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Introduction: As type 2 diabetes mellitus (T2DM) advances, patients receiving basal insulin will eventually require another agent on top of their current regimen in order to achieve glycemic control. One such agent that can be administered in combination with basal insulin is the glucagon-like peptide-1 receptor agonist (GLP-1 RA) lixisenatide. GLP-1 RAs, such as lixisenatide, and basal insulin offer complementary mechanisms of action in their ability to provide glycemic control, thus providing a strong rationale for using them in combination with each other for the treatment of T2DM., Areas Covered: The current data available on the use of lixisenatide added to basal insulin for the management of T2DM is reviewed., Expert Opinion: Lixisenatide as add-on to basal insulin provides overall glycemic control as well as offering a number of other treatment benefits, such as a reduction in both body weight and the risk of hypoglycemia. Therefore, when basal insulin becomes inadequate in managing T2DM, lixisenatide should be considered as an add-on agent to help patients achieve glycemic targets with a low risk of hypoglycemic events.

Objective: There is limited evidence to guide the selection of second-line anti-hyperglycemic agents in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled with sulfonylurea monotherapy and are intolerant to metformin. We compared the efficacy and safety of vildagliptin 50 mg qd and Neutral Protamine Hagedorn (NPH) insulin qd in such patients., Methods: This was a 24 week, multicenter, randomized, open-label study. The co-primary endpoints were (i) proportion of patients achieving HbA1c <7.0% without any confirmed hypoglycemic events (HEs) or weight gain ≥3% (composite endpoint); (ii) rate of confirmed HEs. Treatment satisfaction was assessed using the TSQM-9 questionnaire at study end., Results: A total of 162 patients were randomly assigned to vildagliptin (n = 83) and NPH insulin (n = 79). Similar proportion of patients achieved the composite endpoint in vildagliptin versus NPH insulin group (35.4% versus 34.2%; OR 0.985; 95% CI 0.507, 1.915; p = 0.96). After 24 weeks, 48.8% of patients in the vildagliptin group and 60.8% in the NPH insulin group achieved HbA1c <7.0%; 13.4% in the vildagliptin group and 29.1% in the insulin group had at least one confirmed HE; while 11.0% in the vildagliptin group and 22.8% in the insulin group experienced weight gain. The rate of confirmed HEs was significantly lower in patients receiving vildagliptin versus NPH insulin (1.3 versus 5.1 events per year). The TSQM-9 score for 'convenience' at week 24 increased significantly more with vildagliptin than with NPH insulin., Conclusions: Addition of vildagliptin and NPH insulin resulted in a similar number of patients reaching HbA1c target without HEs or weight gain in T2DM patients inadequately controlled with sulfonylurea. The addition of vildagliptin to sulfonylurea could be considered as a treatment option prior to intensification with insulin, with the advantages of a lower HE rate and greater patient convenience. Study results are limited by a higher drop-out rate in the vildagliptin arm.

Objective: FlexTouch® (FT) is a new prefilled insulin pen with no push-button extension and a low injection force used to deliver several basal insulins, including insulin degludec across a wide dose range (1 - 80 units with FT 100 IU/ml [FT100] and 2 - 160 units with 200 IU/ml [FT200]). This study was carried out to evaluate whether the novel features of FT affect the preferences of the device among patients with diabetes and healthcare professionals compared with the widely used SoloSTAR® pen., Research Design and Methods: A multicenter, randomized, open-label, crossover study compared FT100 and FT200 with SoloSTAR. The study included patients with either type 1 (n = 22) or type 2 diabetes (n = 42), nurses (n = 32) and physicians (n = 32). Subjects were randomized to test each of the FT100, FT200 and SoloSTAR pens in a crossover set up. Subjects performed injections into a foam cushion at 4 - 6 different doses per device (2, 20, 40, 80, 120 and 160 IU)., Results: Overall, a significantly higher proportion of subjects, including dexterity-impaired and pen-naive patients, preferred to use FT100 (93.0%; 119/128) and FT200 (91.4%; 117/128) compared with 2.3% (3/128) and 3.9% (5/128) who preferred SoloSTAR (p < 0.001), respectively., Conclusion: FT100 and FT200 were preferred over SoloSTAR by nurses, physicians and patients with diabetes. This may be due to the novel design of FT, which improves ease of use, preference and confidence in delivering a complete, accurate dose of insulin, even at high doses.

Introduction: Dipeptidyl peptidase-4 inhibitors increase circulating levels of glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide regulating glucose-dependent insulin secretion. In addition, GLP-1 suppresses glucagon secretion, delays gastric emptying and increases satiety. The combination of vildagliptin with the biguanide metformin is of particular interest because of its complementary mode of action, addressing insulin resistance, alpha- and beta cell function in the islet of the pancreas., Areas Covered: Because of the abundance of data supporting the use of vildagliptin alone and in combination with metformin, the present paper aims at giving an overview on the current evidence for its use in patients with type 2 diabetes mellitus., Expert Opinion: The data suggest that vildagliptin offers similar glycemic control compared to sulfonylureas and thiazolidinediones, while having the benefit of being associated with fewer cases of hypoglycemia and less body weight gain. There is increasing evidence that compared with sulfonylureas, vildagliptin has favorable effects on pancreatic alpha- and beta-cell function. Vildagliptin in combination with metformin, improve glycemic control with a favorable safety and tolerability profile, making it an attractive therapeutic option in patients where metformin monotherapy alone is not sufficient.

Background: The primary objective of this prospective controlled study was to investigate the impact of standardized injection-site warming on prandial rapid acting insulin dose and glycemic control when studied under real-world conditions., Methods: All 145 participating patients (51 female, 94 male, 13 type 1 and 132 type 2 patients, age: 61.6 ± 8.4 yrs, HbA1c: 7.19 ± 0.50%) were treated with intensive insulin glargine and short-acting insulin analog therapy. After a 4 week treatment optimization run-in period, patients were randomized to continue therapy for three months without (control) or with a local injection-site warming device (InsuPad * ). Observation parameters included HbA1c, insulin dose, frequency of hypoglycemia, body weight and adverse events., Results: HbA1c improved in both arms until study end (control group: 6.3 ± 0.5%; injection-site warming device: 6.3 ± 0.5%; both p < 0.001 vs. baseline). To achieve this good control, patients in the control group needed to increase the daily prandial insulin dose by 8.1% (from 66 ± 31 U to 71 ± 38 U, p < 0.05) with stable basal insulin requirements. Patients who used the injection-site warming device required less prandial insulin (70 ± 43 U to 55 ± 34 U; -19%, p < 0.001) and slightly more basal insulin (+3.9%). Total daily insulin dose increased in the control group (+3.7%) and decreased with warming device use (-8.6%, p < 0.001). The number of hypoglycemic events (<63 mg/dL) during the observation period was higher in the control group (6.2 ± 9.9/patient vs. injection-site warming device: 3.3 ± 4.8/patient, p < 0.05). Main study limitations can be seen in the open label design reliability of the collected dose information and the very obese patient cohort., Conclusion: When treating obese patients to target with insulin therapy, use of an injection-site warming device for 3 months resulted in a lower frequency of hypoglycemic events and a reduction in prandial insulin analog requirements. If these results are confirmed in other patient populations, an injection-site warming device may be useful in achieving treatment targets with a safer and more efficient basal bolus therapy in insulin-treated patients with type 1 and type 2 diabetes.

Since 2003, blood glucose meters for patient self testing are approved in Europe based on the accuracy performance criteria as defined by the ISO15197 guideline. A new draft ISO guideline is currently under regulatory review, which suggests more strict accuracy acceptance criteria, and which may not be entirely fulfilled by currently commercialized blood glucose meter systems. In order to investigate the compliance of BG*Star and iBG*Star and several other blood glucose meters with the new draft ISO guideline, we performed a post-hoc analysis of data obtained from a recently performed ISO-conforming clinical accuracy performance study. This study was performed with 106 patients, clinically presenting with blood glucose levels distributed over the entire measurement range and in line with the glucose distribution requirements as demanded by the guideline. The YSI 2300 STAT Plus analyzer (glucose oxidase) served as reference method. While all tested meters had been in a high degree of compliance with the current ISO criteria, performance was lower when analyzed in accordance with the new acceptance criteria (95% of readings have to be within ±15 mg/dL for values <100 mg/dL, and within ±15% for values ≥100 mg/dL). The following meters met the new criteria: Accu-Chek Aviva (95.5%/98.6%), BG*Star (98.5%/97.3%), iBG*Star (98.5%/97.3%), FreeStyle Freedom Lite (95.5%/96.6%), and OneTouch Ultra2 (95.5%/96.5%). One meter failed with low blood glucose values (Contour: 90.9%/95.9%). In conclusion, BG*Star and iBG*Star and several other branded meters met the new draft ISO15197 acceptance criteria, when tested in accordance with the instructions for use and with the ISO accuracy testing protocol in a clinical setting.

Objective: Self-monitoring of blood glucose is a key element in diabetes management. Accurate and precise performance of blood glucose monitors (BGMs) ensures that valid values are obtained to guide treatment decisions by patients and physicians. BGStar and iBGStar are hand-held BGMs that use dynamic electrochemistry to correct for potential interferences and thereby minimize system errors., Research Design and Methods: A single-center, in vitro diagnostic device performance evaluation with heparinized oxygenated venous blood samples (intra-assay precision) and control solutions (interassay precision) was performed in a laboratory setting, comparing BGStar and iBGStar with 12 competitors., Main Outcome Measures: The primary outcome was the coefficient of variation percent (CV%) of the BGMs investigated., Results: In inter-assay precision analyses, all but GlucoMen LX had a CV <5%, and in intra-assay precision analyses, 10 of the 14 devices tested had CV <5%. BGStar and iBGStar had a CV <5% in both the inter- and intra-assay precision analyses. The smallest variation was found in the near-normoglycemic glucose range (5.3 - 8.0 mmol/l) for both BGStar and iBGStar in the inter-assay precision analysis., Conclusions: BGStar and iBGStar were proven to have very good inter-assay and high intra-assay precision, demonstrating low scattering of replicate measurements with both clinical samples and control solutions.

Introduction: The global prevalence of type 2 diabetes mellitus (T2DM) is rapidly increasing and is associated with a high risk of microvascular and macrovascular complications. Although some glucose-lowering therapies are associated with hypoglycemia and weight gain, glucagon-like peptide-1 (GLP-1) receptor agonists represent a significant advance in the treatment of T2DM, as they provide effective glycemic control with a low incidence of hypoglycemia and a beneficial effect on body weight, as well as potential improvements in cardiovascular outcomes., Areas Covered: This article evaluates the pharmacological and clinical profile of the once-daily prandial GLP-1 receptor agonist lixisenatide for the treatment of T2DM., Expert Opinion: Once-daily prandial lixisenatide has been evaluated in an extensive clinical trials program, in which it was shown to have a favorable safety and tolerability profile, and to effectively improve metabolic control. The unique pharmacological properties of lixisenatide clearly differentiate it from other GLP-1 receptor agonists. As a once-daily agonist with a high affinity for the GLP-1 receptor, lixisenatide improves overall glycemic control, with particularly strong effects on postprandial plasma glucose levels. These attributes encourage the application of lixisenatide in those patients with extensive postprandial glucose excursions, or in combination with other antidiabetic drugs that have prevailing effects on fasting glucose levels.

Objective: FT (FlexTouch*) is a new disposable insulin injection pen device for use in insulin-treated patients with diabetes mellitus. The aim of this study was to evaluate patient perception of FT versus IL (InnoLet†) with respect to the ease of use and patient preference in a mixed patient cohort with different kinds and degrees of visual or dexterity impairments., Methods: Ninety patients were included into this investigation (54 male/36 female, age [mean ± SD]: 62 ± 8 yrs, disease duration: 18 ± 11 yrs, HbA1c: 7.2 ± 1.0%). After assessment of visual acuity and dexterity skills (by Jebsen-Taylor Hand Function Test), the patients were introduced to the two pen devices in random order, and were asked to perform mock injections with 10 IU, 30 IU and 50 IU doses before completing a 41 item standardized device assessment questionnaire. The questions asked were covering five topics of pen use (confidence in delivering a correct dose, dose setting, performance of the injection, general handling, and others) and could be answered with a rank scale from '1 = very easy' to '5 = very difficult'., Results: FT was ranked superior to IL with respect to the injection procedure (FT: 1.2 ± 0.1 vs. IL: 2.1 ± 0.4, p < 0.001) and general handling (1.3 ± 0.2 vs. 2.3 ± 0.7, p < 0.001), and numerically better with respect to confidence in correct dosing (1.4 ± 0.2 vs. 2.1 ± 0.9, n.s.). The two devices were ranked equally for ease of dose setting (1.6 ± 0.3 vs. 1.7 ± 0.4, n.s.). When ranked individually, FT use was recommended by 92.2% of the patients (IL: 30.0%)., Key Limitations: Patients of this investigation were from one local area (San Jose, CA, USA) only. The subgroups may be considered small for the performed analysis., Conclusions: In summary, FT was perceived to be easier to use than IL in this investigation.

Objectives: Blood glucose meters for patient self-measurement need to comply with the accuracy standards of the ISO 15197 guideline. We investigated the accuracy of the two new blood glucose meters BG*Star and iBG*Star (Sanofi-Aventis) in comparison to four other competitive devices (Accu-Chek Aviva, Roche Diagnostics; FreeStyle Freedom Lite, Abbott Medisense; Contour, Bayer; OneTouch Ultra 2, Lifescan) at different blood glucose ranges in a clinical setting with healthy subjects and patients with type 1 and type 2 diabetes. BGStar and iBGStar are employ dynamic electrochemistry, which is supposed to result in highly accurate results., Methods: The study was performed on 106 participants (53 female, 53 male, age (mean ± SD): 46 ± 16 years, type 1: 32 patients, type 2: 34 patients, and 40 healthy subjects). Two devices from each type and strips from two different production lots were used for glucose assessment (∼200 readings/meter). Spontaneous glucose assessments and glucose or insulin interventions under medical supervision were applied to perform measurements in the different glucose ranges in accordance with the ISO 15197 requirements. Sample values <50 mg/dL and >400 mg/dL were prepared by laboratory manipulations. The YSI glucose analyzer (glucose oxidase method) served as the standard reference method which may be considered to be a limitation in light of glucose hexokinase-based meters., Results: For all devices, there was a very close correlation between the glucose results compared to the YSI reference method results. The correlation coefficients were r = 0.995 for BGStar and r = 0.992 for iBGStar (Aviva: 0.995, Freedom Lite: 0.990, Contour: 0.993, Ultra 2: 0.990). Error-grid analysis according to Parkes and Clarke revealed both 100% of the readings to be within the clinically acceptable areas (Clarke: A + B with BG*Star (100 + 0), Aviva (97 + 3), and Contour (97 + 3); and 99.5% with iBG*Star (97.5 + 2), Freedom Lite (98 + 1.5), and Ultra 2 (97.5 + 2))., Conclusions: This study demonstrated the very high accuracy of BG*Star, iBG*Star, and the competitive blood glucose meters in a clinical setting.

Objective: Insulin-treated patients perform complex treatment activities during daily routine, such as blood glucose measurements and insulin injections. We aimed to identify suitable dexterity and cognitive function tests for diabetes patients, and to compare the patient self-assessment of their dexterity skills with the test results (Jebsen-Taylor hand function test, (JHFT), motoric performance test (MLS), number connection test)., Method: We enrolled 90 diabetes patients (36 females, 54 males): 15 type 1 with clinically suspected dexterity impairment (A: age: 60 ± 9 years), 30 type 2 with clinically suspected dexterity impairment (B: 61 ± 10 years), 30 type 1 or type 2 patients with visual impairment (C: 64 ± 6 years), and 15 type 1 or type 2 patients without obvious impairment (control group: D: 64 ± 5 years)., Results: There were no differences regarding neuropathy and slight impairments in the number connection test in all groups. Patient self-assessment revealed that 33.4% in group A, 33.3% in group B, 36.7% in group C and 13.7% in group D, considered themselves to have dexterity impairment. However in the JHFT test, all patients from A (100%) and B (100%), 33% from C, and 0% from D presented with dexterity impairment by only passing less than four subtests., Conclusions: Impairment of dexterity was much more frequent than believed by the patients themselves. It may be worthwhile to consider these findings when classifying patients regarding their capabilities to perform certain treatments or when assessing diabetes technology with human subjects.

Introduction: Increasing population age, obesity and physical inactivity mean that type 2 diabetes mellitus (T2DM) is increasingly common. Current treatments may be limited by adverse events, drug-drug interactions or contraindication/need for dose adjustment in patients with renal impairment., Areas Covered: This paper reviews studies that evaluate the pharmacokinetics, pharmacodynamics and clinical efficacy and safety of linagliptin , a dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the US, Japan and Europe for the treatment of T2DM., Expert Opinion: Oral linagliptin, 5 mg once daily, is an effective, well-tolerated DPP-4 inhibitor, suitable for use in a wide range of patients with T2DM. It is weight-neutral, without increasing the risk of hypoglycemia, and can be administered either alone or in combination with other diabetes treatments. It has a unique pharmacological profile within its class and, unlike other DPP-4 inhibitors, linagliptin does not require dose adjustment in patients with renal impairment.

Introduction: Pioglitazone is approved in combination with several other blood-glucose-lowering drugs for the treatment of type 2 diabetes mellitus (T2DM). Beyond lowering blood glucose levels, each combination of different blood-glucose-lowering drugs for the treatment of T2DM evolves specific pleiotropic effects, which might be considered on an individual basis in a certain patient., Areas Covered: The objective of this article is to provide a short review of the pathophysiology of T2DM and to provide a rationale for the combination of pioglitazone with other antidiabetic drugs, based on a pathophysiological understanding of T2DM. Therefore, a PubMed search was undertaken covering the search terms 'pioglitazone', 'antidiabetic drugs' and 'combination therapy'., Expert Opinion: Treatment with pioglitazone in T2DM was shown to improve insulin resistance and blood glucose levels without increasing the risk of hypoglycemia. Beyond those metabolic activities, pioglitazone was shown to evolve anti-inflammatory and anti-atherogenic effects. It seems useful to combine different antidiabetic drugs based on the specific needs and contraindications in an individual patient. The treating of T2DM patients by addressing not only glucose control, but also the underlying pathophysiological etiology might help to improve patient prognosis in the long run, especially with regard to the vascular complications., (© 2011 Informa UK, Ltd.)

Adiponectin is an important adipocytokine hormone which circulates in blood as homo-oligomers (trimer, hexamer and high molecular weight (HMW) forms) as well as a truncated form corresponding to the globular domain. Free flow electrophoresis (FFE) used in zone electrophoresis mode revealed the presence of isoforms within these oligomeric forms in plasma. HMW adiponectin oligomer showed two isoforms which carry different charge density at pH 4.7, only one of which is susceptible to dissociation by SDS. The adiponectin hexamer was shown to consist of a doublet and also shown to have at least two isoforms. A truncated form of adiponectin was identified as the main constituent of adiponectin in plasma and appeared to circulate bound to a basic protein, potentially one of the chemokines reported to bind to the globular domain. Analysis of the monomer composition of the oligomers revealed differences in monomeric isoforms used to build up the oligomers.

Pioglitazone, a member of the PPAR-gamma agonist drug family, has been demonstrated to improve both metabolic and vascular insulin resistance when applied to patients with Type 2 diabetes mellitus. The drug is well tolerated with fluid retention and weight gain being the most frequently described side effects. The observed effects (e.g., improvements in glucose and lipid metabolism, improvements of endothelial function and microcirculation, reduction of surrogate markers of atherosclerosis and inflammation and an improvement in hypertension) have made pioglitazone one of the frequently prescribed antidiabetic drugs in the US and Europe. Several trials have shown its potency to reduce carotid intima-media thickness, and outcome studies with pioglitazone have shown its potential to delay the progression of Type 2 diabetes and atherosclerosis and even reduce cardiovascular mortality. The purpose of this review is to provide an overview about recently published clinical results with pioglitazone. They underline the value of this drug when used alone or in combination with other antidiabetic drugs for a successful management of Type 2 diabetes mellitus.

Aim: Diabetes is associated with aberrant coagulation. Relaxin, an insulin-like peptide hormone, is a candidate to be involved in the underlying molecular mechanisms. Therefore, the present study investigated the correlation of relaxin expression with fibrinogen levels in diabetes patients undergoing oral antidiabetic treatment., Method: In total, 192 type 2 diabetes patients were enrolled into the study. The patients were randomized to receive either pioglitazone or glimepiride for 26 weeks. Blood was drawn at baseline and at the end of the study to measure the concentrations of relaxin and fibrinogen with an enzyme-linked immunosorbent assay and a turbimetric method, respectively. In addition, platelets were counted at both time points., Results: Total datasets were available from 161 patients (age 62.5 +/- 8.1 years, mean +/- standard deviation; 58 women, 103 men). The median initial parameter concentrations were: relaxin, 27.4 pg/ml (range 0.4 - 380 pg/ml); fibrinogen, 3.0 g/l (range 1.1 - 7.9 g/l); platelets, 217,000/microl (range 51,000 - 547 000/microl). The data were analyzed according to the increase or decrease of each parameter after therapy compared with baseline. There was a significant correlation of relaxin variation with fibrinogen variation, seen particularly in the female subgroup (p < 0.05). The correlation was independent of the antidiabetic medication., Conclusion: The data suggest that there is a correlation between fibrinogen levels and relaxin expression. Relaxin may exert its cardioprotective properties after pathologic fibrinogen increase. This regulation may be affected by diabetes. As a consequence, cardiovascular risk may increase in women with aberrant relaxin functionality.

Pioglitazone is an antidiabetic drug known to decrease peripheral, hepatic and vascular insulin resistance by the stimulation of PPARgamma. In clinical trials, pioglitazone as monotherapy or in combination with other oral antidiabetic drugs or insulin has demonstrated to effectively improve blood glucose levels, long-term glucose control and the lipid profile. The vascular effects of pioglitazone include improvement of endothelial function and microcirculation, reduction of blood pressure and inflammatory surrogate markers of atherosclerosis, and a reduction of a composite measure of macrovascular events (death, stroke and myocardial infarctions). The drug is well tolerated and has an acceptable side effect profile. Because of its additional microvascular and macrovascular effects, pioglitazone is an attractive and effective treatment option for the management of Type 2 diabetes mellitus.

Technosphere/Insulin (TI) is a formulation of regular human insulin designed for efficient transport across the respiratory epithelium into the circulation. The drug carrier mechanism achieves a fast systemic insulin uptake (maximum time approximately 15-20 min), a fast onset of action (maximum activity approximately 25-30 min) and a short duration of action (approximately 2 h). Bioavailability, relative to subcutaneous injection, was established to be between 30 and 50% with a linear dose-response relationship and low variability. In all published short-term studies, TI was well tolerated. Provided a reliable long-term safety profile, TI may become a suitable alternative to subcutaneous injection for prandial insulin delivery. TI offers the possibility of new treatment regimens, especially in patients with Type 2 diabetes.