Summary | SGLT2 inhibition in cardiology: What a cardiologist needs to knowAugust 28, 2017 - Prof. Naveed Sattar (Oxford, UK)
Multiple randomized trials have demonstrated that statins, blood pressure (BP) reduction, smoking cessation and prevention, and healthy lifestyle result in a lower cardiovascular (CV) risk in patients with diabetes and overall in the general population. While lowering glucose has only a slow and modest effect on CV risk, having diabetes and CVD results in a high CV risk and loss of years of life. For example, 40-year-old patients with diabetes and stroke have a reduction of 16 years in life expectancy.1
The EMPA-REG OUTCOME trial enrolled 7020 diabetes patients with established CVD, who were randomized to treatment with two different doses of the SGLT2 inhibitor empagliflozin or placebo. The HbA1c range of 7-10% decreased by 0.5% after 12 weeks of treatment with empagliflozin and reached a decrease of ~0.3% after 4 years. The overall primary outcome of MACE, which was a combination of fatal and non-fatal MI and stroke, was reduced by 15%. This was an important finding as, until then, no other drug than metformin was found to reduce fatal and non-fatal stroke. Surprisingly, treatment with empagliflozin gave a substantial 38% reduction in CV death. In addition, HF hospitalization was reduced by 35% in the empagliflozin group with an early effect after the start of therapy.
Altogether, improving kidney function and reducing flow and volume by empagliflozin results in beneficial effects on the heart, in addition to possibly directly benefitting the heart.
Prior to the trial, the idea was that empagliflozin acts by removing glucose in the kidney, which also improves many other risk factors like uric acid, oxidative stress and lipids, resulting in a range of beneficial effects on glycemia, blood pressure, arterial stiffness, albuminuria, weight, and differential effects on lipids, thereby reducing atherogenesis. However, the pattern of the results suggests that these are not the causal factors and thus the focus has shifted. Although no significant finding for non-fatal MI and stroke was demonstrated, the trial showed substantial and rapid effects on CV death and HF hospitalization, suggesting that the mechanism of action is not mediated by atherothrombosis, but by vascular actions, renal actions or improved cardiac metabolism.
It is suggested that empagliflozin improves the cardiac-renal axis by reducing fluid in the system, which benefits cardiac function. In addition to inhibiting glucose reabsorption resulting in glycosuria, empagliflozin also causes profound natriuresis by interfering with the sodium-hydrogen exchange in the kidney leading to sodium excess and thereby resulting in decreased body weight, BP and hemoconcentration. The combination of these effects on blood volume result in decreased cardiac wall stress. In addition, the interference of empagliflozin on the sodium-hydrogen exchange in the heart results in cardiac benefits. SGLT2 inhibition causes afferent vasoconstriction resulting in reduction of hypofiltration, less pressure on nephrons, and reduction of albuminuria thereby protecting the kidneys.2 RAAS blockade works on the efferent axis by causing vasodilation, resulting also in a decrease of glomerular pressure, but by a different mechanism. Furthermore, SGLT2 inhibition causes glucose and sodium reabsorption in the proximal tubules and reduces nephron hyperfiltration leading to generalized fluid reduction and generalized decongestion, which affects cardiac preload/afterload, systolic and potentially diastolic dysfunction, HF hospitalization, and potentially fatal arrhythmias.3
Altogether, improving kidney function and reducing flow and volume by empagliflozin results in beneficial effects on the heart, in addition to possibly directly benefitting the heart. A study by Wanner et al. showed a 45% reduction in deterioration of renal function in patients during treatment with empagliflozin, which underwrites the idea that empagliflozin has beneficial effects on the kidney.4
Considering the observed clinical benefit of lower CVD mortality, potential HF and renal benefit, the clinical implications of the EMPA-REG OUTCOME trial are that empagliflozin should be used in patients with diabetes and CV risk. The use of empagliflozin in patients with diabetes without CVD needs further testing. Patients with CVD should be tested for diabetes by HbA1c or fasting glucose levels and those with known or newly developed diabetes without contraindications should be treated with empagliflozin, as is now included in the guidelines.5 The GLP-1 receptor agonist liraglutide also resulted in a decrease of CV mortality, glucose, weight, and showed renal benefits in the LEADER trial, but no reduction of HF hospitalization was seen. Cardiologists should work in tandem with endocrinologist to implement these novel therapies, most likely with a preference for empagliflozin, because it is orally administered.
The EMPA-REG OUTCOME trial introduced a new class of drugs with great CV benefits including reduction in CV death, HF hospitalization, MACE and potential renal benefits in patient with diabetes and CVD.
The CANVAS study, which evaluated the SGLT2 inhibitor canagliflozin, showed substantial HF benefits and similar MACE benefits as with empagliflozin treatment (reduction of ~14%). It did, however, not show a reduction in CVD and all cause death as was observed in the EMPA-REG OUTCOME trial. Moreover, unlike in the EMPA-REG OUTCOME trial, there was a significant amputation and fracture risk, and the risk for CVA was somewhat lower with canagliflozin, while with empagliflozin a non-significantly higher CVA risk was seen. It is unknown whether the differences in findings between the CANVAS and EMPA-REG OUTCOME trials are statistically significant, by lack of a head-to-head comparison. There might be possible population differences; the EMPA-REG OUTCOME trial included only patients with CVD, whereas in the CANVAS trial two-thirds of the patients had existing CVD. It will be interesting to examine whether there are real drug differences for CV death due to the molecular mechanisms of the drugs. Right now, clinicians should take these results at face value; personally, Sattar thinks that the results of empagliflozin look more favorable in terms of outcome and safety than canagliflozin. But, he adds, further trials are needed.
One should be aware that SGLT2 inhibitors should not be used in moderate to severe CKD, not in pregnant and breast-feeding women, and in acute stressful states. Caution should be exercised in the following categories: risk of volume depletion, complicated or recurrent UTIs, conditions of fasting (starvation) because those can precipitate diabetic ketoacidosis with euglycemia, and patients with already elevated hematocrit.
In conclusion, the EMPA-REG OUTCOME trial introduced a new class of drugs with great CV benefits including reduction in CV death, HF hospitalization, MACE and potential renal benefits in patient with diabetes and CVD. Empagliflozin was generally safe and the results changed the guideline recommendations due to the substantial reduction in CV mortality of 30%. The results give new insights in the mechanism of CV death in patients with diabetes and CVD, which is not only mediated by atherogenesis, but also by fluid effects.