Long‐term glycaemic control with metformin–sulphonylurea–pioglitazone triple therapy in PROactive (PROactive 17)

Aims We assessed the long‐term glycaemic effects and the safety profile of triple therapy with the addition of pioglitazone vs. placebo in patients with Type 2 diabetes treated with combined metformin–sulphonylurea therapy in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive). Methods In a post‐hoc analysis, we identified patients treated with metformin plus sulphonylurea combination therapy and not receiving insulin at baseline (n = 1314). In those patients, we compared the effects of pioglitazone (force‐titrated to 45 mg/day, n = 654) vs. placebo (n = 660) on glycated haemoglobin (HbA_1c) reduction, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of ≥ 90 days or ongoing use at death/final visit). Results Significantly greater reductions in HbA_1c and greater proportions of patients with HbA_1c at target were noted with pioglitazone vs, placebo, despite a decrease in the use of other oral glucose‐lowering agents. There was an approximate twofold increase in progression to permanent insulin use in the placebo group vs. the pioglitazone group: 31.1 vs. 16.1%, respectively, when added to combination therapy. The overall safety of the metformin–sulphonylurea–pioglitazone triple therapy was good. Conclusions Intensifying an existing dual oral therapy regimen to a triple oral regimen by adding pioglitazone to the classical metformin–sulphonylurea combination resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The advantages and disadvantages of adding pioglitazone instead of adding basal insulin should be assessed further.     

Long‐term glycaemic effects of pioglitazone compared with placebo as add‐on treatment to metformin or sulphonylurea monotherapy in PROactive (PROactive 18)

Aims To assess the long‐term glycaemic effects, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of ≥ 90 days or ongoing use at death/final visit) with pioglitazone vs. placebo in diabetic patients receiving metformin or sulphonylurea monotherapy at baseline in the PROspective pioglitAzone Clinical Trial in macroVascular Events (PROactive). Methods In PROactive, patients with Type 2 diabetes and macrovascular disease were randomized to pioglitazone (force titrated to 45 mg/day) or placebo, in addition to other existing glucose‐lowering therapies. In a post‐hoc analysis, we categorized patients not receiving insulin at baseline and treated by oral monotherapy into two main cohorts: add‐on to metformin alone (n = 514) and sulphonylurea alone (n = 1001). The follow‐up averaged 34.5 months. Results There were significantly greater reductions in glycated haemoglobin (HbA_1c) with pioglitazone than with placebo and more pioglitazone‐treated patients achieved HbA_1c targets, irrespective of the baseline oral glucose‐lowering regimen and despite a decrease in the use of other glucose‐lowering agents. Approximately twice as many in the placebo groups progressed to permanent insulin use than in the pioglitazone groups across the two cohorts: 3.4% for pioglitazone and 6.5% for placebo when added to metformin monotherapy and 6.3% and 14.8%, respectively, when added to sulphonylurea monotherapy. The overall safety of both dual therapies was good. Conclusions Intensifying an existing oral monotherapy regimen to a dual oral regimen by adding pioglitazone resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The efficacy and safety of adding pioglitazone to either metformin monotherapy or sulphonylurea monotherapy were good.     

Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus

Aim: Colesevelam lowers glucose and low‐density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control. Methods: In this 12‐week, randomized, double‐blind, placebo‐controlled study, subjects with type 2 diabetes and haemoglobin A_1c(HbA_1c) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of ³H‐labelled glucose followed by a 2‐step hyperinsulinemic–euglycemic clamp. Two 75‐g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co‐administration of colesevelam. A final OGTT was conducted at week 12. HbA_1c and fasting plasma glucose (FPG) levels were evaluated pre‐ and post‐treatment. Results: Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady‐state glucose disposal rate. At baseline, co‐administration of colesevelam with oral glucose reduced total area under the glucose curve (AUC_g) but not incremental AUC_g. At week 12, neither total AUC_g nor incremental AUC_g were changed from pre‐treatment values in either group. Post‐load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUC_i) and incremental AUC_i did not differ between groups. Both HbA_1c and FPG improved with colesevelam, but treatment differences were not significant. Conclusions: Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption.     

Glycaemic and nonglycaemic effects of pioglitazone in triple oral therapy of patients with type 2 diabetes

Objectives. To examine pioglitazone as add‐on to metformin and insulin secretagogues in patients with type 2 diabetes and inadequate glycaemic control and its effect on glycaemic control, surrogate measures of insulin sensitivity (adiponectin) and β‐cell function (proinsulin/insulin) and fluid retention. Design and setting. Prospective open‐label study of 54 patients with type 2 diabetes and HbA_1c≥6.5% admitted to outpatient unit at Malmö University Hospital. The patients received 30–45 mg pioglitazone daily during 26 weeks in addition to their existing antidiabetic medication. After 26 weeks, one‐third of patients were followed for 3 months without pioglitazone. Results. HbA_1c decreased (7.8 ± 0.9–6.3 ± 0.9%, P < 0.001) with 61% of patients achieving levels <6.5%. However, in the group followed for another 3 months HbA_1c increased (6.1 ± 0.73–7.1 ± 0.9, n = 18, P < 0.001) after pioglitazone withdrawal. Adiponectin increased (6.1 ± 2.8–13.2 ±5.8 μg mL^?1, P < 0.001) and the proinsulin to insulin ratio decreased (0.89 ± 0.66–0.66 ± 0.53, P < 0.001). Nt‐proBNP increased from 487.3 ± 252.2 to 657.8 ± 392.1 pmol L^?1 (P < 0.001). Conclusions. Pioglitazone is effective in achieving glycaemic targets and reducing risk factors involved in atherosclerosis and improving β‐cell function when used as part of triple oral therapy in patients with type 2 diabetes and secondary drug failure. Nt‐proBNP increase with concomitant decrease in haemoglobin suggests a subclinical sign of fluid retention.     

Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATETM study

Aims: To compare efficacy and safety of two fasting plasma glucose (FPG) titration targets [4.4–6.1 mmol/l (80–110 mg/dl) and 3.9–5.0 mmol/l (70–90 mg/dl)] using a patient‐directed, treat‐to‐target algorithm for once‐daily basal insulin in insulin‐naïve subjects with type 2 diabetes suboptimally treated with oral antidiabetes drugs (OADs). Methods: In this 20‐week, randomized, controlled, open‐label, multicentre, treat‐to‐target study, 244 insulin‐naïve subjects with type 2 diabetes, HbA_1c≥7.0 and ≤9.0% on OAD treatment, were randomized (1 : 1) to one of two treatment arms using 3.9–5.0 or 4.4–6.1 mmol/l FPG as titration targets. Once‐daily insulin detemir doses were adjusted using algorithm‐guided patient‐directed titration to achieve target FPG values. Results: Overall, the combined treatment groups achieved a mean HbA_1c level of 6.9% at the end of the study. Substantial reductions in HbA_1c were seen in both treatment groups, with the majority of subjects in both titration groups at the end of the study achieving the American Diabetes Association (ADA)‐recommended HbA_1c level of <7%. In the 3.9–5.0 mmol/l FPG target treatment group, HbA_1c values decreased from a baseline mean of 8.0% to 6.8% at 20 weeks. In the 4.4–6.1 mmol/l FPG target group, HbA_1c values decreased from 7.9% at baseline to 7.0% at 20 weeks (Intention to treat ‐ last observation carried forward data set). These decreases were significantly different between the two treatment groups (Least squares mean difference = ?0.271, 95% CI ?0.441 to ?0.101, p = 0.0019), favouring the FPG target of 3.9–5.0 mmol/l vs. the 4.4–6.1 mmol/l target. At the end of the study period, 64.3% of subjects in the 3.9–5.0 mmol/l treatment group achieved HbA_1c levels <7% compared with 54.5% of subjects in the 4.4–6.1 mmol/l group (95% CI 1.03–3.37, odds ratio 1.86, p = 0.04). Insulin detemir dosing patterns were similar between treatment groups, with the 3.9–5.0 mmol/l group using slightly greater doses throughout the study period (0.57 U/kg vs. 0.51 U/kg at the end of the study). Overall rates of hypoglycaemia episodes were low and were comparable between treatment groups (7.73 and 5.27 events/subject/year for the 3.9–5.0 and 4.4–6.1 mmol/l groups, respectively). A single event of major hypoglycaemia was reported in the 3.9–5.0 mmol/l group. Mean weight changes from baseline to the end of the study were small and did not differ significantly between treatment groups. Conclusions: The 3.9–5.0 mmol/l FPG target showed superior efficacy compared with the 4.4–6.1 mmol/l target, although both FPG titration targets resulted in substantial reductions of HbA_1c in patients with type 2 diabetes using a patient‐directed insulin titration algorithm. A majority of subjects in both titration groups achieved the ADA‐recommended guideline of <7% HbA_1c at the end of the study with low rates of hypoglycaemia. These data indicate that lowering the fasting glucose target using a self‐directed titration algorithm with once‐daily detemir is safe and increases the likelihood of achieving the target level of HbA_1c. Indeed, using this approach, a majority of patients can achieve an HbA_1c of <7%.     

Potential benefits of early addition of rosiglitazone in combination with glimepiride in the treatment of type 2 diabetes

Aim: To assess the efficacy and tolerability of early combination therapy with rosiglitazone (RSG) and glimepiride (GLIM) vs. GLIM monotherapy in patients with type 2 diabetes mellitus (T2DM). Methods: Strategies for the addition of RSG in combination with GLIM were evaluated with data from two randomized, double‐blind, placebo (PBO)‐controlled studies. Study A – addition of RSG (4 or 8 mg) or PBO to continued GLIM 3 mg once daily; study B – addition of low‐dose RSG (4 mg) prior to uptitration of GLIM (from 2 to 4 mg) vs. continued uptitration of GLIM (from 2 to 8 mg). Results: Study A reported significant reductions in fasting plasma glucose (FPG) from baseline to week 26 with the addition of both 4 and 8 mg RSG to GLIM 3 mg [?21 mg/dl (?1.2 mmol/l), p = 0.0019 and ?43 mg/dl (?2.4 mmol/l), p < 0.0001, respectively] and in haemoglobin A_1c (HbA_1c) (?0.63%, p = 0.00015 and ?1.17%, p < 0.0001, respectively) from a baseline of 8.2 and 8.1%, respectively. At the end of the study, target HbA_1c <7.0% was achieved in 43 and 68% of patients in the RSG 4 mg + GLIM and RSG 8 mg + GLIM groups, respectively, compared with 32% in the PBO + GLIM (GLIM alone) group. In study B, addition of RSG to GLIM reduced mean FPG and HbA_1c levels at week 24 from baseline [?28 mg/dl (?1.5 mmol/l), p < 0.0001, and ?0.68%, p < 0.0001, respectively]. There were no significant changes with GLIM monotherapy in either study. Favourable effects of RSG + GLIM on insulin sensitivity, β‐cell function and cardiovascular disease biomarkers were also observed. All treatments were similarly well tolerated. Conclusions: Early addition of RSG to GLIM is an effective and well‐tolerated treatment option to improve glycaemic control in sulphonylurea‐treated patients with T2DM.     

Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes

Aims: To evaluate the efficacy and safety of initial therapy with a fixed‐dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug‐naÏve patients with type 2 diabetes. Methods: After a 2‐week single‐blind placebo run‐in period, patients with type 2 diabetes, HbA1c of 7.5–12% and not on antihyperglycaemic agent therapy were randomized in a double‐blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up‐titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. Results: From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were ?1.9 and ?1.4% for sitagliptin/metformin and pioglitazone, respectively (between‐group difference = ?0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [?56.0 mg/dl (?3.11 mmol/l) vs. ?44.0 mg/dl (?2.45 mmol/l), p < 0.001] and in 2‐h post‐meal glucose [?102.2 mg/dl (?5.68 mmol/l) vs. ?82.0 mg/dl (?4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [?40.5 mg/dl (?2.25 mmol/l) vs. ?13.0 mg/dl (?0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of β‐cell function (HOMA‐β) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA‐IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (?1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between‐group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between‐group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). Conclusion: Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain.     

Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients

The aim of the study was to compare the effects of the addition of sitagliptin or metformin to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients on body weight, glycemic control, β-cell function, insulin resistance, and inflammatory state parameters. One hundred fifty-one patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA_1c] >7.5%) in therapy with pioglitazone 30 mg/d were enrolled in this study. We randomized patients to take pioglitazone 30 mg plus sitagliptin 100 mg once a day, or pioglitazone 15 mg plus metformin 850 mg twice a day. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA_1c, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment β-cell function index, fasting plasma proinsulin (Pr), Pr/FPI ratio, adiponectin, resistin (R), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein. A decrease of body weight and body mass index was observed with metformin, but not with sitagliptin, at the end of the study. We observed a comparable significant decrease of HbA_1c, FPG, and PPG and a significant increase of homeostasis model assessment β-cell function index compared with baseline in both groups without any significant differences between the 2 groups. Fasting plasma insulin, fasting plasma Pr, Pr/FPI ratio, and HOMA-IR values were decreased in both groups even if the values obtained with metformin were significantly lower than the values obtained with sitagliptin. There were no significant variations of ADN, R, or TNF-α with sitagliptin, whereas a significant increase of ADN and a significant decrease of R and TNF-α values were recorded with metformin. A significant decrease of high-sensitivity C-reactive protein value was obtained in both groups without any significant differences between the 2 groups. There was a significant correlation between HOMA-IR decrease and ADN increase, and between HOMA-IR decrease and R and TNF-α decrease in pioglitazone plus metformin group after the treatment. The addition of both sitagliptin or metformin to pioglitazone gave an improvement of HbA_1c, FPG, and PPG; but metformin led also to a decrease of body weight and to a faster and better improvement of insulin resistance and inflammatory state parameters, even if sitagliptin produced a better protection of β-cell function.     

Association of treatment-achieved HbA1c with incidence of coronary artery disease and severe eye disease in diabetes patients

AimTo examine the association between treatment-achieved HbA_1c values and incidence of both coronary artery disease (CAD) and severe eye disease with different diabetes treatments.MethodsAssociations of treatment-achieved HbA_1c were investigated in various treatment groups [diet only; insulin; sulphonylurea (SU) alone; SU with glinides; and antihyperglycaemic agents other than glinides, SU or insulin] taken from a nationwide claims database of 14,633 Japanese diabetes patients. Cox’s regression analysis examined risks over a 5.1-year follow-up.ResultsA significant linear trend was associated with HbA_1c levels and CAD events in the diet-only group, and CAD risks were significantly higher in insulin and SU groups with HbA_1c ≤ 7.0% and > 8.0% than in the diet-only group with HbA_1c ≤ 7.0%. In contrast to CAD, a linear association was observed regardless of treatment modality between achieved HbA_1c levels and risk of severe diabetic eye disease, but with no significant difference in eye disease risk between groups with HbA_1c ≤ 7.0% and 7.1–8.0% in those treated with either SU alone, SU with glinides, or insulin.ConclusionThese findings suggest that the relationship between treatment-achieved HbA_1c and incidence of both CAD and severe diabetic eye disease differed according to treatment, based on a large-scale real-life database. More research is now needed to confirm these findings and to further investigate the underlying mechanisms.     

Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin

Aim: To compare the tolerability and efficacy of vildagliptin to pioglitazone as add‐on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy over 1‐year duration. Methods: This 52‐week, multicentre, randomized, active‐controlled study compared vildagliptin (50 mg b.i.d., n = 295) and pioglitazone (30 mg daily, n = 281) in patients with inadequate glycaemic control [haemoglobin A1c (HbA_1c) 7.5–11%] receiving a stable dose of metformin (≥1500 mg). The primary objective was to demonstrate non‐inferiority of vildagliptin at 24 weeks in the change in HbA_1c from baseline. The objective of the additional 28 weeks of the study was to assess long‐term safety, while also assessing mean change from baseline to study end in HbA_1c, fasting plasma glucose and body weight. Results: When added to a stable dose of metformin (mean baseline dose approximately 2 g/day), the non‐inferiority of HbA_1c lowering of vildagliptin to pioglitazone over 24 weeks was established at the non‐inferiority margin of 0.3% (between‐group difference = 0.1%). During the remaining 28 weeks, comparable HbA_1c decreases were recorded in both groups. Overall adverse event (AE) rates were similar in both groups, as was the occurrence of peripheral oedema. Hypoglycaemia occurred rarely in both groups. Serious AEs occurred more frequently with pioglitazone group. While mean body weight increased significantly in the pioglitazone group (+2.6 kg) from baseline, there was no significant weight gain with vildagliptin (+0.2 kg). Conclusions: When added to metformin, vildagliptin demonstrates favourable safety and tolerability over 1 year. Vildagliptin provided additional HbA_1c lowering to that achieved with metformin alone and comparable to that achieved with pioglitazone, with only pioglitazone causing weight gain.     

Efficacy of pioglitazone on glycemic control and carotid intima‐media thickness in type 2 diabetes patients with inadequate insulin therapy

Aims/Introduction: The present study was designed to determine the effects of pioglitazone on glycemic control and atherosclerosis in patients with poorly controlled type 2 diabetes on insulin therapy. Materials and Methods: The study was a prospective, randomized controlled trial involving 48 patients with inadequately controlled type 2 diabetes treated with insulin. We assigned patients to oral pioglitazone titrated from 15–30 mg (n = 22) or no pioglitazone (n = 26), to be taken in addition to their glucose‐lowering drugs and other medications. Daily insulin doses and numbers were recorded during the study period. Results: The adjusted mean glycosylated hemoglobin (HbA_1c) values decreased significantly by 1.13 ± 1.50% and 0.55 ± 0.76% in the pioglitazone and control groups, respectively. Significant decrease of HbA_1c level was observed in the pioglitazone group compared with the control group (P < 0.05). The insulin dose lowered by 0.04 ± 0.10 units/kg/day in the pioglitazone group and increased by 0.03 ± 0.10 units/kg/day in the control group (P < 0.05). The number of insulin injections decreased by 0.1 ± 0.6 times/day in the pioglitazone group and increased by 0.2 ± 0.4 times/day in the control group (P < 0.05). The carotid intima‐media thickness estimated by B‐mode echography was carried out in both groups and decreased significantly at the end‐point only in the pioglitazone group, relative to the baseline. Conclusions: These findings show that pioglitazone is useful in improving glycemic control and preventing the progression of atherosclerosis in poorly‐controlled type 2 diabetics on insulin therapy. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00064.x, 2010)     

Treatment choice and effectiveness of adding sulphonylurea or glitazones to metformin for the treatment of type 2 diabetes mellitus

Aim: This study investigates the treatment choice between, and the effectiveness of, adding sulphonylurea or glitazone to ongoing metformin therapy for patients with type 2 diabetes mellitus in the clinical practice setting. Methods: A multicentre observational study using data from clinical records was conducted in Finland, France, Germany, Norway, Poland, Spain and the UK. Data were collected for patients who added sulphonylurea or glitazone to metformin. Effectiveness was defined as a change in haemoglobin A1c (HbA_1c) from baseline to approximately 1 year after the initiation of additional therapy. To allow for comparisons between the two medication regimens, propensity score matching was employed. Treatment choice was analysed using a probit regression model. We hypothesized that treatment choice was associated with factors reflecting patient’s characteristics, patient’s experience with diabetes, patient‘s health or to physician’s characteristics at baseline. Results: Compared with baseline, adding sulphonylurea to metformin reduced HbA_1c by 0.8% (p < 0.0001), while adding glitazone to metformin reduced HbA_1c by 0.9% (p < 0.0001). Percentage at HbA_1c goal (6.5%) increased from 6.9 to 23.8% for the sulphonylurea group and 8.3 to 33.3% for the glitazone group. Both groups had similar changes in high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol and triglycerides. In the probit regression model, age, HbA_1c, weight, treatment for weight reduction, history of macrovascular complications and type of physician were significant factors associated with treatment choice. Conclusions: This study is consistent with the results of long‐term randomized clinical trials in a clinical practice setting. Both regimens were able to reduce HbA_1c by about 1%.     

Effect of HbA1c combined FPG on screening diabetes in health check-up

ObjectiveTo appraise the effectiveness of HbA_1c and fasting plasma glucose (FPG) on screening diabetes in health check-up.MethodsA total of 1 337 individuals (male 850, female 487), aged 27 to 91 years with HbA_1c test were included. Participates with HbA_1c ?6.0% or FPG?6.1 mmol/L underwent oral glucose tolerance test (OGTT). Diabetes mellitus was diagnosed according to the criteria of WHO in 1999, FPG?7.0 mmol/L and/or OGTT 2 h-postload plasm glucose (2 h-PG)?11.1 mmol/L. The sensitivity and specificity of HbA_1c thresholds and FPG or combination test on screening of diabetes were analyzed.ResultsA total of 842 subjects had HbA_1c <6.0%, in which 32 had isolated FPG?6.1 mmol/L, of 495 had HbA_1c?6.0%. Subjects with HbA_1c?6.0% had significant increased disorder indexes than those with HbA_1c<6.0%. 527 subjects who had HbA_1c?6.0% or FPG?6.1 mmol/L underwent OGTT. A total of 234 subjects were newly diagnosed diabetes, including 123 (123/234, 52.56%) with FPG?7.0 mmol/L, and 111 subjects (111/234, 47.43%) with isolated 2 h-PG?11.1 mmol/L. Among 234 new diabetes, 91.88% (215 subjects) had HbA_1c?6.3%, and 77.40% (181 subjects) had HbA_1c?6.5%. HbA_1c?6.3% combined FPG ?7.0 mmol/L increased the positive rate of newly diagnosed diabetes from 91.88% to 96.58%.ConclusionsHbA_1c is a practical and convenient tool for screening undiagnosed diabetes in routine health check-up of a large population. Combined use of HbA_1c?6.3% and/or FPG?7.0 mmol/L is efficient for early detection of diabetes.     

Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss

Background: Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss–independent effects. Aim: To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A_1c (HbA_1c)] are independent of weight loss. Methods: This retrospective analysis of pooled data from seven multicentre, double‐blind, placebo‐controlled studies involved overweight or obese patients with type 2 diabetes (aged 18–70 years). Patients were required to have a body mass index of 27–43 kg/m², HbA_1c of 6.5 to <13%, and stable weight for ≥3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. Results: A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo‐treated patients (?1.39 mmol/l vs. ?0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA_1c compared with placebo (?0.74% vs. ?0.31%; p < 0.0001). For patients with minimal weight loss (≤1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (?0.83 mmol/l vs. ±0.02 mmol/l; p = 0.0052) and HbA_1c?0.29% vs. ±0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA_1c) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. Conclusion: Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non‐esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon‐like peptide‐1 secretion in the lower small intestine.     

A long‐term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized,double‐blind,parallel‐group comparison trial

Aims This study compared the effects of pioglitazone and gliclazide on metabolic control in drug‐naïve patients with Type 2 diabetes mellitus. Methods A total of 1270 patients with Type 2 diabetes were randomized in a parallel‐group, double‐dummy, double‐blind study. Patients with poorly controlled Type 2 diabetes (HbA_1c 7.5–11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA_1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C‐peptide and pro‐insulin levels were measured. Results Mean HbA_1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: ?1.4%; gliclazide: ?1.4%; (90% CI: ?0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference ?0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: ?0.7 to ?0.1)]. Improvements in high‐density lipoprotein cholesterol (HDL‐C) and total cholesterol/HDL‐C were greater with pioglitazone than with gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with pioglitazone than with gliclazide. Conclusions Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA_1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.     

Colestilan monotherapy significantly improves glycaemic control and LDL cholesterol levels in patients with type 2 diabetes: a randomized double‐blind placebo‐controlled study

Aim: To evaluate the plasma glucose‐reducing activity and safety of colestilan, a bile acid sequestrant, in patients with type 2 diabetes. Methods: Patients with fasting plasma glucose (FPG) 7.2–11.1 mmol/l and HbA _1c≥7.0% were randomly allocated in double‐blind manner to receive colestilan or placebo therapy for 12 weeks. Results: A total of 183 patients entered the double‐blind treatment phase. At 12 weeks, colestilan significantly reduced HbA _1c and FPG vs. placebo by 0.9% and 1.2 mmol/l respectively (both p < 0.001). A significant (p < 0.001) 22.5% reduction of LDL cholesterol was also observed in the 172 patients evaluated (colestilan group: n = 86; placebo group: n = 86). However, no significant reduction of fasting insulin was observed (p = 0.087). No incidence of hypoglycaemia was reported in this study. Conclusion: Colestilan improved glycaemic control and reduced LDL cholesterol levels in patients with type 2 diabetes.     

Sibutramine effect on metabolic control of obese patients with type 2 diabetes mellitus treated with pioglitazone

Thiazolidinediones are supposed to be the pharmacologic agents that more physiologically fight the insulin resistance, but a possible adverse effect may be a weight increase. The aim of the study was to test the efficacy and tolerability of sibutramine on the metabolic effect of pioglitazone in obese patients with type 2 diabetes mellitus. All enrolled patients were required to have been diagnosed as being diabetic for at least 6 months and did not have glycemic control with diet and oral hypoglycemic agents such as sulfonylureas or metformin, both to the maximum tolerated dose. After a run-in period in which the eligible patients took a fixed dose of pioglitazone (30 mg/d), the patients were randomized to receive also sibutramine (10 mg/d) or placebo for 6 months. We assessed body mass index, hemoglobin A_1c (HbA_1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), lipid profile, lipoprotein parameters, and lipoprotein (a) at baseline and after 3 and 6 months. No body mass index change was observed after 3 and 6 months in the pioglitazone + placebo (pp) group. Significant decrease was present in the pioglitazone + sibutramine (ps) group after 3 (P < .05) and 6 months (P < .01) compared with the baseline values, and this variation was significant (P < .05) between groups. A significant HbA_1c decrease was observed after 3 (P < .05) and 6 months (P < .01) in both groups with respect to the baseline values. There was no difference in HbA_1c value between the 2 groups. No FPG, PPG, FPI, PPI, and homeostasis model assessment index change was observed at 3 months, whereas a significant decrease was present after 6 months (P < .05), in both groups with respect to the baseline values. There was no difference in FPG, PPG, FPI, PPI, and homeostasis model assessment index value between the pp and ps groups. No significant low-density lipoprotein cholesterol change was observed at 3 months, whereas a significant decrease was present after 6 months (P < .05), in both groups with respect to the baseline values. There was no difference in low-density lipoprotein cholesterol value between the pp and ps groups. No triglyceride variation was present at 3 and 6 months in the pp group and at 3 months in the ps group, whereas a significant decrease was observed at 6 months (P < .05) in the ps group with respect to the baseline values. There was no difference in triglyceride value between both groups. No high-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B, and lipoprotein (a) changes were present in both groups with respect to the baseline values. Sibutramine appears to be a tolerable and efficacious drug when added to pioglitazone for the global management of obese diabetic patients.     

The once‐daily human glucagon‐like peptide‐1 analog,liraglutide, improves β‐cell function in Japanese patients with type 2 diabetes

Aims/Introduction: β‐cell function was evaluated by homeostasis model assessment of β‐cell function (HOMA‐B) index, proinsulin:insulin and proinsulin:C‐peptide ratios in adult, Japanese type 2 diabetes patients receiving liraglutide. Materials and Methods: Data from two randomized, controlled clinical trials (A and B) including 664 Japanese type 2 diabetes patients (mean values: glycated hemoglobin [HbA_1c] 8.61–9.32%; body mass index [BMI] 24.4–25.3 kg/m²) were analyzed. In two 24‐week trials, patients received liraglutide 0.9 mg (n = 268) or glibenclamide 2.5 mg (n = 132; trial A), or liraglutide 0.6, 0.9 mg (n = 176) or placebo (n = 88) added to previous sulfonylurea therapy (trial B). Results: Liraglutide was associated with improved glycemic control vs sulfonylurea monotherapy or placebo. In liraglutide‐treated groups in trials A and B, area under the curve (AUC) _{insulin 0–3 h} was improved (P < 0.001 for all) and the AUC_{insulin 0–3 h}:AUC_{glucose 0–3 h} ratio was increased (estimated treatment difference [liraglutide–comparator] 0.058 [0.036, 0.079]). HOMA‐B significantly increased with liraglutide relative to comparator in trial B (P < 0.05), but not in trial A. The reduction in fasting proinsulin:insulin ratio was 50% greater than in comparator groups. Conclusions: In Japanese type 2 diabetes patients, liraglutide was associated with effective glycemic control, restoration of prandial insulin response and indications of improved β‐cell function. This trial was registered with Clinicaltrials.gov (trial A: no. NCT00393718/JapicCTI‐060328 and trial B: no. NCT00395746/JapicCTI‐060324). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00193.x, 2012)     

Taspoglutide,a once‐weekly glucagon‐like peptide 1 analogue,vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open‐label randomized trial

Aims To compare the efficacy and safety of once‐weekly taspoglutide with insulin glargine in patients with advanced Type 2 diabetes failing metformin and sulphonylurea combination therapy. Methods This open‐label, parallel‐group, multi‐centre trial randomized 1049 patients continuing metformin 1:1:1 to taspoglutide 10 mg once weekly, taspoglutide 20 mg once weekly or insulin glargine once daily with forced titration to fasting plasma glucose ≤ 6.1 mmol/l. Sulphonylureas were discontinued before randomization. The primary endpoint was change in HbA_1c after 24 weeks. Results After 24 weeks, least‐square mean changes from baseline in HbA_1c in patients receiving taspoglutide 10 mg [?8 mmol/mol (se 1)] [?0.77% (se 0.05)] or taspoglutide 20 mg [?11 mmol/mol (se 1)] [?0.98% (se 0.05)] were non‐inferior to insulin glargine [?9 mmol/mol (se 1)] [?0.84% (se 0.05)]; treatment difference of 0.07% (95% CI ?0.06 to 0.21) and ?0.14% (95% CI ?0.28 to ?0.01), for taspoglutide 10 and 20 mg, respectively, vs. insulin glargine. Taspoglutide was associated with more adverse events (mainly gastrointestinal) and significantly less hypoglycaemia than insulin glargine. Conclusions Compared with insulin glargine, taspoglutide provided non‐inferior HbA_1c reductions associated with less hypoglycaemia, but more gastrointestinal adverse events.     

An increase in insulin sensitivity and basal beta-cell function in diabetic subjects treated with pioglitazone in a placebo-controlled randomized study.

AIMS: To investigate the effect of treatment with pioglitazone on beta-cell function and insulin sensitivity in Type 2 diabetes. METHODS: Thirty subjects with diet-controlled Type 2 diabetes were randomized to 3 months treatment with pioglitazone (n = 19) or placebo (n = 11). All subjects underwent basal sampling for homeostatic model assessment (HOMA), followed by an intravenous glucose tolerance test and hyperglycaemic clamp, followed by an euglycaemic hyperinsulinaemic clamp; at baseline and after treatment. RESULTS: All results are expressed as mean (sem). Pioglitazone increased basal insulin sensitivity by 24.7% (7.8) HOMA-%S vs. 2.1% (5.9) in the placebo group (P = 0.02). Stimulated insulin sensitivity, M/I, increased in the pioglitazone group compared with placebo: +15.1 (2.8) l kg(-1) min(-1) vs. +3.2 (2.9) l kg(-1) min(-1), respectively (P = 0.009). Pioglitazone increased adiponectin by 39.3 (6.3), ng/ml compared with a decrease of 0.8 (1.3) ng/ml with placebo (P = 0.00004). HOMA-%B increased with pioglitazone, +11.5% (4.8) vs. -2.0% (4.8) with placebo (P = 0.049), but there was no change in stimulated beta-cell function as determined by hyperglycaemic clamps. There was a significant reduction in the proinsulin/insulin ratio in the pioglitazone group, -0.057 (0.02) compared with placebo, +0.004 (0.02) (P = 0.03). There was a significant reduction in HbA(1c) of 0.6% (0.1) in the pioglitazone group compared with placebo (P = 0.003). There was no significant weight gain associated with pioglitazone therapy: +0.7 (sem 0.6) kg vs. +1.1 (sem 0.5) kg in placebo group (P = NS). CONCLUSIONS: Basal beta-cell function and insulin sensitivity improved following pioglitazone therapy. The improvement in proinsulin to insulin ratio suggests that beta-cells are under less stress.