Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study

BACKGROUND: This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes (HbA1c > or = 7.5% to < or =11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. RESULTS: There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. CONCLUSIONS: Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia.     

A case of secondary diabetes mellitus with acromegaly improved by pioglitazone.

AIM: The acromegaly patient was diagnosed with Type 2 diabetes mellitus. His HbA1c was 10.6% and fasting blood glucose (FBG) 15.3 mmol/l. We prescribed glibenclamide (10 mg/day), but his HbA1c and FBG remained high. At this stage, treatment with short-acting insulin was instigated at a dose of 20 U/day. However, the patient's blood glucose level remained unsatisfactory. We tried using pioglitazone. METHOD: Pioglitazone was prescribed at 30 mg/day in combination with the insulin. RESULTS: The FBG and HbA1c value decreased to 7.2 mmol/l and 7.3%, respectively, within 2 months and insulin was discontinued. Pioglitazone alone was able to control the FBG level. CONCLUSIONS: Pioglitazone treatment might be considered as a choice for similar cases of diabetes secondary to acromegaly.     

Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1-year trial results

AIM: To compare long-term efficacy and safety of nateglinide plus metformin with those of gliclazide plus metformin in patients with type 2 diabetes not adequately controlled with metformin monotherapy. METHODS: Double-blind, double-dummy, multicentre study extended to a total of 52 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to nateglinide (N = 133) or gliclazide (N = 129) add-on treatment. After the initial 6-month study, the majority of patients in the nateglinide group [n = 112 (93.3%)] and in the gliclazide group [n = 101 (92.7%)] entered a 6-month, double-blind, extension study. RESULTS: There was no significant difference between treatment regimens in haemoglobin Alc (HbA1c) change from baseline to 52 weeks (-0.14% for nateglinide vs. -0.27% for gliclazide; p = 0.396). Proportions of patients achieving an endpoint HbA1c of <7% were similar (40 vs. 47.4%) for nateglinide and gliclazide groups. There was no significant between-treatment difference in fasting plasma glucose change from baseline to 52 weeks (nateglinide: -0.2 mmol/l and gliclazide: -0.7 mmol/l; p = 0.096). The decreases in prandial plasma glucose area under the curve(0-4 h) from baseline were -3.26 and -1.86 h x mmol/l in the nateglinide and the gliclazide groups respectively, and the change was statistically significant in the nateglinide group only (p = 0.006). Initial insulin response to a meal was augmented with nateglinide treatment only, without between-treatment difference in 2-h insulin response. The overall rate of hypoglycaemic events was similar with nateglinide and gliclazide combinations with metformin. Nateglinide plus metformin treatment was not associated with weight gain. CONCLUSIONS: No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. Treatment with nateglinide plus metformin for up to 12 months was not associated with weight gain.     

Comparison of repaglinide vs. gliclazide in combination with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic agents.

AIMS: This open-label randomized controlled clinical trial compared the effect on glycaemic control and weight gain of repaglinide vs. gliclazide combined with bedtime NPH insulin in patients with Type 2 diabetes inadequately controlled with oral hypoglycaemic therapy [HbA1c>7.0% (DCCT aligned assay, normal range 4.6-6.2%)]. METHODS: Eighty subjects with Type 2 diabetes were randomized to 13 weeks' open-label treatment with repaglinide 4 mg t.i.d. or gliclazide 160 mg b.i.d. in combination with bedtime NPH insulin (initial dose 0.5 units/kg). The fasting blood glucose (FBG) target was < or =6.0 mmol/l. RESULTS: Baseline characteristics were similar for age, sex, weight, BMI, FBG and HbA1c. Glycaemic control improved similarly in both groups-insulin/gliclazide by (mean) 1.0%, from 9.2 to 8.2% (P=0.001) and by 0.9%, from 9.4 to 8.5% in the insulin/repaglinide group (P=0.005) (P=0.83 between groups). Weight gain averaged (mean +/- sem) 4.1 +/- 0.5 and 3.4 +/- 0.4 kg in the insulin/gliclazide and insulin/repaglinide groups, respectively (P<0.0001 for both groups from baseline) (P=0.29 between groups). The mean number of hypoglycaemic episodes experienced per patient was 2.95 +/- 0.82 (insulin/gliclazide) and 2.3 +/- 0.52 (insulin/repaglinide) (P=0.81 between groups). Both treatments were associated with significant improvements in Diabetes Treatment Satisfaction [Diabetes Treatment Satisfaction Questionnaire-potential range 0 (min) to 36 (max)]; in the insulin/gliclazide group, by 4.9 +/- 1.1 points to 33.3 +/- 0.6 (P<0.0001) and by 3.0 +/- 0.9 points to 34.6 +/- 0.4 (P=0.0006) in the insulin/repaglinide group (P=0.29 between groups). CONCLUSIONS: Over 13 weeks, both repaglinide and gliclazide, when combined with bedtime NPH insulin produce similar significant improvements in glycaemic control (-1%) and similar weight gain.     

The efficacy of self-monitoring of blood glucose in the management of patients with type 2 diabetes treated with a gliclazide modified release-based regimen. A multicentre, randomized, parallel-group, 6-month evaluation (DINAMIC 1 study)

Aim: To determine if therapeutic management programmes for type 2 diabetes that include self‐monitoring of blood glucose (SMBG) result in greater reductions in glycated haemoglobin (HbA1c) compared with programmes without SMBG in non‐insulin requiring patients. Methods: Multicentre, randomized, parallel‐group trial. A total of 610 patients were randomized to SMBG or non‐SMBG groups. Patients in both groups received the same oral antidiabetic therapy using a gliclazide modified release (MR)–based regimen for 27 weeks. The primary efficacy end‐point was the difference between groups in HbA1c at the end of observation. Results: A total of 610 patients were randomized: 311 to the SMBG group and 299 to the non‐SMBG group. HbA1c decreased from 8.12 to 6.95% in the SMBG group and from 8.12 to 7.20% in the non‐SMBG group; between‐group difference was 0.25% (95% CI: 0.06, 1.03; p = 0.0097). Symptoms suggestive of mild to moderate hypoglycaemia was the most commonly reported adverse event, reported by 27 (8.7%) and 21 (7.0%) patients in the SMBG and non‐SMBG groups, respectively; the incidence of symptomatic hypoglycaemia was lower in the SMBG group. Conclusion: In patients with type 2 diabetes, the application of SMBG as an adjunct to oral antidiabetic agent therapy results in further reductions in HbA1c.     

Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes.

AIMS: To compare the metabolic effects of pioglitazone, metformin, and glimepiride in the treatment of Japanese patients with newly diagnosed Type 2 diabetes. METHODS: A total of 114 patients with Type 2 diabetes who had never used oral hypoglycaemic drugs were studied for 12 months. Patients were randomly assigned to pioglitazone (30-45 mg/day, n = 38), metformin (750 mg/day, n = 39), or glimepiride (1.0-2.0 mg/day, n = 37). The effect of treatment on fasting plasma glucose (FPG), glycated haemoglobin (HbA(1c)), 1,5-anhydroglucitol (1,5AG), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, free fatty acids (FFA), and fasting plasma insulin levels was monitored monthly. Body weight and safety data were also collected. RESULTS: Eight patients withdrew from the study (three in the pioglitazone group, two in the metformin group, and three in the glimepiride group). The rate of reduction of HbA(1c) was fastest in patients receiving glimepiride and slowest in patients receiving pioglitazone. Although there were no significant differences among the three groups in HbA(1c) levels at the end of the study, patients taking pioglitazone had relatively lower FPG and 1,5AG levels than patients taking the other two drugs. These results suggest that pioglitazone acts predominantly on nocturnal metabolism rather than at mealtimes. FFA were reduced significantly in those taking pioglitazone (542.2 microEq/l vs. 237.3 microEq/l; P < 0.01) before a decrease in HbA(1c) was apparent. The change in FFA levels correlated with the change in HbA(1c) (r = 0.409, P < 0.01). There were no significant differences in other lipid parameters among the groups. CONCLUSIONS: Pioglitazone, metformin, and glimepiride are equally effective in reducing blood glucose in patients with newly diagnosed Type 2 diabetes. However, their specific characteristics, such as the rapid action on blood glucose levels of glimepiride and the favourable action on FPG and FFA of pioglitazone, should be considered when choosing an appropriate agent.     

The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus

BACKGROUND: To evaluate the glycemic control, lipid effects, and safety of pioglitazone in patients with type 2 diabetes mellitus. DESIGN AND METHODS: Patients (n = 197) with type 2 diabetes mellitus, a hemoglobin A1c (HbA1c) > or = 8.0%, fasting plasma glucose (FPG) > 7.7 mmol/l (140 mg/dl), and C-peptide > 0.331 nmol/l (1 ng/ml) were enrolled in this 23-week multi-center (27 sites), double-blind clinical trial and randomized to receive either a placebo or pioglitazone HCl 30 mg (pioglitazone), administered once daily, as monotherapy. Patients were required to discontinue all anti-diabetic medications 6 weeks before receiving study treatment. Efficacy parameters included HbA1c fasting plasma glucose (FPG), serum C-peptide, insulin, triglycerides (Tg), and cholesterol (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C]). Adverse event rates, serum chemistry, and physical examinations were recorded. RESULTS: Compared with placebo, pioglitazone significantly (P= 0.0001) reduced HbA1c (-1.37% points), FPG (-3.19 mmol/l; -57.5 mg/dl), fasting C-peptide (-0.076+/-0.022 nmol/l), and fasting insulin (-11.88+/-4.70 pmol/l). Pioglitazone significantly (P < 0.001) decreased insulin resistance (HOMA-IR; -12.4+/-7.46%) and improved beta-cell function (Homeostasis Model Assessment (HOMA-BCF); +47.7+/-11.58%). Compared with placebo, fasting serum Tg concentrations decreased (-16.6%; P = 0.0178) and HDL-C concentrations increased (+12.6%; P= 0.0065) with pioglitazone as monotherapy. Total cholesterol and LDL-C changes were not different from placebo. The overall adverse event profile of pioglitazone was similar to that of placebo, with no evidence of drug-induced elevations of serum alanine transaminase (ALT) concentrations or hepatotoxicity. CONCLUSIONS: Pioglitazone improved insulin resistance and glycemic control, as well as Tg and HDL-C - which suggests that pioglitazone may reduce cardiovascular risk for patients with type 2 diabetes.     

Comparison of pioglitazone and metformin efficacy using homeostasis model assessment.

AIMS: To compare clinical efficacy of two different insulin sensitizers, pioglitazone and metformin, and to reveal factors that influence the clinical efficacy. METHODS: Seventy-eight Japanese subjects with Type 2 diabetes mellitus poorly controlled with sulphonylureas [38 men and 40 women, aged 57 +/- 9 years, body mass index 25.2 +/- 1.4 kg/m2, and HbA1c 8.3 +/- 0.6% (means +/- SD)] were randomly assigned to groups for the addition of either pioglitazone or metformin and followed up for 4 months. A decrease in HbA1c levels was compared with baseline factors including homeostasis model assessment of insulin sensitivity (HOMA-R) and beta-cell function (HOMA-beta) with 71 subjects who completed the study. RESULTS: The overall decrease in HbA1c levels was similar for the pioglitazone (-1.2 +/- 0.2%) and metformin (-1.3 +/- 0.1%) groups. In the pioglitazone group, the decrease in HbA1c levels was negatively correlated with baseline HOMA-R (r=-0.698, P<0.0001) and HOMA-beta (r=-0.680, P<0.0001). In contrast, the decrease was positively correlated with baseline HOMA-beta (r=0.556, P=0.0004) in the metformin group. Multivariate analysis revealed that either HOMA-R or HOMA-beta was a main determinant of the decrease in HbA1c levels in the pioglitazone group. In the metformin group, baseline levels of fasting glucose were also included as an independent determinant in addition to HOMA-beta. The subjects with greater HOMA-R (> or =4.0) or HOMA-beta (> or =40%) displayed better response to pioglitazone than to metformin, and vice versa. CONCLUSIONS: In Type 2 diabetic subjects poorly controlled with sulphonylureas, addition of pioglitazone or metformin resulted in a comparable reduction in HbA1c levels. Subjects with greater insulin resistance or preserved beta-cell function displayed better response to pioglitazone, whereas subjects with reduced beta-cell function displayed better response to metformin.     

Effect of pioglitazone on lipids in well controlled patients with diabetes mellitus type 2 -- results of a pilot study.

INTRODUCTION: Patients with diabetes mellitus type 2 are characterized by a typical dyslipoproteinemia. Improvement in glucose control usually also ameliorates this dyslipoproteinemia. It is unclear whether different antidiabetic strategies differ in their effects on the lipid profile. Particularly, it is unknown whether glitazones improve lipid values independently of their effects on glucose metabolism. METHODS: Ten patients well controlled on sulfonylureas (HbA1c 6.9 +/- 0.5 %) with diabetic dyslipoproteinemia were treated with additional pioglitazone (30 mg/d) for 3 months. Every 4 weeks the sulfonylurea dose was adjusted to keep HbA1c and fasting glucose constant. Before and after 3 months of pioglitazone therapy lipid metabolism was determined in detail (cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, VLDL-triglycerides, lipoprotein(a), LDL-subtype distribution by isopycnic density gradient ultracentrifugation). RESULTS: Although glucose control remained unchanged (HbA1c 6.9 +/- 0.5 % vs. 6.8 +/- 0.6 %; fasting glucose concentration 7.7 +/- 1.1 vs. 7.3 +/- 1.3 mmol/l) we observed a significant reduction in triglyceride concentration (1.9 +/- 0.6 vs. 1.4 +/- 0.5 mmol/l, - 26 %, p < 0.01), a significant increase in HDL-cholesterol concentration (1.2 +/- 0.2 vs. 1.4 +/- 0.2 mmol/l, + 14 %, p < 0.05), a significant decrease in LDL/HDL-ratio (3.03 +/- 0.77 vs. 2.51 +/- 0.61, - 24 %, p < 0.05) and non-significant improvements in total cholesterol, LDL-cholesterol, VLDL-triglycerides, and VLDL-cholesterol concentrations. The LDL-subtype profile improved (significant reduction [- 20 %] in small dense LDL). CONCLUSIONS: This pilot study indicates that at comparable fasting glucose concentration and at comparable HbA1c value pioglitazone is superior to sulfonylureas concerning the improvement of diabetic dyslipoproteinemia. Whether this relates to indirect effects (improvement in insulin sensitivity) or direct effects (stimulation of PPARalpha) remains to be determined.     

Age-related increase in haemoglobin A1c and fasting plasma glucose is accompanied by a decrease in beta cell function without change in insulin sensitivity: evidence from a cross-sectional study of hospital personnel.

AIMS: To examine the influence of age on glucose homeostasis in a population of healthy, non-diabetic hospital personnel. METHODS: One hundred and twenty female and 71 male non-diabetic individuals (fasting plasma glucose < 7.0 mmol/l) were fasted overnight prior to blood sampling. Glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and fasting plasma insulin (FPI) were measured using a BioRad Diamat automated HPLC, a Hitachi 747 analyser and a sensitive in-house radioimmunoassay, respectively. Mathematical modelling of the fasting glucose and insulin pairs (homeostasis model assessment (HOMA)) generated indices of pancreatic beta cell function, HOMA-B and tissue insulin sensitivity HOMA-S. RESULTS: Spearman rank correlation analysis showed that in the whole group there was a significant negative correlation between age and HOMA-B (rs = -0.218, P = 0.0022) and a significant positive correlation between age and both HbA1c (rs = 0.307, P = 0.0001) and FPG (rs = 0.26, P = 0.0003). There was no correlation between age and either FPI (rs = -0.08, P = 0.266) or HOMA-S (rs = 0.024, P = 0.75). Analysis by gender showed the above associations to be present in the females (rs = -0.243, P = 0.0076; rs = 0.304, P = 0.0007; rs = 0.32, P = 0.0004 for age vs. HOMA-B, HbA1c, and FPG, respectively). Again there was no correlation of age with FPI or insulin sensitivity. In the males there was a significant correlation of HbA1c with age (rs = 0.35, P = 0.002), but no significant correlation of age with any of the other parameters. CONCLUSIONS: Glycaemic control deteriorates with age in healthy, non-diabetic individuals. Age-related rises in FPG and haemoglobin A1c result from a small but steady decline in pancreatic beta cell function.     

Double-blind, randomized, multicentre study of the efficacy and safety of gliclazide-modified release in the treatment of Chinese type 2 diabetic patients

BACKGROUND AND AIM: Gliclazide-modified release (gliclazide MR) is a new formulation of the sulfonylurea gliclazide designed for once-daily administration. The hydrophilic matrix of hypromellose-based polymer in the new formulation induces a progressive drug release, which parallels the 24-h glycaemic profile in type 2 diabetic patients. The aim of this study was to compare the efficacy and safety of gliclazide MR (once-daily administration) versus gliclazide (twice-daily administration) in Chinese type 2 diabetic patients. MATERIALS AND METHODS: Sixty-three type 2 diabetic Chinese patients who had been on diet control alone or on treatment with metformin or on low dose of sulfonylurea were randomized to either gliclazide MR taken once daily or gliclazide taken twice daily. Dosage of metformin was maintained throughout the study, and the sulfonylurea was stopped. The dose of gliclazide MR was increased at 1-month intervals from 30 mg to 120 mg, while that of gliclazide from 80 mg to 320 mg until metabolic control was achieved [fasting plasma glucose (FPG) < or = 7.7 mmol/l] or the maximum dose reached. Efficacy was mainly evaluated by levels of haemoglobin A1c (HbA1c) and FPG. RESULTS: The mean baseline characteristics of the full analysis set 1 (FAS1) (HbA1c, n = 58) and the FAS2 (FPG, n = 61) were comparable in both groups. The levels of HbA1c decreased similarly in both groups over the treatment period: -1.6 +/- 1.6% (p < 0.001) on gliclazide MR (n = 31) and -1.6 +/- 1.4% (p < 0.001) on gliclazide (n = 27). Decrease in HbA1c was observed irrespective of pre-existing therapy for diabetes: -2.3 +/- 1.5% for patients on diet alone; -0.6 +/- 1.3% for patients switched from sulfonylurea to study drug and -1.4 +/- 0.8% for patients on metformin in combination with study drug. FPG decreased significantly from 177.5 +/- 63.5 to 136.7 +/- 42.2 (p < 0.001, n = 32) on gliclazide MR and not significant from 188.2 +/- 62.6 to 163.7 +/- 67.9 (p = 0.059, n = 29) on gliclazide. Both treatments were very well tolerated with no major hypoglycaemic episodes requiring external assistance; only three patients experienced mild hypoglycaemic episodes. CONCLUSIONS: Once-daily gliclazide MR showed a better trend in improving blood glucose control in comparison with gliclazide in type 2 diabetic Chinese patients irrespective of the pre-existing anti-diabetic treatment. The safety profiles of gliclazide MR and gliclazide were similar with a small number of patients having reported hypoglycaemic episodes. Once-daily dosing with gliclazide MR should improve patient compliance, an important factor in long-term glycaemic control.     

Coefficient of beta-cell failure in patients with type 2 diabetes treated with pioglitazone or acarbose.

AIM: A new method of assessing the coefficient of failure of pancreatic beta-cells from any index of glycaemia has been proposed. This method of analysis has been used to assess data on HbA1c and fasting glucose concentrations from a randomised study comparing pioglitazone with acarbose. METHODS: Patients were treated for 26 weeks with either pioglitazone 45 mg once daily or acarbose 300 mg/day as 3 equal doses. Plasma HbA1c concentration was measured every two months and fasting glucose was measured monthly. The coefficient of failure was determined for each patient from the slope of the least squares regression line over time. RESULTS: The coefficient of failure from HbA1c was - 2.65 +/- 2.13 %/year with pioglitazone and - 1.25 +/- 3.11 %/year with acarbose, indicating improved beta-cell function in each case. The coefficient of failure was improved to a significantly greater extent with pioglitazone ( P < 0.001). Coefficient of failure from fasting blood glucose also showed a greater improvement with pioglitazone (- 53.1 +/- 95.0 mg/dl/year) than with acarbose (- 29.9 +/- 142.5 mg/dl/year; p = 0.049). CONCLUSION: The coefficient of failure showed a significantly greater improvement of beta-cell function with pioglitazone than with acarbose during 26 weeks of treatment.     

Self-monitoring of blood glucose in non-insulin-treated diabetic patients: a longitudinal evaluation of its impact on metabolic control.

AIMS: In the framework of a nationwide outcomes research programme, we assessed the impact of self-monitoring of blood glucose (SMBG) on metabolic control over 3 years in patients with Type 2 diabetes mellitus (DM2) not treated with insulin. METHODS: The study involved 1896 patients who completed, at 6-month intervals for 3 years, a questionnaire investigating SMBG practice. Clinical information was collected by participating clinicians at the same time intervals. The predictive value of SMBG frequency on long-term metabolic control was estimated using multilevel analysis. The impact of SMBG on metabolic control was also evaluated in distinct and homogeneous subgroups of patients showing different likelihood of performing SMBG, identified using a tree-growing technique (RECPAM). RESULTS: Overall, 22% of the patients were on diet alone and 78% were treated with oral agents; 41% practiced SMBG > or = 1/week (10.3% > or = 1/day). The analysis of metabolic control according to the frequency of SMBG failed to show any significant impact of this practice on HbA1c levels over 3 years. Similarly, changes in SMBG frequency during the study were not related to significant changes in HbA1c levels. RECPAM analysis led to the identification of eight classes, characterized by substantial differences in the likelihood of performing SMBG with a frequency of at least 1/week. Nevertheless, in none of the RECPAM classes identified, did SMBG predict a better metabolic control over 3 years of follow-up. In those RECPAM classes indicating that SMBG was mainly performed to avoid hypoglycaemic episodes, SMBG was associated with a decrease in the frequency of hypoglycaemic episodes during the study. CONCLUSIONS: In a large sample of non-insulin-treated Type 2 diabetic patients, the performance and frequency of SMBG did not predict better metabolic control over 3 years. We could not identify any specific subgroups of patients for whom SMBG practice was associated with lower HbA1c levels during the study.     

Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.

AIM: To compare blood glucose control when using insulin glargine twice daily at breakfast- and dinner-times with insulin glargine once daily at dinner time, in unselected people with Type 1 diabetes using insulin aspart at meal-times. METHODS: In this 8-week, two-way, cross-over study, 20 people with Type 1 diabetes were randomized to insulin glargine injection once daily at dinner-time or twice daily at breakfast- and dinner-times, both plus meal-time insulin aspart. Each 4-week treatment period concluded with a 24-h inpatient metabolic profile. RESULTS: Insulin doses, HbA1c, fructosamine concentration and pre-breakfast self-monitored blood glucose (SMBG) concentration did not differ between treatment periods. SMBG concentrations after breakfast, after lunch and before dinner were lower with twice-daily compared with once-daily dinner-time glargine [9.3 +/- 0.5 (+/- se) vs. 6.7 +/- 0.5 mmol/l, P = 0.003; 10.2 +/- 0.9 vs. 7.0 +/- 0.9 mmol/l, P = 0.024; 9.6 +/- 0.5 vs. 6.6 +/- 0.5 mmol/l, P = 0.001]. Mean 24-h SMBG concentration was lower with twice-daily glargine (7.1 +/- 0.5 vs. 8.8 +/- 0.5 mmol/l, P = 0.031). Within-day variability of SMBG concentration was lower with twice-daily glargine (sd 3.2 +/- 0.2 vs. 4.0 +/- 0.3 mmol/l, P = 0.044). Plasma free insulin concentration was higher in the afternoon with twice-daily glargine (21.9 +/- 1.4 vs. 16.1 +/- 1.3 mU/l, P = 0.009), but lower overnight (12.1 +/- 1.7 vs. 17.8 +/- 1.7 mU/l, P = 0.030), compared with once-daily injection. Plasma glucose concentration overnight was higher with twice-daily compared with once-daily glargine (mean 9.0 +/- 0.4 vs. 6.6 +/- 0.4 mmol/l, P = 0.001). CONCLUSIONS: Blood glucose concentration rises in the late afternoon in association with falling plasma insulin levels towards the end of the 24-h period after insulin glargine injection in some people with Type 1 diabetes using once-daily glargine at dinner-time plus a rapid-acting insulin analogue at meal-times. This is prevented by twice-daily injection of insulin glargine.     

Comparative study on the efficacy of pioglitazone in Caucasian and Maori-Polynesian patients with poorly controlled type 2 diabetes

AIM: Although the pharmodynamic properties of the thiazolidinedione (TZD) insulin-sensitizing agents in the treatment of type 2 diabetes are well established, there are no studies comparing the pharmacoefficacy of these drugs in different ethnic groups. The aim of this pilot, prospective study was to examine the hypothesis that the efficacy of TZDs may vary depending on ethnicity. This aim was achieved by comparing the effects of 6-months treatment with pioglitazone (45 mg/day) on glucose control and metabolic and cardiovascular risk factors in Caucasian and Maori-Polynesian patients with poorly controlled type 2 diabetes. METHODS: Ninety-seven patients (40 Caucasian and 57 Maori-Polynesian) with type 2 diabetes were selected for the study from our clinical databases if they were on the maximum tolerated dose of oral agents and had a haemoglobin A(1c) (HbA(1c)) > 8.0% for at least 2 months. All the patients received pioglitazone (45 mg/day) for 6 months in addition to their regular diabetes therapy. Clinical data and blood samples were collected at monthly intervals and the following indices measured: weight, blood pressure, oedema score, HbA(1c), plasma glucose, alanine amino transferase and adiponectin levels and plasma lipid profile, including low-density lipoprotein (LDL)-cholesterol particle size and atherogenic index of plasma (AIP). The data of the 81 patients who finished the study were analysed using analysis of variance, chi-square analysis and multiple regression methods. RESULTS: The absolute change from baseline in mean HbA(1c) (Caucasian -1.4% vs. Maori-Polynesian -1.3%) and fasting glucose levels (Caucasian -2.1 mmol/l vs. Maori-Polynesian -2.8 mmol/l) was similar in the two groups. Pioglitazone caused an improvement in lipid profile in both ethnic groups, with a reduction in mean values of atherogenic fractions (triglyceride: Caucasian -0.5 mmol/l, p < 0.001 vs. Maori-Polynesian -0.3 mmol/l, p = 0.05; very low-density lipoprotein (VLDL)-cholesterol: Caucasian -0.11 mmol/l, p = 0.001 vs. Maori-Polynesian -0.04 mmol/l, p = 0.85; VLDL-triglyceride: Caucasian -0.36 mmol/l, p < 0.001 vs. Maori-Polynesian -0.22 mmol/l, p = 0.14; apolipoprotein B: Caucasian -0.09 mmol/l, p = 0.03 vs. Maori-Polynesian -0.08 mmol/l, p = 0.18). These changes were associated with an increase in LDL-cholesterol particle size (Caucasian +0.23 nm, p = 0.05 vs. Maori-Polynesian +0.26 nm, p = 0.04) and a decrease in AIP (Caucasian -0.14, p < 0.001 vs. Maori-Polynesian -0.08, p = 0.04). While the changes in the lipid indices tended to be greater in the Caucasian group, the difference in lipid response between the two ethnic groups was not statistically significant. Multiple regression analyses showed that the baseline value of the individual lipid fractions was the main determinant of the changes in lipid levels. CONCLUSIONS: These results demonstrated that pioglitazone has similar beneficial effects on glucose control and plasma lipid profile in Caucasian and Maori-Polynesian patients with poorly controlled type 2 diabetes. Our data showed that while the improvement in lipid profile was more pronounced in Caucasian patients than in Maori-Polynesian patients, this difference was not statistically significant.     

Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes.

AIMS: This study compared the effects of 52 weeks' treatment with pioglitazone, a thiazolidinedione that reduces insulin resistance, and glibenclamide, on insulin sensitivity, glycaemic control, and lipids in patients with Type 2 diabetes. METHODS: Patients with Type 2 diabetes were randomized to receive either pioglitazone (initially 30 mg QD, n = 91) or micronized glibenclamide (initially 1.75 mg QD, n = 109) as monotherapy. Doses were titrated (to 45 mg for pioglitazone and 10.5 mg for glibenclamide) to achieve glycaemic targets during the next 12 weeks: fasting blood glucose of < or = 7 mmol/l and 1-h postprandial blood glucose of < or = 10 mmol/l. Patients were maintained on the titrated dose for 40 weeks. RESULTS: Pioglitazone significantly increased insulin sensitivity compared with glibenclamide, as assessed by homeostasis model assessment (17.0% vs. -13.0%; P < 0.001), quantitative insulin sensitivity check index (0.011 vs. -0.007; P < 0.001) and fasting serum insulin (-1.3 pmol/l vs. 23.8 pmol/l; P = 0.007). The glibenclamide group had significantly lower HbA1c than the pioglitazone group after 12 weeks of therapy (7.8% vs. 8.3%, P = 0.015), but significantly higher HbA1c after 52 weeks of therapy (7.8% vs. 7.2%, P = 0.001). Pioglitazone significantly (vs. glibenclamide) increased mean HDL-C (P < 0.001), decreased mean triglycerides (P = 0.019), and decreased mean atherogenic index of plasma (AIP; P = 0.001) and mean total cholesterol/HDL-C (P = 0.004), without significantly elevating mean total cholesterol or mean LDL-C compared with glibenclamide. CONCLUSIONS These data suggest that the effects of pioglitazone are more sustained than those of glibenclamide for improving insulin sensitivity in patients with Type 2 diabetes, and that 52 weeks' treatment with pioglitazone has favourable effects on glycaemic control and lipoprotein profile.     

甘精胰岛素联合口服降糖药物对血糖控制不佳的2型糖尿病患者的疗效观察

目的 评价甘精胰岛素(来得时(R))与盐酸吡格列酮和二甲双胍联合应用治疗口服降糖药物控制不佳的2型糖尿病患者的有效性和安全性.方法 采用随机法将78例口服降糖药物控制不佳的2型糖尿病患者分为A、B两组.A组为甘精胰岛素(来得时(R))组,B组为精蛋白锌胰岛素(诺和灵N)组,两组均口服吡格列酮和二甲双胍,观察治疗后空腹血...     

Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study

Aims: To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5–11.0%). Methods: Patients were randomized to receive the initial combination of 30 mg pioglitazone plus 5 mg linagliptin (n = 259) or pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication. Results: After 24 weeks of treatment, the adjusted mean change (±s.e.) in HbA1c with the initial combination of linagliptin plus pioglitazone was ?1.06% (±0.06), compared with ?0.56% (±0.09) for placebo plus pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was ?0.51% (95% confidence interval [CI] ?0.71, ?0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone; ?1.8 and ?1.0 mmol/l, respectively, equating to a treatment difference of ?0.8 mmol/l (95% CI ?1.2, ?0.4; p < 0.0001). Patients taking linagliptin plus pioglitazone, compared with those receiving placebo plus pioglitazone, were more likely to achieve HbA1c of <7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of ≥0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). β‐cell function, exemplified by the ratio of relative change in adjusted mean HOMA‐IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus pioglitazone patients and none in the placebo plus pioglitazone group. Conclusion: Initial combination therapy with linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment.     

Effects of health maintenance organization coverage of self-monitoring devices on diabetes self-care and glycemic control

BACKGROUND: Increasingly, government mandates require insurance coverage of blood glucose monitors and test strips for patients with type 1 and type 2 diabetes. No data exist on the effects of such coverage on self-monitoring of blood glucose (SMBG), medication compliance, or blood glucose control. We evaluated whether a policy providing free blood glucose monitors increased SMBG and whether initiating SMBG was associated with increased regularity of medication use and improved glucose control (hemoglobin A(1c) [HbA(1c)] level). METHODS: Using interrupted time-series analysis and controlling for preintervention trends, we determined changes in rates of SMBG 2 years before and after the policy among 3219 continuously enrolled patients with diabetes receiving drug therapy within a multispecialty medical group (part of a health maintenance organization) serving approximately 300 000 patients. We also compared changes over time in regularity of medication use (mean days between dispensings) and mean HbA(1c) level among initiators and noninitiators of SMBG. RESULTS: The policy resulted in a small, significant increase in SMBG among insulin-treated patients (n = 1428). Among sulfonylurea-treated patients (n = 1791), the monthly initiation rate of SMBG increased by 14 new patients per 1000 (95% confidence interval [CI], 10 to 17), a doubling of the expected initiation rate. Test strip consumption increased during the first 6 months after the policy by 17.9 strips per cohort member (75% relative increase by 6 months; 95% CI, 50% to 101%). Compared with noninitiators of SMBG, initiators (n = 593) showed sudden, significant improvements in regularity of medication use by 6 months after initiation (-19.5 days between dispensings among those with low refill regularity [95% CI, -27.7 to -11.3]; -9.7 days among those with moderate regularity [95% CI, -12.3 to -7.1]), and in glucose control (-0.63% mean HbA(1c) level [as percentage of total hemoglobin] among those with poor baseline glycemic control [HbA(1c) >10%; 95% CI, -1.14% to -0.12%]). CONCLUSIONS: Providing free glucose monitors improved rates of self-monitoring in this health maintenance organization population, possibly by offering an initial incentive for patients to engage in more desirable patterns of care. Initiating SMBG was associated with increased regularity of medication use and a reduction in high blood glucose levels.     

Is the frequency of self-monitoring of blood glucose related to long-term metabolic control? Multicenter analysis including 24,500 patients from 191 centers in Germany and Austria.

Blood glucose measurements are generally accepted components of a modern diabetes self-management. The value of self-monitoring of blood glucose (SMBG) is, however, discussed controversially and only a few studies addressed the efficacy of SMBG under real-life conditions so far. In order to investigate whether the frequency of SMBG is related to long-term metabolic control, data from the DPV-Wiss-database, a standardized,prospective, computer-based documentation of diabetes care and outcome, were analyzed for patients with type 1(n = 19,491) and type 2 (n = 5,009) diabetes from 191 centers in Germany and Austria. Local HbA1c reference ranges were mathematically adjusted to the DCCT reference. For each patient, data from the most recent year of diabetes care were used. On average,patients with type 1 diabetes performed 4.4 blood glucose measurements/day. Corrected for age, gender, diabetes duration,on intensified (>or=4 daily injections or CSII) therapy (HbA1c reduction of 0.32% for one additional SMBG/day) compared to patients on conventional (1-3 daily injections) therapy(HbA1c-reduction of 0.16% for one additional SMBG/day). In 2,021 patients with insulin-treated type 2 diabetes (2.7 measurements/day), more frequent SMBG was associated with better metabolic control (HbA1c-reduction of 0.16% for one additionalSMBG/day, p < 0.0001), while in 2,988 patients on OAD or diet alone (2.0 measurements/day), more frequent blood glucose measurements were associated with higher HbA1c-levels(HbA1c-increase of 0.14% for one additional SMBG/day,p < 0.0001). These data indicate that more frequent SMBG are associated with better metabolic control in both, patients with type 1 and insulin-treated type 2 diabetes. Since no benefit ofSMBG on metabolic control was found in patients with type 2 diabetes on OAD or diet alone, SMBG should primarily be recommended for those patients with suboptimal metabolic control whereas the benefit of SHBG in non-insulin-treated patients with adequate HbA1c-levels remains uncertain.insulin therapy and center difference, the SMBG frequency was associated with better metabolic control (HbA1c-reduction of0.26% for one additional SMBG/day, p < 0.0001). HbA1c-reduction with higher frequency of SMBG was more pronounced in patients Blood glucose measurements are generally accepted components of a modern diabetes self-management. The value of self-monitoring of blood glucose (SMBG) is, however, discussed controversially and only a few studies addressed the efficacy of SMBG under real-life conditions so far. In order to investigate whether the frequency of SMBG is related to long-term metabolic control, data from the DPV-Wiss-database, a standardized,prospective, computer-based documentation of diabetes care and outcome, were analyzed for patients with type 1(n = 19,491) and type 2 (n = 5,009) diabetes from 191 centers in Germany and Austria. Local HbA1c reference ranges were mathematically adjusted to the DCCT reference. For each patient, data from the most recent year of diabetes care were used. On average,patients with type 1 diabetes performed 4.4 blood glucose measurements/day. Corrected for age, gender, diabetes duration,insulin therapy and center difference, the SMBG frequency wasassociated with better metabolic control (HbA1c-reduction of 0.26% for one additional SMBG/day, p < 0.0001). HbA1c-reduction with higher frequency of SMBG was more pronounced in patients on intensified (>or= 4 daily injections or CSII) therapy (HbA1c reduction of 0.32% for one additional SMBG/day) compared to patients on conventional (1-3 daily injections) therapy(HbA1c-reduction of 0.16% for one additional SMBG/day). In 2,021 patients with insulin-treated type 2 diabetes (2.7 measurements/day), more frequent SMBG was associated with better metabolic control (HbA1c-reduction of 0.16% for one additionalSMBG/day, p < 0.0001), while in 2,988 patients on OAD or diet alone (2.0 measurements/day), more frequent blood glucose measurements were associated with higher HbA1c-levels(HbA1c-increase of 0.14% for one additional SMBG/day, p < 0.0001). These data indicate that more frequent SMBG are associated with better metabolic control in both, patients with type 1 and insulin-treated type 2 diabetes. Since no benefit of SMBG on metabolic control was found in patients with type 2 diabetes on OAD or diet alone, SMBG should primarily be recommended for those patients with suboptimal metabolic control whereas the benefit of SHBG in non-insulin-treated patients with adequate HbA1c-levels remains uncertain.