Dapagliflozin and other sodium-glucose co-transporter 2 (SGLT2) inhibitors substantially reduce hospitalization for heart failure (HHF) and progression of diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM), regardless of the presence of prior cardiovascular or renal disease. The mechanisms of these benefits are uncertain but may in part relate to improvements in risk factors such as blood pressure.
However, SGLT2 inhibitors decrease systolic and diastolic blood pressure (SBP/DPD) only minimally, so their efficacy might depend on pre-treatment BP. In addition, there are concerns about the safety of SGLT2 inhibitors in patients with low to normal SPD, since BP lowering could lead to acute kidney injury, volume depletion/dehydration, falls/fractures, and lower-limb amputations.
Remo H.M. Furtado, MD, PhD, a research fellow with the TIMI Study Group in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, Stephen D. Wiviott, MD, an attending cardiologist at the Brigham and senior investigator in the TIMI Study Group, and colleagues analyzed data from the DECLARE TIMI 58 trial to address these questions.
In Circulation, they conclude dapagliflozin is beneficial for cardio-renal protection in patients with T2DM across all levels of baseline SBP and is safe for patients with normal or near-normal BP.
The 17,160 patients in DECLARE TIMI 58 were ages 40 and older and had T2DM, a glycated hemoglobin between 6.5% and 12%, and established atherosclerotic cardiovascular disease (ASCVD) or multiple ASCVD risk factors. They used dapagliflozin 10 mg once daily or a matching placebo.
Patients with screening SBP >180 mmHg or DBP >100 mmHg were ineligible to participate, but there were no minimum BP thresholds for enrollment.
For the current analysis, the researchers categorized the baseline SBP of the trial population according to current American College of Cardiology/American Heart Association definitions of hypertension:
- Normal (<120 mmHg)—n=2,557
- Elevated (120–129 mmHg)—n=3,686
- Stage 1 (130–139 mmHg)—n=4,385
- Stage 2 (140–159 mmHg)—n=5,501
- Severe (≥160 mmHg)—n=1,031
The sub-analyses focused on HHF and a renal-specific outcome because both were significantly reduced with dapagliflozin in the overall trial population. The renal-specific outcome was a composite of:
- A sustained decrease in estimated glomerular filtration rate by at least 40%; or
- Progression to end-stage renal disease (sustained eGFR <15 mL/min/1.73 m2, need for renal replacement therapy for more than 90 days or renal transplantation); or
- Renal death
Already at the six-month follow-up visit, the reduction of SBP with dapagliflozin was greater than with placebo (by −3.1 mmHg; P<0.0001). The reduction was sustained at the 48-month follow-up (by −2.4 mmHg compared with placebo; P<0.0001).
SBP lowering with dapagliflozin was observed regardless of baseline SBP and regardless of concomitant use of BP-lowering medications.
Cardiovascular and Renal Outcomes
Dapagliflozin reduced the risk of HHF regardless of baseline SBP:
- When baseline SBP was modeled as a continuous variable
- In all five categories of baseline SBP
Notably, patients with SBP <120 mmHg benefitted substantially from dapagliflozin:
- HHF—HR, 0.66 (95% CI, 0.42–1.05)
- Renal-specific outcome—HR, 0.39 (95% CI, 0.19–0.78)
The rates of relevant adverse events studied—volume depletion, amputation, and acute kidney injury—did not differ with dapagliflozin versus placebo overall or within any baseline SBP group.
Blood pressure should not influence the decision about whether to prescribe dapagliflozin for a patient with T2DM who has an indication for an SGLT2 inhibitor.