Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study

Kåre I Birkeland, Johan Bodegard, Jan W Eriksson, Anna Norhammar, Hermann Haller, Gerard C M Linssen, Amitava Banerjee, Marcus Thuresson, Suguru Okami, Elena Garal-Pantaler, Jetty Overbeek, Jil Billy Mamza, Ruiqi Zhang, Toshitaka Yajima, Issei Komuro, Takashi Kadowaki, Kåre I Birkeland, Johan Bodegard, Jan W Eriksson, Anna Norhammar, Hermann Haller, Gerard C M Linssen, Amitava Banerjee, Marcus Thuresson, Suguru Okami, Elena Garal-Pantaler, Jetty Overbeek, Jil Billy Mamza, Ruiqi Zhang, Toshitaka Yajima, Issei Komuro, Takashi Kadowaki

Abstract

Aims: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases.

Methods: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD-free status.

Results: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD-free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all-cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75-2.33) and HR 2.05 (95% CI 1.82-2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all-cause mortality risk: HRs 3.91 (95% CI 3.02-5.07) and 3.14 (95% CI 2.90-3.40), respectively.

Conclusion: In a large multinational study of >750 000 CVRD-free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

Keywords: SGLT2 inhibitor; diabetic nephropathy; heart failure; macrovascular disease; observational study; type 2 diabetes.

Conflict of interest statement

K.I.B. has received grants to his institution from AstraZeneca for this study and for lectures and consulting from Novo Nordisk, Sanofi, Lilly, Boehringer Ingelheim and Merck Sharp & Dohme. J.B. holds a full‐time position at AstraZeneca as an epidemiologist. J.W.E. has received honoraria or research grants from AstraZeneca, NovoNordisk, Bayer, Sanofi and MSD. A.N. has received honoraria from MSD, Astra Zeneca, Eli Lilly, Boehringer Ingelheim and Novo Nordisk. H.H has received lecture fees and travel expenses from Alexion, Baxter, NovoNordisk, Noxxon, Janssen and AstraZeneca. G.C.M.L. has no competing interests. M.T. is employed by an independent statistical consultant company, Statisticon AB, Uppsala, Sweden, of which AstraZeneca Nordic‐Baltic is a client. S.O. is a full‐time employee of AstraZeneca. E.G.P. is an employee of Team Gesundheit GmbH and conducted work on behalf of Kantar Health. J.O. is an employee of the PHARMO Institute for Drug Outcomes Research, an independent research institute that performs financially supported studies for government and related healthcare authorities and for several pharmaceutical companies. R.Z. and T.Y. are full‐time employees of AstraZeneca. I.K. declares grants from Astellas Pharma Inc., Boehringer Ingelheim Japan, Kowa Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Mitsubishi Tanabe Pharma Corp., Shionogi & Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd, Toa Eiyo Ltd, honoraria from Astellas Pharma Inc., Boehringer Ingelheim Japan, Kowa Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Mitsubishi Tanabe Pharma Corp., Shionogi & Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd and Toa Eiyo Ltd, and lecture/other fees from AstraZeneca. T.K. declares grants from Asahi Mutual Life Insurance Co., Boehringer Ingelheim Japan, Daiichi Sankyo Co. Ltd, Kowa Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Corp., MSD K.K., Novo Nordisk Pharma Ltd, Sanofi K.K. and Takeda Pharmaceutical Co. Ltd and lecture/other fees from AstraZeneca K.K., Astellas Pharma Inc., Boehringer Ingelheim Japan, Daiichi Sankyo Co. Ltd, Eli Lilly Japan K.K., Kowa Pharmaceutical Co. Ltd, Kyowa Hakko Kirin Co., Ltd, Mitsubishi Tanabe Pharma Corp., MSD K.K., Ono Pharmaceutical Co. Ltd, Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd, Sanwa Kagaku Kenkyusho Co. Ltd, Taisho Pharmaceutical Co., Ltd and Takeda Pharmaceutical Co, Ltd.

© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Cardiovascular manifestation during follow‐up in initially cardiovascular or renal disease‐free patients with type 2 diabetes. CKD, chronic kidney disease; HF, heart failure
FIGURE 2
FIGURE 2
Pooled death risks associated with the single presence groups of cardiovascular or renal disease (CVRD) compared to a CVRD‐free type 2 diabetes group. Cardiorenal disease defined as heart failure (HF) or chronic kidney disease (CKD). Cardiorenal syndrome defines as the presence of both HF and CKD). *Adjusted for age and sex. **Cardiovascular disease (CVD) death was not obtainable in Germany, Japan and the Netherlands
FIGURE 3
FIGURE 3
Pooled cardiovascular risks associated with the single presence groups of cardiovascular or renal disease (CVRD) compared to a CVRD‐free type 2 diabetes group. Cardiorenal disease defined as heart failure (HF) or chronic kidney disease (CKD). Cardiorenal syndrome defines as the presence of both HF and CKD). *Adjusted for age and sex

References

    1. Federation ID . IDF Diabetes Atlas. 8th ed. Brussels, Belgium: International Diabetes Federation; 2017. .
    1. Birkeland KI, Bodegard J, Norhammar A, et al. How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study. Diabetes Obes Metab. 2018;24:968‐974.
    1. Thrainsdottir IS, Aspelund T, Thorgeirsson G, et al. The association between glucose abnormalities and heart failure in the population‐based Reykjavik study. Diabetes Care. 2005;28(3):612‐616.
    1. Collaboration GBDCKD . Global, regional, and national burden of chronic kidney disease, 1990‐2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2020;395(10225):709‐733.
    1. Braunwald E. Diabetes, heart failure, and renal dysfunction: the vicious circles. Prog Cardiovasc Dis. 2019;62(4):298‐302.
    1. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev. 2017;3(1):7‐11.
    1. Seferovic PM, Petrie MC, Filippatos GS, et al. 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(5):853‐872.
    1. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27(3):699‐703.
    1. Bruck K, Stel VS, Gambaro G, et al. CKD prevalence varies across the european general population. J Am Soc Nephrol. 2016;27(7):2135‐2147.
    1. Gansevoort RT, Correa‐Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339‐352.
    1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296‐1305.
    1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10‐year follow‐up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577‐1589.
    1. Kerr M, Bray B, Medcalf J, O'Donoghue DJ, Matthews B. Estimating the financial cost of chronic kidney disease to the NHS in England. Nephrol Dial Transplant. 2012;27(Suppl 3):iii73‐iii80.
    1. Seuring T, Archangelidi O, Suhrcke M. The economic costs of type 2 diabetes: a global systematic review. Pharmacoeconomics. 2015;33(8):811‐831.
    1. van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all‐cause and cardiovascular mortality. A collaborative meta‐analysis of high‐risk population cohorts. Kidney Int. 2011;79(12):1341‐1352.
    1. Ismail Y, Kasmikha Z, Green HL, McCullough PA. Cardio‐renal syndrome type 1: epidemiology, pathophysiology, and treatment. Semin Nephrol. 2012;32(1):18‐25.
    1. Rangaswami J, Bhalla V, Blair JEA, et al. Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement From the American Heart Association. Circulation. 2019;139(16):e840‐e878.
    1. Rawshani A, Rawshani A, Franzen S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018;379(7):633‐644.
    1. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24(2):302‐308.
    1. de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA. 2011;305(24):2532‐2539.
    1. Gregg EW, Li Y, Wang J, et al. Changes in diabetes‐related complications in the United States, 1990‐2010. N Engl J Med. 2014;370(16):1514‐1523.
    1. Greene SJ, Butler J. Primary prevention of heart failure in patients with type 2 diabetes mellitus. Circulation. 2019;139(2):152‐154.
    1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995‐2008.
    1. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644‐657.
    1. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018;380(4):347‐357.
    1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117‐2128.
    1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295‐2306.
    1. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019;7(8):606‐617.
    1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323‐334.
    1. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347‐357.
    1. Mahaffey KW, Jardine MJ, Bompoint S, et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes and chronic kidney disease in primary and secondary cardiovascular prevention groups: results from the randomized CREDENCE trial. Circulation. 2019;140:739‐750.
    1. Wolf A, Dedman D, Campbell J, et al. Data resource profile: clinical practice research datalink (CPRD) Aurum. Int J Epidemiol. 2019;48:1740‐1740g.
    1. Birkeland KI, Bodegard J, Norhammar A, et al. How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study. Diabetes Obes Metab. 2018;21(4):968‐974.
    1. Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular Events Associated with SGLT‐2 inhibitors versus other glucose‐lowering drugs: the CVD‐REAL 2 study. J Am Coll Cardiol. 2018;71(23):2628‐2639.
    1. Tanabe M, Motonaga R, Terawaki Y, Nomiyama T, Yanase T. Prescription of oral hypoglycemic agents for patients with type 2 diabetes mellitus: a retrospective cohort study using a Japanese hospital database. J Diabetes Investig. 2017;8(2):227‐234.
    1. Tanabe M, Nomiyama T, Motonaga R, Murase K, Yanase T. Reduced vascular events in type 2 diabetes by biguanide relative to sulfonylurea: study in a Japanese hospital database. BMC Endocr Disord. 2015;15:49.
    1. Herings RM, Pedersen L. Pharmacy‐based medical record linkage systems In: Kimmel S, Hennessey S, eds. Pharmacoepidemiology. 5th ed. Oxford, United Kingdom: John Wiley & Sons, Ltd; 2012:270‐286.
    1. van Herk‐Sukel MP, van de Poll‐Franse LV, Lemmens VE, et al. New opportunities for drug outcomes research in cancer patients: the linkage of the Eindhoven Cancer Registry and the PHARMO Record Linkage System. Eur J Cancer. 2010;46(2):395‐404.
    1. Birkeland KI, Jorgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium‐glucose co‐transporter‐2 inhibitors versus other glucose‐lowering drugs (CVD‐REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol. 2017;5(9):709‐717.
    1. Persson F, Nystrom T, Jorgensen ME, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all‐cause mortality in people with type 2 diabetes (CVD‐REAL Nordic) when compared with dipeptidyl peptidase‐4 inhibitor therapy: a multinational observational study. Diabetes Obes Metab. 2018;20(2):344‐351.
    1. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol. 2015;3(2):105‐113.
    1. Avery CL, Loehr LR, Baggett C, et al. The population burden of heart failure attributable to modifiable risk factors: the ARIC (Atherosclerosis Risk in Communities) study. J Am Coll Cardiol. 2012;60(17):1640‐1646.
    1. Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care. 2004;27(8):1879‐1884.
    1. Dunlay SM, Givertz MM, Aguilar D, et al. 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(7):e294‐e324.
    1. Levelt E, Mahmod M, Piechnik SK, et al. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes. Diabetes. 2016;65(1):44‐52.
    1. Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004;63(4):582‐592.
    1. Fang ZY, Yuda S, Anderson V, Short L, Case C, Marwick TH. Echocardiographic detection of early diabetic myocardial disease. J Am Coll Cardiol. 2003;41(4):611‐617.
    1. Lebeche D, Davidoff AJ, Hajjar RJ. Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008;5(11):715‐724.
    1. Waddingham MT, Edgley AJ, Tsuchimochi H, Kelly DJ, Shirai M, Pearson JT. Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy. World J Diabetes. 2015;6(7):943‐960.
    1. Dauriz M, Targher G, Laroche C, et al. Association between diabetes and 1‐year adverse clinical outcomes in a multinational cohort of ambulatory patients with chronic heart failure: results from the ESC‐HFA heart failure long‐term registry. Diabetes Care. 2017;40(5):671‐678.
    1. From AM, Leibson CL, Bursi F, et al. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med. 2006;119(7):591‐599.
    1. Johansson I, Dahlstrom U, Edner M, Nasman P, Ryden L, Norhammar A. Prognostic implications of type 2 diabetes mellitus in ischemic and nonischemic heart failure. J Am Coll Cardiol. 2016;68(13):1404‐1416.
    1. Targher G, Dauriz M, Laroche C, et al. In‐hospital and 1‐year mortality associated with diabetes in patients with acute heart failure: results from the ESC‐HFA heart failure long‐term registry. Eur J Heart Fail. 2017;19(1):54‐65.
    1. Cherney DZI, Repetto E, Wheeler DC, et al. Impact of cardio‐renal‐metabolic comorbidities on cardiovascular outcomes and mortality in type 2 diabetes mellitus. Am J Nephrol. 2020;51(1):74‐82.
    1. Garcia‐Carro C, Vergara A, Agraz I, et al. The new era for reno‐cardiovascular treatment in type 2 diabetes. J Clin Med. 2019;8(6).1‐16.
    1. Braunwald E. Diabetes, heart failure, and renal dysfunction: the vicious circles. Prog Cardiovasc Dis. 2019;62:298‐302.
    1. Ronco C, Ronco F, McCullough PA. A call to action to develop integrated curricula in cardiorenal medicine. Blood Purif. 2017;44(4):251‐259.
    1. Verma S, Juni P, Mazer CD. Pump, pipes, and filter: do SGLT2 inhibitors cover it all? Lancet. 2019;393(10166):3‐5.
    1. Connelly KA, Bhatt DL, Verma S. Can we declare a victory against cardio‐renal disease in diabetes? Cell Metab. 2018;28(6):813‐815.
    1. Brynildsen J, Hoiseth AD, Nygard S, et al. [Diagnostic accuracy for heart failure ‐ data from the Akershus Cardiac Examination 2 Study]. Tidsskr Nor Laegeforen. 2015;135(19):1738‐1744.
    1. Ingelsson E, Arnlov J, Sundstrom J, Lind L. The validity of a diagnosis of heart failure in a hospital discharge register. Eur J Heart Fail. 2005;7(5):787‐791.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa