SGLT2 inhibitor may give clinically relevant BP reductions in T2DM with nocturnal hypertension
24-Hour Blood Pressure-Lowering Effect of an SGLT-2 Inhibitor in Patients with Diabetes and Uncontrolled Nocturnal Hypertension: Results from the Randomized, Placebo-Controlled SACRA Study
Introduction and methods
The oral hypoglycemic agents SGLT2-inhibitors act primary by increasing urinary excretion of glucose, but treatment with empagliflozin has also been associated with weight loss and reduction in blood pressure (BP)[1-5]. The contribution of reductions in 24-hour BP, including nocturnal and morning time periods, to the observed CV benefits achieved with empagliflozin in patients with type 2 diabetes (T2DM) at high CV risk is unknown. It is known, however, that nocturnal hypertension and/or the non-dipper pattern of nighttime BP are strong predictors of CVD, both in patients with hypertension and in the general population [6-8].
T2DM patients with nocturnal hypertension are at particularly high risk of developing CVD [9-11]. The SGLT2 inhibitor and Angiotensin receptor blocker (ARB) Combination theRapy in pAtients with diabetes and uncontrolled nocturnal hypertension (SACRA) study studied the effects of adding empagliflozin to existing antihypertensive therapy on nighttime BP in T2DM patients with uncontrolled nocturnal hypertension. The SACRA study was a Japanese, multicenter, randomized, placebo-controlled, double-blind trial that used ambulatory BP measurement (ABPM). Eligible patients had seated clinical systolic BP (SBP) of 130-159 mmHg or diastolic BP (DBP) of 80-99 mmHg. Nocturnal hypertension was defined as SBP ≥115 mmHg at 2, 3 and 4 am during sleep 5 days prior to randomization, measured using home BP monitoring (HBPM). After an 8-week run-in period, 132 eligible patients were randomized to empagliflozin 10 mg or matching placebo once-daily for 12 weeks. The primary efficacy endpoint was change from baseline in nighttime SBP and DBP.
- A significant reduction from baseline to week 12 in SBP was seen in patients treated with empagliflozin (-6.3 mmHg, P=0.004), but not with placebo (-2.0 mmHg, P=0.367, between-group difference: 4.3, P=0.159).
- Significant reductions in daytime SBP (-11.7 mmHg, P<0.001) and 24-hour SBP (-10.0, P<0.001) were observed in the empagliflozin group but not in the placebo group (-2.1 mmHg, P=0.255 and -2.4, P=0.177, respectively), with significant between-group differences (daytime: -9.5 mmHg, 24-hour: -7.7 mmHg, both P<0.001).
- Empagliflozin, but not placebo, was associated with significant reduction in nighttime DBP (-2.5 mmHg [P=0.016] vs. -0.9 [P=0.380]), daytime DBP (-4.1 mmHg [P<0.001] vs. -0.2 [P=0.812]) and 24-hour DBP (-3.5 mmHg [P<0.001] vs. -0.7 [P=0.377]), with significant between-group differences for daytime (-3.9 mmHg, P=0.001) and 24-hour DBP (-2.9 mmHg, P=0.008).
- Clinic and morning home SBP were also statistically significantly reduced in the empagliflozin group, with significant between-group differences in change from baseline (P<0.001).
- Small, statistically significant greater reductions in body weight (-1.3 kg) and HbA1c (-0.33%) were seen with empagliflozin as compared with placebo, in change from baseline.
- No serious adverse events occurred during treatment and no safety signals were observed. No episodes of hypotension, dehydration, urinary tract infection or acute kidney injury were noted.
In the SACRA study, addition of the SGLT2 inhibitor empagliflozin was associated with significant reductions from baseline in nighttime, clinic, 24-hour ambulatory and morning home BP in T2DM patients with uncontrolled nocturnal hypertension. Most BP parameters were significantly better with empagliflozin vs. placebo, but reductions in nighttime SBP and DBP did not reach statistically significant between group differences. The numerical between-group difference of 4.3 mmHg and the SBP reduction from baseline of 6.3 mmHg may still hint at clinical implications.