Blood pressure management in type 2 diabetes: a review of recent evidence.

The frequent concurrence of elevated blood pressure (BP) and type 2 diabetes markedly elevates the risk of cardiovascular disease and mortality. In this review, we discuss the evidence supporting the role of BP-lowering therapies in preventing cardiovascular events in people with type 2 diabetes and the most appropriate BP treatment target in these individuals. We outline possible reasons for the heterogeneous effect of BP lowering in patients with and without diabetes and consider several pathophysiological mechanisms that could potentially explain such differences. The review introduces a mediation model, delineating the intricate interplay between hypertension and diabetes and their joint contribution to cardiovascular and renal pathologies. Finally, we outline the role of lifestyle changes and other pharmacological options in attenuating cardiometabolic risks in patients with type 2 diabetes. We propose a comprehensive, patient-centred management strategy, integrating various antihypertensive therapeutic approaches and providing clinicians with a systematic framework for better decision-making.

Association between sleep duration and hypertension incidence: Systematic review and meta-analysis of cohort studies.

AIM: Sleep duration has been suggested to be associated with hypertension (HTN). However, evidence of the nature of the relationship and its direction has been inconsistent. Therefore, we performed a meta-analysis to assess the relationship between sleep duration and risk of HTN incidence, and to distinguish more susceptible populations. METHODS: PubMed, Embase, Scopus, Web of Science, and ProQuest were searched from January 2000 to May 2023 for cohort studies comparing short and long sleep durations with 7-8 hours of sleep for the risk of HTN incidence. Random-effect model (the DerSimonian-Laird method) was applied to pool risk ratios (RR) and 95% confidence interval (CI). RESULTS: We included sixteen studies ranging from 2.4 to 18 years of follow-up duration evaluating HTN incidence in 1,044,035 people. Short sleep duration was significantly associated with a higher risk of developing HTN (HR: 1.07, 95% CI: 1.06-1.09). The association was stronger when the sleep duration was less than 5 hours (HR: 1.11, 95% CI: 1.08-1.14). In contrast to males, females (HR: 1.07, 95% CI: 1.04-1.09) were more vulnerable to developing HTN due to short sleep duration. No significant difference between different follow-up durations and age subgroups was observed. Long sleep duration was not associated with an increased incidence of HTN. CONCLUSION: Short sleep duration was associated with higher risk of HTN incidence, however, there was no association between long sleep duration and incidence of HTN. These findings highlight the importance of implementing target-specific preventive and interventional strategies for vulnerable populations with short sleep duration to reduce the risk of HTN.

Cardiovascular Risk Factors in Childhood and Adulthood and Cardiovascular Disease in Middle Age.

Importance: Recent evidence suggests that childhood levels of serum lipids, blood pressure, body mass index (BMI), and smoking contribute to adult risk of cardiovascular disease (CVD). Evidence is lacking on whether this is independent of adult risk levels. Objective: To quantify direct and indirect effects of childhood risk factors on adult CVD via adulthood risk factors using mediation analysis, and to quantify their relative importance during different life-course stages using a life-course approach. Design, Setting, and Participants: This prospective cohort study followed participants from the US, Finland, and Australia from childhood (1970s-1990s) until 2019, with data on CVD risk factors in childhood and adulthood. Longitudinal childhood and adulthood risk factors were summarized to describe BMI, lipids, and blood pressure cumulatively. Childhood and adulthood smoking were assessed with questionnaires. Data analysis was performed May 2022 to August 2023. Main Outcomes and Measures: The primary outcomes were fatal and nonfatal cardiovascular events in adulthood. Mediation analysis was used to estimate the direct and indirect effects of the childhood risk factors with CVD events, reported as incidence rate ratios (RRs) and 95% CIs. Results: A total of 10 634 participants (4506 male participants [42.4%]; mean [SD] age at childhood visit, 13.3 [3.0] years; mean [SD] age at adulthood visit, 32.3 [6.0] years) were included in the cohort. The mean (SD) age at CVD event or censoring was 49.2 (7.0) years. The median (IQR) follow-up time was 23.6 (18.7-30.2) years. Childhood risk factors, (low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides, systolic blood pressure [SBP], smoking, BMI, and a combined score of these) were associated with CVD. BMI (direct effect for incidence RR per 1 SD unit, 1.18; 95% CI, 1.05-1.34) and LDL-C (direct effect incidence RR, 1.16; 95% CI, 1.01-1.34) in particular were found to play an important role via direct pathways, whereas the indirect effects were larger for TC, triglycerides, SBP, and the combined score. Childhood smoking only affected CVD via adulthood smoking. Life-course models confirmed that for the risk of CVD, childhood BMI plays nearly as important role as adulthood BMI, whereas for the other risk factors and the combined score, adulthood was the more important period. Conclusions and Relevance: In this cohort study of 10 634 participants, childhood risk factors were found to be associated both directly and indirectly to adult CVD, with the largest direct effect seen for BMI and LDL-C. These findings suggest that intervention for childhood risk factors, in particular BMI, is warranted to reduce incidence of adult CVD as it cannot be fully mitigated by risk factor management in adulthood.

Trends in cardiovascular disease incidence among 22 million people in the UK over 20 years: population based study.

OBJECTIVE: To investigate the incidence of cardiovascular disease (CVD) overall and by age, sex, and socioeconomic status, and its variation over time, in the UK during 2000-19. DESIGN: Population based study. SETTING: UK. PARTICIPANTS: 1 650 052 individuals registered with a general practice contributing to Clinical Practice Research Datalink and newly diagnosed with at least one CVD from 1 January 2000 to 30 June 2019. MAIN OUTCOME MEASURES: The primary outcome was incident diagnosis of CVD, comprising acute coronary syndrome, aortic aneurysm, aortic stenosis, atrial fibrillation or flutter, chronic ischaemic heart disease, heart failure, peripheral artery disease, second or third degree heart block, stroke (ischaemic, haemorrhagic, and unspecified), and venous thromboembolism (deep vein thrombosis or pulmonary embolism). Disease incidence rates were calculated individually and as a composite outcome of all 10 CVDs combined and were standardised for age and sex using the 2013 European standard population. Negative binomial regression models investigated temporal trends and variation by age, sex, and socioeconomic status. RESULTS: The mean age of the population was 70.5 years and 47.6% (n=784 904) were women. The age and sex standardised incidence of all 10 prespecified CVDs declined by 19% during 2000-19 (incidence rate ratio 2017-19 v 2000-02: 0.80, 95% confidence interval 0.73 to 0.88). The incidence of coronary heart disease and stroke decreased by about 30% (incidence rate ratios for acute coronary syndrome, chronic ischaemic heart disease, and stroke were 0.70 (0.69 to 0.70), 0.67 (0.66 to 0.67), and 0.75 (0.67 to 0.83), respectively). In parallel, an increasing number of diagnoses of cardiac arrhythmias, valve disease, and thromboembolic diseases were observed. As a result, the overall incidence of CVDs across the 10 conditions remained relatively stable from the mid-2000s. Age stratified analyses further showed that the observed decline in coronary heart disease incidence was largely restricted to age groups older than 60 years, with little or no improvement in younger age groups. Trends were generally similar between men and women. A socioeconomic gradient was observed for almost every CVD investigated. The gradient did not decrease over time and was most noticeable for peripheral artery disease (incidence rate ratio most deprived v least deprived: 1.98 (1.87 to 2.09)), acute coronary syndrome (1.55 (1.54 to 1.57)), and heart failure (1.50 (1.41 to 1.59)). CONCLUSIONS: Despite substantial improvements in the prevention of atherosclerotic diseases in the UK, the overall burden of CVDs remained high during 2000-19. For CVDs to decrease further, future prevention strategies might need to consider a broader spectrum of conditions, including arrhythmias, valve diseases, and thromboembolism, and examine the specific needs of younger age groups and socioeconomically deprived populations.

Self-Administration of Aspirin After Chest Pain for the Prevention of Premature Cardiovascular Mortality in the United States: A Population-Based Analysis.

BACKGROUND: Aspirin, an effective, low-cost pharmaceutical, can significantly reduce mortality if used promptly after acute myocardial infarction (AMI). However, many AMI survivors do not receive aspirin within a few hours of symptom onset. Our aim was to quantify the mortality benefit of self-administering aspirin at chest pain onset, considering the increased risk of bleeding and costs associated with widespread use. METHODS AND RESULTS: We developed a population simulation model to determine the impact of self-administering 325 mg aspirin within 4 hours of severe chest pain onset. We created a synthetic cohort of adults ≥ 40 years old experiencing severe chest pain using 2019 US population estimates, AMI incidence, and sensitivity/specificity of chest pain for AMI. The number of annual deaths delayed was estimated using evidence from a large, randomized trial. We also estimated the years of life saved (YOLS), costs, and cost per YOLS. Initiating aspirin within 4 hours of severe chest pain onset delayed 13 016 (95% CI, 11 643-14 574) deaths annually, after accounting for deaths due to bleeding (963; 926-1003). This translated to an estimated 166 309 YOLS (149391-185 505) at the cost of $643 235 (633 944-653 010) per year, leading to a cost-effectiveness ratio of $3.70 (3.32-4.12) per YOLS. CONCLUSIONS: For <$4 per YOLS, self-administration of aspirin within 4 hours of severe chest pain onset has the potential to save 13 000 lives per year in the US population. Benefits of reducing deaths post-AMI outweighed the risk of bleeding deaths from aspirin 10 times over.

Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies.

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Efficacy of decentralised home-based antihypertensive treatment in older adults with multimorbidity and polypharmacy (ATEMPT): an open-label randomised controlled pilot trial.

BACKGROUND: Older patients with multimorbidity and polypharmacy have been under-represented in clinical trials. We aimed to assess the effect of different intensities of antihypertensive treatment on changes in blood pressure, major safety outcomes, and patient-reported outcomes in this population. METHODS: ATEMPT was a decentralised, two-armed, parallel-group, open-label randomised controlled pilot trial conducted in the Thames Valley area, South East England. Individuals aged 65 years or older with multimorbidity (three or more chronic conditions) or polypharmacy (five or more types of medications) and a systolic blood pressure of 115-165 mm Hg were eligible for inclusion. Participants were identified through a search of national hospital discharge databases, identification of patients registered with an online pharmacy, and via targeted advertising on social media platforms. Participants were randomly assigned to receive up to two more classes versus up to two fewer classes of antihypertensive medications. Apart from routine home visits for conducting the baseline assessment, all communication, monitoring, and management of participants by the trial team was conducted remotely. The primary outcome was change in home-measured blood pressure. FINDINGS: Between Dec 15, 2020, and Aug 31, 2022, 230 participants were randomly assigned (n=126 to more vs n=104 to fewer antihypertensive medications). The frequency of serious adverse events was similar across both groups; no cardiovascular events occurred in the more antihypertensive drugs group, compared with six in the fewer antihypertensive drugs group, of which two were fatal. Over a 13-month follow-up period, the mean systolic blood pressure in the group allocated to receive more antihypertensive medications decreased from 134·5 mm Hg (SD 10·7) at baseline to 122·1 mm Hg (10·5). By contrast, in the group allocated to receive fewer antihypertensive medications, it remained relatively unchanged, moving from 134·8 mm Hg (SD 11·2) at baseline to 132·9 mm Hg (15·3); this corresponded to a mean difference of -10·7 mm Hg (95% CI -17·5 to -4·0). INTERPRETATION: Remotely delivered antihypertensive treatment substantially reduced systolic blood pressure in older adults who are often less represented in trials, with no increase in the risk of serious adverse events. The results of this trial will inform a larger clinical trial focusing on assessing major cardiovascular events, safety, physical functioning, and cognitive function that is currently in the planning stages. These results also underscore the efficiency of decentralised trial designs, which might be of broader interest in other settings. FUNDING: National Institute for Health Research Oxford Biomedical Research Centre and the Oxford Martin School.

Gout and incidence of 12 cardiovascular diseases: a case-control study including 152 663 individuals with gout and 709 981 matched controls.

BACKGROUND: Gout, a common crystal arthropathy, is associated with increased risk of cardiovascular disease. We aimed to identify how this risk varies by individual cardiovascular disease across a broad spectrum of conditions. METHODS: In this matched case-control study, we used linked primary and secondary electronic health records from the UK Clinical Practice Research Datalink to assemble a cohort of individuals with a first-time diagnosis of gout between Jan 1, 2000 and Dec 31, 2017, who were aged 80 years or younger at diagnosis, and free of cardiovascular diseases up to 12 months after diagnosis. The control cohort comprised up to five control individuals per patient with gout, matched on age, sex, socioeconomic status, geographical region, and calendar time, randomly selected among individuals free of gout at any time before and during the study period. The cohorts were followed up until June 30, 2019. We investigated the incidence of 12 cardiovascular diseases and used Cox proportional hazards models to examine differences in people with and without gout, overall and by subgroups of sex, age, socioeconomic status, and year of study inclusion. We further adjusted models for known cardiovascular risk factors (blood pressure, BMI, smoking status, cholesterol, type 2 diabetes, chronic kidney disease, and history of hypertension). FINDINGS: We identified 152 663 individuals with gout (mean age 56·2 years [SD 13·3]; 120 324 [78·8%] men and 32 339 [21·2%] women) and 709 981 matched controls (mean age 56·5 years [13·2]; 561 002 [79·0%] men and 148 979 [21·0%] women). Of these individuals, 31 479 (20·6%) with gout and 106 520 (15·0%) without gout developed cardiovascular disease during a median follow-up of 6·5 years (IQR 3·1-10·5). Patients with gout had higher risk of cardiovascular diseases than matched controls (hazard ratio [HR] 1·58 [95% CI 1·52-1·63]). Excess risk of cardiovascular disease in gout was greater in women than men (women: HR 1·88 [1·75-2·02]; men: HR 1·49 [1·43-1·56]), and, among all age groups, was highest in younger individuals (HR in people aged <45 years: 2·22 [1·92-2·57]). Excess risk was observed across all 12 cardiovascular diseases investigated. Patients with gout had higher BMI than matched controls (mean difference 2·90 kg/m2 [95% CI 2·87-2·93]) and higher prevalence of chronic kidney disease, dyslipidaemia, history of hypertension, obesity, and type 2 diabetes. Adjusting for known cardiovascular risk factors attenuated but did not eliminate the excess risk of cardiovascular disease related to gout (adjusted HR 1·31 [1·27-1·36]). INTERPRETATION: Patients with gout had an excess risk of developing a broad range of cardiovascular diseases that extend beyond atherosclerotic diseases and include heart failure, arrhythmias, valve disease, and thromboembolic diseases. Excess risk was highest in women and younger individuals. These findings suggest that strategies to reduce cardiovascular risk in patients with gout need to evolve and be implemented in clinical practice. FUNDING: Research Foundation Flanders.

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 (IL1ß inhibitor) and colchicine (ß-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, IL1ß or ß-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.

The promise of digital healthcare technologies.

Digital health technologies have been in use for many years in a wide spectrum of healthcare scenarios. This narrative review outlines the current use and the future strategies and significance of digital health technologies in modern healthcare applications. It covers the current state of the scientific field (delineating major strengths, limitations, and applications) and envisions the future impact of relevant emerging key technologies. Furthermore, we attempt to provide recommendations for innovative approaches that would accelerate and benefit the research, translation and utilization of digital health technologies.

Prognosis, characteristics, and provision of care for patients with the unspecified heart failure electronic health record phenotype: a population-based linked cohort study of 95262 individuals.

Background: Whether the accuracy of the phenotype ascribed to patients in electronic health records (EHRs) is associated with variation in prognosis and care provision is unknown. We investigated this for heart failure (HF, characterised as HF with preserved ejection fraction [HFpEF], HF with reduced ejection fraction [HFrEF] and unspecified HF). Methods: We included individuals aged 16 years and older with a new diagnosis of HF between January 2, 1998 and February 28, 2022 from linked primary and secondary care records in the Clinical Practice Research Datalink in England. We investigated the provision of guideline-recommended diagnostic investigations and pharmacological treatments. The primary outcome was a composite of HF hospitalisation or all-cause death, and secondary outcomes were time to HF hospitalisation, all-cause death and death from cardiovascular causes. We used Kaplan-Meier curves and log rank tests to compare survival across HF phenotypes and adjusted for potential confounders in Cox proportional hazards regression analyses. Findings: Of a cohort of 95,262 individuals, 1271 (1.3%) were recorded as having HFpEF, 10,793 (11.3%) as HFrEF and 83,198 (87.3%) as unspecified HF. Individuals recorded as unspecified HF were older with a higher prevalence of dementia. Unspecified HF, compared to patients with a recorded HF phenotype, were less likely to receive specialist assessment, echocardiography or natriuretic peptide testing in the peri-diagnostic period, or receive angiotensin-converting enzyme inhibitors, beta blockers or mineralocorticoid receptor antagonists up to 12 months after diagnosis (risk ratios compared to HFrEF, 0.64, 95% CI 0.63-0.64; 0.59, 0.58-0.60; 0.57, 0.55-0.59; respectively) and had significantly worse outcomes (adjusted hazard ratios compared to HFrEF, HF hospitalisation and death 1.66, 95% CI 1.59-1.74; all-cause mortality 2.00, 1.90-2.10; cardiovascular death 1.77, 1.65-1.90). Interpretation: Our findings suggested that absence of specification of HF phenotype in routine EHRs is inversely associated with clinical investigations, treatments and survival, representing an actionable target to mitigate prognostic and health resource burden. Funding: Japan Research Foundation for Healthy Aging and British Heart Foundation.

Sodium-based paracetamol: impact on blood pressure, cardiovascular events, and all-cause mortality.

BACKGROUND AND AIMS: Effervescent formulations of paracetamol containing sodium bicarbonate have been reported to associate with increased blood pressure and a higher risk of cardiovascular diseases and all-cause mortality. Given the major implications of these findings, the reported associations were re-examined. METHODS: Using linked electronic health records data, a cohort of 475 442 UK individuals with at least one prescription of paracetamol, aged between 60 and 90 years, was identified. Outcomes in patients taking sodium-based paracetamol were compared with those taking non-sodium-based formulations of the same. Using a deep learning approach, associations with systolic blood pressure (SBP), major cardiovascular events (myocardial infarction, heart failure, and stroke), and all-cause mortality within 1 year after baseline were investigated. RESULTS: A total of 460 980 and 14 462 patients were identified for the non-sodium-based and sodium-based paracetamol exposure groups, respectively (mean age: 74 years; 64% women). Analysis revealed no difference in SBP [mean difference -0.04 mmHg (95% confidence interval -0.51, 0.43)] and no association with major cardiovascular events [relative risk (RR) 1.03 (0.91, 1.16)]. Sodium-based paracetamol showed a positive association with all-cause mortality [RR 1.46 (1.40, 1.52)]. However, after further accounting of other sources of residual confounding, the observed association attenuated towards the null [RR 1.08 (1.01, 1.16)]. Exploratory analyses revealed dysphagia and related conditions as major sources of uncontrolled confounding by indication for this association. CONCLUSIONS: This study does not support previous suggestions of increased SBP and an elevated risk of cardiovascular events from short-term use of sodium bicarbonate paracetamol in routine clinical practice.

A comparative study of model-centric and data-centric approaches in the development of cardiovascular disease risk prediction models in the UK Biobank.

Aims: A diverse set of factors influence cardiovascular diseases (CVDs), but a systematic investigation of the interplay between these determinants and the contribution of each to CVD incidence prediction is largely missing from the literature. In this study, we leverage one of the most comprehensive biobanks worldwide, the UK Biobank, to investigate the contribution of different risk factor categories to more accurate incidence predictions in the overall population, by sex, different age groups, and ethnicity. Methods and results: The investigated categories include the history of medical events, behavioural factors, socioeconomic factors, environmental factors, and measurements. We included data from a cohort of 405 257 participants aged 37-73 years and trained various machine learning and deep learning models on different subsets of risk factors to predict CVD incidence. Each of the models was trained on the complete set of predictors and subsets where each category was excluded. The results were benchmarked against QRISK3. The findings highlight that (i) leveraging a more comprehensive medical history substantially improves model performance. Relative to QRISK3, the best performing models improved the discrimination by 3.78% and improved precision by 1.80%. (ii) Both model- and data-centric approaches are necessary to improve predictive performance. The benefits of using a comprehensive history of diseases were far more pronounced when a neural sequence model, BEHRT, was used. This highlights the importance of the temporality of medical events that existing clinical risk models fail to capture. (iii) Besides the history of diseases, socioeconomic factors and measurements had small but significant independent contributions to the predictive performance. Conclusion: These findings emphasize the need for considering broad determinants and novel modelling approaches to enhance CVD incidence prediction.

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.