A review of 25 years' experience with the NovoPen family of insulin pens in the management of diabetes mellitus.

NovoPen, the first insulin pen, was introduced in 1985. This review article is an update of a review paper published in 2006 on 20 years' use of the NovoPen family of insulin pens in the management of diabetes mellitus. The literature searches conducted in the earlier review article were updated with search results for new articles published since April 2005. This was followed by an iterative search of references cited in identified publications and by searches of abstracts from proceedings of major international diabetes conferences since 2005. Most of the original studies identified in the 2006 review showed that insulin regimens using the NovoPen family of insulin pens were at least as effective (and in some cases superior) in maintaining glycaemic control and were as safe (in terms of hypoglycaemia) as conventional insulin regimens employing vials and syringes. Most patients preferred the various NovoPen insulin pens over vials and syringes, with some evidence suggesting that the use of discreet devices, such as those of the NovoPen family, facilitates intensive insulin therapy regimens, thereby helping to improve lifestyle flexibility. The new search results showed that the current generation of the device for the adult population, NovoPen 4, retains these benefits and further meets patients' needs by improving ease of use, convenience and discretion, which may be particularly important for those with manual dexterity, visual or auditory impairments. There was also evidence that healthcare professionals would be more likely to recommend NovoPen 4 to their patients than other devices. The recently introduced NovoPen Echo, designed specifically for the paediatric population, combines half-increment dosing with a memory function that can be used to retrieve information about the time and amount of the last dose, potentially reducing the fear of double dosing or missing a dose. Evidence obtained from the new searches suggested that paediatric patients, their parents and healthcare professionals were highly satisfied with NovoPen Echo overall, with most paediatric patients rating it their favourite pen compared with other insulin pens. In conclusion, new data published over the last 5 years on the use of NovoPen devices add to the large body of published evidence supporting the patient-related benefits of durable insulin injection pens in the treatment of diabetes since the first such pen was introduced in 1985. Together, the benefits of NovoPen are considered likely to improve both patients' quality of life and their compliance with therapy.

Insulin degludec/insulin aspart versus biphasic insulin aspart 30 twice daily in insulin-experienced Japanese subjects with uncontrolled type 2 diabetes: Subgroup analysis of a Pan-Asian, treat-to-target Phase 3 Trial.

BACKGROUND: The present study was a subgroup analysis of a Pan-Asian Phase 3 open-label randomized treat-to-target trial evaluating insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) in Japanese subjects with type 2 diabetes inadequately controlled on insulin. METHODS: Eligible subjects (n = 178) were randomized (2: 1) to twice-daily (b.i.d.) IDegAsp or BIAsp 30 with or without metformin for 26 weeks, titrated to a blood glucose target of between 3.9 and <5.0 mmol/L. Changes in HbA1c , the proportion of responders reaching the HbA1c target, and changes in fasting plasma glucose, nine-point self-monitored plasma glucose profiles, and body weight were assessed. RESULTS: At 26 weeks, the decrease in HbA1c was similar in both groups. Fasting plasma glucose was lower with IDegAsp than BIAsp 30 (estimated treatment difference -1.50 mmol/L; 95 % confidence interval [CI] -1.98, -1.01). Overall confirmed hypoglycemia rates were similar; the nocturnal confirmed hypoglycemia rate was lower with IDegAsp than BIAsp 30 (estimated rate ratio 0.44; 95 % CI 0.20, 0.99). No severe hypoglycemic episodes were reported. CONCLUSIONS: The results indicate that IDegAsp b.i.d. improves glycemic control and, compared with BIAsp 30, lowers the rate of nocturnal confirmed hypoglycemia.

Diabetes management and daily functioning burden of non-severe hypoglycemia in Japanese people treated with insulin.

AIMS/INTRODUCTION: The present study investigated the impact of non-severe hypoglycemic events (NSHE) on patients' diabetes management, daily functioning and well-being. MATERIALS AND METHODS: A survey assessing the impact of NSHEs was completed by insulin-treated Japanese people with diabetes, aged ≥20 years with self-reported diabetes, who had experienced at least one NSHE in the past 3 months. Survey questions captured reasons for and the length of the event, and impacts on diabetes management, daily functioning, sleep and well-being. RESULTS: A total of 3,145 people with type 1 diabetes mellitus and type 2 diabetes mellitus were screened, of which 411 respondents were eligible. Increased glucose monitoring was reported by 57 and 54% of respondents after daytime and night-time NSHE, respectively. The average number of additional glucose monitoring tests was 2.4 and 3.0 for daytime and night-time NSHE. Among all respondents, 19% (daytime) and 16% (night-time) changed their insulin dose after an NSHE. After a daytime NSHE, 25% of respondents reported a negative impact on their daily activities or work. After a night-time NSHE, 34 and 23% of respondents reported a negative impact on sleep and next day emotional state, respectively. CONCLUSIONS: NSHEs have a negative impact on the diabetes management, daily functioning, sleep and well-being of Japanese patients.

Insulin Degludec in Clinical Practice: A Review of Japanese Real-World Data.

INTRODUCTION: In this literature review we evaluated the real-world clinical effectiveness of switching Japanese diabetic patients from their current insulin regimen to insulin degludec (IDeg). METHODS: Studies were identified from Japanese Diabetes Society (JDS) abstracts (2014-2015) and PubMed (2012 onwards). Inclusion criteria were: Japanese population, >15 participants, and studies switching patients from basal or basal-bolus insulin regimens to IDeg. Randomized controlled trials and case reports were excluded. Weighted mean changes in safety and effectiveness endpoints were calculated using the number of patients in each study. RESULTS: In total, 81 JDS abstracts and seven manuscripts met the search criteria, representing 4238 patients [1028 with type 1 diabetes (T1D), 602 with type 2 diabetes (T2D), 2608 with unspecified or mixed diabetes]. Glycated hemoglobin (HbA1c) was reported in 93% of studies, with an improvement in 84% of these (51% significant, 33% numerical), no change in 12%, and worsening in 4% (3% numerical, 1% significant). Across all studies, the weighted mean absolute change in HbA1c was -0.3% (-2.7 mmol/mol). Basal insulin dose was reported in 58% of studies and was lower in 60% of these (30% significant, 30% numerical), numerically unchanged in 26%, and higher in 14% (2% significant, 12% numerical). The weighted mean change in basal insulin dose was -4.8% and -3.0% for all studies and for studies with only significant results, respectively. The weighted mean change in basal dose based on all studies was -8.9, -5.5, and -2.9% for the T1D, T2D, and unspecified patient populations, respectively. Hypoglycemia was recorded in 31% of the studies. After switching treatment to IDeg, 55% of studies reported decreased hypoglycemia, 29% no change, and 16% an increase. Quality of life (QoL) was measured in 11% of studies, of which 82% reported improved QoL after switching, and 18% reported no change in QoL. CONCLUSION: Switching from a conventional basal insulin to IDeg has the potential to improve HbA1c with a lower insulin dose. Switching to IDeg may also provide a reduced risk of hypoglycemia and improvement in QoL. FUNDING: Novo Nordisk.

Insulin degludec in a simple or stepwise titration algorithm in a Japanese population of patients with type 2 diabetes: a randomized, 26-week, treat-to-target trial.

AIMS: Managing insulin therapy is a challenge for both patients and healthcare providers.The primary aim of this trial was to compare the efficacy and safety of insulin degludec (IDeg) in a fixed versus flexible dosing schedule. The secondary aim and subject of this manuscript was to compare a simple versus a stepwise titration algorithm. MATERIALS AND METHODS: This was a 26-week, controlled, multicenter, open-label, randomized, treat-to-target phase 3b trial of Japanese patients with type 2 diabetes inadequately treated with insulin glargine and with/without antidiabetic drugs orally. The trial had a 2 × 2 factorial design whereby 458 patients were randomized 1:1:1:1 to one of two titration algorithms and one of two dosing schedules. IDeg dose was adjusted weekly using a clinician-led, treat-to-target approach in order to ensure optimal insulin titration and glycemic control following self-measured blood glucose (SMBG) readings. RESULTS: Mean insulin dose at the end of the trial was similar in both simple and stepwise titration algorithms. Glycemic control improved in both titration algorithms, with noninferiority in glycated hemoglobin (HbA1c) reduction confirmed when comparing simple and stepwise titration algorithms and no significant differences in fasting plasma glucose or SMBG at 26 weeks. No safety concerns were observed in terms of adverse events, and rates of hypoglycemia were not significantly different between the two algorithms. CONCLUSIONS: This trial demonstrated comparable efficacy with noninferior HbA1c and comparable safety of once-daily IDeg using either a simple or stepwise titration algorithm in Japanese patients with type 2 diabetes inadequately controlled with insulin glargine.

NovoPen Echo(®) insulin delivery device.

The introduction of insulin pen devices has provided easier, well-tolerated, and more convenient treatment regimens for patients with diabetes mellitus. When compared with vial and syringe regimens, insulin pens offer a greater clinical efficacy, improved quality of life, and increased dosing accuracy, particularly at low doses. The portable and discreet nature of pen devices reduces the burden on the patient, facilitates adherence, and subsequently contributes to the improvement in glycemic control. NovoPen Echo(®) is one of the latest members of the NovoPen(®) family that has been specifically designed for the pediatric population and is the first to combine half-unit increment (=0.5 U of insulin) dosing with a simple memory function. The half-unit increment dosing amendments and accurate injection of 0.5 U of insulin are particularly beneficial for children (and insulin-sensitive adults/elders), who often require small insulin doses. The memory function can be used to record the time and amount of the last dose, reducing the fear of double dosing or missing a dose. The memory function also provides parents with extra confidence and security that their child is taking insulin at the correct doses and times. NovoPen Echo is a lightweight, durable insulin delivery pen; it is available in two different colors, which may help to distinguish between different types of insulin, providing more confidence for both users and caregivers. Studies have demonstrated a high level of patient satisfaction, with 80% of users preferring NovoPen Echo to other pediatric insulin pens.

Efficacy and safety of once-daily insulin degludec dosed flexibly at convenient times vs fixed dosing at the same time each day in a Japanese cohort with type 2 diabetes: A randomized, 26-week, treat-to-target trial.

AIMS/INTRODUCTION: This trial assessed the efficacy and safety of the possibility of varying the daily injection time of once-daily, long-acting basal insulin degludec (IDeg) in Japanese patients with type 2 diabetes inadequately controlled with insulin glargine. MATERIALS AND METHODS: This was a 26-week, multicenter, open-label, randomized, treat-to-target trial, with a 2 × 2 factorial design comparing IDeg flexible (allowing dosing ±8 h from an agreed dosing time) with IDeg fixed dosing (at the same time each day). It was carried out in 458 adult patients who were inadequately controlled on insulin glargine with or without oral antidiabetic drugs. RESULTS: The majority of doses were taken within 2 h of the agreed dosing time, showing a high level of adherence among Japanese patients. After 26 weeks, IDeg flexible was non-inferior to IDeg fixed with respect to change in glycated hemoglobin from baseline, estimated treatment difference 0.08% points (95% confidence interval -0.05; 0.22). Fasting plasma glucose decreased to a similar level with IDeg flexible and IDeg fixed, estimated treatment difference -0.18 mmol/L (95% confidence interval -0.48; 0.12). The rates of confirmed and nocturnal confirmed hypoglycemia were numerically, but not significantly, higher with IDeg flexible vs IDeg fixed dosing. The rates of adverse events with IDeg flexible and IDeg fixed dosing were similar. CONCLUSIONS: These results showed the efficacy and safety of allowing patients to vary the time they dosed IDeg, when necessary, in Japanese patients with type 2 diabetes. Dosing of IDeg at a time convenient to the patient was non-inferior, with respect to glycated hemoglobin, to dosing at the same time each day.

Comparison of preference for NovoPen(®) 4 with previous insulin pen treatments after 12 weeks in adult patients with type 1 and type 2 diabetes: a multicenter observational study.

BACKGROUND: In separate randomized, crossover trials, patients with diabetes reported a preference for durable insulin pen NovoPen(®) 4 compared with NovoPen 3 and OptiClik(®). OBJECTIVE: This large post-marketing observational study evaluated treatment satisfaction with NovoPen 4 versus previous treatments, which included NovoPen 3 and other devices, in insulin-treated and insulin-naive patients. METHODS: During regular clinical practice in Canada, Germany, and the Netherlands, health care professionals assigned adult patients with type 1 or type 2 diabetes to treatment with insulin administered via NovoPen 4 after training according to the device's instruction manual. The primary end point was change in treatment satisfaction as determined by the Diabetes Treatment Satisfaction Questionnaire given to patients at the beginning and after 12 weeks of treatment. Two additional questionnaires were used at study end to identify why patients preferred either NovoPen 4 or their previously used insulin devices, which included NovoPen 3 and other devices (eg, HumaPen(®) Ergo and OptiPen(®) Pro). Adverse events were also recorded. RESULTS: Two thousand eighteen participants (mean age, 55 years; males, 53%; type 1/type 2 diabetes, 28%/71%; mean duration of disease, 13 years; previously on insulin, 89.8%; insulin-naïve, 2.9%) participated. NovoPen 3 was previously used by 1059, HumaPen Ergo by 256, OptiPen Pro by 217, and other devices by 385 patients. Diabetes Treatment Satisfaction Questionnaire scores increased from a mean (SD) baseline of 26.5 (7.2) to 30.5 (5.0) at study end for a median difference of 4.0 (95% CI, 3.5-4.5; Wilcoxon test score: 22.7; P < 0.0001). Over 70% of patients found NovoPen 4 easier to set, read, correct, inject the dose, and change the insulin cartridge than with their previously used device (P < 0.0001). A total of 83.8% rated NovoPen 4 easier to use overall (P < 0.0001). Health care professionals (97.2%) would recommend NovoPen 4 to other patients. No adverse events associated with the device were recorded. CONCLUSIONS: Patients reported a significant preference for NovoPen 4 compared with previous treatment with NovoPen 3 or other insulin device. The high ratings NovoPen 4 received for ease of use and learning could potentially lead to improved acceptance of and compliance with prescribed insulin therapy. Further study is warranted to determine the possible health benefits of using this insulin device.

[The effect of glucosamine sulphate on the blood levels of cholesterol or triglycerides--a clinical study]. / Glukosaminsulfat påvirker ikke plasmaniveauer af kolesterol og triglycerider--en klinisk undersøgelse.

INTRODUCTION: This study was conducted in order to determine if glucosamine sulphate taken by patients as treatment for chronic joint pain influences the fasting blood levels of cholesterol and triglycerides. MATERIALS AND METHODS: A 3 months', post-marketing, randomised, double-blinded, placebo-controlled, clinical trial was performed with parallel groups of 66 patients over 40 years of age with joint pain of long duration receiving either recommend dosage (1500 mg per day) of glucosamine sulphate or placebo. The primary outcome measures were cholesterol levels (total cholesterol, LDL (low density lipoprotein)-cholesterol and HDL (high density lipoprotein)-cholesterol) and triglycerides in fasting blood (plasma levels). Secondary outcome measures were self reported side-effects. RESULTS: No significant differences between the glucosamine sulphate group and the placebo group with respect to cholesterol and triglycerides were observed. There were no differences between the treatment groups with respect to side-effects. CONCLUSION: This study demonstrates that glucosamine sulphate does not significantly influence blood levels of cholesterol or triglycerides.

Topographic and zonal distribution of tenascin in human articular cartilage from femoral heads: normal versus mild and severe osteoarthritis.

OBJECTIVE: The extracellular matrix glycoprotein tenascin (TN) is upregulated in articular cartilage with severe osteoarthritis (OA). This study gives a detailed description of TN expression in areas of articular cartilage from femoral heads with mild OA showing structural lesions and in structurally normal areas of the same femoral heads compared with normal cartilage and cartilage with severe OA. METHODS: Immunohistochemical evaluation was performed on cryosections stained with antibodies against TN. Sections were selected as follows: from each macroscopically normal femoral head (n=6) a normal central and peripheral biopsy; from each femoral head with macroscopically mild OA (n=8) a central biopsy that showed structural lesions and a peripheral normal biopsy; from each femoral head with severe OA (n=9) a central and a peripheral biopsy with structural lesions. Central biopsies represent load bearing areas, whereas peripheral biopsies are non-load bearing. RESULTS: Central cartilage with mild OA contains significantly higher levels of TN in the superficial zone than structurally normal, peripheral cartilage from the same femoral heads. Normal cartilage and cartilage with severe OA do not display this topographic variation. Central cartilage with mild OA shows significantly higher levels of TN than normal, central cartilage. Peripheral, normal cartilage with mild OA shows significantly less TN than peripheral cartilage with severe OA. CONCLUSIONS: In femoral heads with mild OA, TN is accumulated in areas displaying structural damage. This proposes mild OA to be a localized disorder. Extreme caution is necessary for sampling of articular cartilage, especially from joints with mild OA.