Adding Dapagliflozin to Dual Antihypertensive Therapy

Dapagliflozin may benefit diabetic patients with inadequately controlled hypertension, especially those on beta blockers or calcium channel blockers, according to a study published online in Lancet Diabetes & Endocrinology.

“Our results show clinically meaningful, placebo-adjusted, decreases in systolic blood pressure of 5.1 mm Hg and 5.8 mm Hg in patients treated with a β blocker or calcium-channel blocker, respectively, which are of a similar scale to that which might be anticipated with a conventional diuretic added to ongoing dual antihypertensive therapy,” wrote first author Michael Weber, MD, of SUNY Downstate College of Medicine (Brooklyn, NY), and colleagues.

Past studies have already shown that SGLT2 inhibitors can lower blood pressure, most likely related to osmotic diuresis, mild diuresis, and weight loss. Yet how to best use these new drugs in combination with blood pressure lowering medications remains an open question.

The double-blind placebo-controlled, phase 3 study took place between October 2010 and October 2012, and included patients from 311 health centers in 16 countries on five continents. Participants had inadequately controlled type 2 diabetes (mean HbA1c 8.0%) and hypertension (mean systolic blood pressure 151.3 mmHg, mean diastolic blood pressure 91.4 mmHg), with a mean duration of hypertension of 9.3 years. They were taking oral antihyperglycemics, insulin, or both, in addition to an ACE inhibitor or angiotensin II receptor blocker and another antihypertensive. 

Researchers randomized participants to dapagliflozin 10 mg once daily (n=225) or placebo (n=224). At baseline, 55% were on ACE inhibitors, 45% were on angiotensin II receptor blockers, in addition to a thiazide diuretic, a thiazide-like diuretic, a calcium-channel blocker, a β blocker, or an α adrenergic blocker.

Researchers measured seated systolic blood pressure (SBP) during clinic visits at weeks 1, 2, 4, 8, and 12.  They also measured 24-hour ambulatory blood pressure at baseline and 12 weeks.

Key results at 12 weeks:

• Seated SBP: Significantly lower with dapagliflozin than placebo (placebo-adjusted difference: −4.28 mmHg; P=0.0002)

• Mean 24-hour ambulatory SBP: Significantly lower with dapagliflozin vs placebo (placebo-adjusted difference: −4.45 mmHg; P=0.0012)

• Reduction in HbA1c: Significantly greater with dapagliflozin vs placebo (placebo-adjusted difference: −0.61%; P<0.0001)

• Post-hoc analyses:

♦ Seated SBP: Greater reduction for β blockers and calcium channel blockers than thiazides (placebo-adjusted difference: −5.76 mmHg, −5.13 mmHg, −2.38 mmHg, respectively)

♦ Mean 24-hour ambulatory SBP: Less of a difference between β blockers, calcium channel blockers, and thiazides (placebo-adjusted difference: −6.16, -4.45, and 4.92, respectively)

♦ Weight loss: Less with thiazides than with β blockers and calcium channel blockers (placebo-adjusted difference: −0·49 kg, −1·51 kg, −0·67 kg, respectively)

• Adverse events: Similar with dapagliflozin and placebo (44% vs 42%, respectively)

The authors noted that the results suggesting dapagliflozin has less of an effect on blood pressure in patients who are already on a renin-angiotensin system blocker and a thiazide diuretic are “not wholly unexpected, since adding a drug with a predominantly diuretic-dependent antihypertensive action to patients already receiving a thiazide drug might be less likely to have a major additive effect.” The differences in weight loss between the three antihypertensive drug groups supports this explanation, they added.

The trial was not designed to measure cardiovascular endpoints. A cardiovascular outcomes trial called Dapagliflozin Effect on CardiovascuLAR Events (DECLARE TIMI) is currently underway.

Take-home Points

• Dapagliflozin significantly lowered seated and ambulatory SBP over 12 weeks in patients with type 2 diabetes who were already on two blood pressure-lowering drugs.

• Dapagliflozin was associated with a greater reduction in seated SBP in patients on β blockers and calcium channel blockers, than for those on thiazides.

• Weight loss was less with thiazides than with β blockers and calcium channel blockers.   

The study was funded by Bristol-Myers Squibb and AstraZeneca.

Michael Weber reports research funding, consulting from one or more of the following: Bristol-Myers Squibb, AstraZeneca, Novartis, Forest Pharmaceuticals.

Traci Mansfield is an employee of AstraZeneca and a shareholder of AstraZeneca and Bristol-Myers Squibb. Valerie Cain, Nayyar Iqbal, and Shamik Parikh are employees and shareholders of AstraZeneca. Agata Ptaszynska is an employee and shareholder of Bristol-Myers Squibb.

Reference: Weber MA, et al. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2015 Nov 27. [Epub ahead of print]