Summary | Understanding the mechanisms of SGLT2 inhibition in heart failure and diabetes
Professor Sattar continued by diving deeper into one of the latest developments in the diabetes field; what is known about the effects and mechanism of SGLT2 inhibition. The EMPA-REG OUTCOME trial compared two doses of the SGLT2 inhibitor empagliflozin with placebo, in patients with diabetes and high CV risk. 99% Of participants had existing CV disease. Average age was 63 years old, average HbA1c was 8.1%, and about a quarter of participants had eGFR <60 ml/min/1.73 m2. About 7000 patients were followed over a median observation time of 3.1 years.
It was anticipated that empagliflozin would mostly benefit myocardial infarction (MI) and stroke risk, as it modulates several factors related to CV risk, including glucose and insulin lowering. It was already known that empagliflozin reduces albuminuria, and affects some lipid factors, as well as weight and blood pressure.5 When the first results were presented, however, non-fatal MI and stroke were not significantly affected by treatment with empagliflozin as compared with placebo, with a point-estimate above 1 for stroke, and below 1 for MI. The three-point MACE (major adverse CV events) endpoint was significantly reduced by 14% with empagliflozin vs. placebo (HR: 0.86, 0.74-0.99, P=0.0382), which was mostly driven by a reduction in CV death (HR: 0.62, 95%CI: 0.49-0.77, P=<0.0001). It was also striking that the Kaplan-Meier event curves separated early after start of treatment. In addition, empagliflozin showed a reduction of hospitalization for HF as compared with placebo, by 35% (HR: 0.65, 95%CI: 0.50-0.85, P=0.0017). Furthermore, empagliflozin also reduced all-cause death by 32% in the EMPA-REG OUTCOME trial.5
The CANVAS program compared another SGLT2 inhibitor, canagliflozin, with placebo.6 The pooled CANVAS program also demonstrated a 14% reduction in MACE (CV death, nonfatal MI and non-fatal stroke) after treatment with canagliflozin (HR: 0.86, 95%CI: 0.75-0.97). Again, non-fatal MI and stroke were not significantly reduced. Like empagliflozin, treatment with canagliflozin also showed a significant reduction in HF hospitalization or CV death (HR: 0.78, 95%CI: 0.67-0.91), but less effect on CV death only (HR: 0.87, 95%CI: 0.72-1.06).6 When combining the findings of both SGLT2 inhibitors, a class effect of a benefit on HF hospitalization emerges, and in addition to that, empagliflozin may give mortality reduction.
When speculating on the mechanism of action of SGLT2 inhibition, atherothrombosis does not seem relevant because the benefits occurred too fast, and no benefit on MI and stroke was seen. Thus, it may be a vascular or renal effect, or altered cardiac metabolism. Additionally, the ketone hypothesis has been proposed.7 It is good to remember how these drugs work. SGLT2 inhibitors lead to reduction of sugar reabsorption in the proximal tubule. In diabetes patients, SGLT2 is upregulated, so that 90% of the sugar is reabsorbed early on in the proximal tubule. SGLT2 inhibitors suppress this mechanism, leading to reduced reabsorption of glucose into the bloodstream and consequently loss of sugar in the urine. This glucosuria also leads to loss of calories and water, which lowers blood pressure.
As the name suggests, sodium-glucose cotransporter-2 inhibitors also affect sodium levels. Normally, SGLT2 upregulation leads to sodium reabsorption and diabetes patients will likely be sodium overloaded and water overloaded. As a consequence of increased sodium reabsorption in the proximal tubule, less sodium reaches the macula densa in the kidney. This feeds back to lead to afferent arterial vasodilation, with consequently increased pressure in the kidney through elevated glomerular filtration rate (GFR). SGLT2 inhibition causes sodium to no longer be reabsorbed, and as sodium reaches the macula densa in high concentration, the feedback mechanism leads to arterial vasoconstriction. Consequently, the pressure on the kidneys is normalized. It is thought that this destresses the nephron. Moreover, salt is excreted via the urine7 and albuminuria is reduced. It is suggested that altogether, SGLT2 inhibition results in protection of the kidney.7
These effects of SGLT2 inhibition are also seen with RAAS blockade. Although these effects arise through different mechanisms, combining the two drug classes may have additive benefits. Concerning the proposed reno-protective effects, in EMPA-REG OUTCOME, in comparison with placebo, treatment with empagliflozin indeed reduced the progression to a decline in eGFR greater than 40%, a meaningful eGFR decline (HR: 0.55, 95%CI: 0.40-0.75, P=0.0001).
The ketone hypothesis postulates a switch in cardiac use of ketones instead of glucose, with ketones being a more energy-efficient fuel for the failing heart. Normally in diabetes, a switch takes place in cardiac use from free fatty acids to glucose, which impairs cardiac function. Interestingly, SGLT2 inhibitors have been demonstrated to increase ketone synthesis, which may be beneficial for the heart.10 However, it should be noted that not all researchers in this field are convinced that the ketone hypothesis is relevant to the effects of SGLT2 inhibition.11 Research is ongoing to shed more light on the relevance of the ketone hypothesis.
With regard to the altered hemodynamics induced by SGLT2 inhibiting treatment, Sattar and colleagues developed an early hypothesis, by postulating that SGLT2 inhibition leads to glucose and sodium reduction in the blood, by reducing reabsorption of both factors in the kidneys. This lowers nephron hyperfiltration and in turn reduces generalized decongestion and intravascular volume, which destresses the heart. Cardiac afterload and preload are decreased. And because the heart is stressed less, fewer HF hospitalizations are seen. Also fatal arrhythmias occur less often.12 Sattar recommends to read the review article by Butler et al.13, which elaborates on the volume effects and this hypothesis, in addition to the metabolic effects of SGLT2 inhibition.
The volume effects of SGLT2 inhibition go beyond what is seen with diuretics. Loop diuretics and thiazides for instance only cause natriuresis, and vaptans only aquaresis. SGLT2 inhibition on the other hand affects both glucose and sodium, without causing a change in osmolality, serum potassium, and uric acid and sugar levels go down. This may reflect a more pathophysiologically targeted pathway in diabetes than diuretics. Still, these mechanisms should be explored further.
In a recent paper, Sattar and McGuire rethink how diabetes and obesity may lead to CV disease. 14 Not only by accelerating atherogenesis through the usual risk factors. It may have been overlooked that both diabetes and obesity, particularly when they interact, also lead to fluid overload and sodium and glucose overload. SGLT2 inhibitors may predominantly target this pathway, thereby addressing volume excess and the hemodynamic and glomerular stress directly.14 Ongoing trials my confirm this hypothesis.