Introduction
Inhibitors of the sodium–glucose co-transporter 2 (SGLT-2) were initially developed for the treatment of type 2 diabetes (T2D) for their effect of lowering blood glucose levels through increased excretion of glucose in the urine [
1]. In FDA-mandated cardiovascular safety trials, also identified as cardiovascular outcome (CVOTs) trials [
2], patients with T2D were typically divided by the presence or absence of established cardiovascular disease. However, once their efficacy in reducing the risk of heart failure or progression of chronic kidney disease was ascertained [
3‐
6] and thought to be largely independent of baseline and time-dependent changes in glycated hemoglobin [
7], the hypothesis emerged that their cardiorenal benefits might not necessarily be due to glucose lowering and might also be found in individuals without diabetes. The DAPA-HF (Dapagliflozin And Prevention of Adverse Outcomes in Heart Failure) trial [
8] was the first one to include patients with heart failure and reduced ejection fraction irrespective of the presence of T2D: the trial showed that dapagliflozin reduced the risk of worsening heart failure events and cardiovascular death and improved symptoms in patients with or without T2D.
Since then, other CVOTs have been published which have extended the number and the typology of patients candidate to this class of drugs, giving more information to clinicians to optimize therapy and hopefully reduce their risk of cardiorenal complications. One key question is how the effects of SGLT-2 inhibitors compared in patients with and without T2D, and whether the findings of the completed trials support the hypothesis that SGLT-2 inhibition might be an effective treatment for patients with heart failure, including those without diabetes. The aim of this meta-analysis was to provide an update of all large CVOTs with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D.
Discussion
The present meta-analysis includes the most recent published large RCTs (SCORED, SOLOIST-WHF and EMPEROR-P), thus providing the most contemporary assessment of the total available evidence for SGLT-2 inhibitor therapy and cardiorenal outcomes in patients with or without T2D. The findings of 11 CVOTs involving 77,541 patients show that treatment with SGLT-2 inhibitors reduced the risk of the composite CV death or hospitalization for HF by 23% in the overall population, with low and not significant heterogeneity, suggesting a plausible class effect for the outcome. This interpretation seems also supported by the subgroup analyses indicating the lack of significant difference in the reduced risk of the composite outcome in patients with or without T2D, or in subjects of 65 years of age or younger vs those older than 65 years of age. Although participants in the EMPEROR-P trial [
24] were grouped by different age-threshold (> 70 years vs ≤ 70 years), this may not have altered the estimation of the Hazard Ratio given the absence of heterogeneity and interaction between groups.
To date, the most meaningful class effect of SGLT-2 inhibitors appears to be that on HF hospitalization for the following reasons: (1) the reduced risk for HF hospitalization is > 25% in every CVOT published until now (range 27–39%); (2) there is a complete absence of heterogeneity (I
2 = 0%, P = 0.98) in the meta-analysis; (3) the confidence intervals of the HR are very close to the point estimate; and (4) the reduced risk of hospitalization for HF is significant in every CVOTs. So, we can be confident that the beneficial effect of SGLT-2 inhibitors to reduce the risk of hospitalization for HF is a class effect and is independent of the diabetes status, heart status (presence or absence of HF or established CV disease at baseline) and kidney status (presence or absence of chronic kidney disease at baseline) [
5,
30,
31].
A recent meta-analysis [
32] of 8 CVOTs pooled data of 65,587 patients and found that treatment with SGLT-2 inhibitors reduced the risk of the renal composite endpoint by 39%, including worsening renal function, end-stage kidney disease and death from CV or renal causes, adding evidence to their nephroprotective effect. While confirming nephroprotection by SGLT-2 inhibitors with a pooled reduced risk of renal outcome by 35%, the present meta-analysis including ten CVOTs reporting the renal outcome seems to question the class effect of SGLT-2 inhibitors for the following reasons: (1) the reduced risk of renal outcome is not significant in every CVOTs; (2) apart from canagliflozin, all other inhibitors (dapagliflozin, ertugliflozin, sotagliflozin and empagliflozin) fail to produce a significant nephroprotection in at least one CVOT; (3) there is moderate and borderline significant heterogeneity (I
2 = 35%, P = 0.10) in the present meta-analysis, probably as a consequence of the different criteria used to define the kidney outcome; and (4) the worst results, in terms of wideness of confidence intervals, are observed in patients with HF, independent of the presence of T2D. In particular, the beneficial effect of empagliflozin on the renal outcome was significantly greater in the EMPEROR-R than in the EMPEROR-P trial [
33], suggesting a major protective effect of the drug in patients with HF and a reduced ejection fraction. It is possible that the definition of the renal outcome may have played some role in the striking discordance between the effect of empagliflozin on heart failure and renal outcomes in EMPEROR-P trial. This discordance is extraordinarily puzzling as the effects of SGLT-2 inhibitors on hospitalization for HF and renal outcome had consistently tracked together in previous CVOTs. As empagliflozin reduced the risk of HF hospitalization in these two populations of patients with HF (reduced or preserved ejection fraction) irrespective of their baseline diabetic status, it is conceivable that nephroprotection is not the principal mechanism by which empagliflozin may prevent HF hospitalization [
34]. It has already been shown that SGLT-2 inhibitors led to greater benefits in patients with NYHA class II than in patients with NYHA class III or IV, and that the reduced HF composite outcome is independent of LVEF level (< 40%, 40% to < 50%, or ≥ 50%) [
35,
36].
Several hypotheses have been formulated in the attempt to explain the cardiorenal protective effects of SGLT-2 inhibitors, including, although not limited to a diuretic effect [
37], altered substrate utilization and cellular signaling though increased lipolysis in adipose tissue with subsequent generation of ketone bodies [
38], increased erythropoietin, hemoglobin, and hematocrit levels which can improve tissue oxygenation [
39] and improved the lipid profile and decreasing uric acid level [
40]. Moreover, the increase in the delivery of sodium to the macula densa results in vasoconstriction of the afferent arteriolar with a subsequent reduction in the intraglomerular pressure [
41]. Irrespective of the exact mechanism, the improvement in cardiorenal outcomes by SGLT-2 inhibitors in patients with and without T2D suggest inherent protective properties. To date, it is not yet possible to clearly identify subpopulations of patients without T2D that would benefit the most from treatment with SGLT-2 inhibitors.
This study has potential limitations that include the use of aggregate trial-data levels and some difference in the exact inclusion/exclusion criteria and definition of outcomes among trials. Moreover, not all CVOTs have published the subgroup data for all outcomes and therefore some trials are not included in the analysis for individual endpoints. Strengths of the present meta-analysis are the inclusion of all CVOTs published by September 30, 2021, the very large number of participants, the high quality of the trials which minimizes the risk of bias, and the absence of significant heterogeneity in most analyses, which ranged from absent to low or moderate.
The clinical relevance of these results seems also highlighted by the evidence that for some outcomes the clinical benefit is consistent irrespective of the presence of T2D, advanced age, and cardiorenal disease. On the basis of results of CVOTs, the FDA has approved dapagliflozin (May 5, 2020) and empagliflozin (August 18, 2021) to reduce risk for CV death and HF hospitalization in adults with HF with reduced ejection fraction regardless of whether they have diabetes [
42,
43].
Conclusions
Therapy with SGLT-2 inhibitors results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcome, and moderate reduction of CV, total mortality and MACE. The shift from a common antihyperglycemic drug to an agent with the likely indication of cardiorenal protection is under way and close to the goal. However, it is unlikely that future studies will significantly change the present scenario based on 11 CVOTs with more than 75,000 patients.
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