ABSTRACT
Aims
The American Diabetes Association recommends achieving treatment goals (glycated haemoglobin ≤ 53 mmol/mol [7.0%], blood pressure < 130/80 mmHg, low‐density lipoprotein cholesterol < 1.81 mmol/L and use of sodium–glucose cotransporter‐2 inhibitors or glucagon‐like peptide‐1 receptor agonists), to reduce cardiovascular and kidney complications in people with chronic kidney disease and type 2 diabetes. This exploratory study assessed whether treatment effects of finerenone versus placebo were modified by the number of treatment goals met at baseline.
Materials and Methods
FIDELITY, a prespecified pooled analysis, combined participant‐level data from the randomized, double‐blind, multicentre phase III FIDELIO‐DKD (NCT02540993) and FIGARO‐DKD (NCT02545049) trials. Participants with type 2 diabetes and chronic kidney disease were randomized 1:1 to finerenone or placebo. Composite cardiovascular and kidney outcomes, hospitalization for heart failure or cardiovascular death, hospitalization for heart failure and treatment‐emergent adverse events were assessed by subgroups based on the number of treatment goals achieved.
Results
At baseline, 29%, 40%, 24% and 7% of participants had met 0, 1, 2 and ≥ 3 treatment goals, respectively. Those with more treatment goals met had fewer composite cardiovascular outcomes (events per 100 patient‐years in the placebo group: 6.0, 5.1, 4.3 and 3.5 for 0, 1, 2 and ≥ 3 treatment goals, respectively). Similar patterns were observed for other outcomes. There was no heterogeneity in the effect of finerenone versus placebo on outcomes between subgroups. The safety profile of finerenone (vs. placebo) was similar across subgroups.
Conclusions
Finerenone demonstrated treatment benefits in people with chronic kidney disease and type 2 diabetes, irrespective of treatment goals achieved at baseline.
Keywords: cardiovascular complications, chronic kidney disease, finerenone, type 2 diabetes
1. Introduction
Chronic kidney disease (CKD) develops in 30%–40% of people with type 2 diabetes (T2D) [1, 2]. People with both T2D and CKD are at high risk of progressing to end‐stage kidney disease and experiencing major adverse cardiovascular (CV) events and CV mortality [1, 3].
Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist (MRA), has been shown to reduce the risk of both CV and kidney complications in individuals with T2D and CKD [4, 5]. In FIDELITY, a prespecified pooled analysis of the phase III, randomized, double‐blind, multicentre clinical trials FIDELIO‐DKD (NCT02540993) and FIGARO‐DKD (NCT02545049), treatment with finerenone reduced the risk of the composite kidney outcome by 23% and the composite CV outcome by 14% compared with placebo [4, 5, 6]. The benefits of finerenone were consistent across several post hoc analyses of subgroups, including participants with obesity [7], participants treated with and without sodium–glucose cotransporter‐2 inhibitors (SGLT2is) [8] or glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) [9], and participants with different levels of insulin resistance at baseline [10].
The American Diabetes Association (ADA) Standards of Care in Diabetes guideline recommends a multifactorial approach in addition to lifestyle modification and diabetes education to reduce diabetes complications [11]. This approach includes four main pillars: (1) glycaemic management; (2) blood pressure management; (3) lipid management; and (4) use of therapeutic agents with CV and kidney benefits. Whether the benefits of finerenone observed in the FIDELITY dataset are maintained in participants who do not meet any of these treatment goals, or in participants who meet most goals, remains uncertain. Understanding whether these benefits extend across levels of baseline risk factor control may help inform treatment decisions.
In this FIDELITY subanalysis, the effects of finerenone versus placebo were evaluated in participants with T2D and CKD according to the attainment of ADA‐recommended treatment goals at baseline.
2. Materials and Methods
2.1. Study Design and Participants
The prespecified FIDELITY analysis pooled individual participant‐level data from the FIDELIO‐DKD (NCT02540993) and FIGARO‐DKD (NCT02545049) phase III trials. The designs and outcomes of the individual trials, along with the results from the primary FIDELITY analysis, have been published previously [4, 5, 6, 12, 13]. Briefly, adults (aged ≥ 18 years) with T2D and CKD (urine albumin‐to‐creatinine ratio [UACR] 30 to < 300 mg/g and estimated glomerular filtration rate (eGFR) 25 to ≤ 90 mL/min/1.73 m2, or UACR 300 to ≤ 5000 mg/g and eGFR ≥ 25 mL/min/1.73 m2) were eligible to participate if they had serum potassium levels ≤ 4.8 mmol/L at both screening and run‐in, and had no clinical diagnosis of symptomatic chronic heart failure with reduced ejection fraction. Participants were excluded if they had the following criteria at screening: glycated haemoglobin > 12%, systolic blood pressure < 90 mmHg or uncontrolled arterial hypertension with systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg.
Eligible participants were randomized 1:1 to receive oral finerenone (10 or 20 mg once daily) or placebo, on top of a maximum tolerated labelled dose of renin–angiotensin system (RAS) blockade. In this subanalysis, participants were assessed by subgroups based on attainment of treatment goals at baseline.
2.2. Definition of Treatment Goals
Treatment goals were defined according to the ADA Standards of Care in Diabetes [11]. The following criteria were used to define attainment of treatment goals: (1) glycated haemoglobin ≤ 53 mmol/mol (7.0%); (2) blood pressure < 130/80 mmHg; (3) low‐density lipoprotein cholesterol < 1.81 mmol/L; and (4) use of SGLT2is or GLP‐1RAs. Subgroups were defined based on the number of goals that were met at baseline. Participants were divided into subgroups including those who met 0, 1, 2 and ≥ 3 treatment goals.
2.3. Baseline Measurements
Blood pressure was measured in the sitting position after 5 min of rest using a standard sphygmomanometer. Three consecutive readings were taken within a maximum of 20 min (≥ 1 min between readings). Blood samples were collected and glycated haemoglobin and low‐density lipoprotein cholesterol levels were measured at a central laboratory.
2.4. Outcomes
Efficacy outcomes included a composite CV outcome (time to CV death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for heart failure [HHF]), a composite of HHF or CV death, HHF, and a composite kidney outcome (time to kidney failure [defined as initiation of chronic dialysis for ≥ 90 days, kidney transplantation or a sustained decrease in eGFR to < 15 mL/min/1.73 m2] sustained ≥ 57% eGFR decrease from baseline over ≥ 4 weeks, or kidney‐related death). Additional efficacy outcomes included all‐cause mortality and changes in UACR and eGFR from baseline to month 48. Given that use of SGLT2is or GLP‐1RAs was uncommon at the time of the FIDELIO‐DKD and FIGARO‐DKD trials, the composite outcomes and all‐cause mortality were assessed in a sensitivity analysis excluding use of SGLT2is or GLP‐1RAs as a goal. Safety outcomes included the number of investigator‐reported treatment‐emergent adverse events (TEAEs). All outcomes were assessed by treatment goal attainment subgroup and by treatment arm (finerenone or placebo).
2.5. Statistical Analysis
Baseline clinical characteristics were described as mean ± SD or median (Quartile 1–Quartile 3) for continuous variables and n (%) for categorical variables, according to treatment goal attainment subgroups. Outcome events were adjudicated by an independent adjudication committee. All analyses were performed according to the intention‐to‐treat principle. The association between attainment of treatment goals and efficacy outcomes was assessed using stratified multivariable Cox proportional hazards models for time‐to‐first‐event analyses with randomized treatment group and baseline attainment of treatment goals subgroup included as independent variables, with a treatment‐by‐subgroup interaction term also included in the model. The time‐to‐event analyses were stratified using the following variables: study, pooled region (Europe, North America, Latin America and Asia), CV disease history, eGFR category at screening, and UACR category at screening. All time‐to‐event analyses were also adjusted for factors such as age, sex and systolic blood pressure at baseline.
As treatment goal attainment was defined only at baseline, the proportion of participants in each subgroup was recorded at three subsequent time points (Year 1, Year 2 and Year 3) to assess whether the baseline classification remained valid.
Changes in UACR over time were analysed using a mixed effect model for repeated measures assuming an unstructured covariance matrix and adjusting for treatment, stratification factors (study, history of CV disease, pooled region, screening albuminuria category and screening eGFR category), visit, log‐transformed baseline UACR value nested within type of albuminuria at screening, log‐transformed baseline value over time and treatment by study interaction as covariates; number of treatment goals met at baseline was the subgroup variable. The eGFR slopes were analysed using a 2‐slope linear spline mixed model for repeated measures. A random effect for the intercept, chronic slope (month 4 to planned end‐of‐study visit) and total slope (baseline to permanent discontinuation or end of study) was included to account for variation in participant progression rates over time. Separate unstructured covariance patterns were estimated for each treatment group.
TEAEs were analysed in the safety analysis set, which included all randomized participants who received ≥ 1 dose of the study drug. No adjustments for multiplicity were performed given the exploratory nature of this analysis. Participants with missing data for any measurement in the study were excluded only from the analysis for the specific variable for which data were missing but included in the analysis of other variables. A 2‐sided p‐value < 0.05 was considered statistically significant for main effects, and a 2‐sided p‐value < 0.05 was considered statistically significant for interaction tests, which have less statistical power. All analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC).
3. Results
3.1. Participants and Baseline Characteristics
A total of 12 990 participants were included in the analysis. At baseline, 29%, 40%, 24% and 7% of participants had met 0, 1, 2 and ≥ 3 goals, respectively (Table S1). The distribution of treatment goals met by goal category is described in Table S2. The mean age and the proportion of male participants increased with the number of treatment goals met (Table 1). Larger proportions of participants met a higher number of goals in Asia and Western Europe versus other regions; smaller proportions met treatment goals in Eastern Europe and Latin America. A history of CV disease was more common in participants who had already met some treatment goals compared with no goals, and median UACR at baseline decreased as the number of goals met at baseline increased. The proportion of participants receiving statins, SGLT2is and GLP‐1RAs increased with the number of goals met, whereas the number of participants receiving insulin and analogues decreased (Table 1). In participants achieving one goal, the most frequent goal achieved was glycated haemoglobin ≤ 53 mmol/mol (7.0%), followed by low‐density lipoprotein cholesterol < 1.81 mmol/L, systolic blood pressure < 130 mmHg and diastolic blood pressure < 80 mmHg, with the lowest proportion having the goal use of SGLT2i or GLP‐1RA (Table S2). This distribution was reflected in the combinations of treatment goals, with participants achieving ≥ 3 goals most likely to meet the goals of glycated haemoglobin ≤ 53 mmol/mol (7.0%), systolic blood pressure < 130 mmHg and diastolic blood pressure < 80 mmHg, plus low‐density lipoprotein cholesterol < 1.81 mmol/L (Table S2).
TABLE 1.
Key baseline characteristics by the number of treatment goals met at baseline.
| Characteristics | Number of treatment goals met at baseline | |||
|---|---|---|---|---|
| 0 (n = 3732) | 1 (n = 5208) | 2 (n = 3091) | ≥ 3 (n = 959) | |
| Age, years, mean ± SD | 63.9 ± 9.6 | 64.8 ± 9.6 | 65.6 ± 9.3 | 65.5 ± 9.6 |
| Sex, male, n (%) | 2330 (62.4) | 3691 (70.9) | 2288 (74.0) | 749 (78.1) |
| Race, n (%) | ||||
| White | 2608 (69.9) | 3529 (67.8) | 2051 (66.4) | 681 (71.0) |
| Black/African American | 168 (4.5) | 219 (4.2) | 113 (3.7) | 20 (2.1) |
| Asian | 684 (18.3) | 1166 (22.4) | 782 (25.3) | 228 (23.8) |
| Others a | 272 (7.3) | 294 (5.6) | 145 (4.7) | 30 (3.1) |
| Region, n (%) | ||||
| Western Europe | 629 (16.9) | 1107 (21.3) | 748 (24.2) | 252 (26.3) |
| Eastern Europe | 1250 (33.5) | 1254 (24.1) | 515 (16.7) | 107 (11.2) |
| North America | 453 (12.1) | 803 (15.4) | 584 (18.9) | 209 (21.8) |
| Asia | 742 (19.9) | 1277 (24.5) | 867 (28.0) | 284 (29.6) |
| Latin America | 550 (14.7) | 582 (11.2) | 234 (7.6) | 68 (7.1) |
| Others b | 108 (2.9) | 185 (3.6) | 143 (4.6) | 39 (4.1) |
| Duration of diabetes, years, mean ± SD c | 16.1 ± 8.4 | 15.0 ± 8.8 | 15.2 ± 8.8 | 15.6 ± 8.7 |
| HbA1c, mmol/mol, mean c | 69 | 60 | 54 | 50 |
| HbA1c, %, mean ± SD c | 8.5 ± 1.2 | 7.6 ± 1.4 | 7.1 ± 1.2 | 6.7 ± 0.9 |
| Systolic blood pressure, mmHg, mean ± SD c | 142.7 ± 10.9 | 138.3 ± 13.6 | 131.6 ± 14.6 | 122.1 ± 11.4 |
| Diastolic blood pressure, mmHg, mean ± SD c | 79.6 ± 8.4 | 77.0 ± 9.5 | 73.5 ± 9.5 | 69.2 ± 8.5 |
| History of CV disease, n (%) | 1595 (42.7) | 2330 (44.7) | 1511 (48.9) | 492 (51.3) |
| History of HF, n (%) | 356 (9.5) | 392 (7.5) | 200 (6.5) | 59 (6.2) |
| eGFR, mL/min/1.73 m2, mean ± SD c | 59.5 ± 22.6 | 57.2 ± 21.7 | 56.5 ± 20.7 | 55.8 ± 20.6 |
| eGFR category, mL/min/1.73 m2, n (%) | ||||
| < 25 | 47 (1.3) | 64 (1.2) | 38 (1.2) | 13 (1.4) |
| 25 to < 45 | 1150 (30.8) | 1749 (33.6) | 1001 (32.4) | 324 (33.8) |
| 45 to < 60 | 895 (24.0) | 1372 (26.3) | 887 (28.7) | 272 (28.4) |
| ≥ 60 | 1638 (43.9) | 2022 (38.8) | 1165 (37.7) | 350 (36.5) |
| Missing | 2 (< 0.1%) | 1 (< 0.1%) | 0 | 0 |
| UACR, mg/g, median (Q1–Q3) c |
640.5 (272.3–1399.2) |
540.0 (210.0–1215.2) |
424.4 (152.7–932.8) |
336.3 (109.9–728.4) |
| UACR category, mg/g, n (%) | ||||
| < 30 | 47 (1.3) | 85 (1.6) | 76 (2.5) | 22 (2.3) |
| 30 to < 300 | 959 (25.7) | 1581 (30.4) | 1107 (35.8) | 434 (45.3) |
| ≥ 300 | 2722 (72.9) | 3541 (68.0) | 1908 (61.7) | 503 (52.5) |
| Missing | 4 (0.1) | 1 (< 0.1) | 0 | 0 |
| LDL cholesterol, mmol/L mean ± SD d | 2.81 ± 0.83 | 2.24 ± 0.93 | 1.70 ± 0.77 | 1.35 ± 0.47 |
| Serum potassium, mmol/L, mean ± SD c | 4.4 ± 0.4 | 4.3 ± 0.4 | 4.3 ± 0.4 | 4.3 ± 0.4 |
| Baseline medication use, n (%) | ||||
| RAS inhibitors | 3724 (99.8) | 5203 (99.9) | 3083 (99.7) | 957 (99.8) |
| ACEis | 1559 (41.8) | 2056 (39.5) | 1123 (36.3) | 338 (35.2) |
| ARBs | 2172 (58.2) | 3150 (60.5) | 1960 (63.4) | 622 (64.9) |
| Diuretics | 1932 (51.8) | 2665 (51.2) | 1593 (51.5) | 511 (53.3) |
| Statins | 2341 (62.7) | 3684 (70.7) | 2511 (81.2) | 851 (88.7) |
| Potassium‐lowering agents e | 44 (1.2) | 72 (1.4) | 51 (1.6) | 15 (1.6) |
| Glucose‐lowering therapies | 3690 (98.9) | 5077 (97.5) | 2991 (96.8) | 927 (96.7) |
| Insulin and analogues | 2642 (70.8) | 3009 (57.8) | 1530 (49.5) | 439 (45.8) |
| GLP‐1RAs | 0 | 281 (5.4) | 411 (13.3) | 251 (26.2) |
| SGLT2is | 0 | 256 (4.9) | 376 (12.2) | 241 (25.1) |
Abbreviations: ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; CV, cardiovascular; GLP‐1RA, glucagon‐like peptide‐1 receptor agonist; HbA1c, glycated haemoglobin; HF, heart failure; LDL, low‐density lipoprotein; Q, quartile; RAS, renin–angiotensin system; SGLT2i, sodium–glucose cotransporter‐2 inhibitor; UACR, urine albumin‐to‐creatinine ratio.
Includes American Indian or Alaska Native, Native Hawaiian or Pacific Islander, not reported and multiple (participants who reported belonging to > 1 race).
New Zealand, South Africa, Australia.
n < 0.2% with missing data in the overall population.
A total of 350 (9.4%), 260 (5.0%), 76 (2.5%) and 6 (0.6%) patients had missing data at baseline in the 0, 1, 2 and ≥ 3 treatment goal subgroups, respectively.
Including potassium binders.
3.2. Effect of Treatment Goal Subgroup on CV and Kidney Outcome Incidence Rates
In the placebo arm, participants who met a higher number of treatment goals at baseline had a lower risk of composite CV outcome events: 6.0 events per 100 patient‐years (PY) in those who met 0 goals, 5.1 in those who met 1 goal, 4.3 in those who met 2 goals and 3.5 in those who met ≥ 3 goals. They also had a lower risk of CV death or HHF (3.9, 3.3, 2.9 and 2.2 events per 100 PY, respectively), HHF (1.9, 1.6, 1.7 and 1.4 events per 100 PY, respectively), and composite kidney outcome events (3.1, 2.7, 2.0 and 1.4 events per 100 PY, respectively; Figure 1). Accordingly, a similar pattern was observed for participants randomized to finerenone for all outcomes (Figure 2).
FIGURE 1.
CV and kidney outcome event rate according to the number of treatment goals met at baseline (placebo arm). CV, cardiovascular; HHF, hospitalization for heart failure.
FIGURE 2.
Cox proportional hazards model for (A) CV and (B) kidney outcomes by the number of treatment goals met at baseline. Data are shown for the full analysis set. Events were adjudicated by an independent adjudication committee and considered from randomization up until the end‐of‐study visit. A stratified Cox proportional hazards model including treatment was calculated separately by subgroup category. The interaction p‐value was based on a stratified Cox proportional hazards model including treatment, subgroup and treatment by subgroup interaction. Events based on a sustained decrease in eGFR were considered from randomization up until 5 months after the last eGFR was recorded at a clinic visit. aTime to CV death, nonfatal myocardial infarction, nonfatal stroke or HHF. bTime to onset of kidney failure, a sustained ≥ 57% decrease in eGFR from baseline over ≥ 4 weeks, or kidney‐related death. CV, cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalization for heart failure; PY, patient‐years.
3.3. Effect of Finerenone on CV Outcomes by Treatment Goal Subgroups
The risk of a composite CV outcome event was lower among participants randomized to finerenone compared with placebo (overall relative risk reduction of 14%) irrespective of the number of treatment goals met at baseline (relative risk reductions (hazard ratio [HR]; 95% confidence interval [CI]) of 10% [0.90; 0.76–1.05], 21% [0.79; 0.68–0.92], 12% [0.88; 0.72–1.08] and 11% [0.89; 0.59–1.37] for participants who had met 0, 1, 2 and ≥ 3 goals at baseline, respectively), with no significant heterogeneity observed between groups (p interaction = 0.75; Figure 2). Consistent results were shown for the composite of CV death or HHF, and HHF alone (p interaction = 0.89 and 0.73, respectively), and when absolute rather than relative risk reductions were considered for the composite CV outcome (p interaction = 0.29; Figure S1). The cumulative incidences of each outcome according to the number of treatment goals met at baseline and treatment group are shown in Figures S2–S4; there were fewer events among participants who met more treatment goals at baseline.
Results of the sensitivity analysis excluding use of SGLT2i and GLP‐1RA as a treatment goal were similar, showing an overall risk reduction of 14% and no significant heterogeneity between groups (p interaction = 0.85; Figure S5).
3.4. Effect of Finerenone on Kidney Outcomes by Treatment Goal Subgroups
The risk of a composite kidney outcome event was lower among participants randomized to finerenone compared with placebo (overall relative risk reduction of 24%). Relative risk reductions (HR; 95% CI) of 23% (0.77; 0.60–0.97), 29% (0.71; 0.57–0.88) and 30% (0.70; 0.50–0.97) were observed for participants who had met 0, 1 and 2 goals at baseline, respectively, and a relative risk increase of 11% (1.11; 0.56–2.18) was observed for participants who had met ≥ 3 goals at baseline. The effect of finerenone was not modified by the number of treatment goals met at baseline as no significant heterogeneity was observed between groups (p interaction = 0.61; Figure 2). Results were consistent when absolute rather than relative risk reductions were considered for the composite kidney outcome (p interaction = 0.13; Figure S1). The cumulative incidences of the composite kidney outcome according to the number of treatment goals met at baseline and treatment group are shown in Figure S6; there were fewer events among participants who met more treatment goals at baseline.
Results of the sensitivity analysis excluding use of SGLT2i and GLP‐1RA as a treatment goal were similar, showing an overall risk reduction of 24% and no significant heterogeneity between groups (p interaction = 0.40; Figure S5).
3.5. Effect of Finerenone on All‐Cause Mortality
All‐cause mortality was generally low, ranging from 2.5 to 3.5 events per 100 PY with placebo and from 2.3 to 3.7 with finerenone (Figure S7). The highest number of events was seen in those with no goals achieved. Overall, finerenone reduced the relative risk of all‐cause mortality compared with placebo (HR 0.89; 95% CI 0.79–1.00), and there was no significant heterogeneity between groups (p interaction = 0.0659; Figure S8).
3.6. Effect of Finerenone on UACR and eGFR Changes Over Time by Treatment Goal Subgroups
Compared with placebo, finerenone significantly reduced UACR from baseline to month 4 across treatment goal attainment subgroups (least‐squares [LS] mean treatment ratios of 0.70 [95% CI 0.66–0.74] for 0 goals met; 0.68 [95% CI 0.65–0.71] for 1 goal; 0.68 [95% CI 0.64–0.71] for 2 goals; and 0.62 [95% CI 0.56–0.68] for ≥ 3 goals; Figure S9A–D). This initial UACR reduction with finerenone compared with placebo was sustained throughout the trial regardless of subgroup.
Finerenone attenuated eGFR decline over time compared with placebo in all treatment goals subgroups (Figure S10). In participants with 0 goals met, the change in total eGFR slope from baseline to month 48 was −3.80 for finerenone and −4.35 for placebo, with an LS mean difference of 0.56 (95% CI 0.23 to 0.88) (Figure S10A). The change in total eGFR slope from baseline to month 48 was −3.14 for finerenone and −3.81 for placebo (LS mean difference of 0.67 [95% CI 0.42 to 0.92]) for 1 goal met, −2.86 for finerenone and −3.15 for placebo (LS mean difference of 0.29 [95% CI 0.01 to 0.57]) for 2 goals, and −2.43 for finerenone and −2.71 for placebo (LS mean difference of 0.28 [95% CI −0.21 to 0.78]) for ≥ 3 goals (Figure S10B–D).
3.7. Change in Attainment of Treatment Goals Over Time
In the finerenone group, the proportion of participants achieving ≥ 3 treatment goals rose from 7.6% at baseline to 10.0% at 3 years. Respective proportions in the placebo group were 7.2% and 8.7% (Table S3). Other changes in participant numbers across the goal‐attainment subgroups were minor.
3.8. Safety Outcomes
The number of TEAEs was generally similar between the finerenone and placebo groups, and across the four baseline treatment goal–attainment subgroups (Table 2). Discontinuation due to TEAEs was low for finerenone and placebo across these subgroups. Incidences of serious TEAEs were also balanced across treatment groups and treatment goal–attainment subgroups. TEAEs affecting ≥ 5% of participants in any arm or subgroup are listed in Table S4. Acute kidney injury occurred in < 5% of all participants, with rates of 3.0%, 3.4%, 4.1% and 2.9% in the 0, 1, 2 and ≥ 3 goal‐attainment subgroups, respectively. Rates with placebo were 3.3%, 3.3%, 4.3% and 4.5%, respectively.
TABLE 2.
TEAEs by the number of treatment goals met at baseline.
| Number of treatment goals met at baseline | ||||||||
|---|---|---|---|---|---|---|---|---|
| 0 | 1 | 2 | ≥ 3 | |||||
| Finerenone n = 1899 | Placebo n = 1824 | Finerenone n = 2535 | Placebo n = 2666 | Finerenone n = 1564 | Placebo n = 1517 | Finerenone n = 491 | Placebo n = 467 | |
| Any AE | 1579 (83.1) | 1543 (84.6) | 2173 (85.7) | 2307 (86.5) | 1387 (88.7) | 1334 (87.9) | 443 (90.2) | 408 (87.4) |
| Study drug–related | 296 (15.6) | 218 (12.0) | 473 (18.7) | 351 (13.2) | 334 (21.4) | 213 (14.0) | 101 (20.6) | 77 (16.5) |
| Leading to discontinuation | 118 (6.2) | 86 (4.7) | 151 (6.0) | 132 (5.0) | 110 (7.0) | 99 (6.5) | 35 (7.1) | 33 (7.1) |
| Any SAE | 571 (30.1) | 589 (32.3) | 806 (31.8) | 921 (34.5) | 502 (32.1) | 508 (33.5) | 175 (35.6) | 163 (34.9) |
| Study drug–related | 16 (0.8) | 17 (0.9) | 36 (1.4) | 25 (0.9) | 25 (1.6) | 15 (1.0) | 6 (1.2) | 4 (0.9) |
| Leading to discontinuation | 48 (2.5) | 40 (2.2) | 52 (2.1) | 60 (2.3) | 32 (2.0) | 38 (2.5) | 13 (2.6) | 16 (3.4) |
| Death | 40 (2.1) | 47 (2.6) | 36 (1.4) | 62 (2.3) | 27 (1.7) | 29 (1.9) | 6 (1.2) | 13 (2.8) |
| Any hyperkalaemia‐related TEAE | 234 (12.3) | 118 (6.5) | 364 (14.4) | 190 (7.1) | 238 (15.2) | 98 (6.5) | 72 (14.7) | 42 (9.0) |
| Study drug–related | 148 (7.8) | 67 (3.7) | 224 (8.8) | 109 (4.1) | 151 (9.7) | 51 (3.4) | 48 (9.8) | 22 (4.7) |
| Leading to permanent discontinuation | 24 (1.3) | 9 (0.5) | 39 (1.5) | 15 (0.6) | 36 (2.3) | 11 (0.7) | 11 (2.2) | 3 (0.6) |
| Any serious hyperkalaemia‐related TEAE | 15 (0.8) | 6 (0.3) | 30 (1.2) | 8 (0.3) | 21 (1.3) | 1 (< 0.1) | 3 (0.6) | 1 (0.2) |
| Drug‐related | 9 (0.5) | 3 (0.2) | 18 (0.7) | 3 (0.1) | 13 (0.8) | 1 (< 0.1) | 3 (0.6) | 1 (0.2) |
| Leading to permanent discontinuation | 1 (< 0.1) | 1 (< 0.1) | 7 (0.3) | 0 | 1 (< 0.1) | 1 (< 0.1) | 1 (0.2) | 0 |
| Leading to hospitalization | 14 (0.7) | 3 (0.2) | 25 (1.0) | 6 (0.2) | 19 (1.2) | 0 | 3 (0.6) | 1 (0.2) |
| Fatal | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Serum potassium (mmol/L), num/den a (%) | ||||||||
| > 5.5 mmol/L | 346/1855 (18.7) | 154/1787 (8.6) | 424/2499 (17.0) | 206/2620 (7.9) | 230/1543 (14.9) |
85/1495 (5.7) |
72/484 (14.9) |
25/453 (5.5) |
| > 6.0 mmol/L |
64/1874 (3.4) |
29/1801 (1.6) |
94/2511 (3.7) |
32/2637 (1.2) |
45/1548 (2.9) |
12/1502 (0.8) |
8/485 (1.6) |
7/458 (1.5) |
Note: Unless otherwise specified, data are presented as n (%).
Abbreviations: AE, adverse event; SAE, serious adverse event; TEAE, treatment‐emergent adverse event.
The denominator (den) represents all participants at risk for a treatment‐emergent laboratory abnormality. The numerator (num) represents the number of participants at risk with ≥ 1 treatment‐emergent laboratory assessment meeting the criterion. Participants were required to have both a baseline and postbaseline treatment‐emergent value, and the baseline value could not exceed the displayed threshold. Only assessments from start of treatment until 3 days after any temporary interruption or from restart of study drug until 3 days after permanent interruption of study drug were considered.
In all treatment goal–attainment subgroups, investigator‐reported hyperkalaemia was more common in participants treated with finerenone versus placebo, with similar rates with finerenone treatment across the four goal‐attainment subgroups (Table 2). Serious hyperkalaemia leading to hospitalization or permanent discontinuation was rare (≤ 1.2% in the finerenone arm and ≤ 0.2% in the placebo arm of all four subgroups). No hyperkalaemia‐related deaths were reported.
4. Discussion
In this FIDELITY subanalysis, we observed that subgroups who had met a higher number of ADA‐recommended treatment goals at baseline had a lower risk of adverse CV outcomes, HHF, and adverse kidney outcomes irrespective of whether participants were treated with placebo or finerenone. Decline of eGFR was also slower in all participants who had met a higher number of treatment goals at baseline, irrespective of finerenone or placebo treatment.
These results are consistent with data from the seminal STENO‐2 study [14]. It is noteworthy that in STENO‐2, participants with T2D and microalbuminuria were randomized to standard care or intensified multifactorial intervention, which included tight glucose regulation and the use of RAS blockers, aspirin, and lipid‐lowering agents. Additionally, the investigators found that intensive treatment for 7.8 years was associated with a 51% reduced risk of adverse CV events, a 33%–48% reduced risk of microvascular complications, and a 45% reduced risk of all‐cause mortality over a follow‐up of 21 years [15]. Our results, derived from a post hoc analysis of FIDELITY, included a more contemporary population with T2D and a broad spectrum of CKD. Almost all participants (> 99%) were receiving RAS inhibitors at baseline. Our results are also consistent with the CKD‐REIN cohort study, which showed that reaching treatment targets among people with diabetes and CKD (eGFR 15–60 mL/min/1.73 m2) is prognostic in real‐world practice. In CKD‐REIN, a 30% lower risk of CV and kidney events over 5 years was observed in participants who reached two treatment goals at baseline versus those who reached fewer than two [16]. The goals included UACR < 300 mg/g, glycated haemoglobin < 7.0%, blood pressure < 130/80 mmHg, and prescription of RAS inhibitors. Therefore, the CKD‐REIN study and this FIDELITY post hoc analysis reinforce the importance of multifactorial risk factor control in improving T2D prognosis. The attainment of treatment goals at baseline is likely to be impacted by factors such as access to care, frequency of follow‐up, and medication adherence, as well as disease severity [17], underlining the importance of evidence‐based clinical guidelines and their applications in CKD and T2D management.
Contemporary management guidelines recommend multifactorial treatment to mitigate CV and kidney risks in people with CKD and T2D [2, 18]. In particular, the 2026 ADA guidelines recommend both SGLT2is and GLP‐1RAs, in combination if indicated, to reduce CKD progression and reduce CV risk. Furthermore, both Kidney Disease: Improving Global Outcomes (KDIGO) and ADA guidelines recommend the addition of a nonsteroidal MRA with proven efficacy (finerenone) to further reduce CKD progression and CV risk. However, when the FIDELIO‐DKD and FIGARO‐DKD trials were initiated, SGLT2is and/or GLP‐1RAs were not recommended for people with eGFR < 45 mL/min/1.73 m2 [8, 9, 19, 20, 21]. As a result, the number of participants receiving SGLT2is and/or GLP‐1RAs at baseline was low in this FIDELITY analysis. This fact would have influenced baseline characteristics, such as mean eGFR and median UACR, and would have limited the number of participants who met the treatment goal of ‘use of SGLT2is or GLP‐1RAs’ at baseline. This is reflected in use of SGLT2i or GLP‐1RA treatment being the least frequently achieved of the goals across subgroups. However, sensitivity analyses of efficacy outcomes excluding use of SGLT2is or GLP‐1RAs at baseline as a treatment goal showed no substantial differences from the main analysis in overall relative risk, risk between subgroups, or the effect of finerenone.
This analysis included a large cohort including more than 12 000 participants with T2D and CKD and clearly suggests a lack of treatment heterogeneity by treatment goal attainment in the CV and kidney benefits of finerenone. These benefits are also supported by time‐to‐event analyses stratified by multiple baseline parameters that could otherwise act as potential confounders, including age, sex, region and eGFR/UACR category at baseline. Given the growing role of nonsteroidal mineralocorticoid receptor blockade in the treatment of people with T2D and CKD, understanding that these benefits are independent of treatment goal attainment is of major importance.
The ADA recommends a comprehensive approach to the reduction in risk of diabetes‐related complications. Fundamental elements of this risk reduction include management of glycaemia, blood pressure and lipids, together with incorporation of specific therapies that offer CV and kidney benefits such as SGLT2is and GLP‐1RAs for people with established atherosclerotic CV disease or kidney disease. Research has shown that addressing multiple CV risk factors simultaneously has the potential to offer a large improvement in CV outcomes in people with diabetes [11]. Before the current analysis, it was uncertain whether the previously reported benefits of finerenone on CV and kidney outcomes in people with T2D and CKD would be observed independently of the number of treatment goals met. However, we show here that treatment with finerenone reduced the risk of the composite CV and kidney outcomes and HHF versus placebo irrespective of the number of treatment goals met at baseline. The absolute benefit of finerenone was similar, regardless of the number of treatment goals met. Although a numerical reduction in the relative or absolute risk for the composite kidney outcome was not observed for participants who had met ≥ 3 treatment goals at baseline, this was likely due to the low number of participants in this group (n = 959) and the low number of kidney events observed in these participants (21/491 for finerenone and 19/468 for placebo). Furthermore, no significant heterogeneity was observed between the treatment goal–attainment subgroups for the composite kidney outcome. In line with these composite outcome improvements, finerenone reduced UACR and attenuated chronic eGFR decline across subgroups. UACR reduction has been shown to drive 84% of the finerenone benefit on kidney outcomes [22]. The initial acute eGFR dip observed with finerenone was expected and occurs with other treatments, such as SGLT2is [23]. Finerenone benefits are not modified by this dip.
The risk of adverse events with finerenone was not modified by the number of treatment goals met, as the safety profile of finerenone compared with placebo was similar across the subgroups. As expected, hyperkalaemia rates were higher with finerenone across the four goal‐attainment subgroups (12.3%–15.2% with finerenone and 6.5%–9.0% with placebo). However, the clinical impact was low, with few permanent discontinuations, serious events or hospitalizations. This is in line with the overall FIDELITY population [6]. More recent evidence suggests that hyperkalaemia rates are lower when finerenone and SGLT2is are used together in people with CKD and T2D. In the CONFIDENCE trial, hyperkalaemia was reported in 9.3% of people treated with a finerenone‐and‐empagliflozin combination versus 11.4% of those receiving finerenone alone [24]. Additionally, lower hyperkalaemia rates than in FIDELITY were reported in a real‐world population initiating finerenone, 38% of whom were also receiving SGLT2is [25]. Nevertheless, routine potassium monitoring is recommended after initiation of finerenone in clinical practice [2].
Our findings indicate a clear benefit regardless of the number of treatment goals met at baseline. From a mechanistic standpoint, this is a plausible finding. In people with T2D and albuminuric kidney disease, activation of the mineralocorticoid pathway drives disease progression [26]. This activation may not be fully reversed by risk factor control using other agents, such as SGLT2is, GLP‐1RAs or RAS inhibitors [26, 27], which could partly explain the added beneficial effects of finerenone in this population. In addition, nonsteroidal MRAs show effects on inflammatory and fibrotic pathways across multiple organ systems, which suggest potential for synergistic effects [28]. This informed the KDIGO 2022 recommendation to add an MRA to treatment with RAS inhibitors in the context of eGFR decline and albuminuria [29].
From a clinical perspective, the present results suggest that finerenone should be used regardless of the number of treatment goals that have been met. This implies that for people with an indication for finerenone, treatment should not be delayed until risk factors are controlled. Conversely, even those who achieve all classic treatment goals benefit from finerenone, as it further reduces adverse CV and kidney events.
Limitations of this FIDELITY subanalysis should be acknowledged. First, although FIDELITY was itself a prespecified pooled analysis of two complementary phase III trials, the current analysis was not prespecified and must therefore be interpreted as exploratory. Second, although treatment with finerenone or placebo was randomized, the randomization was not stratified by the number of treatment goals met at baseline. Third, only 7.4% of participants met ≥ 3 treatment goals at baseline (n = 959), with the low number of participants receiving SGLT2is and/or GLP‐1RAs at baseline likely contributing to this. As a result, there were fewer events in this subgroup than in the others, leading to wider CIs, as well as larger variations in the time‐to‐event analyses. The data are nevertheless informative. Finally, the definition of treatment goal attainment was based on baseline measurements and did not account for potential changes in goal achievement during the trial. Although there was a slight increase in the number of participants achieving ≥ 3 treatment goals over the course of 3 years, confounding variables make an analysis over time challenging.
In conclusion, this exploratory analysis suggests that participants who had met more treatment goals at baseline in FIDELITY generally had a lower risk of CV and kidney events. This is most likely because their disease was well controlled, highlighting the importance of adhering to the ADA‐recommended four pillars of treatment to help reduce these risks. Finerenone reduced CV and kidney outcomes compared with placebo, and this effect was observed in all participants regardless of the number of treatment goals met at baseline. These data support the added benefit of finerenone in the management of T2D and CKD, even in people who have well‐controlled disease.
Author Contributions
Formal Analysis: all authors. Writing – original draft: J.S.N. writing – review and editing: all authors. Validation: all authors.
Funding
The FIDELIO‐DKD and FIGARO‐DKD studies and prespecified pooled FIDELITY analysis were funded by Bayer AG. Bayer AG participated in data collection, data analysis, data interpretation and approval of the manuscript.
Conflicts of Interest
J.S.N. reports having received consulting or speaker fees from AstraZeneca, Bayer, BIAL, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Menarini and Merck. A.R.L. reports having received consulting fees from BIAL. F.V.‐N. reports having received consulting or speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Novartis and Ultragenyx. B.P. reports consultant fees from Ardelyx, AstraZeneca, Bayer, Boehringer Ingelheim, Brainstorm Medical, Cereno Scientific, G3 Pharmaceuticals, KBP BioSciences, PhaseBio, Sanofi/Lexicon, Sarfez Pharmaceuticals, scPharmaceuticals, SQ Innovation, Tricida and Vifor Pharma/Relypsa. He has stock options in Ardelyx, Brainstorm Medical, Cereno Scientific, G3 Pharmaceuticals, KBP BioSciences, Sarfez Pharmaceuticals, scPharmaceuticals, SQ Innovation, Tricida and Vifor Pharma/Relypsa. He also holds a patent for site‐specific delivery of eplerenone to the myocardium (US patent #9931412) and a provisional patent for histone acetylation–modulating agents for the treatment and prevention of organ injury (provisional US patent #63/045784). G.F. reports lecture fees and/or that he is a committee member of trials and registries sponsored by Amgen, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier and Vifor Pharma. He is a senior consulting editor for JACC Heart Failure and has received research support from the European Union. L.M.R. reports consultant fees from Bayer. P.R. reports grants and payment of honoraria for lectures, educational events and steering group participation from AstraZeneca, Bayer and Novo Nordisk (all to the Steno Diabetes Center Copenhagen); payment of honoraria for lectures and participation in advisory boards from Boehringer Ingelheim, Sanofi, Gilead and Astellas (all to the Steno Diabetes Center Copenhagen); and receipt of study drugs for free for investigator‐initiated studies from Bayer, Novo Nordisk and Lexicon. S.D.A. has received research support from Abbott Vascular and Vifor International and personal fees from Abbott Vascular, Bayer, Boehringer Ingelheim, BRAHMS, Cardiac Dimensions, Impulse Dynamics, Novartis, Servier and Vifor International. G.S. has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, CSL Vifor, Cytokinetics, Novartis, Pharmacosmos, Bayer, Medtronic and Servier; has received personal fees from Abbott, Edwards Lifesciences, GETZ, Hikma, INTAS, Menarini, Roche and TEVA; and has received grants from Boston Scientific and Merck. C.A.B.S. is a full‐time employee of Bayer, USA. A.L. is a full‐time employee of Bayer SA. M.D.B. is a full‐time employee of Bayer AG, Germany. J.P.F. receives research support from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis and Salamandra.
Supporting information
Table S1: Distribution of the overall FIDELITY population by number of treatment goals met at baseline.
Table S2: Distribution of treatment goals met at baseline by goal category.
Table S3: Number of treatment goals achieved over time.
Table S4: Treatment‐emergent AEs affecting ≥ 5% of participants in any treatment group by goal attainment at baseline.
Figure S1: Absolute risk difference for time to the composite CV and kidney outcomes by number of treatment goals met at baseline.
Figure S2: Cumulative incidences for the composite CV outcome by number of treatment goals met at baseline.
Figure S3: Cumulative incidences for CV death or HHF by number of treatment goals met at baseline.
Figure S4: Cumulative incidences for HHF by number of treatment goals met at baseline.
Figure S5: Sensitivity analysis: Cox proportional hazards model for CV and kidney composite outcomes and all‐cause mortality by the number of treatment goals met at baseline.
Figure S6: Cumulative incidences for the composite kidney outcome by number of treatment goals met at baseline.
Figure S7: All‐cause mortality event rate according to the number of treatment goals met at baseline in placebo and finerenone arms.
Figure S8: Cox proportional hazards model for all‐cause mortality by the number of treatment goals met at baseline.
Figure S9: Change in UACR over time by number of treatment goals met at baseline.
Figure S10. eGFR slopes by number of treatment goals met at baseline.
Acknowledgements
Medical writing assistance was provided by Alison McTavish, MSc (OHMC), with funding from Bayer AG. Open access publication funding provided by FCT (b‐on).
Neves J. S., Leite A. R., Vasques‐Nóvoa F., et al., “Outcomes With Finerenone by Baseline Treatment Goals in Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Analysis,” Diabetes, Obesity and Metabolism 28, no. 7 (2026): 6022–6033, 10.1111/dom.70750.
An abstract reporting part of the results presented here was submitted to the Joint Congress of the European Society for Pediatric Endocrinology and the European Society of Endocrinology (May 10–13, 2025).
Data Availability Statement
The data sets generated during and/or analysed in the current study are available from the corresponding author upon request through www.vivli.org. Availability of the data underlying this publication will be determined according to Bayer's commitment to the EFPIA/PhRMA ‘Principles for responsible clinical trial data sharing’. This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified scientific and medical researchers' participant‐level clinical trial data, study‐level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the United States (US) and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized participant‐level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal. Data access will be granted to anonymized participant‐level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Distribution of the overall FIDELITY population by number of treatment goals met at baseline.
Table S2: Distribution of treatment goals met at baseline by goal category.
Table S3: Number of treatment goals achieved over time.
Table S4: Treatment‐emergent AEs affecting ≥ 5% of participants in any treatment group by goal attainment at baseline.
Figure S1: Absolute risk difference for time to the composite CV and kidney outcomes by number of treatment goals met at baseline.
Figure S2: Cumulative incidences for the composite CV outcome by number of treatment goals met at baseline.
Figure S3: Cumulative incidences for CV death or HHF by number of treatment goals met at baseline.
Figure S4: Cumulative incidences for HHF by number of treatment goals met at baseline.
Figure S5: Sensitivity analysis: Cox proportional hazards model for CV and kidney composite outcomes and all‐cause mortality by the number of treatment goals met at baseline.
Figure S6: Cumulative incidences for the composite kidney outcome by number of treatment goals met at baseline.
Figure S7: All‐cause mortality event rate according to the number of treatment goals met at baseline in placebo and finerenone arms.
Figure S8: Cox proportional hazards model for all‐cause mortality by the number of treatment goals met at baseline.
Figure S9: Change in UACR over time by number of treatment goals met at baseline.
Figure S10. eGFR slopes by number of treatment goals met at baseline.
Data Availability Statement
The data sets generated during and/or analysed in the current study are available from the corresponding author upon request through www.vivli.org. Availability of the data underlying this publication will be determined according to Bayer's commitment to the EFPIA/PhRMA ‘Principles for responsible clinical trial data sharing’. This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified scientific and medical researchers' participant‐level clinical trial data, study‐level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the United States (US) and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized participant‐level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal. Data access will be granted to anonymized participant‐level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.