Sodium-glucose cotransporter 2 (SGLT2) inhibitors are well established as effective treatment options for patients with Type 2 diabetes (T2DM) and concomitant heart failure with reduced ejection fraction (HFrEF). However, recent research suggests that SGLT2 inhibitors can reduce the incidence of cardiovascular death and heart failure hospitalizations in patients with HFrEF, even without T2DM. This evidence points to an emerging indication for the use of SGLT2 inhibitors in HFrEF management.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of oral medications initially approved to treat type 2 diabetes (T2DM). In addition to their antihyperglycemic effects, SGLT2 inhibitors have recently also shown beneficial cardiovascular (CV) outcomes, specifically in patients with heart failure with reduced ejection fraction (HFrEF).13  HFrEF is a condition caused by structural and functional impairments, in which the heart is not able to adequately contract and the left ventricular ejection fraction is defined as ≤ 40%. This deficiency in cardiac output is unable to meet the oxygen needs of the various organs and tissues in the body.4  In 2020, about 6.9 million American adults were estimated to be living with heart failure.5  Despite adherence to the current standard of care, those with HFrEF were still found to have a poor prognosis and quality of life.6  Therefore, further investigation of optimal pharmacological therapy for HFrEF is paramount, considering the large burden that heart failure exacerbations and hospitalizations have on patients and the health care system. In 2020, the cost of care for heart failure was estimated to be $43.6 billion in the United States, with higher costs attributed to HFrEF compared to heart failure with preserved ejection fraction, in which left ventricular ejection fraction is defined as ≥ 50%.5  Therefore, exploring the role of additional therapies, such as SGLT2 inhibitors, in HFrEF treatment is timely and necessary.

SGLT2 inhibitors, including empagliflozin, dapagliflozin, canagliflozin and ertugliflozin, act on SGLT2 transporters, which are proteins located in the proximal renal tubules of the kidney. This action leads to reduced reabsorption of filtered glucose and increased urinary glucose excretion, thus improving diabetes control.7,8  This increased glucose excretion also promotes weight loss in many patients. It is not yet completely understood how SGLT2 inhibitors are responsible for their observed cardioprotective effects, but a leading theory states that the diuretic, glucuretic and natriuretic effects reduce volume burden, thereby reducing ventricular stress.9  This volume depletion can help reduce cardiac preload and afterload, which decreases cardiac stress and injury as well as hypertrophy and fibrosis. The resulting effect on cardiac remodeling slows the progression of heart failure. SGLT2 inhibitors can also decrease arterial pressure and stiffness to shift patients to a ketone-based myocardial metabolism. Other proposed mechanisms include reduced blood pressure, reduced inflammation and improved vascular function.6 

Established evidence-based guidelines and treatments for heart failure have led to a decline in heart disease-related mortality over time.10  Current HFrEF treatment recommendations include angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor-neprilysin inhibitors; beta-blockers (specifically metoprolol succinate, bisoprolol and carvedilol); loop diuretics; aldosterone antagonists; hydralazine/isosorbide dinitrate; and ivabradine.11  Since the 2017 guideline update from the American College of Cardiology (ACC), new evidence has emerged regarding the efficacy of SGLT2 inhibitors in patients with HFrEF with or without diabetes.1113  This data point to a new indication for SGLT2 inhibitors that is independent of their glucose lowering effects.

Recent landmark clinical trials have evaluated the effects of dapagliflozin and empagliflozin in patients with HFrEF with or without T2DM as shown in Table 1.1,2,12,13  Both dapagliflozin and empagliflozin were associated with significant reductions in heart failure hospitalizations and CV related deaths.12,13  This evidence highlights the clinical utility of these SGLT2 inhibitors for patients with HFrEF even without T2DM. Both dapagliflozin and empagliflozin have Food and Drug Administration (FDA) labeled indications for use in HFrEF. A 2021 update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment recommends that empagliflozin or dapagliflozin may now be added to guideline-directed medical therapy for patients with New York Heart Association class II-IV heart failure and left ventricular ejection fraction < 40%, with or without T2DM.11,14  Treatment for HFrEF generally begins with an angiotensinconverting-enzyme inhibitor, angiotensin receptor blocker or angiotensin receptor-neprilysin inhibitor, along with an evidence-based beta-blocker and loop diuretics as needed for volume control. After this initial medical therapy, either the combination of hydralazine and isosorbide dinitrate for Black patients or an aldosterone antagonist or a SGLT2 inhibitor can be started. These recommendations outlining the progression of medical therapy for HFrEF indicate that empagliflozin or dapagliflozin can be initiated fairly early in the course of treatment, rather than waiting for all other guideline-directed medications to be optimized. Lastly, the use of canagliflozin has also shown a significant reduction of CV death or hospitalization for heart failure when compared to placebo in patients with T2DM, however the medication does not have an FDA-labeled indication for use in heart failure.15 

Table 1

Cardiovascular outcomes for empagliflozin and dapagliflozin.7,8,12,13 

Cardiovascular outcomes for empagliflozin and dapagliflozin.7,8,12,13
Cardiovascular outcomes for empagliflozin and dapagliflozin.7,8,12,13

SGLT2 inhibitors are generally safe, well-tolerated and have a once daily oral dosing schedule. Common adverse reactions observed in placebo-controlled clinical trials include female genital mycotic infections (dapagliflozin 6.9%, empagliflozin 5.4%), urinary tract infections (dapagliflozin 4.3%, empagliflozin 9.3%) and increased urination (dapagliflozin 3.8%, empagliflozin 3.4%).7,8  The SGLT2 inhibitor class may also rarely increase the risk for volume depletion, ketoacidosis, urosepsis and pyelonephritis, hypoglycemia, dyslipidemia, acute kidney injury, necrotizing fasciitis of the perineum (Fournier’s gangrene) and bone fractures. Caution must be taken when using these medications in patients with renal impairment and eGFR < 30 mL/min/1.73m2.7,8,14  Lastly, cost is a potential barrier to the use of SGLT2 inhibitors, as these medications are not yet available as generic formulations and are unlikely to be covered by most health insurance plans for patients without concomitant T2DM.7,8 

The significant CV benefits of SGLT2 inhibitors in patients with T2DM raises the question as to whether these medications may have a secondary indication in HFrEF management, independent of T2DM status. While specific mechanisms for these CV benefits are still under investigation, it appears that SGLT2 inhibitors have beneficial effects on volume status, inflammation and cardiac remodeling. Two landmark clinical trials have provided evidence of fewer heart failure hospitalizations and CV-related deaths with the use of SGLT2 inhibitors in patients with HFrEF with or without T2DM.12,13  As a result, heart failure guidelines have begun to incorporate SGLT2 inhibitors in the management of HFrEF. Pharmacists can play an important role in the management of this patient population by recommending initiation of therapy in eligible patients, monitoring for any adverse effects and educating patients about the benefits of therapy.

1.
Zinman
B,
Wanner
C,
Lachin
JM,
et al.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes
.
N Engl J Med
2016
Mar
17
;
374
(
11
):
1094
.
doi:
.
2.
Wiviott
SD,
Raz
I,
Bonaca
MP,
et al.
Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes
.
N Engl J Med
2019
;
380
(
4
):
347
357
.
doi:
.
3.
American Diabetes Association.
9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021
.
Diabetes Care
2021
Jan
;
44
(
Suppl 1
):
S111
S124
.
doi:
.
4.
Chen
Y,
Wong
L,
Liew
O,
et al.
Heart Failure with Reduced Ejection Fraction (HFrEF) and Preserved Ejection Fraction (HFpEF): The Diagnostic Value of Circulating MicroRNAs
.
Cells
2019
Dec
;
8
(
12
):
1651
.
doi:
.
5.
Urbich
M,
Globe
G,
Pantiri
K,
et al.
A Systematic Review of Medical Costs Associated with Heart Failure in the USA (2014–2020)
.
PharmacoEconomics
2020
Nov
;
38
(
11
):
1219
1236
.
doi:
.
6.
Lopaschuk
GD,
Verma
S.
Mechanisms of Cardiovascular Benefits of Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review
.
JACC Basic Transl Sci
2020
Jun
22
;
5
(
6
):
632
644
.
doi:
.
7.
Farxiga (dapagliflozin) [prescribing information]
.
Wilmington, Del.
:
AstraZeneca Pharmaceuticals LP
;
May
2021
.
8.
Jardiance (empagliflozin) [prescribing information]
.
Ridgefield, Conn.
:
Boehringer Ingelheim Pharmaceuticals Inc.
;
May
2021
.
9.
Inzucchi
SE,
Zinman
B,
Fitchett
D,
et al.
How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial
.
Diabetes Care
2018
Feb
;
41
(
2
):
356
363
.
doi:
.
10.
Mensah
G,
Wei
G,
Sorlie
P,
et al.
Decline in Cardiovascular Mortality: Possible Causes and Implications
.
Circ Res
2017
Jan
20
;
120
(
2
):
366
380
.
doi:
.
11.
Yancy
CW,
Jessup
M,
Bozkurt
B,
et al.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America
.
Circulation
2017
Aug
8
;
136
(
6
):
e137
e161
.
doi:
.
Epub 2017 Apr 28.
12.
McMurray
JJV,
Solomon
SD,
Inzucchi
SE,
et al.
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
.
N Engl J Med
2019
Nov
21
;
381
(
21
):
1995
2008
.
doi:
.
Epub 2019 Sep 19.
13.
Packer
M,
Anker
SD,
Butler
J,
et al.
Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure
.
N Engl J Med
2020
Oct
8
;
383
(
15
):
1413
1424
.
doi:
.
Epub 2020 Aug 28.
14.
Maddox
TM,
Januzzi
JL,
Allen
LA,
et al.
2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction. Journal of the American College of Cardiology
.
J Am Coll Cardiol
2021
Feb
16
;
77
(
6
):
772
810
.
doi:
.
Epub 2021 Jan 11.
15.
Neal
B,
Perkovic
V,
Mahaffey
K,
et al.
Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
.
N Engl J Med
2017
Nov
23
;
377
(
21
):
2099
.
doi:
.