Table 2.
Summary of main results from dedicated Phase III trials of SGLT2 inhibitors in patients with T2DM and hypertension
| Trial | Study and participant details | Regimena | BP data, mmHg
|
Safety data
|
||||
|---|---|---|---|---|---|---|---|---|
| Baseline (SD) | PBO-subtracted change to end of DB treatment period (95% CI) | Mean heart rate (bpm), n (SD) | Orthostatic hypotension, n (%) | Renal function-related AEs, n (%) | Volume depletion-related AEs, n (%) | |||
| Dapagliflozin MB102077 (NCT01195662)84 | Design: multicenter, randomized, DB, PBO-controlled Duration: 4-week lead-in, 12-week DB treatment period, 1-week follow-up Participants: T2DM (HbA 7%–10.5%) and 1c inadequately controlled HTN (systolic BP 140–165 mmHg and diastolic BP 85–105 mmHg at enrollment and randomization; mean 24-hour BP via ABPM ≥130/80 mmHg within 1 week of randomization) BP measurements: seated systolic BP, ABPM, seated diastolic BP Coprimary efficacy end point: change from baseline to week 12 in mean seated systolic BP Secondary efficacy end points: change from baseline to week 12 in 24-hour ambulatory systolic BP, seated diastolic BP, and serum uric acid |
DAPA 10 mg vs PBO (oral, once daily) | b | c | d | e | ||
| Full-analysis population | Mean seated systolic BP, mmHg | |||||||
| n=224 | PBO | 151.3 (6.7) | –4.28 (–6.54 to –2.02) | –0.5 | 4 (2%) | 1 (<1%) | 0 | |
| n=225 | DAPA | 151.0 (7.9) | –1.4 | 7 (3%) | 3 (1%) | 1 (<1%) | ||
| Mean 24-hour systolic BP (ABPM), mmHg | As above | As above | As above | As above | ||||
| n=224 | PBO | 149.2 (12.7) | –4.45 (–7.14 to –1.76) | |||||
| n=225 | DAPA | 146.5 (10.4) | ||||||
| Mean seated diastolic BP, mmHg | As above | As above | As above | As above | ||||
| n=224 | PBO | 91.4 (4.8) | –0.97 (–2.32 to 0.39) | |||||
| n=225 | DAPA | 91.2 (4.8) | ||||||
| Subgroup analysisf | Mean seated systolic BP, mmHg | |||||||
| Thiazide diuretic (n=77) | PBO | 151.8 (6.9) | –2.38 (–6.16 to –1.4) | NR | NR | 0 | 0 | |
| Thiazide diuretic (n=92) | DAPA | 151.1 (8.6) | NR | NR | 2 (2%) | 1 (1%) | ||
| Calcium-channel blocker (n=61) | PBO | 150.0 (6.4) | –5.13 (–9.47 to –0.79) | NR | NR | 0 | 0 | |
| Calcium-channel blocker (n=60) | DAPA | 150.1 (7.4) | NR | NR | 0 | 0 | ||
| β-Blocker (n=59) | PBO | 151.4 (6.9) | –5.76 (–10.28 to –1.23) | NR | NR | 0 | 0 | |
| β-Blocker (n=57) | DAPA | 152.6 (7.3) | NR | NR | 1 (2%) | 0 | ||
| EmpagliflozinEMPA-REG BP(NCT01370005)85 | Design: multicenter, randomized, DB, PBO- controlled Duration: 2-week OL PBO run-in, 12-week DB treatment period, 2-week follow-up Participants: T2DM (HbA ≥7%–≤10%) and HTN: 1c mean seated office systolic BP 130–159 mmHg and diastolic BP 80–99 mmHg at screening and successful ABPM ≤1 week prior to randomization BP measurements: 24-hour systolic BP and 24- hour diastolic BP, both via ABPM Coprimary efficacy end point: change from baseline in mean 24-hour systolic BP (via ABPM) at week 12 Key secondary efficacy end point: change from baseline in mean 24-hour diastolic BP (via ABPM) at week 12 |
EMPA 10 mg vs EMPA 25 mg vs PBO (oral, once daily) | g | h | i | |||
| Full-analysis population | 24-hour mean systolic BP (ABPM), mmHg | |||||||
| n=271 | PBO | 131.7 (11.8) | NA | –0.27 (6.1) | 51/254 (20.1%) | NR | 1 (0.4%) | |
| n=276 | EMPA 10 mg | 131.3 (13) | –3.44 (–4.78 to –2.09) | –0.17 (7.7) | 67/259 (25.9%) | NR | 1 (0.4%) | |
| n=276 | EMPA 25 mg | 131.2 (12.1) | –4.16 (–5.50 to –2.83) | –0.74 (6.16) | 76/259 (29.3%) | NR | 0 | |
| 24-hour mean diastolic BP (ABPM), mmHg | As above | As above | As above | As above | ||||
| n=271 | PBO | 75.2 (7.5) | NA | |||||
| n=276 | EMPA 10 mg | 75.1 (8.3) | –1.36 (–2.15 to –0.56) | |||||
| n=276 | EMPA 25 mg | 74.6 (7.5) | –1.72 (–2.51 to –0.93) | |||||
| Subgroup: patients with BP (ABPM) ≥130/80 mmHg at baseline | 24-hour mean systolic BP (ABPM), mmHg | NR for subgroups | NR for subgroups | NR for subgroups | NR for subgroups | |||
| n=150 | PBO | NR | NA | |||||
| n=141 | EMPA 10 mg | NR | –4.18 (–6.13 to –2.22) | |||||
| n=153 | EMPA 25 mg | NR | –5.04 (–6.96 to –3.12) | |||||
| Subgroup: patients with BP (ABPM) <130/80 mmHg at baseline | 24-hour mean systolic BP (ABPM), mmHg | NR for subgroups | NR for subgroups | NR for subgroups | NR for subgroups | |||
| n=121 | PBO | NR | NA | |||||
| n=135 | EMPA 10 mg | NR | –2.69 (–4.78 to –0.6) | |||||
| n=123 | EMPA 25 mg | NR | –2.66 (–4.8 to –0.53) | |||||
| Subgroup: patients with BP (ABPM) ≥130/80 mmHg at baseline | 24-hour mean diastolic BP (ABPM), mmHg | NR for subgroups | NR for subgroups | NR for subgroups | NR for subgroups | |||
| n=150 | PBO | NR | NA | |||||
| n=141 | EMPA 10 mg | NR | –1.85 (–2.96 to –0.74) | |||||
| n=153 | EMPA 25 mg | NR | –1.84 (2.93 to –0.75) | |||||
| Subgroup: patients with BP (ABPM) <130/80 mmHg at baseline | 24-h mean diastolic BP (ABPM), mmHg | NR for subgroups | NR for subgroups | NR for subgroups | NR for subgroups | |||
| n=121 | PBO | NR | NA | |||||
| n=135 | EMPA 10 mg | NR | –1.02 (–2.22 to 0.17) | |||||
| n=123 | EMPA 25 mg | NR | –1.30 (–2.51 to –0.08) | |||||
| Canagliflozin(NCT01939496)86 | Design: multicenter, randomized, DB, PBO-controlled Duration: 2-week single-blind PBO run-in, 6-week DB treatment period, 30-day follow-up Participants: T2DM (HbA1c ≥7%–<10%) and HTN (seated systolic BP ≥130–<160 mmHg and diastolic BP ≥70 mmHg at baseline) BP measurements: ABPM, seated and standing BP (systolic and diastolic) Primary efficacy end point: change from baseline to week 6 in mean 24-hour systolic BP (via ABPM) Key secondary efficacy end point: change from baseline to week 6 in mean 24-hour diastolic BP |
CANA 100 mg vs CANA 300 mg vs PBO (oral, once daily) | j | k | ||||
| Full-analysis population | 24-hour mean systolic BP (ABPM), mmHg | At week 6 | ||||||
| n=56 | PBO | 136.7 (10.3) | NA | NR | 2 (3.9) | 0 | 0 | |
| n=57 | CANA 100 mg | 136.5 (11.5) | –3.3 (–6.7 to 0.2) | NR | 2 (3.8) | 1 (1.8) | 0 | |
| n=56 | CANA 300 mg | 139.6 (10.9) | –4.9 (–8.4 to –1.5) | NR | 4 (7.1) | 0 | 2 (3.6) | |
| 24-hour mean diastolic BP (ABPM), mmHg | As above | As above | As above | |||||
| n=56 | PBO | 78.4 (7.3) | NA | NR | ||||
| n=57 | CANA 100 mg | 78 (8.1) | –1.9 (–4 to 0.1) | NR | ||||
| n=56 | CANA 300 mg | 79.3 (7.9) | –2.9 (–5 to –0.9) | NR | ||||
Notes:
Dose and regimen of glucose-lowering agents and BP-lowering agents were stable throughout the study period.
Change in seated heart rate from baseline to week 12.
Measured orthostatic BP change (ie, not reported as AEs).
Based on list of preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 15.1.
Defined as hypotension, dehydration, or hypovolemia.
Patients who did not take an additional BP-lowering agent from these three subgroups or who received agents from more than one subgroup were excluded from subgroup analysis.
Change from baseline to week 12.
Number of patients with a positive orthostatic BP test/number of patients who had an orthostatic BP measurement at baseline and week 12.
Based on eight preferred terms from MedDRA.
Includes increased serum creatinine.
Defined as postural dizziness, dehydration, and/or orthostatic hypotension.
Abbreviations: ABPM, ambulatory blood pressure monitoring; AE, adverse event; BP, blood pressure; CANA, canagliflozin; CI, confidence interval; DAPA, dapagliflozin; DB, double-blind; EMPA, empagliflozin; HbA1c, glycated hemoglobin; HTN, hypertension; NA, not applicable; NR, not reported; OL, open-label; PBO, placebo; SD, standard deviation; SGLT2, sodium–glucose cotransporter 2; T2DM, type 2 diabetes mellitus.