Gliflozins for the Treatment of Congestive Heart Failure and Renal Failure in Type 2 Diabetes

Abstract

Background

Gliflozins are effective drugs for the treatment of type 2 diabetes. They inhibit sodium glucose cotransporter 2 in the proximal renal tubule, leading to increased glucose excretion. On the basis of findings from relevant studies, gliflozins are also increasingly used in clinical practice to treat congestive heart failure and renal failure.

Methods

This review is based on pertinent publications retrieved from a selective literature search in PubMed and GoogleScholar.

Results

Cardiovascular safety studies revealed early on that gliflozins can lower the hospitalization rate of patients suffering from congestive heart failure with a reduced left-ventricular ejection fraction (HFrEF). They also showed favorable effects on multiple renal endpoints. In recent years, studies such as DAPA-HF and CREDENCE have further documented the benefit of gliflozins in the treatment of congestive heart failure and renal failure in patients with type 2 diabetes, and gliflozins have accordingly been incorporated into the pertinent guidelines. In the recently published EMPEROR-Reduced trial, empagliflozin was found to significantly lower the frequency of a combined cardiovascular endpoint in patients with HFrEF (19.4 % versus 24.7%; hazard ratio [HR] 0.75; 95% confidence interval [0.65; 0.86]; number needed to treat [NNT] 19, p <0.001). In the DAPA-CKD trial, which was also recently published, dapagliflozin was found to significantly lower the frequency of a combined renal endpoint (9.2% versus 14.5%; HR 0.61 [0.51; 0.72]; NNT 19; p <0.001).

Conclusion

On the basis of findings from specific studies, gliflozins will henceforth be a major class of drug for the treatment of HFrEF and renal failure, independently of the presence of type 2 diabetes.

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Type 2 diabetes (T2D) is a risk factor for developing congestive heart failure and/or renal failure, making it a disease of significant public health concern (1, 2). Consequently, one of the goals of T2D management is to reduce the rate of cardiovascular and renal complications. Gliflozins, also referred to as SGLT2 inhibitors, are an effective class of drug to tread T2D. They selectively inhibit sodium glucose cotransporter type 2 (SGLY2) in the proximal renal tubule, leading to increased glucose excretion. In addition, they exert favorable pleiotropic effects on body weight, arterial hypertension and vascular rigidity, as well as albuminuria (3) (efigure). Besides its role in diabetology, gliflozins have emerged on the basis of findings from randomized trials as drugs to treat congestive heart failure and renal failure.

eFigure.

Overview and hypotheses of the mechanism of action of gliflozins (SGLT2 inhibitors) (21–24)

Graphic created by Dr. rer. nat. Lennart T. N. Lenk, Department of Pediatric and Adolescent Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

SGLT2-dependent effects:

1. Increased osmotic diuresis due to glucosuria as well as increased natriuresis. Consecutive preload reduction with improved ventricular filling

2. Afterload reduction by means of reduced arterial rigidity and lowering of blood pressure

3. Provisioning of ketones as an alternative myocardial energy source for ATP synthesis (especially ß-hydroxybutyrate). This pathway reduces the accumulation of free fatty acids by the breakdown of non-esterified fatty acids (NEFA). Thus, consecutive reduction of “lipotoxicity“ and improvement of myocardial contractility

4. Stimulation of the tubuloglomerular feedback mechanism by increased natriuresis. Consecutive vasoconstriction of the afferent vessel and lowering of the glomerular filtration pressure

5. Increase in uric acid excretion and thereby potential cardioprotective effects (association between increased serum uric acid level and increased cardiovascular risk is assumed)

6. Increased glucose excretion and weight reduction

SGLT2-independent effects:

1. Increase in myocardial contractility by inhibition of the sodium-proton exchanger type 1 (= Na+/H+ exchanger 1 = NHE-1, syn. SLC9A1) with positive effect on intracellular calcium content

2. Inhibition of the sodium-proton exchanger type 3 (= Na+/H+ exchanger 1 = NHE-3), which shows increased expression with heart failure; as a result, sodium reabsorption is reduced

3. Reduction of cardiac fibrosis by inhibition of the tissue growth factor (TGF)-ß1, among other mechanisms

4. Induction of anti-inflammatory pathways, e.g. by means of increased differentiation of macrophages to the anti-inflammatory M2 subtype with decreased production of proinflammatory cytokines, such as interleukin (IL-) 6 and leptin

ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; GLUT-2, glucose transporter type 2; HbA1c, hemoglobin A_1c; HDL, high density lipoprotein; LDL, low density lipoprotein; NHE, sodium proton exchanger; SGLT2, sodium-glucose cotransporter type 2

Methods

This review is based on pertinent publications retrieved from a selective literature search in PubMed and Google Scholar. The key search terms used, alone and in various combinations, were “SGLT2 inhibitors“, “diabetes“, “heart failure“, “chronic kidney disease“, “cardiovascular effects“, and “renal effects“. The primary English-language literature up to and including September 2020 as well as the current recommendations of the European Association for the Study of Diabetes [EASD] and the European Society of Cardiology [ESC]) were taken into account. No pertinent Cochrane reviews were identified.

Gliflozins and cardiovascular endpoint studies

The conduct of cardiovascular safety studies is a mandatory requirement for obtaining approval of new antidiabetic agents by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The so-called 3-point major adverse cardiovascular event (3P-MACE) outcome is chosen as the primary endpoint in these trials. 3P-MACE is a composite of cardiovascular mortality, nonfatal myocardial infarction and nonfatal stroke. Currently, four gliflozins are approved for treatment: empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. For empagliflozin, canagliflozin and dapagliflozin, data of the relevant safety studies were published in high-ranking journals. These are listed in table 1.

Table 1. Overview of the cardiovascular safety studies for empagliflozin, canagliflozin and dapagliflozin*.

Acronym	EMPA-REG-OUTCOME	CANVAS	DECLARE-TIMI 58
Title	EMPAgliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients – Removing Excess Glucose	CANagliflozin cardioVascular Assessment Study	Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis in Myocardial Infarction 58
Time of publication	November 2015 (4)	August 2017 (5)	January 2019 (6)
SGLT2 inhibitor	Empagliflozin Dose: 10 mg and 25 mg	Canagliflozin Dose: 100 mg and 300 mg	Dapagliflozin Dose: 10 mg
Number of patients	7020 (mean age: 63 years)	10 142 (mean age: 63 years)	17 160 (mean age: 64 years)
Cardiovascular risk	Established cardiovascular disease in >99% of patients	Established cardiovascular disease in 65.6%; multiple cardiovascular risk factors in 34.4% of patients	Established cardiovascular disease in 40.6%; multiple cardiovascular risk factors in 59.4% of patients
Patients with type 2 diabetes	100% (mean HbA 1c 8.1%)	100% (mean HbA1c 8.2%)	100% (mean HbA 1c 8.3%)
Patients with congestive heart failure	10.1 %	14.4%	10.0%
Median study duration	3.1 years	2.4 years	4.2 years
Primary endpoint	3P-MACE: Cardiovascular mortality, nonfatal myocardial infarction or stroke	3P-MACE: Cardiovascular mortality, nonfatal myocardial infarction or stroke	Composite endpoint: 3P-MACE as well as cardiovascular mortality or hospitalization for heart failure
Hazard ratio for primary endpoint	0.86 (95% confidence interval: [0.74; 0.99]) p<0.001 non-inferiority p = 0.04 superiority	0.86 [0.75; 0.97] p<0.001 non-inferiority p = 0.02 superiority	3P-MACE: 0.93 [0.84; 1.03] p<0.001 non-inferiority p = 0.17 superiority Cardiovascular mortality or hospitalization for heart failure: 0.83 [0.73; 0.95] p<0.001 non-inferiority p = 0.005 superiority
Risk reduction for primary endpoint	ARR = 1.6% points RRR = 13.5% NNT = 62	ARR = 4.6 per 1 000 patient-years RRR = 14.6% NNT = not calculated	ARR = 0.9% points RRR = 16.0% NNT = 109
Further secondary endpoints Hazard ratio [95% CI] Risk reduction ((hypothesis-generating))	Cardiovascular mortality: 0.62 [0.49; 0.77] p < 0.001 ARR = 2.2% points RRR = 37.5% NNT = 46 All-cause mortality: 0.68 [0.57; 0.82] p < 0.001 ARR = 2.6% points RRR = 31.0% NNT = 39 Nonfatal myocardial infarction: 0.87 [0.70; 1.09] p = 0.22 Nonfatal stroke: 1.24 [0.92; 1.67] p = 0.16	Cardiovascular mortality: 0.87 [0.72; 1.06] p = not specified All-cause mortality: 0.87 [0.74; 1.01] p = not specified Nonfatal myocardial infarction: 0.85 [0.69; 1.05] p = not specified Nonfatal stroke: 0.90 [0.71; 1.15] p = not specified	Cardiovascular mortality: 0.98 [0.82; 1.17] p = not specified All-cause mortality: 0.93 [0.82; 1.04] p = not specified Myocardial infarction: 0.89 [0.77; 1.01] p = not specified Ischemic stroke: 1.01 [0.84; 1.21] p = not specified
Secondary endpoints specific for congestive heart failureHazard ratio [95% CI] Risk reduction (hypothesis-generating)	Hospitalization for heart failure: 0.65 [0.50; 0.85] p = 0.002 ARR = 1.4% points RRR = 34.0% NNT = 73	Hospitalization for heart failure: 0.67 [0.52; 0.87] p = not specified	Hospitalization for heart failure: 0.73 [0.61; 0.88] p = not specified
Mean eGFR	Approx. 74 mL/min/1.73 m²	Approx. 77 mL/min/1.73 m²	Approx. 85 mL/min/1.73 m²
Secondary endpoints specific for renal failureHazard Ratio [95% CI] (hypothesis-generating)	Incident or worsening renal failure (progression macroalbuminuria, doubling of the serum creatinine level with eGFR ≤ 45 mL/min/1.73 m², dialysis, or death from renal disease): 0.61 [0.53; 0.70] p < 0.001 ARR = 6.1% points RRR = 32.4% NNT = 17 Initiation of renal-replacement therapy: 0.45 [0.21; 0.97] p = 0.04 ARR = 0.3% points RRR = 53.8% NNT = 310	≥ 40 % reduction in eGFR, dialysis, kidney transplant or death from renal disease 0.60 [0.47; 0.77] p = not specified Progression albuminuria (>30 % increase): 0.73 [0.67; 0.79] p = not specified	≥40 % reduction in eGFR to <60 ml/min/1.73 m², dialysis, renal transplant or death from renal disease: 0.53 [0.43; 0.66] p = not specified

*In Germany, gliflozins are currently approved, alone and in combination, for the treatment of type 2 diabetes (empagliflozin: 10 or 25 mg daily; canagliflozin: 100–300 mg daily; dapagliflozin: 10 mg daily). The information about ARR, RRR and NNT were obtained—if available—from the relevant publications or calculated based on published data. The NNT is the inverse of the ARR; it is listed only in case of a statically significant ARR.

ARR, absolute risk reduction; eGFR, estimated glomerular filtration rate; HbA _1c, hemoglobin A _1c; NNT, „number needed to treat“; RRR, relative risk reduction; SGLT2, sodium-glucose cotransporter type 2; 3P-MACE, 3-point major adverse cardiac events; 95% CI, 95% confidence interval

The EMPA-REG OUTCOME study evaluated empagliflozin in patients with T2D and cardiovascular disease (4). In addition to usual care for T2D, patients received empagliflozin (10 mg or 25 mg/day) or placebo. Treatment with empagliflozin resulted in a statistically significant reduction of 3P-MACE (10.5% versus 12.1%, p<0.001 for non-inferiority, p = 0.04 for superiority). This corresponds to an absolute risk reduction (ARR) of 1.6% points, a relative risk reduction (RRR) of 13.5% and a number needed to treat (NNT) of 62. The difference is explained by a statistically significant reduction in cardiovascular mortality (3.7% versus 5.9% in the placebo group, ARR = 2.2 % points, RRR = 37.5 %, NNT = 46, p<0.001). In contrast, the analysis of individual components found no statistically significant differences with regard to nonfatal myocardial infarction or stroke. All-cause mortality, however, was found lower in the empagliflozin group (5.7% versus 8.3%, ARR = 2.6% points, RRR = 31.0%, NNT = 39, p<0.001).

In CANVAS, canagliflozin was evaluated in patients with T2D and cardiovascular disease (65.6%) or high cardiovascular risk (34.4%) (5). Subjects received either canagliflozin (100–300 mg/day) or placebo. 3P-MACE occurred significantly less frequently in the canagliflozin group compared to the placebo group (26.9 versus 31.5 events per 1000 patient-years, ARR = 4.6 events per 1000 patient-years, RRR = 14.6%, NNT = not specified, p<0.001 for non-inferiority, p = 0.02 for superiority). No statistically significant differences were found for individual components and all-cause mortality.

In DECLARE-TIMI 58, patients with T2D and cardiovascular disease (40.6%) or high cardiovascular risk (59.4%) were randomized to receive either dapagliflozin (10 mg/day) or placebo (6). For 3P-MACE, no statistically significant difference between dapagliflozin group and placebo group was found (8.8% versus 9.4%, p = 0.17 for superiority).

Gliflozins and congestive heart failure

In the safety studies, specific endpoints were analyzed for congestive heart failure.

EMPA-REG OUTCOME showed for empagliflozin a reduction in the rate of hospitalization for heart failure (2.7% versus 4.1%, ARR = 1.4% points, RRR = 34.0%, NNT = 73, p = 0.002) (4). The result of this explorative endpoint was as a trend also found for canagliflozin, but could not be satisfactorily supported statistically (5). In DECLARE-TIMI 58, by contrast, a composite of cardiovascular mortality or hospitalization for heart failure was used as a further primary endpoint, besides 3P-MAC. Treatment with dapagliflozin led to a statistically significant reduction of this endpoint (4.9% versus 5.8%, ARR = 0.9% points, RRR = 16.0%, NNT = 109, p = 0.005), resulting from a reduction in the rate of hospitalization for heart failure (6).

Subsequently, studies were specifically designed to evaluate the role of gliflozins in the management of congestive heart failure with a reduced left-ventricular ejection fraction (HFrEF) (table 2). The DAPA-HF study (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) included patients with overt HFrEF (EF ≤ 40%, NYHA stages II–IV, elevated N-terminal pro-brain natriuretic peptide [NT-proBNP] levels) (7). Both patients with (42.0%) and without T2D (58.0%) were enrolled in the trial. In addition to guideline-recommended heart failure therapy, patients received either dapagliflozin (10 mg/day) or placebo. For the primary endpoint (worsening heart failure or cardiovascular mortality), a statistically significant superiority of the dapagliflozin group (16.3% versus 21.2%, ARR = 4.9% points, RRR = 23.2%, NNT = 21, p < 0.001) was found. The recently published EMPEROR-Reduced trial included HFrEF patients who received either empagliflozin (10 mg/day) or placebo in addition to guideline-adherent heart failure therapy (8). With regard to the primary composite outcome of cardiovascular mortality or hospitalization for heart failure, a significant advantage was demonstrated for the Empagliflozin group (19.4% versus 24.7%, ARR: 5.3% points, RRR: 21.7%, NNT 19, p<0.001). This was largely attributable to a statistically significant reduction in the rate of hospitalization for heart failure, whereas the individual analysis failed to demonstrate a statistically significant reduction of cardiovascular mortality (10.0% versus 10.8%, p = not specified). However, a meta-analysis of the data of the EMPEROR-Reduced and DAPA-HF studies suggests that gliflozin treatment is also associated with a reduction in cardiovascular mortality (pooled hazard ratio 0.86 [0.76; 0.98], p = 0.027) and all-cause mortality (pooled hazard ratio 0.87 [0.77; 0.98], p = 0.018) (9). The subgroup analysis, however, revealed relevant differences in respect to NYHA class and ethnicity (potentially weaker treatment effect in patients with NYHA class III/IV as well as in white patients) (8, 9).

Table 2. Specific studies with focus on heart failure with a reduced ejection fraction (HFrEF): DAPA-HF and EMPEROR-Reduced*.

Acronym	DAPA-HF	EMPEROR-Reduced
Title	Dapagliflozin and Prevention of Adverse outcomes in Heart Failure	Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction
Time of publication	November 2019 (7)	August 2020 (8)
SGLT2 inhibitor	10 mg dapagliflozin	10 mg empagliflozin
Number of patients	4 744	3 730
Patients with type 2 diabetes	45.0% (at baseline examination 42.0%)	49.8%
Patients with congestive heart failure	100% (only HFrEF) NYHA II, III and IV	100% (only HFrEF) NYHA II, III and IV
Median study duration	18.2 months	16 months
Primary endpoint	Composite cardiac endpoint: Worsening of heart failure (hospitalization or urgent outpatient treatment for heart failure, including IV treatment) or cardiovascular mortality	Composite cardiac endpoint: Hospitalization for heart failure or cardiovascular mortality
Hazard ratio for primary endpoint	0.74 (95% confidence interval: [0.65; 0.85]) p < 0.001	0.75 [0.65; 0.86] p<0.001
Risk reduction for primary endpoint	ARR = 4.9% points RRR = 23.2% NNT = 21	ARR = 5,3% points RRR = 21.7% NNT = 19
Secondary endpoints (hypothesis-generating)	Cardiovascular mortality: 0.82 [0.69; 0.98] p = not specified All-cause mortality: 0.83 [0.71; 0.97] p = not specified	Cardiovascular mortality: 0.92 [0.75; 1.12] p = not specified All-cause mortality: 0.92 [0.77; 1.10] p = not specified
Secondary endpoints specific for congestive heart failure Hazard ratio [95% CI] Risk reduction (hypothesis-generating)	Cardiovascular mortality or hospitalization for heart failure: 0.75 [0.65; 0.85] p<0.001 ARR = 4.8% points RRR = 22.9% NNT = 21 Hospitalization for heart failure: 0.70 [0.59; 0.83] p = not specified Urgent outpatient treatment for heart failure (including IV treatment): 0.43 [0.20; 0.90] p = not specified	Total number of hospitalizations for heart failure: 0.70 [0.58; 0.85] p<0.001
Mean eGFR	Approx. 66 mL/min/1.73 m²	Approx. 62 mL/min/1.73 m²
Secondary endpoints specific for renal failure Hazard Ratio [95% CI] (hypothesis-generating)	≥ 50 % reduction in eGFR, end-stage renal disease, dialysis, kidney transplant or death from renal disease: 0.71 [0.44; 1.16] p = not specified	Mean decrease in eGFR per year: –0.55 ± 0.23 vs. –2.28 ± 0.23 mL/min/1.73 m² 1.73 [1.10; 2.37] p<0.001 Composite renal endpoint (chronic dialysis, kidney transplant, ≥ 40 % reduction of eGFR, eGFR<15 ml/min/1.73 m² in patients with a baseline egfr of ≥ 30 ml/min/1.73 m² or egfr<10 ml/min/1.73 m² in patients with a baseline egfr of <30 ml/min/1.73 m²): 0.50 [0.32; 0.77]: 0.50 [0.32; 0.77] p = not specified

* The information about ARR, RRR and NNT were obtained—if available—from the relevant publications or calculated based on published data.

The NNT is the inverse of the ARR; it is listed only in case of a statically significant ARR.

ARR, absolute risk reduction; eGFR, estimated glomerular filtration rate; HFrEF, heart failure with a reduced left-ventricular ejection fraction; IV, intravenous;

NNT, number needed to treat; NYHA, New York Heart Association; RRR, relative risk reduction; SGLT2, sodium-glucose cotransporter type 2; 95% CI, 95% confidence interval

Gliflozins and renal failure

Since chronic kidney disease (CKD) is a common complication of T2D, in the EMPA-REG OUTCOME trial a composite microvascular outcome of laser treatment for retinopathy, vitreous hemorrhage, diabetes-related blindness, or incident/worsening nephropathy was used in a secondary analysis (10). The outcome occurred less frequently in the empagliflozin group compared to the placebo group (14.0% versus 20.5%, ARR = 6.5% points, RRR = 31.9%, NNT = 16, p<0.001) and was almost completely due to renal effects. Another secondary outcomes included incident or worsening nephropathy (defined as macroalbuminuria, doubling of the serum creatinine level along with an estimated glomerular filtration rate [eGFR] of ≤ 45 mL/min/1.73 m², initiation of renal-replacement therapy, or death from renal disease). In patients treated with empagliflozin, a reduction in this endpoint was found (12.7% versus 18.8%, ARR = 6.1% points, RRR = 32.4%, NNT = 17, p<0.001). Despite a statistically significant reduction in the progression to macroalbuminuria (hazard ratio 0.62 [0.54; 0.72], p<0.001), empagliflozin had no effect on the rate of incident albuminuria. However, as this was a post-hoc analysis, its results are of hypothesis-generating nature.

For canagliflozin, CREDENCE, a study with a renal endpoint, was initiated (table 3) (11). Patients with T2D and an eGFR of 30–90 mL/min/1.73 m² and albuminuria (ratio of urine albumin to creatinine of 300 to 5000 mg/g) were randomized. A composite outcome of end-stage kidney disease, a doubling of the serum creatinine level, or death from cardiovascular or renal causes was defined. A statistically significant advantage was found for the canagliflozin group (11.1% versus 15.5%, ARR = 4.3% points, RRR = 28.0%, NNT = 24, p < 0.001). The recently published DAPA-CKD trial also included specific patients with chronic kidney disease (table 3) (12). At baseline, participating patients had an eGFR of 25 to 75 mL/min/1.73 m² and a urinary albumin-to-creatinine ratio of 200 to 5000 mg/g. For the primary composite outcome (decline in eGFR by ≥ 50%, end-stage renal disease and death from renal or cardiovascular causes) a significant advantage in favor of the dapagliflozin group was found (9.2% versus 14.5%, ARR = 5.3% points, RRR = 36.9%, NNT = 19, p<0.001).

Table 3. Specific studies with focus on chronic kidney disease: CREDENCE and DAPA-CKD*.

Acronym	CREDENCE	DAPA-CKD
Title	Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation	Dapagliflozin in Patients with Chronic Kidney Disease
Time of publication	June 2019 (11)	September 2020 (12)
SGLT2 inhibitor	100 mg canagliflozin	10 mg dapagliflozin
Number of patients	4401	4304
Patients with type 2 diabetes	100%(mean HbA 1c 8.3%)	67.5%
Patients with heart failure	14.8%	10.9%
Median study duration	2.6 years	2.4 years
Primary endpoint	Composite renal endpoint: doubling of serum creatinine level, end-stage renal disease (eGFR<15 ml/min/1.73 m², chronic dialysis, kidney transplant), death from renal or cardiovascular causes	Composite renal endpoint: Decrease in eGFR of ≥ 50 %, end-stage renal disease (eGFR<15 ml/min/1.73 m², chronic dialysis, kidney transplant), death from renal or cardiovascular causes
Hazard ratio for primary endpoint	0.70 (95% confidence interval: [0.59; 0.82]) p<0.001	0.61 [0.51; 0.72] p<0.001
Risk reduction for primary endpoint	ARR = 4.3 % points RRR = 28.0% NNT = 24	ARR = 5.3 % points RRR = 36.9 % NNT = 19
Secondary endpoints (hypothesis-generating)	Cardiovascular mortality: 0.78 [0.61; 1.00] p = 0.05 All-cause mortality: 0.83 [0.68; 1.02] p = not specified Cardiovascular mortality, myocardial infarction, stroke: 0.80 [0.67; 0.95] p = 0.01 ARR = 2.4% points RRR = 19.4% NNT = 43	All-cause mortality: 0.69 [0.53; 0.88] p = 0.004 ARR = 2.1% points RRR = 30.8% NNT = 48
Mean eGFR	Approx. 56 mL/min/1.73 m²	Approx. 43 mL/min/1.73 m²
Secondary endpoints specific for renal failure (hypothesis-generating)	Doubling of serum creatinine level, end-stage renal disease (eGFR<15 ml/min/1.73 m², chronic dialysis, kidney transplant, death from renal causes: 0.66 [0.53; 0.81] p<0.001 ARR = 3.2% points RRR = 31.8% NNT = 31	Decrease in eGFR of ≥ 50 %, end-stage renal disease (eGFR<15 ml/min/1.73 m², chronic dialysis, kidney transplant) or death from renal causes: 0.56 [0.45; 0.68] p<0.001 ARR = 4.7% points RRR = 41.6% NNT = 22
Secondary endpoints specific for congestive heart failure(hypothesis-generating)	Cardiovascular death or hospitalization for heart failure:0.69 [0.57; 0.83] p<0.001 ARR = 3.4% points RRR = 29.3% NNT = 30 Hospitalization for heart failure: 0.61 [0.47; 0.80] p<0.001 ARR = 2.4% points RRR = 37.0% NNT = 43	Cardiovascular mortality or hospitalization for heart failure:0.71 [0.55; 0.92] p = 0.009 ARR = 1.8% points RRR = 27.5% NNT = 57

* The information about ARR, RRR and NNT were obtained—if available—from the relevant publications or calculated based on published data.

The NNT is the inverse of the ARR; it is listed only in case of a statically significant ARR.

ARR, absolute risk reduction; eGFR, estimated glomerular filtration rate; HbA _1c, hemoglobin A _1c; NNT, number needed to treat; RRR, relative risk reduction; SGLT2, sodium-glucose cotransporter type 2

The safety of gliflozins

The main adverse drug reactions (ADRs) of gliflozins are summarized in the eTable. Recent information from pharmacovigilance activities is included in this list (4^th Quarter 2003 to 4^th Quarter 2019, OpenVigil 2.1-MedDRA).

eTable. Overview of the side effects observed with empagliflozin and dapagliflozin treatment, by frequency category and MedDRA system organ class*¹.

System organ class	Very common (>10%)	Common (10%–1%)	Uncommon (1%–0.1%)	Rare (0.1%–0.01%)	Very rare (<0.01%)
Infections		Vulvovaginitis (PRR 63) Other genital infections and urinary tract infections (PRR 30) Fungal infections (PRR 30)			Necrotizing fasciitis (Fournier‘s gangrene, PRR 14)
Metabolism	Hypoglycemia (PRR 4,8) Hypoglycemia when in combination with sulfonyl urea or insulin (PRR 30)	Thirst (PRR 17)	Hypovolemia (PRR 101)	Diabetic ketoacidosis (PRR 173)
Nervous system		Dizziness (PRR 1.5)
Gastrointestinal tract			Constipation (ND) Dry mouth (PRR 2)
Skin		Rash *2 (PRR 0.6) Pruritus (PRR 0.8, n. s.)			Angioedema *2 (PRR 0.6)
Musculoskeletal system		Back pain (PRR 0.8, n. s.)
Kidney and urinary tract		Dysuria (PRR 4,2) Polyuria (PRR 20)	Nocturia (PRR 4)
Genital tract			Vulvovaginal pruritus (PRR 16) Genital pruritus (PRR 30) Phimosis*3 (PRR 75)
Laboratory findings		Increased hematocrit (PRR 11.5) Dyslipidemia (PRR 1.8, n. s.)	Elevated blood urea level (PRR 2.3) Weight reduction (PRR 4)
Cardiac disease			Heart failure *4 (PRR 0.24) Cardiac arrest * 4 (PRR 0.36)

*¹ Pooled side-effect data are presented (coded as MedDRA preferred terms, www.meddra.org/how-to-use/basics/hierarchy), based on the Summaries of Product Characteristics (SmPC) of dapagliflozin and empagliflozin and on Proportional Reporting Ratios (PRR) from US pharmacovigilance data (analyzed using OpenVigil 2. www.openvigil.sf.net). If the information provided in the SmPCs was inconsistent, the respective higher frequency class was selected. The PRR expresses the relative risk compared to a background (another drug, another event). For example, vulvovaginitis occurs with gliflozins (here: “common”) about 63 times more frequently than with all other medications (“rare“ to “very rare“). PRRs below 1 show that in patients treated with one of the gliflozins a specific event is unexpectedly uncommon.

*² Side effects in patients treated with a gliflozin which were less common in the pharmacovigilance data than expected. These may not be adverse drug reactions at all.

*³ Event found in the pharmacovigilance data which is not (yet) listed in the SmPCs.

*⁴ Events found in the pharmacovigilance data which were significantly less common than expected in patients treated with one of the gliflozins (and consequently not listed in the SmPCs). These represent potential new indication areas.

ND: no data; MedDRA, Medical Dictionary for Regulatory Activities; n.s.: not statistically significant (p ≥ 0.05); PRR, Proportional Reporting Ratios

As the result of the induced glucosuria, gliflozins lead to an increased rate of urinary tract and genital infections, especially in women (4– 6). The incidence of genital infections varied from 0.9% (dapagliflozin) to about 6.4% (empagliflozin) in safety studies. However, the treatment was rarely discontinued because of these infections. In addition, an increased incidence of euglycemic ketoacidosis was found in patients treated with gliflozins, especially if taken in combination with insulin therapy (13). The DECLARE-TIMI 58 trial found a statistically significant increase in the occurrence of euglycemic ketoacidosis in patient taking dapagliflozin (incidence: 0.3 versus 0.1%; hazard ratio 2.18 [1.10; 4.30], p = 0.02) (6). In contrast, the relevant safety studies for empagliflozin and canagliflozin did not show such an increase (4, 5). Canagliflozin, in turn, was associated with an increased risk of amputation of the lower extremity in the CANVAS PROGRAM (5). Furthermore, an increased risk of fracture was noticed with canagliflozin. These observation were not confirmed for empagliflozin and dapagliflozin.

Discussion

EMPA-REG OUTCOME was the first study to draw attention to gliflozins as promising substances for the treatment of congestive heart failure and renal failure (4). The EMPA-REG OUTCOME patient population was clearly different from those of the two other large safety studies: In the CANVAS PROGRAM and DECLARE-TIMI 58, only 65.6% and 40.6% of patients, respectively, suffered from overt cardiovascular disease (5, 6). This implies that the patients were in better overall health and could explain why no superiority of dapagliflozin over placebo was found for 3P-MACE.

DAPA-HF was the first study to look specifically at the use of a gliflozin in the management of HFrEF (7). At the end of the recruitment period, only 42% of patients had a known T2D diagnosis. An additional 3% of subjects were newly diagnosed with T2D during the study. In subgroup analyses, the positive results for dapagliflozin were found for patients with and without diabetes. However, for an accurate interpretation of the DAPA-HF data it is critical that 67% of patients without diabetes were prediabetic (HbA_1c≥ 5.7%) (14). Thus, ultimately only about 18% of the DAPA-HF patients had a normal glucose metabolism. From the follow-up of the Diabetes Prevention Program Outcomes Study (DPPOS) we know that vascular complications, such as retinopathy, neuropathy and nephropathy, can already be triggered in the prediabetic stage. Patients with prediabetes had a cardiovascular 10-year risk of 16.2%, based on the Framingham risk score. This corresponded to an absolute risk increase of 1.8% points compared to the 10-year risk of 14.4% in the group with overt T2D (15).

In DAPA-HF, the positive effects on congestive heart failure already occurred early after randomization (7). Furthermore, a subgroup analysis showed that the effects of dapagliflozin can be more pronounced in patients with NYHA II compared to patients with NYHA III and IV. This would support the use of gliflozins early in the management of HFrEF patients with (pre-) diabetes. In contrast, an advantage for patients with advanced disease (e.g. worse pump function and lower eGFR) was found in other subgroups. Thus, there are some inconsistencies in the findings of the DAPA-HF trial. Furthermore, only 10.5% and 10.9% of patients (dapagliflozin group and placebo group, respectively) were treated with an angiotensin-receptor neprilysin inhibitor (sacubitril/valsartan). Given the prominent role of sacubitril/valsartan in the treatment of HFrEF, the comparatively small proportion of patients receiving this drug is an important limitation of DAPA-HF (16, 17). It has also been the subject of considerable discussion whether in DAPA-HF an increase in the dose of loop diuretics could have reduced the effectiveness of gliflozins. A relevant subgroup analysis indicated consistent positive effects of dapagliflozin, independently of the preexisting dose of diuretics (18). Following these findings for dapagliflozin, the EMPEROR-Reduced trial, the results of which were published in August 2020, demonstrated a therapeutic benefit in patients with HFrEF for empagliflozin too. According to the authors, the positive effects of empagliflozin were independently of the presence of T2D (8). In comparison to DAPA-HF, EMPEROR-Reduced enrolled patients with a slightly lower EF (mean EF about 27% versus about 31% in DAPA-HF).

On the basis of the existing data, gliflozins were included in the joint 2019 guideline of the European Association for the Study of Diabetes and the European Society of Cardiology (EASD and ESC). The guideline explicitly recommends the use of gliflozins to reduce the hospitalization rate in HFrEF patients with T2D (class 1A recommendation) (19). It can be expected that the new data from EMPEROR-Reduced and also from DAPA-HF will further boost the role of gliflozins in the treatment of HFrEF in future guidelines (9). In addition, ongoing studies are evaluating the potential benefits of empagliflozin (EMPEROR-Preserved) and dapagliflozin (DELIVER) in the treatment of congestive heart failure with preserved ejection fraction (HFpEF).

Early on in cardiovascular safety studies, signs of nephroprotective effects of gliflozins were noticed (4– 6). In the CREDENCE study, a primary renal endpoint was explicitly chosen (11). In patients with T2D and existing pharmacological inhibition of the renin-angiotensin-aldosterone system, canagliflozin led to a statistically significant reduction in the composite renal endpoint. The effects on renal function were measurable despite the fact that for blood sugar control, blood pressure and body weight only minor differences were found between the placebo group and the canagliflozin group. This suggests that gliflozins may have directs molecular effects on the kidney. By increasing natriuresis, gliflozins stimulate the tubuloglomerular feedback mechanism. This results in vasoconstriction of the afferent arterioles and consequently in a decrease in filtration pressure (20). Since AT1 receptor antagonist and ACE inhibitors reduce filtration pressure by means of vasodilation of the efferent vessel, additive nephroprotective effects of these substance classes are conceivable.

For dapagliflozin (DAPA-CKD) and empagliflozin (EMPA-KIDNEY), studies were subsequently designed to evaluate the potential benefits of gliflozins in patients with chronic kidney disease. DAPA-CKD was terminated early because a statistically significant advantage of the dapagliflozin group had already been noticeable in an interim analysis. The recently published final results of DAPA-CKD underscore the potential role of gliflozins as a treatment option in patients with chronic renal disease independently of the presence of T2D (12). It is also remarkable that patients receiving dapagliflozin showed a reduction in the secondary endpoint of all-cause mortality (4.7% versus 6.8%, ARR = 2.1% points, RRR = 30.8%, NNT = 48. p = 0.004).

Overall, gliflozins have a favorable side-effect profile (13). Hypoglycemic episodes usually only occur in combination therapy with other antidiabetic agents, most notably insulin and sulfonylurea drugs. Diabetic ketoacidosis is a rare complication and is often associated with euglycemia. The risk of ketoacidosis can be reduced by pausing treatment with gliflozins when the patient has an acute illness (so-called “sick day break“). Hypotension and hypovolemia result from increased natriuresis and should be balanced by modifying concomitant treatment with diuretics. The increased rate of fractures and amputations with canagliflozin, but not with empagliflozin and dapagliflozin, can currently not be explained conclusively (5). With an incidence of up to 6.4%, genital infections are a comparatively common side effect of gliflozins (4– 6). By applying appropriate hygienic measures and, if necessary, initiating antifungal or anti-infective therapy, it can usually be treated successfully.

Conclusion

Gliflozins are effective substances for the treatment of T2D. In addition, they have been gaining increasing importance in the treatment of HFrEF and chronic renal disease. Based on the currently available evidence, their effects on congestive heart failure and renal failure are independent of a purely antidiabetic activity and can already be observed in early stages of the disease. Future studies will further define the therapeutic significance of gliflozins in specific subgroups.

Questions on the article in issue 8/2021:

Gliflozins for the Treatment of Congestive Heart Failure and Renal Failure in Type 2 Diabetes

The submission deadline is 25 February 2022. Only one answer is possible per question. Please select the answer that is most appropriate

Question 1

What is the mechanism of action of gliflozins?

1. Selective inhibition of the sodium-potassium pump

2. Selective inhibition of the glucose transporter GLUT2

3. Selective inhibition of the sodium-glucose cotransporter-2

4. Selective inhibition of the sodium-chloride cotransporter NCC

5. Selective inhibition of the glucose transporter GLUT4

Question 2

Which section of the renal tubule is the (anatomical) target of gliflozins?

1. the proximal renal tubule

2. the collecting duct

3. the distal renal tubule

4. the glomerulus

5. the macula densa

Question 3

In the EMPA-REG-OUTCOME trial, empagliflozin was evaluated in type 2 diabetes patients with cardiovascular disease and compared with a placebo. What number needed to treat (NNT) was calculated for the composite primary endpoint of 3P-MACE (cardiovascular mortality, nonfatal myocardial infarction/stroke)?

1. NNT = 27

2. NNT = 34

3. NNT = 82

4. NNT = 62

5. NNT = 5

Question 4

In a secondary analysis of the EMPA-REG-OUTCOME trial, a composite microvascular endpoint (laser treatment for retinopathy, vitreous hemorrhage, diabetes-related blindness, incident/worsening nephropathy) was explored. How often did this endpoint occur in the groups compared (empagliflozin group versus placebo group)?

1. 20% versus 16.2%

2. 14% versus 20.5%

3. 16.2% versus 5.5%

4. 7% versus 12.1%

5. 3.5% versus 20.5%

Question 5

In the DAPA-HF trial, a positive effect was observed with dapagliflozin for the composite primary endpoint (worsening of heart failure or cardiovascular mortality). How high were the absolute risk reduction (ARR) and the number needed to treat (NNT)?

1. ARR = 10.1% points and NNT = 11

2. ARR = 12.3% points and NNT = 30

3. ARR = 18.5% points and NNT = 5

4. ARR = 25.3% points and NNT = 2

5. ARR = 4.9% points und NNT = 21

Question 6

Which symptoms/disorders are common (1–10%) adverse events associated with gliflozins?

1. Angioedema

2. Autoimmune diseases

3. Urinary tract and genital infections

4. Necrotizing fasciitis

5. Diabetic ketoacidosis

Question 7

In the CANVAS program, canagliflozin was associated with increased risks which appeared not to be increased with empagliflozin and dapagliflozin. What are these risks?

1. Risk of hospitalization for heart failure

2. Risk of amputation of the lower extremity and risk of fracture

3. Risk of fracture and cardiovascular death

4. Risk of amputation of the lower extremity and risk of hospitalization for heart failure

5. Risk of cardiovascular death and amputation of the lower extremity

Question 8

In the CREDENCE trial, what effect and what hazard ratio (HR) was achieved by canagliflozin with regard to the primary composite renal endpoint (doubling of serum creatinine level, end-stage renal disease, renal or cardiovascular death)?

1. Nephrotoxic effect and HR = 1.3

2. Non-relevant effect on renal function and HR = 0.98

3. Nephroprotective effect and HR = 0.36

4. Nephroprotective effect and HR = 0.70

5. Nephrotoxic effect and HR = 2.1

Question 9

In the DAPA-HF trial, dapagliflozin was used to treat patients with heart failure with a reduced left-ventricular ejection fraction (HFrEF). What important limitations are highlighted in this article?

1. Only a small percentage of patients received sacubitril/valsartan.

2. The study duration was too short.

3. The number of patients was too low.

4. The proportion of patients with type 2 diabetes was too small.

5. Too many patients withdrew from the study prematurely.

Question 10

In which study, no statistically significant difference to placebo was found for dapagliflozin with regard to the composite primary endpoint of 3P-MACE (3-point major adverse cardiac events)?

1. CANVAS

2. AMPA-REG-OUTCOME

3. DAPA-CKD

4. DECLARE-TIMI 58

5. CREDENCE