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

ObjectiveTo 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.MethodsWe 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.ResultsThe 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.ConclusionHigher 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.

The impact of phenotype, ethnicity and genotype on progression of type 2 diabetes mellitus

“…In this study, incident cases were randomized into two intervention groups: a conventional group where the individual received usual care as per national guidelines, and the other which received intensified multifactorial intervention group with lifestyle counselling and additional management for blood pressure and cholesterol. While the overall PRS did not impact on diabetes progression, a sub‐PRS that incorporated only diabetes risk variants linked with insulin resistance showed association with time to insulin prescription (HR 1.39 (95% CI 1.09‐1.77)) in the intensified intervention group …”

“…From the 61 included articles, 56 studies assessed the phenotypic factors affecting diabetes progression, while only four studies investigated genotypic determinants of diabetes progression and one study assessed both phenotypic and genotypic factors . Before 2000, there were only four studies published and between 2000 and 2010; there were 20 studies published, with the remaining 37 studies published after 2010.…”

“…Before 2000, there were only four studies published and between 2000 and 2010; there were 20 studies published, with the remaining 37 studies published after 2010. The 61 studies were comprised of 35 retrospective cohort studies, 19 prospective cohort studies, three cross‐sectional studies, three case‐control studies studies and one randomized controlled trial (RCT) . The sample size ranged from 50 to 366 955 individuals, and most of the studies were from developed countries with European, American and Australian populations.…”

“…Five studies were identified that assessed genotypic factors were associated with diabetes progression . Most of the studies examine the association with progression by developing a polygenic risk score (PRS).…”

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

“…Moreover, a recent Danish study, carried out in a population‐based cohort predominantly treated with MET (55%), has investigated the influence of 48 T2DM susceptibility variants on disease progression assessed as early redemption of either a glucose‐lowering drug or an insulin drug prescription. Results have shown that common T2DM‐associated gene variants do not significantly affect disease progression requiring additional therapies …”