Randomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients With Type 2 Diabetes Mellitus

HomeCirculationVol. 143, No. 5Randomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients With Type 2 Diabetes Mellitus Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBRandomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients With Type 2 Diabetes MellitusThe IDDIA Trial Chi Young Shim, MD, PhD, Jiwon Seo, MD, Iksung Cho, MD, Chan Joo Lee, MD, PhD, In-Jeong Cho, MD, Purevjargal Lhagvasuren, MD, Seok-Min Kang, MD, PhD, Jong-Won Ha, MD, PhD, Gyoonhee Han, PhD, Yangsoo Jang, MD, PhD and Geu-Ru Hong, MD, PhD Chi Young ShimChi Young Shim Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). *Drs Shim and Seo contributed equally. Search for more papers by this author , Jiwon SeoJiwon Seo Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). *Drs Shim and Seo contributed equally. Search for more papers by this author , Iksung ChoIksung Cho Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). Search for more papers by this author , Chan Joo LeeChan Joo Lee Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). Search for more papers by this author , In-Jeong ChoIn-Jeong Cho Division of Cardiology, Department of Internal Medicine, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Korea (I-J.C.). Search for more papers by this author , Purevjargal LhagvasurenPurevjargal Lhagvasuren Department of Cardiology, The Second General Hospital, Ulaanbaatar, Mongolia (P.L.). Search for more papers by this author , Seok-Min KangSeok-Min Kang https://orcid.org/0000-0001-9856-9227 Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). Search for more papers by this author , Jong-Won HaJong-Won Ha Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). Search for more papers by this author , Gyoonhee HanGyoonhee Han College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences and Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea (G.H.). Search for more papers by this author , Yangsoo JangYangsoo Jang https://orcid.org/0000-0002-2169-3112 Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). Search for more papers by this author and Geu-Ru HongGeu-Ru Hong Geu-Ru Hong, MD, PhD, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea, 03722. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4981-3304 Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea (C.Y.S., J.S., I.C., C.J.L., S-M.K., J-W.H., Y.J., G-R.H.). Search for more papers by this author Originally published13 Nov 2020https://doi.org/10.1161/CIRCULATIONAHA.120.051992Circulation. 2021;143:510–512Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 13, 2020: Ahead of Print Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce adverse cardiovascular outcomes in patients with type 2 diabetes mellitus (DM) and risk for cardiovascular disease.1,2 The SGLT2 inhibitor dapagliflozin was also found to reduce the risk of worsening heart failure or cardiovascular mortality in patients with established heart failure regardless of the presence of DM.3 Although left ventricular (LV) diastolic dysfunction is prevalent in patients with DM and is associated with subsequent heart failure and mortality, there has been no randomized, double-blind, placebo-controlled study to test the effects of SGLT2 inhibitors on LV diastolic dysfunction. Therefore, we designed the Impact of Dapagliflozin on Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes Mellitus (IDDIA) trial to test the hypothesis that treatment with the SGLT2 inhibitor dapagliflozin will improve LV diastolic dysfunction, as assessed using diastolic stress echocardiography (DSE), in patients with type 2 DM. This was a randomized, double-blind, placebo-controlled trial and approved by the institutional review board of Severance Hospital (4-2015-1130). All participants provided written informed consent before inclusion in the study. The study was registered at https://www.clinicaltrials.gov (NCT02751398). The data that support the findings of this study are available from the corresponding author on reasonable request.This study was conducted in patients with type 2 DM and glycohemoglobin of 7.0% to 10.0% accompanied by LV diastolic dysfunction at least grade 1 (relaxation abnormality) on resting echocardiography between August 2016 and December 2019. Individuals with type 1 DM, history of diabetic ketoacidosis, recurrent urinary tract infection, renal dysfunction, use of loop diuretics, acute coronary syndrome, stroke within 6 months, LV ejection fraction of <50%, or who could not perform DSE were excluded.Of the 74 participants who were screened, 60 fulfilled the study criteria and were randomly allocated to receive dapagliflozin 10 mg once daily or placebo for 24 weeks (n=30 in each group). Two participants withdrew the consent, and 58 participants completed the study and (n=29 in each group). DSE was performed using a variable load supine bicycle ergometer, as previously described,4 at randomization and 24-week follow-up. Standard measurements were performed per the recommendations of the American Society of Echocardiography.The primary end point was set to assess the change in LV diastolic reserve (DR) at 24 weeks from baseline as assessed by DSE. DR was calculated using the following formula: DR = the change in e’ velocity from a resting state to 25 W of exercise (DR25W) or 50 W of exercise (DR50W).5 The secondary end points were changes at 24 weeks in LV diastolic parameters at rest and during exercise, LV mass index, and left atrial volume index.Comparison of the 2 groups revealed no significant intergroup differences in baseline clinical, hemodynamic, echocardiographic, and laboratory characteristics. The mean DM durations were 4.7±4.5 years. The average e’ velocity at rest was 6.3±1.7 cm/s and 6.5±1.8 cm/s in the dapagliflozin and placebo groups, respectively. Baseline DR25W and DR50W were not different between the groups. After 24 weeks, patients in the dapagliflozin group significantly improved DR25W (0.88±1.24 cm/s versus −0.52±1.53 cm/s; P=0.001) and DR50W (0.59±1.47 cm/s versus −0.58±1.63 cm/s; P=0.035) compared with those in the placebo group (Table). Compared with placebo, dapagliflozin increased the e’ at 25 W of exercise and decreased the E/e’ at 50 W of exercise. However, dapagliflozin did not significantly affect resting e’ velocity, E/e’, LV mass index, and left atrial volume index. There was a significant reduction in body weight (−2.3±2.4 kg versus −0.4±3.3 kg; P=0.015) and increase in hematocrit (2.9±3.1% versus 0.1±2.4%; P<0.001) in the dapagliflozin group compared with the placebo group. Blood pressures and heart rate were not different at baseline and 24 weeks between the 2 groups. Dapagliflozin was well tolerated with no significant adverse effects or clinical events compared with the placebo group.Table. Changes in Diastolic Reserve, Anthropometric, and Echocardiographic Parameters After Exposure to Dapagliflozin or Placebo for 24 WeeksBaseline24 WeekChanges*Dapagliflozin(n=30)Placebo(n=30)P valueDapagliflozin(n=29)Placebo(n=29)P valueDapagliflozin(n=29)Placebo(n=29)Difference†(95% CI)P valuePrimary end point DR25W, cm/s2.30±1.042.60±1.530.4273.06±1.362.10±0.910.0050.88±1.24−0.52±1.531.40 (0.59–2.22)0.001 DR50W, cm/s3.01±1.273.46±1.400.2843.50±1.213.02±1.220.2220.59±1.47−0.58±1.631.17 (0.07–2.28)0.035Anthropometric and echocardiographic data Weight, kg74.1±13.376.0±15.80.61471.8±13.975.6±14.40.303−2.3±2.4−0.4±3.3−1.92 (−3.45 to −0.39)0.015 SBP, mm Hg130.9±14.0135.0±15.00.287124.5±13.8126.6±12.00.532−6.4±12.7−8.3±17.51.97 (−6.08 to 10.0)0.627 DBP, mm Hg82.7±10.381.9±10.70.77578.7±8.778.7±11.50.99−4.0±9.2−3.2±10.3−0.83 (−5.97 to 4.31)0.748 Heart rate, bpm77.9±13.280.2±14.60.53081.1±11.783.3±15.00.5283.2±12.03.1±12.90.07 (−6.48 to 6.62)0.983 e’ at rest, cm/s6.27±1.656.50±1.810.6096.00±1.056.21±1.680.611−0.26±1.49−0.25±1.44−0.01 (−0.78 to 0.75)0.971 e’ at 25 W, cm/s8.82±1.558.89±1.910.8839.18±1.708.37±1.710.0930.41±1.40-0.58±1.430.99 (0.16–1.81)0.020 e’ at 50 W, cm/s9.44±1.749.67±1.540.6699.43±1.599.48±2.400.9450.13±1.37-0.56±1.430.69 (−0.29 to 1.67)0.161 E/e’ at rest11.08±3.409.70±2.790.09110.73±3.4410.21±2.560.518−0.43±2.760.41±2.08−0.83 (−2.13 to 0.46)0.201 E/e’ at 25 W10.49±2.1910.20±2.440.74710.19±2.5710.68±2.720.522−0.59±1.730.47±2.26−1.06 (−2.24 to 0.13)0.078 E/e’ at 50 W11.45±2.5510.61±2.530.36410.90±2.1811.19±2.650.717−0.74±1.640.65±1.28−1.39 (−2.44 to-0.34)0.011 LVMI, g/m294.2±19.293.6±19.00.83891.8±16.593.8±17.10.642−2.5±12.20.2±10.2−2.69 (−8.61 to 3.23)0.366 LAVI, mL/m228.6±7.227.6±8.20.64829.1±7.028.7±8.50.8270.6±4.41.1±5.4−0.49 (−3.06 to 2.09)0.708Diastolic reserve (DR) = e’ at exercise – e’ at rest. DBP indicates diastolic blood pressure; DR25W, diastolic reserve at 25 watts; DR50W, diastolic reserve at 50 watts; LAVI, left atrial volume index; LVMI, left ventricular mass index; and SBP, systolic blood pressure.* Changes in parameters after 24 wk dapagliflozin or placebo treatment.† Absolute mean difference between dapagliflozin and placebo group.The principal finding of the IDDIA trial is that the addition of dapagliflozin to standard antihyperglycemic treatment in patients with type 2 DM was associated with a significant improvement in LV diastolic dysfunction assessed with DSE as compared with placebo. The use of dapagliflozin also resulted in a significant decrease in estimated LV filling pressure during exercise in patients with type 2 DM. This is the first randomized clinical trial to provide data demonstrating the beneficial effect of dapagliflozin on LV diastolic dysfunction in patients with type 2 DM. Because LV diastolic function has been acknowledged as a determinant of symptoms and prognosis related to heart failure, these data provide important evidence for the potential of SGLT2 inhibitors as therapeutic agents for preventing and treating heart failure. We believe that the trial data fill the knowledge gap between the beneficial effect of SGLT2 inhibitors in large clinical trials and the results from observational clinical studies to show improvement of LV diastolic function. In conclusion, dapagliflozin improved LV diastolic dysfunction to a greater extent than placebo in patients with type 2 DM.AcknowledgmentsThe authors thank all physicians, sonographers, and research staff for their hard work and enthusiasm, as well as Drs Dong Suk Han, Don Lee, Jaeyoung Chung, Kukjin Song, Junghwan Seo, Gwilae Lee, Hee-Sup Kim, Jaeyong Han, and Taehyun Park for helping to recruit participants for this study.Sources of FundingThe IDDIA trial was an investigator-initiated trial funded by AstraZeneca. All analyses were conducted independently, and all authors had full access to the data. The authors are fully responsible for the study design; the collection, analysis and interpretation of the data; and the writing of the manuscript. The sponsor played no role in the decision to submit the manuscript for publication. This research was also supported by a grant of the Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI20C1566).Disclosures None.Footnotes*Drs Shim and Seo contributed equally.https://www.ahajournals.org/journal/circThis work was presented as an abstract at American Heart Association Scientific Sessions, November 13 to November 17, 2020.Data sharing: This study adheres to the American Heart Association’s Transparency and Openness Promotion Guidelines. The data that support the findings of this study and research materials, as well as experimental procedures and protocols, are available from the corresponding author upon reasonable request.Geu-Ru Hong, MD, PhD, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Korea, 03722. Email [email protected]acReferences1. 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