Ge-Bu Indication
What is Ge-Bu’s opinion?
- The efficacy of SGLT2 inhibitors in preventing mortality due to heart failure has only been proven for dapagliflozin in patients with reduced ejection fraction.
- Even for patients with reduced ejection fraction, the limited effect size that can be expected should be carefully weighed against the possible adverse effects and costs.
- An even smaller effect size is to be expected in patients without diabetes and with a reduced ejection fraction.
- Without substantiation by mortality data, Ge-Bu regards a reduction of the risk of hospitalisation due to heart failure as an endpoint of limited relevance.
Mode of action and adverse effects of SGLT2 inhibitors
The sodium-glucose cotransporter-2 (SGLT2) inhibitors canagliflozin, dapagliflozin, empagliflozin and ertugliflozin have been authorised in the Netherlands for the treatment of type 2 diabetes mellitus.1 Dapagliflozin and empagliflozin have also been authorised for patients without type 2 diabetes but with chronic symptomatic heart failure (New York Heart Association [NYHA] class II-IV; referred to below as ‘heart failure’) with reduced ejection fraction (left ventricular ejection fraction (LVEF) <40%). Both drugs are also reimbursed by health insurers for this indication. Only empagliflozin has also been authorised for patients with heart failure with preserved ejection fraction. It is, however, as yet not reimbursed for this indication. Only dapagliflozin has also been authorised for patients with chronic kidney damage.2, dapagliflozin represented 57% of all prescribed ‘defined daily doses’ (DDD) of the SGLT2 inhibitors, with empagliflozin representing 38%, canagliflozin 5% and ertugliflozin less than 0.1%.3
Mode of action
SGLT2 inhibitors selectively and reversibly block the SGLT2 in the renal tubule system. This blockage inhibits renal glucose reabsorption, leading to glucose being excreted with the urine. In addition, inhibition of the cotransporter also causes more sodium to be excreted in the urine. This not only lowers blood glucose levels, but also blood pressure and body weight.1 Some SGLT2 inhibitors are also assumed to reduce the preload and afterload (dapagliflozin, empagliflozin) or to slow down the progression of kidney damage (dapagliflozin).1
Efficacy
Ge-Bu has previously discussed the role of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus4 and that of empagliflozin for cardiovascular disorders5. Both articles concluded that their efficacy had been proven only in very limited subgroups, and that the small effect sizes found might not outweigh the expected adverse effects. Hence, they recommended reticence in prescribing them.
Adverse effects
Ge-Bu has also previously discussed the adverse effects of SGLT2 inhibitors in more detail.4 Among the most common adverse effects are skin rashes, urogenital infections and temporary suppression of kidney function. Two less common but very serious potential adverse effects are diabetic ketoacidosis and necrotising fasciitis of the perineum (Fournier gangrene).4,1
Research into efficacy
Meta-analyses on efficacy in heart failure
The authors of the 2022 meta-analysis searched PubMed, Web of Science and the Cochrane Library for randomised studies comparing SGLT2 inhibitors with placebo in patients with heart failure.6 They included ten studies with a total of 23,852 participants with heart failure, with and without preserved ejection fraction and with and without diabetes. The studies included had a median follow-up ranging from 0.75 to 4.2 years. The studies included also comprised three of the four registration studies. The fourth registration study, the DELIVER study, was only published after this meta-analysis.8
A more recent meta-analysis was published on the same day as the DELIVER study, and did include the findings of this study in its analyses.14 Furthermore, this meta-analysis included three other registration studies and the SOLOIST-WHF study.15 However, the data used in this meta-analysis contain an error. The number of deaths from cardiovascular causes reported by the EMPEROR-preserved study was incorrectly copied from the publication.10 This resulted in bias favouring empagliflozin, and thus SGLT2 inhibitors in general, in the result of the analysis of cardiovascular mortality for patients with preserved ejection fraction. This result is the only one that differs substantially from the results of the meta-analysis discussed in more detail below. Hence, despite the inclusion of the DELIVER study, the second meta-analysis does not add any relevant new information to the previous and more complete meta-analysis by Cao et al., and is therefore not discussed in detail here. It is, however, relevant to note that all 14 authors of this meta-analysis reported conflicts of interest.14 This is not the case for the meta-analysis by Cao et al. which is discussed in detail below, as none of its authors reported any conflicts of interest.6 In addition, the influence of the fact that 13 of the 14 authors were involved in the DELIVER study and nine in the DAHA-HF study is unclear. Both of these studies are discussed in greater detail below, and both were funded entirely by AstraZeneca.8,7
Mortality among patients with and without preserved ejection fraction
All-cause mortality was reported as an endpoint in all ten studies included. The hazard ratio (HR) for overall mortality in the SGLT2-inhibitor group relative to the placebo group was 0.90 (95% confidence interval [CI] 0.83 to 0.97). Cardiovascular mortality was reported as an endpoint in nine of the ten studies included. The HR for cardiovascular mortality in the SGLT2-inhibitor group relative to the placebo group was 0.88 (0.80 to 0.96).
Urogenital infections
Urogenital infections was reported as an endpoint in four of the ten studies included. The HR for urogenital infections in the SGLT2-inhibitor group relative to the placebo group was 1.17 (1.03 to 1.33).
Mortality among patients with preserved ejection fraction
The mode of action of SGLT2 inhibitors in patients with heart failure with preserved ejection fraction is particularly relevant, since empagliflozin has been specifically authorised for this group too. A comparable registration request for dapagliflozin seems likely now that the DELIVER study has also been published.8 Results for the subgroup of patients with preserved ejection fraction were reported in three of the ten studies included. In this subgroup, the HR for cardiovascular mortality in the SGLT2-inhibitor group relative to the placebo group was 0.99 (0.84 to 1.15). The HR for all-cause mortality was 1.00 (0.89 to 1.13).
Composite endpoint
Nine of the ten studies reported a composite primary endpoint comprising cardiovascular mortality and first hospitalisation for heart failure. The HR for the occurrence of this composite endpoint in de SGLT2-inhibitor group relative to the placebo group was 0.76 (0,71 to 0.81).
Randomised studies into efficacy for heart failure
The first of these studies compared dapagliflozin with placebo in patients with heart failure with reduced ejection fraction (LVEF<40%)7 while the second did the same for patients with heart failure with preserved ejection fraction (LVEF>40%)8. The third compared empagliflozin with placebo in patients with heart failure with reduced ejection fraction (LVEF<40%)9 and the fourth did the same for patients with heart failure with preserved ejection fraction (LVEF>40%)10.
All four studies used a primary endpoint comprising hospitalisations and interventions for heart failure and cardiovascular mortality. Since the clinical relevance of this endpoint is debatable (see the Background Information below for a detailed discussion), the remainder of the present article focuses mainly on effects on all-cause and cardiovascular mortality. It is important to consider both of these endpoints, as a reduction of the cardiovascular mortality is irrelevant if it does not lead to a reduced overall mortality. In addition, a difference in effect between these two endpoints gives an indication of the specificity of the effect as regards improving cardiovascular functioning. An overview of the findings is provided in table 1.
Table 1. Main findings regarding cardiovascular and all-cause mortality from four randomised studies
| Studie | SGLT2 inhibitor | LVEF | Hazard ratio for cardiovascular mortality (95% CI) | Difference in incidence of cardiovascular mortality per 100 person years | Hazard ratio for all-cause mortality (95% CI) | Difference in incidence of all-cause mortality per 100 person years |
|---|---|---|---|---|---|---|
| DAPA-HF7 | Dapagliflozin | ≤40% | 0.82 (0.69 – 0.98) | 1.4 | 0.83 (0.71 – 0.97) | 1.6 |
| DELIVER8 | Dapagliflozin | >40% | 0.88 (0.74 – 1.05) | 0.5 | 0.94 (0.83 – 1.07) NS | 0.4 |
| EMPEROR-Reduced9 | Empagliflozin | ≤40% | 0.92 (0.75 – 1.12) | 0.5 | 0.92 (0.77 – 1.10) NS | 0.6 |
| EMPEROR-Preserved10 | Empagliflozin | >40% | 0.91 (0.76 – 1.09) | 0.4 | 1.00 (0.87 – 1.15) NS | 0.1 |
LVEF: left-ventricular ejection fraction; NS: non-significant
Dapagliflozin
DAPA-HF study
This randomised double-blind phase 3 study included 4744 patients with heart failure (New York Heart Association [NYHA] class II, III or IV) with an ejection fraction smaller than 40%.7 Participants were randomised to 10 mg a day of oral dapagliflozin or placebo, both in addition to the recommended standard therapy for symptomatic heart failure. The mean age in the dapagliflozin group was 66.2 years, and 41.8% had diabetes, while the corresponding figures for the placebo group were 66.5 years and 41.8%. During a median follow-up of 18.2 months, 227 of the 2373 (9.6%) patients in the dapagliflozin group died from cardiovascular causes, compared to 273 of the 2371 (11.5%) patients in the placebo group. This results in an HR of 0.82 (0.69 to 0.98), corresponding to a difference in the incidence of 1.4 outcomes/100 person years and a ‘number needed to treat’ (NNT) of 72 for one year. Death from any cause occurred in 276 (11.6%) patients in the dapagliflozin group and 329 (13.9%) patients in the placebo group; HR 0.83 (0.71 to 0.97), corresponding to a difference in the incidence of 1.6 outcomes/100 person years and an NNT of 63 for one year.
The primary endpoint was a composite endpoint comprising (time to) unplanned hospitalisation or an urgent visit for intravenous therapy for heart failure, or cardiovascular mortality. This endpoint occurred in 386 patients (16.3%) in the dapagliflozin group and 502 patients (21.2%) in the placebo group; HR 0.74 (0.65 to 0.85).
DELIVER study
This randomised double-blind study included 6263 patients with heart failure (NYHA class II, III or IV) and an ejection fraction larger than 40%.8 The participants were randomised to 10 mg a day oral dapagliflozin or placebo, both in addition to the recommended standard therapy for symptomatic heart failure. The mean age in the dapagliflozin group was 71.8 years, and 44.7% had diabetes, while the corresponding figures for the placebo group were 71.5 years and 44.9%. During a median follow-up of 2.3 years, 231 of the 3131 (7.4%) patients in the dapagliflozin group died from cardiovascular causes compared to 261 of the 3132 (8.3%) patients in the placebo group; HR 0.88 (0.74 to 1.05), a non-significant difference. Death from any cause occurred in 497 (15.9%) patients in the dapagliflozin group and 526 (16.8%) patients in the placebo group; HR 0.94 (0.83 to 1.07), also a non-significant difference.
The primary endpoint was a composite endpoint comprising (time to) unplanned hospitalisation or an urgent visit for intravenous therapy for heart failure, or cardiovascular mortality. This endpoint occurred in 512 patients (16.4%) in the dapagliflozin group and 610 patients (19.5%) in the placebo group; HR 0.82 (0.73 to 0.92).
Empagliflozin
EMPEROR-Reduced study
This randomised double-blind phase 3 study included 3730 patients with heart failure (NYHA class II, III or IV) and an ejection fraction smaller than 40%.9 The participants were randomised to 10 mg a day oral empagliflozin or placebo, both in addition to the recommended standard therapy for symptomatic heart failure. The mean age in the empagliflozin group was 67.2 years, and 49.8% had diabetes, while the corresponding figures for the placebo group were 66.5 years and 49.8%. During a median follow-up of 16 months, 187 of the 1863 (10.0%) patients in the empagliflozin group died from cardiovascular causes, compared to 202 of the 1867 (10.8%) patients in the placebo group; HR 0.92 (0.75 to 1.12), a non-significant difference. Death from any cause occurred in 249 (10.1%) patients in the empagliflozin group and in 266 (10.7%) patients in the placebo group; HR 0.92 (0.77 to 1.10), also a non-significant difference.
The primary endpoint was a composite endpoint comprising (time to) hospitalisation for heart failure or cardiovascular mortality. This endpoint occurred in 361 patients (19.4%) in the empagliflozin group and 462 patients (24.7%) in the placebo group; HR 0.75 (0.65 to 0.86).
EMPEROR-Preserved study
This randomised double-blind phase 3 study included 5988 patients with heart failure (NYHA class II, III or IV) and an ejection fraction larger than 40%.10 The participants were randomised to 10 mg a day oral empagliflozin or placebo, both in addition to the recommended standard therapy for symptomatic heart failure. The mean age in the empagliflozin group was 71.8 years, and 48.9% had diabetes, while the corresponding figures for the placebo group were 71.9 years and 49.2%. During a median follow-up of 26.2 months, 219 of the 2997 (7.3%) patients in the empagliflozin group died from cardiovascular causes, compared to 244 of the 2991 (8.2%) patients in the placebo group; HR 0.91 (0.76 to 1.09), a non-significant difference. Death from any cause occurred in 422 (14.1%) patients in the empagliflozin group and 427 (14.3%) patients in the placebo group; HR 1.00 (0.87 to 1.15). Thus, no difference was found between the two groups.
The primary endpoint was a composite endpoint comprising (time to) hospitalisation for heart failure or cardiovascular mortality. This endpoint occurred in 415 patients (13.8%) in the empagliflozin group and 511 patients (17.1%) in the placebo group; HR 0.79 (0.69 to 0.90).
Subgroup analyses
- Patients with NYHA class III or IV compared to class II;
- patients with a larger ejection fraction compared to those with a smaller one (above the median7, over 30% 9, or over 60% 10;
- patients with atrial fibrillation (dapagliflozin7);
- patients with a BMI ≥30 (empagliflozin9,10).
No statistically significant differences were found between these subgroups.
Diabetes mellitus
Regarding the primary endpoint, no difference was reported between patients with or without diabetes. Exploratory analyses of the DAPA-HF study were published separately.11 These analyses compared the results for all endpoints between patients with and without diabetes. In the group with diabetes, death from cardiovascular causes occurred in 121 of the 1075 (11.3%) patients in the dapagliflozin group and 148 of the 1064 (13.9%) patients in the placebo group; HR 0.79 (0.63 to 1.01), a non-significant difference. The corresponding figures in the group without diabetes were 106 of the 1298 (8.2%) patients in the dapagliflozin group and 125 of the 1307 (9.6%) patients in the placebo group; HR 0.85 (0.66 to 1.10), also non-significant. In the group with diabetes, death from all causes occurred in 143 of the 1075 (13.3%) patients in the dapagliflozin group and 178 of the 1064 (16.7%) patients in the placebo group; HR 0.78 (0.63 to 0.97), corresponding to a difference in incidence of 2.6 outcomes/100 person years and an NNT of 39 for one year. The corresponding figures for the group without diabetes were 133 of the 1298 (10.2%) patients in the dapagliflozin group and 151 of the 1307 (11.6%) patients in the placebo group; HR 0.88 (0.70 to 1.12), a non-significant difference.
Background Information
Composite endpoints
The randomised studies of empagliflozin discussed above both used a composite primary endpoint comprising hospitalisations for heart failure and cardiovascular mortality.9,10 The studies of dapagliflozin additionally used the outcome of ‘urgent visit (resulting in intravenous therapy) for heart failure’.7,8
Do the components match?
When using composite endpoints, it is always important to check whether all components of the endpoint are equally important, show equal effect sizes and occur with equal frequency.12,13 In the four studies discussed, the component of hospitalisation or intervention for heart failure is striking. This component is regarded in guidelines as a treatment goal, and can indeed be very relevant. This is especially the case if the hospitalisation is due to a persistent chronic deterioration of the cardiac function. This, however, is very unclear in the studies discussed above, as it is not clear whether the patients were hospitalised because of a temporary worsening of symptoms or because of sustained disease progression. In the first case, preventing hospitalisation probably yields little relevant health gain for a patient. Hence it is important to note that the composite endpoint showed highly comparable results in all four randomised studies discussed, in patients with or without reduced ejection fraction and with or without type 2 diabetes mellitus, whereas the cardiovascular mortality did differ between these groups. This shows that one component of the composite endpoint (hospitalisation) does not correlate well with the other (cardiovascular mortality). This is an undesirable situation for a composite endpoint.
Cardiovascular versus all-cause mortality
Another problematic aspect is that even a reduction of cardiovascular mortality may have limited value if this does not lead to reduced all-cause mortality. When evaluating the studies discussed it is therefore important to look at both cardiovascular mortality and overall mortality. Hospitalisations for heart failure and the composite endpoint which comprises these hospitalisations are not demonstrably related to relevant health gains for patients.
Improvement with suboptimal treatment?
Finally, one could argue that proving a difference in mortality rates is too difficult in patients who are already receiving optimal standard treatment and thus already have a low mortality rate. Patients who, for various reasons, cannot be given optimal standard therapy might perhaps show a greater reduction of mortality. This, however, was not proven, and it would require specific studies of this subgroup of patients to do so. It is undesirable to prescribe SGLT2 inhibitors to this subgroup purely on the basis of this speculation about a potentially larger effect.
Power and different endpoints
In all four of the studies discussed, the required size of the study sample was calculated based on the composite primary endpoint. The disadvantage is that this results in the study having insufficient power to allow reliable conclusions regarding the individual components of this composite endpoint. Hence, it is as such not surprising that the differences found regarding all-cause and cardiovascular mortality mostly turn out not to be statistically significant. The fact that this outcome was predictable in advance does not detract from the fact that, despite the considerable size of these studies, no statistically significant results were found for these clinically relevant endpoints. This therefore does allow the conclusion that, if there is any effect, it will be very small.
In addition, the appropriate way to arrive at reliable conclusions about endpoints for which the original studies had insufficient power is usually to conduct a meta-analysis. In the current case, the meta-analysis discussed above yielded only a limited difference in mortality for patients with heart failure with reduced ejection fraction, and no difference in mortality for patients with heart failure with preserved ejection fraction, from treatment with an SGLT2 inhibitor.
Study details
Meta-analysis6
Primary endpoint(s): for efficacy, a composite endpoint comprising the first hospitalisation for heart failure or cardiovascular mortality; for safety, serious adverse effects
Main secondary outcome measures: first hospitalisation for heart failure, cardiovascular mortality, all-cause mortality, serious cardiovascular complications, Kansas City Cardiomyopathy Questionnaire, acute kidney damage, urinary tract infections, hypoglycaemia, volume depletion, amputation and bone fractures
Inclusion criteria: randomised studies comparing SGLT2 inhibitors with placebo in patients with heart failure (or a subgroup analysis of patients with heart failure)
Main exclusion criteria: not all required data reported
Number of articles analysed: 10
Number of patients: 23,825
Follow-up: median follow-up ranging from 0.75 to 4.2 years
Funding: none
Conflicts of interest: none
DAPA-HF7
Design: randomised, multi-centre, double-blind, placebo-controlled phase 3 trial
Inclusion criteria: age >18 years, heart failure (New York Heart Association functional class II–IV), ejection fraction (EF) ≤40%, N-terminal prohormone brain natriuretic peptide (NT-proBNP) >600 pg/mL or >400 pg/mL and hospitalisation for heart failure in past 12 months
Main exclusion criteria: type 1 diabetes mellitus, hypotension or eGFR <30 mL/min/1.73 m2 BSA
Intervention: dapagliflozin (10 mg daily)
Primary endpoint(s) and duration: composite endpoint comprising (time to) unplanned hospitalisation or urgent visit for intravenous therapy for heart failure, or cardiovascular mortality
Intended number of patients and power: 844 primary endpoints intended, expected number of patients required 4500
Randomisation: block randomisation, stratified by diabetes status
Blinding: treatments were identical and blinded for patients and researchers
Population analysed: intention-to-treat
Number of patients included: 4744
Trial registration: clinicaltrials.gov: NCT03036124
Funding: AstraZeneca
Conflicts of interest: 32 of the 38 authors
DELIVER8
Design: randomised, multi-centre, double-blind, placebo-controlled phase 3 trial
Inclusion criteria: age ≥40 years, heart failure (New York Heart Association functional class II–IV), ejection fraction (EF) >40%, structural cardiac abnormalities, N-terminal prohormone brain natriuretic peptide (NT-proBNP) >300 pg/mL or >600 pg/mL and atrial fibrillation
Main exclusion criteria: SGLT2 inhibitor during 4 weeks prior to inclusion, type 1 diabetes mellitus or eGFR <25 mL/min/1.73 m2 BSA
Intervention: dapagliflozin (10 mg daily)
Primary endpoint(s) and duration: composite endpoint comprising (time to) unplanned hospitalisation or urgent visit for intravenous therapy for heart failure, or cardiovascular mortality. Follow-up at least 13.5 and at most 39 months
Intended number of patients and power: 6100 patents estimated to yield 1117 primary endpoints, in order to show a hazard ratio of 0.80 with 93% power
Randomisation: block randomisation, stratified by diabetes status
Blinding: blinded for patients and researchers
Population analysed: intention-to-treat
Number of patients included: 6263
Trial registration: clinicaltrials.gov: NCT03619213
Funding: AstraZeneca
Conflicts of interest: 35 of the 42 authors
EMPEROR-Reduced9
Design: randomised, multi-centre, double-blind, placebo-controlled phase 3 trial
Inclusion criteria: age >18 years, chronic heart failure for >3 months (New York Heart Association functional class II–IV), ejection fraction (EF) ≤40%, N-terminal prohormone brain natriuretic peptide (NT-proBNP) >600 pg/mL to >5000 pg/mL depending on ejection fraction and presence of atrial fibrillation, BMI<45
Main exclusion criteria: myocardial or cerebral infarction, or cardiovascular surgery in past 90 days
Intervention: empagliflozin (10 mg daily)
Primary endpoint(s) and duration: composite endpoint comprising (time to) hospitalisation for heart failure or cardiovascular mortality
Intended number of patients and power: 841 primary endpoints intended; expected number of patients required 2850, with an option of including up to 4000, adjusted to 3600 during the study
Randomisation: block randomisation, stratified by region, diabetes status and eGFR
Blinding: treatments were identical and blinded for patients and researchers
Population analysed: intention-to-treat
Number of patients included: 3730
Trial registration: clinicaltrials.gov: NCT03057977
Funding: Boehringer Ingelheim and Eli Lilly
Conflicts of interest: 38 of the 39 auteurs
EMPEROR-Preserved10
Design: randomised, multi-centre, double-blind, placebo-controlled trial
Inclusion criteria: age >18 years, chronic heart failure >3 months (New York Heart Association functional class II–IV), ejection fraction >40%, N-terminal prohormone brain natriuretic peptide (NT-proBNP) >300 pg/mL and atrial fibrillation, or NT-proBNP >900 pg/mL, BMI<45
Main exclusion criteria: myocardial or cerebral infarction or cardiovascular surgery during past 90 days
Intervention: empagliflozin (10 mg dd)
Primary endpoint(s) and duration: composite endpoint comprising (time to) hospitalisation for heart failure or cardiovascular mortality
Intended number of patients and power: 841 primary endpoints intended; expected number of patients required 4126, with an option of including up to 6000
Randomisation: block randomisation, stratified by region, diabetes status, eGFR, BSA and LVEF
Blinding: treatments were blinded for patients and researchers
Population analysed: intention-to-treat
Number of patients included: 5988
Trial registration: clinicaltrials.gov: NCT03057951
Funding: Boehringer Ingelheim and Eli Lilly
Conflicts of interest: 34 of the 41 authors
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