Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment
Gregory G. Schwartz, Michael Szarek, Vera Bittner, Deepak L. Bhatt, Rafael Díaz, Shaun G. Goodman, J. Wouter Jukema, Megan Loy, Garen Manvelian, Robert Pordy, Harvey D. White, Philippe Gabríel Steg, Gregory G. Schwartz, Philippe Gabríel Steg, Deepak L. Bhatt, Vera Bittner, Rafael Díaz, Shaun G. Goodman, Robert A. Harrington, J. Wouter Jukema, Michael Szarek, Harvey D. White, Andreas M. Zeiher, Pierluigi Tricoci, Matthew T. Roe, Kenneth W. Mahaffey, Jay M. Edelberg, Corinne Hanotin, Guillaume Lecorps, Angèle Moryusef, Robert Pordy, William J. Sasiela, Jean‐François Tamby, Philip E. Aylward, Heinz Drexel, Peter Sinnaeve, Mirza Dilić, Renato D. Lópes, Nina Gotcheva, Juan-Carlos Prieto, Yong Huo, Patricio López‐Jaramillo, Ivan Pećin, Željko Reiner, Petr Ošťádal, Margus Viigimaa, Markku S. Nieminen, Vakhtang Chumburidze, Nikolaus Marx, Nicolas Danchin, Evangelos Liberopoulos, Pablo Carlos Montenegro Valdovinos, Hung‐Fat Tse, Róbert Gábor Kiss, Denis Xavier, Doron Zahger, Marco Valgimigli, Takeshi Kimura, Hyo Soo Kim, Sang‐Hyun Kim, Andrejs Ērglis, Aleksandras Laucevičius, Saško Kedev, Khalid Yusoff, Gabriel Arturo Ramos López, Marco Alings, Sigrun Halvorsen, Roger M. Correa Flores, Andrzej Budaj, João Morais, Maria Dorobanţu, Yuri Karpov, Arsen D. Ristic, Terrance Chua, Ján Murín, Zlatko Fras, Anthony J. Dalby, José Tuñón, H. Asita de Silva, Emil Hagström, Ulf Landmesser, Chern‐En Chiang, Piyamitr Sritara, Sema Güneri, Alexander Parkhomenko, Kausik K. Ray, Patrick M. Moriarty, Robert A. Vogel, Bernard Chaitman, Sheryl F. Kelsey, Anders Olsson, Jean‐Lucien Rouleau, Maarten L. Simoons, Karen Alexander, Chiara Meloni, Robert S. Rosenson, Eric J.G. Sijbrands, Pierluigi Tricoci, John H. Alexander, Luciana Armaganijan
Abstract
OBJECTIVE In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02−1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment–baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03−1.12; P = 0.0002) for incident type 2 diabetes. CONCLUSIONS In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.