Letter by Koh Regarding Article, "Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease".

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HomeCirculationVol. 138, No. 8Letter by Koh Regarding Article, “Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, “Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease” Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh Department of Cardiovascular Medicine, Heart Center, Gachon University, Gil Medical Center, and Gachon Cardiovascular Research Institute, Incheon, Korea. Search for more papers by this author Originally published20 Aug 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033867Circulation. 2018;138:846–847To the Editor:Dr Wanner et al reported that empagliflozin and sodium glucose cotransporter 2 (SGLT2) inhibitors improved clinical outcomes and reduced mortality in vulnerable patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease.1 Urinary glucose excretion with empagliflozin decreases with declining renal function, resulting in less potency for glucose lowering in patients with kidney disease. The study moved 1 step further because effects of empagliflozin were consistent across categories of estimated glomerular filtration rate and urine albumin-creatinine ratio at baseline, and the adverse event profile of empagliflozin in patients with estimated glomerular filtration rate <60 mL·min-1·1.73 m2 was consistent with the overall trial population.The final goal in the management of patients with type 2 diabetes mellitus is reduction in total mortality. The leading causes of death in such patients are cardiovascular complications. Physicians need to have the capacity to prescribe antidiabetic agent(s) that can lower both glucose levels and risk of cardiovascular diseases, and ultimately reduce all-cause mortality rates. Therefore, large-scale cardiovascular outcome trials with new antidiabetic medications such as dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and SGLT2 inhibitors have been completed. Most clinical trials with dipeptidyl peptidase-4 inhibitors have shown no inferiority compared with placebo treatments in terms of cardiovascular safety. However, they did not show benefits in terms of adverse cardiovascular events or mortality. Cardiovascular outcome trials with glucagon-like peptide-1 agonists showed inconsistent results. Two large-scale cardiovascular outcome trials with SGLT2 inhibitors showed remarkable results: empagliflozin proved to be superior in preventing cardiovascular and all-cause mortality, and canagliflozin proved to be superior in preventing cardiovascular mortality but not all-cause mortality.2Controlling cardiometabolic risk factors consisting of abdominal obesity, high glucose, high blood pressure, and dyslipidemia by SGLT2 inhibitors is suggested to be the main mechanism for these results.2–4 There is some evidence that SGLT2 inhibitors can attenuate the development of atherosclerosis directly. Atheromatous plaque area in the aortic arch was significantly lower after 8 weeks of empagliflozin treatment compared with control or glimepiride treatment in apolipoprotein E–deficient mice. SGLT2 inhibitors decreased the levels of cytokines and markers associated with oxidative stress and inflammation.4 Another study showed that empagliflozin treatment improved cardiac interstitial fibrosis, coronary arterial thickening, coronary arterial remodeling, vascular dysfunction, cardiac interstitial macrophage infiltration, and cardiac superoxide levels in db/db mice.5Taken together, the remarkable beneficial results of SGLT2 inhibitors seem likely to be multifactorial.2 However, the risk-benefit profile will need further elucidation, and more studies are warranted to reveal further mechanisms: (1) How does empagliflozin prevent cardiovascular and all-cause mortality despite less potency for glucose lowering in patients with kidney disease? Empagliflozin significantly reduced hospitalization for heart failure, suggesting inducing osmotic diuresis. (2) Does empagliflozin show extra effects through renin-angiotensin-aldosterone system? (3) Will empagliflozin have similar effects in excluded patients with advanced kidney disease? (4) Adverse events of fractures and lower limb amputations were not increased with empagliflozin in contrast to canagliflozin. Is this a particular drug effect? It will also be important to confirm these results from other ongoing trials with dapagliflozin and ertugliflozin.Sources of FundingThis work was supported by a grant of the Korean Society of CardioMetabolic Syndrome.DisclosuresDr Koh holds a certificate of patent, 10-1579656 (pravastatin+valsartan).Footnoteshttps://www.ahajournals.org/journal/circ