Despite optimal medical therapy including RAAS inhibitors, many patients continue to develop hypertension, chronic kidney disease and cardiovascular diseases . Moreover, in T1D, primary prevention strategies with RAAS blockers are ineffective . Intensive glucose lowering therapies exert long lasting renal and cardiovascular protective effects, highlighting the need for improved glucose control in patients with T1D and T2D [30–32]. Due to their unique insulin-independent mechanism of action, SGLT2 inhibitors lower blood pressure and improve glycemic control, while at the same time avoiding potential risks of increased insulin doses such as hypoglycaemia, hypertension and weight gain . These agents are also generally safe and well tolerated [22, 34–39]. Our goal was to further clarify the mechanistic basis for the blood pressure lowering effect of empagliflozin, including effects on arterial stiffness and neurohormonal activation measured by heart rate variability, since both of these parameters are associated with systemic blood pressure and correlate with long-term renal and cardiovascular outcomes [5, 40–42]. Our major novel finding was that empagliflozin reduced measures of arterial stiffness under both clamped euglycemic and hyperglycemic conditions. We also observed that after treatment with empagliflozin for 8 weeks, systolic blood pressure decreased significantly in normotensive patients with T1D.
The effect of oral hypoglycemic agents on arterial stiffness
Previous studies in T2D have suggested that oral hypoglycemic agents such as metformin reduce blood pressure, primarily through improving glycemic control [12–14, 43]. In contrast, other oral hypoglycemic agents such as sulfonylureas that increase the risk of severe hypoglycemic events and lead to body weight gain may promote the development of hypertension . Perhaps as a result of increasing weight, these traditional oral hypoglycemic agents do not improve arterial stiffness parameters and a significant proportion of patients develop hypertension with increasing diabetes duration [45, 46]. Since existing oral agents are not approved nor appropriate in T1D, the options for improving glycemic control in patients with T1D are limited to intensifying insulin regimens, which can have the same adverse effects on weight, hypoglycemic risk and blood pressure as in T2D patients [30–32]. This study shows for the first time that an oral hypoglycemic agent that improves glycemic control over an 8-week period in patients with T1D can also reduce arterial stiffness, which may in part be responsible for the antihypertensive effects associated with SGLT2 inhibition.
Regulators of arterial stiffness
Arterial stiffness is influenced by a variety of factors, including neurohormonal mediators and changes in arterial structure . We have previously demonstrated in this cohort that empagliflozin induces a modest increase in plasma RAAS mediators, including aldosterone and angiotensin II, which is likely a compensatory response to effective circulating volume contraction, similar to expected effects of a thiazide diuretic [24, 47]. The mild increase in plasma RAAS levels with empagliflozin was insufficient to counteract the effect of effective circulating volume contraction, resulting in decreases in blood pressure and arterial stiffness. A similar observation was made for vasodilatory NO, for which we observed a decline in plasma levels in our previous work, which was also unlikely to have accounted for decreases in blood pressure or arterial stiffness in this cohort . We therefore concluded that the beneficial hemodynamic changes observed with empagliflozin were unlikely to be influenced by concomitant changes in systemic RAAS and NO activity. Consequently we hypothesized that improved arterial compliance after empagliflozin could be related to changes in autonomic nervous system function, reflected by increased HRV and lower circulating levels of adrenaline and noradrenalin. However, empagliflozin did not affect HRV or plasma adrenergic system markers, suggesting that the mechanisms responsible for blood pressure and arterial stiffness lowering are independent of effects on autonomic nervous system activity. Nevertheless, our results do not exclude the possibility that other neurohormonal factors related to hyperglycaemia may have contributed to changes in blood pressure and arterial stiffness, such as decreased reactive oxygen species generation .
While neither RAAS, NO nor SNS activity can explain our results, we postulate that changes in arterial stiffness with empagliflozin are due to several other factors (Figure 1). First, weight loss independently decreases blood pressure and arterial stiffness . Empagliflozin was associated with a significant reduction in weight of 2.7 kg in our cohort and this may have contributed to benefits on blood pressure and arterial stiffness, as previously reported [22, 24]. This weight loss was likely in part due to loss of fat, since waist circumference declined. Second, decreases in daily insulin doses have been correlated with improved arterial compliance in T2D, and a similar interaction may have occurred in our T1D cohort since total daily insulin doses decreased significantly by the end of treatment [22, 50]. Third, other diuretic agents such as thiazides lower arterial stiffness and these effects are likely in part due to direct effects on vascular smooth muscle relaxation after induction of a negative sodium balance [51, 52]. Similar diuretic effects with SGLT2 inhibition may have contributed to the decline in arterial stiffness in our cohort. Next, empagliflozin-induced weight loss and improved glycemic control may exert anti-inflammatory changes, which favour improvements in blood pressure and arterial stiffness . For example, in experimental models of diabetes, SGLT2 inhibition reduces oxidative stress and suppresses markers of inflammation and fibrosis, including nuclear factor κβ and collagen IV expression [53, 54]. Due to the strong relationship between inflammation, cardiovascular complications and renal disease, future studies should clarify the ability of SGLT2 inhibitors to suppress inflammation in humans .
Arterial stiffness and long term clinical outcomes
Due to their insulin-independent mechanism of action and as shown in animal models , SGLT2 inhibitors have the potential to be used in T1D  in addition to T2D . Furthermore, SGLT2 inhibition may avoid some of the most common treatment-related side effects in T2D that have limited the benefits of traditional oral hypoglycemic agents, including significant weight gain, development and worsening of hypertension and severe hypoglycemic events [33, 39, 57]. Our observations are, to our knowledge, the first to suggest possible functional benefits of an oral hypoglycemic agent on large vessel function in T1D patients. The improvement in arterial compliance is important because previous studies have demonstrated strong, independent associations between macrovascular complications and arterial stiffness in T2D [58, 59]. Increased arterial stiffness is also independently associated with clinically relevant outcomes in T1D patients, including cardiovascular, renal, retinal and autonomic complications . Importantly, the beneficial effects of conventional cardiovascular protective agents such as ACE inhibitors have been in part attributed to improvements in arterial compliance . Ultimately, large ongoing clinical outcomes trials in T2D will determine if changes in arterial stiffness or blood pressure with SGLT2 inhibition translate into long-term renal or cardiovascular protection.
This trial has some limitations. First, the duration of therapy was limited to 8 weeks. Therefore, conclusions regarding longer term clinical benefits cannot be made from this study. Second, further work is needed to explore the interdependence among beneficial effects on arterial stiffness, including weight loss, glycemic control and blood pressure seen with empagliflozin. In particular, we could not determine if changes in blood pressure were based on declines in arterial stiffness, or whether reduced arterial stiffness was responsible for the fall in systolic blood pressure. Nevertheless, consistent changes in these vascular parameters are encouraging and support the rationale for ongoing long-term cardiovascular outcome trials. Third, these results in young patients with uncomplicated T1D cannot be generalized to older T1D patients, T1D patients with hypertension or to those with T2D. Given the important relationship between age and arterial stiffness, future work should determine if SGLT2 inhibition exerts similar effects in older individuals. Finally, measures of arterial stiffness have a high variability. As a consequence, our results should be viewed as exploratory and should be confirmed in future studies.