Adding insulin glargine vs. NPH insulin to metformin results in a more efficient postprandial beta-cell protection in individuals with type 2 diabetes.

AIM: Postprandial release of intact proinsulin (IP) is an independent marker for beta-cell dysfunction in patients with type 2 diabetes. This open-label, parallel-group, two-arm, pilot study compared the beta-cell protective effect of adding insulin glargine (GLA) vs. NPH insulin to ongoing metformin. MATERIAL AND METHODS: Overall, 28 insulin-naive type 2 diabetes subjects (mean +/- SD age, 61.5 +/- 6.7 years; diabetes duration, 9.8 +/- 6.5 years; HbA1c, 7.1 +/- 0.5%; BMI, 30.7 +/- 4.3 kg/m(2)) treated with metformin and sulfonylurea were randomized to add once-daily GLA or NPH at bedtime. At baseline and after 3 months, subjects received a standardized breakfast, lunch and dinner, with pre- and postprandial blood sampling to measure plasma IP, total insulin and blood glucose (BG). RESULTS: Insulin dose after 3 months was comparable in both groups (GLA vs. NPH: 23.6 +/- 13.4 vs. 23.3 +/- 12.7; p = NS ). Both treatments significantly reduced fasting BG levels (GLA: 158 +/- 19 to 121 +/- 23 mg/dl; NPH: 156 +/- 34 to 119 +/- 29 mg/dl; both p < 0.01 vs. baseline). Fasting and postprandial BG levels did not differ between groups. IP levels decreased in both groups (p < 0.05 at all timepoints). Although IP release after breakfast did not differ between treatments, GLA induced a greater reduction in IP release after lunch (p = 0.08) and dinner (p = 0.04). Total plasma insulin levels did not differ between groups. CONCLUSIONS: Adding basal insulin to metformin reduces postprandial beta-cell load. While GLA and NPH had comparable effects at breakfast, GLA reduces beta-cell stress more effectively at dinner, and with a trend at lunch, most probably because of its longer lasting pharmacodynamic profile.

Successful switch from insulin therapy to treatment with pioglitazone in type 2 diabetes patients with residual beta-cell function: results from the PioSwitch study.

AIM: Insulin treatment is considered to be the final option for patients with progressive type 2 diabetes. This study investigated, whether reconverting type 2 patients from insulin treatment to oral treatment using pioglitazone is possible without deterioration of blood glucose control. METHODS: The PioSwitch study was a prospective, open label, proof of concept study. Thiazolidinedione-naïve patients with residual beta-cell function were switched from an existing insulin therapy to treatment with pioglitazone and glimepiride for 6 months. Efficacy was assessed by laboratory parameters and scores for evaluation of metabolic control, beta-cell function, insulin resistance and cardiovascular risk. RESULTS: In total, 98 patients [66 men, 32 women, age (mean +/- s.d.): 59 +/- 9 years; disease duration: 5.6 +/- 3.6 years; Hemoglobin A1c (HbA1c): 6.9 +/- 0.8%; body mass index (BMI): 33.9 +/- 5.2 kg/m(2), initial daily insulin therapy dose: 0.36 +/- 0.3 U/kg body weight] out of 117 screened patients were treated. During the observation period, 23 patients were prematurely terminated because of an increase in HbA1c from baseline > 0.5% or other reasons. In 75 patients (76%), no deterioration of glucose metabolism occurred and additional improvements were seen in the majority of the observation parameters [baseline vs. endpoint; HbA1c: 6.79 +/- 0.74%/6.66 +/- 0.69% (p < 0.05), glucose: 6.4 +/- 1.5/5.2 +/- 1.4 mmol/l (p < 0.001), adiponectin: 7 +/- 3 mg/l/17 +/- 8 mg/l (p < 0.001), C-peptide: 987 +/- 493/1756 +/- 789 (p < 0.001), sensitivity index derived from the intravenous glucose tolerance test (SI(ivGTT)): 1.21 +/- 0.85/1.49 +/- 0.95 (p < 0.05), hsCRP: 3.3 +/- 2.4/2.6 +/- 2.4 mg/l (p < 0.01), macrophage chemo-attractant protein 1 (MCP1): 487 +/- 246/382 +/- 295 ng/l (p < 0.05)]. BMI increased from 33.8 +/- 5.1 to 34.4 +/- 5.3 kg/m(2) (p < 0.001). CONCLUSIONS: The switch from insulin therapy resulting in a moderately HbA1c level, to oral treatment with pioglitazone was successful in a majority of patients with sufficient residual beta-cell function. It allows a simple and less expensive therapy with a better cardiovascular risk marker profile.

Cardiovascular effects of disturbed insulin activity in metabolic syndrome and in type 2 diabetic patients.

The metabolic syndrome is associated with an excess of increase in cardiovascular complications. Disturbances in insulin efficacy and insulin secretion are major features of the metabolic syndrome and might precede the development of diabetes mellitus by decades. Recent investigations highlighted the link between disturbances in insulin physiology and subsequent mechanisms of atherosclerosis. Insulin resistance is an early feature of increasing visceral adipose tissue and is directly associated to the activation of a couple of atherogenic pathways, including inflammation and the activation of the mitogen-activated proteinkinase pathway accelerating the atherogenic process. In patients with normal beta-cell function, insulin resistance is compensated by increased insulin release from the beta cells to keep blood glucose levels compensated. In those patients, genetically predisposed to type 2 diabetes, beta-cell function deteriorates with the development of timely, qualitative and quantitative insulin secretion disorders, and the development of overt diabetes mellitus. The coexistence of insulin resistance with functional beta cell failure results in loss of blood glucose control especially after a meal and increases the cardiovascular risk of these patients far beyond the increased glucose levels.

Prefilled insulin device with reduced injection force: patient perception and accuracy.

OBJECTIVE: The injection force and the patient perception of the Next Generation FlexPen (NGFP) with design modifications aimed at reducing injection force was assessed. The accuracy and precision of the NGFP was also tested under standard conditions. RESEARCH DESIGN AND METHODS: Dosing accuracy was tested (according to ISO 11608 requirements) at 1 IU, 30 IU and 60 IU doses (acceptable limits were 1 +/- 1 IU (0-2 IU), 30 +/- 1.5 IU (28.5-31.5 IU), and 60 +/- 3 IU (57-63 IU)). Pens were tested at reference conditions (18-28 degrees C and relative humidity 25-75%). Delivered doses were measured on a sensitive balance and corrected for the specific density of the insulin aspart used (according to ISO 11608-1). Precision was calculated from the variance around the mean delivered dose. The injection force of NGFP was measured, and user-preference of NGFP and FlexPen (FP) were compared in 50 patients with type 2 diabetes. RESULTS: The mean injection force with NGFP and FP was 12.57 +/- 1.81 N and 17.90 +/- 1.51 N (p<0.001), respectively. Almost twice as many patients rated the injection force as 'good' or 'very good' with NGFP (80%, 72% and 38% when delivering 20 IU, 40 IU and 60 IU, respectively) compared with FP (48%, 32% and 20% when delivering 20 IU, 40 IU and 60 IU, respectively) and 76% of patients rated NGFP as superior, in terms of simplicity and comfort, to FP. NGFP accurately delivered the set doses (means [SD] were 0.98 [0.06] IU, 29.98 [0.18] IU, and 59.93 [0.24] IU for the 1 IU, 30 IU and 60 IU doses, respectively). CONCLUSIONS: These results show that NGFP has a 30% reduction in injection force compared with FP and was rated as 'more simple and comfortable to use' by patients. Furthermore, NGFP was as accurate and as precise as FP.

Pleiotrophic and anti-inflammatory effects of pioglitazone precede the metabolic activity in type 2 diabetic patients with coronary artery disease.

We investigated MMP-9 levels and inflammatory markers during pioglitazone treatment in type 2 diabetic patients with cardiovascular disease. In this randomized multicenter, double blinded, placebo controlled study, 92 type 2 diabetic patients with angiographically proven CHD were randomly assigned to pioglitazone or placebo treatment. At baseline and during a 28 days observational period MMP-9, MCP1, hsCRP, IL-6, sCD40, and P-selectin were monitored. During Pioglitazone treatment, a 12% reduction in MMP-9 and a 18% reduction in hsCRP levels (p<0.05, respectively) could be observed already after 3 days. MCP-1 levels were reduced by 14% after 10 days of treatment (p<0.0001). At the end of the study, these parameters were significantly lower in the pioglitazone group as compared to the placebo group (MMP-9: 392+/-286 versus 427+/-166 ng/ml; hsCRP: 1.9+/-1.7 versus 3.1+/-2.3 ng/L; MCP-1: 413+/-115 versus 471+/-146 pg/ml; p<0.05, respectively). sCD40 levels decreased by 32.5% (p<0.05) and P-selectin decreased by 3.2% (p=0.053) in the pioglitazone group. No change could be found with regard to the other study endpoints. No changes in these parameters could be observed during placebo treatment. Even before effects on glucose metabolism could be obtained, pioglitazone exerts immediate effects on plasma markers of plaque vulnerability and inflammation.

Visfatin: a putative biomarker for metabolic syndrome is not influenced by pioglitazone or simvastatin treatment in nondiabetic patients at cardiovascular risk -- results from the PIOSTAT study.

OBJECTIVE: The aim of the study was to analyze the effect of pioglitazone (PIO) and simvastatin (SIMVA) on adiponectin and visfatin concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications in a prospective randomized clinical trial. RESEARCH DESIGN AND METHODS: One-hundred twenty-five nondiabetic patients with increased cardiovascular risk [78 females, 47 males, age (mean+/-STD:58.6+/-7.8years, BMI:30.8+/-4.2(kg/m2] were included after randomization to PIO+lacebo, SIMVA+placebo, or PIO+SIMVA treatment for 3 months. At baseline and endpoint, measurements of HbA1c, glucose, insulin, LDL cholesterol, adiponectin and visfatin were performed. Insulin resistance was assessed by means of the HOMAIR-score. RESULTS: Improvement in the HOMAIR-score was observed with PIO and the combination, but not with SIMVA alone, which was accompanied by an increase in adiponectin with PIO treatment groups, but a decrease with SIMVA alone (baseline/endpoint: PIO: 14.0+/-8.2 mg/l/ 27.6+/- 14.5 mg/l, p<0.05; PIO+SIMVA: 11.7+/-10.0 mg/l/26.7+/-15.7 mg/l, p<0.05; SIMVA: 15.5+/-12.7 mg/l/ 11.6+/-7.0 mg/l, p<0.05). No change could be observed in the visfatin concentrations (PIO: 47.6+/-14.5 ng/ml/48.0+/-11.6 ng/ml, PIO+SIMVA: 45.1+/-10.9 ng/ml/47.9+/-10.1 ng/ml, SIMVA: 49.2+/- 13.4 ng/ml/52.1+/-16.7 ng/ml, n. s. in all cases). CONCLUSIONS: Insulin resistance and/or cardiovascular risk indicators were not associated with visfatin levels. Regulation of visfatin secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin.

Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control.

New scores and biochemical markers have recently been published for diagnosis of insulin resistance and beta-cell dysfunction (such as intact proinsulin, adiponectin, IRISII-score). One goal of this 6-month prospective controlled study was to evaluate the impact of pioglitazone (45 mg) vs. glimepiride (1-6 mg, in the intend to optimize therapy) on these markers. Observation parameters were: IRIS-II score, HOMA-score, ATP III score, HbA (1c), fasting glucose, lipids, intact proinsulin, adiponectin, and adverse events. The study was completed by 173 patients (66 female, 107 male, age +/- STD: 63 +/- 8 years, disease duration: 7.2 +/- 7.2 years, HbA (1c): 7.53 +/- 0.85 %, pioglitazone arm: 89 patients). The groups were not different for any of the observation parameters at baseline, and a similar reduction in HbA (1c) was seen in both groups (p < 0.001). In the pioglitazone group, reductions were observed for the IRIS-II and HOMA scores (p < 0.001 vs. glimepiride at endpoint) fasting glucose (p < 0.001), insulin (p < 0.001), LDL/HDL ratio (p < 0.001), hsCRP (p < 0.05), intact proinsulin (p < 0.001), and an increase was seen in HDL (p < 0.001), adiponectin (p < 0.001) and BMI (p < 0.001). In conclusion, treatment with pioglitazone resulted in an improvement of markers for insulin resistance and beta-cell dysfunction, independent from blood glucose control. Adiponectin, intact proinsulin, and the IRIS-II score may be suitable parameters for monitoring of these additional beneficial therapeutic effects.

Pharmacological PPARgamma stimulation in contrast to beta cell stimulation results in an improvement in adiponectin and proinsulin intact levels and reduces intima media thickness in patients with type 2 diabetes.

The role of intact proinsulin and adiponectin in endothelial dysfunction and insulin resistance has been receiving increasing attention. This study investigates the effect of PPARgamma stimulation or beta-cell stimulation on metabolic and vascular parameters in patients with type 2 diabetes. In our study, 173 type 2 diabetic patients were recruited and randomly assigned to pioglitazone 45 mg or glimepiride 1 - 6 mg treatment. Intima media thickness of the carotid artery, glycemic control, insulin resistance, adiponectin and intact proinsulin levels were assessed at baseline and after six months of treatment. Despite similar improvements in metabolic control (HbA (1c) after 24 weeks: - 0.8 +/- 0.9% [pioglitazone] vs. - 0.6 +/- 0.8% [glimepiride]; mean +/- SD; p < 0.0001, respectively), improvements in intima media thickness (- 0.033 +/- 0.052 mm; p < 0.0001), proinsulin intact (- 5.92 +/- 10.04 pmol/l; p < 0.0001), adiponectin (10.9 +/- 6.3 microg/ml; p < 0.0001) and HOMA score (- 2.21 +/- 3.40; p < 0.0001) were observed by pioglitazone but not glimepiride treatment. Reduction in intima media thickness was correlated with improved insulin sensitivity (r = 0.29; p = 0.0003), and proinsulin intact levels (r = 0.22; p = 0.006), while an inverse correlation was found with adiponectin levels (r = - 0.37; p < 0.0001). Measurement of adiponectin and intact proinsulin enables characterization of the metabolic situation and an estimation of atherosclerotic risk in patients with type 2 diabetes.

Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study.

BACKGROUND: Patients with type 2 diabetes mellitus are at high risk of cardiovascular disease. Carotid intima-media thickness (IMT) is a strong predictor of myocardial infarction and stroke. METHODS AND RESULTS: We compared the effects of pioglitazone-based therapy (45 mg/d) and glimepiride-based treatment (2.7+/-1.6 mg/d) for 12 and 24 weeks on metabolic control (HbA1c), insulin resistance (homeostasis model assessment), and carotid IMT (B-mode ultrasonography) in a randomized controlled study in 173 orally treated patients with type 2 diabetes (66 women, 107 men; mean+/-SD age, 62.6+/-7.9 years; body mass index, 31.8+/-4.6 kg/m2; HbA1c, 7.5+/-0.9%). Treatment was generally well tolerated in both groups. Despite similar improvements in metabolic control (HbA1c) after 24 weeks (-0.8+/-0.9% [pioglitazone] versus -0.6+/-0.8% [glimepiride]; P=NS), carotid IMT was reduced only in the pioglitazone group after 12 weeks (-0.033+/-0.052 versus -0.002+/-0.047 mm [glimepiride]; P<0.01 between groups) and 24 weeks (-0.054+/-0.059 versus -0.011+/-0.058 mm [glimepiride]; P<0.005 between groups). Insulin resistance was also improved only in the pioglitazone group (homeostasis model assessment, -2.2+/-3.4 versus -0.3+/-3.3; P<0.0001 between groups). Reduction of IMT correlated with improvement in insulin resistance (r=0.29, P<0.0005) and was independent of improvement in glycemic control (r=0.03, P=0.68). CONCLUSIONS: We found a substantial regression of carotid IMT, independent of improved glycemic control, after 12 and 24 weeks of pioglitazone treatment. This finding may have important prognostic implications for patients with type 2 diabetes mellitus.

IRIS II study: the IRIS II score--assessment of a new clinical algorithm for the classification of insulin resistance in patients with Type 2 diabetes.

AIMS: With the increasing availability of new drugs for the treatment of insulin resistance in patients with Type 2 diabetes, simple methods for their identification is an important challenge. The aim of our study was to compute a new algorithm for estimating insulin resistance in a routine clinical setting. METHODS: Clinical data and blood samples were collected from 4265 Type 2 diabetic patients from 149 clinical sites. A clinical algorithm to estimate insulin resistance was developed by stepwise multiple regression analysis. The new generated score was compared with the HOMAIR-score, calculated from fasting insulin and glucose levels measured in a central laboratory. In a subgroup of 48 patients, the score was verified against a frequently sampled intravenous glucose tolerance test with subsequent modified minimal model analysis according to Bergman. RESULTS: Multiple regression analysis revealed fasting blood glucose, BMI, triglycerides and HDL as the most powerful predictors of insulin resistance which were used for further computation of the IRIS II score. A significant overall correlation was found between the HOMAIR-score and the new clinical IRIS II score (r = 0.42; P < 0.0001). Compared with HOMAIR, the new score revealed a specificity of 0.95, a sensitivity of 0.34 and a positive predictive value of 0.95. This was in good agreement with the subset analysis of the intravenous glucose tolerance test, where a sensitivity of 0.37 and a specificity of 0.85 of the IRIS II score was calculated. Patients with insulin resistance according to the IRIS II score revealed an increased odds ratio for overall vascular complications (1.28; 1.11-1.46; P < 0.001). CONCLUSIONS: The new IRIS II score can identify insulin resistance in Type 2 diabetic patients with high predictive value and high specificity.