Risk Related to Pre-Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial

Søren L Kristensen; David Preiss; Pardeep S Jhund; Iain Squire; José Silva Cardoso; Bela Merkely; Felipe Martinez; Randall C Starling; Akshay S Desai; Martin P Lefkowitz; Adel R Rizkala; Jean L Rouleau; Victor C Shi; Scott D Solomon; Karl Swedberg; Michael R Zile; John J V McMurray; Milton Packer; PARADIGM-HF Investigators and Committees

doi:10.1161/CIRCHEARTFAILURE.115.002560

Risk Related to Pre-Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial

Circ Heart Fail. 2016 Jan;9(1):e002560. doi: 10.1161/CIRCHEARTFAILURE.115.002560.

Authors

Søren L Kristensen¹, David Preiss¹, Pardeep S Jhund¹, Iain Squire¹, José Silva Cardoso¹, Bela Merkely¹, Felipe Martinez¹, Randall C Starling¹, Akshay S Desai¹, Martin P Lefkowitz¹, Adel R Rizkala¹, Jean L Rouleau¹, Victor C Shi¹, Scott D Solomon¹, Karl Swedberg¹, Michael R Zile¹, John J V McMurray², Milton Packer¹; PARADIGM-HF Investigators and Committees

Collaborators

PARADIGM-HF Investigators and Committees:
J Vanhaecke, F Ramires, T Katova, M Arnold, J Huang, E Gomez, J Belohlavek, J Refsgaard, O Lederballe, A Gonzalez, Y C Duarte, A Rosenthal, K Peuhkurinen, A A Hagege, M Böhm, J L Arango, K Andersen, M Senni, A Erglis, A Petrulioniene, E B Llamas, A Mosterd, W Cabrera, A S Sibulo Jr, M Negrusz-Kawecka, J Silva-Cardoso, D Vinereanu, S Boytsov, R Wong, A Dukat, L Burgess, K S Kim, C Calvo, M Fu, C H Chen, S Kiatchoosakun, O Kozan, R Starling, J Teerlink, H Dargie, R Foley, G S Francis, M Komajda, S Pocock, E Barkoudah, N Bello, A Brahimi, D Charytan, C Duong, P Finn, H Hartley, A Vazir, L Weinrauch, A P Kaplan, N Brown, B Zuraw, N Greenlaw, J Albisu, A Alvarisqueta, M Amuchastegui, A Astesiano, E Avila, J Beloscar, M Berli, C Borrego, B Bustos, P Calella, J Carbajales, G Caruso, O Caruso, H Casabé, J Cimbaro Canella, F Colombo Berra, R Colque, R Costello, R Dran, F Ferre Pacora, A Gabito, J Glenny, P Guzman, J Ibañez, R Ingaramo, C Kotliar, R Leon de la Fuente, A Liberman, G Liniado, J Llanos, L Lobo Marquez, H Luquez, I Mackinnon, M Mallagray, R Martingano, D Mercado, G Moises Azize, L Parody, R Perez Rey, E Petenian, M Rodríguez, C Rojas, A Romano, A Salvatierra Ruiz, A Sanchez, R Sarjanovich, A Sarries, L Schiavi, H Sessa, J Soler, M Vico, C Zaidman, J Vanhaecke, P Decroly, P Dendale, B Ector, A Friart, A Heyse, L Missault, T Mulleners, W Smolders, H Vandekerckhove, M Vincent, C Weytjens, B Wollaert, F Ramires, C Andrade, R Bassan, F Borelli, R Botelho, J Braga, M Braile, C Costa, F Costa, N Duda, M Garcia, O Greco, M Hernandes, C Jaeger, I Koehler, R Luiz Rech, E Mesquita, J Moraes Jr, J Neto, F Neuenschwander, M Paiva, S Rassi, G Reis, P Rossi, A Rabelo, H Reis, W Saporito, M Simoes, W Souza, F Vilas Boas, T Katova, H Benov, B Boeva-Chompalova, P Chobanska, S Denchev, B Dimov, T Donova, P Georgiev, D Gotchev, A Goudev, T Gruev, V Hergeldjieva, P Lazov, I Manukov, S Marchev, L Mihov, M Milanova, A Mileva-Manolova, V Mincheva-Kabakchieva, Z Parvanova, G Pencheva, S Petranov, D Raev, K Ramshev, V Sirakova, A Staneva, S Tisheva-Gospodinova, G Todorov, M Tokmakova, M Tzekova, P Valchanova, Y Yotov, V Zhelev, M Arnold, S Bergeron, R Bourgeois, S Bourgeois, J Cha, M DeGrâce, D Delgado, F Deslongchamps, D Dion, N Giannetti, T Huynh, J Johnston, P Klinke, J Kornder, R Labonte, C Lauzon, S Lepage, S Mak, G Moe, D Murthy, S Pandey, J Parker, M Rajda, S Robinson, D Rupka, G Sabe-Affaki, F Sestier, R Sheppard, L Yao, F Albornoz, P Avendaño, L Cobos, E Escobar, M Fernandez, J Jalil, F Lanas, P Sepulveda, B Stockins, P Yovaniniz, J Huang, M Gui, H D Hu, Y N Ke, L G Li, X D Li, X L Li, W M Li, S W Liu, X H Liu, G S Ma, N L Sun, G Xu, K Yang, Z Y Yuan, J Zhang, R P Zhao, E Gomez, J Accini, A Almanzar, J Coronel, C Cotes, L Echeverria, F Manzur, E María, H Reynales, M Rodriguez, A Sotomayor, M Urina, J Velasquez, S Vélez, B Vesga, J Belohlavek, H Burianova, J Carda, V Cech, M Cepelak, A Hanustiakova, I Horny, K Kolar, J Krupicka, J Kvasnicka, P Lindovsky, Z Lorenc, F Malek, J Malik, A Mandovec, I Petrova, B Podzemska, P Povolny, M Radvan, M Richter, V Riha, P Sabl, J Slaby, J Svejda, P Telekes, J Ulman, Z Vomacka, S Zemek, O Lederballe, J Refsgaard, H Andersen, K Egstrup, H Elming, N Eske, O Gøtzsche, J Jensen, L Køber, O May, O Pedersen, H Rickers, F Steffensen, A Gonzalez, A Paulino, P Martinez, Y C Duarte, C Delgado, Y Duarte, F L Hidalgo, C Mariscal, R Marmol, A Rosenthal, A Kaasik, J Kaik, E Laane, K Peuhkurinen, T Jaaskelainen, K Kiilavuori, J Taurio, A A Hagege, A Alexeeva-Kovalchuk, F Bauer, P Berdague, J B Berneau, J M Bouvier, L Damien, T Damy, J M Davy, D E Decoulx, N El-Mansour, C Etchecopar, M Galinier, P Gibelin, P Gosse, A Guetlin, J N Labeque, B Livarek, D Logeart, M Martelet, P Nazeyrollas, Y Neuder, M Nourredine, J E Poulard, R RaidRihani, R Sabatier, N T Tran, N Yannick, F Zannad, M Bohm, V Adelberger, A Al-Zoebi, A Bastian, S Behrens, H Bessler, R Braun, B Brehm, M Buhr, G Cieslinski, J vom Dahl, W Daut, H J Demmig, S Denny, H H Ebert, C Fechtrup, S Fischer, H M Frick, S Genth-Zotz, U Gerbaulet, H Germann, S Geßner, G Gola, G Grönefeld, A Hagenow, J Hampf, A Hartmann, G Hauf, C Hegeler-Molkewehrum, P Hegemann, S Hermes, A Himpel-Bönninghoff, S Hoeltz, R Jerwan-Keim, C Kadel, C Karle, I Kindermann, M Knapp, K H Krause, B Krosse, U Kühne, M Kuhrs, M Leicht, M Löbe, H Loos, H Mehling, K Melchior, F Menzel, T Münzel, M Natour, I Naudts, R Naumann, R Nischik, H G Olbrich, W Pohl, M Prohaska, N Proskynitopoulus, S Regner, D Reimer, S Roeder, R Rummel, P Salbach, T Schäfer, T Schaum, I Schenkenberger, A Schindler, A Schmidt, E Schmidt, A Schnabel, R Schneider, W Schneider, A Schreckenberg, F Schreibmüller, M Schreiner, T Schröder, M Schumacher, A Segner, H Seibert, G Siao, K Siao, H Y Sohn, R Stöhring, G Tangerding, G Taubert, A Terhorst, C Tesch, N Toursarkissian, K Tyler, P Uebel, K Weyland, A Wilke, A Yilmaz, C Zemmrich, W Zeh, R Zotz, J L Arango, J Arriola, V Corona, S Leal, E López, R Muñoz, A Ovando, A Paniagua, D Rodríguez, L Velasquez, F Wyss, H F Tse, S K Li, B Yan, G Yip, B Merkely, G Andrassy, P Andreka, J Bakai, K Csapo, A Cziraki, I Édes, T Forster, E Hajko, A Illes, L Jánoskuti, A Kalina, Z Kovacs, Z László, G Lupkovics, A Matoltsy, G Müller, A Nagy, E Noori, N Nyolczas, A Papp, C Salamon, G Szántai, A Szocs, J Tomcsányi, D Toth, I Varjú, A Vertes, K Zámolyi, Z Zilahi, K Andersen, T Gudnason, A Sigurdsson, G Thorgeirsson, A Abhyankar, D Agarwal, R Aggarwal, R Bagirath, D Banker, V Bisne, P Bohra, V Chopra, S Dani, A Dharmadhikari, M Fulwani, M Gadkari, N Ghaisas, H Basavanagowdappa, S Gupta, S Hiremath, P Jagtap, A Jain, V Jain, R Jindal, S Joseph, P Kerkar, M Kumbla, B Malipeddi, G Mathan, A Mehta, M Mohan, L Murthy, A Nair, V Pai, A Pandey, V Prakash, M Rao, N S Rao, N Reddy, P Sarma, P Shah, K Shamsudden, K Sharma, S Sinha, B Thakkar, S Thanvi, P Trivedi, V Vijan, B Yugandhar, D Aronson, T Ben Gal, S Goland, A Katz, A Keren, B Lewis, A Marmor, S Mayler, M Shochat, M Senni, L Anastasio, M Baldin, C Brunelli, G Casolo, C Coppolino, F Cosmi, G Danzi, M Destro, T Di Napoli, A D'Ospina, A Fucili, A Gigantino, N L Liberato, F Lombardi, G Lembo, F Magrini, E Mannarino, D Marchese, C Minneci, M Modena, L Mos, T Napoli, C Opasich, G Pajes, F Perticone, P Pileri, G Poddighe, E Ronchi, P Saba, M Sicuro, F Silvestri, J Salerno Uriarte, V Spagnuolo, M Sprovieri, S Taddei, P Terrosu, M Tespili, J Uriarte, W Vergoni, M Volterrani, A Erglis, G Dormidontova, R Eglite, T Lvova, G Rancane, I Sime, Z Petrulioniene, R Slapikas, W Ahmad, D Chew, O Ismail, T Ong, E B Llamas, M Aguilera, J Arenas, J Carrillo, J González, S Leon, G Llamas, A Macias, A Meaney, O Orihuela, A Pavía, I Rodriguez, T Rodriguez, E Salcido, G Solache, R Velasco, A Mosterd, D Basart, L Bellersen, A Derks, R Dijkgraaf, P Dunselman, J van Eck, C Gurlek, F den Hartog, G Hoedemaker, R Kaplan, J Koolen, L Liem, J Milhous, C de Nooijer, A Pronk, H Brunner-la Rocca, E Ronner, H Swart, G Tjeerdsma, F Willems, E Avilés, G Frago, B González, R Nieto, W Cabrera, R Alegre, R Azañero, J H García, F Godoy, E Avilés, G Frago, B González, R Nieto, W Cabrera, R Alegre, R Azañero, B Orihuela, A Rodriguez, A Rodriguez, Y Roldan, P Torres, J Urquiaga, A S Sibulo Jr, J Anonuevo, A Atilano, A Borromeo, A Ferrolino, A Guerrero, S Locnen, R Rosita, A Ruales, G Vilela, M Negrusz-Kawecka, W Bebenek, B Sobkowicz, K Cymerman, M Dabrowska, M Foczpaniak, E Jazwinska-Tarnawska, A Kabara, D Wronska, F Almeida, N Braganca, M Andor, D Bartos, G Basarab, I Coman, I Copaci, M Cristea, S Dragulescu, D Enache, A Fruntelata, L Iliescu, O Istratoaie, D Lighezan, C Militaru, T Nanea, T Nanea, C Nechita, M Puschita, M Tomescu, M Tudoran, S Boitsov, F Ageev, O Averkov, A Akimov, M Ballyuzek, E Baranov, E Baranova, O Barbarash, O Berkovich, S Berns, N Bessonova, M Boyarkin, O Bulashova, V Chernetsov, I Chukaeva, I Kamensky, Y Dovgalevsky, S Dovgolis, D Duplyakov, L Ermoshkina, S Fitilev, A Galyavich, G Gendlin, A Gofman, B Goloschekin, T Gomova, A Gordienko, Y Karpov, A Kastanayan, O Khromtsova, O Kisliak, Z Kobalava, A Konradi, M Korolev, E Kosmacheva, V Kostenko, N Koziolova, A Kuimov, E Kulibaba, P Lebedev, V Lesnov, R Libis, Y Lopatin, V Makukhin, I Masterov, Y Moiseeva, T Morozova, I Motylev, S Murashkina, V Nosov, V Oleynikov, T Palatkina, E Parmon, L Pimenov, D Privalov, V Rafalsky, A Rebrov, I Reznik, M Ruda, R Saifutdinov, S Sayganov, Y Shvarts, L Shpagina, S Shustov, E Shutemova, M Sitnikova, J Sizova, O Smolenskaya, A Solovieva, I Staroverov, R Struk, A Svistov, N Tarasov, E Tarlovskaya, S Tereschenko, N Trofimov, Y Uspensky, E Vasilieva, N Vezikova, A Vishnevsky, D Volkov, D Yakhontov, A Yakovlev, A Yavdosyuk, A Zateyshchikova, O Zharkov, E Zhilyaev, D Zotov, K Zrazhevsky, R Wong, C Lee, H Ong, D Yeo, A Dukát, L Antalík, A Antalík, D Demešová, M Dvoržák, F Fazekaš, D Foldiová, P Fülöp, P Kabaivanov, J Kovács, V Maček, I Majerčák, J Mazúr, P Olexa, J Pálka, D Pella, S Remišová, J Schichorová, L Burgess, F Ahmed, E Delport, L Jamjam, M Mkhwanazi, Z Mohamed, M Mpe, T Padayachee, N Ranjith, D J van Rensburg, J Saaiman, L van Zyl, L de Teresa, S Kiatchoosakun, K Hengrussamee, D Piyayotai, S Sanguanwong, T Thongsri, M Aktoz, C Barcin, O Yavuzgil, M Yenigun, I Squire, S Apostolakis, M El-Harari, M Fisher, S Leslie, T Levy, M Lynch, R MacFadyen, S Mahmood, M Mamas, W Martin, S Megarry, R Mohindra, R More, A Moriarty, J Murphy, R Muthusamy, L Neyses, A Nightingale, L O'Toole, D Price, J Purvis, A Ryding, Z Yousef, O Akinboboye, A Akyea-Djamson, A Amin, A Amkieh, A Amos, I Anand, V Awasty, D Banish, A Bank, R Bargout, D Barnard, I Berg, M Berk, J Best, R Canadas-Zizzias, K Carr, S Efstratiadis, H Eisen, P Fattal, B Fenster, J Fernandez, A Flores, E Flores, J Floro, G Frivold, B Fuhs, D Goldscher, R Gould, L Grazette, N Laufer, I H Lieber, G Haas, B Hattler, M Hazelrigg, K Heilman, M Heiman, A Heroux, W Herzog, M Hoffman, D Hotchkiss, C Hunter, J Hunter, R Marple, M Maurer, W McKenzie, C Parrott, J Petersen 2nd, T Poling, J Prodafikas, M Ptacin, E Quinlan 3rd, T Quinn, B Rama, K Ramanathan, D Rawitscher, J Rosado, S Rosenthal, M S Oberoi, A Samal, C Schmalfuss, S Schwartz, S Seals, Y Selektor, S Schaefer, T Seto, S Shah, J Shanes, J Sims, S Singh, S Sooudi, R Sotolongo, D Suiter, S Sunderam, U Thadani, J Thrasher, B Trichon, R Vicuna, R Vranian, R Jackson, S Wallach, N Ward, D Weinstein, T Wells, W Wickemeyer, J Wight, C Williams, L Wu, G Xu, J Zebrack, I Mendoza, A Avendaño, M Alvarez, E Silva, G Vergara

Affiliations

¹ From the British Heart Foundation, Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (S.L.K., D.P., P.J., J.J.V.M.); Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark (S.L.K.); Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (I.S.); NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK (I.S.); Department of Cardiology, Porto Medical School, Porto, Portugal (J.S.C.); Heart and Vascular Center Semmelweiss University, Budapest, Hungary (B.M.); Instituo DAMIC, Cordoba National University, Cordoba, Argentina (F.M.); Kaufman Center for Heart Failure, Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (A.S.D); Novartis Pharmaceutical Corporation, East Hanover, NJ (M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Montréal, Québec, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); RHJ Department of Veterans Administration Medical Center, Medical University of South Carolina, Charleston (M.R.Z.); and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (M.P.).
² From the British Heart Foundation, Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (S.L.K., D.P., P.J., J.J.V.M.); Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark (S.L.K.); Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (I.S.); NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK (I.S.); Department of Cardiology, Porto Medical School, Porto, Portugal (J.S.C.); Heart and Vascular Center Semmelweiss University, Budapest, Hungary (B.M.); Instituo DAMIC, Cordoba National University, Cordoba, Argentina (F.M.); Kaufman Center for Heart Failure, Heart and Vascular Institute, Cleveland Clinic, OH (R.C.S.); Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (A.S.D); Novartis Pharmaceutical Corporation, East Hanover, NJ (M.P.L., A.R.R., V.C.S.); Institut de Cardiologie, Université de Montréal, Montréal, Québec, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden (K.S.); RHJ Department of Veterans Administration Medical Center, Medical University of South Carolina, Charleston (M.R.Z.); and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (M.P.). john.mcmurray@glasgow.ac.uk.

PMID: 26754626
PMCID: PMC4718182
DOI: 10.1161/CIRCHEARTFAILURE.115.002560

Abstract

Background: The prevalence of pre-diabetes mellitus and its consequences in patients with heart failure and reduced ejection fraction are not known. We investigated these in the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial.

Methods and results: We examined clinical outcomes in 8399 patients with heart failure and reduced ejection fraction according to history of diabetes mellitus and glycemic status (baseline hemoglobin A1c [HbA1c]: < 6.0% [< 42 mmol/mol], 6.0%-6.4% [42-47 mmol/mol; pre-diabetes mellitus], and ≥ 6.5% [≥ 48 mmol/mol; diabetes mellitus]), in Cox regression models adjusted for known predictors of poor outcome. Patients with a history of diabetes mellitus (n = 2907 [35%]) had a higher risk of the primary composite outcome of heart failure hospitalization or cardiovascular mortality compared with those without a history of diabetes mellitus: adjusted hazard ratio, 1.38; 95% confidence interval, 1.25 to 1.52; P < 0.001. HbA1c measurement showed that an additional 1106 (13% of total) patients had undiagnosed diabetes mellitus and 2103 (25%) had pre-diabetes mellitus. The hazard ratio for patients with undiagnosed diabetes mellitus (HbA1c, > 6.5%) and known diabetes mellitus compared with those with HbA1c < 6.0% was 1.39 (1.17-1.64); P < 0.001 and 1.64 (1.43-1.87); P < 0.001, respectively. Patients with pre-diabetes mellitus were also at higher risk (hazard ratio, 1.27 [1.10-1.47]; P < 0.001) compared with those with HbA1c < 6.0%. The benefit of LCZ696 (sacubitril/valsartan) compared with enalapril was consistent across the range of HbA1c in the trial.

Conclusions: In patients with heart failure and reduced ejection fraction, dysglycemia is common and pre-diabetes mellitus is associated with a higher risk of adverse cardiovascular outcomes (compared with patients with no diabetes mellitus and HbA1c < 6.0%). LCZ696 was beneficial compared with enalapril, irrespective of glycemic status.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Keywords: clinical trial; diabetes mellitus; heart failure; prognosis; treatment outcome.

Publication types

Comparative Study
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aminobutyrates / adverse effects
Aminobutyrates / therapeutic use*
Angiotensin Receptor Antagonists / adverse effects
Angiotensin Receptor Antagonists / therapeutic use*
Angiotensin-Converting Enzyme Inhibitors / adverse effects
Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
Biomarkers / blood
Biphenyl Compounds
Blood Glucose / metabolism
Comorbidity
Diabetes Mellitus / blood
Diabetes Mellitus / diagnosis
Diabetes Mellitus / epidemiology*
Diabetes Mellitus / mortality
Disease-Free Survival
Drug Combinations
Enalapril / adverse effects
Enalapril / therapeutic use*
Female
Glycated Hemoglobin / metabolism
Heart Failure / blood
Heart Failure / diagnosis
Heart Failure / drug therapy*
Heart Failure / mortality
Heart Failure / physiopathology
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Prediabetic State / blood
Prediabetic State / diagnosis
Prediabetic State / epidemiology*
Prediabetic State / mortality
Prevalence
Proportional Hazards Models
Prospective Studies
Risk Assessment
Risk Factors
Single-Blind Method
Stroke Volume*
Tetrazoles / adverse effects
Tetrazoles / therapeutic use*
Time Factors
Treatment Outcome
Valsartan
Ventricular Function, Left*

Substances

Aminobutyrates
Angiotensin Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Biomarkers
Biphenyl Compounds
Blood Glucose
Drug Combinations
Glycated Hemoglobin A
Tetrazoles
hemoglobin A1c protein, human
Enalapril
Valsartan
sacubitril and valsartan sodium hydrate drug combination

Associated data

ClinicalTrials.gov/NCT01035255

Grants and funding

R01 HL123478/HL/NHLBI NIH HHS/United States