SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: The heart and kidney working better together

Robust evidence supports sodium glucose co-transporter 2 inhibitors (SGLT2i) as a foundational therapy for patients with heart failure with reduced ejection fraction (HFrEF). Initially developed to improve glucose control in patients with type 2 diabetes, SGLT2i have beneficial cardiovascular and renal effects in patients with diabetes, HFrEF², and chronic kidney disease (CKD)^{3, 4}.

Pre-specified sub-group analyses from DAPA-HF⁵ and EMPEROR-Reduced⁶ recently evaluated SGLT2i effects on renal outcomes as well as cardiovascular outcomes by baseline renal function in patients with HFrEF. These analyses provide additional evidence supporting the use of SGLT2i in patients with HFrEF regardless of comorbid CKD, while also providing context to discuss whether SGLT2i can claim independent, renal-specific benefits in this population.

In both DAPA-HF and EMPEROR-Reduced, the benefits of SGLT2i with respect to the primary cardiovascular outcome were consistent regardless of baseline CKD status. Renal composite outcomes from the two trials however revealed discordant results. In DAPA-HF, the renal composite outcome was numerically lower in the dapagliflozin arm but was not statistically significant (HR 0.71, 95%CI: 0.44–1.16), possibly due, in part, to a low number of events (67 total). However, a similar renal composite in EMPEROR-Reduced was 50% lower with empagliflozin than placebo, regardless of CKD status (total of 88 events) in a trial with a smaller sample size and shorter median follow-up. Possible explanations for these discrepant findings between trials include differences in composite outcome definitions, baseline eGFR cutoffs, trial execution or statistical chance. Alternatively, while existence of a “class effect” has been suggested for the HF hospitalization benefits of SGLT2i in HFrEF, this may not be the case for renal outcomes in this population. One can juxtapose the reduction in cardiovascular death seen with dapagliflozin in DAPA-HF (but not with empagliflozin in EMPEROR-Reduced) with the renal outcome benefit in EMPEROR-Reduced (but not DAPA-HF). The beneficial renal effects of SGLT2i seen in multiple recent trials are likely attributable to a variety of mechanisms, the sum of which alter the local renal cellular environment and modify bi-directional signaling between the kidney and other interconnected systems (cardiac, vascular, lymphoid, autonomic nervous system, etc). Given the multiple proposed mechanisms that may mediate these benefits, heterogeneous treatment effects between different medications in this class may exist.

Both renal sub-group analyses also analyzed eGFR slope as a key secondary endpoint, albeit with differing statistical approaches. In DAPA-HF, eGFR slope was dichotomized by day 0–14 and day 14–720 given the expected, disproportionate early decline in eGFR with SGLT2i. Patients randomized to dapagliflozin experienced a steeper decline in eGFR from day 0–14 compared to the placebo group, followed by less decline in eGFR from day 14–720. These findings were consistent regardless of baseline diabetes or CKD. In EMPEROR-Reduced, eGFR slope was analyzed from baseline throughout follow-up without early/late dichotomization. Patients in the empagliflozin arm experienced significantly less decline in eGFR over follow-up than placebo, despite the expected disproportionate early eGFR decline with SGLT2i. This beneficial effect was observed in patients with and without baseline CKD, but was more pronounced in patients in patients without CKD (p-interaction=0.045).

Given that traditional renal endpoints such as doubling of serum creatinine or initiation of dialysis tend to occur much later in the course of disease or over longer periods of follow-up, eGFR slope and worsening of albuminuria have been proposed as surrogate markers⁷. An absolute reduction in eGFR slope of 0.5 to 1.0 mL/min/1.73m² or 30% reduction in albuminuria compared with placebo are associated with an ~30% relative risk reduction in clinical outcomes⁸. However, there are important caveats regarding the use of eGFR as a surrogate measure including the potential for less utility in patients with higher baseline eGFR (due to imprecision of the eGFR calculation at higher filtration rates) and for medications that cause an “acute effect” on eGFR decline (as with SGLT2i) due to alteration of tubular-glomerular feedback mechanisms^{8, 9}. In EMPEROR-Reduced, the reduction in eGFR slope for empagliflozin versus placebo (absolute difference 1.73, 95% CI 1.10–2.37 per year) meets the suggested cutoff for beneficial effects with respect to renal function, though change in albuminuria was not reported. In DAPA-HF, urine albumin was not collected and eGFR slope was only reported as a dichotomized variable as noted above, thus making it more difficult to interpret these data.

To place these data in the context of recent SGLT2i trials in patients with CKD, eGFR slope was also used as a secondary endpoint in both CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation)³ and DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease)⁴. Notably, these trials had a limited number of patients with known HF. Nonetheless, both trials showed the expected initial decrease in eGFR for patients randomized to SGLT2i, which was followed by substantial improvement in eGFR slope compared to placebo over time (between-group difference of 1.52 and 0.93 mL/min/1.73m² per year, respectively). eGFR curves for SGLT2i and placebo crossed in both studies at approximately 12 to 14 months after randomization with continued separation—suggesting sustained benefits of SGLT2i throughout the remainder of the study period. These data provide convincing evidence of the renal benefits in patients with CKD, however they cannot be directly extrapolated to patients with HFrEF. Further mechanistic and long-term data in HFrEF (with and without CKD) are needed to better understand how the kidneys respond to SGLT2i in these patients.

As noted above, patients randomized to SGLT2i in both DAPA-HF and EMPEROR-Reduced experienced an initial sharp decline in eGFR followed by a slow continued downward trend over the course of the study period. The clinical significance of this early decline in eGFR with SGLT2i is unclear, however, this pattern has been observed in HFrEF trials of renin-angiotensin system inhibitors (RASi) that have marked long-term cardiovascular and renal benefits^{10, 11}. Concern remains that this early eGFR reduction may lead clinicians to discontinue these therapies despite data that early worsening renal function after RASi initiation does not appear to modify the long-term benefits of treatment (and in fact, may help identify the population who receives a larger magnitude of benefit)¹⁰. Importantly, if SGLT2i result in long-term attenuation of the progressive renal dysfunction that is common in patients with HFrEF, one would expect to see eGFR curves eventually cross followed by continued, sustained separation (i.e., more benefit over time with SGLT2i) (FIGURE). This pattern was observed in the main trial results from EMPEROR-Reduced with curves crossing at approximately 76 weeks. However, when stratified by baseline CKD status, this crossing was only observed in patients without baseline CKD (p-interaction=0.045), where the curves cross at approximately 52-weeks and separate over follow-up. eGFR curves in patients with baseline CKD from EMPEROR-Reduced as well as the overall study population in DAPA-HF (regardless of baseline renal function) did not show the same pattern of crossing of the curves with separation over follow-up. There are multiple potential explanations for these findings including that a longer follow-up duration or larger sample size may be needed to observe the treatment effect. As noted previously, it is also possible that the renal-protective effects of SGLT2i may not be consistent across the class or within different patient populations. However, we must not overextend any conclusions related to these subgroup analyses and secondary/exploratory endpoints when the overall abundance of evidence supports the cardio-renal benefits of SGLT2i.

Figure.

Schematic of several patterns of change in eGFR over time when there is an initial reduction of GFR with treatment and whether or not they are consistent with treatment benefits for the endpoint of GFR slope.

Several other important characteristics of DAPA-HF and EMPEROR-Reduced are worth noting. First, both trials enrolled a significant number of patients with CKD [41% and 53%, respectively]. Though this is representative of the prevalence of CKD in the general HFrEF population¹², each trial enrolled a fairly low number of patients who were Black (4.8% and 6.9%, respectively) despite the high prevalence of HFrEF (and CKD) in this population. We emphasize the continued need for robust data in historically underrepresented populations in trials. Second, background medical therapy for HFrEF was high in both trials. While <20% of patients in each trial were treated with sacubitril/valsartan, the degree of utilization was at least on par with current background therapy use in routine practice given multi-factorial delays in evidence implementation. Thus, these trial data provide strong evidence of the incremental benefits of SGLT2i on top of historical HFrEF therapies, while highlighting the need to redouble efforts in routine practice to optimize use and dosing of evidence-based medications including newer therapies.

Despite the complex interplay between heart failure and renal dysfunction, data from DAPA-HF and EMPEROR-Reduced strongly support the use of SGLT2i in patients with HFrEF regardless of diabetes or CKD status. The potential to slow the progression of renal disease over time and reduce renal events with SGLT2i represents a bonus for these HFrEF medications with significant cardiovascular outcome benefits. SGLT2i offer a unique opportunity for clinicians to treat cardiac and renal disease in concert rather than in discord, thereby adding an important arrow to our HFrEF pharmacologic quiver. We leave you with the question, “Are SGLT2i an ideal marriage counselor to mediate the tension between the heart and kidneys in HFrEF?”