Blood pressure management in type 2 diabetes: integrating clinical trials and genetic data

Background: Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. On the other hand, controversy exists as to whether the threshold of blood pressure for initiation of antihypertensive therapy should differ between people with and without type 2 diabetes. I aimed to integrate individual participant data from major randomised controlled trials and genetic data to fill these knowledge gaps. Objectives: This thesis sought to examine three main objectives: to investigate the effect of pharmacological blood pressure-lowering on the risk of new-onset type 2 diabetes; to investigate the separate effects of blood pressure-lowering drug classes on the risk of new-onset type 2 diabetes; to investigate the effect of pharmacological blood pressure-lowering treatment for the prevention of major cardiovascular disease in persons with and without type 2 diabetes. Methods: For the first and second objectives, I conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC). Analyses were complemented with Mendelian randomisation studies using naturally randomised genetic variants associated with systolic blood pressure and genetic variants in the gene that encodes the therapeutic targets of each drug class. For the third objective, I used one-stage individual participant-level data meta-analysis using the BPLTTC dataset. I expressed the treatment effect per 5 mmHg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mmHg increments from <120 mmHg to ≥170 mmHg). Results: For the first and second objectives, blood pressure-lowering treatment was found to reduce the risk of diabetes by 11% (hazard ratio per 5 mmHg lower systolic blood pressure 0.89 [95% confidence interval [CI] 0.84 to 0.95]). Similarly, in the Mendelian randomisation study, each 5 mmHg genetically influenced lower systolic blood pressure was associated with an 11% lower risk of diabetes (odds ratio 0.89 [95% CI 0.86 to 0.93]). Evidence from genetic data and trials was also consistent in that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduced the risk of diabetes, and beta-blockers increased this risk. There was no effect for calcium channel blockers and findings for thiazide diuretics were inconsistent. For the third objective, over 4.2 years median follow-up (IQR 3.0 to 5.0), a 5 mmHg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0.94 [95% CI 0.91 to 0.98]) compared with those without type 2 diabetes (0.89 [0.87 to 0.92]; p for interaction=0.001). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes (absolute risk reduction -1.54 [95% CI -2.04 to -1.04] in people with diabetes and -1.61 [-1.86 to -1.36] in people without diabetes, p for interaction =1). We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. Conclusions: Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. Additionally, although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted

How much lowering of blood pressure is required to prevent cardiovascular disease in patients with and without previous cardiovascular disease?

Purpose of Review To review the recent large-scale randomised evidence on pharmacologic reduction in blood pressure for the primary and secondary prevention of cardiovascular disease. Recent Findings Based on findings of the meta-analysis of individual participant-level data from 48 randomised clinical trials and involving 344,716 participants with mean age of 65 years, the relative reduction in the risk of developing major cardiovascular events was proportional to the magnitude of achieved reduction in blood pressure. For each 5-mmHg reduction in systolic blood pressure, the risk of developing cardiovascular events fell by 10% (hazard ratio [HR] (95% confidence interval [CI], 0.90 [0.88 to 0.92]). When participants were stratified by their history of cardiovascular disease, the HRs (95% CI) in those with and without previous cardiovascular disease were 0.89 (0.86 to 0.92) and 0.91 (0.89 to 0.94), respectively, with no significant heterogeneity in these effects (adjusted P for interaction = 1.0). When these patient groups were further stratified by their baseline systolic blood pressure in increments of 10 mmHg from  Summary Pharmacologic lowering of blood pressure was effective in preventing major cardiovascular disease events both in people with or without previous cardiovascular disease, which was not modified by their baseline blood pressure level. Treatment effects were shown to be proportional to the intensity of blood pressure reduction, but even modest blood pressure reduction, on average, can lead to meaningful gains in the prevention of incident or recurrent cardiovascular disease

Systolic blood pressure, chronic obstructive pulmonary disease and cardiovascular risk

Objective In individuals with complex underlying health problems, the association between systolic blood pressure (SBP) and cardiovascular disease is less well recognised. The association between SBP and risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD) was investigated. Methods and analysis In this cohort study, 39 602 individuals with a diagnosis of COPD aged 55–90 years between 1990 and 2009 were identified from validated electronic health records (EHR) in the UK. The association between SBP and risk of cardiovascular end points (composite of ischaemic heart disease, heart failure, stroke and cardiovascular death) was analysed using a deep learning approach. Results In the selected cohort (46.5% women, median age 69 years), 10 987 cardiovascular events were observed over a median follow-up period of 3.9 years. The association between SBP and risk of cardiovascular end points was found to be monotonic; the lowest SBP exposure group of <120 mm Hg presented nadir of risk. With respect to reference SBP (between 120 and 129 mm Hg), adjusted risk ratios for the primary outcome were 0.99 (95% CI 0.93 to 1.05) for SBP of <120 mm Hg, 1.02 (0.97 to 1.07) for SBP between 130 and 139 mm Hg, 1.07 (1.01 to 1.12) for SBP between 140 and 149 mm Hg, 1.11 (1.05 to 1.17) for SBP between 150 and 159 mm Hg and 1.16 (1.10 to 1.22) for SBP ≥160 mm Hg. Conclusion Using deep learning for modelling EHR, we identified a monotonic association between SBP and risk of cardiovascular events in patients with COPD. Data availability statement Data may be obtained from a third party and are not publicly available. More details of the data and data sharing is found on the CPRD website (https://www.cprd.com). Targeted-BEHRT source code can be found on the Deep Medicine GitHub site (https://github.com/deepmedicine/Targeted-BEHRT). Example code for conducting an observational study on mock data and estimating risk ratio can also be found in this code repository

Systolic blood pressure and cardiovascular risk in patients with diabetes: a prospective cohort study

Background: Whether the association between systolic blood pressure (SBP) and risk of cardiovascular disease is monotonic or whether there is a nadir of optimal blood pressure remains controversial. We investigated the association between SBP and cardiovascular events in patients with diabetes across the full spectrum of SBP. Methods: A cohort of 49 000 individuals with diabetes aged 50 to 90 years between 1990 and 2005 was identified from linked electronic health records in the United Kingdom. Associations between SBP and cardiovascular outcomes (ischemic heart disease, heart failure, stroke, and cardiovascular death) were analyzed using a deep learning approach. Results: Over a median follow-up of 7.3 years, 16 378 cardiovascular events were observed. The relationship between SBP and cardiovascular events followed a monotonic pattern, with the group with the lowest baseline SBP of <120 mm Hg exhibiting the lowest risk of cardiovascular events. In comparison to the reference group with the lowest SBP (<120 mm Hg), the adjusted risk ratio for cardiovascular disease was 1.03 (95% CI, 0.97–1.10) for SBP between 120 and 129 mm Hg, 1.05 (0.99–1.11) for SBP between 130 and 139 mm Hg, 1.08 (1.01–1.15) for SBP between 140 and 149 mm Hg, 1.12 (1.03–1.20) for SBP between 150 and 159 mm Hg, and 1.19 (1.09–1.28) for SBP ≥160 mm Hg. Conclusions: Using deep learning modeling, we found a monotonic relationship between SBP and risk of cardiovascular outcomes in patients with diabetes, without evidence of a J-shaped relationship

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45–0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51–1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99–592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management

Effects of blood pressure lowering drugs in heart failure:a systematic review and meta-analysis of randomised controlled trials

We aimed to combine evidence from all heart failure trials that have investigated the effects of drugs with blood pressure (BP)-lowering properties to assess the extent to which such drugs reduce BP in heart failure, the association between the net change in BP between treatment arms and cause-specific outcomes and whether treatment effects (efficacy and safety) vary according to baseline BP. We conducted a systematic review and metaanalysis including randomized clinical trials of drugs with BP-lowering properties in patients with chronic heart failure with at least 300 patient-years follow-up. We included a total of 37 trials (91 950 patients) and showed that treatment with drugs with BP-lowering properties resulted in a small but significant decrease in SBP in patients with heart failure with no evidence that the efficacy and safety of those drugs varied according to baseline BP

Genetic susceptibility, elevated blood pressure and risk of atrial fibrillation:A Mendelian randomization study

Background: Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual&#x2019;s genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. Methods: First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a total of one million European population. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. Results: The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mm Hg [OR]: 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. Conclusions: The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF

Stratification of diabetes in the context of comorbidities, using representation learning and topological data analysis

Diabetes is a heterogenous, multimorbid disorder with a large variation in manifestations, trajectories, and outcomes. The aim of this study is to validate a novel machine learning method for the phenotyping of diabetes in the context of comorbidities. Data from 9967 multimorbid patients with a new diagnosis of diabetes were extracted from Clinical Practice Research Datalink. First, using BEHRT (a transformer-based deep learning architecture), the embeddings corresponding to diabetes were learned. Next, topological data analysis (TDA) was carried out to test how different areas in high-dimensional manifold correspond to different risk profiles. The following endpoints were considered when profiling risk trajectories: major adverse cardiovascular events (MACE), coronary artery disease (CAD), stroke (CVA), heart failure (HF), renal failure (RF), diabetic neuropathy, peripheral arterial disease, reduced visual acuity and all-cause mortality. Kaplan Meier curves were plotted for each derived phenotype. Finally, we tested the performance of an established risk prediction model (QRISK) by adding TDA-derived features. We identified four subgroups of patients with diabetes and divergent comorbidity patterns differing in their risk of future cardiovascular, renal, and other microvascular outcomes. Phenotype 1 (young with chronic inflammatory conditions) and phenotype 2 (young with CAD) included relatively younger patients with diabetes compared to phenotypes 3 (older with hypertension and renal disease) and 4 (older with previous CVA), and those subgroups had a higher frequency of pre-existing cardio-renal diseases. Within ten years of follow-up, 2592 patients (26%) experienced MACE, 2515 patients (25%) died, and 2020 patients (20%) suffered RF. QRISK3 model’s AUC was augmented from 67.26% (CI 67.25–67.28%) to 67.67% (CI 67.66–67.69%) by adding specific TDA-derived phenotype and the distances to both extremities of the TDA graph improving its performance in the prediction of CV outcomes. We confirmed the importance of accounting for multimorbidity when risk stratifying heterogenous cohort of patients with new diagnosis of diabetes. Our unsupervised machine learning method improved the prediction of clinical outcomes

Inkjet- and flextrail-printing of silicon polymer-based inks for local passivating contacts

In this work innovative additive printing methods for formation of polycrystalline silicon (poly-Si) and polycrystalline silicon carbide (poly-SiC) layers of local tunnel oxide passivating contacts (TOPCon) is evaluated. Replacement of conventional vacuum processes and vapor-phase deposition by additive printing of Si in fabrication process of high efficiency solar cells reduces processing complexity, and, hence manufacturing costs. Reliable inkjet- and FlexTrail-printing processes are developed for liquid-phase polysilane and organic polysilazane inks that are precursors of Si and SiC, respectively. FlexTrail is introduced as a potential technology to print uniform closed thin films of polysilane free of ruptures. Moreover, from inkjet-printing of the developed polysilane ink, homogenous, closed and crack free thin films of poly-Si are obtained after high temperature annealing. The polysilane ink is formulated considering evaluation of several solvents and photoinduced polymerization conditions. Inkjet-printing process development and optimization according to high frequency rheological characterization of organic polysilazane (OPSZ) is presented. Printed thin films are characterized after high temperature annealing (T = 950 °C, t = 60 min) to be uniform and free of micro cracks