Summary of cardiovascular outcome trials of SGLT2i.

TRIAL	Drug	NO. OF PARTICI-PANTS	MEDIAN FOLLOW-UP, YEARS	MALE GENDER STUDY POPULATION, %, STUDY ARM/PLACEBO ARM	PRE-EXISTING CVD, %	PREEXISTING HEART FAILURE,%	CKD WITH eGFR <60 ml/min/1.73m², %	PRIMARY OUTCOME^	HOSPITALIZATION FOR HEART FAILURE	DEATH FROM CV CAUSES	DEATH FROM ANY CAUSE
EMPA-REG, 2015	Empagliflozin	7020	3.1	71.2/72	>99	10.1	25.9	14% RRR	35% RRR	38% RRR	32% RRR
CANVAS, 2017	Canagliflozin	10,142	126.1 weeks	64.9/63.3	65.5	14.4	20.1	14% RRR	33% RRR	NS	NS
DECLARE-TIMI 58, 2018	Dapagliflozin	17,160	4.2	63.1/62.1	40.6	10.0	7	NS*	27% RRR	NS	NS
VERTIS-CV, 2020	Ertugliflozin	8,246	3.0	70.3/69.3	100	23.7	21.9	NS*	30% RRR	NS	NS
SCORED, 2020	Sotagliflozin	10,584	16 months	55.7/54.5	At least 22%	31%	100	26% RRR	33% RRR	NS	NS

[i] ^ Primary outcome = death from cardiovascular causes, nonfatal MI, or nonfatal stroke; RRR: relative risk reduction; NS: not significant, * significant for noninferiority.

Table 4

Summary of heart failure outcomes trials of SGLT2i. CVD: cardiovascular disease; CKD: chronic kidney disease; eGFR: estimate glomerular filtration rate; RRR: relative risk reduction; NS: not significant.

TRIAL	DRUG	NO. OF PARTICIPANTS	MEDIAN FOLLOW-UP	MALE GENDER STUDY POPULATION, %, STUDY ARM/PLACEBO ARM	PREEXIST-ING CVD, %	PREEXISTING HEART FAILURE, %	CKD WITH eGFR <60 ml/min/1.73 m², %	PRIMARY OUTCOME^^	HOSPITALIZATION FOR HEART FAILURE	DEATH FROM CV CAUSES	DEATH FROM ANY CAUSE
DAPA-HF, 2019	Dapagliflozin	4,744	18.2 months	76.2/77	56.4^#	100	40.6	26% RRR	30% RRR	18% RRR	17%
EMPEROR-Reduced, 2020	Empagliflozin	3,730	16 months	76.5/75.6	51.8^#	100	48.2	25% RRR	31% RRR	NS	NS
EMPEROR-Preserved, 2021	Empagliflozin	5,988	26.2 months	55.4/55.3	35.4^#	100	49.9	21% RRR	29% RRR	NS	NS
SOLOIST-WHF, 2020	Sotagliflozin	1,222	9.0 months	67.4/65.1	58.3^#	100	NA	33% RRR	36% RRR	NS	NS

[i] ^^ Primary outcome = composite of adjudicated CV death or worsening/hospitalization for heart failure; #: ischemic cardiomyopathy.

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DOI: https://doi.org/10.14797/mdcvj.1120 | Journal eISSN: 1947-6108

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Language: English

Page range: 62 - 72

Submitted on: Apr 19, 2022

Accepted on: Jun 28, 2022

Published on: Sep 6, 2022

Published by: Houston Methodist DeBakey Heart & Vascular Center

In partnership with: Paradigm Publishing Services

Keywords:

SGLT2 inhibitors,

cardiovascular outcomes,

renal outcomes,

heart failure,

diabetic ketoacidosis,

DKA

© 2022 Abhishek Kansara, Faiza Mubeen, Jawairia Shakil, published by Houston Methodist DeBakey Heart & Vascular Center
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.

Volume 18 (2022): Issue 4