Lifetime risk of cardiovascular-renal disease in type 2 diabetes: a population-based study in 473,399 individuals.

BACKGROUND: Cardiovascular and renal diseases (CVRD) are major causes of mortality in individuals with type 2 diabetes (T2D). Studies of lifetime risk have neither considered all CVRD together nor the relative contribution of major risk factors to combined disease burden. METHODS: In a population-based cohort study using national electronic health records, we studied 473,399 individuals with T2D in England 2007-2018. Lifetime risk of individual and combined major adverse renal cardiovascular events, MARCE (including CV death and CVRD: heart failure; chronic kidney disease; myocardial infarction; stroke or peripheral artery disease), were estimated, accounting for baseline CVRD status and competing risk of death. We calculated population attributable risk for individual CVRD components. Ideal cardiovascular health was defined by blood pressure, cholesterol, glucose, smoking, physical activity, diet, and body mass index (i.e. modifiable risk factors). RESULTS: In individuals with T2D, lifetime risk of MARCE was 80% in those free from CVRD and was 97%, 93%, 98%, 89% and 91% in individuals with heart failure, chronic kidney disease, myocardial infarction, stroke and peripheral arterial disease, respectively at baseline. Among CVRD-free individuals, lifetime risk of chronic kidney disease was highest (54%), followed by CV death (41%), heart failure (29%), stroke (20%), myocardial infarction (19%) and peripheral arterial disease (9%). In those with HF only, 75% of MARCE after index T2D can be attributed to HF after adjusting for age, gender, and comorbidities. Compared with those with > 1, < 3 and ≥3 modifiable health risk behaviours, achieving ideal cardiovascular health could reduce MARCE by approximately 41.5%, 23.6% and 17.2%, respectively, in the T2D population. CONCLUSIONS: Four out of five individuals with T2D free from CVRD, and nearly all those with history of CVRD, will develop MARCE over their lifetime. Early preventive measures in T2D patients are clinical, public health and policy priorities.

Lower risk of hospitalization for heart failure, kidney disease and death with sodium-glucose co-transporter-2 inhibitors compared with dipeptidyl peptidase-4 inhibitors in type 2 diabetes regardless of prior cardiovascular or kidney disease: A retrospective cohort study in UK primary care.

AIM: To assess if sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduce the risk of all-cause mortality, cardiovascular death and hospitalization for heart failure (HF) or chronic kidney disease (CKD) to a greater extent than dipeptidyl peptidase-4 inhibitors (DPP4is) in people with type 2 diabetes (T2D) with or without established cardiovascular and/or renal disease (CVRD). METHODS: This retrospective cohort study propensity-matched 24 438 patients receiving an SGLT2i 1:1 to a patient receiving a DDP4i, stratified based on the presence of CVRD. The primary outcomes were the time to each of the following: all-cause mortality, cardiovascular death or hospitalization for HF, myocardial infarction, stroke and CKD. RESULTS: Overall, SGLT2is were associated with reductions in all-cause mortality, cardiovascular mortality, hospitalization for HF and hospitalization for CKD compared with DPP4is. In patients with no CVRD history, SGLT2is were associated with reductions in all-cause mortality (HR 0.71, 95% CI 0.57-0.88; P = .002), hospitalization for HF (HR 0.76, 95% CI 0.59-0.98; P = .035) and hospitalization for CKD (HR 0.75, 95% CI 0.63-0.88; P < .001). In patients with established cardiovascular disease (CVD) or at high risk, SGLT2is were associated with reductions in all-cause mortality (HR 0.69, 95% CI 0.59-0.82; P < .001), cardiovascular mortality (HR 0.76, 95% CI 0.62-0.95; P = .014), hospitalization for HF (HR 0.73, 95% CI 0.63-0.85; P < .001), hospitalization for stroke (HR 0.75, 95% CI 0.59-0.94; P = .013) and hospitalization for CKD (HR 0.49, 95% CI 0.43-0.54; P < .001). CONCLUSION: There was consistency across subgroups and sensitivity analyses. SGLT2is were associated with a reduced risk of all-cause mortality and hospitalization for HF and CKD compared with DPP4-is, highlighting the need to introduce SGLT2is early in the management of patients with T2D.

Lower cardiorenal risk with sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes without cardiovascular and renal diseases: A large multinational observational study.

AIMS: We compared the new use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus dipeptidyl peptidase-4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic kidney disease (CKD), in patients with type 2 diabetes without a history of prevalent cardiovascular and renal disease, defined as cardiovascular and renal disease (CVRD) free, managed in routine clinical practice. MATERIALS AND METHODS: In this observational cohort study, patients were identified from electronic health records from England, Germany, Japan, Norway, South Korea and Sweden, during 2012-2018. In total, 1 006 577 CVRD-free new users of SGLT2i or DPP4i were propensity score matched 1:1. Unadjusted Cox regression was used to estimate hazard ratios (HRs) for outcomes: cardiorenal disease, HF, CKD, stroke, myocardial infarction (MI), cardiovascular and all-cause mortality. RESULTS: Baseline characteristics were well balanced between the treatment groups (n = 105 130 in each group) with total follow-up of 187 955 patient years. Patients had a mean age of 56 years, 43% were women and they were indexed between 2013 and 2018. The most commonly used agents were dapagliflozin (91.7% of exposure time) and sitagliptin/linagliptin (55.0%), in the SGLT2i and DPP4i, groups, respectively. SGLT2i was associated with lower risk of cardiorenal disease, HF, CKD, all-cause and cardiovascular mortality; HR (95% confidence interval), 0.56 (0.42-0.74), 0.71 (0.59-0.86), 0.44 (0.28-0.69), 0.67 (0.59-0.77), and 0.61 (0.44-0.85), respectively. No differences were observed for stroke [0.87 (0.69-1.09)] and MI [0.94 (0.80-1.11)]. CONCLUSION: In this multinational observational study, SGLT2i was associated with a lower risk of HF and CKD versus DPP4i in patients with type 2 diabetes otherwise free from both cardiovascular and renal disease.

Heart failure and chronic kidney disease manifestation and mortality risk associations in type 2 diabetes: A large multinational cohort study.

AIMS: To examine the manifestation of cardiovascular or renal disease (CVRD) in patients with type 2 diabetes (T2D) initially free from CVRD as well as the mortality risks associated with these diseases. METHODS: Patients free from CVRD were identified from healthcare records in England, Germany, Japan, the Netherlands, Norway and Sweden at a fixed date. CVRD manifestation was defined by first diagnosis of cardiorenal disease, or a stroke, myocardial infarction (MI) or peripheral artery disease (PAD) event. The mortality risk associated with single CVRD history of heart failure (HF), chronic kidney disease (CKD), MI, stroke or PAD was compared with that associated with CVRD-free status. RESULTS: Of 1 177 896 patients with T2D, 772 336 (66%) were CVRD-free and followed for a mean of 4.5 years. A total of 137 081 patients (18%) developed a first CVRD manifestation, represented by CKD (36%), HF (24%), stroke (16%), MI (14%) and PAD (10%). HF or CKD was associated with increased cardiovascular and all-cause mortality risk: hazard ratio (HR) 2.02 (95% confidence interval [CI] 1.75-2.33) and HR 2.05 (95% CI 1.82-2.32), respectively. HF and CKD were separately associated with significantly increased mortality risks, and the combination was associated with the highest cardiovascular and all-cause mortality risk: HRs 3.91 (95% CI 3.02-5.07) and 3.14 (95% CI 2.90-3.40), respectively. CONCLUSION: In a large multinational study of >750 000 CVRD-free patients with T2D, HF and CKD were consistently the most frequent first cardiovascular disease manifestations and were also associated with increased mortality risks. These novel findings show these cardiorenal diseases to be important and serious complications requiring improved preventive strategies.

Variation in surgical treatment advice for women with stress urinary incontinence: a study using clinical case vignettes.

INTRODUCTION: The aim of this study was to determine how recommendations of gynaecologists on surgical treatment for stress urinary incontinence (SUI) were influenced by patient characteristics. METHODS: Two hundred forty-five gynaecologists in the UK fully responded to an online questionnaire including 18 vignettes describing 7 clinical characteristics of women with SUI (age, body mass index, SUI type, previous SUI surgery, frequency of leakage, bother, physical status). The gynaecologists scored recommendations for surgery ranging from 1 'certainly not' to 5 'certainly yes'. Mean scores were used to calculate the relative impact ('weight') of each clinical characteristic. Latent class analysis was used to distinguish groups of gynaecologists with a particular practice style because they responded to the patient characteristics captured in the case vignettes in a similar way. RESULTS: The gynaecologists' overall average recommendation score was 2.9 (interquartile range 2 to 4). All patient characteristics significantly influenced the recommendation scores (p always < 0.001) but their impact was relatively small. SUI type was most important (weight 23%), followed by previous SUI surgery (weight 21%). Latent class analysis identified five groups of gynaecologists with practice styles that differed mainly with respect to their mean recommendation score, ranging from 1.3 to 4.0. CONCLUSIONS: Surgical treatment advice in response to case vignettes was only minimally influenced by patient characteristics. There were five groups of gynaecologists whose inclination to recommend surgical treatment varied. This suggests that there is lack of consensus on the role of surgery as a treatment for SUI. A considerable number of gynaecologists were reluctant to recommend surgery.

Identifying subtypes of type 2 diabetes mellitus with machine learning: development, internal validation, prognostic validation and medication burden in linked electronic health records in 420 448 individuals.

INTRODUCTION: None of the studies of type 2 diabetes (T2D) subtyping to date have used linked population-level data for incident and prevalent T2D, incorporating a diverse set of variables, explainable methods for cluster characterization, or adhered to an established framework. We aimed to develop and validate machine learning (ML)-informed subtypes for type 2 diabetes mellitus (T2D) using nationally representative data. RESEARCH DESIGN AND METHODS: In population-based electronic health records (2006-2020; Clinical Practice Research Datalink) in individuals ≥18 years with incident T2D (n=420 448), we included factors (n=3787), including demography, history, examination, biomarkers and medications. Using a published framework, we identified subtypes through nine unsupervised ML methods (K-means, K-means++, K-mode, K-prototype, mini-batch, agglomerative hierarchical clustering, Birch, Gaussian mixture models, and consensus clustering). We characterized clusters using intracluster distributions and explainable artificial intelligence (AI) techniques. We evaluated subtypes for (1) internal validity (within dataset; across methods); (2) prognostic validity (prediction for 5-year all-cause mortality, hospitalization and new chronic diseases); and (3) medication burden. RESULTS: Development: We identified four T2D subtypes: metabolic, early onset, late onset and cardiometabolic. Internal validity: Subtypes were predicted with high accuracy (F1 score >0.98). Prognostic validity: 5-year all-cause mortality, hospitalization, new chronic disease incidence and medication burden differed across T2D subtypes. Compared with the metabolic subtype, 5-year risks of mortality and hospitalization in incident T2D were highest in late-onset subtype (HR 1.95, 1.85-2.05 and 1.66, 1.58-1.75) and lowest in early-onset subtype (1.18, 1.11-1.27 and 0.85, 0.80-0.90). Incidence of chronic diseases was highest in late-onset subtype and lowest in early-onset subtype. Medications: Compared with the metabolic subtype, after adjusting for age, sex, and pre-T2D medications, late-onset subtype (1.31, 1.28-1.35) and early-onset subtype (0.83, 0.81-0.85) were most and least likely, respectively, to be prescribed medications within 5 years following T2D onset. CONCLUSIONS: In the largest study using ML to date in incident T2D, we identified four distinct subtypes, with potential future implications for etiology, therapeutics, and risk prediction.

Risk factors, outcomes and healthcare utilisation in individuals with multimorbidity including heart failure, chronic kidney disease and type 2 diabetes mellitus: a national electronic health record study.

BACKGROUND: Heart failure (HF), type 2 diabetes (T2D) and chronic kidney disease (CKD) commonly coexist. We studied characteristics, prognosis and healthcare utilisation of individuals with two of these conditions. METHODS: We performed a retrospective, population-based linked electronic health records study from 1998 to 2020 in England to identify individuals diagnosed with two of: HF, T2D or CKD. We described cohort characteristics at time of second diagnosis and estimated risk of developing the third condition and mortality using Kaplan-Meier and Cox regression models. We also estimated rates of healthcare utilisation in primary care and hospital settings in follow-up. FINDINGS: We identified cohorts of 64 226 with CKD and HF, 82 431 with CKD and T2D, and 13 872 with HF and T2D. Compared with CKD and T2D, those with CKD and HF and HF and T2D had more severe risk factor profile. At 5 years, incidence of the third condition and all-cause mortality occurred in 37% (95% CI: 35.9%, 38.1%%) and 31.3% (30.4%, 32.3%) in HF+T2D, 8.7% (8.4%, 9.0%) and 51.6% (51.1%, 52.1%) in HF+CKD, and 6.8% (6.6%, 7.0%) and 17.9% (17.6%, 18.2%) in CKD+T2D, respectively. In each of the three multimorbid groups, the order of the first two diagnoses was also associated with prognosis. In multivariable analyses, we identified risk factors for developing the third condition and mortality, such as age, sex, medical history and the order of disease diagnosis. Inpatient and outpatient healthcare utilisation rates were highest in CKD and HF, and lowest in CKD and T2D. INTERPRETATION: HF, CKD and T2D carry significant mortality and healthcare burden in combination. Compared with other disease pairs, individuals with CKD and HF had the most severe risk factor profile, prognosis and healthcare utilisation. Service planning, policy and prevention must take into account and monitor data across conditions.