Academic Editors: Zoltán Papp and Ferdinando Carlo Sasso
Sodium-glucose co-transporter (SGLT)-2 inhibitors were initially developed for management of type 2 diabetes but have been shown to offer improved outcomes in heart failure, a condition in which concomitant chronic kidney disease (CKD) is common. Randomised controlled trials initially demonstrated prognostic cardiovascular and renal benefits of SGLT2 inhibitors in high cardiovascular risk individuals with type 2 diabetes particularly in relation to heart failure. Improved outcomes have been replicated in cohorts with established heart failure and/or CKD and appear to extend in those without diabetes. Several specific agents have been considered, with evidence of a class effect, and dapagliflozin and empagliflozin are now incorporated into major international cardiovascular guidelines for management of heart failure with reduced ejection fraction. Beyond glucose lowering effects the mechanisms mediating SGLT2 inhibitors favourable actions are not fully elucidated. Haemodynamic alterations, natriuresis, osmotic diuresis, and weight loss likely contribute to improved outcomes, along with an enhanced cardiometabolic profile. The functional drop in estimated glomerular filtration rate (eGFR) which accompanies SGLT2 inhibitor initiation, before eGFR stabilisation, is likely central in the observed renal benefits. In this review we discuss in detail the evidence for SGLT2 inhibitors in heart failure, particularly with regard to kidney health.
Heart failure remains a condition with substantial unmet needs in management and associated burden for both patients and healthcare resources [1] and is more common among people with diabetes and/or chronic kidney disease (CKD) [2]. Heart failure and CKD frequently co-exist because the two share common risk factors and pathophysiological mechanisms which affect one another [3]. The introduction of sodium-glucose co-transporter (SGLT)-2 inhibitors in the management of type 2 diabetes was accompanied by the emergence of unexpected benefits beyond their glucose-lowering action. Their prognostic benefit in heart failure first emerged in EMPA-REG trial, a trial aimed to assess the effects of empagliflozin on cardiovascular health of high-risk individuals with type 2 diabetes [4]. Thereafter, a series of randomised clinical trials (RCTs) have demonstrated their efficacy across the spectrum of heart and renal disease, which appear to be also present in non-diabetic populations raising enthusiasm across the scientific community. In the present review, we will discuss the evidence regarding the SGLT2 inhibitors action in heart failure and the relevant implications on kidney health.
The EMPA-REG trial was the first study to suggest a beneficial effect of a SGLT2
inhibitor, empagliflozin on cardiovascular outcomes in individuals with type
2 diabetes. More specifically, EMPA-REG aimed to assess the cardiovascular effects
of empagliflozin on patients with diabetes and at high risk for a cardiovascular
event (total n = 7020) compared to placebo [4]. Of the study population, 17.8%
had an estimated glomerular filtration rate (eGFR), between 45–59 and 7.7%
between 30 to 44 mL/min/1.73 m
study | N | Inclusion eGFR (mL/min/1.73 m |
mean eGFR (mL/min/1.73 m |
Diabetes (%) | HF (%) | Primary endpoint | Hazard Ratio (95% CI) for primary endpoint | Hazard Ratio (95% CI) for HF hospitalisation |
EMPEROR-REDUCED (empagliflozin 10 mg) | 3730 | 61.8 | 49.8 | 100 | CV death or hospitalisation for worsening HF | 0.75 (0.65–0.86) | 0.69 (0.59–0.81) | |
DAPA-HF (dapagliflozin 10 mg) | 4744 | 66 | 41.8 | 100 | CV death or worsening HF (hospitalisation or urgent visit for intravenous therapy) | 0.74 (0.65–0.85) | 0.70 (0.59–0.83) | |
SOLOIST-WHF (sotagliflozin 200–400 mg) | 1222 | Median 49.2 | 100% | 100 | CV death or total number of worsening HF events (hospitalisation or urgent visit) | 0.67 (0.52–0.85) | 0.64 (0.49–0.83) | |
EMPEROR-PRESERVED (empagliflozin 10 mg) | 5988 | 60.6 | 49 | 100 | CV death or hospitalisation for HF | 0.79 (0.69 –0.90) | 0.73 (0.61–0.88) | |
CREDENCE (canagliflozin 100 mg) | 4401 | 30–90 | 56.3 | 100 | 14.8 | Sustained doubling of creatinine, sustained eGFR |
0.70 (0.59– 0.82) | 0.61 (0.47 –0.80) |
DAPA-CKD (dapagliflozin 10 mg) | 4304 | 25–75 | 43.2 | 67.5 | 10.8 | Sustained |
0.61 (0.51–0.72) | 0.71 (0.55–0.92)* |
SCORED (sotagliflozin 200–400 mg) | 10584 | 25–60 | Median 44.4 | 100 | 30 | CV death or total number of HF events (hospitalisation or urgent visit) | 0.74 (0.63–0.88) | 0.67 (0.55–0.82) |
CANVAS (canagliflozin 100–300 mg) | 10142 | 76.7 | 100 | 14.4 | CV death, non-fatal myocardial infarction, non-fatal stroke | 0.86 (0.75–0.97) | 0.67 (0.52–0.87) | |
DECLARE-TIMI | 85.4 | 100 | 10 | CV death, myocardial infarction or ischaemic stroke | 0.93 (0.84–1.03) And 0.83 (0.73–0.95) | 0.73 (0.61–0.88) | ||
CV death or hospitalisation for worsening HF | ||||||||
VERTIS (ertugliflozin 5 or 15 mg) | 8246 | 76 | 100 | 24 | CV death, non-fatal myocardial infarction or non-fatal stroke | 0.97 (0.85–1.11) | 0.70 (0.54–0.90) | |
EMPA-REG (empagliflozin 10 mg or 25 mg) | 7020 | 74 | 100 | 10.1 | CV death, non-fatal myocardial infarction, non-fatal stroke | 0.86 (0.74–0.99) | 0.65 (0.50–0.85) | |
HF, heart failure; eGFR, estimated glomerular filtration rate; CV, cardiovascular; ESRD, end-stage renal disease. *composite of CV death or HF hospitalization. |
The Canagliflozin Cardiovascular Assessment Study (CANVAS), then, followed to
suggest what the scientific community had already hoped for, that the EMPA-REG
findings were not drug-specific but rather class-specific [6]. Among 10,142 high
cardiovascular risk individuals with type 2 diabetes and a mean eGFR of 76.7
mL/min/1.73 m
Despite failing to achieve significance in primary endpoints, the DECLARE-TIMI
trial demonstrated that dapagliflozin also had a protective action against
hospitalisation for heart failure in individuals (total n = 17,160) with type 2
diabetes and high cardiovascular risk similarly to empagliflozin and canagliflozin
in EMPA-REG and CANVAS, respectively [9]. This patient cohort had mean and nadir
eGFR of 45.4 and 60 mL/min/1.73 m
The DAPA-CKD [11] that followed, though focusing on renal effects, suggested
that dapagliflozin benefit extends to non-diabetic populations. It enrolled 4304
individuals with an eGFR between 25 and 75 mL/min/1.73 m
The SCORED study [14] aimed to assess whether sotagliflozin, a dual SGLT1(in the
gastrointestinal tract) and 2 inhibitor, would have any comparable effects in a
population with diabetes, high cardiovascular risk and CKD (eGFR 25–60
mL/min/1.73 m
The observed benefits in the aforementioned trials reflected a preventative
action of SGLT2 inhibitors from incident heart failure in individuals with type 2
diabetes and high cardiovascular risk. The answer as to whether they could claim
a role in the management of established heart failure and whether their benefits
may extend to non-diabetic individuals, derived from the studies that followed
and focused on populations with known heart failure. The DAPA-HF trial [15]
assessed 4744 patients with known heart failure [New York Heart Association
(NYHA) class II–IV and an ejection fraction (EF) of 40% or lower], who were
randomised to receive dapagliflozin (at a dose of 10 mg once daily) or placebo on
top of standard therapy. Of note, only 41.8% of the trial population had known
type 2 diabetes, and the cut-off eGFR 30 mL/min/1.73 m
The publication of EMPEROR-REDUCED trial [17] followed a few months later to
demonstrate comparable effects of empagliflozin in addition to standard therapy
in a population (n = 3730) with heart failure NYHA class II–IV and EF of or
below 40%, enriched with patients with markedly low EF; diabetes was present in
49.8%, while the nadir eGFR was 20 mL/min/1.73 m
A meta-analysis [19] of the two trials DAPA-HF and EMPEROR-REDUCED confirmed the
lower hospitalisation risk with treatment with either agent and suggested that
though relatively small, there is a significant reduction in cardiovascular death
(pooled HR 0.86, 95% CI 0.76–0.98; p = 0.027) and all-cause mortality (pooled
HR 0.87, 95% CI 0.77–0.98; p = 0.018) associated with SGLT2 inhibition
in pooled data analysis, implying that the individual trials may have not been
sufficiently powered to demonstrate a robust effect on death. Also, a combined
renoprotective effect was demonstrated in this population with a reduction in the
risk for the renal endpoint of chronic dialysis, renal transplantation, or a
With these trials focusing on heart failure with reduced EF, the question
whether there are beneficial effects of SGLT2 inhibitor treatment in relation to
heart failure with preserved EF was raised. Two trials, DELIVER and EMPEROR
PRESERVED were designed to answer this question. Though, DELIVER is still on
going [20], the findings from EMPEROR PRESERVED have recently been published [21]
making empagliflozin the first pharmacological agent ever reported to confer a
prognostic benefit in heart failure with preserved EF. This study enrolled 5988
patients with NYHA class II–IV heart failure and an EF of more than 40%,
assigned to receive empagliflozin or placebo on top of standard therapy. The
empagliflozin group had a lower risk of the primary outcome of cardiovascular
death or hospitalisation for heart failure with a HR of 0.79 (95% CI 0.69–0.90;
p
The Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial [22] aimed to review the dual SGLT1 and 2 inhibitor effects on heart failure from a slightly different angle. In SOLOIST-WHF the investigators assessed the effects of sotagliflozin, in a patient population (n = 1222) with diabetes and end-stage heart failure but not limited to reduced EF, but also recently discharged after a heart failure decompensation hospitalisation. It appeared that early initiation of sotagliflozin following a heart failure worsening event, led to significant reduction of risk for the primary outcome (composite of cardiovascular death and hospitalisation and urgent visits for heart failure versus) placebo over a 9-month follow-up period. However, this was principally driven by a reduction in the events of worsening heart failure.
In addition, a meta-analysis of 7 large RCTs (DAPA-HF, EMPEROR-Reduced,
SOLOIST-WHF CANVAS, EMPA-REG OUTCOME, DECLARE-TIMI 58 and VERTIS-CV) [23] focused
on patients with known heart failure (n = 16,820) and reported that SGLT2
inhibition reduced the composite endpoint of first heart failure hospitalisation
or cardiovascular death (HR 0.77, 95% CI 0.72–0.83, p
Further to the large outcome trials, the EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heart faiLure) [24], EMBRACE-HF (Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure) [25] and EMPA-RESPONSE-AHF, were smaller studies which aimed to assess other aspects of empagliflozin action in heart failure.
The EMPERIAL trial [24] evaluated measures in relation to symptoms and patient-reported outcomes, rather than crude events of hospitalisation or death with empagliflozin treatment. The study included patients with heart failure with both reduced (n = 312) and preserved (n = 315) EF with or without diabetes, who were randomised to empagliflozin versus placebo. However, at 12 weeks of treatment there was no significant difference in the primary endpoint of 6-minute walk test distance (6MWTD), or in the symptom-assessment questionnaires used [Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS)] compared to placebo.
With an aim to review the effect of SGLT2 inhibition in the context of acute heart failure, the EMPA-RESPONSE-AHF recruited patients within 24 hours of an acute heart failure admission and randomised them to either empagliflozin (n = 40) or placebo (n = 39) for 30 days. Treatment with empagliflozin did not cause any significant difference from placebo in the primary endpoint of dyspnoea score, diuretic response (weight change per 40 mg furosemide), change in N-terminal pro brain natriuretic peptide (NT-proBNP), and length of hospital stay; nevertheless, it was associated with a reduced rate of the secondary combined endpoint of in-hospital worsening heart failure, re-admission or death at 60 days compared with placebo [4 (10%) vs 13 (33%); p = 0.014]. This patient group also showed a significantly higher urinary output up until day 4 compared to placebo, but net fluid loss difference at day 4 did not reach statistical significance [26]. In contrast to what was expected based on SGLT2 inhibitors principal mechanism of action, the fractional urinary sodium excretion did not change and it appeared that the most relevant action in that context is osmotic diuresis via enhanced glucosuria, which also led to an increase in plasma osmolality [27].
The EMBRACE-HF trial [25] randomised 65 patients with heart failure independent of their EF and diabetes status to receive empagliflozin versus placebo for 12 weeks in order to assess the effects on pulmonary artery diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8–12, which was the primary end point) on equivalent doses of loop diuretics between the two groups. Significant reductions in PADP were noted as early as at week 1 and became more prominent with time reaching a 1.7 mm Hg difference (95% CI 0.3–3.2; p = 0.02) versus placebo at week 12. However, empagliflozin treatment did not result in any significant differences in KCCQ-TSS, NT-proBNP and 6MWD.
Overall, these smaller studies though demonstrating miscellaneous—mainly haemodynamic—effects, failed to demonstrate an improvement from a symptom perspective, not at least with the measures utilised.
As a result of the robust evidence from the large RCTs, US Food and Drug Administration (FDA) approved dapagliflozin for use in heart failure with reduced EF in May 2020 to reduce the risk of cardiovascular death and hospitalisation [28], for empagliflozin to follow in August 2021, with the two agents being included in an update on existing Guidelines for Heart Failure by the American Heart Association [29]. Around the same time, the European Society of Cardiology (ESC) published their new guidelines on heart failure which endorsed dapagliflozin and empagliflozin for the treatment of heart failure with reduced EF with a class I recommendation [30].
Further to evidence from RCTs, real world data are consistent with a beneficial effect on heart failure. Data on patients with type 2 diabetes and heart failure enrolled in the Swedish heart failure Registry between 2016 and 2018 were assessed in relation to the initiation of SGLT2 inhibitors and potential cardiovascular effects [31]. The percentage of people initiated on the treatment increased over time from 5.5% to 12% (total n = 6805) at the end of 2018. SGLT2 inhibitor treatment was associated with a reduced risk for cardiovascular death or first heart failure hospitalisation (HR0.70, 95% CI 0.52–0.95), which was evident at median follow-up of 256 days and was independent of the EF, metformin use and renal function. SGLT2 inhibitor use was also associated with a lower risk of all-cause and cardiovascular death, heart failure or cardiovascular hospitalisation, and cardiovascular death or myocardial infarction or stroke.
The OBSERVE-4D study [32]compared the effects of canagliflozin (n = 142,800) versus other SGLT2 inhibitors (n = 110,897) and other antihyperglycaemic agents (n = 460,885) using data from four US administrative databases. Canagliflozin was associated with a marked reduction in hospitalisation for heart failure when compared with other non-SGLT2 inhibitors (meta-analytic HR 0.39, 95% CI 0.26–0.60), while the effect of canagliflozin was similar with that of other SGLT2 inhibitors. Moreover, data from an in Italian real-world study [33], suggested SGLT2 inhibitors were superior to dipeptidyl peptidase-4 (DPP4) inhibitors in all cardiovascular outcomes examined. More specifically, SGLT2 inhibitors were associated with reduced risk of 3-point major cardiovascular events (myocardial infarction, stroke, or all-cause death; HR 0.74, 95% CI 0.58–0.94), heart failure (HR 0.44, 95% CI 0.25–0.95) or other cardiovascular admission (HR 0.72, 95% CI 0.60–0.87), myocardial infarction (HR 0.75, 95% CI 0.56–1.00), and all-cause death (HR 0.49, 95% CI 0.25–0.95).
A propensity score matched analysis from CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) (n = 153,078 in each cohort) showed that SGLT2 inhibitor use was associated with a lower risk of heart failure and the composite of heart failure or death compared to other glucose lowering agents in both patients with and without baseline cardiovascular disease [10, 34]. A lower risk of heart failure hospitalisation, as well as all-cause mortality and major cardiovascular events was also noted in association with SGLT2 inhibitor treatment as compared to other antidiabetic medicationsin EASEL (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World) population-based cohort study (n = 25,258) [35]. Consistently, canagliflozin initiation was associated with reduced heart failure hospitalisation and death rates versus other non-SGLT2 inhibitor agents in a US based cohort [36].
Nevertheless, in a Danish nationwide registry-based cohort study there was no difference in the heart failure hospitalisation risk between new users of SGLT2 inhibitors and GLP1 receptor antagonists [37].
NT-proBNP is the most widely used biomarker in patients with heart failure, the prognostic value of which is more definitive in heart failure with significantly reduced EF, but overall appears to have a role in guiding the management [38]. Troponin, which is also used in clinical practice, was not reported in any of the RCTs.
Findings so far have been conflicting with regards to a “biochemical” response in heart failure to SGLT2 inhibition. All three large RCTs on heart failure (DAPA-HF, EMPEROR-REDUCED and EMPEROR-PRESERVED) have demonstrated significant reductions in NT-proBNP with SGLT2 inhibition treatment, while several smaller ones have not showed similar findings. The CANDLE study aimed to assess the NT-proBNP response to treatment with canagliflozin versus glimepiride, in patients with type 2 diabetes and stable chronic heart failure. However, it had to be discontinued, since canagliflozin failed to reach the non-inferiority endpoint (i.e., failed to achieve a significant and at least equal to glimepiride reduction in NT-proBNP levels at 24 weeks) [39, 40]. On a similar note, the (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) DEFINE-HF study [41] which compared dapagliflozin to placebo in 263 patients, dapagliflozin did not seem to be associated with a more pronounced reduction in NT-proBNP levels than placebo; however, it did result in a higher proportion of patients within the group to report an improvement in symptoms (as assessed by KCCQ-TSS) and achieve a meaningful reduction in NT-proBNP levels. These findings were consistent independently of the presence of diabetes. Empagliflozin in EMPBRACE-HF did not lead to a significant reduction in NT-proBNP levels either, compared to placebo [25]. Overall the effect of SGLT2 inhibition is less definitively described. However, the clinical significance of the changes or absence of them, appears less relevant in the context of improved clinical outcomes; it does though provide a hint, that the mechanisms involved are likely complex.
A series of mechanisms have been proposed, through which SGLT2 inhibitors might exert their favorable actions on the heart and the kidneys and cannot but be perceived as a continuum. The cardiovascular system and the kidneys are physiologically interrelated through haemodynamic, hormonal and molecular mechanisms. The pathophysiological façade of this interconnection is the cardiorenal syndrome. The effects of SGLT2 inhibitors on more than one point of this intersection should be considered. Their glucose-lowering action can only minimally account for, especially given that the beneficial effects of treatment appear evident in impaired renal function that the glucose treatment effect is limited, and even in the absence of diabetes. Moreover, the cardiovascular benefit appears to emerge early on during treatment at approximately 12 weeks [42], suggesting that more acute effects than merely the amelioration of the cardiometabolic profile, must be principally involved, with haemodynamic alterations possibly playing a key role.
Inherent to their mode of action, natriuresis and osmotic diuresis have no wonder been believed to at least partly mediate SGLT2 inhibitors beneficial effects in heart failure. A small but consistent reduction in blood pressure appears to occur early after initiation of treatment and not to be related to baseline blood pressure levels or any changes in heart rate or body weight [43, 44]. In the longer term, weight loss is likely to contribute [45]. Nevertheless, evidence especially with regards to absolute sodium excretion has been inconsistent. Empagliflozin was shown to increase natriuresis and reduce plasma volume in a small study of 20 patients with type 2 diabetes and stable heart failure [46], though in the RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure), it did not result in similar effects [47]. The DAPASALT study [48] was an open-label, non-randomised study which assessed the volume effects of dapagliflozin treatment in patients with type 2 diabetes and normal renal function on a controlled salt intake. A significant reduction was noted in blood pressure and extracellular fluidlevels, without however, any significant change in plasma volume or fractional sodium excretion. Of note, this population did not have known heart failure.As mentioned earlier, the EMPA-RESPONSE-AHF pointed more towards the osmotic diuresis effect in acute heart failure, while the EMBRACE HF showed an improvement in filling pressures but not in NT-proBNP. Though interpretation is difficult, there is suggestion that the mechanistic effects of SGLT2 inhibitors might be more complex than initially presumed, and sodium intakemight play a role [49]. Direct intracellular sodium regulating effects in cardiomyocytes have also been proposed as potential mediating factos of cardioprotection [50].
So far, there is not an abundance of data to shed light on the mechanisms involved specifically in heart failure associated SGLT2 inhibitors benefits. Other actions of SGLT2 inhibitors such as weight loss, reduction of visceral adiposity, amelioration of lipid profile and effects on endothelial function and arterial stiffness are parameters that contribute to an enhanced cardiometabolic profile [51], though they might be less relevant in the context of advanced heart failure. A role for increased ketone body production [52, 53] and ameliorated oxidative stress and inflammation has also been suggested to contribute to reduced cardiovascular risk. The SGLT2 inhibitors renoprotective effect per se is key for the benefits observed in relation to both prevention of incident heart failure and hospitalisation. This is also likely mediated by several mechanisms rather than a single one such as some of those mentioned above (lower blood pressure, natriuresis, body weight reduction) [54], though the increased tubuloglomerulal feedback and resultant reducedintraglomerular hypertension and hyperfiltration, and, therefore, albuminuria are core [55].
Overall, there seems to be a protective effect from both incident heart failure and decompensation of established heart failure. To what extent each of the above mechanisms contributes to the variable benefits of SGLT2 inhibition might well vary according to patient characteristics, i.e., cardiac and renal function, diabetes status, fluid status and total sodium content. It is likely that there are longer-, medium- and shorter-term effects, as a significant change in PADP was noted as early as week 1 [25] of empagliflozin treatment, and improved clinical outcomes are noted within weeks after treatment initiation [22, 42].
With the introduction of SGLT2 inhibitors in clinical practice as hypoglycaemic drugs, concerns were raised regarding the likelihood that their use may be associated with an increased risk of acute kidney injury (AKI) and volume depletion. This was largely driven by specific features of their mechanism of action, including the fact that initiation of SGLT2 inhibitors is accompanied by an initial reduction in eGFR, which is, then, followed by stabilisation of eGFR slope and improved renal outcomes. Alongside induced osmotic diuresis and natriuresis, these are rather mechanistic features of their action than side-effects. On those early days, this initial eGFR drop led to some post-marketing reports of “AKI events” following their initiation. Of note, more than half of these reported “AKI events”, occurred within the first 4 weeks of initiation, which is indicative of their known early effect.
As a result, the FDA advised caution to health care professionals with regards
to their use, especially in the context of other factors that increase AKI risk
such as CKD, heart failure and certain pharmacological agents such as RAAS
inhibitors and diuretics. However, none of the RCTs which have included
populations traditionally considered at “high AKI risk”, have demonstrated any
relevant risk associated with their use. The heart failure trials, DAPA-HF and
EMPEROR-REDUCED [15, 17] showed that the AKI rate was similar between the
treatment and placebo groups in populations with varying stages of heart failure
severity and established renal impairment at baseline (eGFR
Overall, trial data have shown that SGLT2 inhibitors are safe and well tolerated drugs. Mycotic genital infections can be associated with their use, while an increased risk for urinary tract infections has been shown in VERTIS CV [10] and EMPEROR-PRESERVED [21] trials but not in any other. Though an increased risk for Fournier’s gangrene has not been demonstrated in any trial data, due to the severity of the condition formal drug authorities have issued warning and advised vigilance [65, 66].
Regarding volume related adverse events,findings have varied across trials with some suggesting a higher hypovolaemia risk [11, 14, 56] while others not [4, 5, 7, 9] and without a demonstrable link with a specific agent or condition. The large heart failure trials showed that hypovolaemia rate was similar between the treatment and the placebo groups despite most patients also on simultaneous diuretic treatment [15, 17]. A subgroup analysis of DAPA-HF, volume related adverse events were more common with dapagliflozin, than placebo, in patients on higher diuretic doses [16]. Furthermore, a higher risk for diabetic ketoacidosis has been noted in some trials which included patients with type 2 diabetes only [7, 9, 10, 22] but not in others [4, 5] and has not been noted in any non-diabetic populations. Certain factors appear to exacerbate this risk such as ketogenic diet, pregnancy, alcohol consumption etc., hence caution may be advisable in certain populations and circumstances. Therefore, US Food and Drug Administration (FDA), European Medicines Agency (EMA) and UK Medicines & Healthcare products Regulatory Agency (MHRA) have issued relevant warnings and guidance that recommend temporary discontinuation of the drug during acute illness or scheduled surgery [67, 68].
Other unexpected adverse events of significance are a possible toe amputation and fracture risk, both having emerged in CANVAS in association with canagliflozin [56]. More specifically, an increased fracture rate was noted with canagliflozin versus placebo in CANVAS but not CANVAS-R arm of the CANVAS Program [6] or CREDENCE [7]. Other large RCTs have not confirmed such risk linked with the use of other SGLT2 inhibitors either, including in heart failure populations. The increased amputation signal which emerged in association with canagliflozin in an interim safety analysis of CANVAS raised concerns, and caution has been advised in high risk populations [69, 70] even though these findings were not reproduced in other canagliflozin or other SGLT2 inhibitors RCTs.
The abundance of high-quality evidence demonstrating a prognostic benefit from
SGLT2 inhibitor treatment in heart failure, has led to the incorporation of two
class representatives, dapagliflozin and empagliflozin, in the pharmacological
management of heart failure with reduced EF as dictated by the guidelines
published by major international cardiovascular organizations.Though reductions
in cardiovascular mortality have been recorded, the most consistent effect in all
RCTs appears to be in relation to preventing hospitalisation for heart failure.
Treatment benefits affect both patients with diabetes and those without, are
independent of the level of glycaemia [71] and present at all levels of kidney
function tested (minimum eGFR in RCTs 30 mL/min/1.73 m
It is the first time in years following RAAS inhibitors that pharmacological
agents appear to confer prognostic benefit in heart failure and renal disease. In
all large RCTs, SGLT2 inhibitors have been given on top of standard therapy with
80 to 99.9% of each study cohort already on RAAS inhibitors. Moreover, the two
drug categories have very distinct mechanisms of actions and likely complementary
in their overall cardiac and renal benefits; therefore, it is reasonable that
SGLT2 inhibition is recommended as an add-on to RAAS and that the two treatments
are not considered interchangeable. Heart failure is associated with progressive
renal impairment with eGFR decline of 2–3 mL/min/1.73 m
EL, EA—conceived of the presented topic, wrote the manuscript, edited and reviewed the final version of the manuscript. JRJ, ET—wrote part of the manuscript. All the authors read and approved the final manuscript.
Not applicable.
Not applicable.
This research received no external funding.
The authors declare no conflict of interest. Eirini Lioudaki and Emmanuel Androulakis are serving as two of the Guest editors of this journal. We declare that Eirini Lioudaki and Emmanuel Androulak had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Zoltán Papp and Ferdinando Carlo Sasso.