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HOME > Cardiovasc Prev Pharmacother > Volume 3(2); 2021 > Article
Special Article Diabetes and Heart Failure
Eun-Jung Rhee, MDorcid
Cardiovascular Prevention and Pharmacotherapy 2021;3(2):21-30.
DOI: https://doi.org/10.36011/cpp.2021.3.e4
Published online: April 30, 2021
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Division of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to Eun-Jung Rhee, MD Division of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunanro, Jongno-gu, Seoul 03181, Korea. E-mail: hongsiri@hanmail.net
• Received: March 23, 2021   • Accepted: April 13, 2021

Copyright © 2021 Korean Society of Cardiovascular Disease Prevention; Korean Society of Cardiovascular Pharmacotherapy.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Heart failure (HF) in patients with diabetes mellitus has long been considered a consequence of coronary artery disease (CAD). However, recent epidemiological evidence on patients with diabetes showed a significantly increased prevalence of HF in patients with no significant stenosis in the coronary artery. As such, these are thought to be separate entities of diabetic complications. Therefore, HF in patients with diabetes is now considered an independent disease entity of the ‘diabetic heart.’ The mechanism of ‘diabetic heart’ could be due to CAD and diabetic cardiomyopathy caused by altered energy metabolism in the myocardium and advanced glycation end-product accumulation, altered calcium handling, and oxidative stress in the myocardium. Recent cardiovascular outcome trials of anti-diabetic medications have shown the protective effects of certain drugs against HF in patients with and without diabetes. In this review, the relationship between diabetes and the treatment and prevention of HF is summarized.
Heart failure (HF) is a consequence of coronary artery disease (CAD) in patients with diabetes mellitus (DM). However, since it was discovered that even patients without CAD also have an increased risk of HF, extensive research on “diabetic heart” has been conducted. In South Korea, HF is considered a possible yet overlooked complication of DM based on the recently released Diabetes Fact Sheet—Complications. According to the said document, the prevalence of HF in patients with DM has been constantly increasing, while the incidence of ischemic heart disease or ischemic stroke has been decreasing.1)
The American Heart Association (AHA) divides HF into 2 types based on the ejection fraction (EF): HF with reduced EF and HF with preserved EF.2) Meanwhile, heart associations worldwide have different classification systems for the HF stages. For example, the AHA classifies HF into 4 stages (A–D) according to structural cardiac abnormalities. In contrast, the New York Heart Association Functional Classification divides HF into 4 functional classes (I to IV) depending on the cardiocirculatory functional status associated with activities of daily living.
In 1972, Rubler et al.3) first described HF in patients with DM in a case report of 4 diabetic patients with glomerulonephritis who had radiological evidence of myocardial hypertrophy and postmortem findings of myocardial hypertrophy and diffuse fibrosis. In general, diabetic cardiomyopathy is defined as the “structural and functional abnormalities of the myocardium in diabetic patients without CAD or hypertension”.4) However, the mechanism of cardiomyopathy in patients with DM is poorly understood, and there is controversy whether diabetic cardiomyopathy is an actual disease entity or merely a hypothesized disease.
The pathogenesis of HF in patients with DM cannot be explained by a single mechanism. However, the most conspicuous physiological changes in affected patients are the impaired myocardial glucose metabolism and the switching of the heart's primary energy source (fuel) from glucose to less efficient free fatty acids.5) This altered fuel source leads to impaired systolic ejection performance and left ventricular (LV) and atrial failure. Recent cardiovascular outcome trials (CVOTs) on anti-diabetic medications confirmed the excellent therapeutic effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors in preventing HF and the role of thiazolidinedione (TZD) in significantly increasing the risk of HF.6)
This article investigates the pathological mechanism of HF in patients with DM, provides an overview of the HF exacerbation and prevention effects of different anti-diabetic drugs, and explores methods for preventing HF in patients with DM.
According to the 2019 Diabetes Fact Sheet by the Korean Diabetes Association, the prevalence of HF has been increasing, while that of vascular diseases, such as myocardial infarction and stroke, has been decreasing. This suggests that HF is a major complication of DM in South Korea.1) The UK Prospective Diabetes Study reported a correlation between elevated blood sugar and the risk of HF based on the finding that a 1% increase in glycated hemoglobin resulted in a 16% increase in the risk of HF.7) Similarly, the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease analyzed the risk of HF in 31,546 participants according to the baseline glucose status and found that it increased linearly as the blood sugar level increased from normal to diabetic levels.8) In an analysis based on the National Health Insurance database, the author followed 9,720,200 Koreans with no HF diagnosis in the 2009 national medical exam for 6 years (2009–2015) and found that subjects with underlying prediabetes and diabetes had a higher risk of HF (8% and 86%, respectively) than those with normal blood sugar levels.9) These previous studies' findings confirm the positive correlation between blood sugar levels and the risk of HF.
Furthermore, many studies have reported an increased risk of HF in patients with DM. A 1.3- fold risk of HF and a 1.75-fold risk of HF-related hospitalization were shown in patients with DM than those without DM in a sub-analysis of the Studies of Left Ventricular Dysfunction trials, which investigated the HF-preventing effect of enalapril in 4,223 patients with underlying DM by analyzing their risk probability of HF.10) In an analysis of the database by the Kaiser Permanente North Western Division, a U.S. health plan, the risk of HF was found to increase with age, with a higher prevalence among those with DM compared with those without DM.11) In clinical trials on blood sugar control and anti-diabetic medication, the prevalence of HF in patients with DM has been reported to range from 10% to 12%.12)
The prognosis of HF patients with DM has also been reported. In the I-Preserve study, which examined the effects of irbesartan on HF in 4128 patients with HF for 4.1 years, the risks of cardiovascular mortality and hospitalization for HF (HHF) in patients with DM were 1.59- and 1.75-fold higher, respectively, compared with those in patients without DM.13) In addition, in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program, designed to investigate the effect of candesartan on HF, patients with DM had a high risk of HHF, and even diabetic patients with preserved EFs had an increased HHF similar to that in non-diabetic patients with reduced EF.14) Moreover, a sub-analysis of the CHARM program revealed that cardiovascular mortality and the risk of HHF increased by 1.25 times with every 1% increase in glycated hemoglobin.15)
Conversely, some researchers have argued that HF may be a risk factor for DM. HF-related clinical trials have reported a DM prevalence ranging from 21% to 47%, significantly higher than populations without HF.12) Matsue et al.16) also reported that about one-third of the patients hospitalized with HF without a history of DM were found to have prediabetes or diabetes in the tests. In addition, the CHARM program and Eplerenone in Mild Patients Hospitalization and Survival Study in HF (EMPHASIS-HF) trial demonstrated a significant increase in the incidence of DM per 1000 persons among patients with HF and no history of DM compared with the similar age group in the general population (28 vs. 21).17)18)
In summary, the prevalence of HF among diabetic patients is higher compared to nondiabetic individuals, and the risk of HF increases even after adjusting for several factors, leading to the assumption that HF is a complication of DM. Conversely, patients with HF have an increased risk of DM, possibly signifying that HF is a risk factor for DM. From these findings, it follows that the relationship between DM and HF is bidirectional.19)
The direct effect of diabetes on cardiomyopathy can be divided mainly into the effect induced by hyperglycemia and insulin resistance. Hyperglycemia causes the accumulation of advanced glycation end product (AGE) in cardiomyocytes, resulting in elevated levels of proinflammatory cytokines that trigger extracellular matrix remodeling and fibrosis.5) In addition, hyperglycemia and insulin resistance increase oxidative stress and induce myocardial apoptosis. On the other hand, insulin resistance induces lipolysis, leading to myocardial apoptosis and the accumulation of free fatty acids in the myocardium. Furthermore, DM shifts the energy metabolism to utilize free fatty acids instead of glucose, which has the highest myocardial fuel efficiency, degrading the energy efficiency and causing fibrosis in the myocardium. Moreover, insulin resistance leads to abnormal calcium homeostasis in the myocardium, leading to myocardial hypertrophy and abnormal diastolic relaxation.
DM-induced myocardial structural changes were demonstrated in the Strong Heart Study, which analyzed 1,810 diabetic patients and 944 normal controls. Diabetic patients showed greater LV mass and wall thickening and smaller LV systolic chamber size. As such, the LV was smaller and was associated with increased arterial stiffness and decreased myocardial function.20) Based on the cardiac magnetic resonance spectroscopy of the 46 diabetic patients without hypertension, the LV mass to LV end-diastolic volume ratio was higher than normal controls. They also had increased myocardial fat accumulation and inferior myocardial energy efficiency.21) In addition, in an analysis of the intraoperative biopsy results of the 46 patients with non-diabetic aortic stenosis and the 16 patients with diabetic aortic stenosis, the diabetic patients had a higher rate of myocardial fibrosis and perivascular AGE accumulation.22)
In conclusion, DM can lead to vasculopathy-induced ischemic cardiomyopathy due to hyperglycemia and insulin resistance. Meanwhile, diabetic cardiomyopathy occurs even without vasculopathy due to lipid toxicity and AGE accumulation, myocardial fibrosis caused by abnormal calcium handling, and myocardial changes due to impaired energy efficiency by shifting the fuel source from glucose to fatty acids (Figure 1).23)24)
The prevalence of HF associated with anti-diabetic medication in clinical trials has a wide range. Specifically, according to the clinical trials on some of the new anti-diabetic agents, dipeptidyl peptidase-4 (DPP-4) inhibitors did not increase the overall prevalence of HF. Saxagliptin is not recommended because of the increased HF risk in the group administered with this in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53).25) Meanwhile, glucagon-like peptide-1 receptor agonists (GLP-1RA) slightly reduced the risk of HF. Similarly, SGLT2 inhibitors were reported to reduce the risk of HF in studies such as the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME), CANagliflozin cardioVascular Assessment Study (CANVAS), and Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58).6)
It is also essential to determine to what extent blood sugar levels should be lowered in diabetic patients with HF. In a retrospective study involving 1,447 diabetic patients with HF, the lowest mortality rate was observed in the HbA1c range of 7–8%. Similarly, a study that followed 5,815 patients using the U.S. Veterans Affairs Hospital Database reported that the mortality rate was lowest in the HbA1c range of 7.1–7.8%.26)27) In the 2019 guidelines, the AHA recommended that blood sugar control in diabetic patients with HF should be individualized, taking into account the patient's clinical and functional status, self-management ability, social support, side effects and costs of medication, risk of hypoglycemia, and treatment burden.16)
Anti-diabetic drugs are considered to have a class effect despite the different individual effects on HF by drugs within the same class. As demonstrated by previous studies and meta-analyses, TZD is not indicated for the treatment of HF.28) Metformin was initially contraindicated in patients with HF, but this provision was retracted by the Food and Drug Administration in 2006.29) A meta-analysis of 9 cohort studies involving 34,000 patients revealed that metformin administration reduced the risk of HF by 20% with a risk ratio of 0.80 (95% confidence interval, 0.74–0.87).30)
Although no consensus has yet been reached regarding the effect of sulfonylureas on HF, no significant increase in the risk of HF has been observed in the insulin supplement therapy group administered with sulfonylureas in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. The said trial investigated the cardiovascular outcomes of DM2 patients who underwent intensive medical therapy and percutaneous coronary intervention or medical therapy alone.31) In the recently published Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) trial, which compared the effects of glimepiride, sulfonylurea, and linagliptin (a DPP-4 inhibitor) on HF, no significant increase in HF-induced hospitalization was observed in the glimepiride group.32) However, the data from the U.S. Veterans Affairs Hospital Database revealed that a 1.3-fold increase in the risk of HF-induced hospitalization was seen in diabetic patients using sulfonylurea than those with metformin.33) However, since the CAROLINA trial compared sulfonylurea with metformin, it is difficult to determine the particular HF risk factors of sulfonylureas themselves.
The class effect of DPP-4 inhibitors on HF is challenging to determine. In the SAVOR-TIMI 53 trial, the risk of HF increased in the saxagliptin group.34) However, a meta-analysis on CVOTs of DPP-4 inhibitors reported that DPP-4 inhibitors do not increase the risk of HF.35)
Three CVOTs have reported that SGLT2 inhibitors decreased the risk of HF, namely the EMPA-REG OUTCOME, DECLARE-TIMI 58, and CANVAS.36) Based on the meta-analysis of these CVOTs, SGLT2 inhibitors were found to reduce the risk of HF in patients with and without a history of HF by 31%, leading to the assumption that the effect of SGLT2 inhibitors on HF is very strong. Furthermore, the effect of SGLT2 inhibitors on HF was found to be stronger in patients with more impaired kidney function, suggesting that SGLT2 inhibitors contribute to breaking the vicious cycle of the so-called “cardio-renal spectrum,” where the heart and the kidney mutually affect each other in patients with DM.37)
The significant effect of SGLT2 inhibitors on HF in patients with DM raised the question if they have the same effect in HF patients without DM. In 2 recently published CVOTs, the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction and the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure, HF patients with and without DM were equally administered with SGLT2 inhibitors, and both studies reported a significantly reduced risk of HF in both groups.38)39) In addition, a meta-analysis investigating these 2 studies found that SGLT2 inhibitors reduced the risk of HF by 25%, and the difference between patients with and without DM was insignificant, demonstrating the potential of SGLT2 inhibitors in changing the future therapeutic options for HF patients.40)
GLP-1RA improves HF through its positive effect on the myocardium via its antiinflammatory effect, increased glucose utilization, improved LV function, and decreased ischemic damage.41) However, the GLP-1RA CVOTs conducted thus far have reported varying effects on HF. In a meta-analysis investigating 7 different GLP-1RA CVOTs, the odds ratio was calculated at 0.91 (95% CI 0.83-0.99), leading to a 9% reduction in the risk of HF.42)
In summary, SGLT1 inhibitors were reported to have the most consistent positive effect on HF, and TZD was contraindicated in patients with HF, while other drugs had varying effects.
In recent years, the diabetes management guidelines of the American Diabetes Association have recommended that SGLT2 inhibitors should be prescribed for diabetic patients with HF after metformin. Based on the 2020 guidelines, SGLT2 inhibitors are recommended more specifically for diabetic patients with reduced EF (≤45%),43) while TZD should be avoided in patients with HF.
Similarly, the 2019 guidelines of the European Diabetes Association recommend that SGLT2 inhibitors should be utilized as Class I in diabetic patients with HF.44) Metformin (class IIa) and GLP-1RA and DPP-4i (class IIb; neutral) are also recommended for the treatment of HF patients, while saxagliptin and TZAs are contraindicated (class III).
Likewise, the treatment guidelines of the Korean Diabetes Association recommend that SGLT2 inhibitors should be prescribed for diabetic patients with HF, while TZD should be avoided.45) The AHA emphasizes the need for a multidisciplinary team approach in treating HF and DM. They also highlighted the importance of the roles of social workers, pharmacists, dietitians, exercise therapists, renal specialists, and hospitalization specialists, in addition to primary care physicians.24) This suggests medication should be coupled with exercise, diet therapy, and social support when treating HF in patients with DM.
HF was a commonly overlooked complication of DM, though it has been extensively investigated in recent years. An increase in the risk of HF in patients with DM has long been known among Korean researchers. In treating diabetic patients with HF, it is important to select agents that are effective in treating HF specifically in diabetic patients and those commonly used to treat HF in the cardiology division. Of these, SGLT2 inhibitors are recommended as the most effective medications. Recent diabetes management guidelines also recommend SGLT2 inhibitors for the treatment of patients with HF.
In addition to cases of HF with apparent symptoms and reduced EF, which are referred to the cardiology division, asymptomatic cardiomyopathy is completely unpredictable until the occurrence of mortality or morbidity in patients with DM. In addition, when treating patients with DM, it is vital to remember that the risk of HF is already increased even in prediabetes.

Conflict of Interest

The author has no financial conflicts of interest.

Figure 1.
Mechanism of HF in diabetes. Adapted from the article of Dunlay et al. (Circulation 2019;140:e294-324).24)
AGE = advanced glycation end product; CAD = coronary artery disease; HF, heart failure; LVH = left ventricular hypertrophy; RAAS = renin-angiotensin aldosterone system.
cpp-2021-3-e4f1.jpg
  • 1. Korean Diabetes Association. Diabetes fact sheet in Korea: diabetes & complications in Korea [Internet] Seoul: Korean Diabetes Association; 2019 October. Available from https://www.diabetes.or.kr/pro/news/admin.php?category=A&code=admin&mode=view&number=1792
  • 2. Writing Committee Members, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 2013;128:e240-327.PubMed
  • 3. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30:595-602.ArticlePubMed
  • 4. Lehrke M, Marx N. Diabetes mellitus and heart failure. Am J Cardiol 2017;120:S37-47.ArticlePubMed
  • 5. Borghetti G, von Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M. Diabetic cardiomyopathy: current and future therapies. Beyond glycemic control. Front Physiol 2018;9:1514. ArticlePubMedPMC
  • 6. Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus. Circ Res 2019;124:121-41.ArticlePubMedPMC
  • 7. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12.ArticlePubMedPMC
  • 8. Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, Sleight P, Teo K; ONTARGET/TRANSCEND Investigators. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation 2007;115:1371-5.ArticlePubMed
  • 9. Rhee EJ, Kwon H, Park SE, Han KD, Park YG, Kim YH, Lee WY. Associations among obesity degree, glycemic status, and risk of heart failure in 9,720,220 Korean adults. Diabetes Metab J 2020;44:592-601.ArticlePubMedPMC
  • 10. Rørth R, Jhund PS, Mogensen UM, Kristensen SL, Petrie MC, Køber L, McMurray JJ. Risk of incident heart failure in patients with diabetes and asymptomatic left ventricular systolic dysfunction. Diabetes Care 2018;41:1285-91.ArticlePubMed
  • 11. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care 2001;24:1614-9.PubMed
  • 12. Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, Paulus WJ, Komajda M, Cosentino F, de Boer RA, Farmakis D, Doehner W, Lambrinou E, Lopatin Y, Piepoli MF, Theodorakis MJ, Wiggers H, Lekakis J, Mebazaa A, Mamas MA, Tschöpe C, Hoes AW, Seferović JP, Logue J, McDonagh T, Riley JP, Milinković I, Polovina M, van Veldhuisen DJ, Lainscak M, Maggioni AP, Ruschitzka F, McMurray JJ. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:853-72.ArticlePubMed
  • 13. Kristensen SL, Mogensen UM, Jhund PS, Petrie MC, Preiss D, Win S, Køber L, McKelvie RS, Zile MR, Anand IS, Komajda M, Gottdiener JS, Carson PE, McMurray JJ. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with Heart Failure and Preserved Ejection Fraction: a report from the I-Preserve trial (Irbesartan in Heart Failure With Preserved Ejection Fraction). Circulation 2017;135:724-35.ArticlePubMed
  • 14. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB, Solomon SD, Granger CB, Swedberg K, Yusuf S, Pfeffer MA, McMurray JJ; CHARM Investigators. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008;29:1377-85.ArticlePubMed
  • 15. Gerstein HC, Swedberg K, Carlsson J, McMurray JJ, Michelson EL, Olofsson B, Pfeffer MA, Yusuf S; CHARM Program Investigators. The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Arch Intern Med 2008;168:1699-704.ArticlePubMed
  • 16. Matsue Y, Suzuki M, Nakamura R, Abe M, Ono M, Yoshida S, Seya M, Iwatsuka R, Mizukami A, Setoguchi M, Nagahori W, Ohno M, Matsumura A, Hashimoto Y. Prevalence and prognostic implications of prediabetic state in patients with heart failure. Circ J 2011;75:2833-9.ArticlePubMed
  • 17. Preiss D, Zetterstrand S, McMurray JJ, Ostergren J, Michelson EL, Granger CB, Yusuf S, Swedberg K, Pfeffer MA, Gerstein HC, Sattar N; Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Investigators. Predictors of development of diabetes in patients with chronic heart failure in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program. Diabetes Care 2009;32:915-20.ArticlePubMedPMC
  • 18. Preiss D, van Veldhuisen DJ, Sattar N, Krum H, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, Zannad F, McMurray JJ. Eplerenone and new-onset diabetes in patients with mild heart failure: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Eur J Heart Fail 2012;14:909-15.ArticlePubMed
  • 19. Tousoulis D, Oikonomou E, Siasos G, Stefanadis C. Diabetes mellitus and heart failure. Eur Cardiol 2014;9:37-42.PubMedPMC
  • 20. Devereux RB, Roman MJ, Paranicas M, O'Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Howard BV. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 2000;101:2271-6.ArticlePubMed
  • 21. Levelt E, Mahmod M, Piechnik SK, Ariga R, Francis JM, Rodgers CT, Clarke WT, Sabharwal N, Schneider JE, Karamitsos TD, Clarke K, Rider OJ, Neubauer S. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes. Diabetes 2016;65:44-52.ArticlePubMed
  • 22. Falcão-Pires I, Hamdani N, Borbély A, Gavina C, Schalkwijk CG, van der Velden J, van Heerebeek L, Stienen GJ, Niessen HW, Leite-Moreira AF, Paulus WJ. Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. Circulation 2011;124:1151-9.ArticlePubMed
  • 23. Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 2016;12:144-53.ArticlePubMed
  • 24. Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, Deswal A, Dickson VV, Kosiborod MN, Lekavich CL, McCoy RG, Mentz RJ, Piña IL; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America. Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America. Type 2 diabetes mellitus and heart failure: a scientific statement from the American Heart Association and the Heart Failure Society of America: this statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation 2019;140:e294-324.PubMed
  • 25. Sharma A, Cooper LB, Fiuzat M, Mentz RJ, Ferreira JP, Butler J, Fitchett D, Moses AC, O'Connor C, Zannad F. Antihyperglycemic therapies to treat patients with heart failure and diabetes mellitus. JACC Heart Fail 2018;6:813-22.PubMed
  • 26. Elder DH, Singh JS, Levin D, Donnelly LA, Choy AM, George J, Struthers AD, Doney AS, Lang CC. Mean HbA1c and mortality in diabetic individuals with heart failure: a population cohort study. Eur J Heart Fail 2016;18:94-102.ArticlePubMed
  • 27. Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of hemoglobin A1C and mortality in heart failure patients with diabetes. J Am Coll Cardiol 2009;54:422-8.ArticlePubMedPMC
  • 28. Singh S, Loke YK, Furberg CD. Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care 2007;30:2148-53.PubMed
  • 29. Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care 2007;30:e129.ArticlePubMed
  • 30. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, Vanderloo SE, McAlister FA. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 2013;6:395-402.ArticlePubMed
  • 31. BARI 2D Study Group, Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, Orchard TJ, Chaitman BR, Genuth SM, Goldberg SH, Hlatky MA, Jones TL, Molitch ME, Nesto RW, Sako EY, Sobel BE. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009;360:2503-15.ArticlePubMedPMC
  • 32. Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M, Baanstra D, Meinicke T, George JT, von Eynatten M, McGuire DK; Marx N; CAROLINA Investigators. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA 2019;322:1155-66.ArticlePubMedPMC
  • 33. Roumie CL, Min JY; D'Agostino McGowan L, Presley C, Grijalva CG, Hackstadt AJ, Hung AM, Greevy RA, Elasy T, Griffin MR. Comparative safety of sulfonylurea and metformin monotherapy on the risk of heart failure: a cohort study. J Am Heart Assoc 2017;6:e005379.ArticlePubMedPMC
  • 34. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.ArticlePubMed
  • 35. Liu D, Jin B, Chen W, Yun P. Dipeptidyl peptidase 4 (DPP-4) inhibitors and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM): a systematic review and meta-analysis. BMC Pharmacol Toxicol 2019;20:15. ArticlePubMedPMC
  • 36. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-9.ArticlePubMed
  • 37. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America. Circulation 2017;136:e137-61.ArticlePubMed
  • 38. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.ArticlePubMed
  • 39. McMurray JJ, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CE, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.ArticlePubMed
  • 40. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, Packer M. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a metaanalysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819-29.ArticlePubMed
  • 41. Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab 2016;24:15-30.ArticlePubMed
  • 42. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, Køber L, Petrie MC, McMurray JJ. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776-85.ArticlePubMed
  • 43. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care 2020;43:S98-110.PubMed
  • 44. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N, Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC, Piepoli MF, Birkeland KI, Adamopoulos S, Ajjan R, Avogaro A, Baigent C, Brodmann M, Bueno H, Ceconi C, Chioncel O, Coats A, Collet JP, Collins P, Cosyns B, Di Mario C, Fisher M, Fitzsimons D, Halvorsen S, Hansen D, Hoes A, Holt RI, Home P, Katus HA, Khunti K, Komajda M, Lambrinou E, Landmesser U, Lewis BS, Linde C, Lorusso R, Mach F, Mueller C, Neumann FJ, Persson F, Petersen SE, Petronio AS, Richter DJ, Rosano GM, Rossing P, Rydén L, Shlyakhto E, Simpson IA, Touyz RM, Wijns W, Wilhelm M, Williams B, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N, Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC, Windecker S, Aboyans V, Baigent C, Collet JP, Dean V, Delgado V, Fitzsimons D, Gale CP, Grobbee DE, Halvorsen S, Hindricks G, Iung B, Jüni P, Katus HA, Landmesser U, Leclercq C, Lettino M, Lewis BS, Merkely B, Mueller C, Petersen SE, Petronio AS, Richter DJ, Roffi M, Shlyakhto E, Simpson IA, Sousa-Uva M, Touyz RM, Zelveian PH, Scherr D, Jahangirov T, Lazareva I, Shivalkar B, Naser N, Gruev I, Milicic D, Petrou PM, Linhart A, Hildebrandt P, Hasan-Ali H, Marandi T, Lehto S, Mansourati J, Kurashvili R, Siasos G, Lengyel C, Thrainsdottir IS, Aronson D, Di Lenarda A, Raissova A, Ibrahimi P, Abilova S, Trusinskis K, Saade G, Benlamin H, Petrulioniene Z, Banu C, Magri CJ, David L, Boskovic A, Alami M, Liem AH, Bosevski M, Svingen GF, Janion M, Gavina C, Vinereanu D, Nedogoda S, Mancini T, Ilic MD, Fabryova L, Fras Z, Jiménez-Navarro MF, Norhammar A, Lehmann R, Mourali MS, Ural D, Nesukay E, Chowdhury TA; ESC Scientific Document Group. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255-323.ArticlePubMed
  • 45. Korean Diabetes Association. 2019 Treatment guideline for diabetes. 6th ed. [Internet] Seoul: Korean Diabetes Association; 2019 June. Available from https://www.diabetes.or.kr/pro/publish/guide.php?code=guide&mode=view&number=735

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