Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a newly approved class of glucose-lowering
medications with a novel mechanism of action. These agents increase glycosuria, which
leads to improved glucose control. They also produce an osmotic diuresis that, in
part, contributes to blood pressure reduction and calorie loss secondary to glycosuria
leading to weight loss (1,2).
A recent review of SGLT2 inhibitors focuses on the blood pressure–lowering effects
of the two approved glucose-lowering agents, dapagliflozin and canagliflozin (3).
While not approved as antihypertensive agents, they may potentially aid in lowering
blood pressure in patients with diabetes. A review of studies in both hypertensive
and normotensive patients with type 2 diabetes demonstrates a 4–10 mmHg reduction
of systolic blood pressure (3).
In this issue of Diabetes Care, Tikkanen et al. (4) investigate the effectiveness
and safety of the newest agent in this class, empagliflozin, on blood pressure using
24-h ambulatory blood pressure monitoring. This study randomized over 800 subjects
with type 2 diabetes, mean age of 60 years, and good kidney function (i.e., a mean
estimated glomerular filtration rate [eGFR] of 84 mL/min/1.73 m2). These subjects
either were normotensive (<140/90 mmHg) or had stage 1 hypertension (≥140/90 < 160/99
mmHg). They were randomized to either empagliflozin 10 mg daily, empagliflozin 25
mg daily, or placebo. The primary end point was the change in HbA1c over the 12-week
study. The coprimary end point was change in mean 24-h systolic blood pressure for
which the study was 90% powered to see a 4 mmHg difference from placebo. The authors
demonstrated a significant reduction in 24-h systolic and diastolic blood pressures,
4/2 mmHg lower than placebo at the 25 mg dose of empagliflozin.
The use of 24-h ambulatory blood pressure monitoring in the study by Tikkanen et al.
is important and distinctive as it is the gold standard for assessing blood pressure
(5). Moreover, it is the largest study to date to assess blood pressure lowering during
both day and night with the use of SGLT2 inhibitors. Ambulatory blood pressure is
recommended in the U.K. for evaluating all new patients with hypertension by the National
Institute for Health and Care Excellence guidelines (5). Given the hypothesis of the
study and its specific aim, it would have been more compelling if it stratified patients
by level of eGFR (i.e., >45, <60, and >60 mL/min/1.73 m2) to assess the spectrum of
blood pressure lowering across stages of kidney disease as was done with canagliflozin
(6). This would have required substantially more subjects, however. Additionally,
the study could have been powered for a blood pressure end point; however, this class
of drugs is not approved as a blood pressure–lowering agent.
The exact mechanism of blood pressure lowering with these agents is not completely
understood; however, proposed mechanisms are listed in Table 1. Blood pressure reduction
by these agents is assumed to be related to its osmotic diuretic effect, although
they have very slight natriuretic effects much less than low-dose thiazide diuretics.
It is curious that if osmotic diuresis was the sole mechanism, then the antihypertensive
effect would wane as kidney function decreases; however, this is not the case (3).
Similar levels of blood pressure reduction are seen in people with eGFR of 45 mL/min/1.73
m2 as those with 85 mL/min/1.73 m2. Also, there is no reported hyponatremia with these
agents, suggesting their blood pressure lowering is not related to sodium loss (1).
Last, while weight loss has been postulated as a contributing mechanism for blood
pressure lowering, it is unlikely as the blood pressure–lowering effect is seen much
earlier than any significant weight loss (3).
Table 1
Proposed mechanisms for antihypertensive action of SGLT2 inhibitors
Osmotic diuresis
Weight loss after a week or so
Mild natriuresis
Possible indirect effects on nitric oxide release secondary to reduced oxidant stress
by better glycemic control*
*
Observation from preliminary studies in a couple of patients.
An investigation by Cherney et al. (7) studied patients with type 1 diabetes treated
with empagliflozin 25 mg daily for 8 weeks. This study demonstrated significant blood
pressure reductions and there was an assessment of changes in arterial stiffness and
sympathetic nervous system activity. The subjects had measurements of radial artery
and carotid waveforms, augmentation index, heart rate, and aortic pulse wave velocity.
During euglycemic clamp conditions, there was a significant reduction in systolic
blood pressure, radial augmentation index, carotid augmentation index, and aortic
augmentation index in subjects treated with empagliflozin 25 mg daily. The augmentation
index is commonly accepted as a measure of central aortic pressure enhancement by
a reflected pulse wave and is a predictor of adverse cardiovascular events. It is
defined as a ratio calculated from the blood pressure waveform; the greater the augmentation,
the greater the arterial stiffness. There were no significant changes in the measurements
of sympathetic nervous system activity.
SGLT2 inhibitors are a unique class of medications that not only improve glucose control
but also have a demonstrated impact on reducing cardiovascular risk factors (i.e.,
high blood pressure and excessive weight). The long-term effects of these agents on
blood pressure and overall cardiovascular and kidney disease are being assessed in
ongoing cardiovascular and chronic kidney disease outcome trials that should be completed
within the next 3 to 5 years.
The data from the study by Tikkanen et al. (4), taken together with previous studies
of other agents in the class, demonstrate that SGLT2 inhibitors not only lower glucose
but also have other salutary effects (i.e., blood pressure–lowering and weight-reducing
effects). Moreover, they are safe as they are not associated with hypoglycemia except
when used with sulfonylureas or insulin. Future studies should perhaps focus on use
of these agents as antihypertensive agents and hence a potential substitute for diuretics
to avoid adverse metabolic effects in patients with diabetes. It is important to treat
all associated components of the abnormal metabolic profile in patients with diabetes
to optimally reduce the risk of cardiovascular disease. These agents are a powerful
new tool for the diabetologist and clinician in general. They should be considered
for use in patients with type 2 diabetes with hypertension, where indicated. Patients
should be warned of the potential side effects including polyuria, orthostatic hypotension,
hypoglycemia, and genital infections. Patients on diuretics may need dose reductions
to avoid some of these adverse effects.