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1. Glycemic Control and Urinary Tract Infections in Women with Type 1 Diabetes: Results from the DCCT/EDIC

Author

Lenherr, Sara M, Clemens, J Quentin, Braffett, Barbara H, Cleary, Patricia A, Dunn, Rodney L, Hotaling, James M, Jacobson, Alan M, Kim, Catherine, Herman, William, Brown, Jeanette S, Wessells, Hunter, Sarma, Aruna V, Nathan, DM, Zinman, B, Crofford, O, Genuth, S, Brown-Friday, J, Crandall, J, Engel, H, Engel, S, Martinez, H, Phillips, M, Reid, M, Shamoon, H, Sheindlin, J, Gubitosi-Klug, R, Mayer, L, Pendegast, S, Zegarra, H, Miller, D, Singerman, L, Smith-Brewer, S, Novak, M, Quin, J, Genuth, Saul, Palmert, M, Brown, E, McConnell, J, Pugsley, P, Crawford, P, Dahms, W, Brillon, D, Lackaye, ME, Kiss, S, Chan, R, Orlin, A, Rubin, M, Reppucci, V, Lee, T, Heinemann, M, Chang, S, Levy, B, Jovanovic, L, Richardson, M, Bosco, B, Dwoskin, A, Hanna, R, Barron, S, Campbell, R, Bhan, A, Kruger, D, Jones, JK, Edwards, PA, Carey, JD, Angus, E, Thomas, A, Galprin, A, McLellan, M, Whitehouse, F, Bergenstal, R, Johnson, M, Gunyou, K, Thomas, L, Laechelt, J, Hollander, P, Spencer, M, Kendall, D, Cuddihy, R, Callahan, P, List, S, Gott, J, Rude, N, Olson, B, Franz, M, Castle, G, Birk, R, Nelson, J, Freking, D, Gill, L, Mestrezat, W, Etzwiler, D, Morgan, K, Aiello, LP, Golden, E, Arrigg, P, Asuquo, V, Beaser, R, Bestourous, L, and Cavallerano, J

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Infectious Diseases, Clinical Research, Urologic Diseases, Diabetes, Prevention, Reproductive health and childbirth, Renal and urogenital, Infection, Metabolic and endocrine, Adolescent, Adult, Blood Glucose, Body Mass Index, Diabetes Mellitus, Type 1, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Risk Factors, Surveys and Questionnaires, Urinary Incontinence, Urinary Tract Infections, Young Adult, DCCT/EDIC Research Group, diabetes mellitus, risk factors, urinary tract infections, Clinical Sciences, Urology & Nephrology, Clinical sciences
Abstract

PurposeWe examined the relationship between glycemic control and urinary tract infections in women with type 1 diabetes mellitus.Materials and methodsWomen enrolled in the Epidemiology of Diabetes Interventions and Complications study, the observational followup of the Diabetes Control and Complications Trial, were surveyed to assess the rate of physician diagnosed urinary tract infections in the preceding 12 months. The relationship between glycated hemoglobin levels and number of urinary tract infections in the previous 12 months was assessed using a multivariable Poisson regression model.ResultsA total of 572 women were evaluated at year 17. Mean age was 50.7 ± 7.2 years, mean body mass index was 28.6 ± 5.9 kg/m(2), mean type 1 diabetes duration was 29.8 ± 5.0 years and mean glycated hemoglobin was 8.0% ± 0.9%. Of these women 86 (15.0%) reported at least 1 physician diagnosed urinary tract infection during the last 12 months. Higher glycated hemoglobin levels were significantly associated with number of urinary tract infections such that for every unit increase (1%) in recent glycated hemoglobin level, there was a 21% (p=0.02) increase in urinary tract infection frequency in the previous 12 months after adjusting for race, hysterectomy status, urinary incontinence, sexual activity in the last 12 months, peripheral and autonomic neuropathy, and nephropathy.ConclusionsThe frequency of urinary tract infections increases with poor glycemic control in women with type 1 diabetes. This relationship is independent of other well described predictors of urinary tract infections and suggests that factors directly related to glycemic control may influence the risk of lower urinary tract infections.

Published
2016

2. Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

Author

Chen, Zhuo, Miao, Feng, Paterson, Andrew D, Lachin, John M, Zhang, Lingxiao, Schones, Dustin E, Wu, Xiwei, Wang, Jinhui, Tompkins, Joshua D, Genuth, Saul, Braffett, Barbara H, Riggs, Arthur D, Natarajan, Rama, Nathan, DM, Zinman, B, Crofford, O, Genuth, S, Brown-Friday, J, Crandall, J, Engel, H, Engel, S, Martinez, H, Phillips, M, Reid, M, Shamoon, H, Sheindlin, J, Gubitosi-Klug, R, Mayer, L, Pendegast, S, Zegarra, H, Miller, D, Singerman, L, Smith-Brewer, S, Novak, M, Quin, J, Palmert, M, Brown, E, McConnell, J, Pugsley, P, Crawford, P, Dahms, W, Brillon, D, Lackaye, ME, Kiss, S, Chan, R, Orlin, A, Rubin, M, Reppucci, V, Lee, T, Heinemann, M, Chang, S, Levy, B, Jovanovic, L, Richardson, M, Bosco, B, Dwoskin, A, Hanna, R, Barron, S, Campbell, R, Bhan, A, Kruger, D, Jones, JK, Edwards, PA, Carey, JD, Angus, E, Thomas, A, Galprin, A, McLellan, M, Whitehouse, F, Bergenstal, R, Johnson, M, Gunyou, K, Thomas, L, Laechelt, J, Hollander, P, Spencer, M, Kendall, D, Cuddihy, R, Callahan, P, List, S, Gott, J, Rude, N, Olson, B, Franz, M, Castle, G, Birk, R, Nelson, J, Freking, D, Gill, L, Mestrezat, W, Etzwiler, D, Morgan, K, Aiello, LP, Golden, E, Arrigg, P, Asuquo, V, Beaser, R, and Bestourous, L

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Nutrition, Human Genome, Diabetes, Prevention, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adolescent, Adult, Carrier Proteins, Cell Line, Tumor, Cohort Studies, DNA Methylation, Diabetes Mellitus, Type 1, Epigenomics, Female, Genetic Loci, Glycated Hemoglobin, Humans, Male, DCCT/EDIC Research Group, DNA methylation, TXNIP, diabetic complications, epigenetics, metabolic memory
Abstract

We examined whether persistence of epigenetic DNA methylation (DNA-me) alterations at specific loci over two different time points in people with diabetes are associated with metabolic memory, the prolonged beneficial effects of intensive vs. conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We compared DNA-me profiles in genomic DNA of whole blood (WB) isolated at EDIC Study baseline from 32 cases (DCCT conventional therapy group subjects showing retinopathy or albuminuria progression by EDIC Study year 10) vs. 31 controls (DCCT intensive therapy group subjects without complication progression by EDIC year 10). DNA-me was also profiled in blood monocytes (Monos) of the same patients obtained during EDIC Study years 16-17. In WB, 153 loci depicted hypomethylation, and 225 depicted hypermethylation, whereas in Monos, 155 hypomethylated loci and 247 hypermethylated loci were found (fold change ≥1.3; P < 0.005; cases vs. controls). Twelve annotated differentially methylated loci were common in both WB and Monos, including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications. A set of differentially methylated loci depicted similar trends of associations with prior HbA1c in both WB and Monos. In vitro, high glucose induced similar persistent hypomethylation at TXNIP in cultured THP1 Monos. These results show that DNA-me differences during the DCCT persist at certain loci associated with glycemia for several years during the EDIC Study and support an epigenetic explanation for metabolic memory.

Published
2016

3. Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering.

Author

Charytan, DM, Mahaffey, KW, Jardine, MJ, Cannon, CP, Neal, B, Lambers Heerspink, HJ, Agarwal, R, Bakris, GL, de Zeeuw, D, Levin, A, Pollock, C, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V, Di Tanna, GL, Yu, J, Rogers, K, Arnott, C, Wheeler, DC, Charytan, DM, Mahaffey, KW, Jardine, MJ, Cannon, CP, Neal, B, Lambers Heerspink, HJ, Agarwal, R, Bakris, GL, de Zeeuw, D, Levin, A, Pollock, C, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V, Di Tanna, GL, Yu, J, Rogers, K, Arnott, C, and Wheeler, DC

Abstract

INTRODUCTION: Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. RESEARCH DESIGN AND METHODS: We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. RESULTS: HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. CONCLUSIONS: The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22.

Published
2023

7. Heart failure and renal outcomes according to baseline and achieved blood pressure in patients with type 2 diabetes: results from EMPA-REG OUTCOME

Author

Bohm, M, Fitchett, D, Ofstad, A, Brueckmann, M, Kaspers, S, George, J, Zwiener, I, Zinman, B, Wanner, C, Marx, N, Mancia, G, Anker, S, Mahfoud, F, Bohm M., Fitchett D., Ofstad A. P., Brueckmann M., Kaspers S., George J. T., Zwiener I., Zinman B., Wanner C., Marx N., Mancia G., Anker S. D., Mahfoud F., Bohm, M, Fitchett, D, Ofstad, A, Brueckmann, M, Kaspers, S, George, J, Zwiener, I, Zinman, B, Wanner, C, Marx, N, Mancia, G, Anker, S, Mahfoud, F, Bohm M., Fitchett D., Ofstad A. P., Brueckmann M., Kaspers S., George J. T., Zwiener I., Zinman B., Wanner C., Marx N., Mancia G., Anker S. D., and Mahfoud F.

Abstract

Background: The sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin reduced cardiovascular death or heart failure hospitalizations in type 2 diabetes (T2D) in addition to a reduction of SBP. As heart failure patients often present with low SBP, which can challenge treatment initiation, we explored if empagliflozin’s effect on SBP was independent of baseline SBP and heart failure status, and if the effect on cardiovascular and heart failure outcomes was influenced by updated mean SBP or by an early change in SBP after drug initiation. Methods and results: A total of 7020 patients were treated with empagliflozin 10mg, 25mg or placebo and followed for a median of 3.1 years. All of them had BP measurement at baseline. We evaluated changes in SBP in the context of heart failure status at baseline and according to baseline SBP categories (<120, 120–<130, 130–<140, 140–<160, ≥160mmHg). The updated mean SBP during the trial was calculated as a time-dependent variable. We then assessed the association of baseline and updated mean SBP with three-point major adverse cardiovascular events (3P-MACE), hospitalization for heart failure, cardiovascular death, hospitalization for heart failure or cardiovascular death, all-cause death, and incident/worsening nephropathy, and whether treatment effect of empagliflozin vs. placebo on these outcomes differed if adjusted for updated mean SBP. Finally, we evaluated the impact of early decline in SBP (≥5mmHg at week 4) on the treatment effect of empagliflozin vs. placebo on these outcomes. Analyses were performed via Cox regression adjusting for baseline risk factors including a term for treatment subgroup interaction, and by landmark analyses starting at week 4. The difference in SBP reduction at week 12 between empagliflozin and placebo was 3–5mmHg and similar regardless of baseline SBP category or HF status at baseline. Baseline SBP and updated mean SBP categories showed no association with cardiovascular outcomes

Published
2020

12. Dapagliflozin and cardiovascular outcomes in type 2 diabetes

Author

Wiviott, S, Raz, I, Bonaca, M, Mosenzon, O, Kato, E, Cahn, A, Silverman, M, Zelniker, T, Kuder, J, Murphy, S, Bhatt, D, Leiter, L, Mcguire, D, Wilding, J, Ruff, C, Nilsson, G, Fredriksson, M, Johansson, P, Langkilde, A, Sabatine, M, Bansilal, S, Furtado, R, Fish, M, Gabovitch, D, Jevne, A, Ahern, S, Im, K, Goodrich, E, Lowe, C, Fisher, N, Gannon, J, Trindade, S, Towarowski, A, Fox, Y, Johnsson, E, Ranft, S, Faber, B, Wallander, M, Weiss, A, Buskila, A, Abola, M, Ardissino, D, Averkov, O, Aylward, P, Bode, C, Bonnici, F, Bonora, E, Budaj, A, Cernea, S, Chiang, C, Cooper, M, Dalby, A, Deerochanawong, C, Dellborg, M, Diaz, R, Dimulescu, D, Eliaschewitz, F, Goudev, A, Hadjadj, S, Herrera, M, Huo, Y, Jermendy, G, Ji, L, Kadowaki, T, Kiss, R, Kooy, A, Kumar, K, Lewis, B, Litwak, L, Lopez-Sendon, J, Ma, R, Merlini, P, Nauck, M, Nguyen, T, Nicolau, J, Ostgren, C, Ophuis, T, Padilla, F, Pais, P, Park, K, Parkhomenko, A, Ray, K, Rosenstock, J, Ruda, M, Satman, I, Shestakova, M, Smahelova, A, Spinar, J, Strojek, K, Sy, R, Tankova, T, Theroux, P, Tkac, I, Van Gaal, L, Wainstein, J, Harrington, R, Droller, M, Lee, K, Nesto, R, Tuomilehto, J, Hedlin, H, Desai, M, Sayfer, I, Alexanian, S, Awtry, E, Bentley-Lewis, R, Berger, C, Croce, K, Desai, A, Garg, R, Gelfand, E, Gignac, G, Goessling, W, Ho, C, Hochberg, E, Lane, A, Larrey, D, Leeman, D, Lewis, J, Link, M, Mcdonnell, M, Norden, A, Pande, A, Rosenberg, C, Rost, N, Ruberg, F, Schiff, E, Silverman, S, Singhal, A, Wagner, A, Wolpin, B, Aizenberg, D, Fernandez, M, Sala, J, Maffei, L, Luquez, C, Waitman, J, Rista, L, Nardone, L, Sposetti, G, Cantero, M, Alvarisqueta, A, Montana, O, Cuadrado, J, Cartasegna, L, Baccaro, C, Chertkoff, A, Sanabria, H, Vainstein, N, Amerena, J, Arya, K, D'Emden, M, Proietto, J, Moses, R, Colquhoun, D, Stranks, S, Lehman, R, Hamilton, A, Whelan, A, Simpson, R, Purnell, P, Abhayaratna, W, Hammett, C, Mckeirnan, M, Sullivan, D, Bach, L, Hughes, K, Mathieu, C, Vercammen, C, Scheen, A, Duyck, F, Cools, F, De Wolf, L, Verhaegen, A, Nobels, F, Missault, L, Crenier, L, Thoeng, J, Wollaert, B, Vandenbroucke, M, Borges, J, Turatti, L, Lima, F, dos Santos, F, Kerr Saraiva, J, Pereira, M, Pereira, A, Precoma, D, Filho, G, Reis, G, Maia, L, Bacheva, T, Temelkova-Kurktschiev, T, Maneva, S, Stoyanovska, B, Boshnyashka, R, Stoykova, Y, Georgiev, D, Tagarev, Z, Dimitrova, E, Vitkina, M, Yordanova, L, Temelkova, M, Vasileva, S, Kuneva, T, Zyumbyuleva, M, Daskalova, I, Genadieva, V, Boyanov, L, Farah, G, Lazarova, G, Georgieva, M, Krasteva, S, Slavcheva, A, Yabroudi, N, Veleva, N, Zlateva, A, Damyanova, V, Elenkova, A, Kotselova, T, Genov, K, Lyubenova, L, Temelkova, N, Harizanova, B, Zaharieva, S, Bajaj, H, Goldenberg, R, Aronson, R, Twum-Barima, D, Dumas, R, Kouz, S, Kaiser, S, Ajala, B, Cha, J, Teitelbaum, I, Chouinard, G, Woo, V, Dan Dattani, I, Mazza, G, Gaudet, D, Poirier, P, Conway, J, Dion, D, Mckeough, M, Manyari, D, Harris, S, St-Pierre, B, Yale, J, Landry, D, Gupta, M, Hramiak, I, Lau, D, Degrace, M, Gallo, R, Montigny, M, Dzongowski, P, Liutkus, J, Frechette, A, Gosselin, G, Sabbah, E, Langlois, M, Rabasa-Lhoret, R, Bedard, J, Hart, R, Dowell, A, Pandey, A, O'Keefe, D, Hill, L, Weisnagel, S, Muirhead, N, Zimmermann, R, Galiwango, P, Tobe, S, Priestman, B, Zinman, B, Ma, J, Zhao, X, Wang, C, Zhang, A, Dong, Y, Dong, X, Luo, M, Guo, J, Zheng, Z, Li, Y, Liang, Y, Peng, D, Maderic, D, Spinarova, L, Raclavska, L, Ludka, O, Rihacek, I, Karasova, J, Pelikanova, M, Vlasakova, H, Urbancova, K, Zamrazil, V, Hradec, J, Vlasicova, H, Racicka, E, Okenka, L, Naplava, R, Skopecek, J, Palova, S, Krystl, T, Pistek, Z, Oznerova, M, Andresova, A, Sarbochova, R, Taborska, P, Petrova, I, Stanek, L, Reichert, P, Lorenc, Z, Szabo, M, Petit, C, Krempf, M, Boye, A, Dubois, S, Clavel, S, Gourdy, P, Elbaz, M, Jazayeri, S, Gouet, D, Verges, B, Couffinhal, T, Sendeski, M, Klausmann, G, Appel, K, Pein, M, Thieme, R, Schumm-Draeger, P, Jacob, S, Toursarkissian, N, Kleinecke-Pohl, U, Tschope, D, Ott, P, Haak, T, Derwahl, K, Bugger, H, Hui, G, Tsang, C, Zilahi, Z, Puski, L, Vangel, S, Fulop, T, Pall, K, Hidvegi, T, Revesz, K, Koranyi, L, Kajetan, M, Kerenyi, Z, Penzes, J, Herczeg, B, Laszloczky, A, Turi, T, Rapi, J, Pentek, Z, Gaal, Z, Winkler, G, Percs, E, Czigany, A, Harcsa, E, Gurzo, M, Tassaly, J, Horthy, R, Petro, G, Farago, K, Muller, G, Varju, I, Kirschner, R, Kiss, I, Bakai, J, Kancz, S, Marton, Z, Kodur, R, Yajnik, C, Thomas, N, Ayyar, V, Iyengar, P, Bashkin, A, Daoud, D, Itzhak, B, Katz, A, Tsur, A, Nikolsky, E, Atar, S, Grossman, A, Klainman, E, Tsalihin, D, Shotan, A, Turgeman, Y, Ferrario, M, Piatti, P, Zenari, L, Trevisan, R, Bosco, B, Di Lorenzo, L, Mannucci, E, Avogaro, A, Reimers, B, Trimarco, B, Silvestri, O, Salvioni, A, Nakagawa, H, Sueyoshi, A, Fukuda, K, Yasumoto, H, Matsubayashi, S, Kawajiri, K, Togashi, Y, Senokuchi, T, Ohta, Y, Yamauchi, T, Node, K, Alcocer Gamba, M, Herrera Marmolejo, M, De los Rios Ibarra, M, Gonzalez Galvez, G, Garcia Cantu, E, Leguizamo Dimas, A, Luna Ceballos, R, Medina Pech, C, Stobschinski de Alba, C, Gonzalez Gonzalez, J, Padilla Padilla, F, Fanghanel Salmon, G, Robles Torres, F, Lopez Rosas, E, Pelayo Orozco, E, Banda Elizondo, R, Escalona Caamano, A, Frenk Baron, P, Aguilar Salinas, C, Mustieles Rocha, C, Vidrio Velazquez, M, Rodriguez Briones, I, Saldate Alonso, M, Velasco Sanchez, R, Groenemeijer, B, Ronner, E, Kuijper, A, Strikwerda, S, Van Kempen, W, Gijsbers, S, Oude Ophuis, A, Swart, H, Hoogenberg, K, Hovens, M, van Hessen, M, Westerink, J, Kragten, J, Nierop, P, Bax, W, Hartong, S, Nieuwdorp, M, Gonkel, F, Al Windy, N, Troquay, R, Schaafsma, H, Lieverse, A, Knufman, N, Tirador, L, Guenon, M, Ferrolino, A, Atilano, A, Aportadera, M, Que, M, Denopol, M, Tolentino, M, Jimeno, C, Wee, J, Mirasol, R, Panelo, A, Roxas, D, Palmes, P, Silva, A, Salvador, D, Rosita, R, Maravilla, L, Rogelio, G, Pacheco, E, Tin Hay, L, Prado, J, Krzyzagorska, E, Witek, R, Miklaszewicz, B, Sudnik, W, Pomiecko, W, Bochenek, A, Fares, I, Wujkowski, M, Korol, M, Powierza, S, Goch, A, Miekus, P, Siegel, A, Skierkowska, J, Romanczuk, P, Cygler, J, Landa, K, Szyprowska, E, Stachlewski, P, Czerski, T, Pawlowicz, L, Sowinski, D, Romanowski, L, Rudzki, H, Skorski, M, Jasiel-Wojculewicz, H, Stasiewski, A, Kania, G, Mirek-Bryniarska, E, Wojnowski, L, Korzeniak, R, Oh, T, Lee, M, Jang, H, Kim, S, Ku, B, Cha, B, Son, H, Lee, I, Park, J, Yu, S, Shon, H, Rhee, E, Cho, J, Park, T, Nam, J, Pintilei, E, Popescu, A, Nafornita, V, Gutu, O, Dumitrescu, A, Bala, C, Caceaune, E, Mindrescu, N, Morosanu, M, Bradescu, O, Munteanu, M, Voitec, M, Vlaiculescu, M, Hancu, N, Diaconu Sotropa, M, Lupu, S, Mateescu, A, Carlan, L, Marton, R, Lupusoru, D, Mot, A, Coman, A, Zaharie, D, Rebrov, A, Shutemova, E, Bolieva, L, Khalimov, Y, Statsenko, M, Galyavich, A, Koziolova, N, Shapovalova, Y, Pavlysh, E, Strongin, L, Vertkin, A, Vishneva, E, Pavlova, M, Khasanov, N, Antsiferov, M, Gavrisheva, I, Sokolova, N, Vorobyev, S, Morugova, T, Sinitsina, I, Ezhov, A, Kobalava, Z, Belenkiy, D, Supryadkina, T, Kazakov, Y, Oschepkova, E, Dreval, A, Novikova, T, Vishnevsky, A, Chizhov, D, Akatova, E, Vorokhobina, N, Ivanov, I, Dudinskaya, E, Konstantinov, V, Kanderkova, D, Pavlik, L, Raslova, K, Paulovic, V, Babikova, J, Belesova, K, Merciakova, M, Truban, J, Vargova, A, Fabryova, L, Slovenska, M, Plasil, R, Tomasova, L, Kollarova, D, Spodniakova, D, Kosikova, M, Dzuponova, J, Kurcova, I, Skripova, D, Gabrisova, A, Kalinova, S, Ranjith, N, Burgess, L, Mitha, I, Conradie, M, Distiller, L, Pillai, P, Pillay, S, Horak, A, Nethononda, R, van den Berg, E, Nortje, H, Bayat, J, Corbett, C, Abelson, M, van Zyl, L, Pillay, T, Wing, J, Kapp, C, Hidalgo Urbano, R, Gonzalez Juanatey, J, Blanco Coronado, J, Bruguera Cortada, J, Ferreiro Gutierrez, J, Quesada Simon, M, Castro, A, Delgado Alvarez, E, Freixa, R, Boada, A, Larnefeldt, H, Mooe, T, Koskinen, P, Lagerback, P, Linderfalk, C, Liu, B, Berndtsson Blom, K, Tengmark, B, Lindholm, C, Oweling, M, Albertsson, P, Alvarsson, M, Fant, S, Berglund, O, Hsia, C, Fang, C, Ueng, K, Wang, K, Lai, W, Mamanasiri, S, Wongvipaporn, C, Kuanprasert, S, Thongsri, T, Srimahachota, S, Boonyavarakul, A, Suwanwalaikorn, S, Tantiwong, P, Sritara, P, Sriwijitkamol, A, Sanguanwong, S, Chotinaiwattarakul, C, Piyayotai, D, Balci, M, Orbay, E, Saygili, F, Oguz, A, Altuntas, Y, Comlekci, A, Karpenko, O, Tkach, S, Vlasenko, M, Fushtey, I, Pertseva, T, Reshotko, D, Mostovoy, Y, Vizir, V, Kraiz, I, Amosova, K, Batushkin, V, Tseluyko, V, Koval, O, Strang, C, Bodalia, B, Pieters, R, Turner, W, Asamoah-Owusu, N, White, C, Calvert, J, Mcnally, D, Jones, N, Mckaig, G, Thompson, J, Mohr, S, Simpson, H, Conn, P, Mccoye, A, Rivero, O, Yazdani, S, Ince, C, Zeitlin, J, Wharton, T, Platt, G, Anderson, R, Angueira-Serrano, E, Lillestol, M, Hanlon, B, Soufer, J, Garcia, B, Iteld, B, Venugopal, C, Ahmed, A, Duardo-Guerra, Y, Jetty, P, Miranda, A, Wahlen, J, Lederman, S, Cohen, K, Lake, L, French, W, Tahirkheli, N, Baker, 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B., Tran Q. K., Tran N., Nguyen D., and Nguyen V.

Abstract

BACKGROUND The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to ≥60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], ≥1.3; P≥0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P = 0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P = 0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87)

Published
2019

13. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Author

Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P. -L., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., Perkovic, V, Mahaffey, Kw, Agarwal, R, Bakris, G, Brenner, Bm, Cannon, Cp, Charytan, Dm, de Zeeuw, D, Greene, T, Jardine, Mj, Heerspink, Hjl, Levin, A, Meininger, G, Neal, B, Pollock, C, Wheeler, Dc, Zhang, H, Zinman, B, Mcguire, Dk, Holman, R, Home, P, Scharfstein, D, Parfrey, P, Shahinfar, S, August, P, Chang, T, Sinha, Ad, Januzzi, J, Kolansky, D, Amerena, J, Hillis, G, Gorelick, P, Kissela, B, Kasner, S, Lindley, R, Fulcher, G, Ounadjela, S, Hufert, K, von Ingersleben, G, Gaglia, J, Harris, R, Hudson, M, Turchin, A, Cheifetz, A, Sheth, S, Feuerstein, J, Cohen, S, Jardine, M, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D 3rd, Obrador, G, Chertow, G, Hawley, C, Ji, L, Wada, T, Jha, V, Lim, Sk, Lim-Abrahan, Ma, Santos, F, Chae, Dw, Hwang, Sj, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, Jl, Kolesnyk, M, Morren, F, Goykhman, S, David, C, Yost, L, Wang, H, Hettiarachchi, M, 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Belo, D, Bentley-Lewis, R, Berenguer, R, Bermudez, L, Bernardo, M, Biscoveanu, M, Bowman-Stroud, C, Brandon, D, Brusco, O, Busch, R, Canaan, Y, Chilito, A, Christensen, T, Christiano, C, Christofides, E, Chuateco, C, Cohen, K, Cohen, R, Cohen-Stein, D, Cook, C, Coyne, D, Daboul, N, Darwish, R, Daswani, A, Deck, K, Desouza, C, Dev, D, Dhillon, M, Dua, S, Eder, F, Elosegui, Am, El-Shahawy, M, Ervin, J, Esquenazi, A, Evans, J, Fishbane, S, Frias, J, Galindo-Ramos, E, Galphin, C, Ghazi, A, Gonzalez, E, Gorson, D, Gowda, A, Greco, B, Grubb, S, Gulati, R, Hammoud, J, Handelsman, S, Hartman, I, Hershon, K, Hiser, D, Hon, G, Jacob, R, Jaime, M, Jamal, A, Kaupke, C, Keightley, G, Kern, E, Khanna, R, Khitan, Z, Kim, S, Kopyt, N, Kovesdy, C, Krishna, G, Kropp, J, Kumar, A, Kumar, J, Kumar, N, Kusnir, J, Lane, W, Lawrence, M, Lehrner, L, Lentz, J, Levinson, D, Lewis, D, Liss, K, Maddux, A, Maheshwari, H, Mandayam, S, Marar, I, Mehta, B, Middleton, J, Mordujovich, J, Moreda, R, Moustafa, M, Mujica Trenche, S, Narayanan, M, Narvarte, J, Nassar, T, Newman, G, Nichol, B, Nicol, P, Nisnisan, J, Nossuli, Ak, Obialo, C, Olelewe, S, Oliver, M, O'Shaughnessy, A, Padron, J, Pankhaniya, R, Parker, R, Patel, D, Patel, G, Patel, N, Pavon, H, Perez, A, Perez, C, Perlman, A, Pettis, K, Pharr, W, Phillips, A, Purighalla, R, Quesada-Suarez, L, Ranjan, R, Rastogi, S, Rendell, M, Rich, L, Robinson, M, Rodriguez, H, Rosas, S, Saba, F, Sankaram, R, Sarin, R, Schreiman, R, Scott, D, Sekkarie, M, Sensenbrenner, J, Shakeel, M, Shanik, M, Shaw, S, Smith, S, Solomon, R, Sprague, A, Spry, L, Suchinda, P, Sultan, S, Surampudi, P, Sussman, S, Tan, A, Terrelonge, A, Thompson, M, Trespalacios, F, Trippe, B, Trueba, P, Twahirwa, M, Updegrove, J, Van Buren, P, Vannorsdall, M, Varghese, F, Velasquez-Mieyer, P, Ventrapragada, S, Vukotic, G, Wadud, K, Warren, M, Watson, H, Watts, R, Weiner, D, Welker, J, Welsh, J, Williams, S, Zaniewski-Singh, M., Perkovic, Vlado, Jardine, Meg J, Neal, Bruce, Bompoint, Severine, Heerspink, Hiddo J L, Charytan, David M, Edwards, Robert, Agarwal, Rajiv, Bakris, George, Bull, Scott, Cannon, Christopher P, Capuano, George, Chu, Pei-Ling, de Zeeuw, Dick, Greene, Tom, Levin, Adeera, Pollock, Carol, Wheeler, David C, Yavin, Yshai, Zhang, Hong, Zinman, Bernard, Meininger, Gary, Brenner, Barry M, Mahaffey, Kenneth W, collaborator: Perkovic, V, Mahaffey, Kw, Agarwal, R, Bakris, G, Brenner, Bm, Cannon, Cp, Charytan, Dm, de Zeeuw, D, Greene, T, Jardine, Mj, Heerspink, Hjl, Levin, A, Meininger, G, Neal, B, Pollock, C, Wheeler, Dc, Zhang, H, Zinman, B, Mcguire, Dk, Holman, R, Home, P, Scharfstein, D, Parfrey, P, Shahinfar, S, August, P, Chang, T, Sinha, Ad, Januzzi, J, Kolansky, D, Amerena, J, Hillis, G, Gorelick, P, Kissela, B, Kasner, S, Lindley, R, Fulcher, G, Ounadjela, S, Hufert, K, von Ingersleben, G, Gaglia, J, Harris, R, Hudson, M, Turchin, A, Cheifetz, A, Sheth, S, Feuerstein, J, Cohen, S, Jardine, M, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D 3rd, Obrador, G, Chertow, G, Hawley, C, Ji, L, Wada, T, Jha, V, Lim, Sk, Lim-Abrahan, Ma, Santos, F, Chae, Dw, Hwang, Sj, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, Jl, Kolesnyk, M, Morren, F, Goykhman, S, David, C, Yost, L, Wang, H, Hettiarachchi, M, Thimmaiah, R, Koppolu, D, George, S, Schmidt, M, Ignjatovic, J, Chapin, L, Travis, K, Destree, M, Sood, V, Coffee, L, De Brouwer, K, Zaviriukha, V, Starzec, A, Koizumi, M, Lin, G, Chen, E, Lin, P, Leia, C, Mascaro, D, Amigo, A, Limos, A, Abrahamsen, I, Jaffer, S, Ahuad Guerrero, Ra, Albisu, Jp, Alvarisqueta, A, Bartolacci, I, Berli, Ma, Bordonava, A, Calella, P, Cantero, Mc, Cartasegna, Lr, Cercos, E, Coloma, Gc, Colombo, H, Commendatore, V, Cuadrado, J, Cuneo, Ca, Cusumano, Am, Douthat, Wg, Dran, Rd, Farias, E, Fernandez, Mf, Finkelstein, H, Fragale, G, Fretes, Jo, Garcia, Nh, Gastaldi, A, Gelersztein, E, Glenny, Ja, Gonzalez, Jp, Gonzalez Colaso, Pdc, Goycoa, C, Greloni, Gc, Guinsburg, A, Hermida, S, Juncos, Li, Klyver, Mi, Kraft, F, Krynski, F, Lanchiotti, Pv, Leon de la Fuente, Ra, Marchetta, N, Mele, P, Nicolai, S, Novoa, Pa, Orio, Si, Otreras, F, Oviedo, A, Raffaele, P, Resk, Jh, Rista, L, Rodriguez Papini, N, Sala, J, Santos, Jc, Schiavi, Lb, Sessa, H, Smith Casabella, T, Ulla, Mr, Valdez, M, Vallejos, A, Villarino, A, Visco, Ve, Wassermann, A, Zaidman, Cj, Cheung, Nw, Droste, C, Fraser, I, Johnson, D, Mah, Pm, Nicholls, K, Packham, D, Proietto, J, Roberts, A, Roger, S, Tsang, V, Raduan, Ra, Alves da Costa, Fa, Amodeo, C, Andreotti Turatti, La, Bregman, R, Camelo Sanches, Fc, Canani, Lh, Chacra, Ar, Cunha Borges, Jl, Cunha Vêncio, Sa, da Silva Franco, Rj, D'Avila, D, de Souza Portes, E, de Souza, P, Deboni, Lm, Filho, Ff, Geloneze Neto, B, Gomes, M, Kohara, Sk, Keitel, E, Kerr Saraiva, Jf, Kurtz Lisboa, Hr, de Carvalho Contieri, Fl, Milagres, R, Montenegro Junior, R, Moreira de Brito, C, Nazzer Hissa, M, Nazario Sabbag, Âr, Noronha, I, Panarotto, D, Pecoits Filho, R, Pereira, Ma, Saporito, W, Scotton, A, Schuch, T, Simões de Almeida, R, Slompo Ramos, C, Soares Felício, J, Thomé, F, Tibes Hachmann, Jc, Yamada, S, Yoiti Hayashida, C, Zanata Petry, Tb, Zanella, Mt, Andreeva, V, Angelova, A, Dimitrov, S, Genadieva, V, Genova-Hristova, G, Hristozov, K, Kamenov, Z, Koundurdjiev, A, Lozanov, L, Margaritov, V, Nonchev, B, Rangelov, R, Shinkov, A, Temelkova, M, Velichkova, E, Yakov, A, Aggarwal, N, Aronson, R, Bajaj, H, Chouinard, G, Conway, J, Cournoyer, S, Daroza, G, De Serres, S, Dubé, F, Goldenberg, R, Gupta, A, Gupta, M, Henein, S, Khandwala, H, Leiter, L, Madore, F, Mcmahon, A, Muirhead, N, Pichette, V, Rabasa-Lhoret, R, Steele, A, Tangri, N, Torshizi, A, Woo, V, Zalunardo, N, Fernández Montenegro, Ma, Godoy Jorquera, Jg, Medina Fariña, M, Saavedra Gajardo, V, Vejar, M, Chen, N, Chen, Q, Gan, S, Kong, Y, Li, D, Li, W, Li, X, Lin, H, Liu, J, Lu, W, Mao, H, Ren, Y, Song, W, Sun, J, Sun, L, Tu, P, Wang, G, Yang, J, Yin, A, Yu, X, Zhao, M, Zheng, H, Accini Mendoza, Jl, Arcos, E, Avendano, J, Diaz Ruiz, Jea, Garcia Ortiz, Lh, Gonzalez, A, Hernandez Triana, E, Higuera, Jd, Malaver, N, Molina de Salazar, Di, Rosero, R, Terront Lozano, Ma, Valderrama Cometa, L, Valenzuela, A, Vargas Alonso, Rd, Villegas, I, Yupanqui, H, Bartaskova, D, Barton, P, Belobradkova, J, Dohnalova, L, Drasnar, T, Ferkl, R, Halciakova, K, Klokocnikova, V, Kovar, R, Lastuvka, J, Lukac, M, Pesickova, S, Peterka, K, Pumprla, J, Rychlik, I, Saudek, F, Tesar, V, Valis, M, Weiner, P, Zemek, S, Alamartine, E, Borot, S, Cariou, B, Dussol, B, Fauvel, Jp, Gourdy, P, Klein, A, Le Meur, Y, Penfornis, A, Roussel, R, Saulnier, Pj, Thervet, E, Zaoui, P, Burst, V, Faghih, M, Faulmann, G, Haller, H, Jerwan-Keim, R, Maxeiner, S, Paschen, B, Plassmann, G, Rose, L, Gonzalez Orellana, Ra, Haase, Fp, Moreira Diaz, Jp, Ramirez Roca, La, Sánchez Arenales, Ja, Sanchez Polo, Jv, Turcios Juarez, E, Csecsei, G, Csiky, B, Danos, P, Deak, L, Dudas, M, Harcsa, E, Keltai, K, Keresztesi, S, Kiss, K, Konyves, L, Major, L, Mileder, M, Molnar, M, Mucsi, J, Oroszlan, T, Ory, I, Paragh, G, Peterfai, E, Petro, G, Revesz, K, Takacs, R, Vangel, S, Vasas, S, Zsom, M, Abraham, O, Bhushan, R, Deepak, D, Edwin, Fm, Gopalakrishnan, N, Gracious, N, Hansraj, A, Jain, D, Keshavamurthy, Cb, Khullar, D, Manisha, S, Peringat, J, Prasad, N, Satyanarayana, Rk, Sreedhar, R, Sreelatha, M, Sudhakar, B, Vyasam, Rc, Bonadonna, R, Castellino, P, Ceriello, A, Chiovato, L, De Cosmo, S, Derosa, G, Di Carlo, A, Di Cianni, G, Frascà, G, Fuiano, G, Gambaro, G, Garibotto, G, Giorda, C, Malberti, F, Mandreoli, M, Mannucci, E, Orsi, E, Piatti, P, Santoro, D, Sasso, Fc, Serviddio, G, Stella, A, Trevisan, R, Veronelli, Am, Zanoli, L, Akiyama, H, Aoki, H, Asano, A, Iitsuka, T et al, Groningen Kidney Center (GKC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
Aged, Canagliflozin, Cardiovascular Diseases, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Sodium-Glucose Transporter 2 Inhibitors, Type 2 diabetes, 030204 cardiovascular system & hematology, Diabetic nephropathy, Kidney Failure, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, 03.02. Klinikai orvostan, Dapagliflozin, Chronic, 11 Medical and Health Sciences, EMPAGLIFLOZIN, General Medicine, Life Sciences & Biomedicine, Type 2, medicine.drug, medicine.medical_specialty, Nephropathy, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, Diabetes mellitus, General & Internal Medicine, CREDENCE Trial Investigators, medicine, Diabetes Mellitus, Science & Technology, business.industry, urogenital system, diabetic nephropathy, Type 2 Diabetes Mellitus, KIDNEY-DISEASE, medicine.disease, chemistry, business, Kidney disease
Abstract

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of

Published
2019

17. Long‐term efficacy and safety of combined insulin and glucagon‐like peptide‐1 therapy: Evidence from the LEADER trial

Author

Tack, CJ, Jacob, S, Desouza, C, Bain, SC, Buse, JB, Nauck, MA, Petrie, JR, Poulter, NR, Pratley, RE, Stegmann, HVBK, Bosch-Traberg, H, Startseva, E, Zinman, B, and LEADER Publication Committee on behalf of the LEADER Trial Investigators

Subjects
Male, Agonist, medicine.medical_specialty, Combination therapy, medicine.drug_class, insulin analogues, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, glucagon‐like peptide‐1 analogue, Type 2 diabetes, Disease, 030204 cardiovascular system & hematology, glucagon-like peptide-1 analogue, Placebo, Glucagon-Like Peptide-1 Receptor, Endocrinology & Metabolism, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, LEADER Publication Committee on behalf of the LEADER Trial Investigators, Internal medicine, Internal Medicine, Humans, Hypoglycemic Agents, Insulin, Medicine, Aged, Glycated Hemoglobin, liraglutide, business.industry, Liraglutide, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], 1103 Clinical Sciences, Original Articles, Middle Aged, medicine.disease, Glucagon-like peptide-1, 3. Good health, Diabetes Mellitus, Type 2, insulin therapy, Female, Original Article, type 2 diabetes, business, medicine.drug
Abstract

Contains fulltext : 215463.pdf (Publisher’s version ) (Open Access) AIM: Glucagon-like peptide-1 receptor agonist (GLP-1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long-term data are lacking. The aim was to assess the long-term efficacy of the GLP-1RA liraglutide in subgroups by insulin use in the LEADER trial. MATERIALS AND METHODS: LEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal-only insulin, other insulin or no insulin). Insulin was a non-random treatment allocation as part of standard of care therapy. RESULTS: At baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal-only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no-insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal-only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal-only and no-insulin subgroups. CONCLUSIONS: In patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.

Published
2019

20. Kidney, cardiovascular, and safety outcomes of canagliflozin according to baseline albuminuria a credence secondary analysis

Author

Jardine, M, Zhou, Z, Lambers Heerspink, HJ, Hockham, C, Li, Q, Agarwal, R, Bakris, GL, Cannon, CP, Charytan, DM, Greene, T, Levin, A, Li, JW, Neuen, BL, Neal, B, Oh, R, Oshima, M, Pollock, C, Wheeler, DC, de Zeeuw, D, Zhang, H, Zinman, B, Mahaffey, KW, Perkovic, V, Jardine, M, Zhou, Z, Lambers Heerspink, HJ, Hockham, C, Li, Q, Agarwal, R, Bakris, GL, Cannon, CP, Charytan, DM, Greene, T, Levin, A, Li, JW, Neuen, BL, Neal, B, Oh, R, Oshima, M, Pollock, C, Wheeler, DC, de Zeeuw, D, Zhang, H, Zinman, B, Mahaffey, KW, and Perkovic, V

Abstract

Background and objectives The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. Design, setting, participants, & measurements The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. Results Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (Pheterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories wer

Published
2021

21. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial

Author

Sarraju, A, Li, JW, Cannon, CP, Chang, TI, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Greene, T, Heerspink, HJL, Levin, A, Neal, B, Pollock, C, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Perkovic, V, Jardine, M, Mahaffey, KW, Sarraju, A, Li, JW, Cannon, CP, Chang, TI, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Greene, T, Heerspink, HJL, Levin, A, Neal, B, Pollock, C, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Perkovic, V, Jardine, M, and Mahaffey, KW

Abstract

We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P < .001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.

Published
2021

22. Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice

Author

Oshima, M, Jardine, MJ, Agarwal, R, Bakris, G, Cannon, CP, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Lim, SK, Mahaffey, KW, Neal, B, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, Heerspink, HJL, Oshima, M, Jardine, MJ, Agarwal, R, Bakris, G, Cannon, CP, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Lim, SK, Mahaffey, KW, Neal, B, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, and Heerspink, HJL

Abstract

Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.

Published
2021

23. Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study

Author

Biessels, G.J. (Geert Jan), Verhagen, C. (Chloë), Janssen, J. (Jolien), Berg, E. (Esther) van den, Wallenstein, G. (Gudrun), Zinman, B. (Bernard), Espeland, M.A. (Mark A.), Johansen, O.E. (Odd Erik), Biessels, G.J. (Geert Jan), Verhagen, C. (Chloë), Janssen, J. (Jolien), Berg, E. (Esther) van den, Wallenstein, G. (Gudrun), Zinman, B. (Bernard), Espeland, M.A. (Mark A.), and Johansen, O.E. (Odd Erik)

Abstract

Aims/hypothesis: Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes. Methods: The CAROLINA-COGNITION study was part of the randomised, double-blind, active-controlled CAROLINA trial that evaluated the cardiovascular safety of linagliptin vs glimepiride in individuals with age ≥40 and ≤85 years and HbA1c 48–69 mmol/mol (6.5–8.5%) receiving standard care, excluding insulin therapy. Participants were randomised 1:1 using an interactive telephone- and web-based system and treatment assignment was determined by a computer-generated random sequence with stratification by center. The primary cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression-based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning, in participants with a baseline MMSE score ≥24. Prespecified additional analyses included effects on ACD at week 160, in subgroups (sex, age, race, ethnicity, depressive symptoms, cardiovascular risk, duration of type 2 diabetes, albuminuria), and absolute changes in cognitive performance. Participants, caregivers, and people involved in measurements, examinations or adjudication, were all masked to treatment assignment. Results: Of 6033 participants recruited from hospital and primary care sites, 3163 (38.0% female, mean age/diabetes duration 64/7.6 years, MMSE score 28.5, HbA1c 54 mmol/mol [7.1%]) represent the CAROLINA-COGNITION cohort. Over median 6.1 years, ACD occurred in 27.8% (449/1618, linagliptin) vs 27.6% (426/1545, glimepiride), OR 1.01 (95% CI 0.86, 1.18). Also, no differences in ACD were observed at week 160 (OR 1.07 [0.91, 1.25]), between treatments across subgroups, or for absolute cognitive changes. Conclusions/inte

Published
2021
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31. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

Author

Wiviott S. D., Raz I., Bonaca M. P., Mosenzon O., Kato E. T., Cahn A., Silverman M. G., Zelniker T. A., Kuder J. F., Murphy S. A., Bhatt D. L., Leiter L. A., McGuire D. K., Wilding J. P. H., Ruff C. T., Nilsson G. I., Fredriksson M., Johansson P. A., Langkilde A. M., Sabatine M. S., Bansilal S., Furtado R., Fish M. P., Gabovitch D., Jevne A., Ahern S., Im K., Goodrich E. L., Lowe C., Fisher N., Gannon J., Trindade S., Towarowski A., Fox Y., Johnsson E., Ranft S., Faber B., Wallander M., Weiss A., Buskila A., Abola M. T. B., Ardissino D., Averkov O., Aylward P., Bode C., Bonnici F., Bonora E., Budaj A. J., Cernea S., Chiang C. E., Cooper M., Dalby A., Deerochanawong C., Dellborg M., Diaz R., Dimulescu D., Eliaschewitz F. G., Goudev A. R., Hadjadj S., Herrera M., Huo Y., Jermendy G., Ji L., Kadowaki T., Kiss R., Kooy A., Kumar K. M. P., Lewis B., Litwak L., Lopez-Sendon J., Ma R., Merlini P. A., Nauck M. A., Nguyen T. K., Nicolau J. C., Ostgren C. J., Ophuis T. O., Padilla F., Pais P., Park K. S., Parkhomenko A., Ray K., Rosenstock J., Ruda M., Satman I., Shestakova M., Smahelova A., Spinar J., Strojek K., Sy R., Tankova T., Theroux P., Tkac I., Van Gaal L., Wainstein J., Harrington R. A., Droller M. J., Lee K. L., Nesto R. W., Tuomilehto J., Hedlin H., Desai M., Sayfer I., Alexanian S., Awtry E., Bentley-Lewis R., Berger C. J., Croce K., Desai A., Garg R. K., Gelfand E., Gignac G., Goessling W., Ho C., Hochberg E., Lane A., Larrey D., Leeman D. E., Lewis J., Link M. S., McDonnell M. E., Norden A. D., Pande A., Rosenberg C., Rost N., Ruberg F., Schiff E., Silverman S., Singhal A., Wagner A., Wolpin B., Aizenberg D., Fernandez M., Sala J., Maffei L., Luquez C., Waitman J., Rista L., Nardone L., Sposetti G., Cantero M., Alvarisqueta A., Montana O., Cuadrado J., Cartasegna L., Baccaro C., Chertkoff A., Sanabria H., Vainstein N., Amerena J., Arya K., d'Emden M., Proietto J., Moses R., Colquhoun D., Stranks S., Lehman R., Hamilton A., Whelan A., Simpson R., Purnell P., Abhayaratna W., Hammett C., McKeirnan M., Sullivan D., Bach L., Hughes K., Mathieu C., Vercammen C., Scheen A., Duyck F., Cools F., De Wolf L., Verhaegen A., Nobels F., Missault L., Crenier L., Thoeng J., Wollaert B., Vandenbroucke M., Eliaschewitz F., Borges J. L. C., Turatti L., Lima F. G., dos Santos F., Kerr Saraiva J., Pereira M., Pereira A., Precoma D. B., Filho G. F. V., Reis G., Maia L. 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H, Sueyoshi, A, Fukuda, K, Yasumoto, H, Matsubayashi, S, Kawajiri, K, Togashi, Y, Senokuchi, T, Ohta, Y, Yamauchi, T, Node, K, Alcocer Gamba, M, Herrera Marmolejo, M, De los Rios Ibarra, M, Gonzalez Galvez, G, Garcia Cantu, E, Leguizamo Dimas, A, Luna Ceballos, R, Medina Pech, C, Stobschinski de Alba, C, Gonzalez Gonzalez, J, Padilla Padilla, F, Fanghanel Salmon, G, Robles Torres, F, Lopez Rosas, E, Pelayo Orozco, E, Banda Elizondo, R, Escalona Caamano, A, Frenk Baron, P, Aguilar Salinas, C, Mustieles Rocha, C, Vidrio Velazquez, M, Rodriguez Briones, I, Saldate Alonso, M, Velasco Sanchez, R, Groenemeijer, B, Ronner, E, Kuijper, A, Strikwerda, S, Van Kempen, W, Gijsbers, S, Oude Ophuis, A, Swart, H, Hoogenberg, K, Hovens, M, van Hessen, M, Westerink, J, Kragten, J, Nierop, P, Bax, W, Hartong, S, Nieuwdorp, M, Gonkel, F, Al Windy, N, Troquay, R, Schaafsma, H, Lieverse, A, Knufman, N, Tirador, L, Guenon, M, Ferrolino, A, Atilano, A, Aportadera, M, Que, M, Denopol, M, Tolentino, M, Jimeno, C, Wee, J, Mirasol, R, Panelo, A, Roxas, D, Palmes, P, Silva, A, Salvador, D, Rosita, R, Maravilla, L, Rogelio, G, Pacheco, E, Tin Hay, L, Prado, J, Krzyzagorska, E, Witek, R, Miklaszewicz, B, Sudnik, W, Pomiecko, W, Bochenek, A, Fares, I, Wujkowski, M, Korol, M, Powierza, S, Goch, A, Miekus, P, Siegel, A, Skierkowska, J, Romanczuk, P, Cygler, J, Landa, K, Szyprowska, E, Stachlewski, P, Czerski, T, Pawlowicz, L, Sowinski, D, Romanowski, L, Rudzki, H, Skorski, M, Jasiel-Wojculewicz, H, Stasiewski, A, Kania, G, Mirek-Bryniarska, E, Wojnowski, L, Korzeniak, R, Oh, T, Lee, M, Jang, H, Kim, S, Ku, B, Cha, B, Son, H, Lee, I, Park, J, Yu, S, Shon, H, Rhee, E, Cho, J, Park, T, Nam, J, Pintilei, E, Popescu, A, Nafornita, V, Gutu, O, Dumitrescu, A, Bala, C, Caceaune, E, Mindrescu, N, Morosanu, M, Bradescu, O, Munteanu, M, Voitec, M, Vlaiculescu, M, Hancu, N, Diaconu Sotropa, M, Lupu, S, Mateescu, A, Carlan, L, Marton, R, Lupusoru, D, Mot, A, Coman, A, Zaharie, D, Rebrov, A, Shutemova, E, Bolieva, L, Khalimov, Y, Statsenko, M, Galyavich, A, Koziolova, N, Shapovalova, Y, Pavlysh, E, Strongin, L, Vertkin, A, Vishneva, E, Pavlova, M, Khasanov, N, Antsiferov, M, Gavrisheva, I, Sokolova, N, Vorobyev, S, Morugova, T, Sinitsina, I, Ezhov, A, Kobalava, Z, Belenkiy, D, Supryadkina, T, Kazakov, Y, Oschepkova, E, Dreval, A, Novikova, T, Vishnevsky, A, Chizhov, D, Akatova, E, Vorokhobina, N, Ivanov, I, Dudinskaya, E, Konstantinov, V, Kanderkova, D, Pavlik, L, Raslova, K, Paulovic, V, Babikova, J, Belesova, K, Merciakova, M, Truban, J, Vargova, A, Fabryova, L, Slovenska, M, Plasil, R, Tomasova, L, Kollarova, D, Spodniakova, D, Kosikova, M, Dzuponova, J, Kurcova, I, Skripova, D, Gabrisova, A, Kalinova, S, Ranjith, N, Burgess, L, Mitha, I, Conradie, M, Distiller, L, Pillai, P, Pillay, S, Horak, A, Nethononda, R, van den Berg, E, Nortje, H, Bayat, J, Corbett, C, Abelson, M, van Zyl, L, Pillay, T, Wing, J, Kapp, C, Hidalgo Urbano, R, Gonzalez Juanatey, J, Blanco Coronado, J, Bruguera Cortada, J, Ferreiro Gutierrez, J, Quesada Simon, M, Castro, A, Delgado Alvarez, E, Freixa, R, Boada, A, Larnefeldt, H, Mooe, T, Koskinen, P, Lagerback, P, Linderfalk, C, Liu, B, Berndtsson Blom, K, Tengmark, B, Lindholm, C, Oweling, M, Albertsson, P, Alvarsson, M, Fant, S, Berglund, O, Hsia, C, Fang, C, Ueng, K, Wang, K, Lai, W, Mamanasiri, S, Wongvipaporn, C, Kuanprasert, S, Thongsri, T, Srimahachota, S, Boonyavarakul, A, Suwanwalaikorn, S, Tantiwong, P, Sritara, P, Sriwijitkamol, A, Sanguanwong, S, Chotinaiwattarakul, C, Piyayotai, D, Balci, M, Orbay, E, Saygili, F, Oguz, A, Altuntas, Y, Comlekci, A, Karpenko, O, Tkach, S, Vlasenko, M, Fushtey, I, Pertseva, T, Reshotko, D, Mostovoy, Y, Vizir, V, Kraiz, I, Amosova, K, Batushkin, V, Tseluyko, V, Koval, O, Strang, C, Bodalia, B, Pieters, R, Turner, W, Asamoah-Owusu, N, White, C, Calvert, J, Mcnally, D, Jones, N, Mckaig, G, Thompson, J, Mohr, S, Simpson, H, Conn, P, Mccoye, A, Rivero, O, Yazdani, S, Ince, C, Zeitlin, J, Wharton, T, Platt, G, Anderson, R, Angueira-Serrano, E, Lillestol, M, Hanlon, B, Soufer, J, Garcia, B, Iteld, B, Venugopal, C, Ahmed, A, Duardo-Guerra, Y, Jetty, P, Miranda, A, Wahlen, J, Lederman, S, Cohen, K, Lake, L, French, W, Tahirkheli, N, Baker, S, Stoltz, R, Wilson, J, Nadar, V, Brown, J, Larrain, G, Wiseman, A, Ruoff, G, Williams, M, Tan, A, Hartman, I, Singh, N, Graf, R, Wakefield, P, Mcneill, R, Byars, W, Reyes Almodovar, R, Jones, S, Kantaros, L, Hegedosh, N, Graves, M, Bernstein, M, Falkowski, S, Bialow, M, Paraschos, A, Dagher, G, Arif, A, Condit, J, Chaykin, L, Grunstra, B, Earl, J, Unks, D, Srivastava, S, Benson, M, Huffman, C, Miller, G, Willis, J, Bender, K, Martin, E, Blackmore, R, Rohr, K, Chilka, S, Gadowski, G, Fitz-Patrick, D, Benjamin, S, Morin, D, Zias Dilena, A, Acosta, R, Claassen, D, Miranda, F, Raad, G, Inzerello, A, Porter, J, Bhattacharya, A, Gutmann, J, Korpas, D, Syed, M, Zieve, F, Raisinghani, A, Alam, S, Bartkowiak, A, Boccalandro, F, Talano, J, Mercado, A, Krichmar, P, Oldfield, C, Adams, K, Gorman, T, Lewis, D, Shah, R, Shockey, G, Lefebvre, G, Andrawis, N, Tami, L, Bittar, N, Khan, M, Rink, L, Hendrix, E, Wood, J, Robinson, J, Pavon, H, Irfan, M, Gonzalez, E, Singal, R, Shore, K, Saba, F, Bianco, J, Erickson, B, Gorson, D, Puri, S, Arauz-Pacheco, C, Forman, S, Akyea-Djamson, A, Lieber, I, Barker, B, Desai, P, Sotolongo, C, Steinhoff, J, Hill, R, Radin, M, Patel, R, Lieberman, S, Wenocur, H, Dagogo-Jack, S, Lupovitch, S, Ison, R, Bacharach, J, Diogo, J, Mazzella, M, Greenwald, J, Quadrel, M, Mayer, N, Datu, J, Mccartney, M, Bruce, T, Singal, D, Turner, J, Videau, B, Fritz, R, Fox, D, Calatayud, G, Sheldon, W, Kereiakes, D, Thomas, J, Salacata, A, Mccullum, K, Harris, B, de Souza, J, Rahman, A, Blumenthal, S, Narayan, P, Bloch, M, Augenbraun, C, Bernstein, R, Perlman, R, Berman, J, Labryer, L, Wynne, A, Fish, J, Zarich, S, Gabra, N, Popeil, L, Hermany, P, Barreto, A, Pomposini, D, Gonzalez-Campoy, J, Langer, M, Bayron, C, Suneja, R, Kamlet, J, Wheeler, K, Hurley, S, Sharma, S, Wefald, F, Hershon, K, O'Connor, T, Pueblitz, G, Laguerre, J, Amin, M, Alfonso, T, Jaffrani, N, Isserman, S, Portnay, E, Vlastaris, A, Dy, J, Hagan, M, Noveck, H, Kraft, P, Andersen, J, Foley, B, Carr, K, Gelormini, J, Williams, T, Landau, C, Richwine, R, Thakkar, M, Karim, A, Madhun, Z, Francyk, D, Lamantia, J, Baker, B, Zhang, W, Lev, V, Hasan, M, Captain, A, Herzog, W, Friedman, K, Lawson, W, Desai, V, Ow, C, Simons, R, Mandviwala, M, Le, T, Hack, T, Zebrack, J, Henderson, D, Dejulia, J, Mehta, R, Reza, S, Poonawala, R, Awad, A, Velasquez, M, Mohiuddin, S, Salazar Sharma, M, Myrick, G, Gottlieb, D, Ovalle, F, Alfieri, A, Ahmed, S, Bohula, E, Donahoe, S, Longshaw, K, Eshaghian, S, Lash, J, Goldberg, R, Fox, B, Mostel, E, Dobies, D, Ward, H, Burbano, J, Puleo, P, Lenhard, M, Korn, D, Thadani, U, Bradley, A, Kmetzo, J, Heasley, E, Raikhel, M, Mahr, N, Bittar, G, Fuentes, F, Raghu, P, Diep, T, Tran, Q, Tran, N, Nguyen, D, and Nguyen, V

Subjects
Male, medicine.medical_specialty, dapagliflozin, placebo, [SDV]Life Sciences [q-bio], Renal function, Type 2 diabetes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Glucosides, Diabetes mellitus, Internal medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Benzhydryl Compounds, Dapagliflozin, Sodium-Glucose Transporter 2 Inhibitors, ComputingMilieux_MISCELLANEOUS, Aged, Heart Failure, Canagliflozin, business.industry, [SDV.BA]Life Sciences [q-bio]/Animal biology, General Medicine, Middle Aged, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, Hospitalization, Diabetes Mellitus, Type 2, chemistry, Cardiovascular Diseases, Heart failure, Cardiology, Female, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Mace, medicine.drug
Abstract

BACKGROUND The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to ≥60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], ≥1.3; P≥0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P = 0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P = 0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3%vs. 0.1%, P = 0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P≥0.001). CONCLUSIONS In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARETIMI 58 ClinicalTrials.gov number, NCT01730534

Published
2019

33. Cardiovascular and kidney implications of the initial response in estimated glomerular filtration rate to sodium glucose cotransporter-2 inhibition with empagliflozin: the ‘eGFR dip’ in EMPA-REG OUTCOME

Author

Kraus, BJ, additional, Weir, MR, additional, Bakris, GL, additional, Mattheus, M, additional, Cherney, DZI, additional, Sattar, N, additional, Heerspink, HJL, additional, Ritter, I, additional, von Eynatten, M, additional, Zinman, B, additional, Inzucchi, SE, additional, Wanner, C, additional, and Koitka-Webe, A, additional

Published
2021
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39. Risk factors for kidney disorders in patients with type 2 diabetes at high cardiovascular risk: An exploratory analysis (DEVOTE 12)

Author

Amod, A, Buse, JB, McGuire, DK, Pieber, TR, Pop-Busui, R, Pratley, RE, Zinman, B, Hansen, MB, Jia, T, Mark, T, Poulter, NR, and DEVOTE Study Group

Subjects
Male, medicine.medical_specialty, Time Factors, type 2 diabetes mellitus, Endocrinology, Diabetes and Metabolism, insulin analogues, DEVOTE Study Group, Insulin Glargine, Type 2 diabetes, urologic and male genital diseases, Cardiovascular, Kidney, Risk Assessment, CVOT, Endocrinology & Metabolism, Double-Blind Method, chronic renal failure, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Hypoglycemic Agents, In patient, Renal Insufficiency, Chronic, business.industry, Type 2 Diabetes Mellitus, 1103 Clinical Sciences, Exploratory analysis, Acute Kidney Injury, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, diabetic kidney disease, Insulin, Long-Acting, Treatment Outcome, Diabetes Mellitus, Type 2, Heart Disease Risk Factors, 1116 Medical Physiology, Chronic renal failure, Original Article, Female, Kidney disorder, 1115 Pharmacology and Pharmaceutical Sciences, Cardiology and Cardiovascular Medicine, business, Cardiovascular outcomes, Glomerular Filtration Rate
Abstract

Aim: To investigate risk factors associated with kidney disorders in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk. Methods: In DEVOTE, a cardiovascular outcomes trial, 7637 patients were randomised to insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100), with standard of care. In these exploratory post hoc analyses, serious adverse event reports were searched using Standardised MedDRA® Queries related to chronic kidney disease (CKD) or acute kidney injury (AKI). Baseline predictors of CKD, AKI and change in estimated glomerular filtration rate (eGFR) were identified using stepwise selection and Cox or linear regression. Results: Over 2 years, eGFR (mL/min/1.73 m2) decline was small and similar between treatments (degludec: 2.70; glargine U100: 2.92). Overall, 97 and 208 patients experienced CKD and AKI events, respectively. A history of heart failure was a risk factor for CKD (hazard ratio [HR] 1.97 [95% confidence interval [CI] 1.41; 2.75]) and AKI (HR 2.28 [95% CI 1.64; 3.17]). A history of hepatic impairment was a significant predictor of CKD (HR 3.28 [95% CI 2.12; 5.07]) and change in eGFR (estimate: −8.59 [95% CI −10.20; −7.00]). Conclusion: Our findings indicate that traditional, non-modifiable risk factors for kidney disorders apply to insulin-treated patients with T2D at high CV risk. Trial registration: NCT01959529 (ClinicalTrials.gov).

Published
2020

40. The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: analysis of the CREDENCE trial

Author

de Zeeuw, D., Arnott, C., Li, J. -W., Cannon, C. P., Neuen, B. L., Heerspink, H. J. L., Neal, B., Charytan, D. M., Bakris, G., Chang, T. -H., Rosenthal, N., Zinman, B., Perkovic, V., Jardine, M. J., Mahaffey, K. W., Groningen Kidney Center (GKC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
Endocrinology & Metabolism, Science & Technology, 1114 Paediatrics and Reproductive Medicine, 1103 Clinical Sciences, Life Sciences & Biomedicine, 1117 Public Health and Health Services
Published
2020

41. Sex disparities in cardiovascular outcome trials of diabetes populations: a systematic review and meta-analysis

Author

Clemens, K, Woodward, M, Neal, B, Zinman, B, and Cheruvath, P

Abstract

Background: Sex differences have been described in cardiovascular outcome trials (CVOTs) of diabetes populations. Purpose: We systematically reviewed for baseline sex differences in CV risk factors and CV protection therapy in diabetes CVOTs published since 2008. Data Sources: Randomized placebo-controlled trials that evaluated the effect of diabetes medications (oral or injectable) on 3 or 4-point MACE in individuals ≥18 years with type 2 diabetes. Study Selection: Included trials reported baseline sex-specific characteristics including standard medications for the reduction of CV risk. Our primary interest was to examine for sex differences in CV risk factors and CV protection therapy. Data Extraction: Two reviewers independently abstracted study data. Data Synthesis: We included 5 CVOTs of 46 606 participants. We summarized sex-specific data using mean differences (MDs) and relative risks (RR), and pooled estimates using random effects meta-analysis. There were fewer women than men (28.5-35.8% women) across trials. Women were older (MD 1.03 years, 95% CI 0.18 to 1.89), and more often had stroke (RR 1.28, 1.09 to 1.50), heart failure (RR 1.30, 1.21 to 1.40), peripheral arterial disease (RR X, X to X) and chronic kidney disease (RR X, X to X). Women less often used statins (RR 0.90, 0.86 to 0.93) and beta-blockers (RR 0.93, 0.88 to 0.97), and had higher systolic blood pressure (MD 1.66 mmHg, 0.90 to 2.41), low-density lipoprotein cholesterol (MD 0.34 mmol/L, 0.29 to 0.39) and hemoglobin A1c (MD 0.11%, 0.09 to 0.14 or 1.2 mmol/mol, 1.0 to 1.5) than men. Limitations: We could not carry out meaningful subgroup analyses due to a small number of studies. Our study is not generalizable to low CV risk groups or high-risk CV patients in routine care. Conclusions: There were baseline sex disparities in diabetes CVOTs. We suggest ongoing efforts to recruit women in clinical trials, and the promotion of equitable CV management across the sexes.

Published
2020

42. Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials

Author

Monk Fries, T., Leiter, L.A., Rasmussen, S., Mazer, C.D., McGuire, D.K., Verma, S., Bhatt, D.L., Bain, S.C., Pratley, R.E., Buse, J.B., Vrazic, H., and Zinman, B.

Abstract

otherwise, there was no statistical heterogeneity for either GLP-1 RA versus placebo across BMI categories for key CV and kidney outcomes. The lack of statistical heterogeneity from these cardiorenal outcomes implies that liraglutide and semaglutide may be beneficial for many patients and is probable not to depend on their baseline BMI, but further study is needed., Pinteraction =.02), 25, ≥25-&lt, Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (, 35 and ≥35 kg/m2), and CV and kidney outcomes with GLP-1 RA versus placebo were analysed. All baseline BMI data from LEADER (n = 9331) and SUSTAIN 6 (n = 3290) were included (91% and 92% of patients with overweight or obesity, respectively). In SUSTAIN 6, nominally significant heterogeneity of semaglutide efficacy by baseline BMI was observed for CV death/myocardial infarction/stroke (major adverse CV events, primary outcome of both, Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain, 30, ≥30-&lt, therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (&lt

Published
2020
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43. Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: Results from the LEADER and SUSTAIN 6 clinical trials

Author

Sejersten Ripa, M., Honoré, J.B., Rasmussen, S., Buse, J.B., Zinman, B., Bain, S.C., Verma, S., Pratley, R.E., Mann, J.F.E., and Nauck, M.A.

Abstract

The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P =.0136; SUSTAIN 6: 1.56 [1.14; 2.17], P =.0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease.

Published
2020
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44. Cardiovascular risk reduction with liraglutide: An exploratory mediation analysis of the leader trial

Author

Linder, M., Pocock, S., Zinman, B., Nissen, S.E., Nauck, M.A., Mann, J.F.E., Pratley, R.E., Fries, T.M., Buse, J.B., Ørsted, D.D., Poulter, N.R., and Bain, S.C.

Abstract

OBJECTIVE The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: Glycated hemoglobin (HbA1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.

Published
2020
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45. Glomerular Filtration Rate and Associated Risks of Cardiovascular Events, Mortality, and Severe Hypoglycemia in Patients with Type 2 Diabetes: Secondary Analysis (DEVOTE 11)

Author

Amod, A, Buse, JB, McGuire, DK, Pieber, TR, Pop-Busui, R, Pratley, RE, Zinman, B, Hansen, MB, Jia, T, Mark, T, Poulter, NR, and DEVOTE Study Group

Subjects
Insulin degludec, CHRONIC KIDNEY-DISEASE, medicine.medical_specialty, ALBUMINURIA, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, DEVOTE Study Group, Renal function, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, ALL-CAUSE, urologic and male genital diseases, 03 medical and health sciences, Endocrinology & Metabolism, MELLITUS, DEGLUDEC, 0302 clinical medicine, Insulin glargine U100, Diabetes mellitus, Internal medicine, Chronic kidney disease, Internal Medicine, Medicine, Original Research, Severe hypoglycemia, Science & Technology, business.industry, Insulin glargine, Insulin, EMPAGLIFLOZIN, medicine.disease, Cardiovascular disease, female genital diseases and pregnancy complications, 3. Good health, RENAL OUTCOMES, LIRAGLUTIDE, Basal insulin analogs, Glomerular filtration rate, business, FOLLOW-UP, Life Sciences & Biomedicine, Mace, medicine.drug, Kidney disease, INSULIN GLARGINE
Abstract

Introduction The associations of chronic kidney disease (CKD) severity, cardiovascular disease (CVD), and insulin with the risks of major adverse cardiovascular events (MACE), mortality, and severe hypoglycemia in patients with type 2 diabetes (T2D) at high cardiovascular (CV) risk are not known. This secondary, pooled analysis of data from the DEVOTE trial examined whether baseline glomerular filtration rate (GFR) categories were associated with a higher risk of these outcomes. Methods DEVOTE was a treat-to-target, double-blind trial involving 7637 patients with T2D at high CV risk who were randomized to once-daily treatment with either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). Patients with estimated GFR data at baseline (n = 7522) were analyzed following stratification into four GFR categories. Results The risks of MACE, CV death, and all-cause mortality increased with worsening baseline GFR category (P

Published
2020

47. Sex disparities in cardiovascular outcome trials of populations with diabetes: A Systematic Review and Meta-analysis

Author

Clemens, KK, Woodward, M, Neal, B, Zinman, B, Clemens, KK, Woodward, M, Neal, B, and Zinman, B

Abstract

BACKGROUND Sex differences have been described in diabetes cardiovascular outcome trials (CVOTs). PURPOSE We systematically reviewed for baseline sex differences in cardiovascular (CV) risk factors and CV protection therapy in diabetes CVOTs. DATA SOURCES Randomized placebo-controlled trials examining the effect of diabetes medications on major adverse cardiovascular events in people ≥18 years of age with type 2 diabetes. STUDY SELECTION Included trials reported baseline sex-specific CV risks and use of CV protection therapy. DATA EXTRACTION Two reviewers independently abstracted study data. DATA SYNTHESIS We included five CVOTs with 46,606 participants. We summarized sex-specific data using mean differences (MDs) and relative risks (RRs) and pooled estimates using random effects meta-analysis. There were fewer women than men in included trials (28.5–35.8% women). Women more often had stroke (RR 1.28; 95% CI 1.09, 1.50), heart failure (RR 1.30; 95% CI 1.21,1.40), and chronic kidney disease (RR 1.33; 95% CI 1.17; 1.51). They less often used statins (RR 0.90; 95% CI 0.86, 0.93), aspirin (RR 0.82; 95% CI 0.71, 0.95), and b-blockers (RR 0.93; 95% CI 0.88, 0.97) and had a higher systolic blood pressure (MD 1.66 mmHg; 95% CI 0.90, 2.41), LDL cholesterol (MD 0.34 mmol/L; 95% CI 0.29, 0.39), and hemoglobin A1c (MD 0.11%; 95% CI 0.09, 0.14 [1.2 mmol/mol; 1.0, 1.5]) than men. LIMITATIONS We could not carry out subgroup analyses due to the small number of studies. Our study is not generalizable to low CV risk groups nor to patients in routine care. CONCLUSIONS There were baseline sex disparities in diabetes CVOTs. We suggest efforts to recruit women into trials and promote CV management across the sexes.

Published
2020

48. Effect of Canagliflozin on Total Hospitalization for Heart Failure Events in Patients with Type 2 Diabetes and Chronic Kidney Disease

Author

Li, J, Jardine, MJ, Neal, B, Heerspink, HL, Cannon, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Pollock, CA, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, Mahaffey, KW, Arnott, C, Li, J, Jardine, MJ, Neal, B, Heerspink, HL, Cannon, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Pollock, CA, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, Mahaffey, KW, and Arnott, C

Published
2020

49. Mediators of the Effects of Canagliflozin (CANA) on Heart Failure (HF) and CV Death in Patients with Type 2 Diabetes (T2D) and Chronic Kidney Disease (CKD)

Author

Li, J, Neal, B, Heerspink, HL, Arnott, C, Cannon, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Greene, T, Levin, A, Oh, R, Pollock, CA, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Di Tanna, GL, Perkovic, V, Mahaffey, KW, Jardine, M, Li, J, Neal, B, Heerspink, HL, Arnott, C, Cannon, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Greene, T, Levin, A, Oh, R, Pollock, CA, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Di Tanna, GL, Perkovic, V, Mahaffey, KW, and Jardine, M

Published
2020

50. THE EFFECTS OF CANAGLIFLOZIN ON HEART FAILURE AND CARDIOVASCULAR DEATH BY BASELINE PARTICIPANT CHARACTERISTICS: ANALYSIS OF THE CREDENCE TRIAL

Author

Arnott, C, Li, J-W, Cannon, CP, Neuen, B, Heerspink, HL, Neal, B, Charytan, DM, Agarwal, R, Bakris, GL, De Zeeuw, D, Greene, T, Levin, A, Pollock, C, Chang, T, Rosenthal, N, Zhang, H, Zinman, B, Perkovic, V, Jardine, M, Mahaffey, K, Arnott, C, Li, J-W, Cannon, CP, Neuen, B, Heerspink, HL, Neal, B, Charytan, DM, Agarwal, R, Bakris, GL, De Zeeuw, D, Greene, T, Levin, A, Pollock, C, Chang, T, Rosenthal, N, Zhang, H, Zinman, B, Perkovic, V, Jardine, M, and Mahaffey, K

Published
2020

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