All-Cause and Cause-Specific Mortality among Users of Basal Insulins NPH,Detemir, and Glargine

Background

Insulin therapy in type 2 diabetes may increase mortality and cancer incidence, but the impact of different types of basal insulins on these endpoints is unclear. Compared to the traditional NPH insulin, the newer, longer-acting insulin analogues detemir and glargine have shown benefits in randomized controlled trials. Whether these advantages translate into lower mortality among users in real life is unknown.

Objective

To estimate the differences in all-cause and cause-specific mortality rates between new users of basal insulins in a population-based study in Finland.

Methods

23 751 individuals aged ≥40 with type 2 diabetes, who initiated basal insulin therapy in 2006–2009 were identified from national registers, with comprehensive data for mortality, causes of death, and background variables. Propensity score matching was performed on characteristics. Follow-up time was up to 4 years (median 1.7 years).

Results

2078 deaths incurred. With NPH as reference, the adjusted HRs for all-cause mortality were 0.39 (95% CI, 0.30–0.50) for detemir, and 0.55 (95% CI, 0.44–0.69) for glargine. As compared to glargine, the HR was 0.71 (95% CI, 0.54–0.93) among detemir users. Compared to NPH, the mortality risk for both cardiovascular causes as well as cancer were also significantly lower for glargine, and especially for detemir in adjusted analysis. Furthermore, the results were robust in various sensitivity analyses.

Conclusion

In real clinical practice, mortality was substantially higher among users of NPH insulin as compared to insulins detemir or glargine. Considering the large number of patients who require insulin therapy, this difference in risk may have major clinical and public health implications. Due to limitations of the observational study design, further investigation using an interventional study design is warranted.     

Incidence of Type 2 Diabetes in Pre-Diabetic Japanese Individuals Categorized by HbA1c Levels: A Historical Cohort Study

Objective

Reported incidence of type 2 diabetes estimated at the pre-diabetic stage differs widely (2.3–18.1% per year). Because clinicians need to know the risk of incident diabetes after a diagnosis of pre-diabetes, our objective was to estimate precise incidence of diabetes using baseline HbA_1c levels.

Methods

A historical cohort study using electronic medical record data obtained between January 2008 and December 2013. A total of 52,781 individuals with HbA_1c < 6.5% were assigned to one of six groups categorized by baseline HbA_1c level: ≤ 5.5% (n=34,616), 5.6–5.7% (n=9,388), 5.8–5.9% (n=4,664), 6.0–6.1% (n= 2,338), 6.2–6.3% (n=1,257), and 6.4% (n=518). Participants were tracked until a subsequent diagnosis of diabetes or end of follow-up during a period of 5 years.

Results

During the follow-up period (mean 3.7 years), 4,369 participants developed diabetes. The incidence of diabetes in the first year was 0.7, 1.5, 2.9, 9.2, 30.4, and 44.0% in the six HbA_1c groups, respectively. At five years the incidence was 3.6, 8.9, 13.8, 27.5, 51.6, and 67.8%, respectively (p < 0.0001 comparing the HbA_1c ≤5.5% group to the other groups). After adjustment for confounding factors, the hazard ratios compared with the HbA_1c ≤5.5% group were significantly elevated: 2.3 (95%CI 2.0–2.5), 3.4 (95%CI 2.9–3.7), 8.8 (95%CI 8.0–10.1), 26.3 (95%CI 23.3–30.1), and 48.7 (95%CI 40.8–58.1) in the five HbA_1c groups (p < 0.0001).

Conclusion

By fractionating baseline HbA_1c levels into narrower HbA_1c range groups, accuracy of estimating the incidence of type 2 diabetes in subsequent years was increased. The risk of developing diabetes increased with increasing HbA_1c levels, especially with the HbA_1c level ≥ 6.2% in the first follow-up year.     

Association between insomnia symptoms and hemoglobin A1c level in Japanese men

Background

The evidence for an association between insomnia symptoms and blood hemoglobin A_1c (HbA_1c) level has been limited and inconclusive. The aim of this study was to assess whether each symptom of initial, middle, and terminal insomnia influences HbA_1c level in Japanese men.

Methods

This cross-sectional study examined 1,022 male workers aged 22–69 years with no history of diabetes at a Japanese company''s annual health check-up in April 2010. High HbA_1c was defined as a blood level of HbA_1c ≥6.0%. Three types of insomnia symptoms (i.e., difficulty in initiating sleep, difficulty in maintaining sleep, and early morning awakening) from the previous month were assessed by 3 responses (i.e., lasting more than 2 weeks, sometimes, and seldom or never [reference group]).

Results

The overall prevalence of high HbA_1c was 5.2%. High HbA_1c was positively and linearly associated with both difficulty in maintaining sleep (P for trend  = .002) and early morning awakening (P for trend  = .007). More specifically, after adjusting for potential confounding factors, high HbA_1c was significantly associated with difficulty in maintaining sleep lasting more than 2 weeks (adjusted odds ratio, 6.79 [95% confidence interval, 1.86–24.85]) or sometimes (2.33 [1.19–4.55]). High HbA_1c was also significantly associated with early morning awakening lasting more than 2 weeks (3.96 [1.24–12.59]).

Conclusion

Insomnia symptoms, particularly difficulty in maintaining sleep and early morning awakening, were found to have a close association with high HbA_1c in a dose-response relationship.     

Fructosamine Is a Useful Indicator of Hyperglycaemia and Glucose Control in Clinical and Epidemiological Studies – Cross-Sectional and Longitudinal Experience from the AMORIS Cohort

Context

Fructosamine is a glycemic biomarker which may be useful for indication and control of diabetes respectively.

Objective

The objective of the study was to evaluate fructosamine as an indicator of hyperglycaemia and glucose control in subjects with diabetes.

Design, Setting & Patients

From the AMORIS cohort, subjects with serum glucose, fructosamine and HbA_1c from the same examination were studied cross-sectionally and longitudinally (n = 10,987; 5,590 overnight-fasting). The guidelines of the American Diabetes Association were followed for classification of prediabetes and diabetes. Separate analyses were performed in patients with a newly detected or a known diagnosis of type 1 or type 2 diabetes respectively.

Results

All three biomarkers were strongly correlated. With regard to the association between fructosamine and HbA_1c Pearson linear correlation coefficients in the range of 0.67–0.75 were observed in fasting and non-fasting subjects with type 1 or type 2 diabetes. Analyses of glucose control in fasting patients with type 2 diabetes having all three biomarkers measured at three separate occasions within on average 290 days of the index examination showed similar trends over time for glucose, fructosamine and HbA_1c. Discrimination of subjects with and without diabetes across the range of fructosamine levels was good (area under curve (AUC) 0.91–0.95) and a fructosamine level of 2.5 mmol/L classified subjects to diabetes with a sensitivity of 61% and a specificity of 97%.

Conclusions

Fructosamine is closely associated with HbA_1c and glucose respectively and may be a useful biomarker of hyperglycaemia and glucose control in clinical and epidemiological studies.     

Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis

Background

Although insulin analogues are commonly prescribed for the management of diabetes mellitus, there is uncertainty regarding their optimal use. We conducted meta-analyses to compare the outcomes of insulin analogues with conventional insulins in the treatment of type 1, type 2 and gestational diabetes.

Methods

We updated 2 earlier systematic reviews of the efficacy and safety of rapid-and long-acting insulin analogues. We searched electronic databases, conference proceedings and “grey literature” up to April 2007 to identify randomized controlled trials that compared insulin analogues with conventional insulins. Study populations of interest were people with type 1 and type 2 diabetes (adult and pediatric) and women with gestational diabetes.

Results

We included 68 randomized controlled trials in the analysis of rapid-acting insulin analogues and 49 in the analysis of long-acting insulin analogues. Most of the studies were of short to medium duration and of low quality. In terms of hemoglobin A_1c, we found minimal differences between rapid-acting insulin analogues and regular human insulin in adults with type 1 diabetes (weighted mean difference for insulin lispro: –0.09%, 95% confidence interval [CI] –0.16% to –0.02%; for insulin aspart: –0.13%, 95% CI –0.20% to –0.07%). We observed similar outcomes among patients with type 2 diabetes (weighted mean difference for insulin lispro: –0.03%, 95% CI –0.12% to –0.06%; for insulin aspart: –0.09%, 95% CI –0.21% to 0.04%). Differences between long-acting insulin analogues and neutral protamine Hagedorn insulin in terms of hemoglobin A_1c were marginal among adults with type 1 diabetes (weighted mean difference for insulin glargine: –0.11%, 95% CI –0.21% to –0.02%; for insulin detemir: –0.06%, 95% CI –0.13% to 0.02%) and among adults with type 2 diabetes (weighted mean difference for insulin glargine: –0.05%, 95% CI –0.13% to 0.04%; for insulin detemir: 0.13%, 95% CI 0.03% to 0.22%). Benefits in terms of reduced hypoglycemia were inconsistent. There were insufficient data to determine whether insulin analogues are better than conventional insulins in reducing long-term diabetes-related complications or death.

Interpretation

Rapid-and long-acting insulin analogues offer little benefit relative to conventional insulins in terms of glycemic control or reduced hypoglycemia. Long-term, high-quality studies are needed to determine whether insulin analogues reduce the risk of long-term complications of diabetes.Diabetes mellitus is associated with serious long-term complications and premature death.¹ Data from the Health Canada National Diabetes Surveillance System indicate that, in 2004/05, diabetes was diagnosed in about 5.5% (1.8 million) of Canadians aged 20 years and older.² Because the disease goes undetected in many cases, the true prevalence may approach 1.9 million.³Tight glycemic control, to maintain a hemoglobin A_1c concentration of 7.0% or less, is recommended for all patients with diabetes to reduce the risk of long-term complications such as cardiovascular-related death, retinopathy and nephropathy.⁴ Insulin is indicated for all patients with type 1 diabetes and for patients with type 2 diabetes if adequate glycemic control cannot be achieved through exercise, diet or oral antidiabetic therapy.⁴Conventional insulins include regular human insulin and intermediate-acting neutral protamine Hagedorn insulin. However, these agents do not replicate the pattern of basal and postprandial endogenous secretion of insulin. Insulin analogues are modified human insulins developed to address this limitation.⁵ The rapid-acting insulin analogues insulin lispro, insulin aspart and insulin glulisine are marketed in Canada as bolus insulins; the long-acting agents insulin glargine and insulin detemir are marketed as basal insulins.⁶Systematic reviews of the insulin analogues have been published previously.^7–10 However, through our comprehensive search of the literature, we did not identify any reviews of long-acting insulin analogues in the management of type 1 diabetes or gestational diabetes. In this article, we provide an up-to-date, comprehensive systematic review and meta-analysis of outcomes associated with the use of rapid-and long-acting insulin analogues in type 1 and type 2 diabetes (adult and pediatric patients) and gestational diabetes. Detailed methods and complete results are reported elsewhere.^11,12     

Effectiveness of a Supportive Telephone Counseling Intervention in Type 2 Diabetes Patients: Randomized Controlled Study

Objectives

This randomized controlled trial investigated whether a patient-centered supportive counseling intervention comprising monthly telephone-based counseling sessions by practice nurses over 12 months improved diabetes-related medical and psycho-social outcomes above usual care in type 2 diabetes patients with poor glycemic control at baseline (HbA_1c >7.5%) in a primary care setting.

Research Design

Patients were individually randomized into intervention (n = 103) and usual care group (n = 101). The primary outcome was change in HbA_1c-concentration after 12 and 18 months. Secondary outcomes were lipid levels, blood pressure, health-related quality of life and symptoms of depression. Follow-up-measurements were carried out after 6, 12 and 18 months to assess potential immediate and maintained effects of the intervention. For the multivariate analysis, hierarchical linear models were computed for each outcome to assess within-group changes in outcomes over time and between-group differences in patterns of change.

Results

HbA_1c (in %) decreased significantly from baseline to 12-month follow-up measurement both in the intervention (−0.44) and the usual care group (−0.51), but there was no significant between-group intervention effect. Significant improvements in the intervention group along with significant between-group differences were seen for health-related quality of life and, transiently, for systolic blood pressure and depression.

Conclusions

Although we found no beneficial effect of the supportive telephone counseling in terms of a reduction of HbA_1c above usual care, our findings suggest some beneficial effects on cardiovascular risk factors, quality of life and depression. Continuous efforts might be needed to sustain improvements in patient outcomes.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00742547","term_id":"NCT00742547"}}NCT00742547     

Hemoglobin A1c and Arterial and Ventricular Stiffness in Older Adults

Objective

Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA_1c, an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes.

Research Design & Methods

Baseline HbA_1c was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA_1c and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures.

Results

HbA_1c was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA_1c was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM.

Conclusions

In this sample of older adults without diabetes, HbA_1c was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers.     

Characteristics of Glucose Metabolism in Nordic and South Asian Subjects with Type 2 Diabetes

Background

Insulin resistance and type 2 diabetes are more prevalent in people of South Asian ethnicity than in people of Western European origin. To investigate the source of these differences, we compared insulin sensitivity, insulin secretion, glucose and lipid metabolism in South Asian and Nordic subjects with type 2 diabetes.

Methods

Forty-three Nordic and 19 South Asian subjects with type 2 diabetes were examined with intra-venous glucose tolerance test, euglycemic clamp including measurement of endogenous glucose production, indirect calorimetry measuring glucose and lipid oxidation, and dual x-ray absorptiometry measuring body composition.

Results

Despite younger mean ± SD age (49.7±9.4 vs 58.3±8.3 years, p = 0.001), subjects of South Asian ethnicity had the same diabetes duration (9.3±5.5 vs 9.6±7.0 years, p = 0.86), significantly higher median [inter-quartile range] HbA_1c (8.5 [1.6] vs 7.3 [1.6] %, p = 0.024) and lower BMI (28.7±4.0 vs 33.2±4.7 kg/m², p<0.001). The South Asian group exhibited significantly higher basal endogenous glucose production (19.1 [9.1] vs 14.4 [6.8] µmol/kgFFM⋅min, p = 0.003). There were no significant differences between the groups in total glucose disposal (39.1±20.4 vs 39.2±17.6 µmol/kgFFM⋅min, p = 0.99) or first phase insulin secretion (AUC_{0–8 min}: 220 [302] vs 124 [275] pM, p = 0.35). In South Asian subjects there was a tendency towards positive correlations between endogenous glucose production and resting and clamp energy expenditure.

Conclusions

Subjects of South Asian ethnicity with type 2 diabetes, despite being younger and leaner, had higher basal endogenous glucose production, indicating higher hepatic insulin resistance, and a trend towards higher use of carbohydrates as fasting energy substrate compared to Nordic subjects. These findings may contribute to the understanding of the observed differences in prevalence of type 2 diabetes between the ethnic groups.     

Electronic Medical Record Cancer Incidence over Six Years Comparing New Users of Glargine with New Users of NPH Insulin

Background

Recent studies suggested that insulin glargine use could be associated with increased risk of cancer. We compared the incidence of cancer in new users of glargine versus new users of NPH in a longitudinal clinical cohort with diabetes for up to 6 years.

Methods and Findings

From all patients who had been regularly followed at Massachusetts General Hospital from 1/01/2005 to 12/31/2010, 3,680 patients who had a medication record for glargine or NPH usage were obtained from the electronic medical record (EMR). From those we selected 539 new glargine users (age: 60.1±13.6 years, BMI: 32.7±7.5 kg/m²) and 343 new NPH users (61.5±14.1 years, 32.7±8.3 kg/m²) who had no prevalent cancer during 19 months prior to glargine or NPH initiation. All incident cancer cases were ascertained from the EMR requiring at least 2 ICD-9 codes within a 2 month period. Insulin exposure time and cumulative dose were validated. The statistical analysis compared the rates of cancer in new glargine vs. new NPH users while on treatment, adjusted for the propensity to receive one or the other insulin. There were 26 and 28 new cancer cases in new glargine and new NPH users for 1559 and 1126 person-years follow-up, respectively. There were no differences in the propensity-adjusted clinical characteristics between groups. The adjusted hazard ratio for the cancer incidence comparing glargine vs. NPH use was 0.65 (95% CI: 0.36–1.19).

Conclusions

Insulin glargine is not associated with development of cancers when compared with NPH in this longitudinal and carefully retrieved EMR data.     

Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study

Background

Despite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control.

Methodology/Principal Findings

One hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA_1c (HbA_1c) ≥8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA_1c after one year of treatment. At enrolment, mean (standard deviation) HbA_1c was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA_1c, 0.13% (−0.19; 0.44), p = 0.422; Total daily insulin dose, −5.7 U/day (−8.6; −2.9), p<0.001; body weight, −1.74 kg (−3.32; −0.17), p = 0.030. Minor and overall major hypoglycaemia was not significantly different between treatments. Treatments were well tolerated.

Conclusions/Significance

In patients with poorly controlled T1DM, adjunct metformin therapy did not provide any improvement of glycaemic control after one year. Nevertheless, adjunct metformin treatment was associated with sustained reductions of insulin dose and body weight. Further investigations into the potential cardiovascular-protective effects of metformin therapy in patients with T1DM are warranted.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00118937","term_id":"NCT00118937"}}NCT00118937     

Tumor Necrosis Factor-α, Matrix-Metalloproteinases 8 and 9 Levels in the Saliva Are Associated with Increased Hemoglobin A1c in Type 1 Diabetes Subjects

Background

Type 1 diabetes (T1D) is an autoimmune disease resulting in the targeted destruction of pancreatic β-cells and permanent loss of insulin production. Proper glucose management results in better clinical outcomes for T1D and provides a strong rationale to identify non-invasive biomarkers indicative or predictive of glycemic control. Therefore, we investigated the association of salivary inflammation with HbA_1c in a T1D cohort.

Methods

Unstimulated saliva was collected from 144 subjects with T1D at the USF Diabetes Center. BMI, duration of diabetes, and HbA_1c were recorded during clinical visit. Levels of interleukin (IL)-1β, -6, -8, -10, IFN-γ, TNF-α, MMP-3, -8, and -9 were measured using multiplexing immunoassay analysis. To account for smoking status, salivary cotinine levels were also determined.

Results

Multiple linear (HbA_1c) and logistic (self-reported gingival condition) regression analyses were performed to examine the relationships between the Principal Component Analysis (PCA) components and HbA_1c and gingival condition (adjusted for age, duration of diabetes, BMI, and sex; model for HbA_1c also adjusted for gingival condition and model for gingival condition also adjusted for HbA_1c). PCA components 1 (MMP-8 and MMP-9) and 3 (TNF-α) were significantly associated with HbA_1c (β = 0.28 ±0.14, p = 0.045; β = 0.31 ±0.14, p = 0.029), while PCA component 2 (IL-6, IL-1β, and IL-8) was significantly associated with gingival condition (OR 1.60 95% CI 1.09–2.34, p = 0.016). In general, increased salivary inflammatory burden is associated with decreased glycemic control and self-reported gingival condition.

Conclusions

The saliva may represent a useful reservoir of novel noninvasive inflammatory biomarkers predictive of the progression and control of T1D.     

Effectiveness of a Training Course for General Practice Nurses in Motivation Support in Type 2 Diabetes Care: A Cluster-Randomised Trial

Background

Type 2 diabetes is a common metabolic disease with the potential for prevention of complications. The prevention requires a high level of lasting actions from the patients, which may be burdensome. The aim of this trial was to evaluate the effectiveness of a training course for general practice nurses in motivation support at 18 months follow-up in the affiliated type 2 diabetes population.

Methods

Forty general practices with nurse-led diabetes consultations from the area of Aarhus, Denmark were randomised 1∶1 to either intervention or usual practice. Intervention practices were offered a 16-hour Self-determination theory - based course including communication training for general practice nurses delivered over 10 months. The affiliated diabetes populations (aged 40–74 years) were identified from registers (intervention n = 2,005; usual n = 2,029). Primary outcomes were register-based glycated haemoglobin (HbA_1c) -, total cholesterol levels, and well-being measured by the Problem Areas In Diabetes scale (PAID) and the mental component summary score, SF12 (SF12, mcs). Intention-to-treat analyses were performed. Predefined subgroups analyses were performed.

Results

The differences between the intervention- and the control practices’ mean HbA_1c and total cholesterol at follow-up adjusted for baseline values and clustering were respectively: −0.02%-points (95% CI: −0.11 to 0.07; p: 0.67); 0.08 mmol/l (95% CI: 0.01 to 0.15; p: 0.02). Differences in median scores adjusted for clustering were for PAID: 1.25; p = 0.31 and SF12, mcs: 0.99; p = 0.15. Women in intervention practices differed from women in usual practices on mean HbA_1c: −0.12%-points (−0.23 to −0.02; p = 0.02) and SF12, mcs: 2.6; p = 0.01.

Conclusions

Offering a training course for general practice nurses in applying the Self-determination theory in current type 2 diabetes care had no effect compared with usual practice measured by HbA_1c and total cholesterol levels and the well-being at 18 months of follow-up in a comprehensive register-based diabetes population. Subgroup analyses suggested a possible effect in women, which deserves further attention.

Trial Registration

ClinicalTrials.gov (Identifier {"type":"clinical-trial","attrs":{"text":"NCT01187069","term_id":"NCT01187069"}}NCT01187069).     

Four-Year Durability of Initial Combination Therapy with Sitagliptin and Metformin in Patients with Type 2 Diabetes in Clinical Practice; COSMIC Study

Objectives

We investigated the efficacy of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes for 4 years in clinical practice.

Methods

Between 2009 and 2010, we reviewed 1,178 patients with type 2 diabetes (HbA_1c ≥7.5% or 58 mmol/mol) prescribed initial combination therapy with sitagliptin and metformin. After excluding 288 patients without a second follow-up, 890 individuals (age, 58.0 ± 12.5 years; BMI, 25.4 ± 3.5 kg/m²; HbA_1c, 8.6 ± 1.1%) were followed up with every 3–6 months for 4 years. Homeostasis model assessments for insulin resistance and β-cell function (HOMA-β) were recorded at baseline. The response criterion was HbA_1c reduction by ≥0.8% from baseline or attainment of the target HbA_1c (≤7.0% or 53 mmol/mol). At the end of every year of treatment, changes in HbA_1c from the baseline were assessed.

Results

After 1 year, 72.2% of patients with initial combination therapy had responded, defined as HbA_1c reduction ≥0.8% or attainment of the target HbA_1c ≤7.0%. After 4 years, 35.4% of the patients still showed a response, with an HbA_1c level of 7.0 ± 0.9%. A high HbA_1c level at baseline was the most significant independent predictor of the long-term response (P<0.001). In addition, low HOMA-β was a significant predictor of a greater reduction in HbA_1c. This treatment was generally well tolerated over the 4-year follow-up period, without any serious adverse events.

Conclusions

This real-world follow-up study shows a persistent glucose-reducing effect of initial combination therapy with sitagliptin and metformin for up to 4 years.     

Early markers of glycaemic control in children with type 1 diabetes mellitus

Background

Type 1 diabetes mellitus (T1DM) may lead to severe long-term health consequences. In a longitudinal study, we aimed to identify factors present at diagnosis and 6 months later that were associated with glycosylated haemoglobin (HbA_1c) levels at 24 months after T1DM diagnosis, so that diabetic children at risk of poor glycaemic control may be identified.

Methods

229 children <15 years of age diagnosed with T1DM in the Auckland region were studied. Data collected at diagnosis were: age, sex, weight, height, ethnicity, family living arrangement, socio-economic status (SES), T1DM antibody titre, venous pH and bicarbonate. At 6 and 24 months after diagnosis we collected data on weight, height, HbA_1c level, and insulin dose.

Results

Factors at diagnosis that were associated with higher HbA_1c levels at 6 months: female sex (p<0.05), lower SES (p<0.01), non-European ethnicity (p<0.01) and younger age (p<0.05). At 24 months, higher HbA_1c was associated with lower SES (p<0.001), Pacific Island ethnicity (p<0.001), not living with both biological parents (p<0.05), and greater BMI SDS (p<0.05). A regression equation to predict HbA_1c at 24 months was consequently developed.

Conclusions

Deterioration in glycaemic control shortly after diagnosis in diabetic children is particularly marked in Pacific Island children and in those not living with both biological parents. Clinicians need to be aware of factors associated with poor glycaemic control beyond the remission phase, so that more effective measures can be implemented shortly after diagnosis to prevent deterioration in diabetes control.     

Life Expectancy in a Large Cohort of Type 2 Diabetes Patients Treated in Primary Care (ZODIAC-10)

Background

Most longitudinal studies showed increased relative mortality in individuals with type 2 diabetes mellitus until now. As a result of major changes in treatment regimes over the past years, with more stringent goals for metabolic control and cardiovascular risk management, improvement of life expectancy should be expected. In our study, we aimed to assess present-day life expectancy of type 2 diabetes patients in an ongoing cohort study.

Methodology and Principal Findings

We included 973 primary care type 2 diabetes patients in a prospective cohort study, who were all participating in a shared care project in The Netherlands. Vital status was assessed from May 2001 till May 2007. Main outcome measurement was life expectancy assessed by transforming actual survival time to standardised survival time allowing adjustment for the baseline mortality rate of the general population. At baseline, mean age was 66 years, mean HbA_1c 7.0%. During a median follow-up of 5.4 years, 165 patients died (78 from cardiovascular causes), and 17 patients were lost to follow-up. There were no differences in life expectancy in subjects with type 2 diabetes compared to life expectancy in the general population. In multivariate Cox regression analyses, concentrating on the endpoints ‘all-cause’ and cardiovascular mortality, a history of cardiovascular disease: hazard ratio (HR) 1.71 (95% confidence interval (CI) 1.23–2.37), and HR 2.59 (95% CI 1.56–4.28); and albuminuria: HR 1.72 (95% CI 1.26–2.35), and HR 1.83 (95% CI 1.17–2.89), respectively, were significant predictors, whereas smoking, HbA_1c, systolic blood pressure and diabetes duration were not.

Conclusions

This study shows a normal life expectancy in a cohort of subjects with type 2 diabetes patients in primary care when compared to the general population. A history of cardiovascular disease and albuminuria, however, increased the risk of a reduction of life expectancy. These results show that, in a shared care environment, a normal life expectancy is achievable in type 2 diabetes patients.     

Assessing Diabetes Self-Management with the Diabetes Self-Management Questionnaire (DSMQ) Can Help Analyse Behavioural Problems Related to Reduced Glycaemic Control

Aim

To appraise the Diabetes Self-Management Questionnaire (DSMQ)’s measurement of diabetes self-management as a statistical predictor of glycaemic control relative to the widely used SDSCA.

Methods

248 patients with type 1 diabetes and 182 patients with type 2 diabetes were cross-sectionally assessed using the two self-report measures of diabetes self-management DSMQ and SDSCA; the scales were used as competing predictors of HbA_1c. We developed a structural equation model of self-management as measured by the DSMQ and analysed the amount of variation explained in HbA_1c; an analogue model was developed for the SDSCA.

Results

The structural equation models of self-management and glycaemic control showed very good fit to the data. The DSMQ’s measurement of self-management showed associations with HbA_1c of –0.53 for type 1 and –0.46 for type 2 diabetes (both P < 0.001), explaining 21% and 28% of variation in glycaemic control, respectively. The SDSCA’s measurement showed associations with HbA_1c of –0.14 (P = 0.030) for type 1 and –0.31 (P = 0.003) for type 2 diabetes, explaining 2% and 10% of glycaemic variation. Predictive power for glycaemic control was significantly higher for the DSMQ (P < 0.001).

Conclusions

This study supports the DSMQ as the preferred tool when analysing self-reported behavioural problems related to reduced glycaemic control. The scale may be useful for clinical assessments of patients with suboptimal diabetes outcomes or research on factors affecting associations between self-management behaviours and glycaemic control.     

Validation of the IHE Cohort Model of Type 2 Diabetes and the Impact of Choice of Macrovascular Risk Equations

Background

Health-economic models of diabetes are complex since the disease is chronic, progressive and there are many diabetic complications. External validation of these models helps building trust and satisfies demands from decision makers. We evaluated the external validity of the IHE Cohort Model of Type 2 Diabetes; the impact of using alternative macrovascular risk equations; and compared the results to those from microsimulation models.

Methods

The external validity of the model was analysed from 12 clinical trials and observational studies by comparing 167 predicted microvascular, macrovascular and mortality outcomes to the observed study outcomes. Concordance was examined using visual inspection of scatterplots and regression-based analysis, where an intercept of 0 and a slope of 1 indicate perfect concordance. Additional subgroup analyses were conducted on ‘dependent’ vs. ‘independent’ endpoints and microvascular vs. macrovascular vs. mortality endpoints.

Results

Visual inspection indicates that the model predicts outcomes well. The UKPDS-OM1 equations showed almost perfect concordance with observed values (slope 0.996), whereas Swedish NDR (0.952) and UKPDS-OM2 (0.899) had a slight tendency to underestimate. The R ² values were uniformly high (>0.96). There were no major differences between ‘dependent’ and ‘independent’ outcomes, nor for microvascular and mortality outcomes. Macrovascular outcomes tended to be underestimated, most so for UKPDS-OM2 and least so for NDR risk equations.

Conclusions

External validation indicates that the IHE Cohort Model of Type 2 Diabetes has predictive accuracy in line with microsimulation models, indicating that the trade-off in accuracy using cohort simulation might not be that large. While the choice of risk equations was seen to matter, each were associated with generally reasonable results, indicating that the choice must reflect the specifics of the application. The largest variation was observed for macrovascular outcomes. There, NDR performed best for relatively recent and well-treated patients, while UKPDS-OM1 performed best for the older UKPDS cohort.     

Lower Rate of Cardiovascular Complications in Patients on Bolus Insulin Analogues: A Retrospective Population-Based Cohort Study

Background

Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases.

Methods

A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. The incidence of diabetic complications was ascertained by hospital discharge claims. Hazard ratios (HRs) and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients’ characteristics and anti-diabetic drug use. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups.

Results

A total of 2,286 patients were included: 914 receiving human regular insulin and 1,372 rapid-acting insulin analogues. During the follow-up, 286 (31.3%) incident events occurred in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group. After propensity score-based matched-pair analyses, rapid-acting insulin analogues users had a HR of 0.73 (0.58–0.92) for any diabetes-related complication and HRs of 0.73 (0.55–0.93) and 0.55 (0.32–0.96) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications.

Conclusions

Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.     

Inverse Association between Glycated Albumin and Insulin Secretory Function May Explain Higher Levels of Glycated Albumin in Subjects with Longer Duration of Diabetes

Background

Glycated albumin (GA) has been increasingly used as a reliable index for short-term glycemic monitoring, and is inversely associated with β-cell function. Because the pathophysiologic nature of type 2 diabetes (T2D) is characterized by progressive decline in insulin secretion, the aim was to determine whether GA levels were affected by diabetes duration in subjects with T2D.

Methods

To minimize the effect of glucose variability on GA, subjects with stably maintained HbA_1c levels of <0.5% fluctuation across 6 months of measurements were included. Patients with newly diagnosed T2D (n = 1059) and with duration>1 year (n = 781) were recruited and categorized as New-T2D and Old-T2D, respectively. Biochemical, glycemic, and C-peptide parameters were measured.

Results

GA levels were significantly elevated in HbA_1c-matched Old-T2D subjects compared to New-T2D subjects. Duration of diabetes was positively correlated with GA, whereas a negative relationship was found with C-peptide increment (ΔC-peptide). Among insulin secretory indices, dynamic parameters such as ΔC-peptide were inversely related to GA (r = −0.42, p<0.001). Multiple linear regression analyses showed that duration of diabetes was associated with GA (standardized β coefficient [STDβ] = 0.05, p<0.001), but not with HbA_1c (STDβ = 0.04, p<0.095). This association disappeared after additional adjustment with ΔC-peptide (STDβ = 0.02, p = 0.372), suggesting that β-cell function might be a linking factor of close relationship between duration of diabetes and GA values.

Conclusions

The present study showed that GA levels were significantly increased in subjects with longer duration T2D and with decreased insulin secretory function. Additional caution should be taken when interpreting GA values to assess glycemic control status in these individuals.