Guideline for opioid therapy and chronic noncancer pain

Guideline for opioid therapy and chronic noncancer pain: the objective is to inform the prescribing of opioids for adults with chronic noncancer pain.

Performance and carcass characteristics of commercial feedlot cattle from a study of vaccine and direct-fed microbial effects on Escherichia col O157:H7 fecal shedding.

The objective of this study was to quantify cattle performance and carcass characteristics associated with administration of a siderophore receptor and porin proteins-based vaccine (VAC) and a direct-fed microbial (DFM), which were originally evaluated for their impact on O157:H7 fecal shedding in a commercial feedlot population. Cattle (P = 17,148) were randomly allocated into 40 pens grouped by allocation dates into 10 complete blocks; pens within block were randomly allocated to control, VAC, DFM, or VAC + DFM treatment groups in a 2 × 2 factorial design. The DFM (Bovamine) was fed daily at the labeled dose of 10 cfu/animal of Lactobacillus acidophilus for the duration of the intervention period (mean = 86.6 d). The VAC cattle were vaccinated on Days 0 and 21 whereas unvaccinated cattle were not given a placebo or rehandled on Day 21. Data were analyzed using general and generalized linear mixed models that accounted for the study design. Main effects of DFM and VAC are reported as there were no significant treatment interactions for any of the outcomes evaluated. Vaccinated cattle had lower total weight gain (P < 0.01), ADG (P = 0.03), and cumulative DMI during the intervention period (P < 0.01) compared with unvaccinated cattle, whereas the DFM increased total weight gain (P = 0.03) and G:F (P = 0.05) during the intervention period. Daily DMI was decreased (P < 0.01) in vaccinated pens compared with unvaccinated pens during a 5-d period immediately following revaccination. After the intervention period was completed, cattle were sorted following the standard operating procedure for the feedlot and all cattle were fed the DFM from that point until harvest. Each steer was individually identified through harvest. At harvest, vaccinated cattle had more total days on feed (P < 0.01) with a larger HCW (P = 0.01) than nonvaccinated cattle, whereas cattle not fed the DFM during the intervention period had a significantly larger HCW (P < 0.01) than those fed the DFM during the intervention period. We conclude that the use of these DFM and vaccine products have differential and independent effects on cattle performance and carcass characteristics in a commercial feedlot setting. Although the magnitude of these effects may vary among production systems, a more comprehensive understanding of the potential production costs of preharvest food safety pathogen control programs is essential if such programs are to be fully adopted in the industry.

Fecal shedding of non-O157 serogroups of Shiga toxin-producing Escherichia coli in feedlot cattle vaccinated with an Escherichia coli O157:H7 SRP vaccine or fed a Lactobacillus-based direct-fed microbial.

The objectives of this study were to determine whether fecal shedding of non-O157 Shiga toxin-producing Escherichia coli (STEC) in feedlot cattle was affected by the use of an E. coli O157:H7 vaccine or a direct-fed microbial (DFM) and whether the shedding of a particular non-O157 STEC serogroup within feces was associated with shedding of O157 or other non-O157 STEC serogroups. A total of 17,148 cattle in 40 pens were randomized to receive one, both, or neither (control) of the two interventions: a vaccine based on the siderophore receptor and porin proteins (E. coli SRP vaccine, two doses) and a DFM product (low-dose Bovamine). Fresh fecal samples (30 samples per pen) were collected weekly from pen floors for four consecutive weeks beginning approximately 56 days after study allocation. DNA extracted from enriched samples was tested for STEC O157 and non-O157 serogroups O26, O45, O103, O111, O121, and O145 and for four major virulence genes (stx1, stx2, eae, and ehxA) using an 11-gene multiplex PCR assay. Generalized linear mixed models were used to analyze the effects of treatments and make within-sample comparisons of the presence of O-serogroup-specific genes. Results of cumulative prevalence measures indicated that O157 (14.6%), O26 (10.5%), and O103 (10.3%) were the most prevalent STEC O serogroups. However, the vaccine, DFM, or both had no significant effect (P > 0.05) on fecal prevalence of the six non-O157 STEC serogroups in feedlot cattle. Within-sample comparisons of the presence of STEC serogroup-specific genes indicated that fecal shedding of E. coli O157 in cattle was associated with an increased probability (P < 0.05) of fecal shedding of STEC O26, O45, O103, and O121. Our study revealed that neither the E. coli O157:H7 vaccine, which reduced STEC O157 fecal shedding, nor the DFM significantly affected fecal shedding of non-O157 STEC serogroups, despite the fact that the most prevalent non-O157 STEC serogroups tended to occur concurrently with O157 STEC strains within fecal samples.

Pharmacokinetics of oral meloxicam in ruminant and preruminant calves.

The pharmacokinetics of oral meloxicam has been studied in ruminant, but not preruminant calves. Oral meloxicam was administered at 0.5 mg/kg to six ruminant calves via gavage (RG); to six preruminant calves via gavage (PRG); and to six preruminant calves via suckling in milk replacer (PRF). Plasma drug concentrations, determined over 120-h postadministration, were analyzed by compartmental and noncompartmental methods. The rate of drug absorption was faster (P<0.01) in PRF (0.237±0.0478/h) than RG calves (0.0815±0.0188/h), while absorption in PRG calves (0.153±0.128/h) was not different from other groups. C(max) was lower (P=0.03) in PRF (1.27±0.430 µg/mL) than in PRG calves (2.20±0.467 µg/mL), while C(max) of RG calves (1.95±0.955 µg/mL) was not different from other groups. V/F was higher in PRF calves (365±57 mL/kg) than either PRG (177±63 mL/kg, P<0.01) or RG (232±83 mL/kg, P=0.01) calves. These observations were likely due to differences in bioavailability, physiological maturity, and timing of the drug delivery into different compartments of the ruminant gastrointestinal tract. Results suggest that an adjustment in meloxicam dose may be necessary when administered with milk replacer.

GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77.

AIMS/HYPOTHESIS: Latent autoimmune diabetes in adults (LADA) is a slowly progressive form of autoimmune diabetes, with autoantibodies to islet proteins developing in older patients who have no immediate requirement for insulin therapy. Markers of its clinical course are uncharacterised. The aim of this study was to determine whether persistence of, or changes in, GAD65 autoantibodies (GADAs) in the LADA patients who participated in the United Kingdom Prospective Diabetes Study (UKPDS) were associated with disease progression or insulin requirement. METHODS: GADA levels and their relative epitope reactivities to N-terminal, middle and C-terminal regions of human GAD65 were determined in 242 UKPDS patients who were GADA-positive at diagnosis; samples taken after 0.5, 3 and 6 years of follow-up were tested using a radiobinding assay. Comparisons were made of GADA status with clinical details and disease progression assessed by the requirement for intensified glucose-lowering therapy. RESULTS: GADA levels fluctuated between 0.5 and 6 years but persisted in 225 of 242 patients. No association of GADA levels with disease progression or insulin requirement was observed. Antibody reactivity was directed to C-terminal and middle epitopes of GAD65 in >70% patients, and the N-terminal in <9%. There were no changes in epitope reactivity pattern over the 6 year follow-up period, nor any association between epitope reactivity and insulin requirement. CONCLUSIONS/INTERPRETATION: GADAs persist for 6 years after diagnosis of LADA, but levels and reactivity to different GAD65 epitopes are not associated with disease progression.

Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76.

AIMS/HYPOTHESIS: Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes. METHODS: We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors. RESULTS: rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54-0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11-1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27-0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus. CONCLUSIONS/INTERPRETATION: We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.

Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75).

AIMS/HYPOTHESIS: The relative importance of glucose and blood pressure control in type 2 diabetes remains uncertain. We assessed interactive effects of glycaemia and systolic blood pressure (SBP) exposure on the risk of diabetic complications over time. SUBJECTS, MATERIALS AND METHODS: HbA(1c) and SBP, measured annually for a median of 10.4 years in 4,320 newly diagnosed type 2 diabetic patients from the UK Prospective Diabetes Study (UKPDS), were categorised as updated mean values <6.0, 6.0-6.9, 7.0-7.9 or > or =8.0%, and <130, 130-139, 140-149 or > or =150 mmHg, respectively. Clinical outcomes were UKPDS predefined composite endpoints. RESULTS: The incidence of the "any diabetes-related endpoint" in the lowest (HbA(1c) <6.0%, SBP <130 mmHg) and highest (HbA(1c) > or =8%, SBP > or =150 mmHg) category combinations was 15 and 82 per 1,000 person-years, respectively, and 24 and 120 per 1,000 person-years in a Poisson model adjusted to white Caucasian male sex, age 50 to 54 years and diabetes duration of 7.5 to 12.5 years. Updated mean HbA(1c) and SBP effects were additive in an adjusted proportional hazards model with risk reductions of 21% per 1% HbA(1c) decrement and 11% per 10 mmHg SBP decrement. Endpoint rates obtained in the 887 patients randomised in both the glycaemia and hypertension intervention trial arms were consistent with the observational data. Those allocated to both intensive glucose and tight blood pressure control policies had fewer events than those allocated to either policy alone or to neither (p for trend 0.024). CONCLUSIONS/INTERPRETATION: Risk of complications in type 2 diabetes is associated independently and additively with hyperglycaemia and hypertension. Intensive treatment of both these risk factors is required to minimise the incidence of complications.

Reporting of diabetes on death certificates using data from the UK Prospective Diabetes Study.

AIMS: To study the effect of age at death, sex, ethnic group, date of death, underlying cause of death and social class on the frequency of reporting diabetes on death certificates in known cases of diabetes. METHODS: Data were extracted from certificates recording 981 deaths which occurred between 1985 and 1999 in people aged 45 years or more who participated in the UK Prospective Diabetes Study, to which 23 English, Scottish and Northern Ireland centres contributed. Diabetes (9th revision of the International Classification of Diseases; ICD-9 250) entered on parts 1A-1C or 2A-2C of the death certificate was considered as reporting diabetes. Logistic regression analyses were used to determine independent factors associated with the reporting of diabetes. RESULTS: Diabetes was reported on 42% (419/981) of all death certificates and on 46% (249/546) of those with underlying cardiovascular disease causes. Reporting of diabetes was independently associated on all death certificates with per year of age increase (OR 1.02; 95% CI 1.001-1.04, P = 0.037), underlying cause of death (non-cardiovascular causes OR 0.76; 95% CI 0.59-0.98, P = 0.035) and social class (classes I-II OR 1.00; class III OR 1.35; 95% CI 0.96-1.89, P = 0.084, classes IV-V OR 1.48; 95% CI 1.05-2.10, P = 0.027). Stratification by age, sex, and underlying cause of death also revealed significant differences in the frequency of reporting diabetes over time. CONCLUSIONS: The rate of reporting of diabetes on cardiovascular disease death certificates remains poor. This may indicate a lack of awareness of the importance of diabetes as a risk factor for cardiovascular disease.

IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71).

AIMS/HYPOTHESIS: Established autoimmune markers of type 1 diabetes, including islet cell autoantibodies (ICA) and autoantibodies to glutamic acid decarboxylase (GADA) have been used to screen people presenting with type 2 diabetes for latent autoimmune diabetes in adults. We have examined the prevalence of autoantibodies to protein tyrosine phosphatase isoforms IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA) in a cohort of adult UKPDS patients thought to have type 2 diabetes, and investigated the possible role of these autoantibodies in predicting requirement for insulin therapy. METHODS: IA-2A and IA-2betaA were measured by a validated radioimmunoassay with human recombinant autoantigens in 4,169 white Caucasian patients aged 25-65 years and newly diagnosed with type 2 diabetes. The clinical requirement for insulin therapy within 6 years was examined in 2,556 patients not randomised to insulin. RESULTS: IA-2A and IA-2betaA were present in 2.2 and 1.4%, respectively, of these patients. IA-2A were more prevalent in younger patients (p for trend <0.00001), more often associated with the HLA-DR4 allele (26.3 vs 8.0%, p<0.0001), and their presence increased the likelihood of insulin therapy requirement within 6 years from diagnosis [relative risk (95%CI) 12.2 (9.8-15.3)]. The presence of IA-2A together with GADA increased the relative risk of requiring insulin therapy from 5.4 (4.1-7.1) for GADA alone to 8.3 (3.7-18.8) and the corresponding positive predictive value from 33 to 50%. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, the presence of IA-2A is infrequent, associated with the HLA-DR4 haplotype, and highly predictive of future need for insulin therapy. The measurement of IA-2betaA does not provide additional information.

Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70).

AIMS/HYPOTHESIS: We examined the prevalence of islet autoantibodies and their relationship to glycaemic control over 10 years in patients diagnosed clinically with new-onset type 2 diabetes. METHODS: Patient clinical characteristics and autoantibody status were determined at entry to the UK Prospective Diabetes Study (UKPDS) before randomisation to different glucose control policies. Patients were followed for 10 years. RESULTS: Data available on 4,545 of the 5,102 UKPDS patients showed that 11.6% had antibodies to at least one of three antigens: islet cell cytoplasm, glutamic acid decarboxylase and islet autoantibody 2A (IA-2A). Autoantibody-positive patients were younger, more often Caucasian and leaner, with lower beta cell function and higher insulin sensitivity than autoantibody-negative patients. They also had higher HbA1c, and HDL-cholesterol levels, and lower blood pressure, total cholesterol and plasma triglyceride levels. Despite relative hyperglycaemia, autoantibody-positive patients were less likely to have the metabolic syndrome (as defined by the National Cholesterol Education Program Adult Treatment Program III), reflecting a more beneficial overall risk factor profile. Of 3,867 patients with post-dietary run-in fasting plasma glucose (FPG) values between 6.0 and 14.9 mmol/l and no hyperglycaemic symptoms, 9.4% were autoantibody-positive, compared with 25.1% of 678 patients with FPG values of 15.0 mmol/l or higher, or hyperglycaemic symptoms. In both groups, no differences were seen between those with and without autoantibodies in changes to HbA1c over time, but autoantibody-positive patients required insulin treatment earlier, irrespective of the allocated therapy (p<0.0001). CONCLUSIONS/INTERPRETATION: Autoantibody-positive patients can be treated initially with sulphonylurea, but are likely to require insulin earlier than autoantibody-negative patients.

Changing aspirin use in patients with Type 2 diabetes in the UKPDS.

AIMS: To examine the proportion of UK Prospective Diabetes Study (UKPDS) patients with Type 2 diabetes taking aspirin regularly for the primary and secondary prevention of cardiovascular disease (CVD) before and after publication of the 1997 American Diabetes Association (ADA) Clinical Practice Recommendations and the 1998 Joint British Recommendations on the Prevention of Coronary Disease in Clinical Practice. METHODS: UKPDS annual review data from 1996/7 (n = 3190) and 2000/1 (n = 2467) were used to determine the prevalence of patients taking aspirin regularly in relation to known CVD risk factors and pre-existing CVD. RESULTS: Patients taking aspirin regularly were more often male than female (24 vs. 20%, P = 0.0033), older (66 +/- 8 vs. 62 +/- 9 years, P < 0.0001) and less often Afro-Caribbean than White Caucasian or Indian Asian (11 vs. 23 vs. 22%, respectively, P < 0.0001). Between 1996/7 and 2000/1 aspirin use in patients without pre-existing CVD increased from 17 to 31% (P < 0.0001) and for those with pre-existing CVD from 76 to 82% (P = 0.032). CONCLUSION: The majority of patients with pre-existing CVD were taking aspirin regularly. Although aspirin use in those without pre-existing CVD approximately doubled after publication of the ADA and Joint British Recommendations, less than two-thirds of these high-risk patients were being treated according to guidelines. This may relate to a lack of convincing evidence for primary CVD prevention or failure to adhere to guidelines. It may be that more trial data is needed to convince clinicians of the value of aspirin therapy in Type 2 diabetes.

Autoantibodies to the islet cell antigen SOX-13 are associated with duration but not type of diabetes.

AIMS: The autoantigen SOX-13 of the SRY-related high mobility group box is a low-frequency reactant in sera from patients with Type 1 diabetes. We further investigated the potential diagnostic role of anti-SOX-13, and in particular its ability to distinguish Type 1 from Type 2 diabetes, in two large, well-characterized cohorts. METHODS: SOX-13 autoantibody status was ascertained using a radioimmunoprecipitation assay in (i) a random sample of 546 participants in an Australian community-based study (the Fremantle Diabetes Study; FDS) of whom 119 had Type 1 and 427 Type 2 diabetes, and (ii) a sample of 333 subjects with Type 2 diabetes from the United Kingdom Prospective Diabetes Study (UKPDS) stratified by age, anti-glutamic acid decarboxylase (GAD) and islet cell antibody (ICA) status, and requirement for insulin therapy within 6 years of diagnosis. RESULTS: The frequencies of anti-SOX-13 in the FDS subjects were 16.0% and 14.8% for Type 1 and Type 2 patients, respectively, and levels were similar. In the UKPDS subjects, the frequency was 4.5%. In a logistic regression model involving demographic, anthropometric and metabolic variables, only diabetes duration was significantly associated with anti-SOX-13 positivity, especially for duration > 5 years (P < 0.002). When the coexistence of autoantibodies was assessed in the two study samples, there were no significant associations between anti-SOX-13 and ICA, anti-GAD or ICA512/IA-2. CONCLUSIONS: Whilst the frequency of anti-SOX-13 may be increased in some populations of diabetic patients, this reactivity does not usefully distinguish Type 1 from Type 2 diabetes. However, the association with diabetes duration suggests that anti-SOX-13 may be a non-specific marker of tissue damage associated with chronic hyperglycaemia.

High and low perceived self-control of epileptic seizures.

PURPOSE: To define behaviours and to identify psychological, demographic, and epilepsy-related variables associated with high as opposed to low perceived self-control of seizures. METHOD: In a semistructured interview, 100 adults with intractable seizures were asked about their seizure precipitants and attempts at self-control of seizures. They also completed four psychological questionnaires. Latent Class Analysis was used to analyse the interview data to create two groups, High Controllers and Low Controllers, who were then compared on demographic, epilepsy, and psychological characteristics. RESULTS: Being able to identify and seeking out low-risk-for-seizure situations, avoiding high-risk-for-seizure situations, and making attempts at seizure inhibition were seizure behaviours that discriminated High from Low Controllers. The general probability of being a High Controller was greater than that of being a Low Controller. Perceived high self-control of seizures was associated with low chance-health locus of control. For Low Controllers, current age, age at onset of seizures, and duration of epilepsy history were related to psychological variables. A significantly higher proportion of the Low Controllers than High Controllers were women. CONCLUSIONS: Many people with intractable seizures do not accept their epilepsy as a condition over which they have no control. Perceived self-control of seizures, however, involves a complex interaction between epilepsy and psychological factors, with health locus of control an apparently important discriminator between High and Low Controllers.

An economic evaluation of atenolol vs. captopril in patients with Type 2 diabetes (UKPDS 54).

AIMS: To compare the net cost of a tight blood pressure control policy with an angiotensin converting enzyme inhibitor (captopril) or beta blocker (atenolol) in patients with Type 2 diabetes. DESIGN: A cost-effectiveness analysis based on outcomes and resources used in a randomized controlled trial and assumptions regarding the use of these therapies in a general practice setting. SETTING: Twenty United Kingdom Prospective Diabetes Study Hospital-based clinics in England, Scotland and Northern Ireland. SUBJECTS: Hypertensive patients (n = 758) with Type 2 diabetes (mean age 56 years, mean blood pressure 159/94 mmHg), 400 of whom were allocated to the angiotensin converting enzyme inhibitor captopril and 358 to the beta blocker atenolol. MAIN OUTCOME MEASURES: Life expectancy and mean cost per patient. RESULTS: There was no statistically significant difference in life expectancy between groups. The cost per patient over the trial period was 6485 UK pounds in the captopril group, compared with 5550 UK pounds in the atenolol group, an average cost difference of 935 UK pounds (95% confidence interval 188 UK pounds, 1682 UK pounds). This 14% reduction arose partly because of lower drug prices, and also because of significantly fewer and shorter hospitalizations in the atenolol group, and despite higher antidiabetic drug costs in the atenolol group. CONCLUSIONS: Treatment of hypertensive patients with Type 2 diabetes using atenolol or captopril was equally effective. However, total costs were significantly lower in the atenolol group. Diabet. Med. 18, 438-444 (2001)

Relationship between ethnicity and glycemic control, lipid profiles, and blood pressure during the first 9 years of type 2 diabetes: U.K. Prospective Diabetes Study (UKPDS 55).

OBJECTIVE: To assess the relationship among self-reported ethnicity, metabolic control, and blood pressure during treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 2,999 newly diagnosed type 2 diabetic patients recruited to the U.K. Prospective Diabetes Study who were randomized to conventional or intensive glucose control policies if their fasting plasma glucose levels remained >6 mmol/l after a dietary run-in. A total of 2,484 patients (83%) were white Caucasian (WC), 265 patients (9%) were Afro-Caribbean (AC), and 250 patients (8%) were Asian of Indian origin (IA). Variables were assessed at 3, 6, and 9 years. RESULTS: During the 9-year study period, body weight increased more in WC patients (mean 5.0 kg) than in AC (3.0 kg) and IA (2.5 kg) patients (P < 0.001). After adjusting for age, sex, baseline value, treatment allocation, and change in weight, there were no consistent ethnic differences in mean change in fasting plasma glucose or HbA(1c). After adjustment for antihypertensive therapy, increase in systolic blood pressure at 9 years was greatest in AC patients (7 mmHg; P < 0.01 vs. WC patients). Mean diastolic blood pressure, total cholesterol, and LDL cholesterol decreased progressively during the 9 years in each group. In AC patients, the mean increase in HDL cholesterol (0.16 mmol/l) at 3 years, maintained to 9 years, and the mean decrease in plasma triglyceride level (0.4 mmol/l) at 9 years were greater than in WC and IA patients (P < 0.001). CONCLUSIONS: This study shows important ethnic differences in body weight, lipid profiles, and blood pressure, but not glycemic control, during 9 years after diagnosis of type 2 diabetes. AC patients maintained the most favorable lipid profiles, but hypertension developed in more AC patients than WC or IA patients. Ethnicity-specific glycemic control of type 2 diabetes seems unnecessary, but other risk factors need to be addressed independently.

Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with type II diabetes (UKPDS No. 51).

AIMS/HYPOTHESIS: To estimate the economic efficiency of intensive blood-glucose control with metformin compared with conventional therapy primarily with diet in overweight patients with Type II (non-insulin-dependent) diabetes mellitus. METHODS: Cost-effectiveness analysis based on patient level data from a randomised clinical controlled trial involving 753 overweight (> 120% ideal body weight) patients with newly diagnosed Type II diabetes conducted in 15 hospital-based clinics in England, Scotland and Northern Ireland as part of the UK Prospective Diabetes Study. Subjects were allocated at random to an intensive blood-glucose control policy with metformin (n = 342) or a conventional policy primarily with diet (n = 411). The analysis was based on the cost of health care resources associated with metformin and conventional therapy and the estimated effectiveness in terms of life expectancy gained from within-trial effects. RESULTS: Intensive blood-glucose control with metformin produced a net saving of 258 Pounds per patient (1997 United Kingdom prices) over the trial period (median duration of 10.7 years) due to lower complication costs, and increased life expectancy by 0.4 years (costs and benefits discounted at 6%). CONCLUSIONS/INTERPRETATION: As metformin is both cost-saving in the United Kingdom and extends life expectancy when used as first line pharmacological therapy in overweight Type II diabetic patients, its use should be attractive to clinicians and health care managers alike.

Butyrylcholinesterase K variant on chromosome 3 q is associated with Type II diabetes in white Caucasian subjects.

AIMS/HYPOTHESIS: To determine the association of three genes associated with Alzheimer's disease--butyrylcholinesterase (BcHE) on chromosome 3 q, alpha2 macroglobulin (alpha2M) on chromosome 12 p and apolipoprotein E (ApoE) on chromosome 19 q--with Type II (non-insulin-dependent) diabetes mellitus. METHODS: Frequencies of BcHE K variant, alpha2M insertion and/or deletion polymorphism, the ApoE common polymorphisms and promoter variants at ApoE-491 and -291, were examined by fluorescent RFLP in DNA from 276 United Kingdom Prospective Diabetes Study Type II diabetic subjects and 351 non-diabetic subjects from the Diabetes In Families study. Genetic data in diabetic subjects was analysed in relation to clinical characteristics and islet function as assessed by the requirement for insulin therapy 6 years after randomisation. RESULTS: The BcHE K variant allele was more common among Type II diabetic subjects (D) than non-diabetic subjects (ND) (22.8 % D vs 15.8 % ND; p = 0.00 017). Subjects homozygous for the variant were more frequent in the diabetic group (5.8 % D vs 2.6 % ND: p = 0.00 056). The K variant allele frequency was not associated with a requirement for insulin therapy (29.0 % insulin-requiring vs 21.8 % non-insulin-requiring; p = 0.121). There were no associations of alpha2M and ApoE polymorphisms or ApoE promoter variants with clinical characteristics or insulin requirement in diabetic subjects. There were differences in total cholesterol (p = 0.0005) and LDL-cholesterol (p = 0.0009) among non-diabetic subjects in relation to ApoE-491 genotypes. CONCLUSION/INTERPRETATION: The association of the BcHE gene (3q26) with Type II diabetes could be related to an identified susceptibility locus on chromosome 3q27 but appears to be independent of islet function. The absence of diabetes-specific associations with alpha2M, ApoE or ApoE promoter variants suggest that these are not important in the onset of hyperglycaemia.

Effects of three months' diet after diagnosis of Type 2 diabetes on plasma lipids and lipoproteins (UKPDS 45). UK Prospective Diabetes Study Group.

AIMS: To assess the effect of diet on fasting plasma lipids and lipoproteins in patients with newly diagnosed Type 2 diabetes. METHODS: A total of 2,906 patients each underwent 3 months' diet therapy before allocation to therapy in a randomized controlled clinical trial. Lipids and lipoproteins were measured at diagnosis and after 3 months' diet. RESULTS: The mean body weight at diagnosis was 83 kg. Weight decreased after diet by a mean of 4.5 kg; body mass index (BMI) decreased by 1.51 kg/m2; plasma glucose fell by 3 mmol/l from 11 mmol/l; and HbA1c by 2% from 9%. Triglyceride concentrations were reduced in men by -0.41 (95% confidence interval (CI) -0.47 to - 0.35) mmol/l from a geometric mean 1.8 (1 SD interval 1.0-3.0) mmol/l, and in women by -0.23 (-0.28 to -0.18) mmol/l from a similar level. Cholesterol decreased in men by -0.28 (-0.33 to -0.24) mmol/l from 5.5 (1.1) mmol/l, and in women by -0.09 (-0.14 to -0.04) mmol/l from 5.8 (1.2) mmol/l with corresponding changes in LDL cholesterol. HDL cholesterol increased in men by 0.02 (0.01 to 0.04) mmol/l and in women by 0.01 (0 to 0.02) mmol/l. Triglyceride concentration in the top tertile was reduced by 37% in men (> 2.1 mmol/l) and by 23% in women (> 2.2 mmol/l) with regression to mean accounting for 13% and 6%, respectively. Similarly cholesterol in the top tertile was reduced by 12% in men (> 5.8 mmol/l) and 7% in women (> 6.2 mmol/l) with 6% of the decrease in both men and women accounted for by regression to the mean. CONCLUSIONS: Initial dietary therapy in patients with newly diagnosed Type 2 diabetes substantially reduced plasma triglyceride, marginally improved total cholesterol and subfractions, and resulted in a potentially less atherogenic profile, although this did not eliminate the excess cardiovascular risk in patients with Type 2 diabetes.

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.

OBJECTIVE: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. DESIGN: Prospective observational study. SETTING: 23 hospital based clinics in England, Scotland, and Northern Ireland. PARTICIPANTS: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. OUTCOME MEASURES: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA(1c) adjusted for possible confounders at diagnosis of diabetes. RESULTS: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA(1c) was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). No threshold of risk was observed for any end point. CONCLUSIONS: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA(1c) is likely to reduce the risk of complications, with the lowest risk being in those with HbA(1c) values in the normal range (<6.0%).