The implications of competing risks and direct treatment disutility in cardiovascular disease and osteoporotic fracture: risk prediction and cost effectiveness analysis.

Background: Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates. Objectives: Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments. Design, participants, main outcome measures, data sources: Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25-84 years for cardiovascular disease and aged 30-99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making). Results: CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell's c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85-99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise (n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best-worst scaling (n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk. Limitations: Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated. Conclusions: Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making. Study registration: This study is registered as PROSPERO CRD42021249959. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/12/22) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

Before offering a medicine to prevent disease, prescribers must expect it to do more good than harm. This balance depends on how likely it is that the person will develop the disease we want to prevent. But people might first die for other reasons. We call this a 'competing risk'. In most cases, the mathematical tools we use to estimate the chance of developing a disease do not account for competing risks. Another problem is that, when weighing up the benefits and harms of medicines, we ignore the hassle they cause patients, even when they do not cause side effects. We used two examples: statins to prevent heart disease and bisphosphonates to prevent fractures. First, we assessed if existing tools get predictions wrong by not accounting for competing risks. We found that they exaggerate the chance of heart attacks and strokes. However, the exaggeration is greatest among people who would clearly benefit from preventative treatment. So it may not change treatment decisions much. The fracture prediction tool we studied was very inaccurate, exaggerating risk among older people, but underestimating risk among younger people. We made a new fracture risk prediction tool. It gave better predictions, but it was still inaccurate for people aged > 85 years and those with several health problems. Next, we asked people questions designed to put a number on the hassle that statins and bisphosphonates cause. Most people thought that taking either is inconvenient, but the hassle factor for bisphosphonates is bigger. Finally, we updated the mathematical models that the National Institute for Health and Care Excellence used when recommending statins and bisphosphonates. We worked out if competing risks and the hassle of taking medicines make a difference to results. Statins remain a good idea for almost everyone, unless they really hate the idea of taking them. But bisphosphonates would do more harm than good for anyone who agrees with the hassle factor we found.

External validation of the QLifetime cardiovascular risk prediction tool: population cohort study.

BACKGROUND: Prediction of lifetime cardiovascular disease (CVD) risk is recommended in many clinical guidelines, but lifetime risk models are rarely externally validated. The aim of this study was to externally validate the QRiskLifetime incident CVD risk prediction tool. METHODS: Independent external validation of QRiskLifetime using Clinical Practice Research Datalink data, examining discrimination and calibration in the whole population and stratified by age, and reclassification compared to QRISK3. Since lifetime CVD risk is unobservable, performance was evaluated at 10-years' follow-up, and lifetime performance inferred in terms of performance for in the different age-groups from which lifetime predictions are derived. RESULTS: One million, two hundreds sixty thousand and three hundreds twenty nine women and 1,223,265 men were included in the analysis. Discrimination was excellent in the whole population (Harrell's-C = 0.844 in women, 0.808 in men), but moderate to poor stratified by age-group (Harrell's C in people aged 30-44 0.714 for both men and women, in people aged 75-84 0.578 in women and 0.556 in men). Ten-year CVD risk was under-predicted in the whole population, and in all age-groups except women aged 45-64, with worse under-prediction in older age-groups. Compared to those at highest QRISK3 estimated 10-year risk, those with highest lifetime risk were younger (mean age: women 50.5 vs. 71.3 years; men 46.3 vs. 63.8 years) and had lower systolic blood pressure and prevalence of treated hypertension, but had more family history of premature CVD, and were more commonly minority ethnic. Over 10-years, the estimated number needed to treat (NNT) with a statin to prevent one CVD event in people with QRISK3 ≥ 10% was 34 in women and 37 in men, compared to 99 and 100 for those at highest lifetime risk. CONCLUSIONS: QRiskLifetime underpredicts 10-year CVD risk in nearly all age-groups, so is likely to also underpredict lifetime risk. Treatment based on lifetime risk has considerably lower medium-term benefit than treatment based on 10-year risk.

A library of quantitative markers of seizure severity.

OBJECTIVE: Understanding fluctuations in seizure severity within individuals is important for determining treatment outcomes and responses to therapy, as well as assessing novel treatments for epilepsy. Current methods for grading seizure severity rely on qualitative interpretations from patients and clinicians. Quantitative measures of seizure severity would complement existing approaches to electroencephalographic (EEG) monitoring, outcome monitoring, and seizure prediction. Therefore, we developed a library of quantitative EEG markers that assess the spread and intensity of abnormal electrical activity during and after seizures. METHODS: We analyzed intracranial EEG (iEEG) recordings of 1009 seizures from 63 patients. For each seizure, we computed 16 markers of seizure severity that capture the signal magnitude, spread, duration, and postictal suppression of seizures. RESULTS: Quantitative EEG markers of seizure severity distinguished focal versus subclinical seizures across patients. In individual patients, 53% had a moderate to large difference (rank sum r > .3 , p < .05 ) between focal and subclinical seizures in three or more markers. Circadian and longer term changes in severity were found for the majority of patients. SIGNIFICANCE: We demonstrate the feasibility of using quantitative iEEG markers to measure seizure severity. Our quantitative markers distinguish between seizure types and are therefore sensitive to established qualitative differences in seizure severity. Our results also suggest that seizure severity is modulated over different timescales. We envisage that our proposed seizure severity library will be expanded and updated in collaboration with the epilepsy research community to include more measures and modalities.

Derivation and validation of the CFracture competing risk fracture prediction tool compared with QFracture in older people and people with comorbidity: a population cohort study.

BACKGROUND: UK guidelines recommend the QFracture tool to predict the risk of major osteoporotic fracture and hip fracture, but QFracture calibration is poor, partly because it does not account for competing mortality risk. The aim of this study was to derive and validate a competing risk model to predict major osteoporotic fracture and hip fracture (CFracture) and compare its performance with that of QFracture in UK primary care. METHODS: We used UK linked primary care data from the Clinical Practice Research Datalink GOLD database to identify people aged 30-99 years, split into derivation and validation cohorts. In the derivation cohort, we derived models (CFracture) using the same covariates as QFracture with Fine-Gray competing risk modelling, and included the Charlson Comorbidity Index score as an additional predictor of non-fracture death. In a separate validation cohort, we examined discrimination (using Harrell's C-statistic) and calibration of CFracture compared with QFracture. Reclassification analysis examined differences in the characteristics of patients reclassified as higher risk by CFracture but not by QFracture. FINDINGS: The derivation cohort included 1 831 606 women and 1 789 820 men, and the validation cohort included 915 803 women and 894 910 men. Overall discrimination of CFracture was excellent (C-statistic=0·813 [95% CI 0·810-0·816] for major osteoporotic fracture and 0·914 [0·908-0·919] for hip fracture in women; 0·734 [0·729-0·740] for major osteoporotic fracture and 0·886 [0·877-0·895] for hip fracture in men) and was similar to QFracture. CFracture calibration overall and in people younger than 75 years was generally excellent. CFracture overpredicted major osteoporotic fracture and hip fracture in older people and people with comorbidity, but was better calibrated than QFracture. Patients classified as high-risk by CFracture but not by QFracture had a higher prevalence of current smoking and previous fracture, but lower prevalence of dementia, cancer, cardiovascular disease, renal disease, and diabetes. INTERPRETATION: CFracture has similar discrimination to QFracture but is better calibrated overall and in younger people. Both models performed poorly in adults aged 85 years and older. Competing risk models should be recommended for fracture risk prediction to guide treatment recommendations. FUNDING: National Institute for Health and Care Research, Wellcome Trust, Health Data Research UK.

Vitamin D Deficiency (VDD) and Susceptibility towards Severe Dengue Fever-A Prospective Cross-Sectional Study of Hospitalized Dengue Fever Patients from Lahore, Pakistan.

Dengue is a mosquito-borne flaviviral serious febrile illness, most common in the tropical and subtropical regions including Pakistan. Vitamin D is a strong immunomodulator affecting both the innate and adaptive immune responses and plays a pivotal role in pathogen-defense mechanisms. There has been considerable interest in the possible role of vitamin D in dengue viral (DENV) infection. In the present prospective cross-sectional study, we assessed a possible association between serum vitamin D deficiency (VDD) and susceptibility towards severe dengue fever (DF) illness. Serum vitamin D levels were measured at the time of hospitalization in 97 patients diagnosed with dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) at Mayo Hospital, King Edward Medical University, Lahore, PK, from 16 November 2021 to 15 January 2022. In terms of disease severity, 37 (38.1%) patients were DF, 52 (53.6%) were DHF grade 1 and 2, and 8 (8.2%) were DSS. The results revealed that most patients (75 (77.3%)) were vitamin-D-deficient (i.e., serum level < 20 ng/mL), including 27 (73.0%) in DF, 41 (78.8%) in DHF grade 1 and 2, and 7 (87.5%) in DSS. The degree of VDD was somewhat higher in DSS patients as compared to DF and DHF grade 1 and 2 patients. Overall, serum vitamin D levels ranged from 4.2 to 109.7 ng/mL, and the median (IQR) was in the VDD range, i.e., 12.2 (9.1, 17.8) ng/mL. Our results suggest that there may be a possible association between VDD and susceptibility towards severe dengue illness. Hence, maintaining sufficient vitamin D levels in the body either through diet or supplementation may help provide adequate immune protection against severe dengue fever illness. Further research is warranted.

Oral Co-Supplementation of Curcumin, Quercetin, and Vitamin D3 as an Adjuvant Therapy for Mild to Moderate Symptoms of COVID-19-Results From a Pilot Open-Label, Randomized Controlled Trial.

Background: Curcumin, quercetin, and vitamin D3 (cholecalciferol) are common natural ingredients of human nutrition and reportedly exhibit promising anti-inflammatory, immunomodulatory, broad-spectrum antiviral, and antioxidant activities. Objective: The present study aimed to investigate the possible therapeutic benefits of a single oral formulation containing supplements curcumin, quercetin, and cholecalciferol (combinedly referred to here as CQC) as an adjuvant therapy for early-stage of symptomatic coronavirus disease 2019 (COVID-19) in a pilot open-label, randomized controlled trial conducted at Mayo Hospital, King Edward Medical University, Lahore, Pakistan. Methods: Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed, mild to moderate symptomatic COVID-19 outpatients were randomized to receive either the standard of care (SOC) (n = 25) (control arm) or a daily oral co-supplementation of 168 mg curcumin, 260 mg quercetin, and 9 µg (360 IU) of cholecalciferol, as two oral soft capsules b.i.d. as an add-on to the SOC (n = 25) (CQC arm) for 14 days. The SOC includes paracetamol with or without antibiotic (azithromycin). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR test, acute symptoms, and biochemistry including C-reactive protein (CRP), D-dimer, lactate dehydrogenase, ferritin, and complete blood count were evaluated at baseline and follow-up day seven. Results: Patients who received the CQC adjuvant therapy showed expedited negativization of the SARS-CoV-2 RT-PCR test, i.e., 15 (60.0%) vs. five (20.0%) of the control arm, p = 0.009. COVID-19- associated acute symptoms were rapidly resolved in the CQC arm, i.e., 15 (60.0%) vs. 10 (40.0%) of the control arm, p = 0.154. Patients in the CQC arm experienced a greater fall in serum CRP levels, i.e., from (median (IQR) 34.0 (21.0, 45.0) to 11.0 (5.0, 16.0) mg/dl as compared to the control arm, i.e., from 36.0 (28.0, 47.0) to 22.0 (15.0, 25.0) mg/dl, p = 0.006. The adjuvant therapy of co-supplementation of CQC was safe and well-tolerated by all 25 patients and no treatment-emergent effects, complications, side effects, or serious adverse events were reported. Conclusion: The co-supplementation of CQC may possibly have a therapeutic role in the early stage of COVID-19 infection including speedy negativization of the SARS-CoV-2 RT-PCR test, resolution of acute symptoms, and modulation of the hyperinflammatory response. In combination with routine care, the adjuvant co-supplementation of CQC may possibly help in the speedy recovery from early-stage mild to moderate symptoms of COVID-19. Further research is warranted. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT05130671.

Predictive performance of a competing risk cardiovascular prediction tool CRISK compared to QRISK3 in older people and those with comorbidity: population cohort study.

BACKGROUND: Recommended cardiovascular disease (CVD) prediction tools do not account for competing mortality risk and over-predict incident CVD in older and multimorbid people. The aim of this study was to derive and validate a competing risk model (CRISK) to predict incident CVD and compare its performance to that of QRISK3 in UK primary care. METHODS: We used UK linked primary care data from the Clinical Practice Research Datalink (CPRD) GOLD to identify people aged 25-84 years with no previous CVD or statin treatment split into derivation and validation cohorts. In the derivation cohort, we derived models using the same covariates as QRISK3 with Fine-Gray competing risk modelling alone (CRISK) and with Charlson Comorbidity score (CRISK-CCI) as an additional predictor of non-CVD death. In a separate validation cohort, we examined discrimination and calibration compared to QRISK3. Reclassification analysis examined the number of patients recommended for treatment and the estimated number needed to treat (NNT) to prevent a new CVD event. RESULTS: The derivation and validation cohorts included 989,732 and 494,865 women and 946,784 and 473,392 men respectively. Overall discrimination of CRISK and CRISK-CCI were excellent and similar to QRISK3 (for women, C-statistic = 0.863/0.864/0.863 respectively; for men 0.833/0.819/0.832 respectively). CRISK and CRISK-CCI calibration overall and in younger people was excellent. CRISK over-predicted in older and multimorbid people although performed better than QRISK3, whilst CRISK-CCI performed the best. The proportion of people reclassified by CRISK-CCI varied by QRISK3 risk score category, with 0.7-9.7% of women and 2.8-25.2% of men reclassified as higher risk and 21.0-69.1% of women and 27.1-57.4% of men reclassified as lower risk. Overall, CRISK-CCI recommended fewer people for treatment and had a lower estimated NNT at 10% risk threshold. Patients reclassified as higher risk were younger, had lower SBP and higher BMI, and were more likely to smoke. CONCLUSIONS: CRISK and CRISK-CCI performed better than QRISK3. CRISK-CCI recommends fewer people for treatment and has a lower NNT to prevent a new CVD event compared to QRISK3. Competing risk models should be recommended for CVD primary prevention treatment recommendations.

Effect of competing mortality risks on predictive performance of the QFracture risk prediction tool for major osteoporotic fracture and hip fracture: external validation cohort study in a UK primary care population.

Objective: To externally evaluate the QFracture risk prediction tool for predicting the risk of major osteoporotic fracture and hip fracture. Design: External validation cohort study. Setting: UK primary care population. Linked general practice (Clinical Practice Research Datalink (CPRD) Gold), mortality registration (Office of National Statistics), and hospital inpatient (Hospital Episode Statistics) data, from 1 January 2004 to 31 March 2016. Participants: 2 747 409 women and 2 684 730 men, aged 30-99 years, with up-to-standard linked data that had passed CPRD checks for at least one year. Main outcome measures: Two outcomes were modelled based on the QFracture: major osteoporotic fracture and hip fracture. Major osteoporotic fracture was defined as any hip, distal forearm, proximal humerus, or vertebral crush fracture, from general practice, hospital discharge, and mortality data. The QFracture 10 year predicted risk of major osteoporotic fracture and hip fracture was calculated, and performance evaluated versus observed 10 year risk of fracture in the whole population, and in subgroups based on age and comorbidity. QFracture calibration was examined accounting for, and not accounting for, competing risk of mortality from causes other than the major osteoporotic fracture. Results: 2 747 409 women with 95 598 major osteoporotic fractures and 36 400 hip fractures, and 2 684 730 men with 34 321 major osteoporotic fractures and 13 379 hip fractures were included in the analysis. The incidence of all fractures was higher than in the QFracture internal derivation. Competing risk of mortality was more common than fracture from middle age onwards. QFracture discrimination in the whole population was excellent or good for major osteoporotic fracture and hip fracture (Harrell's C statistic in women 0.813 and 0.918, and 0.738 and 0.888 in men, respectively), but was poor to moderate in age subgroups (eg, Harrell's C statistic in women and men aged 85-99 years was 0.576 and 0.624 for major osteoporotic fractures, and 0.601 and 0.637 for hip fractures, respectively). Without accounting for competing risks, QFracture systematically under-predicted the risk of fracture in all models, and more so for major osteoporotic fracture than for hip fracture, and more so in older people. Accounting for competing risks, QFracture still under-predicted the risk of fracture in the whole population, but over-prediction was considerable in older age groups and in people with high comorbidities at high risk of fracture. Conclusions: The QFracture risk prediction tool systematically under-predicted the risk of fracture (because of incomplete determination of fracture rates) and over-predicted the risk in older people and in those with more comorbidities (because of competing mortality). The use of QFracture in its current form needs to be reviewed, particularly in people at high risk of death from other causes.

Effect of competing mortality risks on predictive performance of the QRISK3 cardiovascular risk prediction tool in older people and those with comorbidity: external validation population cohort study.

BACKGROUND: Primary prevention of cardiovascular disease (CVD) is guided by risk-prediction tools, but these rarely account for the risk of dying from other conditions (ie, competing mortality risk). In England and Wales, the recommended risk-prediction tool is QRISK2, and a new version (QRISK3) has been derived and internally validated. We aimed to externally validate QRISK3 and to assess the effects of competing mortality risk on its predictive performance. METHODS: For this retrospective population cohort study, we used data from the Clinical Practice Research Datalink. We included patients aged 25-84 years with no previous history of CVD or statin treatment who were permanently registered with a primary care practice, had up-to-standard data for at least 1 year, and had linkage to Hospital Episode Statistics discharge and Office of National Statistics mortality data. We compared the QRISK3-predicted 10-year CVD risk with the observed 10-year risk in the whole population and in important subgroups of age and multimorbidity. QRISK3 discrimination and calibration were examined with and without accounting for competing risks. FINDINGS: Our study population included 1 484 597 women with 42 451 incident CVD events (4·9 cases per 1000 person-years of follow-up, 95% CI 4·89-4·99), and 1 420 176 men with 53 066 incident CVD events (6·7 cases per 1000 person-years, 6·66-6·78), with median follow-up of 5·0 years (IQR 1·9-9·2). Non-CVD death rose markedly with age (0·4% of women and 0·5% of men aged 25-44 years had a non-CVD death vs 20·1% of women and 19·6% of men aged 75-84 years). QRISK3 discrimination in the whole population was excellent (Harrell's C-statistic 0·865 in women and 0·834 in men) but was poor in older age groups (<0·65 in all subgroups aged 65 years or older). Ignoring competing risks, QRISK3 calibration in the whole population and in younger people was excellent, but there was significant over-prediction in older people. Accounting for competing risks, QRISK3 systematically over-predicted CVD risk, particularly in older people and in those with high multimorbidity. INTERPRETATION: QRISK3 performed well at the whole population level when ignoring competing mortality risk. The tool performed considerably less well in important subgroups, including older people and people with multimorbidity, and less well again after accounting for competing mortality risk. FUNDING: National Institute for Health Research.

Development and validation of a cardiovascular risk prediction model in type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to report current rates of CVD in type 1 diabetes and to develop a CVD risk prediction tool for type 1 diabetes. METHODS: A cohort of 27,527 people with type 1 diabetes without prior CVD was derived from the national register in Scotland. Incident CVD events during 199,552 person-years of follow-up were ascertained using hospital admissions and death registers. A Poisson regression model of CVD was developed and then validated in the Swedish National Diabetes Register (n = 33,183). We compared the percentage with a high 10 year CVD risk (i.e., ≥10%) using the model with the percentage eligible for statins using current guidelines by age. RESULTS: The age-standardised rate of CVD per 100,000 person-years was 4070 and 3429 in men and women, respectively, with type 1 diabetes in Scotland, and 4014 and 3956 in men and women in Sweden. The final model was well calibrated (Hosmer-Lemeshow test p > 0.05) and included a further 22 terms over a base model of age, sex and diabetes duration (C statistic 0.82; 95% CI 0.81, 0.83). The model increased the base model C statistic from 0.66 to 0.80, from 0.60 to 0.75 and from 0.62 to 0.68 in those aged <40, 40-59 and ≥ 60 years, respectively (all p values <0.005). The model required minimal calibration in Sweden and had a C statistic of 0.85. Under current guidelines, >90% of those aged 20-39 years and 100% of those ≥40 years with type 1 diabetes were eligible for statins, but it was not until age 65 upwards that 100% had a modelled risk of CVD ≥10% in 10 years. CONCLUSIONS/INTERPRETATION: A prediction tool such as that developed here can provide individualised risk predictions. This 10 year CVD risk prediction tool could facilitate patient discussions regarding appropriate statin prescribing. Apart from 10 year risk, such discussions may also consider longer-term CVD risk, the potential for greater benefits from early vs later statin intervention, the potential impact on quality of life of an early CVD event and evidence on safety, all of which could influence treatment decisions, particularly in younger people with type 1 diabetes.

Serum kidney injury molecule 1 and ß2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes.

AIMS/HYPOTHESIS: As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts. METHODS: We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case-control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30-75 ml min-1 [1.73 m]-2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function. RESULTS: Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and ß2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets. CONCLUSIONS/INTERPRETATION: Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30-75 ml min-1 [1.73 m]-2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers.

Incidence of Hospitalization for Heart Failure and Case-Fatality Among 3.25 Million People With and Without Diabetes Mellitus.

BACKGROUND: Recent clinical trials of new glucose-lowering treatments have drawn attention to the importance of hospitalization for heart failure as a complication of diabetes mellitus. However, the epidemiology is not well described, particularly for type 1 diabetes mellitus. We examined the incidence and case-fatality of heart failure hospitalizations in the entire population aged ≥30 years resident in Scotland during 2004 to 2013. METHODS: Date and type of diabetes mellitus diagnosis were linked to heart failure hospitalizations and deaths using the national Scottish registers. Incidence rates and case-fatality were estimated in regression models (quasi-Poisson and logistic regression respectively). All estimates are adjusted for age, sex, socioeconomic status, and calendar-year. RESULTS: Over the 10-year period of the study, among 3.25 million people there were 91, 429, 22 959, and 1313 incident heart failure events among those without diabetes mellitus, with type 2, and type 1 diabetes mellitus, respectively. The crude incidence rates of heart failure hospitalization were therefore 2.4, 12.4, and 5.6 per 1000 person-years for these 3 groups. Heart failure hospitalization incidence was higher in people with diabetes mellitus, regardless of type, than in people without. Relative differences were smallest for older men, in whom the difference was nonetheless large (men aged 80, rate ratio 1.78; 95% CI, 1.45-2.19). Rates declined similarly, by 0.2% per calendar-year, in people with type 2 diabetes mellitus and without diabetes mellitus. Rates fell faster, however, in those with type 1 diabetes mellitus (2.2% per calendar-year, rate ratio for type 1/calendar-year interaction 0.978; 95% CI, 0.959-0.998). Thirty-day case-fatality was similar among people with type 2 diabetes mellitus and without diabetes mellitus, but was higher in type 1 diabetes mellitus for men (odds ratio, 0.96; 95% CI, 0.95-0.96) and women (odds ratio, 0.98; 95% CI, 0.97-0.98). Case-fatality declined over time for all groups (3.3% per calendar-year, odds ratio per calendar-year 0.967; 95% CI, 0.961-0.973). CONCLUSIONS: Despite falling incidence, particularly in type 1 diabetes mellitus, heart failure remains ≈2-fold higher than in people without diabetes mellitus, with higher case-fatality in those with type 1 diabetes mellitus. These findings support the view that heart failure is an under-recognized and important complication in diabetes mellitus, particularly for type 1 disease.

Apolipoprotein CIII and N-terminal prohormone b-type natriuretic peptide as independent predictors for cardiovascular disease in type 2 diabetes.

BACKGROUND AND AIMS: Developing sparse panels of biomarkers for cardiovascular disease in type 2 diabetes would enable risk stratification for clinical decision making and selection into clinical trials. We examined the individual and joint performance of five candidate biomarkers for incident cardiovascular disease (CVD) in type 2 diabetes that an earlier discovery study had yielded. METHODS: Apolipoprotein CIII (apoCIII), N-terminal prohormone B-type natriuretic peptide (NT-proBNP), high sensitivity Troponin T (hsTnT), Interleukin-6, and Interleukin-15 were measured in baseline serum samples from the Collaborative Atorvastatin Diabetes trial (CARDS) of atorvastatin versus placebo. Among 2105 persons with type 2 diabetes and median age of 62.9 years (range 39.2-77.3), there were 144 incident CVD (acute coronary heart disease or stroke) cases during the maximum 5-year follow up. We used Cox Proportional Hazards models to identify biomarkers associated with incident CVD and the area under the receiver operating characteristic curves (AUROC) to assess overall model prediction. RESULTS: Three of the biomarkers were singly associated with incident CVD independently of other risk factors; NT-proBNP (Hazard Ratio per standardised unit 2.02, 95% Confidence Interval [CI] 1.63, 2.50), apoCIII (1.34, 95% CI 1.12, 1.60) and hsTnT (1.40, 95% CI 1.16, 1.69). When combined in a single model, only NT-proBNP and apoCIII were independent predictors of CVD, together increasing the AUROC using Framingham risk variables from 0.661 to 0.745. CONCLUSIONS: The biomarkers NT-proBNP and apoCIII substantially increment the prediction of CVD in type 2 diabetes beyond that obtained with the variables used in the Framingham risk score.

Type 2 diabetes, socioeconomic status and life expectancy in Scotland (2012-2014): a population-based observational study.

AIMS/HYPOTHESIS: The aim of this study was to assess the role of socioeconomic status (SES) in the associations between type 2 diabetes and life expectancy in a complete national population. METHODS: An observational population-based cohort study was performed using the Scottish Care Information - Diabetes database. Age-specific life expectancy (stratified by SES) was calculated for all individuals with type 2 diabetes in the age range 40-89 during the period 2012-2014, and for the remaining population of Scotland aged 40-89 without type 2 diabetes. Differences in life expectancy between the two groups were calculated. RESULTS: Results were based on 272,597 individuals with type 2 diabetes and 2.75 million people without type 2 diabetes (total for 2013, the middle calendar year of the study period). With the exception of deprived men aged 80-89, life expectancy in people with type 2 diabetes was significantly reduced (relative to the type 2 diabetes-free population) at all ages and levels of SES. Differences in life expectancy ranged from -5.5 years (95% CI -6.2, -4.8) for women aged 40-44 in the second most-deprived quintile of SES, to 0.1 years (95% CI -0.2, 0.4) for men aged 85-89 in the most-deprived quintile of SES. Observed life-expectancy deficits in those with type 2 diabetes were generally greater in women than in men. CONCLUSIONS/INTERPRETATION: Type 2 diabetes is associated with reduced life expectancy at almost all ages and levels of SES. Elimination of life-expectancy deficits in individuals with type 2 diabetes will require prevention and management strategies targeted at all social strata (not just deprived groups).

Modelling cumulative exposure for inference about drug effects in observational studies.

PURPOSE: To demonstrate a modelling approach that controls for time-invariant allocation bias in estimation of associations of outcome with drug exposure. METHODS: We show that in a model that includes terms for both ever-exposure versus never-exposure and cumulative exposure, the parameter for ever-exposure represents the effect of time-invariant allocation bias, and the parameter for cumulative exposure represents the effect of the drug after adjustment for this unmeasured confounding. This assumes no stepwise effect of the drug on the event rate, no reverse causation, and no unmeasured time-varying confounders. We demonstrated this by modelling the effect of statins on cardiovascular disease, for which the true effect has been well characterised in randomised trials, using time-updated Cox regression models in a national cohort of Type 2 diabetes patients. RESULTS: The crude hazard ratio associated with ever-use of statins was 1.13 in a standard cohort analysis comparing exposed with unexposed person-time intervals. When ever-never use and cumulative exposure are modelled jointly, the effect of statins can be estimated from the cumulative exposure parameter (hazard ratio 0.97 per year of exposure, 95% CI 0.97 to 0.98). The ever-exposed term (hazard ratio 1.20, 1.16 to 1.23) in this model can be interpreted as estimating the allocation bias. CONCLUSIONS: Where stepwise effects on the risk of adverse events are unlikely, as for instance for effects on risk of cancer, joint modelling of ever-never and cumulative exposure can be used to study the effects of multiple drugs and to distinguish causal effects from confounding by allocation.

Development and Validation of a Model to Predict Absolute Vascular Risk Reduction by Moderate-Intensity Statin Therapy in Individual Patients With Type 2 Diabetes Mellitus: The Anglo Scandinavian Cardiac Outcomes Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Collaborative Atorvastatin Diabetes Study.

BACKGROUND: In this study, we aimed to translate the average relative effect of statin therapy from trial data to the individual patient with type 2 diabetes mellitus by developing and validating a model to predict individualized absolute risk reductions (ARR) of cardiovascular events. METHODS AND RESULTS: Data of 2725 patients with type 2 diabetes mellitus from the Lipid Lowering Arm of the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) study (atorvastatin 10 mg versus placebo) were used for model derivation. The model was based on 8 clinical predictors including treatment allocation (statin/placebo). Ten-year individualized ARR on major cardiovascular events by statin therapy were calculated for each patient by subtracting the estimated on-treatment risk from the estimated off-treatment risk. Predicted 10-year ARR by statin therapy was <2% for 13% of the patients. About 30% had an ARR of >4% (median ARR, 3.2%; interquartile range, 2.5%-4.3%; 95% confidence interval for 3.2% ARR, -1.4% to 6.8%). Addition of treatment interactions did not improve model performance. Therefore, the wide distribution in ARR was a consequence of the underlying distribution in cardiovascular risk enrolled in these trials. External validation of the model was performed in data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT; pravastatin 40 mg versus usual care) and Collaborative Atorvastatin Diabetes Study (CARDS; atorvastatin 10 mg versus placebo) of 3878 and 2838 patients with type 2 diabetes mellitus, respectively. Model calibration was adequate in both external data sets, discrimination was moderate (ALLHAT-LLT: c-statistics, 0.64 [95% confidence interval, 0.61-0.67] and CARDS: 0.68 [95% confidence interval, 0.64-0.72]). CONCLUSIONS: ARRs of major cardiovascular events by statin therapy can be accurately estimated for individual patients with type 2 diabetes mellitus using a model based on routinely available patient characteristics. There is a wide distribution in ARR that may complement informed decision making. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00327418 (CARDS) and NCT00000542 (ALLHAT).

Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS).

AIMS/HYPOTHESIS: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with atorvastatin. METHODS: The study population comprised 2,739 people taking part in the Collaborative Atorvastatin Diabetes Study (CARDS) who were randomised to receive atorvastatin 10 mg or placebo and who had post-randomisation HbA1c data. This secondary analysis used Cox regression to estimate the effect of atorvastatin on glycaemia progression, defined as an increase in HbA1c of ≥ 0.5% (5.5 mmol/mol) or intensification of diabetes therapy. Mixed models were used to estimate the effect of atorvastatin on HbA1c as a continuous endpoint. RESULTS: Glycaemia progression occurred in 73.6% of participants allocated placebo and 78.1% of those allocated atorvastatin (HR 1.18 [95% CI 1.08, 1.29], p < 0.001) by the end of follow-up. The HR was 1.22 (95% CI 1.19, 1.35) in men and 1.11 (95% CI 0.95, 1.29) in women (p = 0.098 for the sex interaction). A similar effect was seen in on-treatment analyses: HR 1.20 (95% CI 1.07, 1.35), p = 0.001. The net mean treatment effect on HbA1c was 0.14% (95% CI 0.08, 0.21) (1.5 mmol/mol). The effect did not increase through time. Diabetes treatment intensification alone did not differ with statin allocation. Neither baseline nor 1-year-attained HbA1c predicted subsequent CVD, and the atorvastatin effect on CVD did not vary by HbA1c change (interaction p value 0.229). CONCLUSIONS/INTERPRETATION: The effect of atorvastatin 10 mg on glycaemia progression among those with diabetes is statistically significant but very small, is not significantly different between sexes, does not increase with duration of statin and does not have an impact on the magnitude of CVD risk reduction with atorvastatin.

Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial.

AIMS/HYPOTHESIS: We investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol. METHODS: CRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40-75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n = 147) of CRP and LDL-cholesterol lowering at 1 year. RESULTS: After 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI -40%, -22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change -9.8% [-57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of -41% (-51%, -31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50). CONCLUSIONS/INTERPRETATION: CRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data. Trial registration NCT00327418.