Efficacy and safety of once-daily insulin degludec/insulin aspart compared with once-daily insulin glargine in participants with Type 2 diabetes: a randomized, treat-to-target study.

AIMS: To investigate, in a 26-week, open-label, randomized, treat-to-target trial, the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) once daily vs insulin glargine (IGlar) once daily in adults with Type 2 diabetes, inadequately controlled on basal insulin. METHODS: Participants were randomized (1:1) to IDegAsp once daily or IGlar once daily in combination with existing oral antidiabetic drugs. IDegAsp once daily was administered with the main evening meal or the largest meal of the day (agreed at baseline); dosing time was maintained throughout the trial. Participants titrated their insulin dose weekly to a mean pre-breakfast self-measured plasma glucose target [3.9-4.9 mmol/l (70-89 mg/dl)]. RESULTS: IDegAsp once daily was non-inferior to IGlar once daily in reducing HbA1c after 26 weeks [mean estimated treatment difference IDegAsp once daily - IGlar once daily: -0.03% (95% CI -0.20, 0.14)]. The evening meal glucose increment was significantly lower with IDegAsp once daily vs IGlar once daily [estimated treatment difference IDegAsp once daily - IGlar once daily: -1.32 mmol/l (95% CI -1.93, -0.72); P < 0.05]. The overall confirmed hypoglycaemia rate was higher with IDegAsp once daily (estimated rate ratio 1.43; 95% CI 1.07, 1.92; P < 0.05). The rate of nocturnal hypoglycaemia did not significantly differ between the IDegAsp and IGlar groups [estimated rate ratio 0.80 (95% CI 0.49, 1.30); not significant]. CONCLUSIONS: In participants with Type 2 diabetes inadequately controlled on basal insulin, IDegAsp once daily improved glycaemic control and was non-inferior to IGlar once daily. IDegAsp led to higher rates of overall hypoglycaemia than IGlar, with no significant difference in rates of nocturnal hypoglycaemia.

Treatment intensification with an insulin degludec (IDeg)/insulin aspart (IAsp) co-formulation twice daily compared with basal IDeg and prandial IAsp in type 2 diabetes: a randomized, controlled phase III trial.

AIMS: To evaluate the efficacy and safety of two insulin intensification strategies for patients with type 2 diabetes previously treated with basal insulin--insulin degludec (IDeg) and insulin aspart (IAsp)--administered as a co-formulation (IDegAsp) or as a basal-bolus regimen (IDeg and IAsp in separate injections). METHODS: This 26-week, open-label, treat-to-target, phase IIIb, non-inferiority trial randomized patients (1 : 1) to IDegAsp twice daily with main meals (n = 138; IDegAsp group) or IDeg once daily and IAsp 2-4 times daily (n = 136; IDeg+IAsp group). RESULTS: After 26 weeks, the mean glycated haemoglobin (HbA1c) level was 7.0% (53 mmol/mol) for the IDegAsp group and 6.8% (51 mmol/mol) for the IDeg+IAsp group (Δ%HbA1c from baseline -1.31 and -1.50%, respectively). The non-inferiority of IDegAsp versus IDeg+IAsp was not confirmed for mean change in HbA1c [estimated treatment difference (ETD) 0.18, 95% confidence interval (CI) -0.04, 0.41; p = non-significant]. No significant differences were observed in the proportion of patients achieving HbA1c <7.0% (56.5 and 59.6%, respectively). IDegAsp treatment resulted in a significantly lower total daily insulin dose, a smaller change in body weight, numerically lower rates of confirmed hypoglycaemia (self-reported plasma glucose <3.1 mmol/l; rate ratio 0.81; p = non-significant), and nocturnal confirmed hypoglycaemic episodes (rate ratio 0.80; p = non-significant) versus IDeg+IAsp. Patient-reported outcome scores for social functioning were significantly higher for IDegAsp versus IDeg+IAsp (ETD 2.2; 95% CI 0.3, 4.1; p < 0.05). CONCLUSIONS: Both intensification strategies effectively improved glycaemic control. Although non-inferiority was not confirmed, there were no significant differences between the groups that could affect clinical utility.

Superior glycaemic control with once-daily insulin degludec/insulin aspart versus insulin glargine in Japanese adults with type 2 diabetes inadequately controlled with oral drugs: a randomized, controlled phase 3 trial.

AIMS: This phase 3, 26-week, open-label, treat-to-target trial investigated the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in insulin-naïve Japanese adults with type 2 diabetes. METHODS: Subjects were randomized to once-daily injections of IDegAsp (n = 147) or insulin glargine (IGlar) (n = 149), both ±≤2 oral antidiabetic treatments. IDegAsp was given before the largest meal at the discretion of each subject (and maintained throughout the trial); IGlar was dosed according to label. Both insulins were titrated to a target prebreakfast self-measured plasma glucose of 3.9 to <5.0 mmol/l. RESULTS: After 26 weeks, mean HbA1c was 7% with IDegAsp and 7.3% with IGlar; superiority of IDegAsp to IGlar was shown (estimated treatment difference, ETD; IDegAsp-IGlar: -0.28% points [-0.46; -0.10](95% CI), p < 0.01). At end-of-trial, mean fasting plasma glucose (FPG) was similar for IDegAsp and IGlar (5.7 vs. 5.6 mmol/l; ETD IDegAsp-IGlar: 0.15 mmol/l [-0.29; 0.60](95% CI), p = NS). IDegAsp was associated with numerically lower rates of overall confirmed (27%) and nocturnal confirmed hypoglycaemia (25%) versus IGlar (estimated rate ratio IDegAsp/IGlar: 0.73 [0.50; 1.08](95% CI), p = NS, and 0.75 [0.34; 1.64](95% CI), p = NS, respectively). Mean daily insulin doses were similar between groups at end-of-trial (both: 0.41 U/kg) as were the increases in body weight from baseline (both: 0.7 kg). Adverse event profiles were similar between groups. CONCLUSIONS: IDegAsp provided superior long-term glycaemic control compared to IGlar, with similar FPG and doses and numerically lower rates of overall and nocturnal hypoglycaemia (p = NS).

Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials.

AIM: Hypoglycaemia and the fear of hypoglycaemia are barriers to achieving normoglycaemia with insulin. Insulin degludec (IDeg) has an ultra-long and stable glucose-lowering effect, with low day-to-day variability. This pre-planned meta-analysis aimed to demonstrate the superiority of IDeg over insulin glargine (IGlar) in terms of fewer hypoglycaemic episodes at equivalent HbA1c in type 2 and type 1 diabetes mellitus (T2DM/T1DM). METHODS: Pooled patient-level data for self-reported hypoglycaemia from all seven (five in T2DM and two in T1DM) randomized, controlled, phase 3a, treat-to-target trials in the IDeg clinical development programme comparing IDeg once-daily (OD) vs. IGlar OD were analysed. RESULTS: Four thousand three hundred and thirty subjects (2899 IDeg OD vs. 1431 IGlar OD) were analysed. Among insulin-naïve T2DM subjects, significantly lower rates of overall confirmed, nocturnal confirmed and severe hypoglycaemic episodes were reported with IDeg vs. IGlar: estimated rate ratio (RR):0.83[0.70;0.98](95%) (CI) , RR:0.64[0.48;0.86](95%) (CI) and RR:0.14[0.03;0.70](95%) (CI) . In the overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes were reported with IDeg vs. IGlar [RR:0.83[0.74;0.94](95%) (CI) and RR:0.68[0.57;0.82](95%) (CI) ). In the T1DM population, the rate of nocturnal confirmed episodes was significantly lower with IDeg vs. IGlar during maintenance treatment (RR:0.75[0.60;0.94](95%) (CI) ). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. CONCLUSIONS: The limitations of this study include the open-label design and exclusion of subjects with recurrent severe hypoglycaemia. This meta-analysis confirms that similar improvements in HbA1c can be achieved with fewer hypoglycaemic episodes, particularly nocturnal episodes, with IDeg vs. IGlar across a broad spectrum of patients with diabetes.

Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes.

AIM: This study compared the time-action profiles of the novel albumin-bound basal insulin analogue NN344 with those of insulin detemir and insulin glargine in individuals with type 2 diabetes. METHODS: Twenty-seven insulin-treated men with type 2 diabetes [body mass index 30.8 +/- 2.6 kg/m(2) (mean +/- s.d.), haemoglobin A(1c) 7.6 +/- 1.1%] were enrolled in this randomized, double-blind trial and participated in six euglycaemic glucose clamp experiments [target blood glucose (BG) 5 mmol/l] each. Participants received NN344 in three experiments at a dose of 0.8, 1.6 and 2.8 dosing units (DU) (1 DU corresponds to 6 nmol NN344) per kilogram of body weight. In the other three experiments, the participants received 0.4, 0.8 and 1.4 U/kg of either insulin detemir or insulin glargine. The insulin preparations were characterized with regards to their effects on glucose infusion rates (GIRs) (in particular duration of action and within-subject and between-subject variabilities), BG, C-peptide, free fatty acids (FFA), endogenous glucose production (EGP) and peripheral glucose uptake (PGU) over 24 h post-dose. RESULTS: The mean GIR profiles for all three preparations were similar in shape/flatness and showed increasing effect (area under the curve for GIR: AUC-GIR(total)) with increasing dose [low dose: 647 +/- 580, 882 +/- 634, 571 +/- 647 mg/kg (insulin detemir vs. NN344 vs. insulin glargine]; medium dose: 1203 +/- 816, 1720 +/- 1109, 1393 +/- 1203 mg/kg and high dose: 2171 +/- 1344, 3119 +/- 1549, 2952 +/- 2028 mg/kg; p = 0.48]. The duration of action increased with rising doses of all insulin preparations, without major differences between treatments. BG remained below 7 mmol/l in nearly all the experiments. Within-subject variability was lower for the albumin-bound insulin analogues, insulin detemir and NN344, than for insulin glargine (p < 0.0001). Between-subject variability did not differ between treatments, nor did the effects on BG, C-peptide, FFA, EGP or PGU. CONCLUSIONS: In individuals with type 2 diabetes, the time-action profiles and the duration of action of the albumin-bound insulin analogues, insulin detemir and NN344, were comparable with those of insulin glargine, whereas within-subject variability in the metabolic effect was significantly lower. Therefore, insulin detemir and NN344 seem to be as well suited as insulin glargine for once-daily administration in type 2 diabetes. The better predictability may be an important characteristic of the albumin-bound analogues as insulin detemir has already been shown to improve hypoglycaemia.

Time-action profile of insulin detemir and NPH insulin in patients with type 2 diabetes from different ethnic groups.

AIM: To evaluate the time-action profiles and the dose-response relationship of the long-acting insulin analogues insulin detemir (IDet) and NPH insulin (NPH) in type 2 diabetic patients belonging to different ethnic groups. METHODS: Forty-eight type 2 diabetic patients belonging to different ethnic groups (three groups of 16 African Americans (AA), 16 Hispanics/Latinos (HL) and 16 Caucasians) participated in this double-blind crossover trial. Each patient took part in six 16-h isoglycaemic glucose clamps (clamp target 7.2 mmol/l) and was randomly allocated to three doses (0.3, 0.6 and 1.2 (I)U/kg) of IDet and NPH, respectively. RESULTS: IDet and NPH showed comparable pharmacodynamic effects [the area under the glucose infusion rate curve (AUC(GIR 0-16 h)) (mg/kg)] in the investigated dose range: IDet, 0.3 U/kg, 207 AA, 535 HL, 285 Caucasians; 0.6 U/kg, 1203 AA, 824 HL and 1126 Caucasians; 1.2 U/kg, 1502 AA, 1977 HL and 2269 Caucasians; NPH, 0.3 IU/kg, 733 AA, 1148 HL and 1148 Caucasians; 0.6 IU/kg, 1395 AA, 1976 HL and 1077 Caucasians; 1.2 IU/kg, 2452 AA, 3296 HL and 2455 Caucasians. Both IDet and NPH showed a linear dose-response relationship in all three groups (p = 0.31), without any significant differences in slope (p = 0.71) or intercept (p = 0.51). Comparable results were obtained for pharmacokinetics. CONCLUSIONS: These results confirm a linear dose-response relationship of IDet, without any relevant differences between ethnic groups. This suggests that similar dosing recommendation can be used for IDet in type 2 diabetic patients belonging to different ethnic group.

Insulin detemir under steady-state conditions: no accumulation and constant metabolic effect over time with twice daily administration in subjects with Type 1 diabetes.

AIMS: This study investigated the pharmacodynamic and pharmacokinetic characteristics of the novel long-acting insulin analogue insulin detemir (IDet) under single-dose and steady-state conditions in comparison with those of NPH insulin at steady state. METHODS: Twenty-five subjects with Type 1 diabetes [seven females, 18 males, mean age (+/- sd) 39 +/- 12 years, body mass index 24 +/- 3 kg/m(2)] participated in three 24-h glucose clamps. IDet or NPH were given at 12-h intervals in fixed, individualized doses. The first clamp assessed the metabolic effect of NPH at steady state, the second investigated the effect of two single injections of IDet. Subjects continued IDet treatment for 7-14 days, after which the third clamp was performed to investigate IDet at steady state. RESULTS: At steady state, the metabolic effect of IDet was constant over 24 h while a clear peak in the metabolic effect [expressed as glucose infusion rates (GIR)] was observed with NPH after each injection. The fluctuation in the metabolic effect (maximum GIR divided by the average of the GIR values at the interval ends) was significantly lower in the second 12 h of the experiments with IDet under steady-state conditions compared with NPH (fluctuation(12-24 h) 1.27 +/- 0.17 vs. 1.56 +/- 0.72, P < 0.05). The overall metabolic effect of IDet at steady state was comparable with that of NPH [GIR-area under curve (AUC)(0-24 h): 5697 +/- 1861 vs. 5929 +/- 1965 mg/kg] whereas a significantly lower effect (5187 +/- 1784 mg/kg, P = 0.01 vs. steady state) was observed following the first two IDet injections. GIR values at the end of clamp day 2 (first doses) and clamp day 3 (steady state) were comparable [GIR(trough 24 h) 3.7 +/- 1.7 vs. 3.8 +/- 1.6 mg/(kg x min) NS], indicating that IDet had reached steady state after the first two injections. CONCLUSIONS: IDet administered twice daily reached steady state after the second injection and showed a constant metabolic effect over time under steady-state conditions. This should facilitate basal insulin substitution and decrease the risk of hypoglycaemia in insulin-treated subjects.

Physical exposure assessment in monotonous repetitive work--the PRIM study.

OBJECTIVES: A program called the Project on Research and Intervention in Monotonous Work (PRIM) was initiated in 1994 as a prospective cohort study of work-related musculoskeletal disorders. The group-based exposure assessment strategy, focusing on task-related exposure and used to obtain baseline measures of physical exposures, is reported in this paper. METHODS: Monotonous, repetitive worktasks were evaluated at 19 factories. Tasks with an estimated similarity in physical exposure were aggregated before 103 exposure groups were formed. Subjects from the exposure groups were randomly sampled for measurements, and task-related exposure levels were quantified by 43 single exposure items using a real-time video-based observation method that allowed computerized estimates of repetitiveness, body postures, force, and velocity. In combination with questionnaire-based data on task distribution, the duration of exposure was calculated at the individual level. RESULTS: The video-based observational method and the large number of exposure variables enabled the establishment of detailed quantitative exposure profiles in 103 task-based exposure groups. However, methodological problems associated with the use of grouped exposure assessment were revealed. Despite efforts to optimize group homogeneity, the within-group variance was larger than the between-group variance for several shoulder postural variables. CONCLUSIONS: A task-based exposure-assessment strategy can be successful in solving some of the main problems associated with the assessment of physical workplace exposures. The large within-group variance in exposure to nonneutral shoulder postures may eventually require individual assessment or the inclusion of groups with maximal contrast in exposure or both.

Interpreting parameters in the logistic regression model with random effects.

Logistic regression with random effects is used to study the relationship between explanatory variables and a binary outcome in cases with nonindependent outcomes. In this paper, we examine in detail the interpretation of both fixed effects and random effects parameters. As heterogeneity measures, the random effects parameters included in the model are not easily interpreted. We discuss different alternative measures of heterogeneity and suggest using a median odds ratio measure that is a function of the original random effects parameters. The measure allows a simple interpretation, in terms of well-known odds ratios, that greatly facilitates communication between the data analyst and the subject-matter researcher. Three examples from different subject areas, mainly taken from our own experience, serve to motivate and illustrate different aspects of parameter interpretation in these models.

Increasing inequality in ischaemic heart disease morbidity among employed men in Denmark 1981-1993: the need for a new preventive policy.

BACKGROUND: In the mid 1980s European governments committed themselves to the WHO goal 'reduced inequality in health by year 2000' according to which inequality in health should be reduced by 25% by the year 2000. The study aim is to estimate the time trend in relative risk due to ischaemic heart disease (IHD) morbidity in employment status groups in Denmark in the period from 1981 to 1993 and to recommend a strategy to reduce inequality in health. MATERIAL AND METHODS: The study dealt with change in relative risk of IHD in main employment status AND groups as measured in three successive cohorts. The cohorts were defined as all METHODS: gainfully employed men in Denmark as of 1 January 1981, 1986 and 1991, respectively. Information on employment was retrieved for the three previous years. The cohorts were followed for first admissions with IHD as the principal cause during 5, 5, and 3 years respectively. RESULTS: Managers and white collar workers had an average or low and decreasing relative risk while male blue collar workers had a high and increasing relative risk. Thus the social inequality in IHD is rapidly increasing. Some occupational groups are known to be at high risk. Some of these high-risk groups, such as bus drivers, even have an increasing relative risk. CONCLUSIONS: The general health education has been successful in the prevention of IHD in the high-status groups but has failed to reduce the risk among blue collar workers. Preventive measures against IHD should focus on occupational groups at high, increasing risk and the measures should tailor to their 'subculture.'

Prevalence proportion ratios: estimation and hypothesis testing.

BACKGROUND: Recent communications have argued that often it may not be appropriate to analyse cross-sectional studies of prevalent outcomes with logistic regression models. The purpose of this communication is to compare three methods that have been proposed for application to cross sectional studies: (1) a multiplicative generalized linear model, which we will call the log-binomial model, (2) a method based on logistic regression and robust estimation of standard errors, which we will call the GEE-logistic model, and (3) a Cox regression model. METHODS: Five sets of simulations representing fourteen separate simulation conditions were used to test the performance of the methods. RESULTS: All three models produced point estimates close to the true parameter, i.e. the estimators of the parameter associated with exposure had negligible bias. The Cox regression produced standard errors that were too large, especially when the prevalence of the disease was high, whereas the log-binomial model and the GEE-logistic model had the correct type I error probabilities. It was shown by example that the GEE-logistic model could produce prevalences greater than one, whereas it was proven that this could not happen with the log-binomial model. The log-binomial model should be preferred.

Randomized, placebo controlled trial of withdrawal of slow-acting antirheumatic drugs and of observer bias in rheumatoid arthritis.

Patients with rheumatoid arthritis, in stable treatment with methotrexate, penicillamine, or sulfasalazine, were randomized in a double-blind fashion either to continuation of their usual treatment or to placebo. 112 patients were included; 52 patients who refused participation had no more severe disease than the others. The patients felt worse on placebo than on active drug (p = 0.002). The mean differences in number of tender, painful and swollen joints after one month were 2.4 (p = 0.08), 3.0 (p = 0.12) and 2.2 (p = 0.03), respectively. Treatment failure occurred for 42 patients of whom 33 received placebo (p = 0.000,001). There was no difference in the severity of side effects (p = 0.91). The patients guessed their treatment correctly more often than expected (p = 0.02) because of the perceived effect. None of the two observers guessed better than chance, and there were no differences between the observers' evaluations of the joints. The effect of slow-acting antirheumatic drugs was unequivocal and no observer bias occurred.