Table 2.
Clinical study of SGLT2i.
| Author, Year | Medicines | Research Type | Race | Country | Patient’s Condition (CKD Stage, Proteinuria) | Change in End Indicators | Safety Evaluation |
|---|---|---|---|---|---|---|---|
| Bhatt et al., 2020 [38] | Sotagliflozin | Randomized controlled trial | White, Black, Asian | Multi-center | eGFR: 25 to 60 mL/min/1.73 m2 | The risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, death from renal or cardiovascular causes↓ | Similar incidence of AEs with sotagliflozin and placebo |
| William G Herrington et al., 2022 [39] | Empagliflozin vs. Placebo | Randomized controlled trial | —— | Multi-center | eGFR < 45 mL/min/73 m2: ≥45 to <90 ≥20 to <45 UACR: ≥200 mg/g |
Empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo | The rates of serious AEs were similar in the two groups |
| Perkovic et al., 2019 [40] | Canagliflozin (100 mg) vs. Placebo | Randomized controlled trial | White, Black, Asian, Other | Multi-center | eGFR of 30 to <90 mL/min/1.73 m2 | The event rate of the primary composite outcome of end-stage kidney disease, doubling of the serum creatinine level, or renal or cardiovascular death was significantly lower in the canagliflozin group. The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke and hospitalization for HF |
The risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group. No significant differences in rates of amputation or fracture |
| Wanner et al., 2016 [41] | Empagliflozin | Retrospective analysis | Caucasian, African, Asian, etc. | Multi-center | eGFR < 30 (mL/min/1.73 m2) | Empagliflozin group: event or exacerbation of renal disease, risk of doubling serum creatinine levels, risk of renal replacement therapy↓ | Genital infections↑ |
| McMurray et al., 2021 [42] | Dapagliflozin | Retrospective analysis | White, Black or African American, Asian, Other | Multi-center | eGFR (25 to 75 mL/min/1.73 m2): ≥60 ≥45 to <59 ≥30 to <44 <30 UACR: 200–5000 mg/g |
Dapagliflozin reduced the total number of HF hospitalizations (first and repeat) by 60%. Dapagliflozin reduced the overall slope of eGFR, which was similar in both HF and non-HF patients. Dapagliflozin was also effective in reducing the risk of kidney-specific renal lesions |
Similar incidence of AEs with Dapagliflozin and placebo |
| Dagogo-Jack et al., 2021 [43] | Ertugliflozin | Randomized controlled trial | White, Black, Asian, Other | Multi-center | eGFR: 30 to 60 mL/min/1.73 m2 | Ertugliflozin: HbA1c, body weight, SBP, the risk of HF↓, eGFR→ | Similar incidence of UTIs with ertugliflozin and placebo |
| Heerspink et al., 2017 [44] | Canagliflozin vs. Glimepiride | Retrospective analysis | White, Black or African American, Asian, Other | Multi-center | UACR: ≥30 mg/g | Canagliflozin delayed the progression of renal disease, including eGFR and proteinuria, in type 2 diabetic patients within 2 years | Five patients experiencing acute renal failure or renal failure events, all in the canagliflozin group |
| Fioretto et al., 2018 [45] | Dapagliflozin | Randomized controlled trial | White, Black or African American, Indian/Alaska Native, Other | Multi-center | eGFR: 45 to 59 mL/min/1.73 m2 | Dapagliflozin: HbA1c, body weight, fasting plasma glucose, SBP↓ | Similar incidence of AEs with dapagliflozin and placebo |
| Allegretti et al., 2019 [46] | Bexagliflozin | Randomized controlled trial | White, Black or African American, Asian, Other | Multi-center | eGFR 30–60 mL/min/1.73 m2 | Bexagliflozin: HbA1c levels, body weight, SBP, albuminuria↓ | UTIs, genital mycotic infections↑ |
| Jongs et al., 2021 [47] | Dapagliflozin | Retrospective analysis | White, Black or African American, Asian, Other | Multi-center | eGFR: 25 to 75 mL/min/1.73 m2 UACR: 200–5000 mg/g |
Dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with T2D. Among patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage |
—— |
| Jardine et al., 2021 [48] |
Canagliflozin |
Retrospective analysis | White, Black, Asian | Multi-center | UACR (mg/g) ≤1000 >1000–<3000 ≥3000 mg/g |
Canagliflozin safely reduces kidney and cardiovascular events in people with T2D and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥ 3000 mg/g | —— |
| Pollock et al., 2019 [49] | Dapagliflozin, Saxagliptin | Randomized controlled trial | White, Black, Asian, Other | Multi-center | UACR 30–3500 mg/g | Dapagliflozin and dapagliflozin–saxagliptin reduced UACR versus placebo | AEs or serious AEs were similar across groups |
| Kohan et al., 2016 [50] | Dapagliflozin |
Randomized controlled trial |
Caucasian, African, American, Asian, Other | Multi-center | eGFR (mL/min/1.73 m2): ≥90 ≥60 to <90 ≥30 to <60 <30 |
There was a small transient decrease in mean eGFR of dapagliflozin at Week 1, but it returned to near baseline values at Week 24 and remained stable at Week 102. At Week 102; the mean eGFR changes for dapagliflozin were not significantly different from placebo | Dapagliflozin was more likely than placebo to develop renal AEs in patients ≥65 years of age or CKD Phase 3 |
| Heerspink et al., 2021 [51] | Dapagliflozin | Retrospective analysis | White, Black or African American, Asian, Other | Multi-center | eGFR: 25 to 75 mL/min/1.73 m2 UACR: 200–5000 mg/g |
Dapagliflozin significantly slowed long-term eGFR decline in patients with chronic kidney disease compared with placebo. The mean difference in eGFR slope between patients treated with dapagliflozin versus placebo was greater in patients with T2D, higher HbA1c, and higher UACR | —— |
| Cherney et al., 2021 [52] | Ertugliflozin | Prespecified exploratory analysis | White, Black, Asian, Other | Multi-center | eGFR (mL/min/1.73 m2): G1 ≥ 90 G2 ≥ 60 to <90 G3 < 60 |
Ertugliflozin has a favorable placebo-adjusted eGFR slope 0.75 mL/min per 1.73 m2 per year | —— |
| Natalie A Mordi et al., 2020 [53] | Loop diuretic+Empagliflozin vs. Loop diuretic+Placebo | Randomized controlled trial | —— | England | eGFR < 45 mL/min/1.73 m2 | Empagliflozin caused a significant increase in 24-h urine volume without an increase in urinary sodium when used in combination with loop diuretic. The sodium benefit that Empagliflozin may cause may be transient and only present early | —— |
| Heerspink et al., 2020 [54] | Dapagliflozin | Randomized controlled trial | White, Black, Asian | Multi-center | eGFR: 25 to 75 mL/min/1.73 m2 UACR 200–5000 mg/g |
During the first 2 weeks, there was a greater reduction in the estimated GFR in the dapagliflozin group than in the placebo group. Thereafter, the annual change in the mean eGFR was smaller with dapagliflozin than with placebo | —— |
| Oshima et al., 2020 [55] |
Canagliflozin | Retrospective analysis | White, Black, Asian | Multi-center | eGFR: 30 to 90 mL/min/1.73 m2 UACR 300–3000 mg/g |
Although acute drops in eGFR > 10% occurred in nearly half of all participants following initiation of canagliflozin the benefit of canagliflozin compared with placebo was observed regardless of the acute eGFR decline | —— |
| Neuen et al., 2021 [56] | Canagliflozin | Randomized controlled trial | White, Asian, Black or African American, Other | Multi-center | eGFR (60–90 mL/min/1.73 m2): >60 45 to <60 <45 UACR: >300 mg/g ≤1000 1000 to <3000 ≥3000 |
Canagliflozin reduced the risk of hyperkalemia in patients with T2D and CKD compared with placebo, as well as patient use of potassium binders. There was no adverse effect on the occurrence of hypokalemia | A U-shaped association between serum potassium levels and renal and cardiovascular outcomes, such as an association between serum potassium levels < 4.0 or > 5.0 mmol/L and an increased risk of adverse outcomes |
| Antlanger et al., 2022 [57] | Empagliflozin | Randomized controlled trial and perspective study | —— | Austria | eGFR: 15 to 59 mL/min/1.73 m2 UACR: 30 mg/g |
Empagliflozin treatment resulted in a 1.5 to 2-fold increase in main RAS peptides in patients with diabetes compared with placebo. Compared with placebo, all main RAS peptides increased up to 100-fold more in the empagliflozin group, while plasma ACE activity and ACE2 levels remained suppressed |
—— |
| Sen et al., 2022 [58] | Dapagliflozin | Randomized controlled trial and retrospective analysis | White, Asian or of Middle Eastern | Multi-center | eGFR: ≥25 and ≤50 mL/min/1.73 m2 or eGFR: ≥25 mL/min/1.73 m2 UACR: 500–3500 mg/g |
Compared to placebo, dapagliflozin increased plasma renin, aldosterone and copeptin levels | —— |
| Heerspink et al., 2020 [59] | Dapagliflozin | Randomized controlled trial | White, Black, Asian, Other | Multi-center | eGFR: 25 to 75 mL/min/1.73 m2 UACR ≥ 200 mg/g |
—— | The rate of serious renal-related AEs was significantly lower in the dapagliflozin compared with the placebo group |
| Mayer et al., 2019 [60] | Empagliflozin | Randomized controlled trial | —— | Multi-center | eGFR ≥ 30 mL/min/1.73 m2 |
Empagliflozin treatment in the EMPA-REG OUTCOME trial was associated with an initial reduction in eGFR from baseline to week 4 versus placebo (i.e., treatment initiation period). However, after week 4 until last value on treatment (i.e., the chronic treatment period), placebo-treated patients exhibited a significantly larger decline in eGFR than patients on empagliflozin did. After cessation of therapy, eGFR swiftly increased in empagliflozin treated patients versus those on placebo | —— |
eGFR: estimated glomerular filtration rate; HF: heart failure; HbA1c: glycosylated hemoglobin, type A1C; SBP: systolic blood pressure; UTIs: urinary tract infections; UACR: urinary albumin/creatinine ratio; RAS: renin-angiotensin system; ACE2: angiotensin-converting enzyme 2; T2D: type 2 diabetes. AEs: adverse events.