The effect of sodium-glucose co-transporter-2 inhibitors on markers of subclinical atherosclerosis

Figures & data

Table 1. Summary of observational studies and RCTs assessing the effects of SGLT-2 inhibitors on indices of subclinical atherosclerosis.

Study ID	Country	Type of study	Population (main characteristics)	SGLT2 inhibitor	Follow-up	Main outcomes
SGLT2 inhibitors and IMT
Tanaka et al. [52]	Japan (39 clinical sites)	Multicentre RCT (PROTECT study)	482 adults with T2D and HbA1c = 6.0–10.0%	Ipragliflozin (50 mg once daily) vs. non-SGLT2i standard of care (control group), 1:1 randomization	24 months	Ipragliflozin had a neutral effect on CCA-IMT status, with the estimated group difference in the ipragliflozin vs. the control group being −0.0001 mm (95% CI: [–0.0191 to 0.0189]; p = .989).
Katakami et al. [53]	Japan (22 outpatient clinics)	Multicentre RCT (UTOPIA trial), post hoc analysis	340 adults with T2D and HbA1c = 6.0–9.0% without history of established CVD	Tofogliflozin (20 mg once daily) vs. non-SGLT2i standard of care (control group), 1:1 randomization	2 years	Tofogliflozin had a neutral effect on mean, left and right GSM-CCA values, with the estimated group difference in the tofogliflozin vs. the control group in the change of the mean GSM-CCA being –1.24 (95% CI: [–3.87 to 1.38]; p = .35).
Katakami et al. [54]	Japan (22 outpatient clinics)	Multicentre RCT (UTOPIA trial)	340 adults with T2D and HbA1c = 6.0–9.0% without history of established CVD	Tofogliflozin (20 mg once daily) vs. non-SGLT2i standard of care (control group), 1:1 randomization	2 years	Both patients receiving tofogliflozin and non-SGLT2i antidiabetic treatment (control group) experienced a significant reduction in mean CCA-IMT (mean change = −0.132 mm; SE 0.007 and −0.140 mm; SE 0.006, respectively) and in maximum left and right CCA-IMT measures, without important differences in the progression of subclinical atherosclerosis being observed between the two groups (mean change of CCA-IMT: 0.008 mm; 95% CI: [–0.009 to 0.025], p = .34).
Ardahanli [55]	Turkey	Single-centre, single-arm, observational prospective cohort study	37 adults with T2D without history of established CVD	Empagliflozin (10 mg or 25 mg once daily), no control group	6 months	Treatment with empagliflozin was associated with a significant reduction in CCA-IMT (7.6 ± 1.7 mm at baseline vs. 6.7 ± 1.3 mm after 6 months, p < .001) and in EAT (9.0 ± 2.2 mm at baseline vs. 7.7 ± 1.4 mm after 6 months, p = .001).
Nomiyama et al. [56]	Japan	Multicentre, single-arm, observational prospective cohort study (FUSION trial)	134 adults with T2D and HbA1c >6.5%	Ipragliflozin (50 mg once daily, no control group)	1 year	Treatment with ipragliflozin had a neutral effect on CCA-IMT measurements (0.76 ± 0.16 mm at baseline vs. 0.75 ± 0.15 mm after 52 weeks, p = .40 in right CCA and 0.75 ± 0.18 mm at baseline vs. 0.76 ± 0.17 mm after 52 weeks, p = .41 in left CCA), but it was associated with a reduction in PWV (1632.8 ± 368.5 cm/s at baseline vs. 1572.6 ± 325.4 cm/s after 52 weeks, p < .05).
Irace et al. [57]	Italy	Single-centre observational prospective cohort study	35 adults with T2D and HbA1c = 7.0–9.5%	Empagliflozin (10 mg once daily) vs. incretin-based antidiabetic treatment (liraglutide or sitagliptin)	3 months	Treatment with empagliflozin was associated with a significant reduction in CCA-IMT measurements after 1 and 3 months (0.793 ± 0.15 mm and 0.766 ± 0.127 mm; p < .0001 respectively compared to baseline measurements: 0.831 ± 0.156 mm), while treatment with liraglutide was associated with a significant reduction in CCA-IMT only after 3 months (baseline 0.879 ± 0.12 mm; 3-months 0.802 ± 0.114 mm; p < .001). Patients receiving sitagliptin had no significant changes in CCA-IMT.

BP: blood pressure; BW: body weight; CCA: common carotid artery; CI: confidence interval; CVD: cardiovascular disease; DBP: diastolic blood pressure; DEFENCE: dapagliflozin effectiveness on vascular endothelial function and glycaemic control; EAT: epicardial adipose tissue; eGFR: estimated glomerular filtration rate; GSM: grey-scale median; HbA1c: haemoglobin A1c; IMT: intima-media thickness; MD: mean difference; RCT: randomized control trial; RF: risk factor; SBP: systolic blood pressure; SGLT2i: sodium-glucose cotransporter 2 inhibitors; T2D: type 2 diabetes; UTOPIA: using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients trial.

Table 2. Summary of observational studies and RCTs assessing the effects of SGLT-2 inhibitors on indices of endothelial function.

Study ID	Country	Type of study	Population (main characteristics)	SGLT2 inhibitor	Follow-up	Main outcomes
Shigiyama et al. [58]	Japan (15 outpatient clinics)	Multicentre RCT (DEFENCE study)	80 adults with early T2D and HbA1c = 6.0–8.0% treated with 750 mg metformin, but without history of established CVD	Dapagliflozin (5 mg once daily) vs. 750 mg metformin (control group) as an add-on therapy to 750 mg metformin	16 weeks	Treatment with dapagliflozin was not associated with significant changes in FMD compared to control group (ΔFMD% [FMD at week 16 – FMD at baseline] = 0.85 ± 2.71 and −0.19 ± 2.51, p = .09, respectively). Subgroup analysis revealed that dapagliflozin was associated with significant improvement of FMD among individuals with HbA1c >7.0% (p = .041).
Kishimoto et al. [59]	Japan (39 clinical sites)	Multicentre RCT (PROTECT study) sub-analysis	482 adults with T2D and HbA1c = 6.0–10.0%, FMD values were obtained only by 32 individuals in the non-SGLT2i group and 26 individuals in the SGLT2i arm	Ipragliflozin (50 mg once daily) vs. non-SGLT2i standard of care (control group), 1:1 randomization	24 months	Treatment with ipragliflozin as well as non-SGLT2i standard of care (control group) had a neutral effect on change of FMD measurements at 24 months compared to baseline (5.2 ± 2.6% vs. 5.2 ± 2.6%, p = .98 in the SGLT2i group; 5.0 ± 3.2% vs. 5.4 ± 2.9%, p = .34 in the non-SGLT2i group).
Sposito et al. [60]	Brazil	Single-centre RCT (ADDENDA-BHS2 study)	98 adults with T2D, HbA1c = 7.0–9.0% and CCA-IMT > the 75th percentile (subclinical atherosclerosis) treated with metformin	Dapagliflozin (10 mg once daily) vs. glibenclamide (5 mg once daily), randomization 1:1	12 weeks	Treatment with dapagliflozin was associated with a significant increase in rest FMD ([+3.3 (8.2)%], compared to treatment with glibenclamide [–1.2 (7.5)%], p = .0001). In addition, patients in the non-SGLT2i arm compared to SGLT2i group experienced higher resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = .03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = .02].
Zainordin et al. [61]	Malaysia	Multicentre RCT (EDIFIED trial)	81 adults with T2D, HbA1c = 7.0–10.5% and established CVD treated with metformin and insulin	Dapagliflozin (10 mg once daily) vs. placebo (control group), randomization 1:1	12 weeks	Treatment with dapagliflozin had a neutral effect on ΔFMD, while patients in the control group experienced a non-significant reduction in ΔFMD. No statistically significant differences were observed between the two arms. However, compared to placebo dapagliflozin demonstrated a more beneficial impact on NMD values (19.64 ± 9.71% vs. 15.11 ± 8.44%; p = .038).
Sposito et al. [62]	Brazil	Single-centre RCT (EXCEED-BHS3 Trial)	110 adults with T2D, HbA1c = 7.0–9.0%	Empagliflozin (25 mg once daily) plus evolocumab vs. empagliflozin (control group), randomization 1:1	16 weeks	Subgroup analysis in the SGLT2i arm showed that treatment with empagliflozin was associated with significant improvements in FMD values at 1 and 2 minutes (p < .05).
Tanaka et al. [63]	Japan (16 centres)	Multicentre RCT (EMBLEM Trial)	117 adults with T2D and established CVD	Empagliflozin (10 mg once daily) vs. placebo (control group), randomization 1:1	24 weeks	Treatment with empagliflozin was not associated with significant changes in absolute values of RHI compared to control arm (–0.006 (SD 0.478) in the SGLT2i group and −0.025 (0.454) in the non-SGLT2i group. Also, the adjusted MD in RHI between the two groups was −0.02 (95% CI: −0.199 to 0.158, p = .821)

ADDENDA-BHS2: assessment of dapagliflozin effect on diabetic endothelial dysfunction of brachial artery-Brazilian heart study 2; BP: blood pressure; BW: body weight; CI: confidence interval; CVD: cardiovascular disease; DBP: diastolic blood pressure; DEFENCE: dapagliflozin effectiveness on vascular endothelial function and glycaemic control; EDIFIED: effects of dapagliflozin on endothelial dysfunction in type 2 diabetes with established ischemic heart disease; eGFR: estimated glomerular filtration rate; EXCEED-BHS3 Trial: EXpanded Combination of Evolocumab plus Empagliflozin on Diabetes Trial; FMD: flow-mediated dilation; HbA1c: haemoglobin A1c; MD: mean difference; NMD: nitroglycerin-mediated dilation; 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.

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.

Table 4. Summary of observational studies and RCTs assessing the effects of SGLT-2 inhibitors on EAT thickness.

Study ID	Country	Type of study	Population (main characteristics)	SGLT2 inhibitor	Follow-up	Main outcomes
Requena-Ibáñez et al. [81]	USA	Single-centre RCT (EMPA-TROPISM) sub-analysis	62 adults with HFrEF, without history of T2D	Empagliflozin (10 mg once daily) vs. placebo, randomization 1:1	6 months	Treatment with empagliflozin significantly reduced EAT volume evaluated by MRI (–5.14 mL, 95% CI: [–8.36 to −1.92]) compared to control group (–0.75 mL, 95% CI: [–3.57 to 2.06]; p < .05), and PWV (–0.58 cm/s, 95% CI: [–0.92 to −0.25] in the SGLT2i arm vs. 0.60 cm/s, 95% CI: [0.14–1.06] in the control group; p < .01).
Hiruma et al. [82]	Japan	Single-centre RCT (ASSET study)	44 adults with T2D and HbA1c = 6.0–10.0%	Empagliflozin (10 mg once daily) vs. sitagliptin (50 mg once daily), randomization 1:1	12 weeks	Treatment with empagliflozin was not associated with significant reductions in pericardial, epicardial and paracardial fat content compared to control group.
Sato et al. [83]	Japan	Single-centre RCT	40 adults with T2D and established CAD	Dapagliflozin (10 mg once daily) vs. non-SGLT2i antidiabetic treatment, randomization 1:1	6 months	Treatment with dapagliflozin was associated with significant reduction in EAT volume measured by CT and this improvement was greater in the SGLT2i arm compared to control group (mean change from baseline in EAT volume = −16.4 ± 8.3 vs. 4.7 ± 8.8 cm^3, p = .01).
Yagi et al. [84]	Japan	Single-centre observational prospective cohort study	15 adults with T2D	Canagliflozin (100 mg once daily)	6 months	Treatment with canagliflozin was associated with significant reductions in EAT thickness assessed by echocardiography at 3 months (8.1 ± 2.3 mm, p < .01), as well as at 6 months (7.3 ± 2.0 mm, p < .001) compared to baseline (9.3 ± 2.5 mm).
Bouchi et al. [85]	Japan	Single-centre, single-arm, pilot study	19 adults with T2D, HbA1c = 6.5–9.0% and BMI >25 kg/m^2	Luseogliflozin (2.5 mg once daily, titrated up to 5 mg)	12 weeks	Treatment with luseogliflozin for 12 weeks was associated with significant decrease of EAT volume measured by MRI compared to baseline (from 117 [96–136] cm^3 to 111 [88–134] cm^3, p = .048). The decrease of EAT volume was correlated with the attenuation of systematic inflammation evaluated by CRP (r = 0.493, p = .019).
Fukuda et al. [86]	Japan	Single-centre, single-arm, pilot study	19 adults with T2D, HbA1c = 6.5–9.0% and BMI < 25 kg/m^2	Ipragliflozin (50 mg once daily)	12 weeks	Treatment with ipragliflozin for 12 weeks was associated with significant decrease of EAT volume measured by MRI compared to baseline (from 102 [79–126] cm^3 to 89 [66–109] cm^3, p = .008).

BMI: body mass index; BW: body weight; CI: confidence interval; CAD: coronary artery disease; CT: computed tomography; EAT: epicardial adipose tissue; HbA1c: haemoglobin A1c; HFrEF: heart failure with reduced ejection fraction; MD: mean difference; MRI: magnetic resonance imaging; RCT: randomized control trial; SGLT2i: sodium-glucose cotransporter 2 inhibitors; T2D: type 2 diabetes.

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Data availability statement

This is a review article analysing secondary data, so data sharing is not applicable.