PubMed Health⌕ Search

Biomedical subjects

C A Cull

Publications and source records attributed to C A Cull.

At least 19 recordsLinked to original sources
PubMed2006

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.

Albuminuria↗
PubMed2006

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.

Adult↗
PubMed2005

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.

Adult↗
PubMed2005

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.

Adult↗
PubMed2005

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.

Age Distribution↗
PubMed2004

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.

Age Distribution↗
PubMed2003

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.

Adult↗
PubMed2001

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.

Adult↗
PubMed2001

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.

Blood Glucose↗
PubMed2000

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%).

Cataract Extraction↗
PubMed2000

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study.

OBJECTIVE: To determine the relation between systolic blood pressure 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: 4801 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 complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders. RESULTS: The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, 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 raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.

Adult↗
PubMed2000

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.

Adult↗
PubMed1999

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group.

CONTEXT: Treatment with diet alone, insulin, sulfonylurea, or metformin is known to improve glycemia in patients with type 2 diabetes mellitus, but which treatment most frequently attains target fasting plasma glucose (FPG) concentration of less than 7.8 mmol/L (140 mg/dL) or glycosylated hemoglobin A1c (HbA1c) below 7% is unknown. OBJECTIVE: To assess how often each therapy can achieve the glycemic control target levels set by the American Diabetes Association. DESIGN: Randomized controlled trial conducted between 1977 and 1997. Patients were recruited between 1977 and 1991 and were followed up every 3 months for 3, 6, and 9 years after enrollment. SETTING: Outpatient diabetes clinics in 15 UK hospitals. PATIENTS: A total of 4075 patients newly diagnosed as having type 2 diabetes ranged in age between 25 and 65 years and had a median (interquartile range) FPG concentration of 11.5 (9.0-14.4) mmol/L [207 (162-259) mg/dL], HbA1c levels of 9.1% (7.5%-10.7%), and a mean (SD) body mass index of 29 (6) kg/m2. INTERVENTIONS: After 3 months on a low-fat, high-carbohydrate, high-fiber diet, patients were randomized to therapy with diet alone, insulin, sulfonylurea, or metformin. MAIN OUTCOME MEASURES: Fasting plasma glucose and HbA1c levels, and the proportion of patients who achieved target levels below 7% HbA1c or less than 7.8 mmol/L (140 mg/dL) FPG at 3, 6, or 9 years following diagnosis. RESULTS: The proportion of patients who maintained target glycemic levels declined markedly over 9 years of follow-up. After 9 years of monotherapy with diet, insulin, or sulfonylurea, 8%, 42%, and 24%, respectively, achieved FPG levels of less than 7.8 mmol/L (140 mg/dL) and 9%, 28%, and 24% achieved HbA1c levels below 7%. In obese patients randomized to metformin, 18% attained FPG levels of less than 7.8 mmol/L (140 mg/dL) and 13% attained HbA1c levels below 7%. Patients less likely to achieve target levels were younger, more obese, or more hyperglycemic than other patients. CONCLUSIONS: Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained HbA1c below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years approximately 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.

Adult↗
PubMed1999

A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U.K. Prospective Diabetes Study 44)

OBJECTIVE: To determine the degree to which alpha-glucosidase inhibitors, with their unique mode of action primarily reducing postprandial hyperglycemia, offer an additional therapeutic approach in the long-term treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 1,946 patients (63% men) who were previously enrolled in the U.K. Prospective Diabetes Study (UKPDS). The patients were randomized to acarbose (n = 973), titrating to a maximum dose of 100 mg three times per day, or to matching placebo (n = 973). Mean +/- SD age was 59 +/- 9 years, body weight 84 +/- 17 kg, diabetes duration 7.6 +/- 2.9 years, median (interquartile range) HbA1c 7.9% (6.7-9.5), and fasting plasma glucose (FPG) 8.7 mmol/l (6.8-11.1). Fourteen percent of patients were treated with diet alone, 52% with monotherapy, and 34% with combined therapy. Patients were monitored in UKPDS clinics every 4 months for 3 years. The main outcome measures were HbA1c, FPG, body weight, compliance with study medication, incidence of side effects, and frequency of major clinical events. RESULTS: At 3 years, a lower proportion of patients were taking acarbose compared with placebo (39 vs. 58%, P < 0.0001), the main reasons for noncompliance being flatulence (30 vs. 12%, P < 0.0001) and diarrhea (16 vs. 8%, P < 0.05). Analysis by intention to treat showed that patients allocated to acarbose, compared with placebo, had 0.2% significantly lower median HbA1c at 3 years (P < 0.001). In patients remaining on their allocated therapy, the HbA1c difference at 3 years (309 acarbose, 470 placebo) was 0.5% lower median HbA1c (8.1 vs. 8.6%, P < 0.0001). Acarbose appeared to be equally efficacious when given in addition to diet alone; in addition to monotherapy with a sulfonylurea, metformin, or insulin; or in combination with more complex treatment regimens. No significant differences were seen in FPG, body weight, incidence of hypoglycemia, or frequency of major clinical events. CONCLUSIONS: Acarbose significantly improved glycemic control over 3 years in patients with established type 2 diabetes, irrespective of concomitant therapy for diabetes. Careful titration of acarbose is needed in view of the increased noncompliance rate seen secondary to the known side effects.

Acarbose↗
PubMed1998

UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group.

Patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas 'fail'. The rate of failure and the features of those who fail have been poorly described. To assess secondary failure rates of sulphonylureas, we report on the responses in 1305 patients with newly diagnosed Type 2 DM randomly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospective Diabetes Study (UKPDS). These patients were initially treated by diet for 3 months and had a fasting plasma glucose > 6 mmol l(-1); mean age 53 (SD 9) years; BMI 26.8 (SD 5.0) kg m(-2); and median fasting plasma glucose 9.1 (7.6-12.5 quartiles) mmol l(-1). If their fasting plasma glucose subsequently rose above 15.0 mmol l(-1), or they developed hyperglycaemic symptoms, additional hypoglycaemic therapy was given: metformin, ultratard insulin, and soluble insulin as required. By 6 years, 44% had required additional therapy. Of those randomized to glibenclamide, 48% required additional therapy by 6 years, compared with 40% of those allocated to chlorpropamide (p < 0.01). Sixty-one per cent, 39%, and 23%, respectively, of patients with fasting plasma glucose > or = 10.0 mmol l(-1), > or = 7.8 mmol l(-1) to < 10.0 mmol l(-1) and < 7.8 mmol l(-1) at randomization required additional therapy (p < 0.001). In the initial 3 years, non-obese subjects (BMI < 30 kg m(-2)) were more likely to require additional therapy than obese patients (BMI > or = 30 kg m(-2)) (43% vs 53% at 6 years; p < 0.001). Modelled beta-cell function showed that those with lower function were more likely to fail (p < 0.0001). Thus sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially. Higher failure rates were found in those with higher glucose concentrations, those who were younger, those with lower beta-cell reserve and those randomized to glibenclamide compared with chlorpropamide.

Adult↗
PubMed1997

Approach to maintaining comparability of biochemical data during long-term clinical trials.

Our objective was to design a structured approach to maintaining comparability of biochemical data during a long clinical trial. Maintaining the comparability of clinical and biochemical data obtained in long-term studies is essential, even though analytical methods in the laboratory may be changed, conventions on specimen handling and storage revised, calibration procedures updated, quality-control systems replaced, and secular changes may occur. The United Kingdom Prospective Diabetes Study (UKPDS), a large randomized control trial investigating therapy for type 2 diabetes, was the setting for the study. Data were collected from 5102 subjects randomized since 1977. Our techniques included quality control, external quality assurance, direct comparison of laboratory methods when updating assays and statistical techniques for the detection of unsuspected changes in assay bias, laboratory comparisons of new with old assay methodologies, the realigning of data to current methods, the use of a suitable reference population for long-term monitoring, and rules to aid decision-making about clinical vs statistical significance. Procedures by which comparability of data is assured should be specified for all long-term trials and, where possible, comparison with reference methods should be detailed to allow results from different laboratories to be compared.

Diabetes Mellitus, Type 2↗
PubMed1996

Perceived self-control of seizures in young people with epilepsy.

Evidence now suggests that some people can exert some degree of control over seizure initiation and inhibition. In order to explore this further, 79 young people with epilepsy, attending specialist residential schools, were interviewed regarding awareness of seizure precipitants; recognition of seizure warnings; attempts at seizure inhibition, and ways of self-inducing seizures. Questionnaires with the same content were completed by residential care staff. Results show that many subjects claimed to identify seizure precipitants (63.3%), experienced warnings (70.9%), and had developed means of trying to inhibit seizure occurrence (50.6%). However, in each instance, staff reports were much lower (56.9%, 47.2%, and 22.2%, respectively), and one-to-one concordance was poor. A larger than expected percentage of self-induction was reported for both subjects (8.9%) and staff (9.7%). The implication of these results for both the investigation and treatment of epilepsy are discussed further.

Adolescent↗