Skip to main content

Beyond the Glycaemic Control of Dapagliflozin: Impact on Arterial Stiffness and Macroangiopathy

Abstract

Dapagliflozin is a selective sodium–glucose cotransporter 2 inhibitor (SGLT2i) indicated for the treatment of type 2 diabetes mellitus (T2DM), heart failure with reduced ejection fraction and chronic kidney disease. In all indications, treatment can be initiated in adults with estimated glomerular filtration rate of at least 25 mL/min/1.73 m2. As monotherapy or as an additive therapy, dapagliflozin has been shown to promote better glycaemic control, associated with a reduction in body weight and blood pressure in a wide range of patients. In addition, dapagliflozin has a positive impact on arterial stiffness, helps to control the lipid profile and contributes to a reduced risk of cardiovascular complications. This article reviews the current scientific evidence on the role of dapagliflozin in cardiovascular risk factors including arterial stiffness, cardiovascular disease and heart failure in patients with T2DM, with the aim of helping to translate this evidence into clinical practice. The underuse of SGLT2i in actual clinical practice is also discussed.

FormalPara Key Summary Points
This article reviews the current scientific evidence on the role of dapagliflozin in cardiovascular risk factors, with the aim of helping to translate this evidence into clinical practice.
Dapagliflozin has been shown to promote better glycaemic control, associated with a reduction in body weight and blood pressure in a wide range of patients.
Dapagliflozin has a positive impact on arterial stiffness, helps to control the lipid profile and contributes to a reduced risk of cardiovascular complications.
In all indications, dapagliflozin treatment can be initiated in adults with estimated glomerular filtration rate of at least 25 mL/min/1.73 m2.

Introduction

Dapagliflozin is a reversible and highly selective sodium–glucose cotransporter type 2 inhibitor (SGLT2i) [1, 2]. SGLT2 inhibition by dapagliflozin reduces glucose reabsorption from the glomerular filtrate in the renal proximal tubule with a concomitant reduction in sodium reabsorption, leading to urinary glucose excretion and osmotic diuresis [3, 4]. Dapagliflozin is indicated in adults for the treatment of inadequately controlled type 2 diabetes mellitus (T2DM) in combination with diet and exercise, in monotherapy when metformin is not deemed appropriate, or in addition to other drugs for the treatment of T2DM. Moreover, it is indicated in adults for the treatment of symptomatic chronic heart failure (HF) with reduced ejection fraction (rEF), and for treatment of chronic kidney disease (CKD) with initiation of use in patients with estimated glomerular filtration rate (eGFR) greater than 25 mL/min in all therapeutic indications [3, 4].

In numerous studies, both clinical trials and studies in real clinical practice settings, dapagliflozin has been associated with better glycaemic control, reduced body weight and superior blood pressure (BP) control than its comparators in a wide range of patients [1, 5,6,7,8]. Additionally, dapagliflozin has been associated with numerous cardiovascular (CV) and renal benefits and has a robust safety profile [1]. However, despite evidence of its clinical benefit, studies suggest that there are still a large number of patients with T2DM who could benefit from the use of dapagliflozin [9,10,11,12].

This article reviews the impact of dapagliflozin on arterial stiffness, cardiovascular risk factors and macroangiopathy in patients with T2DM, with the aim of helping to translate this evidence into clinical practice.

Methods

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

PubMed was searched for “Dapagliflozin” or “Hypoglycemic Agents” or “Sodium–Glucose Transporter 2 Inhibitors” and “Diabetes Complications” or “Blood Pressure” or “Hypertension” or “Hyperlipidemias” or “Vascular Stiffness” or “Weight Loss” or “Cardiovascular Diseases” or “Acute Coronary Syndrome” or “Peripheral Arterial Disease” or “Cerebrovascular Disorders” or “Heart Failure”. In addition, the terms “therapeutic inertia” or “prescription pattern” or “real-world use” or “prescription” were also included.

Articles published in English until 1 June 2021 were selected. After determining the relevancy of the abstracts, we retrieved and qualitatively assessed complete texts.

Additional references relevant to our review were found by looking through the reference lists of the selected papers.

Results

Cardiovascular Risk Factors

Arterial Stiffness

Adults with T2DM have a two to four times increased risk of developing macrovascular complications compared to adults without diabetes [13]. Hyperglycaemia and insulin resistance are associated with increased arterial stiffness and increased susceptibility of the arterial wall to atherosclerosis. These are independent of age and contribute to the development of CV events in T2DM [13, 14].

Increased arterial stiffness in large elastic arteries such as the aorta results in increased central blood pressure (BP) and blood flow pulsatility. This has deleterious effects on various organs, especially the heart and those highly perfused organs with vascular beds operating at low resistance, such as the brain or kidney [14]. Therefore, arterial stiffness is hypothesised to underlie macro- and microvascular complications of T2DM, constituting a promising therapeutic target in this group of patients [15, 16]. One of the first studies to examine the impact of dapagliflozin on arterial stiffness included 26 patients with T2DM treated for only 2 days. This study demonstrated how acute treatment with dapagliflozin significantly improved systemic endothelial function, arterial stiffness (estimated by calculating the pulse wave velocity between the carotid and femoral arteries) and renal resistance index, independently of BP changes and in the presence of stable natriuresis [17].

In a prospective, observational study involving 32 patients with T2DM treated with dapagliflozin 10 mg/day for 12 months, there was a significant decrease in arterial stiffness independent of changes in blood glucose, uricaemia, BP or weight [18]. Similarly, in another study with 140 patients with T2DM and obesity, 6-month treatment with dapagliflozin produced a statistically significant decrease in aortic arterial stiffness associated with a decrease in body and visceral fat mass, waist/hip ratio and insulin resistance [19]. Finally, in a randomised study of 44 patients with T2DM and 12 weeks of evolution, the effect on arterial stiffness achieved with dapagliflozin 10 mg/day (n = 24) and gliclazide 30 mg/day (n = 20) was compared. Dapagliflozin was associated with a reduction in vascular stiffness of 11%, accompanied by a decrease in stroke volume of 4%, cardiac output of 5% and mean BP of 5%. The use of gliclazide, on the other hand, did not change any of the aforementioned measurements [5].

Hypertension Control

Hypertension (HT) and T2DM are CV risk factors that act synergistically [20]. There is strong evidence to suggest that dapagliflozin induces a moderate reduction in BP in patients with T2DM, independently of baseline BP, and with a risk of orthostatic reactions similar to placebo [6]. This effect may be explained by the decrease in circulating volume due to its diuretic and natriuretic properties, and is independent of the eGFR [1, 21].

BP lowering associated with dapagliflozin is greater in patients with hypertension than in normotensive subjects [6]. In the aggregate analysis of 13 placebo-controlled clinical trials, BP evolution was assessed in 2360 patients with T2DM treated with dapagliflozin 10 mg/day vs. 2295 patients receiving placebo. In patients with SBP of at least 140 mmHg the mean adjusted decrease in SBP and DBP from baseline to week 24 was − 3.6 mmHg and − 1.2 mmHg in favour of dapagliflozin, respectively [6]. In patients without HT, the decrease in SBP and DBP in favour of dapagliflozin was − 2.6 mmHg and − 1.2 mmHg, respectively. The proportion of patients experiencing orthostatic hypotension was similar between dapagliflozin and placebo: 6.1% vs. 6.6% in patients with HT and 4.0% vs. 4.2% in patients without hypertension, respectively [6].

BP lowering has also been reported in two large clinical trials with dapagliflozin: DECLARE-TIMI 58 (including patients with CV disease or multiple CV risk factors) [22] and DAPA-HF (in patients with heart failure with reduced ejection fraction, HFrEF) [23, 24] (Tables 1 and 2). In the DECLARE-TIMI 58 study, involving more than 17,000 patients, the mean difference in SBP reduction was 2.7 mmHg [95% confidence interval (95% CI) 2.4–3.0 mmHg], and in DBP 0.7 mmHg (95% CI 0.6–0.9) with dapagliflozin compared to placebo [22]. In the DAPA-HF study, which randomised 4744 patients with symptomatic HF and EF less than 40%, the reduction in SBP with dapagliflozin was − 1.92 ± 14.92 mmHg vs. − 0.38 ± 15.27 with placebo (p = 0.002) [23, 24].

Table 1 Main characteristics of the DECLARE-TIMI 58 study
Table 2 Main characteristics of the DAPA-HF study

It is worth mentioning that the effects of dapagliflozin on BP are evident as early as the first week after initiation of treatment, and the decrease in SBP is maintained over the long term, at least for 4 years [6, 25]. Similar results with dapagliflozin have also been observed in real-life studies [7, 8].

Dyslipidaemia

The effect of SGLT2i on lipid metabolism has been linked to their ability to regulate key molecules in lipid synthesis, lipid transport and fatty acid oxidation [26]. Most studies show that treatment with dapagliflozin is associated with moderate reductions in triglyceride (TG) levels with elevations in total cholesterol and high-density lipoprotein cholesterol (HDL-C) [27,28,29,30,31]. However, there are also studies, involving a small number of patients, in which these changes have not been seen [32].

Regarding low-density lipoprotein cholesterol (LDL-C), both increases and decreases in its plasma concentration during dapagliflozin treatment have been reported [27, 30, 31]. However, studies that have assessed changes in LDL-C fractions indicate that dapagliflozin treatment is associated with an increase in large, floating LDL particles with lower atherogenic potential, accompanied by a decrease in small, dense LDL particles, which are more associated with CV disease [33]. Recent studies have also described the association between dapagliflozin and a decrease in other markers associated with cardiovascular disease such as the plasma atherogenic index, defined as log(TG/HDL-C), or the triglyceride/glucose (TyG) index [34]. Overall, dapagliflozin would contribute to a less atherogenic lipid profile, by lowering the most atherogenic LDL fractions and increasing HDL-C.

Metabolic Control and Weight Evolution

Several randomised studies have demonstrated the efficacy of dapagliflozin in metabolic control in a broad range of patients with T2DM as well as a good safety profile. Thus, in comparative trials, dapagliflozin showed superiority in HbA1c and weight reduction over glimepiride at 208 weeks, superiority in HbA1c and weight reduction over saxagliptin at 24 weeks, and greater HbA1c and weight reduction compared to placebo in insulin-treated subjects with poor metabolic control. In addition, patients on dapagliflozin had a lower incidence of hypoglycaemia than patients treated with glimepiride and insulin [25, 35]. Similar results have been reported consistently in patients with baseline HbA1c of 9% or above with HT, CV disease, chronic kidney disease and in patients over 65 years of age [1, 36,37,38].

Regarding monotherapy, in an analysis of six randomised controlled trials involving 2033 patients (with baseline HbA1c between 7.46% and 8.35%), dapagliflozin 10 mg/day for 12–24 weeks was associated with a mean HbA1c reduction of − 0.65% (95% CI − 0.81 to − 0.49) and a weight reduction of − 1.64 kg (95% CI − 1.95 to − 1.33) compared with placebo [39]. Also in poorly controlled patients on metformin monotherapy (mean baseline HbA1c 8.06%), after 102 weeks of follow-up, a − 0.78% reduction in baseline HbA1c was observed with dapagliflozin 10 mg/day, compared to a 0.02% increase with placebo. In combination with other hypoglycaemic agents as additive therapy, dapagliflozin has also been shown to be effective at reducing HbA1c levels [1].

To analyse the dynamics of blood glucose levels throughout the day, a study with 50 patients per arm (with HbA1c between 7.5% and 10.5%) evaluated the effect of dapagliflozin compared to placebo as additive therapy to other hypoglycaemic agents using continuous glucose monitoring. The change in mean 24-h blood glucose was − 18.2 mg/dL with dapagliflozin and + 5.8 mg/dL with placebo. The proportion of time spent in the target glucose range (70–180 mg/dL) was significantly increased with dapagliflozin vs. placebo (69.6% vs. 52.9%; p < 0.001) [40].

It is worth noting that approximately two-thirds of the weight loss with dapagliflozin was at the expense of fat mass measured by dual-energy X-ray absorptiometry, while half of the fat lost was visceral fat when measured by MRI [41]. Finally, dapagliflozin has also been associated with significant decreases in uric acid concentrations, an effect that could contribute to the decreased CV risk seen with this drug [42].

Macroangiopathic Complications

Acute Coronary Syndrome

The largest CV safety study of dapagliflozin is DECLARE-TIMI 58 (Table 1) [22]. This study evaluated the effect of dapagliflozin 10 mg/day vs. placebo in 17,160 patients with T2DM and established CV disease (41%) or multiple CV risk factors (59%). After a median follow-up of 4.2 years, dapagliflozin demonstrated non-inferiority to placebo for the composite of cardiovascular death, non-fatal acute myocardial infarction (AMI) and non-fatal stroke (3P-MACE, primary safety endpoint) (Table 3) [22]. In patients with previous AMI (n = 3584), dapagliflozin reduced the relative risk of 3P-MACE by 16% and its absolute risk by 2.6% [15.2% vs. 17.8%; hazard ratio (HR) 0.84; 95% CI 0.72–0.99, p = 0.039]. This was mainly by decreasing the risk of reinfarction due to type 2 AMI (related to mismatch between myocardial oxygen supply and demand rather than plaque rupture and atherothrombosis), and especially in those patients who started dapagliflozin treatment within 24 months of AMI [43]. However, no benefit was found in patients without previous AMI (7.1% vs. 7.1%; HR 1.00; 95% CI 0.88–1.13; p = 0.97) [43].

Table 3 Efficacy results from the DECLARE-TIMI 58 study

In terms of real-life studies, the CVD-REAL NORDIC study evaluated 10,227 patients treated with dapagliflozin and 30,681 patients treated with any dipeptidyl peptidase 4 inhibitor (DPP4i) during the period between 2012 and 2015. Dapagliflozin was associated with a lower risk of 3P-MACE (HR 0.79, 95% CI 0.67–0.94), HF (HR 0.62, 95% CI 0.50–0.77) and all-cause mortality (HR 0.59, 95% CI 0.49–0.72) compared with DPP4i. However, the reduction in AMI was favourable for dapagliflozin but did not reach statistical significance compared with DPP4i (HR 0.91, 95% CI 0.72–1.16) [44]. In another study with 209,867 patients per arm, the use of SGLT2i (30.7% with dapagliflozin) was associated with a lower risk of AMI (5.1% vs. 6.4%; HR 0.82; 95% CI 0.70–0.96) vs. DPP4i, with a similar effect for all SGLT2i [45].

In the CVD-REAL 2 cohort study, with 193,124 patients per arm (60% of those treated with SGLT2i were receiving dapagliflozin), a modest risk reduction against DPP4i was observed for both AMI (HR 0.88, 95% CI 0.80–0.98, p = 0.020) and stroke (HR 0.85, 95% CI 0.77–0.93, p = 0.0004) [46]. Finally, in another cohort study of more than 200,000 patients (CVD REAL study), the use of SGLT2i (49% of patients on dapagliflozin) was associated with a slightly reduced risk of AMI and stroke compared to other hypoglycaemic agents (insulin, DPP4i, sulfonylureas, glucagon-like peptide 1 agonists or metformin) [47].

These results are in line with a meta-analysis of 14 real-life studies involving more than 3 million patients with T2DM in which the use of SGLT2i is associated with a reduced risk of AMI, stroke, HF, all-cause mortality and CV mortality, but not unstable angina or atrial fibrillation [48].

Peripheral Arterial Disease

A few years ago, concerns were raised about the possible increased risk of lower limb amputations during treatment with SGLT2i [49]. However, a meta-analysis of 27 clinical trials confirmed that dapagliflozin was not associated with an increased risk of peripheral artery disease (PAD) or lower limb amputations [49]. Nor was an increased risk of amputation observed with dapagliflozin in another meta-analysis that included 12 clinical trials and 18 observational studies with SGLT2i [50].

Similarly, the DECLARE-TIMI 58 trial found that people with PAD similarly benefitted from the positive effect of dapagliflozin in terms of reduced CV death, HF hospitalisation and reduced progression of kidney disease, without an increased risk of lower limb events [51].

In real-life studies in a cohort study including 11,431 patients on SGLT2i and 93,972 on DPP4i, the use of SGLT2i was associated with a reduced need for lower limb revascularisation procedures (HR 0.73, 95% CI 0.54–0.98, p = 0.036) or amputation (HR 0.43, 95% CI 0.30–0.62, p < 0.0001) compared to DPP4i [52]. In conclusion, dapagliflozin is not associated with an increased number of adverse events associated with PAD, either in clinical trials or in real-life studies.

Cerebrovascular Disease

In the DECLARE-TIMI 58 study [22] as well as in a pre-specified meta-analysis of 21 phase 2b/3 clinical trials [53] and the CVD-REAL NORDIC study [44], dapagliflozin showed a neutral effect on stroke risk [22, 53]. However, as in the case of AMI, in other large real-life cohort studies, dapagliflozin was associated with a reduced risk of stroke compared with DPP4i (CVD-REAL 2: HR 0.85; 95% CI 0.77–0.93, p = 0.0004) or overall with other hypoglycaemic agents (CVD-REAL: HR 0.83; 95% CI 0.71–0.97, p = 0.02) [46, 47]. Similarly, in a meta-analysis of 14 real-life studies involving more than 3 million patients, the use of SGLT2i was associated with a significant reduction in the risk of stroke [48].

Experimental studies have suggested that this protective effect of SGLT2i against stroke is mediated by its antioxidant and anti-inflammatory effects, by anti-apoptotic mechanisms and the production of ultrastructural enhancements in neurons and at the blood–brain barrier [54].

Heart Failure

Up to 50% of people with T2DM may develop HF [55]. The major advance in recent years related to dapagliflozin is the demonstration of its clinical benefits for the treatment of HFrEF, both in people with and without T2DM [22, 24]. In the DECLARE-TIMI 58 study, dapagliflozin 10 mg/day showed superiority over placebo in preventing the composite endpoint of HF hospitalisation or CV death (4.9% vs. 5.8%; HR 0.83, 95% CI 0.73–0.95, p = 0.005) (Table 3). Exploratory analysis of the components of the composite variable revealed that the difference in treatment effect was mainly due to HF hospitalisation (HR 0.73, 95% CI 0.61–0.88). The benefit was observed in patients with and without established CV disease, with or without baseline HF and in those with HF with reduced or preserved EF, and was consistent across subgroups including age, sex, renal function and region [22, 56].

The benefit of dapagliflozin in the treatment of HFrEF was confirmed in the DAPA-HF study, a phase 3 trial in which 4744 patients (42% with T2DM) with symptomatic HF and EF less than 40% (functional class II to IV) were randomised to receive dapagliflozin 10 mg/day or placebo, added to standard HF therapy (Tables 2 and 4) [23, 57,58,59]. After a median follow-up of 18.2 months, the primary composite endpoint, which included HF worsening (hospitalisation or urgent visit leading to intravenous therapy for HF) or CV death, occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and 502 of 2371 patients (21.2%) in the placebo group (HR 0.74; 95% CI 0.65–0.85, p < 0.001), resulting in a relative risk reduction with dapagliflozin of 26%. In this case, both worsening HF (10.0% vs. 13.7%; HR 0.70, 95% CI 0.59–0.83) and CV death (9.6% vs. 11.5%; HR 0.82, 95% CI 0.69–0.98) were significantly lower in the dapagliflozin-treated group [23]. The benefit was observed in both people with and without T2DM, and it is worth highlighting that the benefit with dapagliflozin on the primary endpoint reached statistical significance as early as 28 days after the start of treatment [58, 59]. Furthermore, the greatest benefits occurred in patients with a history of HF hospitalisation in the 12 months prior to baseline. Dapagliflozin was also associated with improved symptoms, function, quality of life and overall health status in people with HF and reduced EF [58].

Table 4 Efficacy outcomes of the DAPA-HF study

A meta-analysis, including nine randomised clinical trials with dapagliflozin in patients with structural heart disease and HF (EF less than or equal to 50%, NYHA classification I or higher, or NT-proBNP 600 pg/mL or higher), confirmed the beneficial effect in terms of decreased risk of HF hospitalisation [relative risk (RR) 0.72; 95% CI 0.63–0.83], CV death (RR 0.80; 95% CI 0.68–0.93), and all-cause mortality (HR 0.83; 95% CI 0.71–0.71) [60]. Similar results are observed in patients with chronic kidney disease as demonstrated by the DAPA-CKD trial, which included 68% of patients with T2DM. In this study, dapagliflozin was associated with a 29% reduction in the risk of hospitalisation for HF or CV death, mainly due to a decrease in HF hospitalisations (Tables 5 and 6) [61].

Table 5 Main baseline characteristics of participants in the DAPA-CKD study
Table 6 Efficacy results at the end of the DAPA-CKD study

The beneficial effects of dapagliflozin and other SGLT2i on the risk of HF hospitalisation in patients with T2DM and their superiority to other hypoglycaemic agents have also been confirmed in real life, even including patients with no previous diagnosis of HF [45, 46, 48, 62, 63]. The use of dapagliflozin in patients with preserved EF or acute HF is being evaluated in the DELIVER and DICTATE AHF studies, respectively [64, 65]. Meanwhile, international societies such as the American Diabetes Association (ADA) [55], the American College of Cardiology (ACC) [66] or the European Society of Cardiology (ECS) [67] advise the preferential use of SGLT2i in people with T2DM and HF with reduced EF. Among the aetiopathogenic mechanisms that would help explain the beneficial effect of dapagliflozin on heart failure, the following should be highlighted: (i) metabolic effects, including reduction of glucotoxicity, visceral fat or uric acid, as well as an increase in haematocrit; (ii) haemodynamic effects, especially osmotic diuresis and natriuresis reducing preload (volaemia) and afterload (blood pressure) while improving glomerulotubular balance; and (iii) direct effects on the myocardium, encompassing the increase of beta-hydroxybutyrate (more efficient for myocardial disease as an energy source than glucose or fatty acids), the direct inhibitory effect on myocardial sodium–hydrogen exchanger type 1 (NHE-1) favouring calcium entry into the mitochondria, or the reduction of pro-inflammatory adipokines derived from epicardial and perivascular fat [68].

Discussion

In this review we show evidence of the clinical benefit of dapagliflozin beyond glycaemic control in clinical trials and in real practice studies (Table 7). However, in daily practice, we may not be doing it right.

Table 7 Summary of the main benefits of dapagliflozin on arterial stiffness, cardiovascular risk factors and macroangiopathy in patients with T2DM

Therapeutic inertia is common in the field of T2DM [69]. The evidence shown in this review suggests that the use of dapagliflozin is associated with numerous clinical benefits beyond glycaemic control, facilitating the control of CV risk factors and decreasing the incidence of CV events. However, SGLT2i are a family of drugs that are underutilised in actual clinical practice in patients with T2DM [9,10,11,12, 70]. In the context of cardiology, there is also a risk of underuse of dapagliflozin for the treatment of HFrEF [71].

An analysis of 1,054,727 patients with T2DM in the USA, conducted between 2013 and 2016, showed that only 7.2% initiated new treatment with any SGLT2i [11]. Patients less likely to initiate this therapy were those with previous AMI, HF, renal disease, severe hypoglycaemia, and those over the age of 75 or black [11].

Along the same lines, in a multinational cohort study of over 238,619 patients with T2DM, a decrease in the use of sulfonylureas and an increase in DPP4i and SGLT2i was observed between 2012 and 2017. However, in 2017 only 10.1–15.3% of patients were on SGLT2i while 19.1–27.6% were on some DPP4i [72]. A more recent study conducted between 2016 and 2019 evaluated hypoglycaemic prescriptions in adults with T2DM who were receiving metformin and had established CV disease (ischaemic heart disease or stroke, excluding patients with stage 4 and 5 chronic kidney disease). Regarding the 383,750 patients identified, only 9.5% were receiving SGLT2i. Factors associated with a higher likelihood of SGLT2i prescription were age less than or equal to 65 years, being male and Caucasian, having private insurance, or consulting with an endocrinologist or cardiologist [73]. Similarly, in another cohort study of more than 20,000 patients with T2DM and established CV disease, analysed between 2013 and 2019, only 1.4% were found to receive SGLT2i [9].

Several factors could be contributing to the low rate of SGLT2i prescription, including therapeutic inertia or concerns about treatment cost [74]. Although in the case of HF, evidence suggests that dapagliflozin is likely to be a cost-effective therapy for the treatment of HF with reduced EF in the UK, German and Spanish healthcare systems [59].

Conclusions

In short, dapagliflozin is a treatment that has shown long-term efficacy and safety as an oral antidiabetic, but also has numerous clinical benefits beyond glycaemic control [1]. Dapagliflozin can reduce arterial stiffness in people with T2DM, which is associated with an increased susceptibility to atherosclerosis regardless of age [18]. Dapagliflozin is also associated with a significant decrease in BP [6] and a favourable lipid profile, producing a decrease in the most atherogenic LDL fractions and an increase in HDL-C [6, 33].

As for macroangiopathy, the strongest findings suggest that dapagliflozin significantly reduces the risk of 3P-MACE, mainly mediated by a decreased risk of reinfarction in patients with a previous infarction [43]. In reducing the risk of AMI or stroke, dapagliflozin may have a neutral or slightly protective effect relative to other hypoglycaemic agents as indicated by real-life studies. Furthermore, there is no evidence that dapagliflozin worsens the progression of PAD or the risk of amputation [50].

Furthermore, dapagliflozin is associated with an improvement in symptoms, quality of life and a reduction in the risk of hospital admission in people with HF and reduced EF, regardless of the presence of T2DM and from an eGFR of at least 25 mL/min/1.73 m2, and has also been incorporated into the therapeutic arsenal for HFrEF [55, 66, 67]. Although the use of SGLT2i in clinical practice is below 10% in patients with T2DM, an increase in its prescription is expected in the coming years. Given the large and compelling evidence of the clinical benefit of dapagliflozin, we recommend the generalization of its use to all patients with T2DM who meet the indications.

References

  1. Dhillon S. Dapagliflozin: a review in type 2 diabetes. Drugs. 2019;79(10):1135–46. https://doi.org/10.1007/s40265-019-01148-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83–90. https://doi.org/10.1111/j.1463-1326.2011.01517.x.

    CAS  Article  PubMed  Google Scholar 

  3. European Medicines Agency. Forxiga. https://www.ema.europa.eu/en/medicines/human/EPAR/forxiga. Accessed Apr 30, 2022.

  4. US Food And Drug Administration. Drugs@FDA: FDA-Approved Drugs. Farxiga. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=202293. Accessed Apr 30, 2022.

  5. van Bommel EJM, Smits MM, Ruiter D, et al. Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes. J Hypertens. 2020;38(9):1811–9. https://doi.org/10.1097/HJH.0000000000002480.

    CAS  Article  PubMed  Google Scholar 

  6. Sjöström CD, Johansson P, Ptaszynska A, List J, Johnsson E. Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diab Vasc Dis Res. 2015;12(5):352–8. https://doi.org/10.1177/1479164115585298.

    CAS  Article  PubMed  Google Scholar 

  7. McGurnaghan SJ, Brierley L, Caparrotta TM, et al. The effect of dapagliflozin on glycaemic control and other cardiovascular disease risk factors in type 2 diabetes mellitus: a real-world observational study. Diabetologia. 2019;62(4):621–32. https://doi.org/10.1007/s00125-018-4806-9.

    CAS  Article  PubMed  Google Scholar 

  8. Morieri ML, Consoli A, Sesti G, et al. Comparative effectiveness of dapagliflozin vs DPP-4 inhibitors on a composite endpoint of HbA1c, body weight and blood pressure reduction in the real world. Diabetes Metab Res Rev. 2021;37(1):e3353. https://doi.org/10.1002/dmrr.3353.

    CAS  Article  PubMed  Google Scholar 

  9. Hamid A, Vaduganathan M, Oshunbade AA, et al. Antihyperglycemic therapies with expansions of US Food and Drug Administration indications to reduce cardiovascular events: prescribing patterns within an Academic Medical Center. J Cardiovasc Pharmacol. 2020;76(3):313–20. https://doi.org/10.1097/FJC.0000000000000864.

    CAS  Article  PubMed  Google Scholar 

  10. Schernthaner G, Shehadeh N, Ametov AS, et al. Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes. Cardiovasc Diabetol. 2020;19(1):185. https://doi.org/10.1186/s12933-020-01154-w.

    Article  PubMed  PubMed Central  Google Scholar 

  11. McCoy RG, Dykhoff HJ, Sangaralingham L, et al. Adoption of new glucose-lowering medications in the U.S.—the case of SGLT2i: nationwide cohort study. Diabetes Technol Ther. 2019;21(12):702–12. https://doi.org/10.1089/dia.2019.0213.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim SH, Chang TI, Mahaffey KW. A call for a new paradigm for diabetes care in the era of sodium–glucose cotransporter 2 inhibitors (SGLT2is). Cardiol Ther. 2020;9(2):219–25. https://doi.org/10.1007/s40119-020-00190-7.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kozakova M, Palombo C. Diabetes mellitus, arterial wall, and cardiovascular risk assessment. Int J Environ Res Public Health. 2016;13(2):201. https://doi.org/10.3390/ijerph13020201.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Prenner SB, Chirinos JA. Arterial stiffness in diabetes mellitus. Atherosclerosis. 2015;238(2):370–9. https://doi.org/10.1016/j.atherosclerosis.2014.12.023.

    CAS  Article  PubMed  Google Scholar 

  15. Chirinos JA, Segers P, Hughes T, Townsend R. Large-artery stiffness in health and disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019;74(9):1237–63. https://doi.org/10.1016/j.jacc.2019.07.012.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Patoulias D, Papadopoulos C, Stavropoulos K, Zografou I, Doumas M, Karagiannis A. Prognostic value of arterial stiffness measurements in cardiovascular disease, diabetes, and its complications: the potential role of sodium–glucose co-transporter-2 inhibitors. J Clin Hypertens (Greenwich). 2020;22(4):562–71. https://doi.org/10.1111/jch.13831.

    CAS  Article  Google Scholar 

  17. Solini A, Giannini L, Seghieri M, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138. https://doi.org/10.1186/s12933-017-0621-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Hidalgo Santiago JC, Maraver Delgado J, Cayón Blanco M, López Saez JB, Gómez-Fernández P. Effect of dapagliflozin on arterial stiffness in patients with type 2 diabetes mellitus. Med Clin (Barc). 2020;154(5):171–4. https://doi.org/10.1016/j.medcli.2019.05.028.

    CAS  Article  Google Scholar 

  19. Hong J-Y, Park K-Y, Kim J-D, Hwang W-M, Lim D-M. Effects of 6 months of dapagliflozin treatment on metabolic profile and endothelial cell dysfunction for obese type 2 diabetes mellitus patients without atherosclerotic cardiovascular disease. J Obes Metab Syndr. 2020;29(3):215–21. https://doi.org/10.7570/jomes20040.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Smulyan H, Lieber A, Safar ME. Hypertension, diabetes type II, and their association: role of arterial stiffness. Am J Hypertens. 2016;29(1):5–13. https://doi.org/10.1093/ajh/hpv107.

    CAS  Article  PubMed  Google Scholar 

  21. Petrykiv S, Sjöström CD, Greasley PJ, Xu J, Persson F, Heerspink HJL. Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function. Clin J Am Soc Nephrol. 2017;12(5):751–9. https://doi.org/10.2215/CJN.10180916.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57. https://doi.org/10.1056/NEJMoa1812389.

    CAS  Article  PubMed  Google Scholar 

  23. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303.

    CAS  Article  PubMed  Google Scholar 

  24. McMurray JJV, DeMets DL, Inzucchi SE, et al. A trial to evaluate the effect of the sodium–glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail. 2019;21(5):665–75. https://doi.org/10.1002/ejhf.1432.

    CAS  Article  PubMed  Google Scholar 

  25. Del Prato S, Nauck M, Durán-Garcia S, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17(6):581–90. https://doi.org/10.1111/dom.12459.

    CAS  Article  PubMed  Google Scholar 

  26. Szekeres Z, Toth K, Szabados E. The effects of SGLT2 inhibitors on lipid metabolism. Metabolites. 2021;11(2):87. https://doi.org/10.3390/metabo11020087.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Calapkulu M, Cander S, Gul OO, Ersoy C. Lipid profile in type 2 diabetic patients with new dapagliflozin treatment; actual clinical experience data of six months retrospective lipid profile from single center. Diabetes Metab Syndr. 2019;13(2):1031–4. https://doi.org/10.1016/j.dsx.2019.01.016.

    Article  PubMed  Google Scholar 

  28. Mazidi M, Rezaie P, Gao H-K, Kengne AP. Effect of sodium–glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6(6): e004007. https://doi.org/10.1161/JAHA.116.004007.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jabbour SA, Frías JP, Guja C, Hardy E, Ahmed A, Öhman P. Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly, or dapagliflozin, added to metformin monotherapy, on body weight, systolic blood pressure, and triglycerides in patients with type 2 diabetes in the DURATION-8 study. Diabetes Obes Metab. 2018;20(6):1515–9. https://doi.org/10.1111/dom.13206.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Chen M-B, Wang H, Cui W-Y, Xu H-L, Zheng Q-H. Effect of SGLT inhibitors on weight and lipid metabolism at 24 weeks of treatment in patients with diabetes mellitus: a systematic review and network meta-analysis. Medicine (Baltimore). 2021;100(6): e24593. https://doi.org/10.1097/MD.0000000000024593.

    CAS  Article  Google Scholar 

  31. Cha S-A, Park Y-M, Yun J-S, et al. A comparison of effects of DPP-4 inhibitor and SGLT2 inhibitor on lipid profile in patients with type 2 diabetes. Lipids Health Dis. 2017;16(1):58. https://doi.org/10.1186/s12944-017-0443-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Fadini GP, Bonora BM, Zatti G, et al. Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial. Cardiovasc Diabetol. 2017;16(1):42. https://doi.org/10.1186/s12933-017-0529-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Hayashi T, Fukui T, Nakanishi N, et al. Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin. Cardiovasc Diabetol. 2017;16(1):8. https://doi.org/10.1186/s12933-016-0491-5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Imre E, Gunhan HG, Erel P, Ustay O. SGLT2 inhibitors improve plasma atherogenic biomarkers in patients with type 2 diabetes: a real world retrospective observational study. Minerva Endocrinol (Torino). 2021. https://doi.org/10.23736/S2724-6507.21.03465-5.

    Article  Google Scholar 

  35. Rosenstock J, Mathieu C, Chen H, Garcia-Sanchez R, Saraiva GL. Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin. Arch Endocrinol Metab. 2018;62(4):424–30. https://doi.org/10.20945/2359-3997000000056.

    Article  PubMed  Google Scholar 

  36. Sanz-Serra P, Pedro-Botet J, Flores-Le Roux JA, Benaiges D, Chillarón JJ. Dapagliflozina: Más allá del control glucémico en el tratamiento de la diabetes mellitus tipo 2. Clin Investig Arterioscler. 2015;27(4):205–11. https://doi.org/10.1016/j.arteri.2014.11.001.

    Article  PubMed  Google Scholar 

  37. Fioretto P, Mansfield TA, Ptaszynska A, Yavin Y, Johnsson E, Parikh S. Long-term safety of dapagliflozin in older patients with type 2 diabetes mellitus: a pooled analysis of phase IIb/III studies. Drugs Aging. 2016;33(7):511–22. https://doi.org/10.1007/s40266-016-0382-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020;173(4):278–86. https://doi.org/10.7326/M20-0864.

    Article  PubMed  Google Scholar 

  39. Feng M, Lv H, Xu X, Wang J, Lyu W, Fu S. Efficacy and safety of dapagliflozin as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Medicine (Baltimore). 2019;98(30):e16575. https://doi.org/10.1097/MD.0000000000016575.

    CAS  Article  Google Scholar 

  40. Henry RR, Strange P, Zhou R, et al. Effects of dapagliflozin on 24-hour glycemic control in patients with type 2 diabetes: a randomized controlled trial. Diabetes Technol Ther. 2018;20(11):715–24. https://doi.org/10.1089/dia.2018.0052.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97(3):1020–31. https://doi.org/10.1210/jc.2011-2260.

    CAS  Article  PubMed  Google Scholar 

  42. Bailey CJ. Uric acid and the cardio-renal effects of SGLT2 inhibitors. Diabetes Obes Metab. 2019;21(6):1291–8. https://doi.org/10.1111/dom.13670.

    CAS  Article  PubMed  Google Scholar 

  43. Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation. 2019;139(22):2516–27. https://doi.org/10.1161/CIRCULATIONAHA.119.039996.

    CAS  Article  PubMed  Google Scholar 

  44. Persson F, Nyström T, Jørgensen ME, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: a multinational observational study. Diabetes Obes Metab. 2018;20(2):344–51. https://doi.org/10.1111/dom.13077.

    CAS  Article  PubMed  Google Scholar 

  45. Filion KB, Lix LM, Yu OH, et al. Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study. BMJ. 2020;370: m3342. https://doi.org/10.1136/bmj.m3342.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kohsaka S, Lam CSP, Kim DJ, et al. Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP-4 inhibitors: an analysis from the CVD-REAL 2 multinational cohort study. Lancet Diabetes Endocrinol. 2020;8(7):606–15. https://doi.org/10.1016/S2213-8587(20)30130-3.

    CAS  Article  PubMed  Google Scholar 

  47. Kosiborod M, Birkeland KI, Cavender MA, et al. Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: results from the CVD-REAL study. Diabetes Obes Metab. 2018;20(8):1983–7. https://doi.org/10.1111/dom.13299.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Li C-X, Liang S, Gao L, Liu H. Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: a real-world systematic review and meta-analysis. PLoS One. 2021;16(2): e0244689. https://doi.org/10.1371/journal.pone.0244689.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Dicembrini I, Tomberli B, Nreu B, et al. Peripheral artery disease and amputations with sodium–glucose co-transporter-2 (SGLT-2) inhibitors: a meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2019;153:138–44. https://doi.org/10.1016/j.diabres.2019.05.028.

    CAS  Article  PubMed  Google Scholar 

  50. Heyward J, Mansour O, Olson L, Singh S, Alexander GC. Association between sodium–glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: a systematic review and meta-analysis. PLoS One. 2020;15(6): e0234065. https://doi.org/10.1371/journal.pone.0234065.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Bonaca MP, Wiviott SD, Zelniker TA, et al. Dapagliflozin and cardiac, kidney, and limb outcomes in patients with and without peripheral artery disease in DECLARE-TIMI 58. Circulation. 2020;142(8):734–47. https://doi.org/10.1161/CIRCULATIONAHA.119.044775.

    Article  PubMed  Google Scholar 

  52. Lee H-F, Chen S-W, Liu J-R, et al. Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor. Cardiovasc Diabetol. 2020;19(1):160. https://doi.org/10.1186/s12933-020-01118-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016;15:37. https://doi.org/10.1186/s12933-016-0356-y.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Al Hamed FA, Elewa H. Potential therapeutic effects of sodium glucose-linked cotransporter 2 inhibitors in stroke. Clin Ther. 2020;42(11):e242–9. https://doi.org/10.1016/j.clinthera.2020.09.008.

    CAS  Article  PubMed  Google Scholar 

  55. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2021. Diabetes Care. 2021;44(Suppl 1):S125–50. https://doi.org/10.2337/dc21-S010.

    Article  Google Scholar 

  56. Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139(22):2528–36. https://doi.org/10.1161/CIRCULATIONAHA.119.040130.

    CAS  Article  PubMed  Google Scholar 

  57. Serenelli M, Böhm M, Inzucchi SE, et al. Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Eur Heart J. 2020;41(36):3402–18. https://doi.org/10.1093/eurheartj/ehaa496.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Kosiborod MN, Jhund PS, Docherty KF, et al. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial. Circulation. 2020;141(2):90–9. https://doi.org/10.1161/CIRCULATIONAHA.119.044138.

    CAS  Article  PubMed  Google Scholar 

  59. McEwan P, Darlington O, McMurray JJV, et al. Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF. Eur J Heart Fail. 2020;22(11):2147–56. https://doi.org/10.1002/ejhf.1978.

    Article  PubMed  Google Scholar 

  60. Cai R-P, Xu Y-L, Su Q. Dapagliflozin in patients with chronic heart failure: a systematic review and meta-analysis. Cardiol Res Pract. 2021;2021: 6657380. https://doi.org/10.1155/2021/6657380.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46. https://doi.org/10.1056/NEJMoa2024816.

    CAS  Article  PubMed  Google Scholar 

  62. Kosiborod M, Cavender MA, Fu AZ, et al. lower risk of heart failure and death in patients initiated on sodium–glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium–glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249–59. https://doi.org/10.1161/CIRCULATIONAHA.117.029190.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Norhammar A, Bodegård J, Nyström T, Thuresson M, Nathanson D, Eriksson JW. Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE-TIMI 58 trial: a nationwide observational study. Diabetes Obes Metab. 2019;21(5):1136–45. https://doi.org/10.1111/dom.13627.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Cox ZL, Collins SP, Aaron M, et al. Efficacy and safety of dapagliflozin in acute heart failure: rationale and design of the DICTATE-AHF trial. Am Heart J. 2021;232:116–24. https://doi.org/10.1016/j.ahj.2020.10.071.

    CAS  Article  PubMed  Google Scholar 

  65. Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail. 2021. https://doi.org/10.1002/ejhf.2249.

    Article  PubMed  Google Scholar 

  66. Writing Committee, Maddox TM, Januzzi JL, et al. Update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;77(6):772–810. https://doi.org/10.1016/j.jacc.2020.11.022.

    Article  Google Scholar 

  67. Seferović PM, Coats AJS, Ponikowski P, et al. European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure. Eur J Heart Fail. 2020;22(2):196–213. https://doi.org/10.1002/ejhf.1673.

    Article  PubMed  Google Scholar 

  68. Gorgojo-Martínez JJ. New glucose-lowering drugs for reducing cardiovascular risk in patients with type 2 diabetes mellitus. Hipertens Riesgo Vasc. 2019;36(3):145–61. https://doi.org/10.1016/j.hipert.2019.03.005.

    Article  PubMed  Google Scholar 

  69. Khunti K, Gomes MB, Pocock S, et al. Therapeutic inertia in the treatment of hyperglycaemia in patients with type 2 diabetes: a systematic review. Diabetes Obes Metab. 2018;20(2):427–37. https://doi.org/10.1111/dom.13088.

    Article  PubMed  Google Scholar 

  70. Mata-Cases M, Franch-Nadal J, Real J, Vlacho B, Gómez-García A, Mauricio D. Evaluation of clinical and antidiabetic treatment characteristics of different sub-groups of patients with type 2 diabetes: data from a Mediterranean population database. Prim Care Diabetes. 2021;15(3):588–95. https://doi.org/10.1016/j.pcd.2021.02.003.

    Article  PubMed  Google Scholar 

  71. Khan MS, Butler J, Greene SJ. The time is now for sodium glucose co-transporter 2 inhibitors for heart failure: a call to overcome clinical inertia. Circ Heart Fail. 2020;13(12): e008030. https://doi.org/10.1161/CIRCHEARTFAILURE.120.008030.

    CAS  Article  PubMed  Google Scholar 

  72. Greiver M, Havard A, Bowles JK, et al. Trends in diabetes medication use in Australia, Canada, England, and Scotland: a repeated cross-sectional analysis in primary care. Br J Gen Pract. 2021;71(704):e209–18. https://doi.org/10.3399/bjgp20X714089.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Chahine N, Al-Kindi S. Under-prescription of SGLT2 inhibitors in patients with diabetes and cardiovascular disease in the United States. J Am Coll Cardiol. 2020;75(11 Suppl 1):1915–1915. https://doi.org/10.1016/S0735-1097(20)32542-0.

    Article  Google Scholar 

  74. Lam D, Shaikh A. Real-life prescribing of SGLT2 inhibitors: how to handle the other medications including glucose-lowering drugs and diuretics. Kidney360. 2021;2(4):742–6. https://doi.org/10.34067/KID.0000412021.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Pablo Rivas and Permanyer for the editorial support of this study as well as José Aparicio, member of AstraZeneca’s medical department for his continuous support during the development of this manuscript.

Funding

This study and the journal’s Rapid Service Fee was sponsored by AstraZeneca.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Author Contributions

José M. González-Clemente/María García-Castillo: Review of the literature, drafting of the sections: Arterial stiffness and Acute Coronary Syndrome. Ignacio Llorente Gómez-Segura/Eduardo Matute-Troncoso: Review of the literature, drafting of the sections: Cerebrovascular disease and therapeutic inertia. Juan J. Gorgojo-Martínez/Alberto Jiménez-Buiza: Review of the literature, drafting of the sections: Heart Failure and metabolic control. Cristina Tejera-Pérez/Alberto Jiménez-Buiza: Review of the literature, drafting of the sections: Peripheral Arterial Disease and BP control. Albert Lecube-Torelló/Aitziber Izarra-Navarro: Review of the literature, drafting of the Dyslipidaemia section, as well as revision of the manuscript.

Disclosures

José M. González-Clemente, Juan J. Gorgojo-Martínez, Ignacio Llorente Gómez-Segura, Cristina Tejera-Pérez, and Albert Lecube-Torelló have received fees from AstraZeneca for their participation in expert meetings. María García-Castillo, Alberto Jiménez-Buiza, Eduardo Matute-Troncoso and Aitziber Izarra-Navarro are AstraZeneca employees.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Albert Lecube.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

González-Clemente, J.M., García-Castillo, M., Gorgojo-Martínez, J.J. et al. Beyond the Glycaemic Control of Dapagliflozin: Impact on Arterial Stiffness and Macroangiopathy. Diabetes Ther 13, 1281–1298 (2022). https://doi.org/10.1007/s13300-022-01280-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13300-022-01280-6

Keywords

  • Dapagliflozin
  • Sodium–glucose transporter 2 inhibitors
  • Type 2 diabetes mellitus
  • Cardiovascular diseases
  • Heart failure
  • Therapeutic inertia