title: A combined analysis of 48 type 2 diabetes genetic risk variants shows no discriminative value to predict time to first prescription of a glucose lowering drug in Danish patients with screen detected type 2 diabetes.
abstract: OBJECTIVE
  To investigate the genetic influence of 48 type 2 diabetes susceptibility variants on disease progression measured as risk of early prescription redemption of glucose lowering drugs in screen-detected patients with type 2 diabetes.
  
  
  METHODS
  We studied type 2 diabetes progression in 1,480 patients with screen-detected type 2 diabetes from the ADDITION-Denmark study using information of redeemed prescriptions from the Register of Medicinal Products Statistics from 2001-2009 in Denmark. Patients were cluster randomized by general practitioners, who were randomized to treat type 2 diabetes according to either a conventional or a multifactorial intensive treatment algorithm. We investigated the genetic influence on diabetes progression by constructing a genetic risk score (GRS) of all 48 validated type 2 diabetes susceptibility variants, a GRS of 11 variants linked to β-cell function and a GRS of 3 variants linked to insulin sensitivity and assessed the association between number of risk alleles and time from diagnosis until first redeemed prescription of either any glucose lowering drug or an insulin drug.
  
  
  RESULTS
  The GRS linked to insulin sensitivity only nominally increased the risk of an early prescription redemption with an insulin drug by 39% (HR [95% C.I.] = 1.39 [1.09-1.77], p = 0.009] in patients randomized to the intensive treatment group. Furthermore, the strongest univariate predictors of diabetes progression for the intensive treatment group (measured as time to first insulin) were younger age (HR [95% C.I.] = 0.96 [0.93-0.99]), increased BMI (1.05 [1.01-1.09]), increased HbA1c (1.50 [1.36-.66]), increased TG (1.24 [1.11-1.39]) and reduced fasting serum HDL (0.37 [0.17-0.80]) at baseline. Similar results were obtained for the conventional treatment group.
  
  
  CONCLUSIONS
  Higher levels of HbA1c, fasting circulating levels of triglyceride, lower HDL, larger BMI and younger age are significant determinants of early pharmacological intervention in type 2 diabetes. However, known common type 2 diabetes-associated gene variants do not appear to significantly affect disease progression.
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; School of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Malene
authors.initials: M
authors.lastname: Hornbak
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristine Højgaard
authors.initials: KH
authors.lastname: Allin
authors.affiliation: Steno Diabetes Center A/S, Gentofte, Denmark; Section for Social and Clinical Pharmacy, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Majken Linnemann
authors.initials: ML
authors.lastname: Jensen
authors.affiliation: Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup Hospital, Glostrup, Denmark.
authors.forename: Cathrine Juel
authors.initials: CJ
authors.lastname: Lau
authors.affiliation: Public Research Centre for Health, Centre for Health Studies, Strassen, Luxembourg.
authors.forename: Daniel
authors.initials: D
authors.lastname: Witte
authors.affiliation: Steno Diabetes Center A/S, Gentofte, Denmark.
authors.forename: Marit Eika
authors.initials: ME
authors.lastname: Jørgensen
authors.affiliation: Department of Public Health, Section of General Practice Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Annelli
authors.initials: A
authors.lastname: Sandbæk
authors.affiliation: Department of Public Health, Section of General Practice Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.affiliation: School of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Andersson
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Institute of Biomedical Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Section of Molecular Diabetes & Metabolism, Institute of Clinical Research & Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000368:Aged; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D007004:Hypoglycemic Agents