Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality?

Diabetes mellitus is a major risk factor for cardiovascular morbidity and mortality. Current therapeutic strategies have not provided constant beneficial cardiovascular-related results. Sodium-glucose co-transporters 2 (SGLT-2) inhibitors have emerged as a novel antidiabetic class of drugs that exert favourable results in a variety of other cardiovascular risk factors too, such as increased blood pressure and body weight. The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study was the first trial that evaluated cardiovascular outcomes in patients with diabetes with the use of empagliflozin, a member of this new class of drugs. Empagliflozin was associated with remarkable reduction of cardiovascular morbidity and mortality and all-cause death. On the contrary, stroke incidence was slightly increased, although the result did not reach statistical significance. It could be assumed that a drug providing such beneficial effects on cardiovascular outcomes, would have also the same impact in stroke risk. This finding could theoretically be attributed to 'play of chance'. However, an increase of haematocrit was observed in EMPA-REG and other SGLT-2 inhibitors studies. Accumulating evidence suggests a direct association between increased haematocrit and stroke risk. Could this 'stroke paradox' be a result of the increased haematocrit levels noted with SGLT-2 inhibitors? The aim of this review is to critically assess both possibilities, given that increased stroke rates (if indeed true) should not be neglected and unattended.

Current challenges in antihypertensive treatment in the elderly.

Arterial hypertension affects more than 25% of the global population, and its prevalence is increasing with age. Arterial stiffening occurs with aging and results in a pattern of increased systolic and decreased diastolic blood pressure (BP). In the elderly population, elevated BP has been related with increased cardiovascular risk. Trials on this population have shown great benefits for morbidity and mortality from reducing systolic BP (SBP) levels to less than 150 mmHg. Most guidelines for the management of elderly hypertensive patients agree on BP reduction to less than 150/90 mmHg. However, there is still uncertainty whether further BP reduction could provide beneficial results. The recently published SPRINT trial demonstrated that reducing SBP to between 120 and 125 mmHg in patients over the age of 75 years is related with increased survival and is expected to affect future recommendations. On the contrary, the limited data that are available for octogenarians and frail nursing home patients create concerns for more aggressive BP strategies in these subgroups, and thus they should be treated more conservatively. Among the various antihypertensive classes of drugs, diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers were proved beneficial in the elderly and are favored as first choices for the management of elderly hypertensive individuals. Given the common coexistence of other comorbidities and polypharmacy, physicians should be careful when initiating or uptitrating treatments to avoid potential adverse events or interaction with other drugs or diseases.

Sodium-glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class?

Diabetes mellitus is a major issue of public health, affecting more than 300 million people worldwide. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) in the renal proximal tubule are a novel class of agents for the treatment of type 2 diabetes mellitus. Inhibition of the SGLT-2 results in reduced glucose reabsorption and improvement in glycemic control. Alongside glucose excretion, SGLT-2 inhibitors also have mild natriuretic and diuretic effects, combining actions of a proximal tubule diuretic and an osmotic diuretic; these properties are expected to lead to small blood pressure (BP) reductions. Clinical studies with dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin used either as monotherapy or add-on therapy and compared with placebo or active treatment have also examined the effect of these agents on BP as a secondary endpoint. Although with some differences between individual agents, all of the approved SGLT-2 inhibitors provided a mild but meaningful reduction in office SBP and DBP. Recent studies with the use of ambulatory blood pressure monitoring suggest that the magnitude of this BP reduction can be even greater. The aim of this review is to systematically summarize and present the studies reporting the effect of approved SGLT-2 inhibitors on BP.