In this retrospective study, we demonstrated that a combination of ARNI and SGLT2i was associated with a more significant improvement in cardiac function and a lower risk of cardiovascular death and HHF in diabetic patients with HFrEF. An increase in the LV-EF and a reduction in the mitral E/e’ ratio were observed 1−6 months after the initiation of ARNI-SGLT2i combination therapy. These improvements were larger than those seen in patients who received either ARNI or SGLT2i alone, as well as those who did not receive either of the two. It is interesting to note that the improvement in cardiac function was more prominent after the initiation of ARNI therapy, regardless of baseline SGLT2i use, compared to the vice-versa. These findings suggest that the combination of ARNI and SGLT2i could improve clinical outcomes in diabetic patients with HFrEF, and the early initiation of combination therapy may provide additional benefits.
Until the mid-2010s, RAS blockers, beta blockers, and MRA were the mainstay of the treatment of HFrEF. However, the mortality and HHF remained high, creating a need for the development of new treatments. The development of ARNI marked a major breakthrough in the treatment of HF, since it was able to reduce the risk of cardiovascular death by 20% and that of HHF by 21%, compared to treatment with the RAS blocker, enalapril. Subsequent studies reported that the prognostic benefits by ARNI are derived from and translated to robust improvements in echocardiographic parameters.[5, 17, 18] Although the overall prognosis is worse in diabetic patients with HFrEF than in non-diabetic patients with HFrEF,[19, 20] ARNI was observed to be beneficial even in the presence of diabetes. Several mechanisms have been suggested to explain the consistent cardioprotective effects of ARNI in patients with diabetes. First, the inhibition of neprilysin increases the concentration of various vasoactive peptides including natriuretic peptide, bradykinin, angiotensin I, angiotensin II, and glucagon-like peptide. The elevated levels of vasoactive peptides improve glycemic control by increasing insulin sensitivity and metabolism, enhance the mobilization of lipids from adipose tissue, improve muscular oxidative capacity, and enhance adiponectin release. All of these are crucial for pathologic cardiac remodeling.[6, 21, 22] Secondly, the increased levels of cyclic guanosine monophosphate prevent the loss of protective effects of protein kinase G, which promotes diastolic relaxation, improves ventriculoatrial coupling, and blunts cardiomyocyte stiffness and hypertrophy.[6, 23] The cardiovascular benefits of SGLT2i—another breakthrough class of drugs for the treatment of HFrEF—have been reported in several randomized controlled trials, especially their role in reducing the risk of composite worsening of HF.[2, 3, 7–9] There are several mechanisms suggested for the protective effect of SGLT2i on HF. In hemodynamic aspects, SLGT2i decreases preload and afterload, and reduces plasma and interstitial volume. In addition, SGLT2i acts on proximal renal tubule, and promotes reduction in intraglomerular pressure through restored tubule-glomerular feedback. Alleviated renal stress could improve cardiac function through reduced sympathetic nerve system activation, inflammation, and reactive oxygen species generation. Additional protective mechanisms of SGLT2i against HF are thought to be a result of improved efficiency of myocardial energy metabolism.[24–27]
Since ARNI and SGLT2i have different mechanisms of cardioprotective action, a combination of these drugs may exhibit synergistic effects. Representative trials of SGLT2i, such as DAPA-HF and EMPEROR-Reduced trials have shown consistent benefits in the treatment of HFrEF, regardless of the use of ARNI.[3, 10, 11] However, evidence of synergism has mostly been inferred from subgroup-analysis. In order to compare the effects of combination therapy with those of each individual drug, we divided the patients into 4 groups based on the use of ARNI and SGLT2i, and analyzed the outcomes after propensity-score matching. We found that diabetic patients with HFrEF treated with a combination of ARNI and SGLT2i showed a lower risk of HHF and cardiovascular death compared to those treated with only one or neither of these drugs. Our findings are consistent with those of prior studies, and further support the idea that ARNI and SGLT2i act through independent mechanisms and offer additional benefits in the treatment of HF.
Additionally, we compared the changes in echocardiographic parameters, which are indicative of the response to treatment, and can also translate into prognostic benefits. Improvements in echocardiographic parameters were observed 1−6 months after the initiation of treatment and were maintained until 12−24 months after initiation, suggesting that the early initiation of combination therapy may result in better prognosis in diabetic patients with HFrEF. Additionally, analysis of the patients in group 1, who received ARNI-SGLT2i combination therapy, showed a more pronounced increase in the LV-EF and decrease in the mitral E/e’ ratio with the addition of ARNI to SGLT2i therapy, compared to the addition of SGLT2i to ARNI therapy. This indicates ARNI resulted in prominent LV reverse remodeling regardless of SGLT2i. These findings are consistent with those of the PROVE-HF and EVAUATE-HF trials, in which the patients treated with ARNI showed a significant improvement in the LV function parameters.[5, 17] Although the additional reverse remodeling effect of SGLT2i was not significant in patients who were already receiving an ARNI, it was noted that the improvement in echocardiographic parameters and reduction in risk of cardiovascular death and HHF were more prominent in patients receiving combination therapy, than in those being treated with ARNI alone. Therefore, we believe that the inconspicuous changes in LV function after the addition of SGLT2i to ARNI therapy do not negate the cardioprotective effect of SGLT2i. Instead, this finding indicates that SGLT2i not only triggers LV reverse remodeling but also has favorable effects on HF, which may be associated with fundamental “myocardial effects,” such as myocardial energy metabolism.[24, 25, 29] Further studies using various imaging modalities and evaluating biomarkers, are required to investigate the effective mechanism of action of SGLT2i when it is added to ARNI treatment regimens.
This study had several limitations. It was a retrospective study, without pre-scheduled echocardiography. Propensity score matching for the study population was done to shortlist the participants, and the echocardiographic measurements taken within certain time-intervals were assessed. Secondly, data on the improvement of symptoms due to drug therapy could not be obtained due to the retrospective nature of the study. Thirdly, this study focused on the diabetic patients with HFrEF, meaning that these findings cannot be generalized to the rest of the population. Given the consistent benefits of ARNI and SGLT2i observed in non-diabetic patients with HFrEF in previous studies,[2, 3, 6] further studies to investigate whether our findings can be extrapolated to non-diabetic patients with HFrEF are warranted.