Effect of sodium–glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis

Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Type 2 diabetes mellitus (T2DM) can cause diabetic cardiomyopathy, which typically manifests first as left ventricular hypertrophy, diastolic dysfunction, and impaired systolic reserve before gradually showing clinical indications of heart failure with preserved ejection fraction (HFpEF), followed by systolic dysfunction and heart failure with reduced ejection fraction (HFrEF) [1]. T2DM also increases the risk of coronary heart disease and subsequent HF, especially HFrEF [2]. Besides, both in HFrEF and HFpEF patients, comorbid T2DM is associated with a worse prognosis [3‐5].

The effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on the prognosis (including all-cause death, cardiovascular death, and HF hospitalization) of T2DM [6‐9] patients with or without HF [10‐12] have been demonstrated in large-scale randomized controlled trials (RCTs) and meta-analyses. Based on clinical evidence, SGLT2i was recommended by the latest guidelines of the American Diabetes Association and the European Association for the Study of Diabetes in patients with T2DM and HF [13], and several agents were recommended by the Heart Failure Association of the European Society of Cardiology in T2DM patients at high cardiovascular risk or with established cardiovascular disease, especially symptomatic HFrEF [14]. However, the mechanism and intermediate links of the drugs remain to be clarified.

Cardiac anatomical and functional parameters partially predict the prognosis and quality of life of patients with T2DM and patients with HF and serve as important surrogate endpoints. Experiments in rodent T2DM models revealed the benefits of SGLT2i on left ventricular hypertrophy [15] and dilation [16], as well as cardiac systolic [15] and diastolic functions [15, 17]. In rodent and porcine nondiabetic HFrEF models, SGLT2i improved left ventricular ejection fraction (LVEF) [18‐20] but not diastolic function [20], and showed conflicting results in left ventricular structure [18‐21]. In animal models of HFpEF with or without T2DM, SGLT2i improved left ventricular structure [22] and diastolic function [22, 23], but did not affect LVEF [23].

Recent clinical studies have also reported conflicting results. In T2DM patients, the DAPA-LVH trial showed that SGLT2i reversed left ventricular hypertrophy compared to placebo [24], but the EMPA-HEART CardioLink-6 trial showed nonsignificant results [25]. The impacts on LVEF [25, 26], global longitudinal strain (GLS) [24, 27], and diastolic function [25, 28] were also inconsistent in different studies. Similarly, in patients with T2DM and HF, the effects of SGLT2i on left ventricular hypertrophy [27, 29], cardiac function [27, 30, 31], and neurohormonal parameters [32, 33] were inconsistent. Whether such diversity was due to insufficient sample size or heterogeneity among studies remains to be explored.

To make better use of up-to-date clinical evidence, we conducted this meta-analysis to further clarify the effect of SGLT2i on cardiac structure, cardiac function, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level and the Kansas City Cardiomyopathy Questionnaire (KCCQ) score in T2DM patients with or without chronic HF. Subgroup analyses were performed based on the stage A–B or stage C HF population and HF types.

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [34].

A total of 21 RCTs [10, 24, 25, 29‐31, 33, 39‐52] were recognized eligible in this meta-analysis, including 3 in crossover design [41, 44, 50]. A total of 10,978 participants were enrolled, including 6236 in the SGLT2i group and 4821 in the control group. Seventy percent of the participants were male, and the mean age ranged from 56 to 73 years old. The mean follow-up period ranged from 14 days to one year, including three studies [41, 50, 51] less than 3 months. Participants with T2DM that were mostly in stage A–B HF were enrolled in 10 studies [24, 25, 39, 40, 44, 46, 48, 49, 51, 52], and patients with T2DM and stage C HF were enrolled in 11 studies [10, 29‐31, 33, 41‐43, 45, 47, 50]. LVMI, LVEDVI, LVESVI, LAVI, LVEF, GLS, the E/e’ ratio, plasma NT-proBNP level, and the KCCQ score were reported in 6 [24, 25, 29, 44, 45, 52], 3 [25, 29, 30], 3 [25, 29, 30], 4 [25, 29, 45, 52], 9 [24, 25, 29‐31, 39, 40, 44, 45], 4 [24, 39, 44, 51], 8 [24, 25, 30, 31, 44, 45, 49, 52], 11 [10, 24, 25, 31, 41, 44‐46, 48‐50] and 3 [10, 42, 43] studies, respectively. Cardiac structure and function were evaluated by magnetic resonance imaging in 4 studies [24, 25, 29, 51], echocardiography in 8 studies [24, 30, 31, 39, 44, 45, 49, 52], and impedance cardiography in 1 study [40]. The treatment for the control group was placebo in 15 studies [10, 24, 25, 29, 33, 40‐44, 46, 47, 50‐52], and conventional treatment or other antidiabetic drugs in 6 studies [30, 31, 39, 45, 48, 49]. Baseline characteristics of the eligible studies were presented in Table 1.

This meta-analysis comprehensively and quantitively analyses the effects of SGLT2i on cardiac structure, cardiac function, plasma NT-proBNP level and the KCCQ score in T2DM patients with or without chronic HF. The main findings of this study included the following: (1) SGLT2i showed no significant effects on LVMI, LVEDVI, LVESVI, and LAVI; (2) SGLT2i improved LVEF in HFrEF patients but not in HFpEF patients or stage A–B HF patients with T2DM, and showed no significant effects on GLS in stage A–B HF patients with T2DM; (3) SGLT2i reduced the E/e’ ratio in the overall population and stage A–B HF patients but not in stage C HF patients; (4) SGLT2i improved the plasma NT-proBNP level in the overall population and stage C HF patients, and showed no significant results in stage A–B HF patients; and (5) SGLT2i improved the KCCQ score in stage C HF patients with T2DM.

Our searching and analysis results on the LVM, LVEDV, and LVESV were the same as those reported in a recently published meta-analysis [53], thus were not presented in this article. Pooled analysis of two studies [24, 25] reporting LVM measured by MRI in stage A–B HF population showed a significant reduction after the use of SGLT2i compared to placebo or other antidiabetic drugs (MD − 3.04 g, 95% CI − 5.14 to − 0.94, p = 0.005; I² = 0%). The inconsistency in the results of SGLT2i regarding LVM and LVMI may be attributed to the concomitant effect of weight loss, which was also observed in studies included in our analysis and a previous meta-analysis [24, 29, 31, 39, 54]. Since LVMI was calculated by LVM indexed by body surface area (BSA), which was influenced by both temporal height and weight of the individual, weight loss would obscure the estimation of the actual anatomical change of the heart. This was previously discussed in the study by Brown et al. [24], showing that SGLT2i significantly reduced LVM as well as LVM indexed by height or baseline BSA but not that indexed by real-time BSA. LVM was demonstrated to be a risk factor for the decline of LVEF [55] as well as all-cause and cardiovascular mortality [56] in stage A–B HF. The decrease of LVM might be related to the reduction of the incidence of stage C HF observed in previous RCTs. Despite larger sample sizes than the studies reporting LVM, the use of SGLT2i showed no significant effects on LVEDV, LVESV, LVEDVI, LVESVI, and LAVI, suggesting a null or faint effect of the drug on the dilation of cardiac chambers. Since the increase of LVM usually reflects both enlargement of the left ventricle and thickening of the walls, the results above may imply an effect of SGLT2i on the wall thickness rather than on the ventricle volume, which is to be demonstrated in future studies.

Taken together, the results of the overall and subgroup analyses suggested that SGLT2i significantly reduced LVEF in HFrEF patients but not in HFpEF patients, showing benefits in patients with obvious systolic dysfunction. However, the results in HFrEF subgroup suffered from a low certainty in the GRADE evidence profile, calling for more future studies in the population. The effect of SGLT2i on GLS, a more sensitive parameter reflecting even mild systolic dysfunction [57‐59], was not significant in the pooled analysis. Nevertheless, GLS was reported in four RCTs in stage A–B HF patients with T2DM but not yet in stage C HF patients. Ongoing trials such as ERTU-GLS (NCT03717194) in the T2DM and stage C HF population would provide more evidence. As for diastolic dysfunction, the E/eʹ ratio was reduced by SGLT2i in the overall population and stage A–B HF patients, but not in stage C HF patients. The discrepancy between the subgroups could be due to the mild and more reversible impairment of the diastolic dysfunction in stage A–B HF patients, whereas large-scale trials are still needed.

The use of SGLT2i significantly reduced the plasma NT-proBNP level in the stage C HF population. However, the effect on NT-proBNP level between the SGLT2i and control group was − 333 pg/ml in the T2DM subgroup in the DAPA-HF trial [10] (median baseline level in the SGLT2i group: 1479 pg/ml), and − 103 pg/ml in the whole population of EMPEROR-Reduced trial [42] (median baseline level in the SGLT2i group: 1894 pg/ml) declaring no significant difference in patients with and without T2DM. Those changes were moderate and inconsistent with the remarkable influence of SGLT2i on the cardiovascular events [60], suggesting that NT-proBNP could not be considered to be a satisfying surrogate endpoint for efficacy assessment in this case.

In the pre-SGLT2i age, the change of NT-proBNP level used to be expected to predict the effect size of HF therapy on cardiovascular outcomes. One meta-analysis [61] suggested a significant association between changes in NT-proBNP level and the risk of hospital stay for HF worsening. In the PARADIGM-HF trial [62], the use of angiotensin receptor-neprilysin inhibitor in HFrEF patients induced a 30% decline in NT-proBNP level after the run-in period of 4–6 weeks, and the reduction was associated with the change in cardiovascular mortality and HF hospitalization rate. However, the relationship was less strong in the PARAGON-HF trial [63] in HFpEF patients, which showed a considerable effect of SGLT2i on the reduction of NT-proBNP but a moderate effect on the primary outcome in the subgroups of men and patients with higher LVEF. Moreover, the termination of the GUIDE-IT trial [64] due to futility suggested against the add-on NT-proBNP-guided strategy versus guideline-directed medical therapy alone in HFrEF patients. Updated evidence from the trials in SGLT2i further supported the view that the NT-proBNP could not be used generally as a predictor of the hard endpoints, but may be indicative for specific drugs or in certain subgroups of patients.

Pooled results of the three large-scale RCTs reporting the KCCQ score showed significant improvement by SGLT2i compared with placebo in T2DM patients with stage C HF. As for the magnitude of the effect, analysis of the T2DM subgroup in DAPA-HF trial [10] showed that more patients reported an increase of at least 5 points in the SGLT2i group compared with the placebo group (58.9% vs 49.9%), yielding a number needed to treat of 14 patients with dapagliflozin for one to be clinically better in eight months, which showed a considerable benefit [65]. The MD in the change of the KCCQ score was 4.1 points (95% CI 1.3 to 7.0) in the SOLOIST-WHF trial and 2.41 (95% CI 0.64 to 4.17) in the T2DM subgroup in EMPEROR-Reduced trial, but the numbers needed to treat were not calculable. The benefit on symptoms and quality of life associated with SGLT2i was consistent with the noteworthy reduction in the risk of hospitalization for heart failure in the T2DM subgroup of the DAPA-HF and EMPEROR-Reduced trials.

Despite the clinically significant improvement of quality of life and cardiovascular outcomes by SGLT2i, the debate on the underlying mechanism of the drug is still on the way. The most known mechanism of SGLT2i is based on excess excretion of fluid and glucose and modest removal of sodium [66]. Diuresis alleviates cardiac preload, leading to reduced blood pressure [67], left ventricular wall stress, and left ventricular filling pressure. This could be the reason for the reduction of the NT-proBNP level and the E/e’ ratio that we have observed. However, the significant effect of SGLT2i on LVM but not ventricular volume could not be fully interpreted by the theory above. Other possible mechanisms such as more efficient energy source of ketone bodies and fatty acids rather than glucose [19, 68], relieving inflammation [69, 70], and reducing fibrosis and oxidative stress [15], may also play a role. The previously prompted hypothesis of the inhibition of cardiac Na+–H+ Exchanger-1 was however challenged in a recent in vitro study [71]. Still, further research is required to illuminate the complete picture.

Previous systemic and narrative reviews [72‐75] summarized completed and ongoing studies available on the same topic as ours. However, they were mostly conducted before the releasing of results of several important recent studies and thus lacked sufficient data for quantitative analyses. This meta-analysis included only RCTs but not observational studies to minimize the possible risk of bias, and used the GRADE tool to assess the certainty of the evidence for each outcome. Although conducted strictly following the PRISMA guidelines, the meta-analysis still has some limitations. First, in subgroup analyses, we stratified the T2DM population as stage A–B and stage C HF patients. But in some studies recognized as stage A–B HF, HF patients were not fully excluded. Second, heterogeneity in clinical characteristics and study methods was not completely avoidable, in consideration of which we used a random-effects model for all the analyses. Third, subgroup analyses based on the dosage forms of SGLT2i and the modality of imaging were not conducted due to insufficient data, which remain to be clarified in future studies.

Large-scale RCTs focusing on the effects of SGLT2i in different populations are required to provide more evidence for individualized intervention. The results of the ongoing EMPA-TROPISM (NCT03485222) [76], EMPA-HEART (EUDRACT 2016-0022250-10) [77], ERTU-GLS (NCT03717194), NATRIURETIC (NCT04535960), VERTICAL (NCT04490681), EMPERIAL-Preserved and EMPERIAL-Reduced (NCT03448406, NCT03448419) [78] trials would enhance knowledge of this topic. Although the efficacy and safety of SGLT2i in several dosage forms have been repeatedly verified in T2DM patients with or without HF to support the clinical application, the underlying mechanism remains to be clarified to achieve a more comprehensive understanding.

We found in this meta-analysis that SGLT2i improves the parameters of cardiac diastolic function, plasma NT-proBNP level, and the KCCQ score in T2DM patients with or without chronic HF, but did not significantly affect cardiac structural parameters indexed by body surface area. The LVEF level was improved only in HF patients with reduced ejection fraction. Future studies are anticipated to further elucidate the mechanisms and intermediate links in the effect of SGLT2i.