Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from ...23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.
This study sought to investigate the progression and regression of diabetic retinopathy (DR) and the effects of population risk factors on the rates of transition across retinopathy stages.
The study ...cohort consisted of 44,871 observed DR events between the calendar years 1990 and 2011 for 4,758 diabetic patients who were diagnosed at 35 years of age or older. The first retinal observation was recorded within a year from diagnosis, and the result was recorded as free of retinopathy. A multistate Markov model was applied for analyzing the development of DR and its relation to the patterns of changes in risk factors.
We observed a consistent risk effect of HbA1c on the progression (no retinopathy to mild background DR BDR hazard ratio per SD of HbA1c HR 1.42 95% CI 1.32-1.52, mild BDR to observable BDR HR 1.32 95% CI 1.08-1.60, and observable BDR to severe nonproliferative/proliferative DR HR 2.23 95% CI 1.16-4.29). Similarly, systolic blood pressure (SBP) and diastolic blood pressure increased the risk for the transition from the asymptomatic phase to mild BDR (HR 1.20 95% CI 1.11-1.30) and the mild BDR to observable BDR (HR 1.87 95% CI 1.46-2.40), respectively. Regression from mild BDR to no DR was associated with lower SBP (HR 0.79 95% CI 0.64-0.97) and lower HbA1c (HR 0.76 95% CI 0.64-0.89).
Progression and regression of DR were strongly associated with blood pressure and glycemic exposure.
Improved identification of individuals with type 2 diabetes at high cardiovascular (CV) risk could help in selection of newer CV risk-reducing therapies. The aim of this study was to determine ...whether retinal vascular parameters, derived from retinal screening photographs, alone and in combination with a genome-wide polygenic risk score for coronary heart disease (CHD PRS) would have independent prognostic value over traditional CV risk assessment in patients without prior CV disease.
Patients in the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study were linked to retinal photographs, prescriptions, and outcomes. Retinal photographs were analyzed using VAMPIRE (Vascular Assessment and Measurement Platform for Images of the Retina) software, a semiautomated artificial intelligence platform, to compute arterial and venous fractal dimension, tortuosity, and diameter. CHD PRS was derived from previously published data. Multivariable Cox regression was used to evaluate the association between retinal vascular parameters and major adverse CV events (MACE) at 10 years compared with the pooled cohort equations (PCE) risk score.
Among 5,152 individuals included in the study, a MACE occurred in 1,017 individuals. Reduced arterial fractal dimension and diameter and increased venous tortuosity each independently predicted MACE. A risk score combining these parameters significantly predicted MACE after adjustment for age, sex, PCE, and the CHD PRS (hazard ratio 1.11 per SD increase, 95% CI 1.04-1.18, P = 0.002) with similar accuracy to PCE (area under the curve AUC 0.663 vs. 0.658, P = 0.33). A model incorporating retinal parameters and PRS improved MACE prediction compared with PCE (AUC 0.686 vs. 0.658, P < 0.001).
Retinal parameters alone and in combination with genome-wide CHD PRS have independent and incremental prognostic value compared with traditional CV risk assessment in type 2 diabetes.
Research has suggested that the retinal vasculature may act as a surrogate marker for diseased cerebral vessels. Retinal vascular parameters were measured using Vessel Assessment and Measurement ...Platform for Images of the Retina (VAMPIRE) software in two cohorts: (i) community-dwelling older subjects of the Lothian Birth Cohort 1936 (n = 603); and (ii) patients with recent minor ischaemic stroke of the Mild Stroke Study (n = 155). Imaging markers of small vessel disease (SVD) (white matter hyperintensities WMH on structural MRI, visual scores and volume; perivascular spaces; lacunes and microbleeds), and vascular risk measures were assessed in both cohorts. We assessed associations between retinal and brain measurements using structural equation modelling and regression analysis. In the Lothian Birth Cohort 1936 arteriolar fractal dimension accounted for 4% of the variance in WMH load. In the Mild Stroke Study lower arteriolar fractal dimension was associated with deep WMH scores (odds ratio OR 0.53; 95% CI, 0.32-0.87). No other retinal measure was associated with SVD. Reduced fractal dimension, a measure of vascular complexity, is related to SVD imaging features in older people. The results provide some support for the use of the retinal vasculature in the study of brain microvascular disease.
There are few observational studies evaluating the risk of AKI in people with type 2 diabetes, and even fewer simultaneously investigating AKI and CKD in this population. This limits understanding of ...the interplay between AKI and CKD in people with type 2 diabetes compared with the nondiabetic population.
In this retrospective, cohort study of participants with or without type 2 diabetes, we used electronic healthcare records to evaluate rates of AKI and various statistical methods to determine their relationship to CKD status and further renal function decline.
We followed the cohort of 16,700 participants (9417 with type 2 diabetes and 7283 controls without diabetes) for a median of 8.2 years. Those with diabetes were more likely than controls to develop AKI (48.6% versus 17.2%, respectively) and have preexisting CKD or CKD that developed during follow-up (46.3% versus 17.2%, respectively). In the absence of CKD, the AKI rate among people with diabetes was nearly five times that of controls (121.5 versus 24.6 per 1000 person-years). Among participants with CKD, AKI rate in people with diabetes was more than twice that of controls (384.8 versus 180.0 per 1000 person-years after CKD diagnostic date, and 109.3 versus 47.4 per 1000 person-years before CKD onset in those developing CKD after recruitment). Decline in eGFR slope before AKI episodes was steeper in people with diabetes versus controls. After AKI episodes, decline in eGFR slope became steeper in people without diabetes, but not among those with diabetes and preexisting CKD.
Patients with diabetes have significantly higher rates of AKI compared with patients without diabetes, and this remains true for individuals with preexisting CKD.
There is considerable interindividual variation in sulfonylurea response in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) variants have been identified to be strongly associated with type 2 ...diabetes risk, probably due to decreased beta-cell function. We hypothesized that variation in TCF7L2 would influence response to sulfonylureas but not metformin. We studied the effect of TCF7L2 rs12255372 and rs7903146 genotypes on glycemic response.
The DARTS/MEMO (Diabetes Audit and Research Tayside/Medicines Monitoring Unit) collaboration database includes prescribing, biochemistry, and clinical phenotype of all patients with diabetes within Tayside, Scotland, from 1992. Of these, the TCF7L2 genotype was determined in 4,469 patients with type 2 diabetes recruited to GoDARTS (Genetics of Diabetes Audit and Research Tayside) between 1997 and July 2006. A total of 901 incident sulfonylurea users and 945 metformin users were identified. A logistic regression was used with treatment failure defined as an A1C >7% within 3-12 months after treatment initiation. Covariates included the TCF7L2 genotype, BMI, sex, age diagnosed, drug adherence, and drug dose. A1C pretreatment was available in a subset of patients (sulfonylurea n = 579; metformin n = 755).
Carriers of the risk allele were less likely to respond to sulfonylureas with an odds ratio (OR) for failure of 1.95 (95% CI 1.23-3.06; P = 0.005), comparing rs12255372 T/T vs. G/G. Including the baseline A1C strengthened this association (OR 2.16 95% CI 1.21-3.86, P = 0.009). A similar, although slightly weaker, association was seen with rs7903146. No association was seen between metformin response and either single nucleotide polymorphism, after adjustment for baseline A1C.
TCF7L2 variants influence therapeutic response to sulfonylureas but not metformin. This study establishes that genetic variation can alter response to therapy in type 2 diabetes.
Type 2 diabetes mellitus (DM) plus chronic heart failure (CHF) is a common but lethal combination and therapeutic options are limited. Metformin is perceived as being relatively contraindicated in ...this context, although mounting evidence indicates that it may be beneficial. This study was carried out to investigate the use of metformin therapy for treating patients with DM and CHF in a large population-based cohort study. The Health Informatics Centre–dispensed prescribing database for the population of Tayside, Scotland (population ∼400,000) was linked to the Diabetes Audit and Research in Tayside Scotland (DARTS) information system. Patients with DM and incident CHF from 1994 to 2003 receiving oral hypoglycemic agents but not insulin were identified. Cox regression was used to assess differences in all-cause mortality rates between patients prescribed metformin and patients prescribed sulfonylureas with adjustment for co-morbidities and other therapies. Four hundred twenty-two study subjects (mean ± SD 75.4 ± 0.5 years of age, 46.2% women) were identified: metformin monotherapy (n = 68, mean age 75.5 ± 1.1 years, 48.5% women), sulfonylurea monotherapy (n = 217, mean age 76.7 ± 0.7 years, 45.2% women), and combination (n = 137, mean age, 73.4 ± 0.7 years, 46.7% women). Fewer deaths occurred in metformin users, alone or in combination with sulfonylureas, compared to the sulfonylurea monotherapy cohort at 1 year (0.59, 95% confidence interval 0.36 to 0.96) and over long-term follow up (0.67, 95% confidence interval 0.51 to 0.88). In conclusion, this large observational data suggest that metformin may be beneficial in patients with CHF and DM. These findings need to be verified by a prospective clinical trial.
The impact of CYP2C19 genotype on clopidogrel outcomes is one of the most well established pharmacogenetic interactions, supported by robust evidence and recommended by the Food and Drug ...Administration and clinical pharmacogenetics implementation consortium. However, there is a scarcity of large-scale real-world data on the extent of this pharmacogenetic effect, and clinical testing for the CYP2C19 genotype remains infrequent. This study utilizes the UK Biobank dataset, including 10 365 patients treated with clopidogrel, to offer the largest observational analysis of these pharmacogenetic effects to date.
Incorporating time-varying drug exposure and repeated clinical outcome, we adopted semiparametric frailty models to detect and quantify exposure-based effects of CYP2C19 (*2,*17) variants and nongenetic factors on the incidence risks of composite outcomes of death or recurrent hospitalizations due to major adverse cardiovascular events (MACE) or hemorrhage in the entire cohort of clopidogrel-treated patients.
Out of the 10 365 clopidogrel-treated patients, 40% (4115) experienced 10 625 MACE events during an average follow-up of 9.23 years. Individuals who received clopidogrel (coverage >25%) with a CYP2C19*2 loss-of-function allele had a 9.4% higher incidence of MACE incidence rate ratios (IRR), 1.094; 1.044-1.146, but a 15% lower incidence of hemorrhage (IRR, 0.849; 0.712-0.996). These effects were stronger with high clopidogrel exposure. Conversely, the gain-of-function CYP2C19*17 variant was associated with a 5.3% lower incidence of MACE (IRR, 0.947; 0.903-0.983). Notably, there was no evidence of *2 or *17 effects when clopidogrel exposure was low, confirming the presence of a drug-gene interaction.
The impact of CYP2C19 on clinical outcomes in clopidogrel-treated patients is substantial, highlighting the importance of incorporating genotype-based prescribing into clinical practice, regardless of the reason for clopidogrel use or the duration of treatment. Moreover, the methodology introduced in this study can be applied to further real-world investigations of known drug-gene and drug-drug interactions and the discovery of novel interactions.
To investigate the impact of type 2 diabetes on incidence of major dementia subtypes, Alzheimer and vascular dementia, using electronic medical records (EMR) in the GoDARTS bioresource.
GoDARTS ...(Genetics of Diabetes Audit and Research in Tayside Scotland) comprises a large case-control study of type 2 diabetes with longitudinal follow-up in EMR. Dementia case subjects after recruitment were passively identified in the EMR, and using a combination of case note review, an Alzheimer-specific weighted genetic risk score (wGRS), and
genotype, we validated major dementia subtypes. We undertook a retrospective matched cohort study to determine the risk of type 2 diabetes status for incident dementia accounting for competing risk of death.
Type 2 diabetes status was associated with a significant risk of any dementia (cause-specific hazard ratio csHR 1.46, 95% CI 1.31-1.64), which was attenuated, but still significant, when competing risk of death was accounted for (subdistribution sdHR 1.26, 95% CI 1.13-1.41). The accuracy of EMR-defined cases of Alzheimer or vascular dementia was high-positive predictive value (PPV) 86.4% and PPV 72.8%, respectively-and wGRS significantly predicted Alzheimer dementia (HR 1.23, 95% CI 1.12-1.34) but not vascular dementia (HR 1.02, 95% CI 0.91-1.15). Conversely, type 2 diabetes was strongly associated with vascular dementia (csHR 2.47, 95% C 1.92-3.18) but not Alzheimer dementia, particularly after competing risk of death was accounted for (sdHR 1.02, 95% CI 0.87-1.18).
Our study indicates that type 2 diabetes is associated with an increased risk of vascular dementia but not with an increased risk of Alzheimer dementia and highlights the potential value of bioresources linked to EMR to study dementia.
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