Insulin-like growth factor-1, growth hormone and disease outcomes in acromegaly: A population study.

CONTEXT: A lack of consensus remains about the relative importance of insulin-like growth factor-1 (IGF-1) and growth hormone (GH) in predicting adverse outcomes in patients with acromegaly. OBJECTIVE: To describe the differing association between IGF-1 and GH and major disease outcomes in acromegaly. DESIGN: Retrospective cohort study. PATIENTS: United Kingdom National Health Service patients with acromegaly who had an IGF-1 and/or a GH measurement recorded following diagnosis, prior to December 2019. MEASUREMENTS: A composite endpoint including all-cause mortality (ACM), type 2 diabetes (DM), major adverse cardiovascular events (MACE) or cancer was the primary outcome. These outcomes were also analysed individually. Follow-up period was capped at 5 years. RESULTS: A maximum of 417 cases and 332 cases were eligible for the IGF-1 and GH analyses, respectively, comprising 1041.5 and 938.9 years of follow-up. There was a direct association between increased IGF-1 concentration and adjusted event risk for the composite endpoint (hazard ratio [HR] = 1.2; 95% confidence interval [CI] = 1.02-1.5); in GH, the HR was 1.1 (1.0-1.2). For the individual endpoints in relation to IGF-1 level, the HRs were ACM (1.2; 0.93-1.5), MACE (1.2; 0.64-2.1), DM (1.53; 1.09-2.2) and cancer (1.3; 0.95-1.7). For GH, the HRs were ACM (1.1; 0.97-1.2), MACE (0.99; 0.73-1.3), DM (1.1; 0.99-1.2) and cancer (0.90; 0.66-1.2). CONCLUSIONS: In this contemporary data set with extended follow-up, IGF-1 and GH concentrations showed an association with major adverse outcomes from acromegaly.

Effectiveness of the capsaicin 8% patch in the management of peripheral neuropathic pain in European clinical practice: the ASCEND study.

BACKGROUND: In randomised studies, the capsaicin 8% patch has demonstrated effective pain relief in patients with peripheral neuropathic pain (PNP) arising from different aetiologies. METHODS: ASCEND was an open-label, non-interventional study of patients with non-diabetes-related PNP who received capsaicin 8% patch treatment, according to usual clinical practice, and were followed for ≤52 weeks. Co-primary endpoints were percentage change in the mean numeric pain rating scale (NPRS) 'average daily pain' score from baseline to the average of Weeks 2 and 8 following first treatment; and median time from first to second treatment. The primary analysis was intended to assess analgesic equivalence between post-herpetic neuralgia (PHN) and other PNP aetiologies. Health-related quality of life (HRQoL, using EQ-5D), Patient Global Impression of Change (PGIC) and tolerability were also assessed. RESULTS: Following first application, patients experienced a 26.6% (95% CI: 23.6, 29.62; n = 412) reduction in mean NPRS score from baseline to Weeks 2 and 8. Equivalence was demonstrated between PHN and the neuropathic back pain, post-operative and post-traumatic neuropathic pain and 'other' PNP aetiology subgroups. The median time from first to second treatment was 191 days (95% CI: 147, 235; n = 181). Forty-four percent of all patients were responders (≥30% reduction in NPRS score from baseline to Weeks 2 and 8) following first treatment, and 86.9% (n = 159/183) remained so at Week 12. A sustained pain response was observed until Week 52, with a 37.0% (95% CI: 31.3, 42.7; n = 176) reduction in mean NPRS score from baseline. Patients with the shortest duration of pain (0-0.72 years) experienced the highest pain response from baseline to Weeks 2 and 8. Mean EQ-5D index score improved by 0.199 utils (responders: 0.292 utils) from baseline to Week 2 and was maintained until Week 52. Most patients reported improvements in PGIC at Week 2 and at all follow-up assessments regardless of number of treatments received. Adverse events were primarily mild or moderate reversible application site reactions. CONCLUSION: In European clinical practice, the capsaicin 8% patch provided effective and sustained pain relief, substantially improved HRQoL, improved overall health status and was generally well tolerated in a heterogeneous PNP population. TRIAL REGISTRATION: NCT01737294 Date of registration - October 22, 2012.

Health utility of patients with advanced gastrointestinal stromal tumors (GIST) after failure of imatinib and sunitinib: findings from GRID, a randomized, double-blind, placebo-controlled phase III study of regorafenib versus placebo.

BACKGROUND: In this analysis we report patients with advanced gastrointestinal stromal tumors (GIST) refractory to imatinib and sunitinib therapy as derived from the EuroQol-5D (EQ-5D) for progression-free (PF) and progressive disease health status. METHODS: Data were analyzed from a phase III trial conducted at 57 hospitals in 17 countries (trial registration number, NCT01271712). Patients with advanced GIST were randomized (2:1) to receive blinded treatment using oral regorafenib 160 mg daily or placebo, plus best supportive care (BSC) in both groups, for the first 3 weeks of each 4-week cycle. EQ-5D-3L was administered on day 1 of each cycle before contact with their physician and before any study-related procedures. The effect of disease progression on the utility of EQ-5D was tested with paired-samples comparison and general linear mixed modeling (GLMM). RESULTS: One hundred and eighty five patients [93 % of the intention-to-treat (ITT) population] completed 803 EQ-5D questionnaires: 77.7 % in progression-free (PF) state, 6.5 % at progression, 13.9 % following first progression, and 1.9 % after second progression. Mean baseline utility was 0.767 (SD 0.221) with no significant between-group differences for active treatment and BSC. The first post-progression health state was 0.647 (SD 0.343), suggesting significantly impaired health-related quality of life after confirmed disease progression showed a decrease of -0.120 (paired samples t test, p = 0.001). GLMM showed no effect of study treatment or cycle number on utility. CONCLUSIONS: We demonstrate a significant and clinically meaningful difference in health state utility values between PF and progression. Utility values remained stable over successive regorafenib cycles after controlling for disease status and treatment type.

Treatment of rheumatoid arthritis with etanercept with reference to disease-modifying anti-rheumatic drugs: long-term safety and survival using prospective, observational data.

OBJECTIVE: The objective of this study was to examine the long-term safety of etanercept (ETN) in comparison with conventional DMARDs in a large observational cohort of RA patients in the UK. METHODS: Data were made available from the British Society of Rheumatology Biologics Register for a cohort of patients with RA treated with ETN and a reference cohort of RA patients treated with conventional DMARDs (maximum follow-up 10 years). The adjusted risk of events was compared using Cox proportional hazards models. RESULTS: There were 3529 eligible ETN-treated patients (16,919 person-years) and 2864 conventional DMARD-treated patients (11,095 person-years), with notable differences between groups at baseline. Crude mortality rates were 12.0 vs 20.1 events per 1000 person-years for ETN and conventional DMARD patients, respectively, with an adjusted hazard ratio (aHR) of 0.72 (95% CI 0.54, 0.96). There was no difference in the long-term risk of serious infections (aHR = 1.02, 95% CI 0.83, 1.25). However, the risk was increased for ETN in the first 2 years (aHR = 1.56, 95% CI 1.16, 2.09; aHR = 1.32, 95% CI 1.06, 1.65). The aHRs (95% CIs) of various outcomes were cancer, 0.84 (0.68, 1.03); lymphoproliferative malignancy specifically, 0.51 (0.28, 0.95); all other serious adverse events, 0.70 (0.56, 0.87) and cardiac events specifically, 0.52 (0.37, 0.72). CONCLUSION: There was no evidence of adverse outcome from long-term exposure to ETN. There was evidence of improved survival, reduced cardiovascular events and reduced lymphoproliferative malignancies.

The medico-legal aspects of prescribing vitamin D.

Vitamin D is a particularly important sterol hormone and its effects beyond bone are increasingly recognized. Over the last decade clinical interest has grown in vitamin D, with increased recognition of deficiency and hence increased prescribing of vitamin D products. However, the increased prescription of vitamin D has generally been met with unlicensed vitamin D products which potentially expose the patient to clinical risk. This review discusses the issues relating to the clinical use of unlicensed vitamin D products, safety concerns that may arise from this, as well as discussing the medico-legal responsibilities of the prescriber and dispenser.

Estimation of health-related utility (EQ-5D index) in subjects with seasonal allergic rhinoconjunctivitis to evaluate health gain associated with sublingual grass allergen immunotherapy.

BACKGROUND: Grass allergen immunotherapy (AIT) reduces symptom severity in seasonal allergic rhinoconjunctivitis (ARC) but its impact on general health-related utility has not been characterised for the purposes of economic evaluation. The aim of this study was to model the preferred measure of utility, EQ-5D index, from symptom severity and estimate incremental quality adjusted life years (QALYs) associated with SQ-standardised grass immunotherapy tablet (GRAZAX®, 75,000 SQ-T/2,800 BAU, ALK, Denmark). METHODS: Data were analysed from five consecutive pollen seasons in a randomised placebo controlled trial of GRAZAX®. Binomial and Gaussian mixed effects modelling related weekly EQ-5D index score to daily symptom and medication scores (DSS & DMS respectively). In turn, daily EQ-5D index was estimated from ARC symptoms and medication use. RESULTS: DSS and DMS were the principal predictors of 'perfect' health (EQ-5D = 1.000; binomial) and 'imperfect' health (EQ-5D < 1.000; Gaussian). Each unit increase in DSS and DMS reduced the odds of 'perfect' health (EQ-5D = 1.000) by 27% and 16% respectively, and reduced 'imperfect' health by 0.17 and 0.13, respectively. Gender remained the only other significant main fixed effect (Male odds ratio [OR] = 1.82). Incremental estimated EQ-5D index utility for GRAZAX® was observed from day -30 to day +70 of the pooled pollen season; mean daily utility for GRAZAX® = 0.938 units (95%CI 0.932-0.943) vs. 0.914 (0.907-0.921) for placebo, an incremental difference of 0.0238 (p < 0.001). This translates into an incremental 0.0324 Quality Adjusted Life Years over the five year study period. CONCLUSIONS: ARC symptoms and medication use are the main predictors of EQ-5D index. The incremental QALYs observed for GRAZAX® may not fully describe the health benefits of this treatment, suggesting that economic modelling may be conservative.

The short-term impact of vitamin D-based hip fracture prevention in older adults in the United Kingdom.

PURPOSE: Vitamin D is a relatively inexpensive drug yet an important hormone in terms of calcium and bone homeostasis. Treatment with vitamin D is associated with reduced fracture risk particularly in an elderly population. Therefore, we assessed the budgetary impact of routine prescription of 800 IU daily colecalciferol on hip fracture among older adults in the United Kingdom. METHODS: Using meta-analysis findings for treatment effect and UK-estimates of incidence, we performed a health economic evaluation of treating the UK population aged 65 and over with 800 IU of vitamin D daily, assessing the impact upon hip fracture costs using incremental attributable costs and excess mortality for a range of age- gender-based treatment strategies. RESULTS: Using only a 1-year horizon, considering only reduction in hip fracture, prescribing colecalciferol 800 IU daily to all adults aged 65 and over, could reduce the number of incident hip fractures from 65,400 to 45,700, saving almost 1,700 associated deaths, whilst saving the UK taxpayer £22 million. CONCLUSIONS: As the UK government seeks to reduce public expenditure in all sectors, investment in prescribed prophylactic colecalciferol 800 IU therapy for adults aged 65 and over is likely to yield cost savings through reduction hip fracture alone in the first year.

Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study.

BACKGROUND: Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a function of HbA(1c) in people with type 2 diabetes. METHODS: Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly. FINDINGS: For combined cohorts, compared with the glycated haemoglobin (HbA(1c)) decile with the lowest hazard (median HbA(1c) 7.5%, IQR 7.5-7.6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA(1c) decile (6.4%, 6.1-6.6) was 1.52 (95% CI 1.32-1.76), and in the highest HbA(1c) decile (median 10.5%, IQR 10.1-11.2%) was 1.79 (95% CI 1.56-2.06). Results showed a general U-shaped association, with the lowest HR at an HbA(1c) of about 7.5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1.49 (95% CI 1.39-1.59). INTERPRETATION: Low and high mean HbA(1c) values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA(1c) value. FUNDING: Eli Lilly and Company.

Deriving health state utilities for the numerical pain rating scale.

BACKGROUND: The use of patient reported outcome measures within cost-effectiveness analysis has become commonplace. However, specific measures are required that produce values, referred to as 'utilities', that are capable of generating quality adjusted life years. One such measure - the EQ-5D - has come under criticism due to the inherent limitations of its three-level response scales. In evaluations of chronic pain, the numerical pain rating scale (NPRS) which has eleven levels is routinely used which has a greater measurement range, but which can not be used in cost-effetiveness analyses. This study derived utility values for a series of EQ-5D health states that replace the pain dimensions with the NPRS, thereby allowing a potentially greater range of pain intensities to be captured and included in economic analyses. METHODS: Interviews were undertaken with 100 member of the general population. Health state valuations were elicited using the time trade-off approach with a ten year time horizon. Additionally, respondents were asked where the EQ-5D response scale descriptors of moderate and extreme pain lay on the 11-point NPRS scale. RESULTS: 625 valuations were undertaken across the study sample with the crude mean health state utilities showing a negative non-linear relationship with respect to increasing pain intensity. Relative to a NPRS of zero (NPRS0), the successive pain levels (NPRS1-10) had mean decrements in utility of 0.034, 0.043, 0.061, 0.121, 0.144, 0.252, 0.404, 0.575, 0.771 and 0.793, respectively. When respondents were asked to mark on the NPRS scale the EQ-5D pain descriptors of moderate and extreme pain, the median responses were '4' and '8', respectively. CONCLUSIONS: These results demonstrate the potential floor effect of the EQ-5D with respect to pain and provide estimates of health reduction associated with pain intensity described by the NPRS. These estimates are in excess of the decrements produced by an application of the EQ-5D scoring tariff for both the United States and the United Kingdom.

Characterization and Associated Costs of Constipation Relating to Exposure to Strong Opioids in England: An Observational Study.

PURPOSE: Opioid use is associated with gastrointestinal adverse events, including nausea and constipation. We used a real-world dataset to characterize the health care burden associated with opioid-induced constipation (OIC) with particular emphasis on strong opioids. METHODS: This retrospective cohort study was conducted using the Clinical Practice Research Datalink, a large UK primary care dataset linked to hospital data. Patients prescribed opioids during 2016 were selected and episodes of opioid therapy constructed. Episodes with ≥84 days of exposure were classified as chronic, with date of first prescription as the index date. The main analysis focused on patients prescribed strong opioids who were laxative naive. Constipation was defined by ≥2 laxative prescriptions during the opioid episode. Patients for whom initial laxative therapy escalated by switch, augmentation, or dose were defined as OIC unstable, and the first 3 lines of OIC escalation were classified. Health care costs accrued in the first 12 months of the opioid episode were aggregated and compared. FINDINGS: A total of 27,629 opioid episodes were identified; 5916 (21.4%) involved a strong opioid for patients who were previously laxative naive. Of these patients, 2886 (48.8%) were defined as the OIC population; 941 (33.26%) were classified as stable. Of the 1945 (67.4%) episodes classified as unstable, 849 (43.7%), 360 (18.5%), and 736 (37.8%) had 1, 2, and ≥3 changes of laxative prescription, respectively. Patients without OIC had lower costs per patient year (£3822 [US$5160/€4242]) compared with OIC (£4786 [US$6461/€5312]). Costs increased as patients had multiple changes in therapy: £4696 (US$6340/€5213), £4749 (US$6411/€5271), and £4981 (US$6724/€5529) for 1, 2, and ≥3 changes, respectively. The adjusted cost ratio relative to non-OIC was 1.14 (95% CI, 1.09-1.32) for those classified as stable and 1.19 (95% CI, 1.09-1.32) for those with ≥3 laxative changes. Similar patterns were observed for patients taking anyopioid, with costs increased for those classified as having OIC (£3727 [US$5031/€4137] vs £2379 [US$3212 /€2641),and for those patients classified as unstable versus stable (£3931 [US$5307/€4363] vs £3432 [US$4633/€3810). Costs increased with each additional line of therapy from £3701 (US$4996/€4108), £3916 (US$5287/€4347), and £4318 (US$5829/€4793). IMPLICATIONS: OIC was a common adverse event of opioid treatment and was poorly controlled for a large number of patients. Poor control was associated with increased health care costs. The impact of OIC should be considered when prescribing opioids. These results should be interpreted with consideration of the caveats associated with the analysis of routine data.

Estimation of health care costs as a function of disease severity in people with psoriatic arthritis in the UK.

OBJECTIVES: The primary aim of this study was to estimate annual health care costs for biologic-naïve patients with PsA in the UK. The relationship between disease severity, defined by physical limitations, and costs was also explored. METHODS: This study utilized data from the British Society of Rheumatology Biologics Register (BSRBR) to develop a multivariate model estimating disease severity from parameters available in routine primary care data. The HAQ Disability Index was used to determine disease severity. This algorithm was then applied to routine data from The Health Improvement Network (THIN). Annual costs were estimated for drugs, contacts with a general practitioner and other health care professionals, tests, hospital outpatient attendances and inpatient admissions from a National Health Service perspective using official tariffs. The relationship between disease severity and health care costs was estimated using a generalized linear model. RESULTS: Three hundred and fifty-six cases with PsA were identified in the BSRBR and 4492 in THIN. Total mean annual health care costs ranged from £11 to £20 782 with a mean of £1446 (s.d. £1756). When costs were sub-grouped by the predicted HAQ score, the mean annual observed costs ranged from £548 per person for the least severely affected (HAQ ≤ 1.2) to £4832 for the most severely affected (HAQ > 2.6). Prescription costs and secondary care episodes accounted for more than a third of total care costs each (38 and 34%, respectively). When the relationship between disease severity and costs was examined, estimated HAQ was found to be a significant predictor of total health care costs. CONCLUSIONS: Treatment of people with PsA resulted in considerable financial costs and these costs varied markedly by disease severity.

The association between C-reactive protein and the likelihood of progression to joint replacement in people with rheumatoid arthritis: a retrospective observational study.

BACKGROUND: This study sought to evaluate the association between systemic inflammation as measured by C-reactive protein and total joint replacement and the association between change in CRP status (low, < or = 10 mg/L and high, >10 mg/L) measured over one year and total joint replacement in patients diagnosed with rheumatoid arthritis. METHODS: A cohort of patients was selected from The Health Improvement Network (THIN) dataset of anonymised patient-level data from UK general practice with a confirmed chronic rheumatic diagnosis. Surgery-free survival was evaluated using Cox proportional hazards regression models (CPHM). RESULTS: 2,421 cases had at least one CRP measurement of which 125 cases (5.2%) had at least one major joint replacement. In CPHM, each additional unit increase in log mean CRP (range 1 to 6) was associated with a hazard ratio (HR) for major orthopaedic surgery of 1.36 (95% CI 1.10 to 1.67; p = 0.004), after controlling for age at first rheumatoid presentation and average body mass index over the same observation period. Repeated CRP observations around one year apart were recorded in 1,314 subjects. After controlling for confounding factors, in cases whose CRP remained high (>10 mg/L), the HR for joint replacement increased more than two-fold (p = 0.040) relative to cases whose CRP remained low. In patients whose CRP increased from low to high, the HR was 1.86 compared to those who remained in a low state (p = 0.217). By comparison, among those subjects whose CRP was reduced from a high to low state, the hazard ratio was more than halved (1.46) from to those who remained high (p = 0.441). Although underpowered, the trend evident from CRP change corroborates the association of TJR progression with mean CRP. CONCLUSION: CRP level predicts progression to major joint replacement after standardisation for relevant risk factors as did change in CRP status between low and high states observed over one year.

Multivariate models of health-related utility and the fear of hypoglycaemia in people with diabetes.

AIM: The aim was to statistically model the degree of fear of hypoglycaemia experienced by people with diabetes, and then model the resulting change in health-related utility associated with differing severity and frequency of hypoglycaemia. METHODS: The study used pooled data from two previous postal surveys among subjects with confirmed diabetes conducted in Cardiff, UK (n = 1305 responses). The fear of hypoglycaemia was characterised using the Hypoglycaemia Fear Survey (HFS [eight question worry sub-scale only]), and health-related utility using the EQ5D(index). The data were then analysed using univariate and multivariate analysis. RESULTS: Following detailed preliminary analysis, a two-stage approach was used since fear was important when estimating the EQ5D(index). Fear was then modelled as a function of the severity and frequency of hypoglycaemia while controlling for other factors such as diabetes-related complications. Each severe hypoglycaemic event resulted in a change of 5.881 units on the HFS. One or more symptomatic hypoglycaemic events over the same period results in a corresponding change of 1.773 units on the HFS. A 1 unit increase on the HFS results in a 0.008 unit decrease on the EQ5D(index). CONCLUSION: While controlling for other factors, the fear of hypoglycaemia was an important determinant of health-related utility. The magnitude of fear of hypoglycaemia was associated with the severity and frequency of hypoglycaemia. Hypoglycaemia was associated with a considerable decrement in health-related utility as a function of increased fear. Measures should be taken to minimise the severity and frequency of hypoglycaemia.

The effect of withdrawal of rosiglitazone on treatment pathways, diabetes control and patient outcomes: a retrospective cohort study.

AIMS: To describe the withdrawal of rosiglitazone and the impact upon glycaemic control; intensification of therapy; and progression to major adverse cardiovascular events (MACE), cancer and mortality. METHODS: Data were from the Clinical Practice Research Datalink (CPRD), a longitudinal U.K. database. Rosiglitazone use was profiled from launch (2000) until withdrawal (2010). Patients discontinuing from July 2010 were included in the analysis to ascertain the impact on glycaemic control; therapy intensification; and progression to MACE, death and cancer. For comparison, patients were matched to those maintained on pioglitazone as a control group. RESULTS: Rosiglitazone use peaked in May 2007. Of patients prescribed rosiglitazone at discontinuation 54.1% patients used a dual-therapy regimen; most commonly with metformin (46.7%). 65.1% patients remained at the same stage of the diabetes pathway following discontinuation. 51.7% of patients replaced rosiglitazone with pioglitazone. Patients discontinuing were more likely (HR=2.29), to subsequently intensify therapy than controls. After discontinuation of rosiglitazone there was a significant increase in HbA1c, from a median of 6.9% to 7.3%. In matched analysis, there was a significantly greater increase in HbA1c for rosiglitazone patients (0.33% versus 0.10%). Following discontinuation, crude rates for MACE, cancer and mortality were 8.4, 17.9 and 15.8 pkpy, respectively. None was significantly different in the matched analysis. CONCLUSION: Withdrawal of rosiglitazone was associated with worsening glucose control and subsequent intensification of treatment regimen.

Antibiotic treatment failure in four common infections in UK primary care 1991-2012: longitudinal analysis.

OBJECTIVE: To characterise failure of antibiotic treatment in primary care in the United Kingdom in four common infection classes from 1991 to 2012. DESIGN: Longitudinal analysis of failure rates for first line antibiotic monotherapies associated with diagnoses for upper and lower respiratory tract infections, skin and soft tissue infections, and acute otitis media. SETTING: Routine primary care data from the UK Clinical Practice Research Datalink (CPRD). MAIN OUTCOME MEASURES: Adjusted rates of treatment failure defined by standardised criteria and indexed to year 1 (1991=100). RESULTS: From 58 million antibiotic prescriptions in CPRD, we analysed 10,967,607 monotherapy episodes for the four indications: 4,236,574 (38.6%) for upper respiratory tract infections; 3,148,947 (28.7%) for lower respiratory tract infections; 2,568,230 (23.4%) for skin and soft tissue infections; and 1,013,856 (9.2%) for acute otitis media. In 1991, the overall failure rate was 13.9% (12.0% for upper respiratory tract infections; 16.9% for lower respiratory tract infections; 12.8% for skin and soft tissue infections; and 13.9% for acute otitis media). By 2012, the overall failure rate was 15.4%, representing an increase of 12% compared with 1991 (adjusted value indexed to first year (1991) 112, 95% confidence interval 112 to 113). The highest rate was seen in lower respiratory tract infections (135, 134 to 136). While failure rates were below 20% for most commonly prescribed antibiotics (amoxicillin, phenoxymethylpenicillin (penicillin-V), and flucloxacillin), notable increases were seen for trimethoprim in the treatment of upper respiratory tract infections (from 29.2% in 1991-95 to 70.1% in 2008-12) and for ciprofloxacin (from 22.3% in 1991-95 to 30.8% in 2008-12) and cefalexin (from 22.0% in 1991-95 to 30.8% in 2008-12) in the treatment of lower respiratory tract infections. Failure rates for broad spectrum penicillins, macrolides, and flucloxacillin remained largely stable. CONCLUSIONS: From 1991 to 2012, more than one in 10 first line antibiotic monotherapies for the selected infections were associated with treatment failure. Overall failure rates increased by 12% over this period, with most of the increase occurring in more recent years, when antibiotic prescribing in primary care plateaued and then increased.

External validation of the UKPDS risk engine in incident type 2 diabetes: a need for new type 2 diabetes-specific risk equations.

OBJECTIVE: To evaluate the performance of the UK Prospective Diabetes Study Risk Engine (UKPDS-RE) for predicting the 10-year risk of cardiovascular disease end points in an independent cohort of U.K. patients newly diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study using routine health care data collected between April 1998 and October 2011 from ∼350 U.K. primary care practices contributing to the Clinical Practice Research Datalink (CPRD). Participants comprised 79,966 patients aged between 35 and 85 years (388,269 person-years) with 4,984 cardiovascular events. Four outcomes were evaluated: first diagnosis of coronary heart disease (CHD), stroke, fatal CHD, and fatal stroke. RESULTS: Accounting for censoring, the observed versus predicted 10-year event rates were as follows: CHD 6.1 vs. 16.5%, fatal CHD 1.9 vs. 10.1%, stroke 7.0 vs. 10.1%, and fatal stroke 1.7 vs. 1.6%, respectively. The UKPDS-RE showed moderate discrimination for all four outcomes, with the concordance index values ranging from 0.65 to 0.78. CONCLUSIONS: The UKPDS stroke equations showed calibration ranging from poor to moderate; however, the CHD equations showed poor calibration and considerably overestimated CHD risk. There is a need for revised risk equations in type 2 diabetes.

Mortality and other important diabetes-related outcomes with insulin vs other antihyperglycemic therapies in type 2 diabetes.

CONTEXT: The safety of insulin in the treatment of type 2 diabetes mellitus (T2DM) has recently undergone scrutiny. OBJECTIVE: The objective of the study was to characterize the risk of adverse events associated with glucose-lowering therapies in people with T2DM. DESIGN AND SETTING: This was a retrospective cohort study using data from the UK General Practice Research Database, 2000-2010. PATIENTS: Patients comprised 84 622 primary care patients with T2DM treated with one of five glucose-lowering regimens: metformin monotherapy, sulfonylurea monotherapy, insulin monotherapy, metformin plus sulfonylurea combination therapy, and insulin plus metformin combination therapy. There were 105 123 exposure periods. MAIN OUTCOME MEASURES: The risk of the first major adverse cardiac event, first cancer, or mortality was measured. Secondary outcomes included these individual constituents and microvascular complications. RESULTS: In the same model, and using metformin monotherapy as the referent, the adjusted hazard ratio (aHR) for the primary end point was significantly increased for sulfonylurea monotherapy (1.436, 95% confidence interval [CI] 1.354-1.523), insulin monotherapy (1.808, 95% CI 1.630-2.005), and insulin plus metformin (1.309, 95% CI 1.150-1.491). In glycosylated hemoglobin/morbidity subgroups, patients treated with insulin monotherapy had aHRs for the primary outcome ranging from 1.469 (95% CI 0.978-2.206) to 2.644 (95% CI 1.896-3.687). For all secondary outcomes, insulin monotherapy had increased aHRs: myocardial infarction (1.954, 95% CI 1.479-2.583), major adverse cardiac events (1.736, 95% CI 1.441-2.092), stroke (1.432, 95% CI 1.159-1.771), renal complications (3.504, 95% CI 2.718-4.518), neuropathy (2.146, 95% CI 1.832-2.514), eye complications (1.171, 95% CI 1.057-1.298), cancer (1.437, 95% CI 1.234-1.674), or all-cause mortality (2.197, 95% CI 1.983-2.434). When compared directly, aHRs were higher for insulin monotherapy vs all other regimens for the primary end point and all-cause mortality. CONCLUSIONS: In people with T2DM, exogenous insulin therapy was associated with an increased risk of diabetes-related complications, cancer, and all-cause mortality. Differences in baseline characteristics between treatment groups should be considered when interpreting these results.

The impact of treatment non-compliance on mortality in people with type 1 diabetes.

AIMS: To determine if a diagnostic record of poor treatment compliance (medication non-compliance and/or non-attendance at medical appointments) was associated with all-cause mortality in people with type 1 diabetes. METHODS: This is an observational cohort study of data extracted from The Health Improvement Network (THIN) database, comprising data on patients served by over 350 primary care practices in the U.K. Participants were included in the study if they had diagnostic codes indicative of type 1 diabetes. Treatment non-compliance was defined as missing one or more scheduled appointment, or one or more codes indicating medication non-compliance. RESULTS: Of 2946 patients with type 1 diabetes, 867 (29.4%) had a record of either appointment non-attendance or medication non-compliance in the 30 month compliance assessment period. The crude, unadjusted mortality rate for those patients who were treatment non-compliant was 1.462 (95% CI 0.954-2.205). Following adjustment for confounding factors, treatment non-compliance was associated with increased all-cause mortality (HR=1.642; 95% CI 1.055-2.554). CONCLUSIONS: Treatment non-compliance was associated with increased all-cause mortality in patients with type 1 diabetes. Understanding and addressing factors that contribute to patient treatment non-compliance will be important in improving the life expectancy of patients with type 1 diabetes.

Omega-3 Fatty acids and mortality outcome in patients with and without type 2 diabetes after myocardial infarction: a retrospective, matched-cohort study.

BACKGROUND: There are conflicting data regarding the benefits of omega-3 (n-3) fatty acids, most recently in patients with type 2 diabetes. OBJECTIVE: Our goal was to evaluate the impact of licensed, highly purified n-3 fatty acids on all-cause mortality after myocardial infarction (MI). METHODS: This was a retrospective, matched-cohort study using data from the General Practice Research Database. Patients initiating treatment with 1 g of n-3 fatty acids in the 90 days after first MI were identified and each matched to 4 nonexposed patients. Progression to death was compared using time-dependent Cox models to account for potential differences in exposure to other cardiovascular risk-modifying treatments. RESULTS: A total of 2466 eligible subjects exposed to n-3 fatty acids were matched. The majority of patients had concurrent treatment with lipid-lowering therapies, antihypertensives, and antiplatelets after first MI, with subjects exposed to n-3 fatty acids having a greater likelihood of concurrent exposure. For those initiating n-3 fatty acids within 90 days of first MI, the adjusted hazard ratio (aHR) was 0.782 (95% CI, 0.641-0.995; P = 0.0159); for those initiating treatment within 14 days, the aHR was 0.680 (95% CI, 0.481-0.961; P = 0.0288). In patients with type 2 diabetes at baseline, the aHRs were 0.714 (95% CI, 0.454-1.124) and 0.597 (95% CI, 0.295-1.211) when initiation was within 90 and 14 days, respectively. Use of n-3 fatty acids resulted in a consistent survival benefit under a range of scenarios quantitatively consistent with the overall effect. CONCLUSION: After MI, early treatment with licensed n-3 fatty acids was associated with improvement in all-cause mortality in patients with and without type 2 diabetes, against a background of contemporary cardiovascular risk-modifying treatments.

Primary prevention of diabetic retinopathy with fibrates: a retrospective, matched cohort study.

OBJECTIVES: To compare the progression of diabetic retinopathy (DR) in people with type 2 diabetes treated with fibrates with that of non-exposed controls. DESIGN: Retrospective, matched cohort study. SETTING: UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: 5038 people with type 2 diabetes with a history of fibrate exposure but without evidence of DR were identified. Three thousand one hundred and seventy-six (63%) people could be randomly matched to one non-exposed control; of these, 2599 (81.8%) were matched without any missing blood pressure or glycated haemoglobin (HbA1c) values. MAIN OUTCOME MEASURES: The primary endpoint was first recorded DR with a secondary endpoint of all-cause mortality or first DR. Time to clinical endpoints was compared using Cox proportional hazards models. RESULTS: Mean follow-up was 5.1 and 5.0 years for fibrate-exposed and non-exposed patients, respectively. For fibrate-exposed participants, there was a reduction in DR: 33.4 events/1000 person-years vs 40.4 (p=0.002), and in death or DR: 50.6 vs 60.2 (p<0.001). For those matched with full systolic blood pressure and HbA1c data, crude event rates were 34.3 versus 43.9 for DR (p<0.001) and 51.2 vs 63.4 (p<0.001) for death or DR. Following adjustment, DR was significantly delayed for those treated with fibrates, with an adjusted HR (aHR) of 0.785 (p<0.001) for participants with complete data and an aHR of 0.802 (p<0.001) for all participants. CONCLUSIONS: The treatment with fibrates in people with type 2 diabetes was independently associated with reduced progression to a first diagnosis of DR.