To analyse the association between refill adherence to lipid-lowering medications, and the risk of cardiovascular disease (CVD) and mortality in patients with type 2 diabetes mellitus.
National population-based cohort of Swedish patients with type 2 diabetes mellitus.
86?568 patients aged =18 years, registered with type 2 diabetes mellitus in the Swedish National Diabetes Register, who filled at least one prescription for lipid-lowering medication use during 2007-2010, 87% for primary prevention.
Refill adherence of implementation was assessed using the medication possession ratio (MPR), representing the proportion of days with medications on hand during an 18-month exposure period. MPR was categorised by five levels (=20%, 21%-40%, 41%-60%, 61%-80% and >80%). Patients without medications on hand for =180 days were defined as non-persistent. Risk of CVD (myocardial infarction, ischaemic heart disease, stroke and unstable angina) and mortality by level of MPR and persistence was analysed after the exposure period using Cox proportional hazards regression and Kaplan-Meier, adjusted for demographics, socioeconomic status, concurrent medications and clinical characteristics.
The hazard ratios for CVD ranged 1.33-2.36 in primary prevention patients and 1.19-1.58 in secondary prevention patients, for those with MPR =80% (p
To evaluate the effect of lipid-lowering therapy (LLT) in primary prevention on cardiovascular disease (CVD) and death in type 1 diabetes.
We used the Swedish National Diabetes Register (NDR) to perform a propensity score-based study. Propensity scores for treatment with LLT were calculated from 32 baseline clinical and socioeconomic variables. The propensity score was used to estimate the effect of LLT in the overall cohort (by stratification). We estimated risk of acute myocardial infarction, stroke, coronary heart disease, and cardiovascular and all-cause mortality in individuals with and without LLT using Cox regression. A total of 24,230 individuals included in 2006-2008 NDR with type 1 diabetes without a history of CVD were followed until 31 December 2012; 18,843 were untreated and 5,387 treated with LLT (97% statins). The mean follow-up was 6.0 years.
The propensity score allowed balancing of all 32 covariates, with no differences between treated and untreated after accounting for propensity score. Hazard ratios (HRs) for treated versus untreated were as follows: cardiovascular death 0.60 (95% CI 0.50-0.72), all-cause death 0.56 (0.48-0.64), fatal/nonfatal stroke 0.56 (0.46-0.70), fatal/nonfatal acute myocardial infarction 0.78 (0.66-0.92), fatal/nonfatal coronary heart disease 0.85 (0.74-0.97), and fatal/nonfatal CVD 0.77 (0.69-0.87).
This observational study shows that LLT is associated with 22-44% reduction in the risk of CVD and cardiovascular death among individuals with type 1 diabetes without history of CVD and underlines the importance of primary prevention with LLT to reduce cardiovascular risk in type 1 diabetes.
To compare the risk associated with systolic blood pressure that meets current recommendations (that is, below 140 mm Hg) with the risk associated with lower levels in patients who have type 2 diabetes and no previous cardiovascular disease.
Population based cohort study with nationwide clinical registries, 2006-12. The mean follow-up was 5.0 years.
861 Swedish primary care units and hospital outpatient clinics.
187?106 patients registered in the Swedish national diabetes register who had had type 2 diabetes for at least a year, age 75 or younger, and with no previous cardiovascular or other major disease.
Clinical events were obtained from the hospital discharge and death registers with respect to acute myocardial infarction, stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), coronary heart disease, heart failure, and total mortality. Hazard ratios were estimated for different levels of baseline systolic blood pressure with clinical characteristics and drug prescription data as covariates.
The group with the lowest systolic blood pressure (110-119 mm Hg) had a significantly lower risk of non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% confidence interval 0.64 to 0.91; P=0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P=0.04), non-fatal cardiovascular disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P=0.03) compared with the reference group (130-139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality.
Lower systolic blood pressure than currently recommended is associated with significantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality could be due to concomitant disease rather than antihypertensive treatment.
Cites: Clin Chem. 1972 Jun;18(6):499-5024337382
Cites: J Am Coll Cardiol. 2012 Jan 3;59(1):74-8322192672
We implemented a novel method for providing contextual adverse event rates for a randomised controlled trial (RCT) programme through coordinated analyses of five RA registries, focusing here on cardiovascular disease (CVD) and mortality.
Each participating registry (Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (East Europe, Latin America, India) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan)) defined a main cohort from January 2000 onwards. To address comparability and potential bias, we harmonised event definitions and defined several subcohorts for sensitivity analyses based on disease activity, treatment, calendar time, duration of follow-up and RCT exclusions. Rates were standardised for age, sex and, in one sensitivity analysis, also HAQ.
The combined registry cohorts included 57 251 patients with RA (234 089 person-years)-24.5% men, mean (SD) baseline age 58.2 (13.8) and RA duration 8.2 (11.7) years. Standardised registry mortality rates (per 100 person-years) varied from 0.42 (CORRONA) to 0.80 (NOAR), with 0.60 for RCT patients. Myocardial infarction and major adverse cardiovascular events (MACE) rates ranged from 0.09 and 0.31 (IORRA) to 0.39 and 0.77 (SRR), with RCT rates intermediate (0.18 and 0.42), respectively. Additional subcohort analyses showed small and mostly consistent changes across registries, retaining reasonable consistency in rates across the Western registries. Additional standardisation for HAQ returned higher mortality and MACE registry rates.
This coordinated approach to contextualising RA RCT safety data demonstrated reasonable differences and consistency in rates for mortality and CVD across registries, and comparable RCT rates, and may serve as a model method to supplement clinical trial analyses for drug development programmes.
In patients with diabetes and obesity specifically, no studies have examined mortality after bariatric surgery. We did a nationwide study in Sweden to examine risks of cardiovascular disease and mortality in patients with obesity and diabetes who had undergone bariatric surgery (Roux-en-Y gastric bypass [RYGB]).
In this nationwide, matched, observational cohort study, we merged data for patients who had undergone RYGB registered in the Scandinavian Obesity Surgery Registry with other national databases, and identified matched controls (on the basis of sex, age, BMI, and calendar time [year]) who had not undergone bariatric surgery from the National Diabetes Registry. We assessed risks of cardiovascular disease and death using a Cox proportional-hazards regression model and other methods to examine the treatment effect while accounting for residual confounding. Primary outcomes were total mortality, cardiovascular death, and fatal or non-fatal myocardial infarction.
Between Jan 1, 2007, and Dec 31, 2014, we obtained data for 6132 patients who had undergone RYGB and 6132 control patients who had not. Median follow-up was 3·5 years (IQR 2·1-4·7). We noted a 58% relative risk reduction (hazard ratio [HR] 0·42, 95% CI 0·30-0·57; p
To investigate the relative safety of various glucose-lowering agents as add-on medication to metformin in type 2 diabetes in an observational study linking five national health registers.
Patients with type 2 diabetes who had been on metformin monotherapy and started another agent in addition to metformin were eligible for inclusion. The study period was 2005-2012. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality, cardiovascular disease (CVD), coronary heart disease (CHD), stroke and congestive heart failure (CHF) were estimated using Cox proportional hazards models, weighted for a propensity score.
Of the 20?422 patients included in the study, 43% started on second-line treatment with sulphonylurea (SU), 21% basal insulin, 12% thiazolidinedione (TZD), 11% meglitinide, 10% dipeptidyl peptidase-4 (DPP-4) inhibitor, 1% glucagon-like peptide-1 (GLP-1) receptor agonist and 1% acarbose. At the index date, the mean patient age was ~60?years for all groups except the GLP-1 receptor agonist (56.0?years) and SU (62.9?years) groups. Diabetes duration and glycated haemoglobin levels were similar in all groups. When compared with SU, basal insulin was associated with an 18% higher risk and TZD with a 24% lower risk of mortality [HR 1.18 (95% CI 1.03-1.36) and 0.76 (95% CI 0.62-0.94)], respectively. DPP-4 inhibitor treatment was associated with significantly lower risks of CVD, fatal CVD, CHD, fatal CHD and CHF.
This nationwide observational study showed that second-line treatment with TZD and DPP-4 inhibitor as add-on medication to metformin were associated with significantly lower risks of mortality and cardiovascular events compared with SU, whereas basal insulin was associated with a higher risk of mortality.
Decreased systolic blood pressure is associated with increased risk of all-cause mortality in patients with type 2 diabetes and renal impairment: A nationwide longitudinal observational study of 27,732 patients based on the Swedish National Diabetes Register.
Previous studies have shown a U-shaped relationship between systolic blood pressure and risk of all-cause of mortality in patients with type 2 diabetes and renal impairment.
To evaluate the associations between time-updated systolic blood pressure and time-updated change in systolic blood pressure during the follow-up period and risk of all-cause mortality in patients with type 2 diabetes and renal impairment.
A total of 27,732 patients with type 2 diabetes and renal impairment in the Swedish National Diabetes Register were followed for 4.7?years. Time-dependent Cox models were used to estimate risk of all-cause mortality. Time-updated mean systolic blood pressure is the average of the baseline and the reported post-baseline systolic blood pressures.
A time-updated systolic blood pressure??10?mmHg between the last two observations was associated with higher risk of all-cause mortality (-10 to -25?mmHg; hazard ratio: 1.24, 95% confidence interval: 1.17-1.32).
Both low systolic blood pressure and a decrease in systolic blood pressure during the follow-up are associated with a higher risk of all-cause mortality in patients with type 2 diabetes and renal impairment.
In the development of new drugs for severe asthma, it is a challenge from an ethical point of view to randomize severe asthma patients to placebo, and to obtain long-term safety data due to discontinuations. The aim of this study was to evaluate the feasibility of using electronic health record (EHR) data to create a real-world reference population of uncontrolled asthmatic patients to supplement the concurrent control/placebo group in long-term studies of asthma.
EHR data from 36 primary care centres and a University hospital in Sweden were linked to Swedish mandatory health registers (2005-2013), creating a population covering 33 890 asthma patients, including data on co-morbidities, risk factors and laboratory/respiratory measurements. A severe asthma EHR reference cohort was established. We used logistic regression to estimate the propensity score (probability) of each RCT or EHR patient existing in the EHR cohort given their covariates.
We created an EHR-derived reference cohort of 240 patients, matching the placebo group (N?=?151) in an RCT of severe asthma. The exacerbation rate during follow-up in the EHR study population was 1.24 (weighted) compared to 0.9 in the RCT placebo group. Patients in the EHR cohort were of similar age as in the RCT placebo group, 50.6 years versus 50.1 years; had slightly higher body mass index 27.0 kg/m2 versus 27.3 kg/m2; and consisted of 40% versus 34% males.
The results indicate that EHRs provide an opportunity to supplement the control group in RCTs of severe diseases.
People with type 1 diabetes are at elevated risk of mortality and cardiovascular disease, yet current guidelines do not consider age of onset as an important risk stratifier. We aimed to examine how age at diagnosis of type 1 diabetes relates to excess mortality and cardiovascular risk.
We did a nationwide, register-based cohort study of individuals with type 1 diabetes in the Swedish National Diabetes Register and matched controls from the general population. We included patients with at least one registration between Jan 1, 1998, and Dec 31, 2012. Using Cox regression, and with adjustment for diabetes duration, we estimated the excess risk of all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, acute myocardial infarction, stroke, cardiovascular disease (a composite of acute myocardial infarction and stroke), coronary heart disease, heart failure, and atrial fibrillation. Individuals with type 1 diabetes were categorised into five groups, according to age at diagnosis: 0-10 years, 11-15 years, 16-20 years, 21-25 years, and 26-30 years.
27?195 individuals with type 1 diabetes and 135?178 matched controls were selected for this study. 959 individuals with type 1 diabetes and 1501 controls died during follow-up (median follow-up was 10 years). Patients who developed type 1 diabetes at 0-10 years of age had hazard ratios of 4·11 (95% CI 3·24-5·22) for all-cause mortality, 7·38 (3·65-14·94) for cardiovascular mortality, 3·96 (3·06-5·11) for non-cardiovascular mortality, 11·44 (7·95-16·44) for cardiovascular disease, 30·50 (19·98-46·57) for coronary heart disease, 30·95 (17·59-54·45) for acute myocardial infarction, 6·45 (4·04-10·31) for stroke, 12·90 (7·39-22·51) for heart failure, and 1·17 (0·62-2·20) for atrial fibrillation. Corresponding hazard ratios for individuals who developed type 1 diabetes aged 26-30 years were 2·83 (95% CI 2·38-3·37) for all-cause mortality, 3·64 (2·34-5·66) for cardiovascular mortality, 2·78 (2·29-3·38) for non-cardiovascular mortality, 3·85 (3·05-4·87) for cardiovascular disease, 6·08 (4·71-7·84) for coronary heart disease, 5·77 (4·08-8·16) for acute myocardial infarction, 3·22 (2·35-4·42) for stroke, 5·07 (3·55-7·22) for heart failure, and 1·18 (0·79-1·77) for atrial fibrillation; hence the excess risk differed by up to five times across the diagnosis age groups. The highest overall incidence rate, noted for all-cause mortality, was 1·9 (95% CI 1·71-2·11) per 100?000 person-years for people with type 1 diabetes. Development of type 1 diabetes before 10 years of age resulted in a loss of 17·7 life-years (95% CI 14·5-20·4) for women and 14·2 life-years (12·1-18·2) for men.
Age at onset of type 1 diabetes is an important determinant of survival, as well as all cardiovascular outcomes, with highest excess risk in women. Greater focus on cardioprotection might be warranted in people with early-onset type 1 diabetes.
Swedish Heart and Lung Foundation.
CommentIn: Lancet. 2018 Aug 11;392(10146):453-454 PMID 30129445
The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents.
Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib).
There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person-years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis.
In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent.