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1. Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis

Author

Agodoa, L, Algra, A, Asselbergs, F W, Beckett, N, Berge, E, Black, H, Brouwers, F P J, Brown, M, Bulpitt, C J, Byington, B, Cutler, J, Devereaux, R B, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S E, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L H, Lueders, S, MacMahon, S, Mancia, G, Matsuzaki, M, Mehlum, M H, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Poulter, N R, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J A, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W H, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z Y, Anderson, C, Baigent, C, Brenner, BM, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Pitt, B, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundström, J, Turnbull, F, Viberti, G, Wang, J, Nazarzadeh, Milad, Bidel, Zeinab, Canoy, Dexter, Copland, Emma, Bennett, Derrick A, Dehghan, Abbas, Davey Smith, George, Holman, Rury R, Woodward, Mark, Gupta, Ajay, Adler, Amanda I, Wamil, Malgorzata, Sattar, Naveed, Cushman, William C, McManus, Richard J, Teo, Koon, Davis, Barry R, Chalmers, John, Pepine, Carl J, and Rahimi, Kazem

Published
2022
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2. Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis

Author

Adler, A, Agodoa, L, Algra, A, Asselbergs, F W, Beckett, N, Berge, E, Black, H, Brouwers, F P J, Brown, M, Bulpitt, C J, Byington, B, Chalmers, J, Cushman, W C, Cutler, J, Davis, B R, Devereaux, R B, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A K, Holman, R R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S E, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L H, Lueders, S, MacMahon, S, Mancia, G, Matsuzaki, M, Mehlum, M H, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pepine, C J, Pfeffer, M, Poulter, N R, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J A, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W H, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z Y, Anderson, C, Baigent, C, Brenner, BM, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Pitt, B, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundström, J, Turnbull, F, Viberti, G, Wang, J, Copland, Emma, Canoy, Dexter, Nazarzadeh, Milad, Bidel, Zeinab, Ramakrishnan, Rema, Woodward, Mark, Chalmers, John, Teo, Koon K, Pepine, Carl J, Davis, Barry R, Kjeldsen, Sverre, Sundström, Johan, and Rahimi, Kazem

Published
2021
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3. Clinical Utility of Short-Term Blood Pressure Measures to Inform Long-Term Blood Pressure Management

Author

Wang, N, Harris, K, Woodward, M, Harrap, S, Mancia, G, Poulter, N, Chalmers, J, Rodgers, A, Wang N., Harris K., Woodward M., Harrap S., Mancia G., Poulter N., Chalmers J., Rodgers A., Wang, N, Harris, K, Woodward, M, Harrap, S, Mancia, G, Poulter, N, Chalmers, J, Rodgers, A, Wang N., Harris K., Woodward M., Harrap S., Mancia G., Poulter N., Chalmers J., and Rodgers A.

Abstract

Background: Decisions about hypertension management are substantially influenced by blood pressure (BP) levels measured before and soon after starting BP lowering drugs. We aimed to assess the utility of short-term BP changes in individuals in terms of long-term treatment response. Methods: Post hoc analyses of 2 randomized trials with 4-to-6 weeks active run-in for all participants, followed by randomization to active BP lowering treatment (combination perindopril±indapamide) or placebo. We categorized individuals by degree of systolic BP (SBP) change during active run-in treatment and assessed associations with subsequent postrandomization placebo-corrected BP reduction, cardiovascular events, and tolerability. We included individuals with baseline BP ≥140/90 mm Hg from the PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study; 4275 individuals with cerebrovascular disease) and ADVANCE trial (The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; 6610 individuals with diabetes). Results: During the active run-in period, the proportion of participants with initial SBP changes in 4 categories (SBP increase, 0-9.9 mm Hg decrease, 10-19.9 mm Hg decrease, and ≥20 mm Hg decrease) were 17%, 27%, 28%, and 28% in PROGRESS and 21%, 22%, 24%, and 33% in ADVANCE. Randomization to active therapy achieved similar placebo-corrected long-term BP reductions across the 4 initial SBP change groups in both trials (P-values for heterogeneity >0.1). There was no significant difference in achieving BP <140/90 mm Hg at follow-up, major cardiovascular events, nor treatment tolerability according to the SBP change during active run-in period (all P-values >0.1). Conclusions: An individual's apparent BP change immediately after commencing therapy has limited clinical utility. Therefore, more emphasis should be given to use of evidence-based regimens and measures over the long-term to ensure sustained BP control. Registration: U

Published
2023

5. Estimated GFR and the Effect of Intensive Blood Pressure Lowering After Acute Intracerebral Hemorrhage

Author

Anderson, C.S., Chalmers, J., Arima, H., Davis, S., Heeley, E., Huang, Y., Lavados, P., Neal, B., Parsons, M.W., Lindley, R., Morgenstern, L., Robinson, T., Stapf, C., Tzourio, C., Wang, J.G., Chen, S., Chen, X.Y., Cui, L., Liu, Z., Lu, C., Wang, J., Wu, S., Xu, E., Yang, Q., Zhang, C., Zhang, J., Beer, R., Schmutzhard, E., Redondo, P., Kaste, M., Soinne, L., Tatlisumak, T., Wartenberg, K., Ricci, S., Klijn, K., Azevedo, E., Chamorro, A., Arnold, M., Fischer, U., Kaul, S., Pandian, J., Boyini, H., Singh, S., Rabinstein, A.A., Estol, C., Silva, G., Olavarria, V.V., Robinson, T.G., Simes, R.J., Bousser, M.-G., Hankey, G., Jamrozik, K., Johnston, S.C., Li, S., Bailey, K., Cheung, T., Delcourt, C., Chintapatla, S., Ducasse, E., Erho, T., Hata, J., Holder, B., Knight, E., Leroux, M., Sassé, T., Odgers, E., Walsh, R., Wolfowicz, Z., Chen, G., Fuentes, S., Peng, B., Schneble, H.-M., Wang, M.-X., Billot, L., Heritier, S., Li, Q., Woodward, M., Abimbola, S., Anderson, S., Chan, E., Cheng, G., Chmielnik, P., Leighton, S., Liu, J.-Y., Rasmussen, B., Saxena, A., Tripathy, S., Armenis, M., Baig, M.A., Naidu, B., Starzec, G., Steley, S., Moles, A., Ruiz, A., Zimmermann, M., Marinho, J., Alves, S., Angelim, R., Araujo, J., Kawakami, L., Bustos, C., Gonzalez, F., Munoz Venturelli, P., Chen, X., Jia, R., Li, N., Qu, S., Shu, Y., Song, A., Sun, J., Xiao, J., Zhao, Y., Huang, Q., Vicaut, E., Chamam, A., Viaud, M.-C., Dert, C., Fiedler, U., Jovis, V., Kabla, S., Marchand, S., Pena, A., Rochaud, V., Mallikarjuna, K., Hasan, N., Berge, E., Sandset, E.C., Forårsveen, A.S., Richardson, D., Kumar, T., Lewin, S., Poulter, N., Field, J., Anjum, A., Wilson, A., Perelmuter, H., Agarie, A.M., Barboza, A.G., Recchia, L.A., Miranda, I.F., Rauek, S.G., Duplessis, R.J., Dewey, H., Walker, L., Petrolo, S., Bladin, C., Sturm, J., Crimmins, D., Griffiths, D., Schutz, A., Zenteno, V., Miteff, F., Spratt, N., Kerr, E., Levi, C.R., Phan, T.G., Ma, H., Sanders, L., Moran, C., Wong, K., Read, S., Henderson, R., Wong, A., Hull, R., Skinner, G., Hand, P., Yan, B., Tu, H., Campbell, B., Blacker, D.J., Wijeratne, T., Pathirage, M., Jasinararchchi, M., Matkovic, Z., Celestino, S., Gruber, F., Vosko, M.R., Diabl, E., Rathmaier, S., Pfausler, B., Helbok, R., Fazekas, F., Fischer, R., Poltrum, B., Zechner, B., Trummer, U., Rutgers, M.P., Peeters, A., Dusart, A., Duray, M.-C., Parmentier, C., Ferrao-Santos, S., Brouns, R., De Raedt, S., De Smedt, A., VanHooff, R.-J., De Keyser, J., Martins, S.C.O., de Almeida, A.G., Broudani, R., Titton, N.F., de Freitas, G.R., Cardoso, F.M., Giesel, L.M., Lima, N.A., Jr, Ferraz de Almeida, A.C., Gomes, R.B., Borges dos Santos, T.S., Veloso Soares, E.M., Neto, O.L.A., Silva, G.S., Gomes, D.L., de Carvalho, F.A., Miranda, M., Marques, A., Zétola, V.F., de Matia, G., Lange, M.C., Montes, J., Reccius, A., Soto, A., Rivas, R., Klapp, C., Illanes, S., Aguilera, C., Castro, A., Figueroa, C., Benavides, J., Salamanca, P., Concha, M.C., Pajarito, J., Araya, P., Guerra, F., Li, Y., Liu, G., Wang, B., Chong, Y., He, M., Wang, L., Liu, J., Zhang, X., Lai, C., Jiang, H., Cui, S., Tao, Q., Zhang, Y., Yao, S., Xu, M., Xiao, H., Hu, J., Tang, J., Ji, H., Jiang, M., Yu, F., Yang, X., Guo, X., Wang, Y., Wu, L., Gao, Y., Sun, D., Huang, X., Liu, L., Li, P., Jiang, Y., Li, H., Lu, H., Zhou, J., Yuan, C., Qi, X., Qiu, F., Qian, H., Wang, W., Sun, W., Li, F., Liu, R., Peng, Q., Ren, Z., Fan, C., Wang, H., Wang, T., Shi, F., Duan, C., Chen, Z., Tan, X., Zhao, Z., Chen, J., Han, T., Zhang, L., Hu, Q., Hou, Q., Zhao, X., Zeng, G., Ma, L., Wang, F., Zeng, L., Guo, Z., Fu, Y., Song, Y., Tai, L., Liu, X., Su, X., Yang, Y., Dong, R., Xu, Y., Tian, S., Cheng, S., Su, L., Xie, X., Xu, T., Geng, D., Yan, X., Fan, H., Zhao, N., Wang, S., Yang, J., Yan, M., Li, L., Li, Z., Xu, X., Lian, Y., Sun, H., Liu, D., Wang, N., Tang, Q., Han, Z., Feng, L., Cui, Y., Tian, J., Chang, H., Sun, X., Liu, C., Wen, Z., Lin, Q., Sun, L., Hu, B., Zou, M., Bao, Q., Lin, X., Zhao, L., Tian, X., Wang, X., Li, X., Hao, L., Duan, Y., Wang, R., Wei, Z., Ren, S., Ren, H., Dong, Y., Cheng, Y., Liu, W., Han, J., Zhang, Z., Zhu, J., Qian, J., Sun, Y., Liu, K., Long, F., Peng, X., Zhang, Q., Yuan, Z., Wang, C., Huang, M., He, P., You, Y., Xia, J., Zhou, L., Hou, Y., Qi, Y., Mei, L., Lu, R., Ping, L., Zhou, S., Zhang, S., Zou, R., Guo, J., Li, M., Wei, W., Curtze, S., Saarela, M., Strbian, D., Scheperjans, F., De Broucker, T., Henry, C., Cumurciuc, R., Ibos-Augé, N., Zéghoudi, A.-C., Pico, F., Dereeper, O., Simian, M.-C., Boisselier, C., Mahfoud, A., Timsit, S., Merrien, F.M., Guillon, B., Sevin, M., Herisson, F., Magne, C., Ameri, A., Cret, C., Stefanizzi, S., Klapzcynski, F., Denier, C., Sarov-Riviere, M., Reiner, P., Mawet, J., Hervé, D., Buffon, F., Touzé, E., Domigo, V., Lamy, C., Calvet, D., Pasquini, M., Alamowitch, S., Favrole, P., Muresan, I.-P., Crozier, S., Rosso, C., Pires, C., Leger, A., Deltour, S., Cordonnier, C., Henon, H., Rossi, C., Zuber, M., Bruandet, M., Tamazyan, R., Join-Lambert, C., Juettler, E., Krause, T., Maul, S., Endres, M., Jungehulsing, G.J., Hennerici, M., Griebe, M., Sauer, T., Knoll, K., Huber, R., Knauer, K., Knauer, C., Raubold, S., Schneider, H., Hentschel, H., Lautenschläger, C., Schimmel, E., Dzialowski, I., Foerch, C., Lorenz, M., Singer, O., Meyer dos Santos, I.M.R., Hartmann, A., Hamann, A., Schacht, A., Schrader, B., Teíchmann, A., Wartenberg, K.E., Mueller, T.J., Jander, S., Gliem, M., Boettcher, C., Rosenkranz, M., Beck, C., Otto, D., Thomalla, G., Cheng, B., Wong, K.S., Leung, T.W., Soo, Y.O.Y., Prabhakar, S., Kesavarapu, S.R., Gajjela, P.K., Chenna, R.R., Ummer, K., Basheer, M., Andipet, A., Jagarlapudi, M.K.M., Mohammed, A.U.R., Pawar, V.G., Eranki, S.S.K., Singh, Y., Akhtar, N., Borah, N.C., Ghose, M., Choudhury, N., Ichaporia, N.R., Shendge, J., Khese, S., Pamidimukkala, V., Inbamuthaiah, P., Nuthakki, S.R., Tagallamudi, N.M.R., Gutti, A.K., Khurana, D., Kesavarapu, P., Jogi, V., Garg, A., Samanta, D., Sarma, G.R.K., Nadig, R., Mathew, T., Anandan, M.A., Caterbi, E., Zini, A., Cavazzuti, M., Casoni, F., Pentore, R., Falzone, F., Mazzoli, T., Greco, L.M., Menichetti, C., Coppola, F., Cenciarelli, S., Gallinella, E., Mattioni, A., Condurso, R., Sicilia, I., Zampolini, M., Corea, F., Barbi, M., Proietti, C., Toni, D., Pieroni, A., Anzini, A., Falcou, A., Demichele, M., Klijn, C.J.M., Tveiten, A., Thortveit, E.T., Pettersen, S., Holand, N., Hitland, B., Johnsen, S.H., Eltoft, A., Wasay, M., Kamal, A., Iqrar, A., Ali, L., Begum, D., Gama, G., Fonseca, L., Moreira, G., Veloso, L.M., Pinheiro, D., Paredes, L., Rozeira, C., Gregorio, T., Segura Martin, T., Ayo, O., Garcia-Garcia, J., Feria Vilar, I., Gómez Fernández, I., Amaro, S., Urra, X., Obach, V., Cervera, A., Silva, Y., Serena, J., Castellanos, M., Terceno, M., Van Eendenburg, C., Weck, A., Findling, O., Lüdi, R., Warburton, E.A., Day, D., Butler, N., Bumanlag, E., Caine, S., Steele, A., Osborn, M., Dodd, E., Murphy, P., Esisi, B., Brown, E., Hayman, R., Baliga, V.K.V., Minphone, M., Kennedy, J., Reckless, I., Pope, G., Teal, R., Michael, K., Manawadu, D., Kalra, L., Lewis, R., Mistry, B., Cattermole, E., Hassan, A., Mandizvidza, L., Bamford, J., Brooks, H., Bedford, C., Whiting, R., Baines, P., Hussain, M., Harvey, M., Fotherby, K., McBride, S., Bourke, P., Morgan, D., Jennings-Preece, K., Price, C., Huntley, S., Riddell, V.E., Storey, G., Lakey, R.L., Subramanian, G., Jenkinson, D., Kwan, J., David, O., Tiwari, D., James, M., Keenan, S., Eastwood, H., Shaw, L., Kaye, P., Button, D., Madigan, B., Williamson, D., Dixit, A., Davis, J., Hossain, M.O., Ford, G.A., Parry-Jones, A., O'Loughlin, V., Jarapa, R., Naing, Z., Lovelock, C., O'Reilly, J., Khan, U., Bhalla, A., Rudd, A., Birns, J., Werring, D.J., Law, R., Perry, R., Jones, I., Erande, R., Roffe, C., Natarajan, I., Ahmad, N., Finney, K., Lucas, J., Mistri, A., Eveson, D., Marsh, R., Haunton, V., Fugate, J.E., Lepore, S.W., Zheng, Danni, Sato, Shoichiro, Arima, Hisatomi, Heeley, Emma, Delcourt, Candice, Cao, Yongjun, Chalmers, John, and Anderson, Craig S.

Published
2016
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6. Cumulative Systolic Blood Pressure Load and Cardiovascular Risk in Patients With Diabetes

Author

Wang, N, Harris, K, Hamet, P, Harrap, S, Mancia, G, Poulter, N, Williams, B, Zoungas, S, Woodward, M, Chalmers, J, Rodgers, A, Wang N., Harris K., Hamet P., Harrap S., Mancia G., Poulter N., Williams B., Zoungas S., Woodward M., Chalmers J., Rodgers A., Wang, N, Harris, K, Hamet, P, Harrap, S, Mancia, G, Poulter, N, Williams, B, Zoungas, S, Woodward, M, Chalmers, J, Rodgers, A, Wang N., Harris K., Hamet P., Harrap S., Mancia G., Poulter N., Williams B., Zoungas S., Woodward M., Chalmers J., and Rodgers A.

Abstract

Background: Standard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time. Objectives: The purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes. Methods: A post hoc analysis of patients with type 2 diabetes followed by the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - Observational Study). Cumulative SBP load was defined as the area under curve for SBP values ≥130 mm Hg divided by the area under curve for all measured SBP values over a 24-month exposure period. HRs for the association between cumulative SBP load with major cardiovascular events and death were estimated using Cox models. Results: Over a median 7.6 years of follow-up, 1,469 major cardiovascular events, 1,615 deaths, and 660 cardiovascular deaths were observed in 9,338 participants. Each 1-SD increase in cumulative SBP load was associated with a 14% increase in major cardiovascular events (HR: 1.14; 95% CI: 1.09-1.20), 13% increase in all-cause mortality (HR: 1.13; 95% CI: 1.13-1.18), and 21% increase in cardiovascular death (HR: 1.21; 95% CI: 1.13-1.29). For the prediction of cardiovascular events and death, cumulative SBP load outperformed mean SBP, time-below-target SBP, and visit-to-visit SBP variability in terms of Akaike information criterion and net reclassification indexes. Conclusions: Cumulative SBP load may provide better prediction of major cardiovascular events compared with traditional BP measures among patients with type 2 diabetes. These findings reinforce the importance of both the magnitude and duration of exposure to elevated SBP in assessing cardiovascular risk. (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study [ADVANCE-ON]; NCT00949286)

Published
2022

7. Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension

Author

Stergiou, G, Brunstrom, M, Macdonald, T, Kyriakoulis, K, Bursztyn, M, Khan, N, Bakris, G, Kollias, A, Menti, A, Muntner, P, Orias, M, Poulter, N, Shimbo, D, Williams, B, Adeoye, A, Damasceno, A, Korostovtseva, L, Li, Y, Muxfeldt, E, Zhang, Y, Mancia, G, Kreutz, R, Tomaszewski, M, Stergiou G., Brunstrom M., MacDonald T., Kyriakoulis K. G., Bursztyn M., Khan N., Bakris G., Kollias A., Menti A., Muntner P., Orias M., Poulter N., Shimbo D., Williams B., Adeoye A. M., Damasceno A., Korostovtseva L., Li Y., Muxfeldt E., Zhang Y., Mancia G., Kreutz R., Tomaszewski M., Stergiou, G, Brunstrom, M, Macdonald, T, Kyriakoulis, K, Bursztyn, M, Khan, N, Bakris, G, Kollias, A, Menti, A, Muntner, P, Orias, M, Poulter, N, Shimbo, D, Williams, B, Adeoye, A, Damasceno, A, Korostovtseva, L, Li, Y, Muxfeldt, E, Zhang, Y, Mancia, G, Kreutz, R, Tomaszewski, M, Stergiou G., Brunstrom M., MacDonald T., Kyriakoulis K. G., Bursztyn M., Khan N., Bakris G., Kollias A., Menti A., Muntner P., Orias M., Poulter N., Shimbo D., Williams B., Adeoye A. M., Damasceno A., Korostovtseva L., Li Y., Muxfeldt E., Zhang Y., Mancia G., Kreutz R., and Tomaszewski M.

Abstract

Antihypertensive drug therapy is one of the most efficient medical interventions for preventing disability and death globally. Most of the evidence supporting its benefits has been derived from outcome trials with morning dosing of medications. Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping blood pressure (BP) profile and morning BP surge, with increased incidence of cardiovascular events during the first few morning hours. These observations provide justification for complete 24-h BP control as being the primary goal of antihypertensive treatment. Bedtime administration of antihypertensive drugs has also been proposed as a potentially more effective treatment strategy than morning administration. This Position Paper by the International Society of Hypertension reviewed the published evidence on the clinical relevance of the diurnal variation in BP and the timing of antihypertensive drug treatment, aiming to provide consensus recommendations for clinical practice. Eight published outcome hypertension studies involved bedtime dosing of antihypertensive drugs, and all had major methodological and/or other flaws and a high risk of bias in testing the impact of bedtime compared to morning treatment. Three ongoing, well designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing. Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose.

Published
2022

8. Effects of glucose and blood pressure reduction on subclinical cardiac damage: Results from ADVANCE

Author

Juraschek, S, Wang, D, Mcevoy, J, Harrap, S, Harris, K, Mancia, G, Marre, M, Neal, B, Patel, A, Poulter, N, Williams, B, Chalmers, J, Woodward, M, Selvin, E, Juraschek S. P., Wang D., McEvoy J. W., Harrap S., Harris K., Mancia G., Marre M., Neal B., Patel A., Poulter N. R., Williams B., Chalmers J., Woodward M., Selvin E., Juraschek, S, Wang, D, Mcevoy, J, Harrap, S, Harris, K, Mancia, G, Marre, M, Neal, B, Patel, A, Poulter, N, Williams, B, Chalmers, J, Woodward, M, Selvin, E, Juraschek S. P., Wang D., McEvoy J. W., Harrap S., Harris K., Mancia G., Marre M., Neal B., Patel A., Poulter N. R., Williams B., Chalmers J., Woodward M., and Selvin E.

Abstract

Objective: Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial. Methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Research Controlled Evaluation (ADVANCE) study was a factorial, randomized trial designed to test the effects of intensive blood glucose (hemoglobin A1c ≤6.5% versus usual care) and intensive BP (combination of perindopril-indapamide versus placebo) control on vascular events in adults with diabetes. Using mixed effects tobit models, we determined the effect of the randomized interventions on change in subclinical cardiac injury (high sensitivity cardiac troponin T [hs-cTnT]) and strain (N-terminal b-type pro natriuretic peptide [NT-proBNP]), 1 year after randomization. Results: Among the 682 participants, mean age was 66.1 (SD, 6.5) years; 40% were women. Mean baseline hemoglobin A1c was 7.4% (SD, 1.5) and systolic/diastolic BP was 147 (SD,21)/81 (SD,11) mmHg. After 1 year, intensive versus standard glucose control did not significantly change hs-cTnT (1.5%; 95%CI:-4.9,8.2) or NT-proBNP (−10.3%; 95%CI: −20.2%,0.9%). Intensive versus standard BP control also did not affect hs-cTnT (−2.9%; 95%CI: −8.9,3.6), but did significantly lower NT-proBNP by 21.6% (95%CI:-30.2%,-11.9%). Changes in systolic BP at 1 year (versus baseline) were strongly associated with NT-proBNP (P = 0.004), but not hs-cTnT (P = 0.95). Conclusions: In adults with diabetes, intensive BP control reduced NT-proBNP without increasing hs-cTnT, supporting the benefits and safety of intensive BP control in adults with diabetes. This trial is registered at clinicaltrials.gov, number: NCT00145925.

Published
2022

12. The comparative effects of intensive glucose lowering in diabetes patients aged below or above 65 years: Results from the ADVANCE trial

Author

Ohkuma, T, Chalmers, J, Cooper, M, Hamet, P, Harrap, S, Marre, M, Mancia, G, Poulter, N, Woodward, M, Ohkuma T., Chalmers J., Cooper M., Hamet P., Harrap S., Marre M., Mancia G., Poulter N., Woodward M., Ohkuma, T, Chalmers, J, Cooper, M, Hamet, P, Harrap, S, Marre, M, Mancia, G, Poulter, N, Woodward, M, Ohkuma T., Chalmers J., Cooper M., Hamet P., Harrap S., Marre M., Mancia G., Poulter N., and Woodward M.

Abstract

Aims: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (<65 and ≥ 65 years), and examine whether the effects differ according to patients’ characteristics in the older patient group. Materials and Methods: The effects of intensive glucose lowering (to a target glycated haemoglobin [HbA1c] concentration of ≤48 mmol/mol [6.5%]) on major clinical outcomes were evaluated by Cox regression models according to subgroups defined by baseline age of <65 or ≥ 65 years in the ADVANCE trial (n = 11 140). Results: Over a median follow-up of 5 years, intensive glucose lowering significantly decreased the risk of the composite of major macrovascular and microvascular events (hazard ratio 0.90, 95% confidence interval 0.82-0.98), with no heterogeneity in the effects across age subgroups (p for heterogeneity = 0.44). Relative effects on all-cause death, cardiovascular death, and components of major vascular events were also similar (P for heterogeneity ≥0.06), except for severe hypoglycaemia, which was of greater risk for patients aged <65 years. Absolute benefits and harms were broadly consistent across subgroups. Among patients aged ≥65 years, randomized treatment effects did not differ significantly across different levels of cognitive function or coexisting chronic illnesses. Conclusions: Our results suggest that an intensive glycaemic control strategy to reduce HbA1c to 48 mmol/mol (6.5%) provided broadly similar benefits and harms and may be recommended for older, as well as younger, patients.

Published
2021

13. History of lower-limb complications and risk of cancer death in people with type 2 diabetes

Author

Mohammedi, K, Harrap, S, Mancia, G, Marre, M, Poulter, N, Chalmers, J, Woodward, M, Mohammedi K., Harrap S., Mancia G., Marre M., Poulter N., Chalmers J., Woodward M., Mohammedi, K, Harrap, S, Mancia, G, Marre, M, Poulter, N, Chalmers, J, Woodward, M, Mohammedi K., Harrap S., Mancia G., Marre M., Poulter N., Chalmers J., and Woodward M.

Abstract

Background: Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes. Methods: We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models. Results: Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th–75th percentile, 4.7–5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3–6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21–1.94), p = 0.0004], PAD [1.32 (1.02–1.70), p = 0.03] or neuropathy (1.41 (1.11–1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers. Conclusions: PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 dia

Published
2021

14. Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control

Author

Tremblay, J, Haloui, M, Attaoua, R, Tahir, R, Hishmih, C, Harvey, F, Marois-Blanchet, F, Long, C, Simon, P, Santucci, L, Hizel, C, Chalmers, J, Marre, M, Harrap, S, Cifkova, R, Krajcoviechova, A, Matthews, D, Williams, B, Poulter, N, Zoungas, S, Colagiuri, S, Mancia, G, Grobbee, D, Rodgers, A, Liu, L, Agbessi, M, Bruat, V, Fave, M, Harwood, M, Awadalla, P, Woodward, M, Hussin, J, Hamet, P, Tremblay J., Haloui M., Attaoua R., Tahir R., Hishmih C., Harvey F., Marois-Blanchet F. -C., Long C., Simon P., Santucci L., Hizel C., Chalmers J., Marre M., Harrap S., Cifkova R., Krajcoviechova A., Matthews D. R., Williams B., Poulter N., Zoungas S., Colagiuri S., Mancia G., Grobbee D. E., Rodgers A., Liu L., Agbessi M., Bruat V., Fave M. -J., Harwood M. P., Awadalla P., Woodward M., Hussin J. G., Hamet P., Tremblay, J, Haloui, M, Attaoua, R, Tahir, R, Hishmih, C, Harvey, F, Marois-Blanchet, F, Long, C, Simon, P, Santucci, L, Hizel, C, Chalmers, J, Marre, M, Harrap, S, Cifkova, R, Krajcoviechova, A, Matthews, D, Williams, B, Poulter, N, Zoungas, S, Colagiuri, S, Mancia, G, Grobbee, D, Rodgers, A, Liu, L, Agbessi, M, Bruat, V, Fave, M, Harwood, M, Awadalla, P, Woodward, M, Hussin, J, Hamet, P, Tremblay J., Haloui M., Attaoua R., Tahir R., Hishmih C., Harvey F., Marois-Blanchet F. -C., Long C., Simon P., Santucci L., Hizel C., Chalmers J., Marre M., Harrap S., Cifkova R., Krajcoviechova A., Matthews D. R., Williams B., Poulter N., Zoungas S., Colagiuri S., Mancia G., Grobbee D. E., Rodgers A., Liu L., Agbessi M., Bruat V., Fave M. -J., Harwood M. P., Awadalla P., Woodward M., Hussin J. G., and Hamet P.

Abstract

Aims/hypothesis: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. Methods: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study. Results: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10−21 and p = 9.6 × 10−31, respectively) and a 4.4-fold (p = 6.8 × 10−33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. Conclusions/interpretation: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy. Graphical abstract: [Figure not available: see fulltext.]

Published
2021

15. Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis

Author

Rahimi, K, Bidel, Z, Nazarzadeh, M, Copland, E, Canoy, D, Wamil, M, Majert, J, Mcmanus, R, Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Boersma, E, Brouwers, F, Brown, M, Brugts, J, Bulpitt, C, Byington, R, Cushman, W, Cutler, J, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Chalmers, J, Davis, B, Pepine, C, Teo, K, Rahimi K., Bidel Z., Nazarzadeh M., Copland E., Canoy D., Wamil M., Majert J., McManus R., Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Boersma E., Brouwers F. P. J., Brown M., Brugts J. J., Bulpitt C. J., Byington R. P., Cushman W. C., Cutler J., Devereaux R. B., Dwyer J. P., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., Wang J., Chalmers J., Davis B. R., Pepine C. J., Teo K. K., Rahimi, K, Bidel, Z, Nazarzadeh, M, Copland, E, Canoy, D, Wamil, M, Majert, J, Mcmanus, R, Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Boersma, E, Brouwers, F, Brown, M, Brugts, J, Bulpitt, C, Byington, R, Cushman, W, Cutler, J, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Chalmers, J, Davis, B, Pepine, C, Teo, K, Rahimi K., Bidel Z., Nazarzadeh M., Copland E., Canoy D., Wamil M., Majert J., McManus R., Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Boersma E., Brouwers F. P. J., Brown M., Brugts J. J., Bulpitt C. J., Byington R. P., Cushman W. C., Cutler J., Devereaux R. B., Dwyer J. P., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., Wang J., Chalmers J., Davis B. R., Pepine C. J., and Teo K. K.

Abstract

Background: The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods: We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (<55 years, 55–64 years, 65–74 years, 75–84 years, and ≥85 years) and blood pressure categories (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg systolic blood pressure and from <70 mm Hg to ≥110 mm Hg diastolic). We used a fixed effects one-stage approach and applied Cox proportional hazard models, stratified by trial, to analyse the data. The primary outcome was defined as either a composite of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring hospital admission. Findings: We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg

Published
2021

16. The impact of frailty on the effectiveness and safety of intensive glucose control and blood pressure-lowering therapy for people with type 2 diabetes: Results from the ADVANCE trial

Author

Nguyen, T, Harris, K, Woodward, M, Chalmers, J, Cooper, M, Hamet, P, Harrap, S, Heller, S, Macmahon, S, Mancia, G, Marre, M, Poulter, N, Rogers, A, Williams, B, Zoungas, S, Chow, C, Lindley, R, Nguyen T. N., Harris K., Woodward M., Chalmers J., Cooper M., Hamet P., Harrap S., Heller S., MacMahon S., Mancia G., Marre M., Poulter N., Rogers A., Williams B., Zoungas S., Chow C. K., Lindley R. I., Nguyen, T, Harris, K, Woodward, M, Chalmers, J, Cooper, M, Hamet, P, Harrap, S, Heller, S, Macmahon, S, Mancia, G, Marre, M, Poulter, N, Rogers, A, Williams, B, Zoungas, S, Chow, C, Lindley, R, Nguyen T. N., Harris K., Woodward M., Chalmers J., Cooper M., Hamet P., Harrap S., Heller S., MacMahon S., Mancia G., Marre M., Poulter N., Rogers A., Williams B., Zoungas S., Chow C. K., and Lindley R. I.

Abstract

OBJECTIVE To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

Published
2021

17. Combination blood pressure lowering in the presence or absence of background statin and aspirin therapy: a combined analysis of PROGRESS and ADVANCE Trials

Author

Wang, N, Harris, K, Chalmers, J, Harrap, S, Mancia, G, Marre, M, Poulter, N, Tzourio, C, Williams, B, Zoungas, S, Woodward, M, Rodgers, A, Wang N., Harris K., Chalmers J., Harrap S., Mancia G., Marre M., Poulter N., Tzourio C., Williams B., Zoungas S., Woodward M., Rodgers A., Wang, N, Harris, K, Chalmers, J, Harrap, S, Mancia, G, Marre, M, Poulter, N, Tzourio, C, Williams, B, Zoungas, S, Woodward, M, Rodgers, A, Wang N., Harris K., Chalmers J., Harrap S., Mancia G., Marre M., Poulter N., Tzourio C., Williams B., Zoungas S., Woodward M., and Rodgers A.

Abstract

Objectives:To assess the effects of combination BP lowering on cardiovascular events and mortality in the presence of aspirin and/or statin therapy in a combined analysis of the ADVANCE and PROGRESS trials.Methods:We conducted an analysis of 14 682 participants allocated combination therapy with perindopril and indapamide or placebo followed up for a mean of 4.2 years. Participants were stratified into four groups defined by background use of medications at baseline: statin, aspirin, both or neither. Linear mixed effect models were used to assess differences in BP and Cox proportional hazard models were used to estimate the risks of major cardiovascular events, all-cause mortality and treatment discontinuation.Results:At baseline, 14% of patients were on both aspirin and statin, 35% on aspirin, 9% on statins and 42% on neither aspirin/statins. Compared with placebo, combination BP therapy reduced mean SBP by 5.7 mmHg in ADVANCE and 12.1 mmHg in PROGRESS, with no difference (P > 0.447) between patients by baseline use of aspirin/statin. Combination BP therapy reduced the risk of major cardiovascular events (hazard ratio 0.78, 95% CI 0.71-0.86), with no significant difference (P = 0.600) between aspirin/statin subgroups. Rates of treatment discontinuation were similar with combination BP therapy compared with placebo (18.4 versus 18%), with no evidence of difference across the subgroups (P = 0.340). Conclusion:BP lowering with perindopril and indapamide reduces the risk of major cardiovascular events independent of baseline use of aspirin and/or statins.

Published
2021

18. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis

Author

Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Brouwers, F, Brown, M, Bulpitt, C, Byington, R, Chalmers, J, Cushman, W, Cutler, J, Davis, B, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pepine, C, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Brouwers F. P. J., Brown M., Bulpitt C. J., Byington R. P., Chalmers J., Cushman W. C., Cutler J., Davis B. R., Devereaux R. B., Dwyer J., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pepine C. J., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., Wang J., Adler, A, Agodoa, L, Algra, A, Asselbergs, F, Beckett, N, Berge, E, Black, H, Brouwers, F, Brown, M, Bulpitt, C, Byington, R, Chalmers, J, Cushman, W, Cutler, J, Davis, B, Devereaux, R, Dwyer, J, Estacio, R, Fagard, R, Fox, K, Fukui, T, Gupta, A, Holman, R, Imai, Y, Ishii, M, Julius, S, Kanno, Y, Kjeldsen, S, Kostis, J, Kuramoto, K, Lanke, J, Lewis, E, Lewis, J, Lievre, M, Lindholm, L, Lueders, S, Macmahon, S, Mancia, G, Matsuzaki, M, Mehlum, M, Nissen, S, Ogawa, H, Ogihara, T, Ohkubo, T, Palmer, C, Patel, A, Pepine, C, Pfeffer, M, Pitt, B, Poulter, N, Rakugi, H, Reboldi, G, Reid, C, Remuzzi, G, Ruggenenti, P, Saruta, T, Schrader, J, Schrier, R, Sever, P, Sleight, P, Staessen, J, Suzuki, H, Thijs, L, Ueshima, K, Umemoto, S, van Gilst, W, Verdecchia, P, Wachtell, K, Whelton, P, Wing, L, Woodward, M, Yui, Y, Yusuf, S, Zanchetti, A, Zhang, Z, Anderson, C, Baigent, C, Brenner, B, Collins, R, de Zeeuw, D, Lubsen, J, Malacco, E, Neal, B, Perkovic, V, Rodgers, A, Rothwell, P, Salimi-Khorshidi, G, Sundstrom, J, Turnbull, F, Viberti, G, Wang, J, Adler A., Agodoa L., Algra A., Asselbergs F. W., Beckett N. S., Berge E., Black H., Brouwers F. P. J., Brown M., Bulpitt C. J., Byington R. P., Chalmers J., Cushman W. C., Cutler J., Davis B. R., Devereaux R. B., Dwyer J., Estacio R., Fagard R., Fox K., Fukui T., Gupta A. K., Holman R. R., Imai Y., Ishii M., Julius S., Kanno Y., Kjeldsen S. E., Kostis J., Kuramoto K., Lanke J., Lewis E., Lewis J. B., Lievre M., Lindholm L. H., Lueders S., MacMahon S., Mancia G., Matsuzaki M., Mehlum M. H., Nissen S., Ogawa H., Ogihara T., Ohkubo T., Palmer C. R., Patel A., Pepine C. J., Pfeffer M. A., Pitt B., Poulter N. R., Rakugi H., Reboldi G., Reid C., Remuzzi G., Ruggenenti P., Saruta T., Schrader J., Schrier R., Sever P., Sleight P., Staessen J. A., Suzuki H., Thijs L., Ueshima K., Umemoto S., van Gilst W. H., Verdecchia P., Wachtell K., Whelton P., Wing L., Woodward M., Yui Y., Yusuf S., Zanchetti A., Zhang Z. -Y., Anderson C., Baigent C., Brenner B. M., Collins R., de Zeeuw D., Lubsen J., Malacco E., Neal B., Perkovic V., Rodgers A., Rothwell P., Salimi-Khorshidi G., Sundstrom J., Turnbull F., Viberti G., and Wang J.

Abstract

Background: The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods: We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from <120 to ≥170 mm Hg). The primary outcome was a major cardiovascular event (defined as a composite of fatal and non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital), analysed as per intention to treat. Findings: Data for 344 716 participants from 48 randomised clinical trials were available for this analysis. Pre-randomisation mean systolic/diastolic blood pressures were 146/84 mm Hg in participants with previous cardiovascular disease (n=157 728) and 157/8

Published
2021

19. Correction to: Polygenic risk scores predict diabetes complications and their response to intensive blood pressure and glucose control (Diabetologia, (2021), 64, 9, (2012-2025), 10.1007/s00125-021-05491-7)

Author

Tremblay J., Tremblay, J, Haloui, M, Attaoua, R, Tahir, R, Hishmih, C, Harvey, F, Marois-Blanchet, F, Long, C, Simon, P, Santucci, L, Hizel, C, Chalmers, J, Marre, M, Harrap, S, Cífková, R, Krajčoviechová, A, Matthews, D, Williams, B, Poulter, N, Zoungas, S, Colagiuri, S, Mancia, G, Grobbee, D, Rodgers, A, Liu, L, Agbessi, M, Bruat, V, Favé, M, Harwood, M, Awadalla, P, Woodward, M, Hussin, J, Hamet, P, Tremblay J., Haloui M., Attaoua R., Tahir R., Hishmih C., Harvey F., Marois-Blanchet F. C., Long C., Simon P., Santucci L., Hizel C., Chalmers J., Marre M., Harrap S., Cífková R., Krajčoviechová A., Matthews D. R., Williams B., Poulter N., Zoungas S., Colagiuri S., Mancia G., Grobbee D. E., Rodgers A., Liu L., Agbessi M., Bruat V., Favé M. J., Harwood M. P., Awadalla P., Woodward M., Hussin J. G., Hamet P., Tremblay J., Tremblay, J, Haloui, M, Attaoua, R, Tahir, R, Hishmih, C, Harvey, F, Marois-Blanchet, F, Long, C, Simon, P, Santucci, L, Hizel, C, Chalmers, J, Marre, M, Harrap, S, Cífková, R, Krajčoviechová, A, Matthews, D, Williams, B, Poulter, N, Zoungas, S, Colagiuri, S, Mancia, G, Grobbee, D, Rodgers, A, Liu, L, Agbessi, M, Bruat, V, Favé, M, Harwood, M, Awadalla, P, Woodward, M, Hussin, J, Hamet, P, Tremblay J., Haloui M., Attaoua R., Tahir R., Hishmih C., Harvey F., Marois-Blanchet F. C., Long C., Simon P., Santucci L., Hizel C., Chalmers J., Marre M., Harrap S., Cífková R., Krajčoviechová A., Matthews D. R., Williams B., Poulter N., Zoungas S., Colagiuri S., Mancia G., Grobbee D. E., Rodgers A., Liu L., Agbessi M., Bruat V., Favé M. J., Harwood M. P., Awadalla P., Woodward M., Hussin J. G., and Hamet P.

Published
2021

20. May Measurement Month 2019: An analysis of blood pressure screening results from Italy

Author

Torlasco, C, Faini, A, Pengo, M, Borghi, C, Grassi, G, Ferri, C, Muiesan, M, Salvetti, M, Sechi, L, Minuz, P, Mulatero, P, Pucci, G, Volpe, M, Carugo, S, Sarzani, R, Mule, G, Beaney, T, Poulter, N, Xia, X, Parati, G, Torlasco C., Faini A., Pengo M., Borghi C., Grassi G., Ferri C., Muiesan M. L., Salvetti M., Sechi L., Minuz P., Mulatero P., Pucci G., Volpe M., Carugo S., Sarzani R., Mule G., Beaney T., Poulter N. R., Xia X., Parati G., Torlasco, C, Faini, A, Pengo, M, Borghi, C, Grassi, G, Ferri, C, Muiesan, M, Salvetti, M, Sechi, L, Minuz, P, Mulatero, P, Pucci, G, Volpe, M, Carugo, S, Sarzani, R, Mule, G, Beaney, T, Poulter, N, Xia, X, Parati, G, Torlasco C., Faini A., Pengo M., Borghi C., Grassi G., Ferri C., Muiesan M. L., Salvetti M., Sechi L., Minuz P., Mulatero P., Pucci G., Volpe M., Carugo S., Sarzani R., Mule G., Beaney T., Poulter N. R., Xia X., and Parati G.

Abstract

Cardiovascular (CV) diseases are burdened by high mortality and morbidity, being responsible for half of the deaths in Europe. Although hypertension is recognized as the most important CV risk factor, hypertension awareness, and blood pressure (BP) control are still unsatisfactory. In 2017 and 2018, respectively >10 000 and >5000 individuals took part in the May Measurement Month (MMM) campaign in Italy, of whom 30.6% and 26.3% were found to have high BP, respectively. To raise public awareness on the importance of hypertension and to collect BP data on a nation-wide scale in Italy. In the frame of the MMM campaign, an opportunistic cross-sectional survey of volunteers aged ≥18 years was carried out in May 2019. BP measurement, the definition of hypertension, and statistical analysis followed the standard MMM protocol. Screening was conducted in multiple sites by health personnel. Among the 10 182 people screened (females: 52.3%, mean age 58 ± 16years) mean BP was 127/78 mmHg, and 3171 (31.1%) participants had arterial hypertension, of whom 62.1% were aware of being hypertensive. Diabetes, body mass index >25 kg/m2 were associated with higher BP and previous myocardial infarction with lower BP. For the third consecutive year we collected a nation-wide snapshot of BP control in a large sample of individuals. The high participation, with some yearly fluctuations likely due to the limitations of the sampling technique, confirms the power of this kind of health campaign in reaching a significant number of people to raise awareness on health topics.

Published
2021

21. Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis

Author

Nazarzadeh, Milad, primary, Bidel, Zeinab, additional, Canoy, Dexter, additional, Copland, Emma, additional, Bennett, Derrick A, additional, Dehghan, Abbas, additional, Davey Smith, George, additional, Holman, Rury R, additional, Woodward, Mark, additional, Gupta, Ajay, additional, Adler, Amanda I, additional, Wamil, Malgorzata, additional, Sattar, Naveed, additional, Cushman, William C, additional, McManus, Richard J, additional, Teo, Koon, additional, Davis, Barry R, additional, Chalmers, John, additional, Pepine, Carl J, additional, Rahimi, Kazem, additional, Agodoa, L, additional, Algra, A, additional, Asselbergs, F W, additional, Beckett, N, additional, Berge, E, additional, Black, H, additional, Brouwers, F P J, additional, Brown, M, additional, Bulpitt, C J, additional, Byington, B, additional, Cutler, J, additional, Devereaux, R B, additional, Dwyer, J, additional, Estacio, R, additional, Fagard, R, additional, Fox, K, additional, Fukui, T, additional, Imai, Y, additional, Ishii, M, additional, Julius, S, additional, Kanno, Y, additional, Kjeldsen, S E, additional, Kostis, J, additional, Kuramoto, K, additional, Lanke, J, additional, Lewis, E, additional, Lewis, J, additional, Lievre, M, additional, Lindholm, L H, additional, Lueders, S, additional, MacMahon, S, additional, Mancia, G, additional, Matsuzaki, M, additional, Mehlum, M H, additional, Nissen, S, additional, Ogawa, H, additional, Ogihara, T, additional, Ohkubo, T, additional, Palmer, C, additional, Patel, A, additional, Pfeffer, M, additional, Poulter, N R, additional, Rakugi, H, additional, Reboldi, G, additional, Reid, C, additional, Remuzzi, G, additional, Ruggenenti, P, additional, Saruta, T, additional, Schrader, J, additional, Schrier, R, additional, Sever, P, additional, Sleight, P, additional, Staessen, J A, additional, Suzuki, H, additional, Thijs, L, additional, Ueshima, K, additional, Umemoto, S, additional, van Gilst, W H, additional, Verdecchia, P, additional, Wachtell, K, additional, Whelton, P, additional, Wing, L, additional, Yui, Y, additional, Yusuf, S, additional, Zanchetti, A, additional, Zhang, Z Y, additional, Anderson, C, additional, Baigent, C, additional, Brenner, BM, additional, Collins, R, additional, de Zeeuw, D, additional, Lubsen, J, additional, Malacco, E, additional, Neal, B, additional, Perkovic, V, additional, Pitt, B, additional, Rodgers, A, additional, Rothwell, P, additional, Salimi-Khorshidi, G, additional, Sundström, J, additional, Turnbull, F, additional, Viberti, G, additional, and Wang, J, additional

Published
2022
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25. Effects of intensive glycemic control on clinical outcomes among patients with type 2 diabetes with different levels of cardiovascular risk and hemoglobin A1c in the ADVANCE trial

Author

Tian, J, Ohkuma, T, Cooper, M, Harrap, S, Mancia, G, Poulter, N, Wang, J, Zoungas, S, Woodward, M, Chalmers, J, Tian J., Ohkuma T., Cooper M., Harrap S., Mancia G., Poulter N., Wang J. -G., Zoungas S., Woodward M., Chalmers J., Tian, J, Ohkuma, T, Cooper, M, Harrap, S, Mancia, G, Poulter, N, Wang, J, Zoungas, S, Woodward, M, Chalmers, J, Tian J., Ohkuma T., Cooper M., Harrap S., Mancia G., Poulter N., Wang J. -G., Zoungas S., Woodward M., and Chalmers J.

Abstract

OBJECTIVE To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c)atbaseline. RESEARCH DESIGN AND METHODS We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models. RESULTS During 5 years’ follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83–0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction 5 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P 5 0.15) or HbA1c levels (P 5 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41–2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P 5 0.09 and 0.18, respectively). CONCLUSIONS The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c.

Published
2020

26. Self-rated health scores predict mortality among people with type 2 diabetes differently across three different country groupings: findings from the ADVANCE and ADVANCE-ON trials

Author

Hua, X, Lung, T, Woodward, M, Salomon, J, Hamet, P, Harrap, S, Mancia, G, Poulter, N, Chalmers, J, Clarke, P, Hua X., Lung T. W. C., Woodward M., Salomon J. A., Hamet P., Harrap S. B., Mancia G., Poulter N., Chalmers J., Clarke P. M., Hua, X, Lung, T, Woodward, M, Salomon, J, Hamet, P, Harrap, S, Mancia, G, Poulter, N, Chalmers, J, Clarke, P, Hua X., Lung T. W. C., Woodward M., Salomon J. A., Hamet P., Harrap S. B., Mancia G., Poulter N., Chalmers J., and Clarke P. M.

Abstract

Aims: To explore whether there is a different strength of association between self-rated health and all-cause mortality in people with type 2 diabetes across three country groupings: nine countries grouped together as 'established market economies'; Asia; and Eastern Europe. Methods: The ADVANCE trial and its post-trial follow-up were used in this study, which included 11 140 people with type 2 diabetes from 20 countries, with a median follow-up of 9.9 years. Self-rated health was reported on a 0–100 visual analogue scale. Cox proportional hazard models were fitted to estimate the relationship between the visual analogue scale score and all-cause mortality, controlling for a range of demographic and clinical risk factors. Interaction terms were used to assess whether the association between the visual analogue scale score and mortality varied across country groupings. Results: The visual analogue scale score had different strengths of association with mortality in the three country groupings. A 10-point increase in visual analogue scale score was associated with a 15% (95% CI 12–18) lower mortality hazard in the established market economies, a 25% (95% CI 21–28) lower hazard in Asia, and an 8% (95% CI 3–13) lower hazard in Eastern Europe. Conclusions: Self-rated health appears to predict 10-year all-cause mortality for people with type 2 diabetes worldwide, but this relationship varies across groups of countries.

Published
2020

27. 2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0

Author

Ryom, L, Cotter, A, De Miguel, R, Beguelin, C, Podlekareva, D, Arribas, J, Marzolini, C, Mallon, P, Rauch, A, Kirk, O, Molina, J, Guaraldi, G, Winston, A, Bhagani, S, Cinque, P, Kowalska, J, Collins, S, Battegay, M, De Miguel Buckley, R, D'Arminio Monforte, A, Bracchi, M, Dedes, N, Horban, A, Katlama, C, Latysheva, I, Lundgren, J, Mccormack, S, Mussini, C, Pozniak, A, Pulido, F, Raffi, F, Reiss, P, Stellbrink, H, Vasylyev, M, Gibbons, S, Livio, F, Behrens, G, Bower, M, Compston, J, De Wit, S, Fabbri, L, Fux, C, Gisslen, M, Martinez, E, Miro, J, Negredo, E, Poulter, N, Sebastiani, G, Berenguer, J, Boesecke, C, Bruno, R, Konov, S, Lacombe, K, Mauss, S, Mendao, L, Peters, L, Puoti, M, Rockstroh, J, Ambrosioni, J, De Castro, N, Fatkenheuer, G, Furrer, H, Oprea, C, Volny-Anne, A, Sullivan, A, Mulcahy, F, Wensing, A, Ryom L., Cotter A., De Miguel R., Beguelin C., Podlekareva D., Arribas J. R., Marzolini C., Mallon P. G. M., Rauch A., Kirk O., Molina J. M., Guaraldi G., Winston A., Bhagani S., Cinque P., Kowalska J. D., Collins S., Battegay M., De Miguel Buckley R., D'Arminio Monforte A., Bracchi M., Dedes N., Horban A., Katlama C., Latysheva I., Lundgren J. D., McCormack S., Mussini C., Pozniak A., Pulido F., Raffi F., Reiss P., Stellbrink H. -J., Vasylyev M., Gibbons S., Livio F., Behrens G., Bower M., Compston J., De Wit S., Fabbri L. M., Fux C. A., Gisslen M., Martinez E., Miro J. M., Negredo E., Poulter N., Sebastiani G., Berenguer J., Boesecke C., Bruno R., Konov S., Lacombe K., Mauss S., Mendao L., Peters L., Puoti M., Rockstroh J. K., Ambrosioni J., De Castro N., Fatkenheuer G., Furrer H., Oprea C., Volny-Anne A., Sullivan A., Mulcahy F., Wensing A., Ryom, L, Cotter, A, De Miguel, R, Beguelin, C, Podlekareva, D, Arribas, J, Marzolini, C, Mallon, P, Rauch, A, Kirk, O, Molina, J, Guaraldi, G, Winston, A, Bhagani, S, Cinque, P, Kowalska, J, Collins, S, Battegay, M, De Miguel Buckley, R, D'Arminio Monforte, A, Bracchi, M, Dedes, N, Horban, A, Katlama, C, Latysheva, I, Lundgren, J, Mccormack, S, Mussini, C, Pozniak, A, Pulido, F, Raffi, F, Reiss, P, Stellbrink, H, Vasylyev, M, Gibbons, S, Livio, F, Behrens, G, Bower, M, Compston, J, De Wit, S, Fabbri, L, Fux, C, Gisslen, M, Martinez, E, Miro, J, Negredo, E, Poulter, N, Sebastiani, G, Berenguer, J, Boesecke, C, Bruno, R, Konov, S, Lacombe, K, Mauss, S, Mendao, L, Peters, L, Puoti, M, Rockstroh, J, Ambrosioni, J, De Castro, N, Fatkenheuer, G, Furrer, H, Oprea, C, Volny-Anne, A, Sullivan, A, Mulcahy, F, Wensing, A, Ryom L., Cotter A., De Miguel R., Beguelin C., Podlekareva D., Arribas J. R., Marzolini C., Mallon P. G. M., Rauch A., Kirk O., Molina J. M., Guaraldi G., Winston A., Bhagani S., Cinque P., Kowalska J. D., Collins S., Battegay M., De Miguel Buckley R., D'Arminio Monforte A., Bracchi M., Dedes N., Horban A., Katlama C., Latysheva I., Lundgren J. D., McCormack S., Mussini C., Pozniak A., Pulido F., Raffi F., Reiss P., Stellbrink H. -J., Vasylyev M., Gibbons S., Livio F., Behrens G., Bower M., Compston J., De Wit S., Fabbri L. M., Fux C. A., Gisslen M., Martinez E., Miro J. M., Negredo E., Poulter N., Sebastiani G., Berenguer J., Boesecke C., Bruno R., Konov S., Lacombe K., Mauss S., Mendao L., Peters L., Puoti M., Rockstroh J. K., Ambrosioni J., De Castro N., Fatkenheuer G., Furrer H., Oprea C., Volny-Anne A., Sullivan A., Mulcahy F., and Wensing A.

Abstract

Background: The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years. Guideline highlights: The 2019 Guidelines were extended with a new section focusing on drug–drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment-naïve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two-drug regimen with dolutegravir and lamivudine, and a three-drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10-year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management. Treatment of resistant tuberculosis (TB) was streamlined with the World Health Organization (WHO) recommendations, and new tables on immune reconstitution inflammatory syndrome, on when to start ART in the presence of opportunistic infections and on TB drug dosing were included. Conclusions: The EACS Guidelines underwent major revisions of all sections in 2019. They are available in four different formats including a new interactive web-based version and are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish.

Published
2020

30. Hypertension and relationship between blood pressure variations with overweight, obesity and excessive alcohol intake in adult population of Congo – Brazzaville

Author

Ellenga Mbolla, B., primary, Kouala Landa, C., additional, Makani Bassakouahou, J., additional, Monabeka, M.G., additional, Ngamami Ep. Mongo, S.F., additional, Eyeni Sinomono, T., additional, Bouithy, S., additional, Chocolat, J.R., additional, Monabeka, H.G., additional, Beaney, T., additional, and Poulter, N., additional

Published
2022
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35. Publisher Correction:Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author

Surendran, P, Feofanova, EV, Lahrouchi, N, Ntalla, I, Karthikeyan, S, Cook, J, Chen, L, Mifsud, B, Yao, C, Kraja, AT, Cartwright, JH, Hellwege, JN, Giri, A, Tragante, V, Thorleifsson, G, Liu, DJ, Prins, BP, Stewart, ID, Cabrera, CP, Eales, JM, Akbarov, A, Auer, PL, Bielak, LF, Bis, JC, Braithwaite, VS, Brody, JA, Daw, EW, Warren, HR, Drenos, F, Nielsen, SF, Faul, JD, Fauman, EB, Fava, C, Ferreira, T, Foley, CN, Franceschini, N, Gao, H, Giannakopoulou, O, Giulianini, F, Gudbjartsson, DF, Guo, X, Harris, SE, Havulinna, AS, Helgadottir, A, Huffman, JE, Hwang, S-J, Kanoni, S, Kontto, J, Larson, MG, Li-Gao, R, Lindstrom, J, Lotta, LA, Lu, Y, Luan, J, Mahajan, A, Malerba, G, Masca, NGD, Mei, H, Menni, C, Mook-Kanamori, DO, Mosen-Ansorena, D, Muller-Nurasyid, M, Pare, G, Paul, DS, Perola, M, Poveda, A, Rauramaa, R, Richard, M, Richardson, TG, Sepulveda, N, Sim, X, Smith, AV, Smith, JA, Staley, JR, Stanakova, A, Sulem, P, Theriault, S, Thorsteinsdottir, U, Trompet, S, Varga, TV, Velez Edwards, DR, Veronesi, G, Weiss, S, Willems, SM, Yao, J, Young, R, Yu, B, Zhang, W, Zhao, J-H, Zhao, W, Evangelou, E, Aeschbacher, S, Asllanaj, E, Blankenberg, S, Bonnycastle, LL, Bork-Jensen, J, Brandslund, I, Braund, PS, Burgess, S, Cho, K, Christensen, C, Connell, J, De Mutsert, R, Dominiczak, AF, Dorr, M, Eiriksdottir, G, Farmaki, A-E, Gaziano, JM, Grarup, N, Grove, ML, Hallmans, G, Hansen, T, Have, CT, Heiss, G, Jorgensen, ME, Jousilahti, P, Kajantie, E, Kamat, M, Karajamaki, A, Karpe, F, Koistinen, HA, Kovesdy, CP, Kuulasmaa, K, Laatikainen, I, Lannfelt, L, Lee, I-T, Lee, W-J, Linneberg, A, Martin, LW, Moitry, M, Nadkarni, G, Neville, MJ, Palmer, CNA, Papanicolaou, GJ, Pedersen, O, Peters, J, Poulter, N, Rasheed, A, Rasmussen, KL, Rayner, NW, Magi, R, Renstrom, F, Rettig, R, Rossouw, J, Schreiner, PJ, Sever, PS, Sigurdsson, EL, Skaaby, T, Sun, YV, Sundstrom, J, Thorgeirsson, G, Esko, T, Trabetti, E, Tsao, PS, Tuomi, T, Turner, ST, Tzoulaki, I, Vaartjes, I, Vergnaud, A-C, Willer, CJ, Wilson, PWF, Witte, DR, Yonova-Doing, E, Zhang, H, Aliya, N, Almgren, P, Amouyel, P, Asselbergs, FW, Barnes, MR, Blakemore, AI, Boehnke, M, Bots, ML, Bottinger, EP, Buring, JE, Chambers, JC, Chen, Y-DI, Chowdhury, R, Conen, D, Correa, A, Davey Smith, G, Boer, RAD, Deary, IJ, Dedoussis, G, Deloukas, P, Di Angelantonio, E, Elliott, P, Felix, SB, Ferrieres, J, Ford, I, Fornage, M, Franks, PW, Franks, S, Frossard, P, Gambaro, G, Gaunt, TR, Groop, L, Gudnason, V, Harris, TB, Hayward, C, Hennig, BJ, Herzig, K-H, Ingelsson, E, Tuomilehto, J, Jarvelin, M-R, Jukema, JW, Kardia, SLR, Kee, F, Kooner, JS, Kooperberg, C, Launer, LJ, Lind, L, Loos, RJF, Majumder, AAS, Laakso, M, McCarthy, MI, Melander, O, Mohlke, KL, Murray, AD, Nordestgaard, BG, Orho-Melander, M, Packard, CJ, Padmanabhan, S, Palmas, W, Polasek, O, Porteous, DJ, Prentice, AM, Province, MA, Relton, CL, Rice, K, Ridker, PM, Rolandsson, O, Rosendaal, FR, Rotter, JI, Rudan, I, Salomaa, V, Samani, NJ, Sattar, N, Sheu, WH-H, Smith, BH, Soranzo, N, Spector, TD, Starr, JM, Sebert, S, Taylor, KD, Lakka, TA, Timpson, NJ, Tobin, MD, Van der Harst, P, Van der Meer, P, Ramachandran, VS, Verweij, N, Virtamo, J, Volker, U, Weir, DR, Zeggini, E, Charchar, FJ, Wareham, NJ, Langenberg, C, Tomaszewski, M, Butterworth, AS, Caulfield, MJ, Danesh, J, Edwards, TL, Holm, H, Hung, AM, Lindgren, CM, Liu, C, Manning, AK, Morris, AP, Morrison, AC, O'Donnell, CJ, Psaty, BM, Saleheen, D, Stefansson, K, Boerwinkle, E, Chasman, DI, Levy, D, Newton-Cheh, C, Munroe, PB, Howson, JMM, and United Kingdom Research and Innovation

Subjects
Genetics & Heredity, Understanding Society Scientific Group, Science & Technology, business.industry, Published Erratum, Million Veteran Program, MEDLINE, Computational biology, 06 Biological Sciences, Biology, Blood pressure, Text mining, Meta-analysis, EPIC-InterAct, Genetics, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business, Life Sciences & Biomedicine, EPIC-CVD, 11 Medical and Health Sciences, LifeLines Cohort Study, Developmental Biology
Abstract

In the version of this article originally published, the e-mail address of corresponding author Patricia B. Munroe was incorrect. The error has been corrected in the HTML and PDF versions of the article.

Published
2021
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41. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial

Author

de Galan, B. E., Zoungas, S., Chalmers, J., Anderson, C., Dufouil, C., Pillai, A., Cooper, M., Grobbee, D. E., Hackett, M., Hamet, P., Heller, S. R., Lisheng, L., MacMahon, S., Mancia, G., Neal, B., Pan, C. Y., Patel, A., Poulter, N., Travert, F., Woodward, M., and for the ADVANCE Collaborative group

Published
2009
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43. Effectiveness of two-drug therapy versus monotherapy as initial regimen in hypertension: A propensity score-matched cohort study in the UK Clinical Practice Research Datalink

Author

Marinier, K, Macouillard, P, de Champvallins, M, Deltour, N, Poulter, N, Mancia, G, Marinier K., Macouillard P., de Champvallins M., Deltour N., Poulter N., Mancia G., Marinier, K, Macouillard, P, de Champvallins, M, Deltour, N, Poulter, N, Mancia, G, Marinier K., Macouillard P., de Champvallins M., Deltour N., Poulter N., and Mancia G.

Abstract

Purpose: To compare the effectiveness on blood pressure (BP) of initial two-drug therapy versus monotherapy in hypertensive patients. Methods: Using the Clinical Practice Research Datalink, linked with Hospital Episode Statistics and Office for National Statistics, we identified a cohort of adults with uncontrolled hypertension, initiating one or two antihypertensive drug classes between 2006 and 2014. New users of two drugs and monotherapy were matched 1:2 by propensity score. Main exposure was “as-treated,” ie, until first regimen change. Primary and secondary endpoints were systolic and diastolic BP control and major adverse cardiovascular event (MACE), respectively. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard models. Results: Of 54 523 eligible patients, 3256 (6.0%) were initiated to a two-drug combination. Of these, 2807 were matched to 5614 monotherapy users. Mean exposure duration was 12.7 months, with 76.5% patients changing their initial regimen. Two-drug therapy was associated with a clinically significant BP control increase in all hypertensive patients (HR = 1.17 [95%CI: 1.09-1.26]), more so in patients with grade 2-3 hypertension (HR = 1.28 [1.17-1.41]). An increase of 27% in BP control (HR = 1.27 [1.08-1.49]) was observed in patients initiating an ACEi+CCB combination compared with initiators of either single class. No significant association was found between two-drug therapy and MACE. Several sensitivity analyses confirmed the main findings. Conclusions: Few patients initiated therapy with two drugs, reflecting UK guidelines' recommendation to start with monotherapy. This study supports the greater effectiveness of two-drug therapy as the initial regimen for BP control.

Published
2019

44. Acute Increases in Serum Creatinine after Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus: The ADVANCE Trial

Author

Ohkuma, T, Jun, M, Rodgers, A, Cooper, M, Glasziou, P, Hamet, P, Harrap, S, Mancia, G, Marre, M, Neal, B, Perkovic, V, Poulter, N, Williams, B, Zoungas, S, Chalmers, J, Woodward, M, Ohkuma T., Jun M., Rodgers A., Cooper M. E., Glasziou P., Hamet P., Harrap S., Mancia G., Marre M., Neal B., Perkovic V., Poulter N., Williams B., Zoungas S., Chalmers J., Woodward M., Ohkuma, T, Jun, M, Rodgers, A, Cooper, M, Glasziou, P, Hamet, P, Harrap, S, Mancia, G, Marre, M, Neal, B, Perkovic, V, Poulter, N, Williams, B, Zoungas, S, Chalmers, J, Woodward, M, Ohkuma T., Jun M., Rodgers A., Cooper M. E., Glasziou P., Hamet P., Harrap S., Mancia G., Marre M., Neal B., Perkovic V., Poulter N., Williams B., Zoungas S., Chalmers J., and Woodward M.

Abstract

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome (P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase (P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration - URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925.

Published
2019

45. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci

Author

Erzurumluoglu, AM, Liu, M, Jackson, VE, Barnes, DR, Datta, G, Melbourne, CA, Young, R, Batini, C, Surendran, P, Jiang, T, Adnan, SD, Afaq, S, Agrawal, A, Altmaier, E, Antoniou, AC, Asselbergs, FW, Baumbach, C, Beirut, L, Bertelsen, S, Boehnke, M, Bots, ML, Brazel, DM, Chambers, JC, Chang-Claude, J, Chen, C, Corley, J, Chou, Y-L, David, SP, de Boer, RA, de Leeuw, CA, Dennis, JG, Dominiczak, AF, Dunning, AM, Easton, DF, Eaton, C, Elliott, P, Evangelou, E, Faul, JD, Foroud, T, Goate, A, Gong, J, Grabe, HJ, Haessler, J, Haiman, C, Hallmans, G, Hammerschlag, AR, Harris, SE, Hattersley, A, Heath, A, Hsu, C, Iacono, WG, Kanoni, S, Kapoor, M, Kaprio, J, Kardia, SL, Karpe, F, Kontto, J, Kooner, JS, Kooperberg, C, Kuulasmaa, K, Laakso, M, Lai, D, Langenberg, C, Le, N, Lettre, G, Loukola, A, Luan, J, Madden, PAF, Mangino, M, Marioni, RE, Marouli, E, Marten, J, Martin, NG, McGue, M, Michailidou, K, Mihailov, E, Moayyeri, A, Moitry, M, Müller-Nurasyid, M, Naheed, A, Nauck, M, Neville, MJ, Nielsen, SF, North, K, Perola, M, Pharoah, PDP, Pistis, G, Polderman, TJ, Posthuma, D, Poulter, N, Qaiser, B, Rasheed, A, Reiner, A, Renström, F, Rice, J, Rohde, R, Rolandsson, O, Samani, NJ, Samuel, M, Schlessinger, D, Scholte, SH, Scott, RA, Sever, P, Shao, Y, Shrine, N, Smith, JA, Starr, JM, Stirrups, K, Stram, D, Stringham, HM, Tachmazidou, I, Tardif, J-C, Thompson, DJ, Tindle, HA, Tragante, V, Trompet, S, Turcot, V, Tyrrell, J, Vaartjes, I, van der Leij, AR, van der Meer, P, Varga, TV, Verweij, N, Völzke, H, Wareham, NJ, Warren, HR, Weir, DR, Weiss, S, Wetherill, L, Yaghootkar, H, Yavas, E, Jiang, Y, Chen, F, Zhan, X, Zhang, W, Zhao, W, Zhou, K, Amouyel, P, Blankenberg, S, Caulfield, MJ, Chowdhury, R, Cucca, F, Deary, IJ, Deloukas, P, Di Angelantonio, E, Ferrario, M, Ferrières, J, Franks, PW, Frayling, TM, Frossard, P, Hall, IP, Hayward, C, Jansson, J-H, Jukema, JW, Kee, F, Männistö, S, Metspalu, A, Munroe, PB, Nordestgaard, BG, Palmer, CNA, Salomaa, V, Sattar, N, Spector, T, Strachan, DP, Understanding Society Scientific Group, EPIC-CVD, GSCAN, Consortium for Genetics of Smoking Behaviour, CHD Exome+ Consortium, van der Harst, P, Zeggini, E, Saleheen, D, Butterworth, AS, Wain, LV, Abecasis, GR, Danesh, J, Tobin, MD, Vrieze, S, Liu, DJ, and Howson, JMM

Abstract

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P

Published
2020

46. Comparison of Circulating Biomarkers in Predicting Diabetic Kidney Disease Progression With Autoantibodies to Erythropoietin Receptor

Author

Oshima, M, Hara, A, Toyama, T, Jun, M, Pollock, C, Jardine, M, Harrap, S, Poulter, N, Cooper, ME, Woodward, M, Chalmers, J, Perkovic, V, Wong, MG, Wada, T, Oshima, M, Hara, A, Toyama, T, Jun, M, Pollock, C, Jardine, M, Harrap, S, Poulter, N, Cooper, ME, Woodward, M, Chalmers, J, Perkovic, V, Wong, MG, and Wada, T

Abstract

Introduction: Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts. Methods: In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 μmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes. Results: Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit, P < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers. Conclusion: Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus.

Published
2021

47. Variability in estimated glomerular filtration rate and the risk of major clinical outcomes in diabetes: Post hoc analysis from the ADVANCE trial

Author

Jun, M, Harris, K, Heerspink, HJL, Badve, SV, Jardine, MJ, Harrap, S, Hamet, P, Marre, M, Poulter, N, Kotwal, S, Gallagher, M, Perkovic, V, Chalmers, J, Woodward, M, Jun, M, Harris, K, Heerspink, HJL, Badve, SV, Jardine, MJ, Harrap, S, Hamet, P, Marre, M, Poulter, N, Kotwal, S, Gallagher, M, Perkovic, V, Chalmers, J, and Woodward, M

Abstract

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20-month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CVeGFR ]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CVeGFR : low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all-cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow-up of 2.9 years following the 20-month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20-month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91-1.27 and 1.22, 95% CI: 1.03-1.45, respectively) with evidence of a positive linear trend (p = .015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D.

Published
2021

48. The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial

Author

Nguyen, TN, Harris, K, Woodward, M, Chalmers, J, Cooper, M, Hamet, P, Harrap, S, Heller, S, MacMahon, S, Mancia, G, Marre, M, Poulter, N, Rogers, A, Williams, B, Zoungas, S, Chow, CK, Lindley, RI, Nguyen, TN, Harris, K, Woodward, M, Chalmers, J, Cooper, M, Hamet, P, Harrap, S, Heller, S, MacMahon, S, Mancia, G, Marre, M, Poulter, N, Rogers, A, Williams, B, Zoungas, S, Chow, CK, and Lindley, RI

Abstract

OBJECTIVE: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

Published
2021

49. The power of genetic diversity in genome-wide association studies of lipids

Author

Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), Willer, C. J. (Cristen J.), Graham, S. E. (Sarah E.), Clarke, S. L. (Shoa L.), Wu, K. H. (Kuan-Han H.), Kanoni, S. (Stavroula), Zajac, G. J. (Greg J. M.), Ramdas, S. (Shweta), Surakka, I. (Ida), Ntalla, I. (Ioanna), Vedantam, S. (Sailaja), Winkler, T. W. (Thomas W.), Locke, A. E. (Adam E.), Marouli, E. (Eirini), Hwang, M. Y. (Mi Yeong), Han, S. (Sohee), Narita, A. (Akira), Choudhury, A. (Ananyo), Bentley, A. R. (Amy R.), Ekoru, K. (Kenneth), Verma, A. (Anurag), Trivedi, B. (Bhavi), Martin, H. C. (Hilary C.), Hunt, K. A. (Karen A.), Hui, Q. (Qin), Klarin, D. (Derek), Zhu, X. (Xiang), Thorleifsson, G. (Gudmar), Helgadottir, A. (Anna), Gudbjartsson, D. F. (Daniel F.), Holm, H. (Hilma), Olafsson, I. (Isleifur), Akiyama, M. (Masato), Sakaue, S. (Saori), Terao, C. (Chikashi), Kanai, M. (Masahiro), Zhou, W. (Wei), Brumpton, B. M. (Ben M.), Rasheed, H. (Humaira), Ruotsalainen, S. E. (Sanni E.), Havulinna, A. S. (Aki S.), Veturi, Y. (Yogasudha), Feng, Q. (QiPing), Rosenthal, E. A. (Elisabeth A.), Lingren, T. (Todd), Pacheco, J. A. (Jennifer Allen), Pendergrass, S. A. (Sarah A.), Haessler, J. (Jeffrey), Giulianini, F. (Franco), Bradford, Y. (Yuki), Miller, J. E. (Jason E.), Campbell, A. (Archie), Lin, K. (Kuang), Millwood, I. Y. (Iona Y.), Hindy, G. (George), Rasheed, A. (Asif), Faul, J. D. (Jessica D.), Zhao, W. (Wei), Weir, D. R. (David R.), Turman, C. (Constance), Huang, H. (Hongyan), Graff, M. (Mariaelisa), Mahajan, A. (Anubha), Brown, M. R. (Michael R.), Zhang, W. (Weihua), Yu, K. (Ketian), Schmidt, E. M. (Ellen M.), Pandit, A. (Anita), Gustafsson, S. (Stefan), Yin, X. (Xianyong), Luan, J. (Jian'an), Zhao, J.-H. (Jing-Hua), Matsuda, F. (Fumihiko), Jang, H.-M. (Hye-Mi), Yoon, K. (Kyungheon), Medina-Gomez, C. (Carolina), Pitsillides, A. (Achilleas), Hottenga, J. J. (Jouke Jan), Willemsen, G. (Gonneke), Wood, A. R. (Andrew R.), Ji, Y. (Yingji), Gao, Z. (Zishan), Haworth, S. (Simon), Mitchell, R. E. (Ruth E.), Chai, J. F. (Jin Fang), Aadahl, M. (Mette), Yao, J. (Jie), Manichaikul, A. (Ani), Warren, H. R. (Helen R.), Ramirez, J. (Julia), Bork-Jensen, J. (Jette), Karhus, L. L. (Line L.), Goel, A. (Anuj), Sabater-Lleal, M. (Maria), Noordam, R. (Raymond), Sidore, C. (Carlo), Fiorillo, E. (Edoardo), McDaid, A. F. (Aaron F.), Marques-Vidal, P. (Pedro), Wielscher, M. (Matthias), Trompet, S. (Stella), Sattar, N. (Naveed), Mollehave, L. T. (Line T.), Thuesen, B. H. (Betina H.), Munz, M. (Matthias), Zeng, L. (Lingyao), Huang, J. (Jianfeng), Yang, B. (Bin), Poveda, A. (Alaitz), Kurbasic, A. (Azra), Lamina, C. (Claudia), Forer, L. (Lukas), Scholz, M. (Markus), Galesloot, T. E. (Tessel E.), Bradfield, J. P. (Jonathan P.), Daw, E. W. (E. Warwick), Zmuda, J. M. (Joseph M.), Mitchell, J. S. (Jonathan S.), Fuchsberger, C. (Christian), Christensen, H. (Henry), Brody, J. A. (Jennifer A.), Feitosa, M. F. (Mary F.), Wojczynski, M. K. (Mary K.), Preuss, M. (Michael), Mangino, M. (Massimo), Christofidou, P. (Paraskevi), Verweij, N. (Niek), Benjamins, J. W. (Jan W.), Engmann, J. (Jorgen), Kember, R. L. (Rachel L.), Slieker, R. C. (Roderick C.), Lo, K. S. (Ken Sin), Zilhao, N. R. (Nuno R.), Kleber, M. E. (Marcus E.), Delgado, G. E. (Graciela E.), Huo, S. (Shaofeng), Ikeda, D. D. (Daisuke D.), Iha, H. (Hiroyuki), Yang, J. (Jian), Liu, J. (Jun), Leonard, H. L. (Hampton L.), Marten, J. (Jonathan), Schmidt, B. (Borge), Arendt, M. (Marina), Smyth, L. J. (Laura J.), Canadas-Garre, M. (Marisa), Wang, C. (Chaolong), Nakatochi, M. (Masahiro), Wong, A. (Andrew), Hutri-Kahonen, N. (Nina), Sim, X. (Xueling), Xia, R. (Rui), Huerta-Chagoya, A. (Alicia), Fernandez-Lopez, J. C. (Juan Carlos), Lyssenko, V. (Valeriya), Ahmed, M. (Meraj), Jackson, A. U. (Anne U.), Irvin, M. R. (Marguerite R.), Oldmeadow, C. (Christopher), Kim, H.-N. (Han-Na), Ryu, S. (Seungho), Timmers, P. R. (Paul R. H. J.), Arbeeva, L. (Liubov), Dorajoo, R. (Rajkumar), Lange, L. A. (Leslie A.), Chai, X. (Xiaoran), Prasad, G. (Gauri), Lores-Motta, L. (Laura), Pauper, M. (Marc), Long, J. (Jirong), Li, X. (Xiaohui), Theusch, E. (Elizabeth), Takeuchi, F. (Fumihiko), Spracklen, C. N. (Cassandra N.), Loukola, A. (Anu), Bollepalli, S. (Sailalitha), Warner, S. C. (Sophie C.), Wang, Y. X. (Ya Xing), Wei, W. B. (Wen B.), Nutile, T. (Teresa), Ruggiero, D. (Daniela), Sung, Y. J. (Yun Ju), Hung, Y.-J. (Yi-Jen), Chen, S. (Shufeng), Liu, F. (Fangchao), Yang, J. (Jingyun), Kentistou, K. A. (Katherine A.), Gorski, M. (Mathias), Brumat, M. (Marco), Meidtner, K. (Karina), Bielak, L. F. (Lawrence F.), Smith, J. A. (Jennifer A.), Hebbar, P. (Prashantha), Farmaki, A.-E. (Aliki-Eleni), Hofer, E. (Edith), Lin, M. (Maoxuan), Xue, C. (Chao), Zhang, J. (Jifeng), Concas, M. P. (Maria Pina), Vaccargiu, S. (Simona), van der Most, P. J. (Peter J.), Pitkanen, N. (Niina), Cade, B. E. (Brian E.), Lee, J. (Jiwon), van Der Laan, S. W. (Sander W.), Chitrala, K. N. (Kumaraswamy Naidu), Weiss, S. (Stefan), Zimmermann, M. E. (Martina E.), Lee, J. Y. (Jong Young), Choi, H. S. (Hyeok Sun), Nethander, M. (Maria), Freitag-Wolf, S. (Sandra), Southam, L. (Lorraine), Rayner, N. W. (Nigel W.), Wang, C. A. (Carol A.), Lin, S.-Y. (Shih-Yi), Wang, J.-S. (Jun-Sing), Couture, C. (Christian), Lyytikainen, L.-P. (Leo-Pekka), Nikus, K. (Kjell), Cuellar-Partida, G. (Gabriel), Vestergaard, H. (Henrik), Hildalgo, B. (Bertha), Giannakopoulou, O. (Olga), Cai, Q. (Qiuyin), Obura, M. O. (Morgan O.), van Setten, J. (Jessica), Li, X. (Xiaoyin), Schwander, K. (Karen), Terzikhan, N. (Natalie), Shin, J. H. (Jae Hun), Jackson, R. D. (Rebecca D.), Reiner, A. P. (Alexander P.), Martin, L. W. (Lisa Warsinger), Chen, Z. (Zhengming), Li, L. (Liming), Highland, H. M. (Heather M.), Young, K. L. (Kristin L.), Kawaguchi, T. (Takahisa), Thiery, J. (Joachim), Bis, J. C. (Joshua C.), Nadkarni, G. N. (Girish N.), Launer, L. J. (Lenore J.), Li, H. (Huaixing), Nalls, M. A. (Mike A.), Raitakari, O. T. (Olli T.), Ichihara, S. (Sahoko), Wild, S. H. (Sarah H.), Nelson, C. P. (Christopher P.), Campbell, H. (Harry), Jager, S. (Susanne), Nabika, T. (Toru), Al-Mulla, F. (Fahd), Niinikoski, H. (Harri), Braund, P. S. (Peter S.), Kolcic, I. (Ivana), Kovacs, P. (Peter), Giardoglou, T. (Tota), Katsuya, T. (Tomohiro), Bhatti, F. (Fatima), de Kleijn, D. (Dominique), de Borst, G. J. (Gert J.), Kim, E. K. (Eung Kweon), Adams, H. H. (Hieab H. H.), Ikram, M. A. (M. Arfan), Zhu, X. (Xiaofeng), Asselbergs, F. W. (Folkert W.), Kraaijeveld, A. O. (Adriaan O.), Beulens, J. W. (Joline W. J.), Shu, X.-O. (Xiao-Ou), Rallidis, L. S. (Loukianos S.), Pedersen, O. (Oluf), Hansen, T. (Torben), Mitchell, P. (Paul), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Perusse, L. (Louis), Bouchard, C. (Claude), Tonjes, A. (Anke), Chen, Y. I. (Yii-Der Ida), Pennell, C. E. (Craig E.), Mori, T. A. (Trevor A.), Lieb, W. (Wolfgang), Franke, A. (Andre), Ohlsson, C. (Claes), Mellstrom, D. (Dan), Cho, Y. S. (Yoon Shin), Lee, H. (Hyejin), Yuan, J.-M. (Jian-Min), Koh, W.-P. (Woon-Puay), Rhee, S. Y. (Sang Youl), Woo, J.-T. (Jeong-Taek), Heid, I. M. (Iris M.), Stark, K. J. (Klaus J.), Volzke, H. (Henry), Homuth, G. (Georg), Evans, M. K. (Michele K.), Zonderman, A. B. (Alan B.), Polasek, O. (Ozren), Pasterkamp, G. (Gerard), Hoefer, I. E. (Imo E.), Redline, S. (Susan), Pahkala, K. (Katja), Oldehinkel, A. J. (Albertine J.), Snieder, H. (Harold), Biino, G. (Ginevra), Schmidt, R. (Reinhold), Schmidt, H. (Helena), Chen, Y. E. (Y. Eugene), Bandinelli, S. (Stefania), Dedoussis, G. (George), Thanaraj, T. A. (Thangavel Alphonse), Kardia, S. L. (Sharon L. R.), Kato, N. (Norihiro), Schulze, M. B. (Matthias B.), Girotto, G. (Giorgia), Jung, B. (Bettina), Boger, C. A. (Carsten A.), Joshi, P. K. (Peter K.), Bennett, D. A. (David A.), De Jager, P. L. (Philip L.), Lu, X. (Xiangfeng), Mamakou, V. (Vasiliki), Brown, M. (Morris), Caulfield, M. J. (Mark J.), Munroe, P. B. (Patricia B.), Guo, X. (Xiuqing), Ciullo, M. (Marina), Jonas, J. B. (Jost B.), Samani, N. J. (Nilesh J.), Kaprio, J. (Jaakko), Pajukanta, P. (Paivi), Adair, L. S. (Linda S.), Bechayda, S. A. (Sonny Augustin), de Silva, H. J. (H. Janaka), Wickremasinghe, A. R. (Ananda R.), Krauss, R. M. (Ronald M.), Wu, J.-Y. (Jer-Yuarn), Zheng, W. (Wei), den Hollander, A. I. (Anneke, I), Bharadwaj, D. (Dwaipayan), Correa, A. (Adolfo), Wilson, J. G. (James G.), Lind, L. (Lars), Heng, C.-K. (Chew-Kiat), Nelson, A. E. (Amanda E.), Golightly, Y. M. (Yvonne M.), Wilson, J. F. (James F.), Penninx, B. (Brenda), Kim, H.-L. (Hyung-Lae), Attia, J. (John), Scott, R. J. (Rodney J.), Rao, D. C. (D. C.), Arnett, D. K. (Donna K.), Walker, M. (Mark), Koistinen, H. A. (Heikki A.), Chandak, G. R. (Giriraj R.), Yajnik, C. S. (Chittaranjan S.), Mercader, J. M. (Josep M.), Tusie-Luna, T. (Teresa), Aguilar-Salinas, C. A. (Carlos A.), Villalpando, C. G. (Clicerio Gonzalez), Orozco, L. (Lorena), Fornage, M. (Myriam), Tai, E. S. (E. Shyong), van Dam, R. M. (Rob M.), Lehtimaki, T. (Terho), Chaturvedi, N. (Nish), Yokota, M. (Mitsuhiro), Liu, J. (Jianjun), Reilly, D. F. (Dermot F.), McKnight, A. J. (Amy Jayne), Kee, F. (Frank), Jockel, K.-H. (Karl-Heinz), McCarthy, M. I. (Mark, I), Palmer, C. N. (Colin N. A.), Vitart, V. (Veronique), Hayward, C. (Caroline), Simonsick, E. (Eleanor), van Duijn, C. M. (Cornelia M.), Lu, F. (Fan), Qu, J. (Jia), Hishigaki, H. (Haretsugu), Lin, X. (Xu), Marz, W. (Winfried), Parra, E. J. (Esteban J.), Cruz, M. (Miguel), Gudnason, V. (Vilmundur), Tardif, J.-C. (Jean-Claude), Lettre, G. (Guillaume), Elders, P. J. (Petra J. M.), Damrauer, S. M. (Scott M.), Kumari, M. (Meena), Kivimaki, M. (Mika), van der Harst, P. (Pim), Spector, T. D. (Tim D.), Loos, R. J. (Ruth J. F.), Province, M. A. (Michael A.), Psaty, B. M. (Bruce M.), Brandslund, I. (Ivan), Pramstaller, P. P. (Peter P.), Christensen, K. (Kaare), Ripatti, S. (Samuli), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Grant, S. F. (Struan F. A.), Kiemeney, L. A. (Lambertus A. L. M.), de Graaf, J. (Jacqueline), Loeffler, M. (Markus), Kronenberg, F. (Florian), Gu, D. (Dongfeng), Erdmann, J. (Jeanette), Schunkert, H. (Heribert), Franks, P. W. (Paul W.), Linneberg, A. (Allan), Jukema, J. W. (J. Wouter), Khera, A. V. (Amit, V), Männikkö, M. (Minna), Järvelin, M.-R. (Marjo-Riitta), Kutalik, Z. (Zoltan), Cucca, F. (Francesco), Mook-Kanamori, D. O. (Dennis O.), van Dijk, K. W. (Ko Willems), Watkins, H. (Hugh), Strachan, D. P. (David P.), Grarup, N. (Niels), Sever, P. (Peter), Poulter, N. (Neil), Rotter, J. I. (Jerome, I), Dantoft, T. M. (Thomas M.), Karpe, F. (Fredrik), Neville, M. J. (Matt J.), Timpson, N. J. (Nicholas J.), Cheng, C.-Y. (Ching-Yu), Wong, T.-Y. (Tien-Yin), Khor, C. C. (Chiea Chuen), Sabanayagam, C. (Charumathi), Peters, A. (Annette), Gieger, C. (Christian), Hattersley, A. T. (Andrew T.), Pedersen, N. L. (Nancy L.), Magnusson, P. K. (Patrik K. E.), Boomsma, D. I. (Dorret, I), de Geus, E. J. (Eco J. C.), Cupples, L. A. (L. Adrienne), van Meurs, J. B. (Joyce B. J.), Ghanbari, M. (Mohsen), Rsen, P. G. (Penny Gordon-La), Huang, W. (Wei), Kim, Y. J. (Young Jin), Tabara, Y. (Yasuharu), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Zeggini, E. (Eleftheria), Kuusisto, J. (Johanna), Laakso, M. (Markku), Ingelsson, E. (Erik), Abecasis, G. (Goncalo), Chambers, J. C. (John C.), Kooner, J. S. (Jaspal S.), de Vries, P. S. (Paul S.), Morrison, A. C. (Alanna C.), North, K. E. (Kari E.), Daviglus, M. (Martha), Kraft, P. (Peter), Martin, N. G. (Nicholas G.), Whitfield, J. B. (John B.), Abbas, S. (Shahid), Saleheen, D. (Danish), Walters, R. G. (Robin G.), Holmes, M. V. (Michael, V), Black, C. (Corri), Smith, B. H. (Blair H.), Justice, A. E. (Anne E.), Baras, A. (Aris), Buring, J. E. (Julie E.), Ridker, P. M. (Paul M.), Chasman, D. I. (Daniel, I), Kooperberg, C. (Charles), Wei, W.-Q. (Wei-Qi), Jarvik, G. P. (Gail P.), Namjou, B. (Bahram), Hayes, M. G. (M. Geoffrey), Ritchie, M. D. (Marylyn D.), Jousilahti, P. (Pekka), Salomaa, V. (Veikko), Hveem, K. (Kristian), Asvold, B. O. (Bjorn Olav), Kubo, M. (Michiaki), Kamatani, Y. (Yoichiro), Okada, Y. (Yukinori), Murakami, Y. (Yoshinori), Thorsteinsdottir, U. (Unnur), Stefansson, K. (Kari), Ho, Y.-L. (Yuk-Lam), Lynch, J. A. (Julie A.), Rader, D. J. (Daniel J.), Tsao, P. S. (Philip S.), Chang, K.-M. (Kyong-Mi), Cho, K. (Kelly), O'Donnell, C. J. (Christopher J.), Gaziano, J. M. (John M.), Wilson, P. (Peter), Rotimi, C. N. (Charles N.), Hazelhurst, S. (Scott), Ramsay, M. (Michele), Trembath, R. C. (Richard C.), van Heel, D. A. (David A.), Tamiya, G. (Gen), Yamamoto, M. (Masayuki), Kim, B.-J. (Bong-Jo), Mohlke, K. L. (Karen L.), Frayling, T. M. (Timothy M.), Hirschhorn, J. N. (Joel N.), Kathiresan, S. (Sekar), Boehnke, M. (Michael), Natarajan, P. (Pradeep), Peloso, G. M. (Gina M.), Brown, C. D. (Christopher D.), Morris, A. P. (Andrew P.), Assimes, T. L. (Themistocles L.), Deloukas, P. (Panos), Sun, Y. V. (Yan, V), and Willer, C. J. (Cristen J.)

Abstract

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4‐23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.

Published
2021

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