Table 3.
Summary of observational studies and RCTs assessing the effects of SGLT-2 inhibitors on indices of arterial stiffness.
| Study ID | Country | Type of study | Population (main characteristics) | SGLT2 inhibitor | Follow-up | Main outcomes |
|---|---|---|---|---|---|---|
| Patoulias et al. [66] | Greece | Single-centre, single-arm, observational prospective cohort study | 46 adults with T2D receiving stable medication for T2D and hypertension | Empagliflozin (16 patients) or dapagliflozin (30 patients) | 10 months | Treatment with either empagliflozin or dapagliflozin was not associated with significant improvements neither in PWV (p = .65), nor in other markers of arterial stiffness, like AIx (p = .99). |
| Katakami et al. [67] | Japan (22 outpatient clinics) | Multicentre RCT (UTOPIA trial) sub-analysis | 340 adults with T2D and HbA1c = 6.0–9.0% without history of established CVD, evaluation of brachial-ankle PWV was obtained in 154 patients (80 in the tofogliflozin group and 74 in the non-SGLT2i group) | Tofogliflozin (20 mg once daily) vs. non-SGLT2i standard of care (control group), 1:1 randomization | 104 weeks | Treatment with tofogliflozin was associated with significant improvements in mean, right and left brachial-ankle PWV compared to control group (–104.7 cm/s, 95% CI: [–177.0 to –32.4]; p = .005, –109.3 cm/s, 95% CI: [–184.3 to –34.3]; p = .005 and –98.3 cm/s, 95% CI: [–172.6 to –24.1]; p = .01, respectively), even after adjusting for classical CVD RFs. |
| Kourtidou et al. [68] | Greece | Cross-sectional study | 40 adults with T2D (15 patients in the SGLT2i arm 25 patients in the non-SGLT2i group) | n/a | – | Compared to patients receiving other antidiabetic agents, treatment with SGLT2i was associated with lower Aix (21.9 ± 11.3 vs. 29.7 ± 12%; p < .05), decreased AIx@75 (21.3 ± 10.9 vs. 32.6 ± 11.3%, p < .005), but it was not associated with significant changes in other indices of arterial stiffness (PWV) and subclinical atherosclerosis (CCA-IMT). |
| Karalliedde et al. [69] | United Kingdom | Single-centre RCT | 33 adults with T2D and eGFR >60 mL/min and residual microalbuminuria after maximum tolerated RAS inhibition | Dapagliflozin (10mg once daily) vs. placebo as an add-on therapy to ramipril (10 mg once daily), randomization 1:1 | 24 weeks | Treatment with dapagliflozin was not associated with significant improvements in mean aortic PWV compared to control group (9.06 ± 1.91 m/s at baseline, 9.13 ± 2.03 m/s after 24 weeks, mean change = −0.5 m/s, 95% CI: [−1 to 2]; p = .84 in the SGLT2i group vs. 9.88 ± 2.12 m/s at baseline, 10.0 ± 1.84 m/s after 24 weeks, mean change = 0.12 m/s, 95% CI: [−0.89 to 1.13]; p = .81 in the control group). |
| Bosch et al. [70] | Germany | Single-centre, double-blind, cross-over RCT, post hoc analysis | 58 adults with T2D, and HbA1c = 6.5–10.0% and eGFR >60 mL/min | Empagliflozin (25 mg once daily) vs. placebo | 6 weeks | Treatment with SGLT2i was associated with significant improvements in arterial stiffness indices like central SBP (113.6 ± 12.1 vs. 118.6 ± 12.9 mmHg, p < .001), and central pulse pressure (39.1 ± 10.2 vs. 41.9 ± 10.7 mmHg, p = .027) compared to control group. |
| Papadopoulou et al. [71] | Greece | Single-centre, double-blind RCT | 85 adults with T2D treated with one or combination therapy of non-SGLT2i antidiabetic agents | Dapagliflozin (10 mg once daily) vs. placebo, randomization 1:1 | 12 weeks | Treatment with dapagliflozin was associated with significant reductions in 24 h HR-adjusted AIx and with a significant difference in change of estimated 24-h PWV (–0.16 ± 0.32 vs. 0.02 ± 0.27; p = .007) comparing to placebo group. |
| Hong et al. [72] | Korea | Single-centre, retrospective observational study | 140 adults with T2D and obesity without history of established CVD | Dapagliflozin (10 mg once daily) vs. metformin (control group) | 6 months | Treatment with dapagliflozin for 6 months was not associated with significant improvements either in aorta or in extremities PWV values. However, subgroup analysis demonstrated that treatment with dapagliflozin was associated with significant reduction in aortic PWV (6.76 ± 1.51 m/s vs. 7.33 ± 1.48 m/s at baseline, p < .01) only among participants who lost BW. |
| Hidalgo Santiago et al. [73] | Spain | Single-centre, Prospective Observational Study | 32 adults with T2D | Dapagliflozin (10 mg once daily) | 12 months | Treatment with dapagliflozin led to significant reduction in carotid-femoral PWV (–9.1 m/s, 95% CI [8.4 to 10.1] vs. −9.65 m/s, 95% CI [8.75 to 11.2]; p = .02). |
| Solini et al. [74] | Italy | Pilot study | 26 adults with T2D without history of established CVD | Dapagliflozin (10 mg QD) vs. hydrochlorothiazide (12.5 mg QD) (control group) | 2 days | Compared to control group, treatment with SGLT2i significantly increased FMD (2.8 ± 2.2 vs. 4.0 ± 2.1%, p < .05), and significantly decreased aortic PWV (10.1 ± 1.6 to 8.9 ± 1.6 m/s, p < .05) even after adjustments for BP. |
| Striepe et al. [75] | Germany | Single-centre, double-blind, crossover RCT | 76 adults with T2D | Empagliflozin (25 mg once daily) vs. placebo (control group) | 6 weeks | Treatment with empagliflozin was associated with significant reductions in ambulatory 24-hour central SBP (p = .059), central DBP (p = .001) and significant difference in PWV (−0.08 ± 0.35 m/s, p = .016) compared to control group. |
| Bechlioulis et al. [76] | Greece | Single-centre, single-blind, crossover RCT | 62 adults with T2D with HbA1c >7%, without a known history of HF | Empagliflozin (25 mg once daily) vs. liraglutide (titrated gradually to 1.8 mg once daily) randomization 1:1, after 3 months SGLT2i was added to the GLP-1 arm and vice versa. | 9 months | The differences between the SGLT2i and GLP1-RA groups in ΔPWV (p = .812 and p = .436, respectively) and ΔΑΙx (p = .740 and p = .870) were not statistically significant neither at 3 nor at 9 months. The differences between the SGLT2i and GLP1-RA groups in ΔPWV and ΔΑΙx were not statistically significant for the total population of the study comparing baseline measurements with those after 9 months. |
AIx: augmentation index; BP: blood pressure; BW: body weight; CI: confidence interval; CVD: cardiovascular disease; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; FMD: flow-mediated dilation; HbA1c: haemoglobin A1c; HR: heart rate; MD: mean difference; PWV: pulse wave velocity; RAS: renin angiotensin system; RCT: randomized control trial; RF: risk factor; RHI: reactive hyperaemia index; SBP: systolic blood pressure; SGLT2i: sodium-glucose cotransporter 2 inhibitors; T2D: type 2 diabetes.