Insufficient Glycemic Control Research Articles

Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: Pooled analysis of data from three placebo-controlled phase III trials

AimsTo evaluate the efficacy/safety of dipeptidyl peptidase-4 inhibitor, linagliptin, in subjects with insufficiently controlled type 2 diabetes mellitus (T2DM), and factors influencing treatment response. MethodsPooled analysis of data from 2258 subjects in three 24-week phase III, randomized, placebo-controlled, parallel-group studies, who received oral linagliptin (5mg/day) or placebo as monotherapy, added-on to metformin, or added-on to metformin plus sulfonylurea was performed. ResultsAmong 388 subjects with HbA1c ≥9.0%, adjusted mean baseline HbA1c (9.4% both groups) declined to 8.3% in linagliptin group and 9.1% in placebo group at 24weeks (P<.0001) and adjusted mean change from baseline was 1.2% (vs. 0.4%, placebo). Linagliptin significantly lowered fasting plasma glucose levels vs. placebo (1.6mmol/l vs. 0.4mmol/l); treatment difference, 1.1mmol/l (95% CI, −1.7 to −0.5). Treatment and washout of previous oral antidiabetes drugs were the only factors to independently affect HbA1c change at week 24. Adverse event rates were similar for linagliptin (61.9%) and placebo (62.7%). Hypoglycemia was rare with linagliptin monotherapy/add-on to metformin (≤1%) and increased when linagliptin was added to metformin plus sulfonylurea (linagliptin, 17.9% vs. placebo, 8.3%). ConclusionsLinagliptin was an effective, well-tolerated treatment in subjects with T2DM and insufficient glycemic control, both as monotherapy or added-on to metformin/metformin plus sulfonylurea.

Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control

BackgroundSulfonylureas (SUs) are commonly used in the treatment of type 2 diabetes (T2DM), usually as second-line treatment after the failure of metformin. However, SUs are associated with poor durability, hypoglycemia and weight gain. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor in development for the treatment of T2DM. In Phase II/III trials, empagliflozin reduced hyperglycemia, body weight and blood pressure, with a low incidence of hypoglycemia. The aim of this Phase III study is to compare the effects of empagliflozin and the SU glimepiride as second-line therapy in patients with T2DM inadequately controlled with metformin immediate release (IR) and diet/exercise.MethodAfter a 2-week placebo run-in, patients were randomized to receive empagliflozin 25 mg once daily (qd) or glimepiride 1–4 mg qd double-blind for 2 years, in addition to metformin IR. Patients who participate in the initial 2-year randomization period will be eligible for a 2-year double-blind extension. The primary endpoint is change from baseline in HbA1c. Secondary endpoints are change from baseline in body weight, the incidence of confirmed hypoglycemia and changes in systolic and diastolic blood pressure. Exploratory endpoints include markers of insulin secretion, body composition and responder analyses. Safety endpoints include the incidence of adverse events (AEs) (including macro- and microvascular adverse events) and changes from baseline in clinical laboratory parameters.ResultsBetween August 2010 and June 2011, 1549 patients were randomized and 1545 patients were treated. At baseline, mean (SD) age was 55.9 (10.4) years, HbA1c was 7.92 (0.84)%, body mass index was 30.11 (5.59) kg/m2, systolic blood pressure was 133.5 (15.9) mmHg and diastolic blood pressure was 79.5 (9.4) mmHg.DiscussionThis is the largest study to compare the efficacy and safety of an SGLT2 inhibitor with an SU in patients with T2DM inadequately controlled on metformin to date. In addition to determining the effects of these treatments on glycemic control over the long term, this study will investigate effects on beta-cell function, cardiovascular risk factors and markers of renal function/damage. The results will help to inform the choice of second-line treatment in patients with T2DM who have failed on metformin.Trial registrationClinicaltrials.gov NCT01167881.

Incidence and predictors of hypoglycaemia in type 2 diabetes – an analysis of the prospective DiaRegis registry

BackgroundHypoglycaemia is a serious adverse effect of antidiabetic drug therapy. We aimed to determine incidence rates of hypoglycaemia in type-2 diabetic patients and identify predictors of hypoglycaemia when treatment is intensified.MethodsDiaRegis is a prospective German registry that follows 3810 patients with type-2 diabetes referred for treatment intensification because of insufficient glycaemic control on one or two oral antidiabetic drugs.ResultsOut of a total of 3347 patients with data available for the present analysis 473 (14.1%) presented any severity hypoglycaemia over a follow-up of 12 months. 0.4% were hospitalized (mean of 1.3±0.6 episodes), 0.1% needed medical assistance (1.0±0.0), 0.8% needed any help (1.1±0.5) and 10.1% no help (3.4±3.7), and 8.0% had no specific symptoms (3.6±3.5). Patients with incident hypoglycaemia had longer diabetes duration, higher HbA1c and a more frequent smoking history; more had co-morbid disease conditions such as coronary artery disease, peripheral arterial disease, amputation, heart failure, peripheral neuropathy, diabetic retinopathy and clinically relevant depression at baseline. Multivariable adjusted positive predictors of incident hypoglycaemia over the follow-up were prior anamnestic hypoglycaemia, retinopathy, depression, insulin use and blood glucose self-measurement, but not sulfonylurea use as previously reported for anamnestic or recalled hypogylcaemia. On the contrary, glitazones, DPP-4 inhibitors and GLP-1 analogues were associated with a reduced risk of hypoglycaemia.ConclusionsHypoglycaemia is a frequent adverse effect in ambulatory patients when antidiabetic treatment is intensified. Particular attention is warranted in patients with prior episodes of hypoglycaemia, microvascular disease such as retinopathy and in patients receiving insulin. On the other hand glitazones, DPP-4 inhibitors and GLP-1 analogues are associated with a reduced risk.

Glycaemic efficacy of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors as add‐on therapy to metformin in subjects with type 2 diabetes—a review and meta analysis

During recent years, two strategies of incretin-based therapy [glucagon-like peptide-1 (GLP-1) receptor agonism and dipeptidyl peptidase-4 (DPP-4) inhibition] have entered the market for pharmacological management of type 2 diabetes. A main indication for this therapy is as add-on to on-going metformin therapy in subjects with type 2 diabetes who have insufficient glycaemic control with metformin alone. The aim of this study was to compare improvements in glycaemic control and changes in body weight, as well as adverse events, in comparable studies with incretin-based therapy as add-on to metformin. Studies having a duration of 16-30 weeks were identified from PubMed. A total of 27 study groups in 21 studies fulfilled the criteria of examining incretin-based therapy as add-on to metformin at clinically recommended doses in patients with type 2 diabetes for 16-30 weeks; 7 of these used a short-acting GLP-1 receptor agonist (exenatide BID), 7 used longer acting GLP-1 receptor agonists (liraglutide or exenatide LAR), whereas 14 studies examined DPP-4 inhibitors. In all studies, incretin-based therapy reduced HbA1c concentrations. The reduction in HbA1c was significantly greater in study groups with long-acting GLP-1 receptor agonists than with the other two groups (both p < 0.001), whereas there were no differences between exenatide BID and DPP-4 inhibitors. Across all study groups, there was a negative linear correlation between baseline HbA1c and change in HbA1c (r = -0.70; p < 0.001). Fasting glucose also fell significantly more in study groups given liraglutide or exenatide LAR than in those given exenatide BID or DPP-4 inhibitors (both p < 0.001). Furthermore, body weight was reduced by a similar extent in the two groups with GLP-1 receptor agonists and was not significantly altered in the groups with DPP-4 inhibitors. Lipids, blood pressure and heart rate were not reported consistently, which did not allow general conclusions. Adverse events were rare, apart from increased incidence of nausea and vomiting with GLP-1 receptor agonists. Incretin-based therapy efficiently improves glycaemia when added to metformin in patients with type 2 diabetes, and within 16-30 weeks there is a more pronounced reduction in HbA1c with long-acting GLP-1 receptor agonists (liraglutide and exenatide LAR) than with exenatide BID and DPP-4 inhibitors, although the magnitude of the effect is dependent on the baseline values. Both strategies appear to be associated with a very low risk of adverse events, including hypoglycaemia. Finally, the injectable GLP-1 receptor agonists also reduce body weight (whereas the DPP-4 inhibitors are weight neutral) but are also associated with a greater incidence of gastrointestinal side effects and a tendency to increase heart rate.

Prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes in Austria

Mortality of cardiovascular diseases in patients with type 1 diabetes is increased 2- to 20-fold compared to non-diabetic individuals. In young adults with type 1 diabetes, cardiovascular events are more often the cause of premature death than nephropathy. The aim of this study was to evaluate the prevalence and extent of cardiovascular risk factors in children and adolescents with type 1 diabetes in Austria. In a cross sectional study data of children with type 1 diabetes <18 years of age treated at the Children's department of the University Hospitals of Vienna and Graz were collected. We recorded body mass index, waist circumference, blood pressure, HbA1c, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol according to age, sex, age at manifestation, diabetes duration, and insulin requirement. From 264 patients (49.4% male) complete data were available. Of all patients, 76.1% had one or more risk factors, 20.8% had two or more, 10.2% had three or more, and 4.9% had four or more risk factors. Insufficient glycemic control was the most frequent risk factor, present in 60.6% of our patients, followed by elevated triglycerides (22.7%) and increased body mass index (20.1%). Higher prevalence of risk factors was correlated with increasing age, diabetes duration, HbA1c, and insulin requirement. In conclusion, children and adolescents with type 1 diabetes have a much higher prevalence of cardiovascular risk factors compared to non-diabetic individuals. To prevent future cardiovascular events, achieving the best possible glycemic control, early detection of further risk factors, and adequate intervention are highly important.

Clinical inertia: viewpoints of general practitioners and diabetologists

Large clinical studies have enabled best practice guidelines to be issued. Intended to serve practitioners in their daily practice, the guidelines are also excellent tools for assessing physician performance. It was therefore demonstrated that despite the observation of insufficient glycaemic control, physicians did not systematically increase drug treatments. As a result, they have been accused of clinical inertia! In this journal, we first try to reveal what is behind this concept and to differentiate true inertia from pseudo inertia. Secondly, we consider how general practitioners and diabetologists, through their respective positions, can develop a synergy that is able to fight against inertia but that can especially, improve the glycaemic control of our patients.

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

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%). 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. 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. 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.

Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks

To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone over 76 weeks (24-week short-term + 52-week long-term extension) in treatment-naÏve type 2 diabetes mellitus patients with inadequate glycaemic control. In this phase 3, parallel-group, double-blind, active-controlled study, 1306 patients 18-77 years of age (HbA1c 8.0-12.0%) were randomized to saxagliptin 5 mg + 500 mg metformin, saxagliptin 10 mg + 500 mg metformin, saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1-5 of the short-term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin-based treatment groups. No titration of metformin was permitted during the long-term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120-min postprandial glucose (PPG) and PPG-area under the curve (AUC) from baseline to week 76 were analysed using a repeated-measures model. At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin, saxagliptin 10 mg and metformin were -2.31 (-2.44, -2.18), -2.33 (-2.46, -2.20), -1.55 (-1.70, -1.40) and -1.79% (-1.93, -1.65), respectively (post hoc and nominal p < 0.0001 vs. metformin and saxagliptin monotherapies for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin). The proportions of patients requiring rescue or discontinuation for insufficient glycaemic control were lower for saxagliptin + metformin than for either monotherapy. Little or no attenuation in PPG-AUC or 120-min PPG was observed between weeks 24 and 76 for saxagliptin + metformin, indicating persistent efficacy. Adverse event rates were similar across groups; hypoglycaemic events occurred at a low frequency. Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycaemic control for up to 76 weeks, with greater improvements in glycaemic parameters compared with either drug alone.

Multifocal ERG Defects Associated with Insufficient Long-Term Glycemic Control in Adolescents with Type 1 Diabetes

To investigate the relationship between long-term glycemic control and localized neuroretinal function in adolescents with type 1 diabetes (T1D) without diabetic retinopathy (DR). Standard (103 hexagons) and slow-flash (61 hexagons) multifocal ERGs (standard mfERG and sf mfERG) were recorded in 48 patients and 45 control subjects. Hexagons with delayed responses were identified as abnormal. Negative binomial regression analysis was conducted with the number of abnormal hexagons as the outcome variable. Glycated hemoglobin (HbA(1c)) levels, time since diagnosis of T1D, age at diagnosis of T1D, age at testing, and sex were the covariates. Another model replacing HbA(1c) closest to the date of testing with a 1-year average was also generated. There were more abnormal hexagons for mfOPs in patients than in control subjects (P = 0.005). There was no significant difference in the mean number of abnormal hexagons for standard mfERG responses between patients and control subjects (P = 0.11). Negative binomial regression analysis for the standard mfERG data demonstrated that a 1-unit increase in HbA(1c) was associated with an 80% increase in the number of abnormal hexagons (P = 0.002), when controlling for age at testing. Analysis using the 1-year HbA(1c) averages did not result in significant findings. Poor long-term glycemic control is associated with an increase in areas of localized neuroretinal dysfunction in adolescents with T1D and no clinically visible DR. Stricter glucose control during the early stages of the disease may prevent neuroretinal dysfunction in this cohort.

Combined Pioglitazone and Metformin Treatment Maintains the Beneficial Effect of Short-Term Insulin Infusion in Patients with Type 2 Diabetes: Results from a Pilot Study

The aim of our study was to examine the efficacy of short-term intravenous insulin intervention followed by oral pioglitazone/metformin therapy to prevent patients from continuous insulin application. This prospective, open-label, 4-month pilot study comprised of 14 diabetes patients (5 female, 9 male; age 60 +/- 2 years; body mass index 29 +/- 3.2 kg/m(2); hemoglobin A1c [HbA1c] 7.6 +/- 1.1%) with (1) insufficient glycemic control under a dose of metformin >or=1700 mg/day and/or metformin plus additional oral antidiabetes drugs (OADs) and (2) appropriate residual beta-cell function. Initially, an inpatient 34 h continuous intravenous insulin infusion was performed, and metformin was given (2x 850 mg/day). Insulin was stopped, and pioglitazone 30 mg/day was added at the second inpatient day. Patients were followed for four months. Efficacy parameters [change of HbA1c, fasting blood glucose [FBG], intact proinsulin, adiponectin, and high-sensitivity C-reactive protein (hsCRP)] were assessed after initial normalization of blood glucose values by intravenous insulin and at the study end point. During the acute insulin intervention, FBG levels were stabilized in all study subjects. In the following OAD treatment period, five patients showed an improvement of HbA1c > 0.5% [35.7%; seven patients remained stable (50.0%), two patients were nonresponders (14.3%)]. Fasting glucose values dropped after insulin infusion (-17.7%; p < .001). This effect was maintained during the consecutive OAD treatment period (glucose +0.3%, not significant (NS); HbA1c -6.0%; p < .05). The initial decrease in fasting intact proinsulin levels was also maintained during the study (end value -41%, p < .05). Improvements in hsCRP values (postinsulin value, -15%, NS; end value -37%; p < .05) and adiponectin values (postinsulin value +15%, NS; end value +128%; p < .001) were demonstrated at end point only after continued glitazone intake. Our pilot study demonstrated that a beneficial effect of a short-term intravenous insulin application on glycemic control was effectively maintained by pioglitazone/metformin treatment for at least 4 months. In addition, the oral therapy significantly improved cardiovascular risk parameters.

Competact, a Fixed Combination of Pioglitazone and Metformin, Improves Metabolic Markers in Type 2 Diabetes Patients with Insufficient Glycemic Control by Metformin Alone—Results from a Post-Marketing Surveillance Trial Under Daily Routine Conditions

In patients with type 2 diabetes, glycemic control to target goals can only be achieved for a while by single-drug treatment. Antidiabetes therapy has to be adapted according to the individual course of the disease. This trial investigates the impact of Competact (Takeda Pharma, Aachen, Germany) (marketed as ActoplusMet in the United States)-a fixed combination of 850 mg of metformin with 15 mg of pioglitazone-for diabetes treatment in patients with insufficient glycemic control by metformin alone. This observational drug monitoring trial was performed at 1,480 study sites in Germany, and 4,866 complete patient data sets were included into the final analyses. Mean +/- SD age was 60.8 +/- 9.6 years (2,171 women, 2,691 men; disease duration, 6.7 +/- 4.7 years; body mass index [BMI], 31.0 +/- 5.2 kg/m(2)). In total, 43.8% of the patients received lipid-lowering drugs (antihypertensive medication, 74.3%). Main inclusion criteria were type 2 diabetes, metformin monotherapy, and an initial hemoglobin A1c (HbA1c) value between 6.6% and 9.9%. Parameters of glycemic control (HbA1c, fasting blood glucose [FBG]), blood pressure (BP), inflammation (high-sensitivity C-reactive protein [hsCRP]), and lipid metabolism (total cholesterol, high-density lipoprotein [HDL]-cholesterol, non-HDL-cholesterol, and triglycerides) were collected at baseline and after 4 months. All investigated parameters improved significantly (all P < 0.001) after 4 months of therapy with Competact (baseline vs. end point: systolic BP, 139.7 +/- 15.1 vs. 134.4 +/- 12.0 mm Hg; diastolic BP, 83.1 +/- 8.9 vs. 80.5 +/- 7.5 mm Hg; HbA1c, 7.8 +/- 1.0% vs. 7.0 +/- 0.8%; FBG, 9.0 +/- 2.6 vs. 7.0 +/- 1.7 mM; cholesterol, 5.7 +/- 1.1 mM vs. 5.3 +/- 0.9 mM; HDL-cholesterol, 1.2 +/- 0.4 mM vs. 1.3 +/- 0.4 mM; non-HDL-cholesterol, 4.5 +/- 1.2 mM vs. 4.0 +/- 0.9 mM; triglycerides, 2.5 +/- 1.0 mM vs. 2.1 +/- 0.8 mM; hsCRP, 3.2 +/- 2.6 mg/L vs. 2.7 +/- 2.3 mg/L). It is noteworthy that the BMI was not affected by Competact (31.0 +/- 5.2 kg/m(2) vs. 31.1 +/- 6.1 kg/m(2), P = 0.221). These observational results, obtained from a non-selected patient population under daily routine conditions, show the beneficial effects of a pioglitazone/metformin combination for diabetes patients with insufficient glycemic control under daily routine conditions.

Management of Diabetes in Patients with Chronic Kidney Disease

Management of patients with diabetes mellitus and chronic kidney disease (CKD) is a challenging task because multiple factors in each condition may impact the other. Glycemic control offers significant benefits in the prevention of diabetic kidney disease (DKD), but other associated morbidities are also important to address. Patients with diabetes with insufficient glycemic and blood pressure control are at a high risk for developing both cardiovascular disease and progression of nephropathy. This article discusses proper screening, identification, and management in the different stages of DKD, with special considerations for dialysis and transplant patients. We also review information on altered metabolism of medications and the appropriate use of diabetic agents, including recommendations for management of glucose control in CKD.

Increased plasma urotensin-II levels are associated with diabetic retinopathy and carotid atherosclerosis in Type 2 diabetes

Human U-II (urotensin-II), the most potent vasoconstrictor peptide identified to date, is associated with cardiovascular disease. A single nucleotide polymorphism (S89N) in the gene encoding U-II (UTS2) is associated with the onset of Type 2 diabetes and insulin resistance in the Japanese population. In the present study, we have demonstrated a relationship between plasma U-II levels and the progression of diabetic retinopathy and vascular complications in patients with Type 2 diabetes. Eye fundus, IMT (intima-media thickness) and plaque score in the carotid artery, BP (blood pressure), FPG (fasting plasma glucose), HbA(1c) (glycated haemoglobin), U-II, angiogenesis-stimulating factors, such as VEGF (vascular endothelial growth factor) and heregulin-beta(1), and lipid profiles were determined in 64 patients with Type 2 diabetes and 24 non-diabetic controls. FPG, HbA(1c) and VEGF levels were significantly higher in patients with Type 2 diabetes than in non-diabetic controls. Diabetes duration, insufficient glycaemic and BP control, plasma U-II levels, IMT, plaque score and nephropathy grade increased significantly across the subjects as follows: non-diabetic controls, patients with Type 2 diabetes without retinopathy (group N), patients with Type 2 diabetes with simple (background) retinopathy (group A) and patients with Type 2 diabetes with pre-proliferative and proliferative retinopathy (group B). The prevalence of obesity and smoking, age, low-density lipoprotein, triacylglycerols (triglycerides) and heregulin-beta(1) were not significantly different among the four groups. In all subjects, U-II levels were significantly positively correlated with IMT, FPG, and systolic and diastolic BP. Multiple logistic regression analysis revealed that, of the above parameters, U-II levels alone had a significantly independent association with diabetic retinopathy. In conclusion, the results of the present study provide the first evidence that increased plasma U-II levels may be associated with the progression of diabetic retinopathy and carotid atherosclerosis in patients with Type 2 diabetes.

A Lifetime Modelled Economic Evaluation Comparing Pioglitazone and Rosiglitazone for the Treatment of Type 2 Diabetes Mellitus in the UK

Adding pioglitazone or rosiglitazone to existing therapy are alternative treatment options for patients with type 2 diabetes mellitus who have insufficient glycaemic control while receiving the maximal tolerated dose of metformin monotherapy. Our objective was to develop a lifetime model of type 2 diabetes mellitus and its sequelae in order to compare the costs and benefits of pioglitazone versus rosiglitazone in combination with metformin. A decision-analytic model employing a first order Monte Carlo simulation of a Markov process was constructed. The model incorporated surrogate outcome measures from a large randomised controlled trial (RCT) [n = 802] that compared the glycaemic and lipid control of pioglitazone and rosiglitazone monotherapy. These efficacy data were used with a recently validated and peer-reviewed UKPDS (UK Prospective Diabetes Study) algorithm to simulate the progression of these surrogate outcomes to final health outcomes, including quality of life (QOL) and mortality, and to calculate the risks of diabetic complications and death. The model perspective was of the UK NHS and included direct healthcare costs only (pounds, 2004/5 values). Patient outcomes measured in the model included life-expectancy (LE) and QALYs. The base-case analysis was run for 56-year-old male Caucasions with a haemoglobin A(1c) (HbA(1c)) of 7.57% and a body mass index of 33.14 kg/m(2). Patients treated with pioglitazone experienced a reduction in the total cholesterol to high-density lipoprotein-cholesterol (TC : HDL-C) ratio of 0.34, whereas the TC : HDL-C ratio increased by 0.65 in those receiving rosiglitazone (p < 0.001). The HbA(1c) profile was similar between the treatment groups (p = 0.13), as were other known risk factors for diabetes complications. The lifetime healthcare costs per patient estimated by the model were 9585 pounds for pioglitazone and 10,299 pounds for rosiglitazone. Patients treated with pioglitazone had a discounted LE of 8.83 years versus 8.79 years for those treated with rosiglitazone. Patients treated with pioglitazone also gained additional QALYs (6.8070 vs 6.7686). With improved health outcomes and lower costs, treatment with pioglitazone dominated rosiglitazone treatment. Evidence from the only large head-to-head RCT comparing rosiglitazone and pioglitazone suggests that more favourable changes in serum lipid profiles in patients treated with pioglitazone translate into improved health outcomes in terms of reduced morbidity and mortality and greater gains in QOL. In addition, this analysis indicates that treatment with pioglitazone is associated with lower costs than rosiglitazone. Therefore, in the UK, adjunctive pioglitazone may represent a cost-effective treatment choice for patients with type 2 diabetes who have insufficient glycaemic control while receiving the maximal tolerated dose of metformin monotherapy.

A Lifetime Modelled Economic Evaluation Comparing Pioglitazone and Rosiglitazone for the Treatment of Type 2 Diabetes Mellitus in the UK

Introduction Adding pioglitazone or rosiglitazone to existing therapy are alternative treatment options for patients with type 2 diabetes mellitus who have insufficient glycaemic control while receiving the maximal tolerated dose of metformin monotherapy. Our objective was to develop a lifetime model of type 2 diabetes mellitus and its sequelae in order to compare the costs and benefits of pioglitazone versus rosiglitazone in combination with metformin.

Insulin Glargine and Educational Intervention in Patients with Type 2 Diabetes in Clinical Practice: Long-Term Improvement in Glycaemic Control Without Weight Gain

In clinical practice it is often difficult to achieve the stringent HbA1c targets set by organizations such as the American Diabetes Association (ADA) for patients with Type 2 diabetes. This is due to a number of factors including insufficient glycaemic control with oral antidiabetic agents (OADs) combined with physician and/or patient reluctance to commence insulin therapy; inadequate insulin titration due to fear of hypoglycaemia; and a lack of patient education regarding correct diabetes management. Self-managed patients in an outpatient setting need to be motivated and compliant in order to optimize treatment success ([Mudaliar and Edelman, 2001]), to which distinct barriers exist ([Brown et al., 2002]). The benefits of educational programmes in improving health outcomes, including metabolic control, have been documented; however, such programmes are under-utilized ([Graziani et al., 1999]). The current retrospective analysis assessed the effect of 30 months' treatment following initiation of once-daily insulin glargine (glargine; LANTUS), a long-acting basal insulin analogue, plus ongoing previous oral or prandial insulin therapy, in conjunction with an educational programme, on glycaemic control, body weight, and incidence of severe hypoglycaemia in patients with Type 2 diabetes undergoing routine diabetes care in a clinical practice in Germany.

PDB31 A LIFETIME MODELLED ECONOMIC EVALUATION COMPARING PIOGLITAZONE AND ROSIGLITAZONE FORTHE TREATMENT OF TYPE-2 DIABETES MELLITUS IN THE UK

Introduction Adding pioglitazone or rosiglitazone to existing therapy are alternative treatment options for patients with type 2 diabetes mellitus who have insufficient glycaemic control while receiving the maximal tolerated dose of metformin monotherapy. Our objective was to develop a lifetime model of type 2 diabetes mellitus and its sequelae in order to compare the costs and benefits of pioglitazone versus rosiglitazone in combination with metformin.

Factors affecting therapeutic response of adhesive capsulitis in type II diabetes mellitus

Forty-eight patients with type II diabetes mellitus were recruited for the study. Fifty-one shoulder joints with adhesive capsulitis were treated in this population. A physical therapy protocol including Transcutaneous Electrical Nerve Stimulation, pulsed ultrasound and exercises was applied to each patient. The patients were assessed on entry and termination of treatment and at 3 months post-treatment by Visual Analogue Scale for rest and activity pain intensity, active and passive range of motion of shoulder and Constant scores. The scores were compared between 18 patients with good glycemic control and no neuropathy and 30 patients with insufficient glycemic control and neuropathy. The results indicate that glycemia levels and neuropathy have no effect on response to physical therapy.

Usefulness of miglitol in patients with diabetes mellitus type 2 and insufficient control of the blood glucose

Miglitol belongs to the group of the inhibitors of the alpha-glucosidases and in several studies has demonstrated its usefulness in the improvement of the glycemic control in the different types of diabetic patients. The goal of our study was to analyze the usefulness of miglitol in the blood glucose and lipid control in a group of patients with diabetes type 2 treated with sulfonylureas and insulin, with insufficient glycemic control. A group of 33 patients with diabetes mellitus type 2 treated with sulfonylureas and insulin and with insufficient glycemic control (HbA1c>7.5%) was studied. All patients were treated with miglitol during 3 months with progressive doses: the first week 50 mg twice a day, subsequently and during one month 50 mg three times a day. At the beginning of the study and up to three months the following variables were measured; weight, height, BMI (body mass index), systolic and diastolic blood pressure, HbA1c, number of episodes of peripheral hypoglycemia, basal glucose, albuminuria, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides, as well as transaminases (GOT, GPT, gamma GT and bilirubin). The median age was 64.1 +/- 12.5 years, and the median length of diabetes mellitus was 9.1 +/- 7 years. The median value of BMI was 27.7 +/- 6.9 kg/cm2. The blood glucose and HbA1c values decreased 4.8% and 5.8%, respectively. A decrease in the number of hypoglycemia episodes (39.4% previous quarter versus 3% quarter wih miglitol) was observed. Also decreased the dose of sulfonylureas needed by the patients (86.2 +/- 24.3 mg/day versus 64.6 +/- 21.9 mg/day; p<0.05) (25%). Total cholesterol, HDL-cholesterol, and LDL-cholesterol levels were not modified, but indeed a reduction of the levels of triglycerides (145.2 +/- 111 mg/dl versus 133.1 +/- 79 mg/dl; p<0.05) (8.3%) was detected. Fifteen percent of patients showed side effects (digestive discomfort) that disappeared two or three weeks after beginning the treatment. Miglitol is a useful drug in order to improve the glycemic control in diabetic type 2 patients treated previously with other drugs and with insufficient control of the blood glucose. Its side effects are limited and transitory.

Insufficient glycemic control increases nuclear factor-kappa B binding activity in peripheral blood mononuclear cells isolated from patients with type 1 diabetes.

The redox-sensitive transcription factor nuclear factor-kappa B (NF-kappa B) is believed to contribute to late diabetic complications. It is unknown whether NF-kappa B is influenced by glycemic control. To determine whether NF-kappa B is activated in patients with insufficient glycemic control (HbA1c > 10%), we developed a tissue culture-independent electrophoretic mobility shift assay (EMSA)-based semiquantitative detection system that allowed us to determine NF-kappa B activation in ex vivo-isolated peripheral blood mononuclear cells (PBMCs). We included 43 patients with type 1 diabetes in this cross-sectional study. 10 of those received the antioxidant thioctic acid (600 mg/day p.o.) for 2 weeks. Monocytes of patients with HbA1c levels > 10% demonstrated significantly higher NF-kappa B binding activity in an EMSA and a stronger NF-kappa B staining in immunohistochemistry than monocytes of patients with HbA1c levels of 6-8%. The increase in NF-kappa B activation correlated with an increase in plasmatic markers of lipid peroxidation. Treatment with the antioxidant thioctic acid decreased NF-kappa B binding activity. Hyperglycemia induces activation of the transcription factor NF-kappa B in ex vivo-isolated PBMCs of patients with type 1 diabetes. NF-kappa B activation is at least partially dependent on oxidative stress, since the antioxidant thioctic acid significantly lowered the extent of NF-kappa B binding activity.