A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

Science Translational Medicine

Volumn 8, Issue 341, 2016, Pages

  Scott, Robert A ^a   Freitag, Daniel F ^u   Li, Li ^d,dh   Chu, Audrey Y ^e   Surendran, Praveen ^b   Young, Robin ^b   Grarup, Niels ^f   Stancáková, Alena ^g   Chen, Yuning ^h   Varga, Tibor V ⁱ   Yaghootkar, Hanieh ^j   Luan, Jian'an ^a   Zhao, Jing Hua ^a   Willems, Sara M ^a,k   Wessel, Jennifer ^l,m   Wang, Shuai ^h   Maruthur, Nisa ^n,o,p   Michailidou, Kyriaki ^b   Pirie, Ailith ^b   Van Der Lee, Sven J ^k   Gillson, Christopher ^a   Al Olama, Ali Amin ^b   Amouyel, Philippe ^q   Arriola, Larraitz ^r,s,t   Arveiler, Dominique ^u   Aviles Olmos, Iciar ^v   Balkau, Beverley ^w,x   Barricarte, Aurelio ^t,y   Barroso, Inês ^c,z   Garcia, Sara Benlloch ^b   Bis, Joshua C ^aa   Blankenberg, Stefan ^ab   Boehnke, Michael ^ac   Boeing, Heiner ^ad   Boerwinkle, Eric ^ae,af   Borecki, Ingrid B ^ag   Bork Jensen, Jette ^f   Bowden, Sarah ^ah   Caldas, Carlos ^z   Caslake, Muriel ^ai   Cupples, L Adrienne ^h,aj   Cruchaga, Carlos ^ag   Czajkowski, Jacek ^ag   Den Hoed, Marcel ^ak   Dunn, Janet A ^al   Earl, Helena M ^z   Ehret, Georg B ^am   Ferrannini, Ele ^an   Ferrieres, Jean ^ao   Foltynie, Thomas ^v   Ford, Ian ^ai   Forouhi, Nita G ^a   Gianfagna, Francesco ^ap,aq   Gonzalez, Carlos ^ar   Grioni, Sara ^as   Hiller, Louise ^al   Jansson, Jan Håkan ^at,au   Jørgensen, Marit E ^av,aw   Jukema, J Wouter ^ax   Kaaks, Rudolf ^ay   Kee, Frank ^az   Kerrison, Nicola D ^a   Key, Timothy J ^ba   Kontto, Jukka ^bb   Kote Jarai, Zsofia ^bc   Kraja, Aldi T ^ag   Kuulasmaa, Kari ^bb   Kuusisto, Johanna ^g,bd   Linneberg, Allan ^be,bf,bg   Liu, Chunyu ^bh   Marenne, Gaëlle ^c   Mohlke, Karen L ^bi   Morris, Andrew P ^bj,bk   Muir, Kenneth ^bl,bm   Müller Nurasyid, Martina ^bn,bo,bp   Munroe, Patricia B ^bq   Navarro, Carmen ^t,br   Nielsen, Sune F ^bs   Nilsson, Peter M ⁱ   Nordestgaard, Børge G ^bs   Packard, Chris J ^ai   Palli, Domenico ^bt   Panico, Salvatore ^bu   Peloso, Gina M ^bv,bw   Perola, Markus ^bb,bx   Peters, Annette ^bn,bp   Poole, Christopher J ^bm,by   Quirós, J Ramón ^bz   Rolandsson, Olov ^au   Sacerdote, Carlotta ^ca,cb,cc   Salomaa, Veikko ^bb   Sánchez, María José ^t,cd   Sattar, Naveed ^ai   Sharp, Stephen J ^a   Sims, Rebecca ^ce   Slimani, Nadia ^cf   Smith, Jennifer A ^ac   Thompson, Deborah J ^b   Trompet, Stella ^ax   Tumino, Rosario ^cg   Van Der A, Daphne L ^ch   Van Der Schouw, Yvonne T ^ci   Virtamo, Jarmo ^bb   Walker, Mark ^cj   Walter, Klaudia ^c   Abraham, Jean E ^b   Amundadottir, Laufey T ^ck   Butterworth, Adam S ^b   Aponte, Jennifer L ^d   Dupuis, Josée ^h   Easton, Douglas F ^b   Eeles, Rosalind A ^bc,cl   Erdmann, Jeanette ^cm   Franks, Paul W ^i,au,cn   Frayling, Timothy M ^j   Hansen, Torben ^f   Howson, Joanna M M ^b   Jørgensen, Torben ^co,cp,cq   Kooner, Jaspal ^cr,cs,ct   Laakso, Markku ^g   McCarthy, Mark I ^bk,cu   Pankow, James S ^cv   Pedersen, Oluf ^f   Riboli, Elio ^cw   Rotter, Jerome I ^cx   Saleheen, Danish ^cy   Samani, Nilesh J ^cz,da   Schunkert, Heribert ^bp,db   Vollenweider, Peter ^dc   O'Rahilly, Stephen ^z,dd,de   Deloukas, Panos ^bq   Danesh, John ^u   Goodarzi, Mark O ^df   Kathiresan, Sekar ^bv,bw,dg   Meigs, James B ^bv,dg   Ehm, Margaret G ^d   Wareham, Nicholas J ^a   Waterworth, Dawn M ^d   more..

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^c WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^d GLAXOSMITHKLINE   (United States)

^e BRIGHAM AND WOMEN S HOSPITAL   (United States)

^f University of Copenhagen   (Denmark)

^g UNIVERSITY OF EASTERN FINLAND   (Finland)

^h BOSTON UNIVERSITY   (United States)

ⁱ LUND UNIVERSITY   (Sweden)

^j UNIVERSITY OF EXETER MEDICAL SCHOOL   (United Kingdom)

^k ERASMUS MEDICAL CENTER   (Netherlands)

^l INDIANA UNIVERSITY   (United States)

^m INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

ⁿ JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^o JOHNS HOPKINS UNIVERSITY   (United States)

^p JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

^q UNIV LILLE   (France)

^r Basque Government   (Spain)

^s BIODONOSTIA HEALTH RESEARCH INSTITUTE   (Spain)

^t CIBER EPIDEMIOLOGÍA Y SALUD PÚBLICA CIBERESP   (Spain)

^u UNIVERSITÉ DE STRASBOURG   (France)

^v UNIVERSITY COLLEGE LONDON   (United Kingdom)

^w CENTRE FOR RESEARCH IN EPIDEMIOLOGY AND POPULATION HEALTH   (France)

^x UNIVERSITÉ PARIS SACLAY   (France)

^y INSTITUTO DE SALUD PÚBLICA DE NAVARRA   (Spain)

^z UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^aa UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^ab UNIVERSITY HEART CENTER HAMBURG   (Germany)

^ac UNIVERSITY OF MICHIGAN   (United States)

^ad GERMAN INSTITUTE OF HUMAN NUTRITION   (Germany)

^ae UNIVERSITY OF TEXAS SCHOOL OF PUBLIC HEALTH   (United States)

^af BAYLOR COLLEGE OF MEDICINE   (United States)

^ag WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^ah UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^ai UNIVERSITY OF GLASGOW   (United Kingdom)

^aj NATIONAL HEART LUNG AND BLOOD INSTITUTE   (United States)

^ak UPPSALA UNIVERSITY   (Sweden)

^al UNIVERSITY OF WARWICK   (United Kingdom)

^am JOHNS HOPKINS UNIVERSITY   (United States)

^an INSTITUTE OF CLINICAL PHYSIOLOGY   (Italy)

^ao TOULOUSE UNIVERSITY HOSPITAL   (France)

^ap UNIVERSITY OF INSUBRIA   (Italy)

^aq IRCCS NEUROMED   (Italy)

^ar CATALAN INSTITUTE OF ONCOLOGY   (Spain)

^as Unit of Epidemiology   (Italy)

^at Research Unit   (Sweden)

^au UMEÅ UNIVERSITY   (Sweden)

^av STENO DIABETES CENTER   (Denmark)

^aw UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^ax LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^ay GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^az QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

^ba UNIVERSITY OF OXFORD   (United Kingdom)

^bb NATIONAL PUBLIC HEALTH INSTITUTE   (Finland)

^bc INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^bd KUOPIO UNIVERSITY HOSPITAL   (Finland)

^be Research for Prevention and Health   (Denmark)

^bf International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health   (Denmark)

^bg UNIVERSITY OF COPENHAGEN   (Denmark)

^bh NATIONAL INSTITUTES OF HEALTH   (United States)

^bi UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^bj UNIVERSITY OF LIVERPOOL   (United Kingdom)

^bk UNIVERSITY OF OXFORD   (United Kingdom)

^bl UNIVERSITY OF MANCHESTER   (United Kingdom)

^bm UNIVERSITY OF WARWICK   (United Kingdom)

^bn INSTITUTE OF EPIDEMIOLOGY   (Germany)

^bo UNIVERSITY OF MUNICH   (Germany)

^bp DZHK GERMAN CENTRE FOR CARDIOVASCULAR RESEARCH   (Germany)

^bq QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^br DEPARTMENT OF EPIDEMIOLOGY   (Spain)

^bs GENTOFTE UNIVERSITY HOSPITAL   (Denmark)

^bt CANCER RESEARCH AND PREVENTION INSTITUTE ISPO   (Italy)

^bu UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^bv MASSACHUSETTS GENERAL HOSPITAL   (United States)

^bw BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^bx UNIVERSITY OF HELSINKI   (Finland)

^by UNIVERSITY HOSPITALS COVENTRY AND WARWICKSHIRE NHS TRUST   (United Kingdom)

^bz Public Health Direc   (Spain)

^ca UNIVERSITY OF TURIN   (Italy)

^cb Center for Cancer Prevention   (Italy)

^cc Human Genetics Foundation   (Italy)

^cd ANDALUSIAN SCHOOL OF PUBLIC HEALTH   (Spain)

^ce CARDIFF UNIVERSITY   (United Kingdom)

^cf INTERNATIONAL AGENCY FOR RESEARCH ON CANCER   (France)

^cg CIVILE M P AREZZO HOSPITAL   (Italy)

^ch NATIONAL INSTITUTE FOR PUBLIC HEALTH AND THE ENVIRONMENT   (Netherlands)

^ci UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^cj NEWCASTLE UNIVERSITY   (United Kingdom)

^ck NATIONAL CANCER INSTITUTE   (United States)

^cl INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^cm UNIVERSITY OF LÜBECK   (Germany)

^cn HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^co Research Centre for Prevention and Health   (Denmark)

^cp UNIVERSITY OF COPENHAGEN   (Denmark)

^cq AALBORG UNIVERSITY   (Denmark)

^cr NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^cs IMPERIAL COLLEGE HEALTHCARE NHS TRUST   (United Kingdom)

^ct EALING HOSPITAL NHS TRUST   (United Kingdom)

^cu UNIVERSITY OF OXFORD   (United Kingdom)

^cv UNIVERSITY OF MINNESOTA   (United States)

^cw IMPERIAL COLLEGE LONDON   (United Kingdom)

^cx HARBOR UCLA MEDICAL CENTER   (United States)

^cy UNIVERSITY OF PENNSYLVANIA   (United States)

^cz UNIVERSITY OF LEICESTER   (United Kingdom)

^da GLENFIELD HOSPITAL   (United Kingdom)

^db TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^dc LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

^dd MRC Metabolic Diseases Unit   (United Kingdom)

^de Queen Mary University of London and Barts NIHR BRC NHS Trust National Institute for Health and Care Research   (United Kingdom)

^df CEDARS SINAI MEDICAL CENTER   (United States)

^dg HARVARD MEDICAL SCHOOL   (United States)

^dh PAREXEL INTERNATIONAL   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; PLACEBO; CANNABINOID 2 RECEPTOR; CNR2 PROTEIN, HUMAN; DIPEPTIDYL PEPTIDASE IV; DPP4 PROTEIN, HUMAN; GLP1R PROTEIN, HUMAN; MCHR1 PROTEIN, HUMAN; SEROTONIN 2C RECEPTOR; SLC5A1 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 1; SOMATOSTATIN RECEPTOR;

ARTICLE; CARDIOVASCULAR RISK; CNR2 GENE; DPP4 GENE; DRUG TARGETING; EXOME; GENE; GENETIC ASSOCIATION; GENETIC CODE; GENETIC VARIATION; GENOTYPING TECHNIQUE; GLP1R GENE; HEART PROTECTION; HTR2C GENE; HUMAN; ISCHEMIC HEART DISEASE; MCHR1 GENE; META ANALYSIS (TOPIC); NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); SEQUENCE ANALYSIS; SLC5A1 GENE; ALLELE; CORONARY ARTERY DISEASE; GENETICS; GENOTYPE;

ALLELES; CORONARY DISEASE; DIABETES MELLITUS, TYPE 2; DIPEPTIDYL PEPTIDASE 4; GENOTYPE; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; HUMANS; OBESITY; RECEPTOR, CANNABINOID, CB2; RECEPTOR, SEROTONIN, 5-HT2C; RECEPTORS, SOMATOSTATIN; SODIUM-GLUCOSE TRANSPORTER 1;

EID: 84973167573     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aad3744     Document Type: Article

References (115)

1. U.S. Food and Drug Administration, Guidance for Industry Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes (U.S. FDA, Silver Spring, MD, 2008); http://www.fda.gov/downloads/drugs/guidancecomplianceregulatory-information/guidances/ucm071627.pdf
2. R. M. Plenge, E. M. Scolnick, D. Altshuler, Validating therapeutic targets through human genetics. Nat. Rev. Drug Discov. 12, 581-594 (2013).
3. M. R. Nelson, H. Tipney, J. L. Painter, J. Shen, P. Nicoletti, Y. Shen, A. Floratos, P. C. Sham, M. J. Li, J. Wang, L. R. Cardon, J. C. Whittaker, P. Sanseau, The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856-860 (2015).
4. B. F. Voight et al, Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet 380, 572-580 (2012).
5. J. Zacho, A. Tybjærg-Hansen, J. S. Jensen, P. Grande, H. Sillesen, B. G. Nordestgaard, Genetically elevated C-reactive protein and ischemic vascular disease. N. Engl. J. Med. 359, 1897-1908 (2008).
6. J. C. Cohen, E. Boerwinkle, T. H. Mosley Jr., H. H. Hobbs, Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264-1272 (2006).
7. Myocardial Infarction Genetics Consortium Investigators, Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371, 2072-2082 (2014).
8. M. R. Nelson, D. Wegmann, M. G. Ehm, D. Kessner, P. St. Jean, C. Verzilli, J. Shen, Z. Tang, S.-A. Bacanu, D. Fraser, L. Warren, J. Aponte, M. Zawistowski, X. Liu, H. Zhang, Y. Zhang, J. Li, Y. Li, L. Li, P. Woollard, S. Topp, M. D. Hall, K. Nangle, J. Wang, G. Abecasis, L. R. Cardon, S. Zöllner, J. C. Whittaker, S. L. Chissoe, J. Novembre, V. Mooser, An abundance of rare functional variants in 202 drug target genes sequenced in 14, 002 people. Science 337, 100-104 (2012).
9. A. Keinan, A. G. Clark, Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336, 740-743 (2012).
10. J. A. Tennessen, A. W. Bigham, T. D. O'Connor, W. Fu, E. E. Kenny, S. Gravel, S. McGee, R. Do, X. Liu, G. Jun, H. M. Kang, D. Jordan, S. M. Leal, S. Gabriel, M. J. Rieder, G. Abecasis, D. Altshuler, D. A. Nickerson, E. Boerwinkle, S. Sunyaev, C. D. Bustamante, M. J. Bamshad, J. M. Akey; Broad GO; Seattle GO; NHLBI Exome Sequencing Project, Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337, 64-69 (2012).
11. A. Coventry, L. M. Bull-Otterson, X. Liu, A. G. Clark, T. J. Maxwell, J. Crosby, J. E. Hixson, T. J. Rea, D. M. Muzny, L. R. Lewis, D. A. Wheeler, A. Sabo, C. Lusk, K. G. Weiss, H. Akbar, A. Cree, A. C. Hawes, I. Newsham, R. T. Varghese, D. Villasana, S. Gross, V. Joshi, J. Santibanez, M. Morgan, K. Chang, W. Hale IV, A. R. Templeton, E. Boerwinkle, R. Gibbs, C. F. Sing, Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nat. Commun. 1, 131 (2010).
12. W. Fu, T. D. O'Connor, G. Jun, H. M. Kang, G. Abecasis, S. M. Leal, S. Gabriel, M. J. Rieder, D. Altshuler, J. Shendure, D. A. Nickerson, M. J. Bamshad; NHLBI Exome Sequencing Project, J. M. Akey, Analysis of 6, 515 exomes reveals the recent origin of most human protein-coding variants. Nature 493, 216-220 (2013).
13. J. A. Lovshin, D. J. Drucker, Incretin-based therapies for type 2 diabetes mellitus. Nat. Rev. Endocrinol. 5, 262-269 (2009).
14. P. Cure, A. Pileggi, R. Alejandro, Exenatide and rare adverse events. N. Engl. J. Med. 358, 1969-1970 (2008).
15. A. Astrup, S. Rössner, L. Van Gaal, A. Rissanen, L. Niskanen, M. Al Hakim, J. Madsen, M. F. Rasmussen, M. E. J. Lean; NN8022-1807 Study Group, Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Lancet 374, 1606-1616 (2009).
16. M. A. Pfeffer, B. Claggett, R. Diaz, K. Dickstein, H. C. Gerstein, L. V. Køber, F. C. Lawson, L. Ping, X. Wei, E. F. Lewis, A. P. Maggioni, J. J. V. McMurray, J. L. Probstfield, M. C. Riddle, S. D. Solomon, J.-C. Tardif; ELIXA Investigators, Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247-2257 (2015).
17. J. Sivertsen, J. Rosenmeier, J. J. Holst, T. Vilsbøll, The effect of glucagon-like peptide 1 on cardiovascular risk. Nat. Rev. Cardiol. 9, 209-222 (2012).
18. J. Wessel et al., Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat. Commun. 6, 5897 (2015).
19. Exome Aggregation Consortium, M. Lek, K. Karczewski, E. Minikel, K. Samocha, E. Banks, T. Fennell, A. O'Donnell-Luria, J. Ware, A. Hill, B. Cummings, T. Tukiainen, D. Birnbaum, J. Kosmicki, L. Duncan, K. Estrada, F. Zhao, J. Zou, E. Pierce-Hoffman, D. Cooper, M. DePristo, R. Do, J. Flannick, M. Fromer, L. Gauthier, J. Goldstein, N. Gupta, D. Howrigan, A. Kiezun, M. Kurki, A. L. Moonshine, P. Natarajan, L. Orozco, G. Peloso, R. Poplin, M. Rivas, V. Ruano-Rubio, D. Ruderfer, K. Shakir, P. Stenson, C. Stevens, B. Thomas, G. Tiao, M. Tusie-Luna, B. Weisburd, H.-H. Won, D. Yu, D. Altshuler, D. Ardissino, M. Boehnke, J. Danesh, E. Roberto, J. Florez, S. Gabriel, G. Getz, C. Hultman, S. Kathiresan, M. Laakso, S. McCarroll, M. McCarthy, D. McGovern, R. McPherson, B. Neale, A. Palotie, S. Purcell, D. Saleheen, J. Scharf, P. Sklar, S. Patrick, J. Tuomilehto, H. Watkins, J. Wilson, M. Daly, D. MacArthur, Analysis of protein-coding genetic variation in 60, 706 humans. BioRxiv 10.1101/030338 (2015).
20. J. L. Moreno, K. C. Willett, A. R. Desilets, Exenatide as a novel weight loss modality in patients without diabetes. Ann. Pharmacother. 46, 1700-1706 (2012).
21. T. Vilsbøll, M. Christensen, A. E. Junker, F. K. Knop, L. L. Gluud, Effects of glucagon-like peptide-1 receptor agonists on weight loss: Systematic review and meta-analyses of randomised controlled trials. BMJ 344, d7771 (2012).
22. L. E. Robinson, T. A. Holt, K. Rees, H. S. Randeva, J. P. O'Hare, Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: Systematic review and meta-analysis. BMJ Open 3, e001986 (2013).
23. L. J. Schmidt, W. Habacher, T. Augustin, E. Krahulec, T. Semlitsch, A systematic review and meta-analysis of the efficacy of lixisenatide in the treatment of patients with type 2 diabetes. Diabetes Obes. Metab. 16, 769-779 (2014).
24. The Emerging Risk Factors Collaboration, Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829-841 (2011).
25. A. Harkavyi, A. Abuirmeileh, R. Lever, A. E. Kingsbury, C. S. Biggs, P. S. Whitton, Glucagonlike peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease. J. Neuroinflamm. 5, 19 (2008).
26. Y. Li, K. B. Duffy, M. A. Ottinger, B. Ray, J. A. Bailey, H. W. Holloway, D. Tweedie, T. Perry, M. P. Mattson, D. Kapogiannis, K. Sambamurti, D. K. Lahiri, N. H. Greig, GLP-1 receptor stimulation reduces amyloid-b peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. J. Alzheimers Dis. 19, 1205-1219 (2010).
27. A. P. Gregory, C. A. Dendrou, K. E. Attfield, A. Haghikia, D. K. Xifara, F. Butter, G. Poschmann, G. Kaur, L. Lambert, O. A. Leach, S. Prömel, D. Punwani, J. H. Felce, S. J. Davis, R. Gold, F. C. Nielsen, R. M. Siegel, M. Mann, J. I. Bell, G. McVean, L. Fugger, TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488, 508-511 (2012).
28. L. L. Kjems, J. J. Holst, A. Vølund, S. Madsbad, The influence of GLP-1 on glucose-stimulated insulin secretion: Effects on b-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52, 380-386 (2003).
29. J. Dushay, C. Gao, G. S. Gopalakrishnan, M. Crawley, E. K. Mitten, E. Wilker, J. Mullington, E. Maratos-Flier, Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes. Diabetes Care 35, 4-11 (2012).
30. J. R. Ussher, D. J. Drucker, Cardiovascular actions of incretin-based therapies. Circ. Res. 114, 1788-1803 (2014).
31. M. Grimm, J. Han, C. Weaver, P. Griffin, C. T. Schulteis, H. Dong, J. Malloy, Efficacy, safety, and tolerability of exenatide once weekly in patients with type 2 diabetes mellitus: An integrated analysis of the DURATION trials. Postgrad. Med. 125, 47-57 (2013).
32. J. Flannick et al., Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet. 46, 357-363 (2014).
33. D. I. Swerdlow et al, HMG-coenzyme A reductase inhibition, type 2 diabetes, and body-weight: Evidence from genetic analysis and randomised trials. Lancet 385, 351-361 (2015).
34. M.-B. Toft-Nielsen, S. Madsbad, J. J. Holst, Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J. Clin. Endocrinol. Metab. 86, 3853-3860 (2001).
35. L. A. Scrocchi, T. J. Brown, N. MaClusky, P. L. Brubaker, A. B. Auerbach, A. L. Joyner, D. J. Drucker, Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254-1258 (1996).
36. J. E. Ayala, D. P. Bracy, F. D. James, M. A. Burmeister, D. H. Wasserman, D. J. Drucker, Glucagon-like peptide-1 receptor knockout mice are protected from high-fat diet-induced insulin resistance. Endocrinology 151, 4678-4687 (2010).
37. R. Seifert, K. Wenzel-Seifert, Constitutive activity of G-protein-coupled receptors: Cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch. Pharmacol. 366, 381-416 (2002).
38. J.-P. Fortin, J. C. Schroeder, Y. Zhu, M. Beinborn, A. S. Kopin, Pharmacological characterization of human incretin receptor missense variants. J. Pharmacol. Exp. Ther. 332, 274-280 (2010).
39. C. Koole, D. Wootten, J. Simms, C. Valant, L. J. Miller, A. Christopoulos, P. M. Sexton, Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: Allosteric rescue of loss of function mutation. Mol. Pharmacol. 80, 486-497 (2011).
40. R. Collins, What makes UK Biobank special? Lancet 379, 1173-1174 (2012).
41. D. J. Drucker, M. A. Nauck, The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696-1705 (2006).
42. M. Firmann, V. Mayor, P. M. Vidal, M. Bochud, A. Pécoud, D. Hayoz, F. Paccaud, M. Preisig, K. S. Song, X. Yuan, T. M. Danoff, H. A. Stirnadel, D. Waterworth, V. Mooser, G. Waeber, P. Vollenweider, The CoLaus study: A population-based study to investigate the epidemiology and genetic determinants of cardiovascular risk factors and metabolic syndrome. BMC Cardiovasc. Disord. 8, 6 (2008).
43. D. F. Wyszynski, D. M. Waterworth, P. J. Barter, J. Cohen, Y. A. Kesäniemi, R. W. Mahley, R. McPherson, G. Waeber, T.P. Bersot, S.S. Sharma, V. Nolan, L.T. Middleton, S.S. Sundseth, L.A. Farrer, V. Mooser, S. M. Grundy, Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project). Am. J. Cardiol. 95, 194-198 (2005).
44. N. G. Forouhi, J. Luan, S. Hennings, N. J. Wareham, Incidence of Type 2 diabetes in England and its association with baseline impaired fasting glucose: The Ely study 1990-2000. Diabet. Med. 24, 200-207 (2007).
45. N. Day, S. Oakes, R. Luben, K. T. Khaw, S. Bingham, A. Welch, N. Wareham, EPIC-Norfolk: Study design and characteristics of the cohort. European Prospective Investigation of Cancer. Br. J. Cancer 80 (Suppl. 1), 95-103 (1999).
46. E. D. L. Rolfe, R. J. F. Loos, C. Druet, R. P. Stolk, U. Ekelund, S. J. Griffin, N. G. Forouhi, N. J. Wareham, K. K. Ong, Association between birth weight and visceral fat in adults. Am. J. Clin. Nutr. 92, 347-352 (2010).
47. J. S. Kooner, J. C. Chambers, C. A. Aguilar-Salinas, D. A. Hinds, C. L. Hyde, G. R. Warnes, F. J. Gómez Pérez, K. A. Frazer, P. Elliott, J. Scott, P. M. Milos, D. R. Cox, J. F. Thompson, Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat. Genet. 40, 149-151 (2008).
48. J. B. Echouffo-Tcheugui, R. K. Simmons, K. M. Williams, R. S. Barling, A. T. Prevost, A. L. Kinmonth, N. J. Wareham, S. J. Griffin, The ADDITION-Cambridge trial protocol: A cluster-randomised controlled trial of screening for type 2 diabetes and intensive treatment for screen-detected patients. BMC Public Health 9, 136 (2009).
49. R. Saxena et al., MAGIC investigators, Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat. Genet. 42, 142-148 (2010).
50. R. A. Scott et al, Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat. Genet. 44, 991-1005 (2012).
51. A. K. Manning et al, A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat. Genet. 44, 659-669 (2012).
52. T. Johnson et al., Blood pressure loci identified with a gene-centric array. Am. J. Hum. Genet. 89, 688-700 (2011).
53. M. den Hoed et al., Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat. Genet. 45, 621-631 (2013).
54. M. D. Mailman, M. Feolo, Y. Jin, M. Kimura, K. Tryka, R. Bagoutdinov, L. Hao, A. Kiang, J. Paschall, L. Phan, N. Popova, S. Pretel, L. Ziyabari, M. Lee, Y. Shao, Z. Y. Wang, K. Sirotkin, M. Ward, M. Kholodov, K. Zbicz, J. Beck, M. Kimelman, S. Shevelev, D. Preuss, E. Yaschen-ko, A. Graeff, J. Ostell, S. T. Sherry, The NCBI dbGaP database of genotypes and phenotypes. Nat. Genet. 39, 1181-1186 (2007).
55. B. M. Wolpin et al, Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat. Genet. 46, 994-1000 (2014).
56. M. A. Nalls et al, Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat. Genet. 46, 989-993 (2014).
57. J. Zhang, H. Kesteloot, Anthropometric, lifestyle and metabolic determinants of resting heart rate. A population study. Eur. Heart J. 20, 103-110 (1999).
58. W. J. Gauderman, J. M. Morrison, QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies (2006); http://hydra.usc.edu/gxe.
59. Emerging Risk Factors Collaboration, N. Sarwar, P. Gao, S. R. K. Seshasai, R. Gobin, S. Kaptoge, E. Di Angelantonio, E. Ingelsson, D. A. Lawlor, E. Selvin, M. Stampfer, C. D. A. Stehouwer, S. Lewington, L. Pennells, A. Thompson, N. Sattar, I. R. White, K. K. Ray, J. Danesh, Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet 375, 2215-2222 (2010).
60. N. G. Forouhi, Z. Ye, A. P. Rickard, K. T. Khaw, R. Luben, C. Langenberg, N. J. Wareham, Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: Results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia 55, 2173-2182 (2012).
61. M. M. Swarbrick, B. Waldenmaier, L. A. Pennacchio, D. L. Lind, M. M. Cavazos, F. Geller, R. Merriman, A. Ustaszewska, M. Malloy, A. Scherag, W.-C. Hsueh, W. Rief, F. Mauvais-Jarvis, C. R. Pullinger, J. P. Kane, R. Dent, R. McPherson, P.-Y. Kwok, A. Hinney, J. Hebebrand, C. Vaisse, Lack of support for the association between GAD2 polymorphisms and severe human obesity. PLOS Biol. 3, e315 (2005).
62. InterAct Consortium, Design and cohort description of the InterAct Project: An examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study. Diabetologia 54, 2272-2282 (2011).
63. E. Riboli, K. J. Hunt, N. Slimani, P. Ferrari, T. Norat, M. Fahey, U. R. Charrondière, B. Hémon, C. Casagrande, J. Vignat, K. Overvad, A. Tjønneland, F. Clavel-Chapelon, A. Thiébaut, J. Wahrendorf, H. Boeing, D. Trichopoulos, A. Trichopoulou, P. Vineis, D. Palli, H. B. Bueno-De-Mesquita, P. H. M. Peeters, E. Lund, D. Engeset, C. A. González, A. Barricarte, G. Berglund, G. Hallmans, N. E. Day, T. J. Key, R. Kaaks, R. Saracci, European Prospective Investigation into Cancer and Nutrition (EPIC): Study populations and data collection. Public Health Nutr. 5, 1113-1124 (2002).
64. B. G. Nordestgaard, M. Benn, P. Schnohr, A. Tybjaerg-Hansen, Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 298, 299-308 (2007).
65. J. Danesh, R. Saracci, G. Berglund, E. Feskens, K. Overvad, S. Panico, S. Thompson, A. Fournier, F. Clavel-Chapelon, M. Canonico, R. Kaaks, J. Linseisen, H. Boeing, T. Pischon, C. Weikert, A. Olsen, A. Tjønneland, S. P. Johnsen, M. K. Jensen, J. R. Quirós, C. A. G. Svatetz, M.-J. S. Pérez, N. Larrañaga, C. N. Sanchez, C. M. Iribas, S. Bingham, K.-T. Khaw, N. Wareham, T. Key, A. Roddam, A. Trichopoulou, V. Benetou, D. Trichopoulos, G. Masala, S. Sieri, R. Tumino, C. Sacerdote, A. Mattiello, W. M. M. Verschuren, H. B. Bueno-de-Mesquita, D. E. Grobbee, Y. T. van der Schouw, O. Melander, G. Hallmans, P. Wennberg, E. Lund, M. Kumle, G. Skeie, P. Ferrari, N. Slimani, T. Norat, E. Riboli, EPIC-Heart: The cardiovascular component of a prospective study of nutritional, lifestyle and biological factors in 520, 000 middle-aged participants from 10 European countries. Eur. J. Epidemiol. 22, 129-141 (2007).
66. S. Bingham, E. Riboli, Diet and cancer-the European Prospective Investigation into Cancer and Nutrition. Nat. Rev. Cancer 4, 206-215 (2004).
67. J. Shepherd, S. M. Cobbe, I. Ford, C. G. Isles, A. R. Lorimer, P. W. MacFarlane, J. H. McKillop, C. J. Packard; West of Scotland Coronary Prevention Study Group, Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med. 333, 1301-1308 (1995).
68. J. Shepherd, G. J. Blauw, M. B. Murphy, E. L. E. M. Bollen, B. M. Buckley, S. M. Cobbe, I. Ford, A. Gaw, M. Hyland, J. W. Jukema, A. M. Kamper, P. W. Macfarlane, A. E. Meinders, J. Norrie, C. J. Packard, I. J. Perry, D. J. Stott, B. J. Sweeney, C. Twomey, R. G. J. Westendorp; PROSPER study group, Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet 360, 1623-1630 (2002).
69. A. Evans, V. Salomaa, S. Kulathinal, K. Asplund, F. Cambien, M. Ferrario, M. Perola, L. Peltonen, D. Shields, H. Tunstall-Pedoe, K. Kuulasmaa; MORGAM Project, MORGAM (an international pooling of cardiovascular cohorts). Int. J. Epidemiol. 34, 21-27 (2005).
70. S. Kulathinal, J. Karvanen, O. Saarela, K. Kuulasmaa, Case-cohort design in practice-experiences from the MORGAM Project. Epidemiol. Perspect. Innov. 4, 15 (2007).
71. The Atherosclerosis Risk in Communities (ARIC) Study: Design and objectives. The ARIC investigators. Am. J. Epidemiol. 129, 687-702 (1989).
72. T. L. Assimes et al, Lack of association between the Trp719Arg polymorphism in kinesinlike protein-6 and coronary artery disease in 19 case-control studies. J. Am. Coll. Cardiol. 56, 1552-1563 (2010).
73. G. Hallmans, A. Agren, G. Johansson, A. Johansson, B. Stegmayr, J.-H. Jansson, B. Lindahl, Rolandsson, S. Söderberg, M. Nilsson, I. Johansson, L. Weinehall, Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort-evaluation of risk factors and their interactions. Scand. J. Public Health Suppl. 61, 18-24 (2003).
74. W. B. Kannel, T. R. Dawber, A. Kagan, N. Revotskie, J. Stokes III, Factors of risk in the development of coronary heart disease-Six year follow-up experience. The Framingham Study. Ann. Intern. Med. 55, 33-50 (1961).
75. S. A. Hills, B. Balkau, S. W. Coppack, J. M. Dekker, A. Mari, A. Natali, M. Walker, E. Ferrannini; EGIR-RISC Study Group, The EGIR-RISC STUDY (The European group for the study of insulin resistance: Relationship between insulin sensitivity and cardiovascular disease risk): 1. Methodology and objectives. Diabetologia 47, 566-570 (2004).
76. M. E. J. Lean, R. Carraro, N. Finer, H. Hartvig, M. L. Lindegaard, S. Rössner, L. Van Gaal, A. Astrup; NN8022-1807 Investigators, Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults. Int. J. Obes. 38, 689-697 (2014).
77. A. S. Kelly, K. D. Rudser, B. M. Nathan, C. K. Fox, A. M. Metzig, B. J. Coombes, A. K. Fitch, E. M. Bomberg, M. J. Abuzzahab, The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: A randomized, placebo-controlled, clinical trial. JAMA Pediatr. 167, 355-360 (2013).
78. J. Rosenstock, L. J. Klaff, S. Schwartz, J. Northrup, J. H. Holcombe, K. Wilhelm, M. Trautmann, Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care 33, 1173-1175 (2010).
79. K. Elkind-Hirsch, O. Marrioneaux, M. Bhushan, D. Vernor, R. Bhushan, Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 2670-2678 (2008).
80. I. Aviles-Olmos, J. Dickson, Z. Kefalopoulou, A. Djamshidian, P. Ell, T. Soderlund, P. Whitton, R. Wyse, T. Isaacs, A. Lees, P. Limousin, T. Foltynie, Exenatide and the treatment of patients with Parkinson's disease. J. Clin. Invest. 123, 2730-2736 (2013).
81. S. Madsbad, O. Schmitz, J. Ranstam, G. Jakobsen, D. R. Matthews; NN2211-1310 International Study Group, Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211). Diabetes Care 27, 1335-1342 (2004).
82. Y. Seino, M. F. Rasmussen, M. Zdravkovic, K. Kaku, Dose-dependent improvement in glycemia with once-daily liraglutide without hypoglycemia or weight gain: A double-blind, randomized, controlled trial in Japanese patients with type 2 diabetes. Diabetes Res. Clin. Pract. 81, 161-168 (2008).
83. M. Marre, J. Shaw, M. Brändle, W. M. W. Bebakar, N. A. Kamaruddin, J. Strand, M. Zdravkovic, T. D. Le Thi, S. Colagiuri; LEAD-1 SU study group, Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet. Med. 26, 268-278 (2009).
84. M. Nauck, A. Frid, K. Hermansen, N. S. Shah, T. Tankova, I. H. Mitha, M. Zdravkovic, M. Düring, D. R. Matthews; LEAD-2 Study Group, Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes. Diabetes Care 32, 84-90 (2009).
85. T. Forst, G. Michelson, F. Ratter, M. M. Weber, S. Anders, M. Mitry, B. Wilhelm, A. Pfützner, Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet. Med. 29, 1115-1118 (2012).
86. B. Zinman, J. Gerich, J. B. Buse, A. Lewin, S. Schwartz, P. Raskin, P. M. Hale, M. Zdravkovic, L. Blonde; LEAD-4 Study Investigators, Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 32, 1224-1230 (2009).
87. D. Russell-Jones, A. Vaag, O. Schmitz, B. K. Sethi, N. Lalic, S. Antic, M. Zdravkovic, G. M. Ravn, R. Simó; Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group, Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): A randomised controlled trial. Diabetologia 52, 2046-2055 (2009).
88. D. Kim, L. MacConell, D. Zhuang, P. A. Kothare, M. Trautmann, M. Fineman, K. Taylor, Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 30, 1487-1493 (2007).
89. T. Kadowaki, M. Namba, A. Yamamura, H. Sowa, A. M. Wolka, R. G. Brodows, Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes. Endocr. J. 56, 415-424 (2009).
90. T. J. Moretto, D. R. Milton, T. D. Ridge, L. A. MacConell, T. Okerson, A. M. Wolka, R. G. Brodows, Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled, parallelgroup study. Clin. Ther. 30, 1448-1460 (2008).
91. D. M. Kendall, M. C. Riddle, J. Rosenstock, D. Zhuang, D. D. Kim, M. S. Fineman, A. D. Baron, Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28, 1083-1091 (2005).
92. R. A. DeFronzo, R. E. Ratner, J. Han, D. D. Kim, M. S. Fineman, A. D. Baron, Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28, 1092-1100 (2005).
93. J. B. Buse, R. R. Henry, J. Han, D. D. Kim, M. S. Fineman, A. D. Baron; Exenatide-113 Clinical Study Group, Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628-2635 (2004).
94. C. M. Apovian, R. M. Bergenstal, R. M. Cuddihy, Y. Qu, S. Lenox, M. S. Lewis, L. C. Glass, Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am. J. Med. 123, 468.e9-468.e17 (2010).
95. J. B. Buse, R. M. Bergenstal, L. C. Glass, C. R. Heilmann, M. S. Lewis, A. Y. M. Kwan, B. J. Hoogwerf, J. Rosenstock, Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: A randomized, controlled trial. Ann. Intern. Med. 154, 103-112 (2011).
96. A. Gill, B. J. Hoogwerf, J. Burger, S. Bruce, L. Macconell, P. Yan, D. Braun, J. Giaconia, J. Malone, Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: A double-blind, placebo-controlled, randomized pilot study. Cardiovasc. Diabetol. 9, 6 (2010).
97. J. Liutkus, J. Rosas Guzman, P. Norwood, L. Pop, J. Northrup, D. Cao, M. Trautmann, A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin. Diabetes Obes. Metab. 12, 1058-1065 (2010).
98. B. Zinman, B. J. Hoogwerf, S. Durán García, D. R. Milton, J. M. Giaconia, D. D. Kim, M. E. Trautmann, R. G. Brodows, The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: A randomized trial. Ann. Intern. Med. 146, 477-485 (2007).
99. R. A. DeFronzo, C. Triplitt, Y. Qu, M. S. Lewis, D. Maggs, L. C. Glass, Effects of exenatide plus rosiglitazone on b-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care 33, 951-957 (2010).
100. G. Derosa, I. G. Franzetti, F. Querci, A. Carbone, L. Ciccarelli, M. N. Piccinni, E. Fogari, P. Maffioli, Exenatide plus metformin compared with metformin alone on b-cell function in patients with Type 2 diabetes. Diabet. Med. 29, 1515-1523 (2012).
101. G. Derosa, I. G. Franzetti, F. Querci, A. Carbone, L. Ciccarelli, M. N. Piccinni, E. Fogari, P. Maffioli, Variation in inflammatory markers and glycemic parameters after 12 months of exenatide plus metformin treatment compared with metformin alone: A randomized placebocontrolled trial. Pharmacotherapy 33, 817-826 (2013).
102. Y. Gao, K. H. Yoon, L.-M. Chuang, V. Mohan, G. Ning, S. Shah, H. C. Jang, T.-J. Wu, D. Johns, J. Northrup, R. Brodows, Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea. Diabetes Res. Clin. Pract. 83, 69-76 (2009).
103. Y. Seino, A. Takami, G. Boka, E. Niemoeller, D. Raccah; PDY6797 investigators, Pharmacodynamics of the glucagon-like peptide-1 receptor agonist lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus poorly controlled on sulphonylureas with/without metformin. Diabetes Obes. Metab. 16, 739-747 (2014).
104. R. E. Ratner, J. Rosenstock, G. Boka; DRI6012 Study Investigators, Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: A randomized, double-blind, placebocontrolled trial. Diabet. Med. 27, 1024-1032 (2010).
105. G. B. Bolli, M. Munteanu, S. Dotsenko, E. Niemoeller, G. Boka, Y. Wu, M. Hanefeld, Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet. Med. 31, 176-184 (2014).
106. M. Pinget, R. Goldenberg, E. Niemoeller, I. Muehlen-Bartmer, H. Guo, R. Aronson, Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes. Metab. 15, 1000-1007 (2013).
107. M. C. Riddle, R. Aronson, P. Home, M. Marre, E. Niemoeller, P. Miossec, L. Ping, J. Ye, J. Rosenstock, Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin. Diabetes Care 36, 2489-2496 (2013).
108. M. C. Riddle, T. Forst, R. Aronson, L. Sauque-Reyna, E. Souhami, L. Silvestre, L. Ping, J. Rosenstock, Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine. Diabetes Care 36, 2497-2503 (2013).
109. B. Ahrén, A. Leguizamo Dimas, P. Miossec, S. Saubadu, R. Aronson, Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care 36, 2543-2550 (2013).
110. J. Rosenstock, M. Hanefeld, P. Shamanna, K. W. Min, G. Boka, P. Miossec, T. Zhou, I. Muehlen-Bartmer, R. E. Ratner, Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in Type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J. Diabetes Complications 28, 386-392 (2014).
111. Y. Seino, K. W. Min, E. Niemoeller, A. Takami; EFC10887 GETGOAL-L Asia Study Investigators, Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes. Metab. 14, 910-917 (2012).
112. C. Y. Pan, P. Han, X. Liu, S. Yan, P. Feng, Z. Zhou, X. Lv, H. Tian, Y. Jin Kui, B. Su, S. Shang, E. Niemoeller, Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: A randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-MAsia). Diabetes Metab. Res. Rev. 30, 726-735 (2014).
113. V. A. Fonseca, R. Alvarado-Ruiz, D. Raccah, G. Boka, P. Miossec, J. E. Gerich; EFC6018 GetGoalMono Study Investigators, Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy. Diabetes Care 35, 1225-1231 (2012).
114. A. P. Morris et al, Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981-990 (2012).
115. M. Lorenz, C. Pfeiffer, A. Steinsträsser, R. H. A. Becker, H. Rütten, P. Ruus, M. Horowitz, Effects of lixisenatide once daily on gastric emptying in type 2 diabetes-Relationship to postprandial glycemia. Regul. Pept. 185, 1-8 (2013).