Table 1.
SGLT2 inhibitor trials looking at the efficacy of SGLT2 inhibitors on cardiovascular outcomes in patients without diabetes.
| Author, year, country | N, Median age, F (%), DM (%) | Type of Study | Selection criteria | Treatment group | Comparison group | Median follow-up | Primary outcome | Secondary outcome | Effect size | Study conclusion |
|---|---|---|---|---|---|---|---|---|---|---|
| Gallego et al., 2021, Canada [39] | 84, 62, 36 %, DM (0 %) | EMPA-TROPISM trial— Randomized double-blind placebo- controlled trial | Adult age > 18 with NYHA class II and III HF with LVEF < 50 % with stable s/s and medical treatment within 3 months | Empagliflozin (10 mg/day) | Placebo | 6 months | Left ventricular end diastolic volume (LVEDV)and left ventricular end systolic volume (LVESV) | Left ventricular mass, left ventricular ejection fraction, quality of life, peak oxygen consumption | Significant reduction in LVEDV (-25.1 ± 260 ml) vs (-1.5 ± 254 ml) (p < 0.001); LVESV (-26.6 ± 20.5) vs (-0.5 ± 21.9) (p < 0.001); Reduction of LV mass (p < 0.001); improvement of LV ejection fraction (p < 0.001); improvement of peak O2 consumption and quality of life | Role of SGLT2 inhibitor in treatment of heart failure with reduced ejection fraction independent of glycemic status |
| Anker et al., 2020, Germany [40] | 1874, 67.6, 24.8 %, DM (50 %) |
Randomized double-blind parallel group placebo-controlled event driven trial | Adult age 18 years with NYHA class II, III and IV HF with LVEF of 40 % | Empagliflozin (10 mg/day) | Placebo | 16 months | Cardiovascular death, hospitalization for HF, total hospitalization for HF, adverse renal outcome | Time for cardiovascular death; time for first renal composite outcome | The hazard ratio for time to first event of cardiovascular death 0.78 (0.64 – 0.97). Hazard ratio for first and recurrent hypertensive HF 0.76 (0.57 – 1.01) Time to cardiovascular death 0.92 (0.68 – 1.24) | Empagliflozin decreased the risk of primary outcome and total hospitalization for HF by 25–30 % and decreased the rate of decline of eGFR and risk of adverse effect by 50 % |
| McMurray et al., 2019, UK [41] | 4744, 66.2, 23.8 %, DM (55 %) | DAPA-HF— Randomized double-blinded, placebo-controlled clinical trialPhase 3 | Patients with NYHA class II, III and IVLVEF of 40 % | Dapagliflozin (10 mg/day) | Placebo | 24 months | Worsening heart failure (hospitalization or urgent visit resulting in intravenous treatment for HF Cardiovascular death | Composite of hospitalization for HF or cardiovascular death.Total number of hospitalizations for HF and cardiovascular deaths | HR for primary outcome in treatment group compared to placebo is 0.74 (0.65–0.85)Worsening HF in 10 % of Dapagliflozin vs 13.7 % of placebo with HR of 0.70 (0.59–0.83)HR of death from CVD is 0.82 (0.69–0.98)Similar finding similar in patient with and without diabetes | Among patients with HF with reduced EF, the risk of worsening HF or death from cardiovascular disease was lower among those who received Dapagliflozin compared to those who received placebo irrespective of diabetes. |
| Nassif et al., 2019, US [42] | 263, 62.2, 27.5 %, DM 61.8 %) | DEFINE-HF—Randomized double-blinded, placebo-controlled linical trial | HF with NYHA class II & III LVEF of 40 %eGFR 30 ml/min/1.73 m2 | Dapagliflozin (10 mg/day) | Placebo | 12 weeks | Mean NT-proBNPProportion of patients with 5 points increase in HF specific health status on the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score or a 20 % decrease in NT-proBNP | Proportion of patients with meaningful change in KCCQ, mean BNP, change in SBP and HbA1c | Patients treated with Dapagliflozin had a clinically meaningful improvement of 5 points in KCCQ or at least a 20 % reduction in NT-proBNP compared to placebo (p = 0.003)Similar results seen in patients with or without diabetes | Addition of Dapagliflozin for 12 weeks did not affect mean NT-proBNP but significant increased proportion of patients experienced clinically meaningful improvement in HF disease specific health status and natriuretic peptide |
| Dayem et al., 2023, Egypt [43] | 100, 55.24, 16 %, DM (0 %) | DACAMI trial—Double blinded randomized controlled trial | Patients with anterior ST elevation MI (STEMI) patient who underwent PCI with LVEF < 50 % | Dapagliflozin (10 mg/day) | Placebo | 12 weeks | Change in cardiac function determined by measure of cardiac function change between baseline and 12 weeks post cardiac event and echo parameter (LVEF, LVEDV, LV mass) at baseline four weeks and 12 weeks post event | Not reported | Mean drop in NT ProBNP in treatment group compared to control group is 10.17 % (p = 0.03)Decrease left ventricular mass by 11.46 % (p = 0.02) | Dapagliflozin plays a role in prevention of left ventricular dysfunction and maintain cardiac function post ant STEMI |
| Diaz-Cruz et al., 2020, Mexico [44] | 30, 50, 53.3 %, DM (0 %) | Double blinded placebo-controlled linical trial | Patients with pre-diabetes and prehypertension and were sedentary with the no diabetes, hypertension, renal, cardiac, thyroid disease | Dapagliflozin (10 mg/day) | Placebo | 12 weeks | Variability in blood pressure | Not reported | Significant decrease in 24-hour SBP (p = 0.04) and nighttime SBP (p = 0.01) and deep circadian blood pressure pattern (p = 0.04) | 3 months use of Dapagliflozin decreased blood pressure by lowering 24 h SBP, nighttime SBP, mean arterial pressure, nocturnal hypertensionCervicovaginal infection and UTI did not affect adherence to treatment |
| Packer et al., 2020, US [45] | 3730, 67.2, 23.5 %, DM (49.8 %) | Double blinded parallel group placebo-controlled event driven trial | Patients with NYHA class II, III and IV HF with LVEF of 40 % | Empagliflozin (10 mg/day) | Placebo | 16 months | Composite of cardiovascular deaths or hospitalization for worsening HF | Total number of hospitalization due to HF | HR for CVD or hospitalization for HF is 0.75 (0.65–0.86) (p < 0.001)Decrease in total number of hospitalizations for HF in treatment group is 0.70 (0.58–0.85) (p < 0.001) | Empagliflozin decreased risk of cardiovascular or hospitalization for HF irrespective of diabetes |
| Zanchi et al., 2020, Switzerland [46] | 40, 34.1, 40 %, DM (0 %) | Double-blind, randomized placebo-controlled trial | Adult 18–50 years of age with HbA1c < 6.5 %, urine albumin-creatinine ratio < 3.3 mg/mmol. Normal urine dipstick, hematology, chemistry and normal ultrasound | Empagliflozin (10 mg/day) | Placebo | 1 month | Acute and chronic effect on renal tissue oxygenation | Effect on body weight, blood pressure, renal tubular function, hematocrit | No acute or sustained changes were found in renal cortical or medullary tissue oxygenation 24-hour SBP and DBP decreased significantly after 1 month of Empagliflozin therapy | Empagliflozin has effect on blood pressure reduction |
| Petrie et al., 2020, UK [47] | 4744, 66, 23 %, DM (55 %) | Double-blind, randomized placebo-controlled trial | Adult 18–85 years with NYHA class II and II HF with LVEF < 50 % | Dapagliflozin (10 mg/day) | Placebo | 24 months | Composite of first episode of worsening HF or cardiovascular death | Hospital admission for worsening HF or CVDTotal number of hospital admission for HF and cardiovascular death | Significant reduction of risk of primary composite outcome of first episode of worsening HF in nondiabetics (HR of 0.73; p = 0.002) | Dapagliflozin was effective in reducing cardiovascular mortality and morbidity in patients with HF and reduced EF |
| Ibanez et al., 2021, US [48] | 84, 62, 36 %, DM (0 %) | EMPA-TROPISM-Double-blind, randomized placebo-controlled trial | Adult aged 18–85 years with NYHA class II and IIIHF with LVEF < 50 % | Empagliflozin (10 mg/day) | Placebo | 6 months | Effect of SGLT2 in nondiabetic patient with HFrEFInterstitial myocardial fibrosisAortic stenosisEpicardial adipose tissue | Not reported | Significant reduction in epicardial adipose tissue (p < 0.05), decreased interstitial myocardial fibrosis (p < 0.01) and significant reduction in aortic stiffness (p < 0.01) Significant reduction in inflammatory biomarker | Empagliflozin significantly improved adiposity, interstitial myocardial fibrosis, aortic stiffness and inflammatory markers in nondiabetic patient with HFrEF |
| Anker et al., 2021, Germany [49] | 5988, 71.8, 44.6 %, DM (49 %) |
EMPEROR- Preserved- Randomized double blind parallel group placebo-controlled event driven trial |
Adult 18 years with HF with class II to IV with LVEF of > 40 % | Empagliflozin (10 mg/day) | Placebo | 26.2 months | Composite of cardiovascular death or hospitalization due to HF | Adjudicated hospitalization for HF Rate of decline in eGFR |
The hazard of primary outcome (hospitalization for HF) was lower in Empagliflozin group HR 0.79 (p < 0.001) and the effect appeared consistent in patients with or without diabetes | Empagliflozin reduced the risk of cardiovascular deaths or hospitalization for HF in patients with LVEF of 40 % regardless of presence or absence of diabetes |
HF – heart failure, LVEF – left ventricular ejection fraction, HR – hazards ratio, SBP – systolic blood pressure, DBP – diastolic blood pressure, BNP – brain natriuretic peptide, HFrEF – heart failure with reduced ejection fraction, PCI – percutaneous intervention, STEMI – ST elevation MI, eGFR – estimated GFR.