Cardiovascular (CV) disease (CVD) is the main cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Despite optimal glycaemic control, standard antihyperglycaemic therapy failed to impact CV events in intervention trials; therefore, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued a guidance to the pharmaceutical industry to specifically assess the CV outcomes and safety of new glucose-lowering drugs. Amongst them, sodium-glucose transporter 2 (SGLT2) inhibitors proved to not only provide good tolerance, few adverse effects, and good glycometabolic control, but also striking reduction in the risk of CV events. In this review, data from the main randomised controlled trials are presented, including post-hoc analyses looking into several aspects of CV protection. Moreover, the main findings from observational real-world studies to date are described, overall reassuring as regards to CV safety and efficacy of SGLT2 inhibitors. Finally, several mechanisms which might contribute to the cardioprotective effect of SGLT2 inhibition are depicted, including findings from recent mechanistic studies.

Introduction

Cardiovascular (CV) disease (CVD), the leading global killer, represents the main cause of morbidity and mortality in people with type 2 diabetes mellitus (T2DM) [1,2]. This relates to an accelerated atherosclerosis due to a multifactorial pathogenesis including hyperglycaemia, insulin resistance, hyperinsulinaemia, and oxidative stress [3–5]. Intervention trials on the efficacy of antihyperglycaemic agents did not impact CVD events, despite optimal glycaemic control expressed as normalised levels of glycated haemoglobin A1c (HbA1c) [6,7]. Additionally, some glucose-lowering agents seemed to be associated with an increase in CVD mortality [8]. This caused the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to issue a guidance to the pharmaceutical industry in 2008 stating that ‘concerns about cardiovascular risk should be more thoroughly addressed during drug development’. This set the standards that new medications should have a proven CV safety profile [9]. Consequently, trials to evaluate new antihyperglycaemic compounds have been designed to specifically assess CV outcomes [10]. Amongst them were sodium-glucose transporter 2 (SGLT2) inhibitors.

CV outcome trials of SGLT2 inhibitors

The SGLT2, located in the proximal renal tubule, is the main mediator of glucose reabsorption from the glomerular filtrate. It has, therefore, been identified as an interesting new target for lowering plasma glucose [11]. As depicted in Figure 1, SGLT2 inhibitors, the newest class of oral glucose-lowering compounds, act as glucose-lowering drugs by increasing urinary glucose excretion (Figure 1).

Site of SGLT2 inhibition in the kidney

Figure 1
Site of SGLT2 inhibition in the kidney

In the glomerulus, SGLT2 are localised in the S1 segment of the proximal tubule, which includes its beginning and middle portions. Normally, SGLT2 is responsible for 90% of glucose reabsorption, whereas SGLT1 accounts for the remaining 10%. Therefore, pharmacological inhibition of SGLT2 leads to increased renal glucose excretion and lower plasma glucose levels.

Figure 1
Site of SGLT2 inhibition in the kidney

In the glomerulus, SGLT2 are localised in the S1 segment of the proximal tubule, which includes its beginning and middle portions. Normally, SGLT2 is responsible for 90% of glucose reabsorption, whereas SGLT1 accounts for the remaining 10%. Therefore, pharmacological inhibition of SGLT2 leads to increased renal glucose excretion and lower plasma glucose levels.

The efficacy and safety of SGLT2 inhibitors have been evaluated in several randomised controlled trials (RCTs). The uniform result is that they are characterised by good tolerance, very few adverse effects, and an important reduction in fasting plasma glucose, HbA1c, blood pressure (BP) and body weight. In addition, due to their unique mechanism of action, SGLT2 inhibitors can be combined with any antihyperglycaemic medication, including insulin [12,13]. A recent meta-analysis, including all RCTs with a duration of at least 12 weeks, confirmed the persistence of glycaemic control and body weight reduction up to 2 years of treatment with SGLT2 inhibitors compared with placebo or other glucose-lowering drugs [14].

As required by FDA and EMA, some of these RCTs were conducted with a three-point major adverse CV event (MACE) as the composite primary end point, i.e. first of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke. In some studies, hospitalisation for acute coronary syndrome (ACS), urgent coronary revascularisation, and heart failure hospitalisation (HHF) were also included as well [9]. To date, the CV safety of SGLT2 inhibitors is being evaluated in nine trials, of which two are completed while results from seven are expected within the next couple of years [10].

This review presents the outcome of the most important CV outcome trial (CVOT) completed to date, namely the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study and the Canagliflozin Cardiovascular Assessment Study (CANVAS) programme. A summary of the most important data from these CVOTs are presented in Table 1 and a more detailed description presented below. Furthermore, some potential mechanisms of action by means of which SGLT2 inhibitors may act are discussed.

Table 1
Main characteristics and results of CVOTs on SGLT2 inhibitors
EMPA-REG OUTCOME (HR (95% CI))CANVAS programme (HR (95% CI))
Number of patients 7020 10142 
Baseline mean age (years) 63 63 
Subjects with baseline established CVD (% of total study population) 99% 66% 
Three-point MACE (HR (95% CI)) 0.86 (0.74–0.99) 0.86 (0.74–0.99) 
CV death (HR (95% CI)) 0.62 (0.49–0.77) 0.87 (0.72–1.06) 
Non-fatal MI (HR (95% CI)) 0.87 (0.70–1.09) 0.89 (0.73–1.09) 
Stroke (HR (95% CI)) 1.18 (0.89–1.56) 0.87 (0.69–1.09) 
HF hospitalisation (HR (95% CI)) 0.65 (0.50–0.85) 0.67 (0.52–0.87) 
All-cause mortality (HR (95% CI)) 0.68 (0.57–0.82) 0.87 (0.74–1.01) 
EMPA-REG OUTCOME (HR (95% CI))CANVAS programme (HR (95% CI))
Number of patients 7020 10142 
Baseline mean age (years) 63 63 
Subjects with baseline established CVD (% of total study population) 99% 66% 
Three-point MACE (HR (95% CI)) 0.86 (0.74–0.99) 0.86 (0.74–0.99) 
CV death (HR (95% CI)) 0.62 (0.49–0.77) 0.87 (0.72–1.06) 
Non-fatal MI (HR (95% CI)) 0.87 (0.70–1.09) 0.89 (0.73–1.09) 
Stroke (HR (95% CI)) 1.18 (0.89–1.56) 0.87 (0.69–1.09) 
HF hospitalisation (HR (95% CI)) 0.65 (0.50–0.85) 0.67 (0.52–0.87) 
All-cause mortality (HR (95% CI)) 0.68 (0.57–0.82) 0.87 (0.74–1.01) 

Abbreviations: CI, confidence interval; HR, hazard ratio.

EMPA-REG OUTCOME

The EMPA-REG OUTCOME study is a randomised, double-blind trial including 7020 patients with T2DM and pre-existing CVD, randomly assigned to receive empagliflozin (10 or 25 mg) or placebo, on top of ongoing therapy including glucose-lowering agents. The hypothesis was non-inferiority for the primary outcome, MACE, in empagliflozin groups compared with placebo [15]. Over a median follow-up of 3.1 years, the primary end point was, independently from the dose significantly reduced in subjects treated with empagliflozin (hazard ratio (HR): 0.86; 95% confidence interval (95% CI): 0.74–0.99; P=0.0038). In addition, there was a significant relative reduction in HHF (35%) and all-cause mortality (32%). Of interest, is that the contribution to risk reduction in the single components of the three-point MACE differed: there was an important decrease in CV mortality (HR: 0.62; 95% CI: 0.49–0.77;P<0.001), no significant reduction in MI (HR: 0.87; P=0.22), and a non-significant increase in stroke (HR: 1.24; P=0.22) [15]. The causes of CV death included a broad spectrum of conditions (sudden death, acute heart failure, acute MI, stroke, and unknown causes), which do not recognise atherosclerosis as the common pathogenetic mechanism. Of great interest is that the separation of the Kaplan–Meier curves for CV mortality in EMPA-REG OUTCOME occurred very early, within a month, making it unlikely that the explanation is an influence on progression of atherosclerosis. This is further supported by the absence of a decrease in non-fatal MI or stroke, conditions strongly associated with atherosclerosis [16]. In contrast, there was a more or less rapid reduction in HHF, which increased by time [17,18]. In order to investigate these results, post-hoc analyses have recently been performed, showing that the reduction in HHF and CV death remains significant after adjustment for HbA1c levels and traditional CV risk factors, such as BP, lipid profile, body mass index (BMI), renal function, and uric acid [19–21]. Furthermore, after stratifying the subjects by their derived HF risk, CV death and HF hospitalisation outcomes consistently improved in the treatment group regardless of baseline HF risk, suggesting that empagliflozin prevents acute cardiac decompensation [22]. Following these results, a new indication for empagliflozin was approved by the FDA in December 2016 to reduce CV death in adults with T2DM [23].

All of these findings suggest that the mechanisms of action of empagliflozin go beyond the predictable glucometabolic benefit and remain to be elucidated.

CANVAS programme

The CANVAS programme is a combined analysis of two prospective, double-blind, multicentre, placebo-controlled trials, including a total of 10142 patients with T2DM of whom 66% are with established CVD and 34% with multiple CV risk factors. The latter, CANVAS-R, focused on renal outcomes [24]. The similar study design allowed a joint analysis, but the median follow-up, 5.7 years for CANVAS and 2.1 years for CANVAS-R, differed markedly [24,25]. All participants were randomised to 100 or 300 mg of canagliflozin or placebo on top of standard care treatment. The primary composite end point, MACE, was the same as in EMPA-REG OUTCOME, whereas the secondary end point was an albuminuria progression (composite of persistent 40% reduction in estimated glomerular filtration rate, need for renal replacement therapy, or all-cause death). The main results have been recently published and can be summarised as follows: (i) MACE was significantly reduced in patients treated with canagliflozin (HR: 0.86; 95% CI: 0.75–0.97; P=0.02), (ii) progression of albuminuria was less frequent in the canagliflozin group (HR: 0.73; 95% CI: 0.67–0.79), and (iii) there was a significant reduction in HHF in patients treated with canagliflozin (HR: 0.67; 95% CI: 0.52–0.87) [24]. Interestingly, recent post-hoc analyses of CANVAS programme emphasised the protective effect of the medication on the composite outcome of CV death and HHF, with greater benefits in patients with a history of HF [26]. This focus on HF outcomes is in accordance with the results described for empagliflozin, suggesting a protective class effect on cardiac function, which deserves further examination even in patients without T2DM. Although rare, a complication was a two-fold increase in the risk for lower-leg amputation in patients treated with canagliflozin than placebo (6.3 compared with 3.4 events/1000 patient-years respectively) and a 26% relative risk increase in bone fractures in treated subjects, which will be subjected to attentive evaluation in real-life studies [24].

CV effects of SGLT2 inhibitors in retrospective studies

Besides information from CVOT data of interest for the understanding of the potential of SGLT2 inhibitors have been presented in the form of observational studies reflecting all-day practice. Main characteristics and findings from these studies are presented in Table 2 and further details in the following text.

Table 2
Main characteristics and findings of retrospective studies on SGLT2 inhibitors
DAPA-RWE U.K.DAPA-RWE SwedenCVD-REALCVD-REAL 2
Study typePopulation-based, open cohortPopulation-based, open cohortReal-worldReal-world
Number of patients 22124 21758 309056 235064 
Type of SGLT2 inhibitor Dapagliflozin Dapagliflozin Dapagliflozin, empagliflozin or canagliflozin Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, luseogliflozin or tofogliflozin 
Comparator Other glucose-lowering drugs Insulin Other glucose-lowering drugs Other glucose-lowering drugs 
Baseline mean age (years) 58 65 57 57 
Subjects with baseline established CVD (% of total study population) 20 13 27 
All-cause mortality (effect size (95% CI)) 0.50 (0.33–0.75)1 0.44 (0.28–0.70)1 0.49 (0.41–0.57) 0.51 (0.37–0.70) 
CVD (effect size (95% CI)) 0.89 (0.61–1.30)2 0.51 (0.30–0.86)3 0.85 (0.72–1.00)4 0.81 (0.74–0.88)4 
   0.83 (0.71–0.97)5 0.68 (0.55–0.84)5 
HF hospitalisation (HR (95% CI)) n.a. n.a. 0.61 (0.510.73) 0.64 (0.50–0.82) 
DAPA-RWE U.K.DAPA-RWE SwedenCVD-REALCVD-REAL 2
Study typePopulation-based, open cohortPopulation-based, open cohortReal-worldReal-world
Number of patients 22124 21758 309056 235064 
Type of SGLT2 inhibitor Dapagliflozin Dapagliflozin Dapagliflozin, empagliflozin or canagliflozin Dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, luseogliflozin or tofogliflozin 
Comparator Other glucose-lowering drugs Insulin Other glucose-lowering drugs Other glucose-lowering drugs 
Baseline mean age (years) 58 65 57 57 
Subjects with baseline established CVD (% of total study population) 20 13 27 
All-cause mortality (effect size (95% CI)) 0.50 (0.33–0.75)1 0.44 (0.28–0.70)1 0.49 (0.41–0.57) 0.51 (0.37–0.70) 
CVD (effect size (95% CI)) 0.89 (0.61–1.30)2 0.51 (0.30–0.86)3 0.85 (0.72–1.00)4 0.81 (0.74–0.88)4 
   0.83 (0.71–0.97)5 0.68 (0.55–0.84)5 
HF hospitalisation (HR (95% CI)) n.a. n.a. 0.61 (0.510.73) 0.64 (0.50–0.82) 

Abbreviations: aIRR, adjusted incidence rate ratio; CVD-REAL, Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Transporter 2 Inhibitor; DAPA-RWE U.K., Dapagliflozin Real-World Evaluation.

1

Effect size reported and incidence rate ratio.

2

Composite end point of MI and ischaemic heart disease, stroke or TIA and heart failure, or left ventricular dysfunction in the low-risk population.

3

Main diagnosis in the in-patient register of MI, ischaemic stroke, unstable angina pectoris, heart failure, or CV death.

4

HR for MI.

5

HR for stroke.

Dapagliflozin real-world evaluation

Available data for dapagliflozin originate from retrospective cohort studies, Dapagliflozin Real-World Evaluation (DAPA-RWE) U.K., and the DAPA-RWE Sweden.

The first study, based in U.K., is a population-based, retrospective open cohort study comparing 22124 T2DM subjects treated with dapagliflozin with matched controls receiving standard antihyperglycaemic therapy. The data source was The Health Improvement Network database (THIN), including electronic patient records from over 640 general practices in the U.K. Death from any cause was less frequent in patients treated with dapagliflozin (HR: 0.50, 95% CI: 0.33–0.75; P=0.001), regardless of the baseline CV risk [27].

Dapagliflozin was also evaluated in DAPA-RWE Sweden Study as regards to risk associations with all-cause mortality and fatal or nonfatal CVD in 21758 patients with T2DM. Specifically, in the present study the SGLT2 inhibitor and the dipeptidyl peptidase-4 (DPP-4) inhibitors were both compared with insulin and both showed a lower risk of all-cause mortality and CVD; as regards to dapagliflozin, the HR for the two outcomes were 0.44 (95% CI: 0.28–0.70) and 0.51 (95% CI: 0.30–0.86) respectively. The analysis of patients who had established CVD at baseline revealed a lower association between dapagliflozin and CVD risk than insulin while DPP-4 inhibitors did not show such benefit [28,29].

Comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors

The Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL) study is a large real-world observational study in patients initiating SGLT2 inhibitors (dapagliflozin, empagliflozin or canagliflozin) compared with other glucose-lowering drugs, in 1:1 match. Data were collected from medical claims, primary care/hospital records and national registries from the United States, Sweden, Denmark, Norway, Germany, and the U.K., with starting dates ranging from November 2012 to July 2013. The primary outcome was HHF, and secondary outcomes were total mortality and a composite of total mortality and HHF [30]. The SGLT2 inhibitors were associated with a lower risk of HHF and all-cause death compared with other antihyperglycaemic medications (HR: 0.61, 95% CI: 0.51–0.73; P<0.001 and HR: 0.49; 95% CI: 0.41–0.57; P<0.001 respectively) [31]. Kosiborod et al. [32] recently analysed the CVD-REAL data as regards to the association between initiation of SGLT2 inhibitors and MI and stroke rates, reporting a modest reduction in such atherothrombotic events (MI: HR: 0.85; 95% CI: 0.72–1.00; P=0.05; stroke: HR: 0.83; 95% CI: 0.71–0.97; P=0.02). Since a majority of subjects in CVD-REAL did not have established CVD at baseline, the findings indicated that SGLT2 inhibitors may be of benefit in a low-risk population. In an additional analysis of the CVD-REAL population, subdividing the patients on the basis of known CVD at the time of the initiation of antihyperglycaemic therapy, the relative risk of the associations amongst SGLT2 inhibitor therapy HF and death were similar in the two subgroups while the absolute event rates differed substantially. In patients without CVD (87% of the total cohort), the event rates were very low (for death: 0.5/100 patient-years in those on SGLT2 inhibitors and 0.9/100 patient-years for those on other glucose-lowering drugs. The corresponding HF rates were 0.1 and 0.9/100 patient-years. Patients with established CVD at baseline (13%) had significantly higher event rates: 1.8 compared with 3.6/100 patient-years for death and 2.3 compared with 3.2/100 patient-years for HF respectively [33]. Thus, the number needed to treat in a hypothetical randomised trial would be considerably lower in a patient population with established CVD at baseline than in those without. As already described, available data from randomised trials are essentially based on patients with established CVD or high risk for CVD. Hence, real-life studies such as CVD-REAL, provide a chance to investigate primary CV prevention in patients with T2DM.

Recently, new findings from CVD-REAL 2 study were published, including 235064 subjects from South Korea, Japan, Singapore, Israel, Australia, and Canada, initiating glucose-lowering therapy (SGLT2 inhibitors or other glucose-lowering drugs) [34]. The methods were similar to those previously described for CVD-REAL, apart from the inclusion of patients treated with ipragliflozin, tofogliflozin, and luseogliflozin. The SGLT2 inhibitor-based therapy was associated with a lower risk of death (HR: 0.51; 95% CI: 0.37–0.70; P<0.001), HF (HR: 0.64; 95% CI: 0.50–0.82; P=0.001), MI (HR: 0.81; 95% CI: 0.74–0.88; P<0.001), and stroke (HR: 0.68, 95% CI: 0.55–0.84; P<0.001) compared with treatment based on other antihyperglycaemic medications. Twenty-seven percent of this cohort had established CVD, but the risk reduction by SGLT2 therapy was not separated for patients with and without CVD.

Overall, data from the large real-life studies were consistent with the major findings of EMPA-REG OUTCOME and the CANVAS programme, i.e. reassuring as regarding CV safety and efficacy of SGLT2 inhibitors. However, some study limitations should be considered. First, due to the observational nature of these analyses, the presence of possible confounders cannot be ruled out despite matching and supplementary statistical adjustments. Second, data collection and medication prescription varied depending on the country of data origin. Despite the development of specific propensity score matching for each cohort, and despite the consistency of the results across different geographic areas, this heterogeneity has to be taken into account, e.g. considering possible underreporting of previous CVD. Third, information on adverse effects is often incomplete in retrospective reports. Finally, clinical experience with SGLT2 inhibitors in a real-world setting is still limited and there is a need for longer observation times, since a high number of patients-years of follow up based on short time experiences from many patients cannot replace information based on several years of observations of the studied population.

In summary, observational studies provided important information about SGLT2 therapy in a population with and without established CVD, despite lacking the evidence level of perspective trials. The Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI) 58 trial, testing the effects of dapagliflozin, will include a large group of subjects without established CVD, therefore filling the knowledge gaps about CV risk reduction by SGLT2 inhibitors in low-risk patients [35].

Potential mechanisms of CV benefits of SGLT2 inhibitors

Reduction in BP and arterial stiffness

Most trial participants were on antihypertensive medications with well-controlled BP [19]. Nevertheless, a lasting reduction in systolic (3–5 mm Hg) and diastolic (2 mm Hg) BP was documented across the groups randomised to SGLT2 inhibitors without any compensatory increase in heart rate [36]. These findings have, regardless of background therapy, been confirmed by dedicated 24-h ambulatory BP measurement [37]. Partly, this reduction reflects the ability of SGLT2 inhibitors to decrease left ventricular preload (reduced plasma volume due to a diuretic effect) and postload (lower BP). It is still unlikely that this is the strongest factor in the reduction in MACE since studies investigating the effect of BP-lowering therapy on CV events did not report evident benefits before 1 year of treatment [19,38]. Moreover, BP lowering is of particular importance for reducing stroke, but as outlined, this was not a significant outcome of the SGLT2 inhibitors.

Post-hoc analyses of EMPA-REG OUTCOME revealed a significant reduction in pulse pressure, mean arterial pressure, and the double product [39]. There are data also available from an 8-week-long mechanistic trial in patients with type 1 diabetes, demonstrating that empagliflozin reduces arterial stiffness by decreasing systolic BP and radial, carotid arterial and aortic augmentation index and carotid-radial pulse wave velocity [40].

In a small, elegantly planned study, Solini et al. [41] performed complete non-invasive vascular evaluation comparing 48-h treatment with dapagliflozin or hydrochlorothiazide, showing substantial improvement in carotid-femoral pulse-wave velocity, augmentation index, and renal resistive index with SGLT2 inhibition, independently of BP reduction, which was similar in the two groups. These results support the hypothesis of a fast, direct beneficial effect of SGLT2 inhibitors on the vasculature possibly mediated by reduction in oxidative stress in addition to the favourable haemodynamic changes. However, the mechanisms probably involve other, direct and indirect, pathways, and remain to be explored.

Weight loss and body fat mass reduction

SGLT2 inhibitors cause glycosuria, resulting in a loss of approximately 200–300 kilocalories per day, leading to a weight loss of ~3 kilograms over up to 102 weeks [29,36]. This effect should be beneficial, considering that other glucose-lowering medications, such as sulphonylureas, thiazolidinediones and insulin are associated with weight gain [19]. Nevertheless, such small change alone is unlikely to contribute to the early reduction in MACE. Similar early benefit in CV outcomes has, e.g. not been reported when intensive lifestyle interventions succeeded in substantial weight loss (Look AHEAD trial) [42]. Moreover, the weight decrease is clearly less than expected from the chronic calorie loss, indicating the presence of compensatory mechanism inducing not only increased food intake, but also counteracting metabolic changes [43,44]. Studies using dual-energy X-ray absorptiometry and dual impedance analysis support that most of this weight loss is due to reduction in visceral fat mass [45,46]. This feature of SGLT2 inhibitors therapy probably contributes to their favourable CV impact, since visceral adiposity is known to be a risk factor for increased atherosclerosis. In fact, an ongoing trial, the compensatory changes in energy balance during dapagliflozin treatment in T2DM (ENERGIZE), is looking at the changes in fat distribution by means of specific magnetic resonance imaging [47].

Endothelial dysfunction, inflammation, and oxidative stress

Dysfunction of endothelial cells is the primary event inducing atherosclerosis by triggering inflammation and oxidative stress. In the presence of diabetes, chronic hyperglycaemia causes endothelial dysfunction by forming glycation products which activate several intracellular pathways, resulting in enhanced expression of adhesion molecules, secretion of inflammatory cytokines (such as interleukin-6 and tumour necrosis factor), higher activation of oxidases, and concomitant reduction in glutathione availability [48–50].

The effect of SGLT2 inhibitors on endothelial function is probably beneficial, but further research is needed to fully clarify its mechanisms. In this regard, following in vitro experiments, a Japanese study in rodents showed that therapy with six different SGLT2 inhibitors (canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, luseogliflozin) provided a significant reduction in several pro-inflammatory cytokines and inflammatory markers, suggesting a beneficial class effect [51]. In humans, the previously cited study by Solini et al. [41] reported a rapid and significant improvement in endothelial function after treatment with dapagliflozin but not hydrochlorothiazide as assessed by means of brachial artery flow-mediated vasodilatation. One trial, the Dapagliflozin Effectiveness on the Vascular Endothelial Function and Glycemic Control (DEFENCE), evaluated the effect of SGLT2 inhibition on human endothelium as a primary end point [52]. Patients with recently diagnosed T2DM were randomised to dapagliflozin plus metformin or metformin alone and endothelial function was evaluated using brachial artery flow-mediated vasodilatation. There was a significant improvement in the dapagliflozin group. Consequently, it is reasonable to assume that dapagliflozin provides these benefits through mechanisms that go beyond glycaemic control, since the effect on endothelial function was statistically valid only in patients with poorly controlled diabetes treated with the SGLT2 inhibitor despite the achievement of an improved glycaemic control in both study groups [52].

Shift in fuel metabolism

In people with diabetes, the heart is affected by metabolic inflexibility, meaning it becomes unable to switch between β-oxidation of free fatty acids (FFAs) and glucose as the predominant fuel source [53]. Normally, the main fuel supply of cardiomyocytes are FFAs (~60–70% of total fuel for oxidative metabolism) followed by glucose (~30%) and, in smaller amounts, lactate, ketones, and amino acids. Indeed, the healthy heart is able to switch from one source to another depending on conditions: FFAs are preferred during fasting, whereas in the fed state high insulin levels promote glucose uptake and utilisation. Conversely, during hypoxic states (such as ischaemia or increased workload), mitochondrial energy production switches to glucose utilisation, which has a lower oxygen cost [54]. By contrast, insulin resistance prevents the heart from using glucose, increasing β-oxidation of FFAs and lipolysis, causing incremental energy cost and reactive oxygen species overproduction [50,55]. In conclusion, the heart in patients with diabetes is in a state of protracted starvation despite abundant fuel supply as, e.g. confirmed by positron emission tomography and phosphorus-magnetic resonance spectroscopy studies carried out in T2DM patients [56].

In the effort to explain the results of EMPA-REG OUTCOME, Ferrannini et al. [57,58] launched the ‘thrifty substrate hypothesis’ postulating that SGLT2 inhibitors improve myocardial function in patients at high CV risk by enhancing ketongenesis. Studies with SGLT2 inhibitors treatment report on a modest but consistent rise in plasma ketone concentration, due to the enhanced FFAs delivery to the hepatocytes in presence of large glucose subtraction and consequent hormonal changes. Specifically, it is hypothesised that SGLT2 inhibitors mimic a prolonged fast while depleting the glucose pool, forcing the failing heart to use energetically efficient fuel sources, i.e. ketone bodies, alternative to FFAs. This shift in fuel metabolism could help explain the degree of beneficial CV effects reported in the EMPA-REG OUTCOME [57,58].

Changes in haematocrit and haemoglobin

A recent mediation analysis of the EMPA-REG OUTCOME study by Inzucchi et al. [59] highlighted the pivotal role of haematocrit and haemoglobin for the effect of empagliflozin on the reduction in the risk of CV death. The increase in haematocrit during the first week of empagliflozin therapy reflects its diuretic action and the reduction in the circulatory load. This haemodynamic change leads to a decrease in cardiac filling pressures, which may improve left ventricular function and reduce the likelihood of heart failure. Moreover, oxygen delivery to the myocardial tissue may improve due to the increased haematocrit.

Renal function and sodium balance

Since SGLT2 is a cotransporter of glucose and sodium, its inhibition leads to an increase in sodium excretion exposing the macula densa to higher sodium concentrations with, as subsequent feedback, a vasoconstriction in the afferent arterioles, which in turn reduces the intraglomerular pressure. This protects the kidneys and avoids volume overload. Moreover, depletion of total body sodium seems to have a beneficial effect on cardiomyocytes, with secondary decrease in intracellular calcium and an up-regulation of antioxidant pathways [60].

Moreover, it is believed that the resistance to diuretics and to endogenous natriuretic peptides, reported in patients with HF, is due to an enhanced activity of the sodium-hydrogen exchanger. SGLT2 inhibitors interfere with the sodium-hydrogen exchanger activity, leading to decreased intravascular volume and haemoconcentration, ultimately reducing cardiac wall stress and thus hypertrophy, fibrosis, and systolic dysfunction [61,62].

Conclusion and perspectives

In summary, there are two completed trials on SGLT2 inhibitors, EMPA-REG OUTCOME and the CANVAS programme, which specifically evaluated CV outcomes, providing striking results and new insights into T2DM pathophysiology. Several other trials are ongoing and results are expected in the next couple of years. The first to report will be Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58) enrolling over 17000 subjects with CVD or multiple CV risk factors and evaluating the traditional composite MACE but including HHF as a co-primary end point.

So far, data from the real-world reports are encouragingly providing support to the concept that SGLT2 inhibitors are cardioprotective, probably through a variety of mechanisms, both direct and indirect.

Thus, SGLT2 inhibitors have the potential to become a cornerstone in the continued effort to decrease CVD morbidity and mortality in T2DM.

Competing interests

The authors declare that there are no competing interests associated with this manuscript.

Abbreviations

     
  • BP

    blood pressure

  •  
  • CANVAS

    Canagliflozin Cardiovascular Assessment Study

  •  
  • CI

    confidence interval

  •  
  • CV

    cardiovascular

  •  
  • CVD

    CV disease

  •  
  • CVD-REAL

    Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitor

  •  
  • CVOT

    CV outcome trial

  •  
  • DAPA-RWE

    dapagliflozin real-world evaluation

  •  
  • DPP-4

    dipeptidyl peptidase-4

  •  
  • EMA

    European Medicines Agency

  •  
  • EMPA-REG OUTCOME

    Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

  •  
  • FDA

    Food and Drug Administration

  •  
  • FFA

    free fatty acid

  •  
  • HbA1c

    glycated haemoglobin A1c

  •  
  • HHF

    heart failure hospitalisation

  •  
  • HR

    hazard ratio

  •  
  • MACE

    major adverse CV event

  •  
  • MI

    myocardial infarction

  •  
  • RCT

    randomised controlled trial

  •  
  • SGLT2

    sodium-glucose transporter 2

  •  
  • T2DM

    type 2 diabetes mellitus

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