Addition of pioglitazone to stable insulin therapy in patients with poorly controlled type 2 diabetes: results of a double-blind, multicentre, randomized study

AIM: To determine the effects of pioglitazone treatment combined with insulin on glucose and lipid metabolism in patients with type 2 diabetes. METHODS: In a multicentre, double-blind study, 690 patients [body mass index, 33.19 kg/m2 +/- 5.47; haemoglobin A1c (A1C), 9.78 +/- 1.51; mean duration, 12.9 years] with diabetes poorly controlled with a stable insulin dose (> 30 U/day for > or =30 days) were randomly allocated to pioglitazone 30 or 45 mg once daily for 24 weeks. RESULTS: In the pioglitazone 30- and 45-mg groups, respectively, 71 and 70% of patients completed the study. At 24 weeks, statistically significant, dose-dependent mean decreases from baseline were seen in the pioglitazone 30- and 45-mg groups for A1C (-1.17 and -1.46%, respectively) and fasting plasma glucose (-31.9 and -45.8 mg/dl, respectively). Insulin dosage also decreased significantly (-4.5 and -7.3 U, respectively; p < or = 0.05) from baseline. Decreases in triglycerides [pioglitazone 45 mg: -5.9% (p < or = 0.05)], very low-density lipoprotein cholesterol [pioglitazone 45 mg: -6.2% (p < or = 0.05)] and free fatty acids [-0.94 (p < or = 0.05) and -2.13 (p < 0.0001) mg/dl, respectively] and increases in high-density lipoprotein cholesterol (9.7 and 13.0%, respectively; p < 0.0001) also were observed from baseline. Small but significant increases in total and low-density lipoprotein cholesterol (p < 0.01) from baseline were observed. Mean weight gain was 2.9 and 3.4 kg in the respective groups; lower limb oedema was reported in 13 and 12% of patients, respectively. The incidences of oedema, weight gain and heart failure were not higher than anticipated in this population. No evidence of hepatotoxicity or clinically significant elevations in liver function test parameters was seen. CONCLUSIONS: In patients with poorly controlled type 2 diabetes, addition of pioglitazone to insulin significantly improved glycaemic control, had a positive effect on important components of the lipid profile in a dose-dependent manner and was generally well tolerated.     

Effect of nutrition on postprandial glucose control in hospitalized patients with type 2 diabetes receiving fully automated closed-loop insulin therapy

Fully automated closed-loop insulin delivery may offer a novel way to manage diabetes in hospital. However, postprandial glycaemic control remains challenging. We aimed to assess the effect of nutritional intake on postprandial glucose control in hospitalized patients with type 2 diabetes receiving fully closed-loop insulin therapy. The effects of different meal types and macronutrient composition on sensor glucose time-in-target (TIT, 3.9-10.0 mmol/L) and mean sensor glucose were assessed with hierarchical linear models using a Bayesian estimation approach. TIT was lower and the mean sensor glucose slightly higher, after breakfast compared with lunch and dinner, whereas the insulin dose was higher. Across meals, when carbohydrates were replaced by fat, or to a lesser extent by protein, postprandial glucose control improved. For breakfast, a 3.9% improvement in TIT was observed when 10% of the energy from carbohydrates was replaced by fat. Improvements were slightly lower during lunch and dinner (3.2% and 3.4%) or when carbohydrates were replaced by protein (2.2 and 2.7%, respectively). We suggest that reducing carbohydrate at the expense of fat or protein, could further improve glucose control during fully closed-loop insulin therapy in hospital.     

Acarbose and metabolic control in patients with type 2 diabetes with newly initiated insulin therapy

AIM: This study was designed to investigate the effect of acarbose in patients with type 2 diabetes with newly initiated insulin treatment who had previously been insufficiently controlled with oral antihyperglycaemic agents [haemoglobin A(1c) (HbA(1c)) >/= 8%]. METHODS: In this 20-week double-blind, placebo-controlled study, 163 patients were randomized to receive acarbose up to 100 mg three times a day or matching placebo. Both the groups were newly initiated with insulin, which was adjusted according to blood glucose values. Primary efficacy parameter was the change in HbA(1c) from baseline; changes in daily insulin doses were also assessed. RESULTS: Mean HbA(1c) was significantly reduced by acarbose compared with placebo (2.31 vs. 1.81%, p = 0.033). Insulin doses were comparable at the end of the study. There was no difference in blood glucose and triglyceride levels between the treatment groups. Postprandial serum insulin levels increased in both treatment arms owing to insulin administration but less so under acarbose. In contrast to the placebo group, an increase in body mass index was prevented for acarbose-treated patients. CONCLUSION: As adjunct administration to newly initiated insulin therapy, acarbose enhances the optimization of blood glucose control in patients with type 2 diabetes.     

Correlation between changes of blood pressure with insulin resistance in type 2 diabetes mellitus with 4 weeks of pioglitazone therapy

OBJECTIVE:

To examine effects of pioglitazone (PIO) on systolic, diastolic, pulse and mean blood pressures (SBP, DBP, PP and MP, respectively) in type 2 diabetes mellitus (T2DM).

MATERIALS AND METHODS:

One hundred and six normotensive patients with T2DM with mean fasting blood glucose (FBS; 183 ± 6 mg/dl) were randomly divided into two groups. Test group was treated with 15 mg of PIO in addition to metformin 500 mg three times per day in both groups. SBP, DBP, PP and MP and fasting insulin, FBS and lipid profiles were measured before and after PIO therapy.

RESULTS:

There was a significant reduction in SBP (123 ± 2 vs. 118 ± 2 mmHg, P < 0.05), PP (41 ± 1 vs. 37 ± 1 mmHg, P < 0.05), and MP (95 ± 1 vs. 91 ± 1, P < 0.05). Clinical reduction in DBP was observed but not significant (82 ± 2 vs. 81 ± 1 mmHg, P > 0.05). There was a significant correlation between decline in SBP and DBP with respective baseline values (r = 0.76, P < 0.001 and r = 0.62, P < 0.001, respectively). Changes in PP and MP strongly correlated with baseline values (r = 0.51, P < 0.05 and r = 0.56, P < 0.05, respectively). There was a parallel reduction of FBS (183 ± 2 vs. 121 ± 3, P < 0.001) but reduction in IR or lipid profiles was not significant in test group. Changes in BP were not significant in control group ( P > 0.05).

CONCLUSION:

PIO treatment of T2DM showed early reduction of SBP and MP within first 4 weeks. Results suggest that pharmacodynamic effects of PIO mainly affect the systolic component. We hereby suggest that reduction of BP by PIO is independent from mechanisms of changes in IR and dyslipidaemia in normotensive diabetic patients.     

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.     

Efficacy of two telemonitoring systems to improve glycaemic control during basal insulin initiation in patients with type 2 diabetes: The TeleDiab-2 randomized controlled trial

TeleDiab-2 was a 13-month randomized controlled trial evaluating the efficacy and safety of two telemonitoring systems to optimize basal insulin (BI) initiation in subjects with inadequately controlled type 2 diabetes (HbA1c, 7.5%-10%). A total of 191 participants (mean age 58.7 years, mean HbA1c 8.9%) were randomized into three groups: group 1(G1, standard care, n = 63), group 2 (G2, interactive voice response system, n = 64) and group 3 (G3, Diabeo-BI app software, n = 64). The two telemonitoring systems proposed daily adjustments of BI doses, in order to facilitate the achievement of fasting blood glucose (FBG) values targeted at ~100 mg/dL. At 4 months follow-up, HbA1c reduction was significantly higher in the telemonitoring groups (G2: −1.44% and G3: −1.48% vs. G1: −0.92%; P < 0.002). Moreover, target FBG was reached by twice as many patients in the telemonitoring groups as in the control group, and insulin doses were also titrated to higher levels. No severe hypoglycaemia was observed in the telemonitoring groups and mild hypoglycaemia frequency was similar in all groups. In conclusion, both telemonitoring systems improved glycaemic control to a similar extent, without increasing hypoglycaemic episodes.     

Efficacy and safety of empagliflozin in combination with insulin in Chinese patients with type 2 diabetes and insufficient glycaemic control: A phase III,randomized, double-blind,placebo-controlled,parallel study

Aim

To evaluate the efficacy and safety of empagliflozin in combination with insulin ± oral antidiabetic drugs (OADs) over 24 weeks, in Chinese patients with type 2 diabetes (T2D) who had insufficient glycaemic control.

Materials and Methods

This was a randomized, double-blind, placebo-controlled, parallel group, multicentre phase III study. Adult patients with T2D and insufficient glycaemic control who received insulin ± up to two OADs were randomized (1:1:1) to receive empagliflozin 10 or 25 mg, or placebo for 24 weeks. The primary endpoint was change from baseline in HbA1c at week 24.

Results

Of 219 randomized patients, 73 patients were in each treatment group; baseline characteristics were comparable among the groups. There was a significantly larger decrease from baseline in HbA1c (adjusted mean treatment difference −0.99 and −0.98 for in the empagliflozin 10 and 25 mg groups, respectively; P < .0001) with both doses of empagliflozin than with placebo. There were also significantly larger decreases from baseline in fasting plasma glucose, 2-hour postprandial glucose and body weight with both empagliflozin doses than with placebo. Among patients in the empagliflozin 10 mg, 25 mg and placebo groups, 17.8%, 9.6% and 11.0% reported confirmed hypoglycaemic events, respectively (nominal P = .2422 and .7661 in the empagliflozin 10 and 25 mg groups, respectively), and no Clinical Events Committee-confirmed diabetic ketoacidosis events were reported.

Conclusions

In Chinese patients with T2D, empagliflozin combined with insulin ± OADs improved glycaemic control and was well tolerated, without an increased risk of hypoglycaemia.     

Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients

Objective: We examined the effects of rosiglitazone treatment on profiles of adipocytokines levels, postprandial insulin and glucose excursion, lipids levels, comparing with those of pioglitazone treatment in patients with type 2 diabetes mellitus (T2DM). Methods: Changes in body weight, haemoglobin A_1c (HbA_1c), glucose/insulin/C‐peptide/free fatty acid (FFA) during 75 g oral glucose tolerance test (OGTT), HDL‐/LDL‐cholesterol, triglyceride (TG) and adipocytokines [tumour necrosis factor (TNF)‐α, leptin and adiponectin] were measured in T2DM patients treated with rosiglitazone, 8 mg/day (n = 35), or pioglitazone, 45 mg/day (n = 21), for 3 months. Results: After rosiglitazone or pioglitazone treatment, HbA_1c (8.6–7.2 vs. 8.3–6.9%, rosiglitazone vs. pioglitazone), fasting plasma glucose (190–144 vs. 178–140 mg/dl), fasting FFA (729–595 vs. 641–526 μEq/l), mean plasma glucose‐OGTT (292–229 vs. 285–233 mg/dl) and mean FFA‐OGTT (580–430 vs. 488–377 μEq/l) decreased similarly and all were statistically significant (p < 0.01). The insulinogenic index (ΔI_0–120/ΔG_0–120) (0.19–0.30 vs. 0.17–0.26) and Matsuda index of insulin sensitivity (2.0–3.1 and 2.7–4.3) increased (p < 0.01) similarly, despite increase in body weight (85–88 vs. 81–84 kg). TNF‐α (3.8–3.4 vs. 5.2–4.5 pg/ml) decreased (p < 0.05) and adiponectin (6.3–17.8 vs. 7.1–16.4 μg/ml) increased (p < 0.01), while leptin did not change following either treatment. After rosiglitazone treatment, plasma HDL‐cholesterol (34–38 mg/dl) and LDL‐cholesterol (103–120 mg/dl) increased (p < 0.01), while TGs (177–167 mg/dl) did not change significantly. After pioglitazone treatment, plasma HDL‐cholesterol (34–37 mg/dl) increased (p < 0.05), while LDL‐cholesterol (104–105 mg/dl) did not change and TGs (153–106 mg/dl) decreased (p < 0.01). Conclusions: Rosiglitazone and pioglitazone have similar beneficial effects on glycaemic control insulin sensitivity, insulin secretion and plasma adipocytokine levels. However, pioglitazone has a more beneficial effect on the plasma lipid profile than rosiglitazone.     

Reaching glycaemic targets while minimizing hypoglycaemia in insulin-treated type 2 diabetes patients

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by both insulin resistance and β-cell failure, resulting in a decline in insulin secretion and increased blood glucose levels. By the time T2DM is clinically diagnosed, only 50% of normal β-cell function remains, leading to altered control of fasting and/or postprandial glucose. The aim of this review is to summarize the options for introduction of basal insulin, in particular insulin glargine, and the advantages and disadvantages of using insulin glargine vs. alternative insulins or vs. oral agents. Overall, the studies included in this review show that insulin glargine is associated with a lower risk of hypoglycaemia vs. both neutral protamine Hagedorn insulin and premixed insulin formulations, alongside clinically important improvements in glycaemic control. Furthermore, insulin glargine is associated with greater improvements in glycaemic control vs. intensification of oral therapy. Thus, insulin glargine should be a preferred option when starting insulin therapy for people with T2DM.     

Leptin concentrations are related to glycaemic control, but do not change with short-term oral antidiabetic therapy in female patients with type 2 diabetes mellitus

This study evaluated the relation of leptin with glycaemic control and the effect of 14 days of diet, or diet combined with gliclazide, glipizide-GITS or metformin treatment, on leptin concentration in 51 female patients with type 2 diabetes mellitus. Leptin levels were similar both at baseline and after treatment in diabetic and control groups. Diabetic patients with basal fasting plasma glucose (FPG) < 10 mmol/l or with basal postprandial plasma glucose (PPPG) < 13.9 mmol/l had significantly higher leptin levels than diabetic patients with basal FPG > or = 10 mmol/l or with basal PPPG > or = 13.9 mmol/l (19.6+/-8.7 vs. 13.65+/-5.4 microg/l, p < 0.05; and 20.2+/-7.9 vs. 12.9+/-5.2 microg/l, p < 0.05, respectively). Mode of treatment did not influence leptin levels. Delta leptin showed a weak correlation with basal FPG (r = 0.346; p < 0.05), basal and post-treatment PPPG (r = 0.335, p < 0.05 and r = 0.325, p < 0.05, respectively) and a moderate correlation with post-treatment FPG (r = 0.391, p < 0.01). In conclusion, leptin level is not affected by the presence of type 2 diabetes mellitus and by short-term treatment with diet or oral antidiabetic drugs but is directly related to glycaemic control in female patients with type 2 diabetes mellitus.     

Addition of pioglitazone or bedtime insulin to maximal doses of sulfonylurea and metformin in type 2 diabetes patients with poor glucose control: a prospective, randomized trial

PURPOSE: To compare the efficacy of adding pioglitazone or bedtime isophane (NPH) insulin to maximal doses of metformin and an insulin secretagogue in patients with poor glucose control. METHODS: We conducted a nonblinded, open-label, randomized controlled trial involving 62 patients with type 2 diabetes and glycosylated hemoglobin (HbA1C) levels >8.0%. Patients received either pioglitazone or bedtime NPH insulin in addition to their usual diabetes medication for 16 weeks. Outcome measurements of glycemic control, hypoglycemia, blood pressure, lipid levels, microalbuminuria, and quality of life were assessed at baseline and at 16 weeks. RESULTS: HbA1C levels were lowered to a similar degree in each treatment arm (pioglitazone: -1.9% +/- 1.5%; insulin: -2.3% +/- 1.5%; P = 0.32), but hypoglycemia was less common among patients who received pioglitazone than those who received insulin (37% [11/30] vs. 68% [19/28], P=0.02). Pioglitazone, but not insulin, resulted in an increase in high-density lipoprotein (HDL) cholesterol levels. Both treatments had similar effects on weight, other lipid values, blood pressure, and urine microalbumin levels. CONCLUSION: Adding pioglitazone or bedtime insulin for 16 weeks improved glycemic control in type 2 diabetic patients with secondary oral agent failure. Pioglitazone was associated with less hypoglycemia and improved HDL cholesterol levels.     

Earlier triple therapy with pioglitazone in patients with type 2 diabetes

Aims: This study assessed the efficacy of add‐on pioglitazone vs. placebo in patients with type 2 diabetes uncontrolled by metformin and a sulphonylurea or a glinide. Methods: This multicentre, double‐blind, parallel‐group study randomized 299 patients with type 2 diabetes to receive 30 mg/day pioglitazone or placebo for 3 months. After this time, patients continued with pioglitazone, either 30 mg [if glycated haemoglobin A1c (HbA_1c) ≤6.5%] or titrated up to 45 mg (if HbA_1c >6.5%), or placebo for a further 4 months. The primary efficacy end‐point was improvement in HbA_1c (per cent change). Secondary end‐points included changes in fasting plasma glucose (FPG), insulin, C‐peptide, proinsulin and lipids. The proinsulin/insulin ratio and homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of β‐cell function (HOMA‐B) were calculated. Results: Pioglitazone add‐on therapy to failing metformin and sulphonylurea or glinide combination therapy showed statistically more significant glycaemic control than placebo addition. The between‐group difference after 7 months of triple therapy was 1.18% in HbA_1c and ?2.56 mmol/l for FPG (p < 0.001). Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA_1c level of <8.5% achieved the HbA_1c target of < 7.0% by final visit compared with 4.9% in the placebo group. When the baseline HbA_1c level was ≥ 8.5%, 13% achieved the HbA_1c target of < 7.0% in the pioglitazone group and none in the placebo group. HOMA‐IR, insulin, proinsulin and C‐peptide decreased and HOMA‐B increased in the pioglitazone group relative to the placebo group. Conclusions: In patients who were not well controlled with dual combination therapy, the early addition of pioglitazone improved HbA_1c, FPG and surrogate measures of β‐cell function. Patients were more likely to reach target HbA_1c levels (< 7.0%) with pioglitazone treatment if their baseline HbA_1c levels were < 8.5%, highlighting the importance of early triple therapy.     

Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes

Aim: This study assessed the efficacy and safety of two different dosing regimens of fixed‐dose combination (FDC) rosiglitazone (RSG) plus glimepiride (GLIM) compared with RSG or GLIM monotherapy in drug‐naive subjects with type 2 diabetes mellitus (T2DM). Methods: Drug‐naive subjects (n = 901) were enrolled into this 28‐week, double‐blind, parallel‐group study if their glycosylated haemoglobin A_1c (HbA_1c) was >7.5% but ≤12%. Subjects were randomized to receive either GLIM [4 mg once daily (OD) maximal], RSG (8 mg OD maximal) or RSG/GLIM FDC regimen A (4 mg/4 mg OD maximal) or RSG/GLIM FDC regimen B (8 mg/4 mg OD maximal). Patients were assessed for efficacy and safety every 4 weeks for the first 12 weeks of the study, and at weeks 20 and 28. The primary efficacy endpoint was change in HbA_1c from baseline. Key secondary endpoints included the proportion of patients achieving recommended HbA_1c and fasting plasma glucose (FPG) targets; change from baseline in FPG, insulin, C‐reactive protein (CRP), adiponectin, free fatty acids and lipids; and percentage change in homeostasis model assessment‐estimated insulin sensitivity and β‐cell function. Safety evaluations included adverse‐event (AE) monitoring and clinical laboratory evaluations. Results: At week 28, both RSG/GLIM FDC regimens significantly reduced HbA_1c (mean ± s.d.: ?2.4 ± 1.4% FDC regimen A; ?2.5 ± 1.4% FDC regimen B) to a greater extent than RSG (?1.8 ± 1.5%) or GLIM (?1.7 ± 1.4%) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 vs. both RSG and GLIM). Significantly more subjects achieved HbA_1c target levels of ≤6.5 and <7% with either RSG/GLIM FDC regimen compared with RSG or GLIM alone (model‐adjusted odds ratio, p < 0.0001 for both comparisons). Similarly, a significantly greater reduction in FPG levels was observed in subjects treated with the RSG/GLIM FDC [mean ± s.d. (mg/dl): ?69.5 ± 57.5 FDC regimen A; ?79.9 ± 56.8 FDC regimen B) compared with RSG (?56.6 ± 58.1) or GLIM (?42.2 ± 66.1) monotherapy (model‐adjusted mean treatment difference, p < 0.0001 for both comparisons). Improvement in CRP was also observed in subjects who were treated with a RSG/GLIM FDC or RSG monotherapy compared with GLIM monotherapy. RSG/GLIM FDC was generally well tolerated, with no new safety or tolerability issues identified from its monotherapy components, and a similar AE profile was observed across FDC regimens. The most commonly reported AE was hypoglycaemia, and the incidence of confirmed symptomatic hypoglycaemia (3.6–5.5%) was comparable among subjects treated with an RSG/GLIM FDC and GLIM monotherapy. Conclusions: Compared with RSG or GLIM monotherapy, the RSG/GLIM FDC improved glycaemic control with no significant increased risk of hypoglycaemia. RSG/GLIM FDC provides an effective and well‐tolerated treatment option for drug‐naive individuals with T2DM.     

Addition of canagliflozin to insulin improves glycaemic control and reduces insulin dose in patients with type 2 diabetes mellitus: A randomized controlled trial

The aim of this study was to evaluate the efficacy of canagliflozin in reducing the required insulin dose and the risk of hypoglycaemia in type 2 diabetes (T2D). This study was conducted in patients with T2D treated with insulin. They were randomly assigned to the control (n = 17) and canagliflozin (n = 17, plus 100 mg/day canagliflozin) groups. In both groups, a defined insulin dose adjustment protocol was applied to achieve the same level of glycaemic control. The change from baseline in daily insulin dose was significantly smaller in the canagliflozin group (3.9 units/day) than in the control group (13.4 units/day; P = 0.040). Low blood glucose index and predicted % of blood glucose (BG) <70 mg/dL, which are hypoglycaemia-related variables, worsened significantly in the control group but both remained unchanged in the canagliflozin group. The standard deviation for night-time BG levels improved significantly only in the canagliflozin group. Supplementation of insulin therapy with 100 mg canagliflozin in patients with T2D reduced the required insulin dose and hypoglycaemic risk and flattened night-time glycaemic fluctuations while maintaining the same level of glycaemic control.