Letter by Koh Regarding Article, "Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)".

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HomeCirculationVol. 139, No. 3Letter by Koh Regarding Article, “Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, “Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study)” Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh Department of Cardiovascular Medicine, Heart Center, Gachon University, Gil Medical Center, Incheon, Korea. Gachon Cardiovascular Research Institute, Incheon, Korea. Search for more papers by this author Originally published14 Jan 2019https://doi.org/10.1161/CIRCULATIONAHA.118.037209Circulation. 2019;139:416–417To the Editor:The study by Dr Rådholm and colleagues should be noted because a great portion of participants were using standard therapies for heart failure at baseline. Overall, cardiovascular death or hospitalized heart failure was reduced in those treated with canagliflozin in comparison with those treated with placebo, and the benefit on cardiovascular death or hospitalized heart failure was greater in patients with a prior history of heart failure in comparison with those without heart failure at baseline.1In comparison with other antihyperglycemic agents, inhibitors of sodium glucose cotransporter 2 (SGLT2) have demonstrated remarkable and greater benefits, possibly by controlling cardiometabolic risk factors, including abdominal obesity, high blood pressure, and dyslipidemia beyond the glucose-lowering effect.2,3 In patients with kidney disease, however, the glucose-lowering effect of SGLT2 inhibitors decreases because urinary glucose excretion was less with declining renal function in patients with chronic kidney disease. In fact, the effects of empagliflozin were consistent across categories of estimated glomerular filtration rate.4Despite the impressive benefits of SGLT2 inhibitors, the mechanisms, in particular those underlying the protective effects on heart failure, have not yet been investigated much. SGLT2 inhibitors decreased cardiac afterload via osmotic diuresis, thus improving cardiac function. These results suggest that the most important cardiovascular benefits of SGLT2 inhibitors are likely to originate from their role in hemodynamic modulation, in particular in patients who have heart failure. The current study strongly supports this hypothesis, and canagliflozin exhibited benefits in renal function even in the presence of renin-angiotensin-aldosterone system blockers. It is likely that canagliflozin may afford additional benefits in combination with renin-angiotensin-aldosterone system blockers.2Of note, different effects have been observed with different glucose-lowering drugs. Canagliflozin was found to increase bone fractures, but empagliflozin did not. In subgroup analysis, Asians benefit from canagliflozin, but not from empagliflozin. In comparison with nonusers, users of β-blockers or diuretics benefit more from canagliflozin, whereas empagliflozin had similar effects. Although the current study did not address these issues, different effects may be seen because of various study end points or in heterogeneous ethnic populations, and thus should be reconfirmed in other subsequent studies. In addition, a recent study showed similar effects of SGLT2 inhibitors and other glucose-lowering drugs in patients in Korea and Japan, and in patients from Western countries, as well, suggesting that the benefits seen in a randomized trial are a class effect.5 Heart failure is reclassified depending on the severity in ejection fraction. As the authors discussed, the limitation in the numbers of nonsevere disease participants should be reconfirmed, too.SGLT2 inhibitors represent a new class of antidiabetic treatment for patients with type 2 diabetes mellitus. Although there are several disadvantages, SGLT2 inhibitors are among the most promising drugs from a cardiovascular perspective, because they have multifactorial positive properties for managing cardiometabolic risk factors.2 It will be important to confirm the advantages and disadvantages from other ongoing trials of SGLT2 inhibitors to further elucidate the risk-benefit profile of SGLT2 inhibitors. We hope that the risks of adverse cardiovascular events and death in patients with type 2 diabetes mellitus can indeed be alleviated by this new class of antidiabetic agents.AcknowledgmentsWe deeply appreciate Yabing Chen, PhD, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, for her constructive comments.DisclosuresDr Koh holds a certificate of patent, 10-1579656 (pravastatin+valsartan). This work was supported by a grant of the Korean Society of CardioMetabolic Syndrome.Footnoteshttps://www.ahajournals.org/journal/circ