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
1 Section for Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet2 Experimental Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet3 Drug Research Academy B, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet4 Steno Diabetes Center A/S, Gentofte, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: MLiJ@steno.dk.5 Research Centre for Prevention and Health, Glostrup University Hospital6 Public Research Centre for Health, Centre for Health Studies, Strassen, Luxembourg7 Steno Diabetes Center8 Afdeling for Almen Medicin, Københavns Universitet9 Department of Pharmacology Pharmacotherapy, Faculty of Pharmaceutical Sciences, Københavns Universitet10 Drug Research Academy B, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet11 Section for Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet12 Department of Pharmacology Pharmacotherapy, Faculty of Pharmaceutical Sciences, Københavns Universitet
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. CONCLUSION: 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.