Comparison of a twice daily injection of insulin aspart 50 with insulin aspart 30 in patients with poorly controlled type 2 diabetes

Objective: To compare the efficacy and safety of a twice daily injection of insulin aspart (BIAsp) 30 and BIAsp50 in patients with type 2 diabetes mellitus (T2DM) poorly controlled with oral hypoglycemic agents (OHAs).

Methods: In this 12 week prospective, randomized, parallel trial, a total of 80 T2DM patients, 59?±?10?years old with a disease duration of 9.3?±?6.6?years and HbA1c >7% despite large doses of metformin and sulfonylurea administration, were randomized to receive BIAsp30 (n?=?40) or BIAsp50 (n?=?40). The primary endpoint was a change in HbA1c at week 12.

Results: The changes in HbA1c from baseline were ?2.5%?±?1.0% in the BIAsp50 group and ?2.5%?±?1.2% in the BIAsp30 group (p?=?.897). No difference was observed in the rate of HbA1c target achievement (<7.0%) between BIAsp50 (42.5%) and BIAsp30 (32.5%) (p?=?.495). The change in fasting plasma glucose (FPG) in the BIAsp50 group was lower than that in the BIAsp30 group (p?<?.001), while the change in two-hour postprandial blood glucose (2hPBG) was higher and blood glucose excursion was lower in the BIAsp50 group than that in the BIAsp30 group (p?<?.001, p?<?.001). A significant improvement in HbA1c was observed with BIAsp50 in subgroups with baseline blood glucose excursion >7.8?mmol/L or 2hPBG >17.6?mmol/L compared with BIAsp30. There were no differences in hypoglycemia or body weight between groups.

Conclusions: Compared with BIAsp30, BIAsp50 showed greater efficacy in patients with baseline BG excursion >7.8?mmol/L or 2hPBG >17.6?mmol/L as well as good safety for hypoglycemia.

Clinical trial registration: ChiCTR-IIR-16008958.     

The selection of healthy volunteers for clinical investigation: the case for volunteer pools

SUMMARY

Objective: To compare the metabolic effects of rosiglitazone, an antidiabetic agent of the thiazolidinedione class, in patients with type 2 diabetes with fair to moderate glycaemic control (glycosylated haemoglobin (HbA1c)?<?9%) and poor glycaemic control (HbA1c?>?9%).

Research design and methods: Data were pooled from two 26-week, randomised, placebo-controlled, double-blind studies of rosiglitazone (4 and 8?mg/day).

Results: After 26 weeks of treatment, HbA1c was significantly reduced (p?<?0.05) compared with baseline and placebo in patients taking rosiglitazone 8mg/day for both HbA1c stratifications, with greater reductions in patients with baseline HbA1c >9%. After 26 weeks of treatment, reductions in fasting plasma glucose (FPG) were significant (p?<?0.05) compared with baseline and placebo in both rosiglitazone treatment groups for both HbA1c stratifications, with greater reductions in the group with poor glycaemic control. Rosiglitazone significantly improved insulin sensitivity (p?<?0.05) compared with baseline in patients with baseline HbA1c <9%. Rosiglitazone significantly improved beta-cell function (p?<?0.05) compared with baseline with more improvement in the group with baseline HbA1c >9%. These improvements were statistically significant compared with placebo, regardless of HbA1c stratification.

Conclusion: Rosiglitazone significantly improved HbA1c and FPG levels in patients with type 2 diabetes, with the greatest improvements observed in patients with baseline HbA1c levels >9%.     

Characteristics of patients with type 2 diabetes mellitus initiating insulin therapy: baseline data from the INSTIGATE study*

ABSTRACT

Objective: To describe the characteristics at baseline of patients with type 2 diabetes mellitus who are initiating insulin.

Methods: Prospective, observational multi-centre, open-label study in five European countries of patients with type 2 diabetes who were initiating insulin as part of their usual care.

Results: A total of 1172 patients were enrolled, with mean age 63.3 years and body mass index 29.9?kg/m². The majority (90%) of patients were taking one or more oral anti-diabetic agents; the percentage not taking anti-diabetic medication in the previous four weeks was highest in Germany (23.4%) and Spain (15.1%). The prevalence of microvascular diseases (range: 16.1%–36.1%) varied considerably between countries but for macrovascular (30.4%–38.6%) and other diabetes-related diagnoses (72.6%–76.6%) such as hypertension and dyslipidaemia the differences were less pronounced. In Germany, reported use of lipid-lowering (26.7%) and anti-platelet (27.1%) therapies was much less than in other countries (ranges: 53.2%–78.1% and 48.3%–61.1%, respectively). The majority of evaluable patients in each country had demonstrated poor control over a long period of time. Prior to initiating insulin, the most recent mean (±SD) HbA1_c was 9.58?±?1.81%, fasting plasma glucose was 12.18?±?4.32?mmol/L and 78.5% had metabolic syndrome. IDF targets for HDL- and LDL-cholesterol, and blood pressure were met in 76.8%, 33.1% and 18.9% of patients, respectively.

Conclusions: Insulin treatment was only initiated after HbA1_c values were considerably higher than recommended in treatment guidelines for a sustained period of time.     

Effects of a Fixed Mixture of 25% Insulin Lispro and 75% NPL on Plasma Glucose during and after Moderate Physical Exercise in Patients with Type 2 Diabetes

Summary

Objective: To compare the plasma glucose (PG) response with a fixed mixture of 25% insulin lispro and 75% NPL (Mix25), prior to a meal and 3?h before exercise, to human insulin 30/70 (30/70) in patients with type 2 diabetes.

Research design and methods: Thirty-seven patients were treated in a randomized, open-label, 8-week, two-period crossover study. Mix25 was injected 5?min before breakfast and dinner throughout the study, as was 30/70 on inpatient test days and on outpatient dose titration days. Following the 4-week outpatient phase, patients were hospitalized, and exercised at a heart rate of 120 beats/min on a cycle ergometer two times for 30?min, separated by 30?min rest, starting 3?h after a 339 kcal breakfast.

Results: The 2-h postprandial PG was significantly lower with Mix25 ((mean?±?SEM) 10.5?±?0.4 mmol/lvs 11.6?±?0.4 mmol/l; p?=?0.016). Maximum decrease in PG from onset of exercise to end of exercise was significantly less with Mix25 (-3.6?±?0.29 mmol/l vs -4.7?±?0.31 mmol/l; p?=?0.001). The maximum decrease in PG over 6?h, after exercise onset, was significantly less with Mix25 (-4.3?±?0.4 mmol/l vs -5.9?±?0.4 mmol/l; p?<?0.001). The frequency of hypoglycemia (blood glucose (BG) < 3 mmol/l or symptoms) during the inpatient test was not different between treatments. During the outpatient phase, the frequency of patient-recorded hypoglycemia was significantly lower with Mix25 (0.7?±?0.2 episodes/30d vs 1.2?±?0.3 episodes/30 d; p?=?0.042).

Conclusions: Mix25 resulted in better postprandial PG control without an increase in exercise-induced hypoglycemia. The smaller decrease in PG during the postprandial phase after exercise may suggest a lower risk of exercise-induced hypoglycemia with Mix25 than with human insulin 30/70, especially for patients in tight glycemic control.     

Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study

ABSTRACT

Objective: PREDICTIVE^* is a large, observational study of the empirical use of insulin detemir in patients with type 1 or type 2 diabetes (T1DM/T2DM). This post hoc analysis evaluates insulin-naïve patients with T2DM uncontrolled on oral antidiabetic drugs (OADs) who were initiated and remained on once-daily insulin detemir for 12 weeks.

Research design and methods: This observational, multinational, multi-center, open-label prospective study evaluated the efficacy and safety of insulin detemir in 1653 insulin-naïve patients with T2DM (mean age 60.8?±?10.9 years, BMI 29.8?±?4.8?kg/m², and HbA_1C 8.82?±?1.50%). Statistical comparisons were made between baseline and 12-week follow up data. Our study was subject to the usual limitations of observational studies.

Main outcome measures: Endpoints were: incidence of serious adverse drug reactions, including number of hypoglycemic events (total, major, and nocturnal), glycemic parameters, and weight change.

Results: Following insulin initiation, no significant change occurred in the number of nocturnal hypoglycemic events or total hypoglycemic events (p?=?0.4513), and no serious adverse drug reactions were observed during the 12 weeks of treatment. HbA_1C decreased by a mean 1.25% (SD?±?1.25%; p?<?0.0001), with 30% of patients (n?=?383) achieving HbA_1C <7% at 12 weeks. Mean changes in fasting blood glucose and fasting blood glucose variability were –3.62?mmol/L (SD?±?2.93; p?<?0.0001) and ?0.48?mmol/L (SD?±?1.03; p?<?0.0001), respectively. Body weight decreased by a mean 0.5?kg (SD?±?3.3; p?<?0.0001), with weight loss or no weight change occurring in a substantial percentage of patients in each BMI category (<25, 25–30, 30–35, and >35?kg/m²). Patients with higher baseline BMI lost the most weight, with the greatest weight loss (–1.20?kg) reported in those with BMI >35?kg/m².

Conclusions: Empirical use of insulin detemir as an insulin initiation strategy can improve glycemic control with good tolerability, including a low risk of hypoglycemia and a weight benefit, in a majority of insulin-naïve patients uncontrolled on OADs.     

Assessment of long-term immunological and pulmonary safety of inhaled human insulin with up to 24 months of continuous therapy

ABSTRACT

Background: This study was performed to characterize the long-term safety and efficacy of inhaled human insulin (EXU; Exubera (insulin human [rDNA origin]) Inhalation Powder).

Scope: Patients with type 1 or type 2 diabetes (N?=?1290) who had successfully completed one of six controlled EXU open-label trials elected to receive open-label treatment with EXU for up to 3 years, after which they were randomized to discontinue EXU or to continue therapy for 6 months, then discontinue. Immunologic safety was assessed by insulin antibody (IAb) binding, and pulmonary safety was assessed by tests for forced expiratory volume in 1 second (FEV₁) and carbon monoxide diffusing capacity (DL_CO). In addition, changes over time in IAbs were compared with changes in FEV₁, DL_CO, hypoglycemia, and efficacy.

Findings: Antibody binding increased in patients with either type 1 or type 2 diabetes after initiation of EXU and plateaued within 6–12 months (increases were higher in patients with type 1 diabetes than in patients with type 2 diabetes). Decreases in FEV₁ occurred primarily during the first 3–6 months of EXU therapy. Among adult patients in the All Subjects set, the mean (±?SE) annualized rate of decline in FEV₁ was ?0.053?±?0.007 liters/year (95% CI, ?0.065, ?0.040) in adult patients with type 1 diabetes, and ?0.076?±?0.005 liters/year (95% CI, ?0.085, ?0.067) in patients with type 2 diabetes. Changes in DL_CO occurred primarily during the first 3–6 months of EXU therapy. Among adult patients, in the All Subjects set, the mean (±?SE) annual decline in DL_CO was ?0.738?±?0.097?mL/min/mmHg/year (95% CI, ?0.927, ?0.548) and ?0.688?±?0.082 mL/min/mmHg/year (95% CI, ?0.849, ?0.527) in patients with type 1 and type 2 diabetes, respectively.

Antibody binding did not correlate with changes in glycemic control, lung function, dose, or hypoglycemia. Following discontinuation of EXU, IAbs decreased to near baseline levels.

Conclusion: These results are consistent with other trials showing long-term maintenance of safety and efficacy of EXU despite insulin antibody formation and small treatment group differences in pulmonary function. A limitation of the study was the lack of a comparator therapy.     

Effects of vildagliptin versus saxagliptin on daily acute glucose fluctuations in Chinese patients with T2DM inadequately controlled with a combination of metformin and sulfonylurea

Objective The present study aimed to compare the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin and saxagliptin on 24?hour acute glucose fluctuations in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with a combination of metformin and sulfonylurea.

Research design and methods This was a 24 week, prospective, randomized, open-label, active-controlled study. Patients (N?=?73) with T2DM who had inadequate glycemic control (HbA1c 7.0%–10.0%) with a stable dosage of metformin plus gliclazide for more than 3 months were randomized to receive either vildagliptin 50?mg twice daily (BID, n?=?37) or saxagliptin 5?mg once daily (QD, n?=?36). Change in mean amplitude of glycemic excursions (MAGE) was assessed at the end of 24 weeks.

Results At baseline, the mean (±SD) age was 62.9?±?6.55 years, disease duration was 7.0?±?2.33 years, and HbA1c was 8.4?±?0.68%. After 24 weeks of treatment, the MAGE decreased from 5.81?±?1.16?mmol/L to 4.06?±?0.86?mmol/L (p<0.001) in the vildagliptin group and from 5.66?±?1.14?mmol/L to 4.79?±?1.25?mmol/L (p?=?0.003) in the saxagliptin group. The mean change in MAGE in the vildagliptin group was significantly greater than that in the saxagliptin group (1.74?±?0.48?mmol/L vs. 0.87?±?0.40?mmol/L, p<0.001). The mean change in HbA1c, from baseline to the study endpoint, in the vildagliptin and saxagliptin groups, was 1.22?±?0.40% and 1.07?±?0.36%, respectively, with no significant difference between the groups (p?=?0.091). The overall safety and tolerability of vildagliptin and saxagliptin were similar. The limitations of the study were a small number of patients and open-label administration of the study drug.

Conclusion Vildagliptin produced a significantly greater reduction in acute glucose fluctuations compared with saxagliptin when added to a dual combination of metformin and sulfonylurea in Chinese patients with T2DM.

Chinese clinical trial registration number ChiCTR-TRC-13003858.     

Initial combination therapy with vildagliptin plus metformin in drug-naïve patients with T2DM: a 24-week real-life study from Asia

Aims: To assess the effectiveness and safety of vildagliptin/metformin initial combination therapy in drug-naïve patients with type 2 diabetes mellitus (T2DM).

Methods: INITIAL was a 24-week prospective, observational study in T2DM patients with glycated hemoglobin (HbA1c)?≥?7.5%, and prescribed vildagliptin/metformin as initial combination therapy. The primary endpoint was change in HbA1c from baseline to week 24. Key secondary endpoints were HbA1c change from baseline to week 12, proportion of patients achieving HbA1c ≤7.0%, change in body weight at 12 and 24 weeks, change in HbA1c by sub-groups (baseline HbA1c, age, body mass index [BMI], dosage strength, co-morbidities) from baseline to week 24, and safety.

Results: A total of 532 patients were enrolled. The mean age, HbA1c, and BMI were 49.6?±?11.27 years, 9.3?±?1.57%, and 26.7?±?4.50?kg/m², respectively. Cardiovascular risk factors present at baseline were dyslipidemia (30.1%), hypertension (29.7%), and obesity (20.9%). The mean reductions in HbA1c from baseline to week 12 (?1.6?±?1.59%) and 24 (?1.9?±?1.70%) were statistically significant (p?Conclusions: Overall, in a relatively young drug-naïve T2DM Asian study population with high baseline HbA1c and often associated with cardiovascular risk factors, vildagliptin/metformin combination therapy was associated with significant and clinically relevant HbA1c reduction from baseline. This effect was seen at week 12, was maintained over 24 weeks, and was accompanied by good tolerability.     

An International Study of the Effects of Rosiglitazone plus Sulphonylurea in Patients with Type 2 Diabetes

Summary

This was an open-label, randomised 26-week study to determine the effects of adding 4mg rosiglitazone (Avandia?) daily to existing sulphonylurea (SU) therapy in patients with type 2 diabetes from India, Brazil, The Philippines, Thailand, Argentina and Tunisia. Of the 348 patients, 175 received 2mg rosiglitazone twice daily plus SU (RSG?+?SU) and 173 received SU alone (at their normal dose). The RSG?+?SU group showed a significant reduction in HbA1c (mean HbA1c 9.05% at baseline, 7.92% at 26 weeks, mean change ?1.13 (95% CI ?1.37, ?0.89)). Mean HbA1cessentially remained unchanged in the control group (8.9 to 9.0%). The RSG?+?SU group showed a significant decrease in fasting plasma glucose concentration

(FPG) (mean FPG 198.7?mg/dl at baseline, 160.3?mg/dl at 26 weeks, mean change ?38.4 (95% CI ?47.1, ?29.7)) while the controls showed a non-significant increase from 194 to 200?mg/dl. Significantly more patients in the RSG?+?SU group achieved FPG < 140?mg/dl, > 0.7% decrease in HbA1c, and > 30?mg/dl decrease in FPG between baseline and week 26 than the controls (p?=?0.0001 in each case). Adverse events were similar in both groups; more patients in the RSG?+?SU group reported hypoglycaemia, but most cases were mild. This study shows that adding rosiglitazone to existing SU treatment improves glycaemic control and is well-tolerated in patients with type 2 diabetes from a wide range of non-Western countries.     

Transferring type 2 diabetes patients with uncontrolled glycaemia from biphasic human insulin to biphasic insulin aspart 30: experiences from the PRESENT study

ABSTRACT

Aim: The Physician's Routine Evaluation of Safety and Efficacy of NovoMix* 30 Therapy (PRESENT) aims to assess the safety and efficacy of biphasic insulin aspart (BIAsp30) used in routine clinical practice.

Methods: This was a large, multi-national, multi-centre, prospective, 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30. Efficacy endpoints included changes in HbA_1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and proportion who achieved target HbA_1c <?7%. Changes from baseline were analysed using paired t-test. Safety endpoints were incidence and rate of hypoglycaemic episodes. A subgroup of patients previously uncontrolled (HbA_1c ≥?7.0%) on biphasic human insulin (BHI) were analysed.

Results: Glycaemia improved significantly (mean ± SD): HbA_1c by 1.58 ± 1.69% points (from 9.32 ± 1.64% to 7.70 ± 1.29%), FPG by 2.92 ± 3.71?mmol/L and PPPG by 4.75 ± 4.87?mmol/L. The incidence of hypoglycaemic episodes decreased over time, from 38.7% (baseline) to 20.8% (6?months). Episodes were mostly minor (reduced from 37.7 to 20.6% at 6?months), occurring during the day (reduced from 31.5 to 17.1% at 6?months). Major episodes were less frequently reported (reduced from 5.0 to 0.4% at 6?months). The rate of hypoglycaemia (episodes/patient year) from baseline to end of study decreased over time for overall (8.9–2.2), major (0.7–0.1), minor (8.2–2.2) and nocturnal (2.9–0.5) episodes.

Conclusions: In this observational study, in the type 2 diabetes mellitus patients who were poorly controlled on BHI, glycaemia improved when transferred to BIAsp30, and a lower incidence or rate of hypoglycaemia was observed in these patients.     

Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes

ABSTRACT

Background: Type 2 diabetes is characterised by a progressive decline in HbA_1c control over time. Early combination therapy, rather than sequential introduction of individual oral glucose-lowering agents, has been proposed to prevent this gradual rise in HbA_1c. This observational study assessed the effect of early dual combination oral glucose-lowering therapies within 6 months of diagnosis in newly diagnosed, drug-naïve patients with type 2 diabetes.

Patients and methods: This was an observational, open-label, non-randomised study in newly diagnosed patients with type 2 diabetes, aged 35–70 years, with HbA_1c levels >?8.0% at diagnosis or >?7.0% at the 3–6-month follow-up. Patients were allocated to dietary management alone if the HbA_1c level was 7.0–8.0% at diagnosis. Metformin combined with gliclazide, repaglinide, or pioglitazone was given at diagnosis if the HbA_1c was >?8.0%. Similar treatments were introduced at 3–6 months if the HbA_1c was >?7.0%. Over a 3-year period, HbA_1c was measured at 3-monthly intervals. All patients underwent regular dietetic review. Target HbA_1c was ≤?7.0%.

Results: 416 patients were considered eligible for inclusion, with a mean (±?SD) age of 54.1 ± 9.2 years, BMI of 33.5 ± 6.1?kg/m², and baseline HbA_1c of 8.6 ± 1.7%. A mixed model analysis of variance on the 178 patients who started with combination therapy, either immediately or after a 3–6 month period on diet, showed that metformin plus gliclazide, repaglinide, or pioglitazone was associated with a gradual increase in HbA_1c values. Amongst those patients treated with the metformin/pio­glitazone combination there was an estimated 0.1% increase in HbA_1c/year. This was much less pronounced than the rises seen in HbA_1c/year of 0.5% with the met­formin/gliclazide and metformin/repaglinide combinations.

Conclusions: This preliminary analysis of an obervational, non-randomised, open-label ongoing study has shown that early use of combination therapy at time of diagnosis or within the first 3–6 months following diagnosis with metformin plus pioglitazone in newly diagnosed type 2 diabetes results in a slower deterioration in glycaemic control than that with metformin combined with either gliclazide or repaglinide. This may be due to the β?cell protective properties of pioglitazone. These results need to be confirmed by further studies with a more robust design and methodology.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized,double-blind,placebo-controlled study

ABSTRACT

Objectives: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD).

Research design and methods: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients 18–80 years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA_1c] 7.0–10.0%) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5?mg, alogliptin 25?mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted.

Main outcome measures: The primary efficacy endpoint was change in HbA_1c from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG?≥?200?mg/dL [11.10?mmol/L]) and rescue for hyperglycemia.

Results: Least squares (LS) mean change in HbA_1c was significantly (p?<?0.001) greater for alogliptin 12.5?mg (?0.66%) or 25?mg (?0.80%) than for placebo (?0.19%). A significantly (p?≤?0.016) larger proportion of patients achieved HbA_1c?≤?7% with alogliptin 12.5?mg (44.2%) or 25?mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p?=?0.003) greater with alogliptin 12.5?mg (?19.7?mg/dL [?1.09?mmol/L]) or 25?mg (?19.9?mg/dL [?1.10?mmol/L]) than with placebo (?5.7?mg/dL [?0.32?mmol/L]). The percentage of patients with marked hyperglycemia was significantly (p?<?0.001) lower for alogliptin (≤25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo.

Conclusions: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety.

Clinical trial registration: NCT00286494, clinicaltrials.gov.     

Factors that influence the efficacy of acarbose and metformin as initial therapy in Chinese patients with newly diagnosed type 2 diabetes: a subanalysis of the MARCH trial

Objective To conduct a subanalysis of the randomized MARCH (Metformin and AcaRbose in Chinese as the initial Hypoglycemic treatment) trial to investigate whether specific characteristics are associated with the efficacy of either acarbose or metformin as initial therapy.

Research design and methods A total of 657 type 2 diabetes patients who were randomly assigned to 48 weeks of therapy with either acarbose or metformin in the MARCH trial were divided into two groups based upon their hemoglobin A1c (HbA1c) levels at the end of follow-up: HbA1c?<7% (<53?mmol/mol) and ≥7% (≥53?mmol/mol). Univariate, multivariate, and stepwise linear regression analyses were applied to identify the factors associated with treatment efficacy.

Main outcome measures Because this was a subanalysis, no measurement was performed.

Results Univariate analysis showed that the efficacy of acarbose and metformin was influenced by HbA1c, fasting blood glucose (FBG), and 2 hour postprandial venous blood glucose (2hPPG) levels, as well as by changes in body mass index (BMI) (p?≤?0.006). Multivariate analysis and stepwise linear regression analyses indicated that lower baseline 2hPPG values and greater changes in BMI were factors that positively influenced efficacy in both treatment groups (p?≤?0.05). Stepwise regression model analysis also revealed that a lower baseline homeostasis model assessment-estimated insulin resistance (HOMA-IR) and higher serum insulin area under the curve (AUC) were factors positively influencing HbA1c normalization in all patients (p?≤?0.032).

Conclusions Newly diagnosed type 2 diabetes patients with lower baseline 2hPPG and HOMA-IR values are more likely to achieve glucose control with acarbose or metformin treatment. Furthermore, the change in BMI after acarbose or metformin treatment is also a factor influencing HbA1c normalization. A prospective study with a larger sample size is necessary to confirm our results as well as measure β cell function and examine the influence of the patients’ dietary habits.     

A randomized clinical trial evaluating the efficacy and safety of the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To examine the efficacy and safety of the once-weekly (q.w.) dipeptidyl peptidase-4 inhibitor, omarigliptin, in patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.

Methods: In a randomized, double-blind trial, patients with T2DM on a stable dose of metformin monotherapy (≥1500?mg/day) with glycated hemoglobin (HbA1c) of 7.0–10.5% were randomized to omarigliptin 25?mg q.w. or matching placebo (n?=?201 in both) for 24 weeks (primary timepoint) followed by an additional 80-week treatment period.

Results: At week 24, from a mean baseline HbA1c of 8.0–8.1%, the least squares (LS) mean (95% CI) change from baseline in HbA1c (primary end-point) was –0.54% (–0.69%, –0.40%) in the omarigliptin group and 0.00% (–0.14%, 0.15%) in the placebo group, for a between-group difference of –0.55% (–0.75%, –0.34%); p?p?=?.011) and –0.5 mmol/L (–0.9, –0.1) (p?=?.010), respectively. At week 24, the incidences of symptomatic hypoglycemia and subjects with one or more adverse event (AE), serious AEs, and discontinuations due to an AE were similar in the omarigliptin and placebo groups. Over 104 weeks, omarigliptin treatment provided a clinically meaningful reduction in HbA1c.

Conclusions: In patients with T2DM, adding omarigliptin 25?mg q.w. to metformin monotherapy improved glycemic control over 104 weeks and was generally welltolerated with a low risk of hypoglycemia.     

Effectiveness and safety of vildagliptin and vildagliptin add-on to metformin in real-world settings in Egypt – results from the GUARD study

Objective: The GUARD study evaluated the effectiveness, safety, and tolerability of vildagliptin treatment with or without metformin in patients with type 2 diabetes mellitus (T2DM) in real-life settings. Here we present the results of the GUARD study for the patient subset from Egypt.

Research design and methods: This was a 24?±?6 weeks, prospective, non-interventional study that enrolled adult patients with T2DM receiving vildagliptin or vildagliptin?+?metformin combination therapy as per local prescribing information.

Main outcome measures: The primary effectiveness endpoint was change in HbA1c levels from baseline to week 24?±?6 endpoint. Safety was assessed by reporting of adverse events and serious adverse events (SAEs).

Results: Of 2786 patients enrolled from Egypt, 655 received vildagliptin and 2131 received vildagliptin?+?metformin. Overall, at baseline, mean (± standard deviation [SD]) age was 49.5?±?9.49 years, BMI was 31.5?±?4.85?kg/m², HbA1c was 8.4?±?0.86%, and duration of T2DM was 2.3?±?3.78 years. At week 24, significant reductions in mean (±SD) HbA1c were observed in the vildagliptin (?1.47?±?0.79%) and vildagliptin?+?metformin (?1.62?±?0.82%) groups (both p?Conclusion: In a real-world setting, vildagliptin, with or without metformin, resulted in significant reductions in HbA1c and was well tolerated in patients with T2DM from Egypt. Limitations of the study include non-randomization and the open-label, observational nature of the study.     

Cost-effectiveness of insulin detemir compared to NPH insulin for type 1 and type 2 diabetes mellitus in the Canadian payer setting: modeling analysis*

ABSTRACT

Objective: This study was conducted to quantify the long-term cost-effectiveness of insulin detemir (Levemir^?) versus intermediate-acting neutral protamine Hagedorn (NPH) insulin for the treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in Canada, and to assess the sensitivity of results to dis-utilities for hypoglycemic events.

Research design and methods: The web-based IMS-CORE diabetes model has a menu-driven interface programmed in hypertext markup language (HTML). It was used to project lifetime (60 years for T1DM and 35 years for T2DM) clinical and economic outcomes for patients on detemir vs. NPH. Cohort characteristics, utilities, and costs were derived from published literature. For T1DM, clinical trial data for HbA_1c improvement (detemir ?0.94%?±?1.07; NPH ?0.82%?±?1.01) from baseline, and rates of hypoglycemic events (major events: 0.20 vs. 0.80 per patient-year for detemir vs. NPH, respectively) were modeled. For T2DM, observational study data for HbA_1c improvement (detemir ?0.18%) from baseline, and reductions in hypoglycemic events (major events: 0.0995 vs. 1.33 per patient-year for detemir vs. NPH, respectively) were modeled. Base-case hypoglycemia dis-utilities were ?0.0118 for major and ?0.0035 for minor events. Sensitivity analyses were conducted on discount rate and hypoglycemia dis-utility.

Outcome measures: Outcomes included costs of treatment/management and costs (and incidence) of diabetes-related complications. Incremental cost-effectiveness ratios (ICERs) were calculated from differences in total costs and quality-adjusted life-years (QALYs).

Results: Average total costs for T1DM were $CAN 83?622?±?4585 for detemir and $CAN 72?016?±?4593 for NPH. QALYs increased by 0.475 years with detemir, with an ICER of $CAN 24?389/QALY. Average direct costs for T2DM were $CAN 74?919?±?6391 (detemir) and $CAN 69?230?±?6840 (NPH). QALYs increased by 0.305 years. The ICER was $CAN 18?677. Although detemir was associated with slightly lower costs for most complications, results were driven by the differences in rates and costs for hypoglycemic events, and their assumed dis-utility. Study limitations include the use of single trials for clinical assumptions and the lack of analyses for patient risk sub-groups.

Conclusions: Findings provide evidence for the cost-effectiveness of detemir vs. NPH in treating T1 and T2DM in Canada, and support the key role of assumptions regarding the impact of hypoglycemic events. Additional work is needed to determine the extent to which results are robust for different sub-groups of patients and for variation in assumptions around HbA_1c improvements and hypoglycemic event rates.     

Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind,placebo-controlled,clinical trial

ABSTRACT

Objective: To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.

Research design and methods: During a 12-week observation period 236 patients were treated with metformin 500 or 750?mg/day. 169 patients with a confirmed HbA_1c level ≥ 6.5% were randomized (stratified according to metformin dosage) to receive pioglitazone 15?mg/day for 12 weeks then increased to 30?mg/day for a further 16 weeks (n?=?83), or placebo (n?=?86). Outcome measures included HbA_1c, fasting blood glucose (FBG), percentage of patients achieving HbA_1c?<?6.5%, lipid profile, and other metabolic parameters.

Results: Mean HbA_1c was reduced by 0.67% in patients receiving pioglitazone plus metformin versus an increase of 0.25% in those receiving metformin alone (p?<?0.0001). After 8 weeks’ treatment and until the end of the study, HbA_1c was significantly lower with pioglitazone plus metformin and more patients in this group achieved an HbA_1c?<?6.5% (38.6% vs. 8.1%; p?<?0.0001). FBG was also reduced by a significantly greater amount in patients receiving pioglitazone plus metformin compared with metformin monotherapy (?20.5 vs. 1.9?mg/dl; p?<?0.0001). Combination therapy was associated with significantly increased HDL-cholesterol, total cholesterol, and adiponectin, and significantly decreased levels of fasting insulin, free fatty acids, and homeostasis model assessment insulin resistance (HOMA-R) compared with metformin monotherapy. Overall, combination therapy and monotherapy were equally well tolerated and the incidence of adverse effects ‘possibly’ related to therapy was 15.7% and 11.6% (p?=?0.505), respectively. Edema occurred slightly more often in the combination group (6.0 vs. 1.2%).

Conclusion: Pioglitazone plus metformin significantly improved glycemic control (HbA_1c and FBG), and markers associated with increased insulin resistance and cardiovascular risk compared with metformin monotherapy.

Clinical trial registration number: UMIN 000001110.     

Recalculation of cardiovascular risk score as a surrogate marker of change in clinical care of diabetes patients: the Alphabet POEM project (Practice Of Evidence-based Medicine)

SUMMARY

Aims: To assess the impact of evidence-based strategies on the care of subjects with diabetes, in particular on their coronary heart disease (CHD) risk, using the Alphabet Strategy template and coronary heart disease (CHD) risk calculators as novel audit tools.

Methods: Diabetes and cardiovascular parameters were collected on 400 consecutive type 2 diabetes patients attending the outpatient clinic. The subjects were men and women aged 21-75 years with necessary follow-up data from referral or first chronological available letter in the notes (T0) to the most recent follow-up visit (Tfu). The average follow-up period was 5 years. Absolute CHD risk was calculated using the Framingham risk function and the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. The results were analysed using Student's paired t-test and chi-squared test.

Results (T0 vs.Tfu): Advice: smoking status improved 18.3 vs. 15.5%: p?=?0.3. Blood pressure: systolic blood pressure improved 145.8?±?21.1 vs. 140.1?±?20.5mmHg: p?<?0.0001. Diastolic blood pressure improved 82.0?±?12.2 vs. 76.5?±?11.0mmHg: p?<?0.0001. Cholesterol: total cholesterol improved 5.8?±?1.6 vs. 4.9?±?1.0 mmol/L: p?<?0.0001; high density lipoprotein (HDL) cholesterol improved 1.05 vs. 1.26 mmol/L: p?<?0.001. Diabetes control: glycated haemoglobin (HbA1c)% worsened 7.9?±?1.8 vs. 8.1?±?1.5: p?<?0.0001. However, when adjusted for duration of diabetes, this improved non-significantly by 12% overall. Eye examination: improved 86.5 vs. 97.5%: p?<?0.001. Feet examination: improved 69.8 vs. 83.5%: p?<?0.001. Guardian drugs: significantly more patients were on aspirin (29.0 vs. 83.5%: p?<?0.001), angiotensin converting enzyme (ACE) inhibitors (32.0 vs. 64.5%: p?<?0.001), and lipid lowering therapy (16.8 vs. 55.0%: p?<?0.001). Heart disease risk scores: a significant reduction in Framingham 10-year absolute cardiac risk was achieved (20.6?±?10.04% vs. 16.7?±?9.1%: p?=?0.001). Using the UKPDS risk engine, there was a non-significant reduction in absolute CHD risk over the follow-up period (23.8?±?14.8% vs. 23.7?±?15.5: p?=?NS). There were significant improvements between age-adjusted risk score (Tadj) and follow-up values (Tfu) (Framingham: 23.67% (Tadj) vs. 16.7% (Tfu); UKPDS 31.2% (Tadj) vs. 23.7% (Tfu)). For UKPDS stroke risk, a significant improvement was seen from Tadj to Tfu (19.0% (Tadj) vs. 16.4% (Tfu): p?<?0.001), with a significant deterioration noted between T0 and Tfu (11.5% (T0) vs. 16.4% (Tfu): p?<?0.0001).

Conclusions:The Alphabet Strategy is a novel evidence-based approach to clinical diabetes care, which produced a statistically significant improvement in most of the assessed parameters. The Alphabet Practice Of Evidence-based Medicine (POEM) template is a useful clinical tool for diabetes care and audit. It includes most of the components of diabetes audit required by the National Service Framework (NSF) and the United Kingdom GP contract.     

The role of microalbuminuria and insulin resistance as significant risk factors for white matter lesions in Japanese type 2 diabetic patients

ABSTRACT

Objective: The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Microalbuminuria, which is associated with diabetes, has been flagged as a novel predictor for cerebrovascular events. This preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with microalbuminuria and insulin resistance in patients with type 2 diabetic mellitus (DM) not receiving insulin treatment.

Patients and methods: Based on brain magnetic resonance imaging (MRI) findings, 90 type 2 diabetic patients were divided into two groups: a WML-positive group (57?±?8 years, mean?±?SD, n?=?34) and a WML-negative group (57?±?6 years, n?=?56). The level of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin (F-IRI), homeostasis model assessment (HOMA) index, and hemoglobin A _1c (HbA1c).

Results: The body mass index was higher in the WML-positive group than in the WML-negative group (p?<?0.01). Plasma levels of triglycerides were higher while high-density lipoprotein cholesterol (HDL-C) was lower in the WML-positive group than in the WML-negative group (p?<?0.05 and p?<?0.0001, respectively). Fasting plasma glucose (p?<?0.005), insulin concentrations (p?<?0.0001), HOMA index (p?<?0.0001), and urinary albumin excretion (p?<?0.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the microalbuminuria and insulin resistance (p?<?0.005, p?<?0.0005, respectively).

Conclusion: The results of this preliminary study indicate that the presence of WML was associated with the microalbuminuria and insulin resistance in these Japanese patients with type 2 DM; larger cohort studies are warranted to confirm these findings.     

Patient characteristics,drug adherence patterns,and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine

ABSTRACT

Objective: Examine real-world effectiveness and hypoglycemia cost burden in patients with type?2 diabetes newly initiated on exenatide or insulin glargine.

Design and methods: Retrospective cohort study describing patient characteristics, drug adherence patterns, and 1-year hypoglycemia rates with associated costs using an administrative claims database. Adult subjects with type?2 diabetes had an initial claim for exenatide or insulin glargine between May?1, 2005 and June?30, 2007, and had continuous eligibility for ≥?6 months pre- and ≥?12 months post-initiation.

Results: The exenatide cohort (n?=?3262) was 53?±?10?years (±SD); 54% female. The insulin glargine cohort (n?=?3038) was 56?±?12?years; 41% female. The mean Deyo-Charlson comorbidity index score was 1.45 for exenatide versus 1.82 for insulin glargine (p?<?0.001). Baseline OAD use rates for exenatide and insulin glargine, respectively, were 77% versus 69% metformin; 47% versus 65% sulfonylurea; 50% versus 49% thiazolidinedione; 56% versus 60% multiple OAD. For patients with two or more pharmacy claims for exenatide or insulin glargine, the 12-month medication possession ratio (MPR) was 68?±?29% for exenatide and 58?±?28% for insulin glargine (p?<?0.001). MPR ≥?80% was higher for exenatide (p?<?0.001) and fewer patients discontinued therapy (p?<?0.001). The probability of a hypoglycemic event was significantly lower for exenatide (p?<?0.005), resulting in lower associated annual costs.

Conclusions: This study provides the first real-world observational comparison of type?2 diabetes patients newly initiated on exenatide or insulin glargine. Exenatide patients had a lower comorbidity burden, better drug adherence, and a lower rate of hypoglycemic events with associated costs. Retrospective database analyses examine medical care utilization in large populations using a relatively inexpensive and expedient approach. However, data are only representative of a commercial health-care plan with limited information on multiple variables usually collected during clinical trials.