Efficacy and safety of mineralocorticoid receptor antagonists for patients with heart failure and diabetes mellitus: a systematic review and meta-analysis

Four studies with 4742 individuals were identified. The main findings of the present study were that MRA treatment was associated with improved clinical outcomes compared with those regimens without MRAs in patients with DM and HF. From a safety perspective, the most serious adverse effect of MRAs (spironolactone and eplerenone) is the development of hyperkalaemia. However, as adverse effects were mentioned in only 50 % of the studies, there was not sufficient evidence to draw conclusions on the issue of safety.

There are a number of limitations in this study. First, only four studies were available; the included studies were all observational and none of them were randomized controlled trials. There were three post-hoc sub-analyses of randomized controlled trials concerning MRAs in heart failure and just one prospective cohort study. Two students scored the quality of each of the articles, and quality scores for each study are shown in Table 2. However, the quality of individual research included in our analysis was not necessarily high. Eschalier et al. [30] did not provide the detailed information about characteristics of the subject investigated. Khosraviani et al. [32] failed to offer an elaborated description of the study design. Thus, the level of evidence for this meta-analysis does not seem to be high.

Secondly, any systematic review may suffer from publication or selection bias. Publication bias can be assessed graphically with a funnel plot, which could not be assessed owing to having just four available studies. Thirdly, methodology defects have been found in some of these studies, including failure to collect data prospectively and inadequate baseline comparisons. Some baseline characteristics were different among the studies. For example, studies used different MRAs (spironolactone, eplerenone), different controls (placebo control or blank control), different dosages of the active and control medicines, and different follow-up times and background therapies. Lastly, significant heterogeneities were detected when the effects of MRAs on CV mortality or HF hospitalization were evaluated. The heterogeneity among the studies might be affected by various factors, such as study designs, study quality and patient characteristics. Therefore, a random-effect model was used to synthesize the data. But because only two studies reported these events, we could not perform meta-regression meta-analysis to examine the source of the heterogeneity.

Due to the limited quantity and quality of the included studies, it is premature to draw conclusion about the efficacy of MRAs in patients with HF and DM. However, it should be noted that the absence of sufficient scientific evidence does not mean that the treatment is ineffective. The safety of MRA therapy for those patients remains to be further determined. The possible electrolyte trouble could have a multifactorial origin. We observed that when using MRAs, many patients also used others drugs, including ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and aspirin, but medical therapy was not different at baseline between the two groups. When the treatment with MRAs was undertaken, ACE inhibitors or ARBs were generally not discontinued, but patients underwent a modulation of their dosages or their dose was left unchanged. This suggests that ACE inhibitors or ARBs could be associated with the increased risk of hyperkalaemia; MRAs alone might not have caused this adverse effect. At the stage of the addition of MRA to therapy, a gradual up-titration of the MRA dose or a concomitant thoughtful reduction of the dose of ACE inhibitor or ARB could prevent the occurrence of hyperkalaemia, except in cases of severe impairment of kidney function. In addition, DM is an independent risk factor for the development of hyperkalaemia [33].

Several implications for research arise from this review. First, more randomized controlled trials of higher quality, with larger sample size and adequate follow up are needed to further evaluate the effect of MRAs. Second, the only extensively researched MRAs to date are spironolactone and eplerenone, further research on other MRAs such as canrenone is encouraged in these disease areas. Third, we should closely observe the incidence of adverse events, such as electrolyte abnormalities, gynecomastia, menstrual irregularities, acute kidney injury and the effects on serum glucose levels. Fourth, further study can focus on developing novel MRAs that have similar outcomes as spironolactone but lower rates of hyperkalaemia such as finerenone [34, 35]. Fifth, further study is needed with a focus on evaluating the outcomes of efficacy and safety in patients with heart failure associated with chronic renal failure, especially in patients with diabetic nephropathy, which are better represented in the literature regarding MRA efficacy and safety.