A New Optimized Percutaneous Access System for CIPII.

In recent years, continuous intraperitoneal insulin infusion (CIPII) has become a favored treatment alternative for patients with subcutaneous insulin resistance, mainly due to its ability of mimicking physiological conditions of insulin absorption. CIPII has been shown to improve glycemic control as well as to reduce hypoglycemic events and to lead to increased patient satisfaction and quality of life (QoL). Among CIPII delivery systems, Diaport stands out due to its low side effects, its demonstrated clinical efficacy and the potential for integration into closed-loop systems.

Need for Outcome Scenario Analysis of Clinical Trials in Diabetes.

Since the FDA requirement for cardiovascular safety of all new antihyperglycemic drugs to enter the market, the number and extent of phase 3 clinical trials has markedly increased. Unexpected trial results imply an enormous economic, personal and time cost and has deleterious effects over R&D. To prevent unforeseen developments in clinical trials, we recommend performing a comprehensive prospective outcome scenario analysis before launching the trial. In this commentary, we discuss the most important factors to take in consideration for prediction of clinical trial outcome scenarios and propose a theoretical model for decision making.

Interferences and Limitations in Blood Glucose Self-Testing: An Overview of the Current Knowledge.

In general, patients with diabetes performing self-monitoring of blood glucose (SMBG) can strongly rely on the accuracy of measurement results. However, various factors such as application errors, extreme environmental conditions, extreme hematocrit values, or medication interferences may potentially falsify blood glucose readings. Incorrect blood glucose readings may lead to treatment errors, for example, incorrect insulin dosing. Therefore, the diabetes team as well as the patients should be well informed about limitations in blood glucose testing. The aim of this publication is to review the current knowledge on limitations and interferences in blood glucose testing with the perspective of their clinical relevance.

Dipeptidyl-peptidase-4 Inhibitors and Heart Failure: Class Effect, Substance-Specific Effect, or Chance Effect?

OPINION STATEMENT: The increased risk of heart failure hospitalizations related to treatment with the DPP-4 inhibitor saxagliptin observed in the SAVOR TIMI 53 trial, is likely not to be a chance effect, but rather a previously unrecognized side effect of this drug, as this risk was very consistently apparent across all subgroups of this large multicenter, prospective, randomized trial. Whether this side effect might represent a class effect of all DPP-4 inhibitors remains to be seen. Results of randomized prospective multicenter trials with the DPP-4 inhibitors alogliptin and vildagliptin have in fact generated new uncertainties and clearly not totally excluded the possibility of a class side effect. A meta-analysis of 59 randomized controlled trials with various DPP-4 inhibitors evaluating data from 36,620 patients with diabetes and a minimal observation period of 24 weeks, confirmed a 21 % increase of heart failure events compared to placebo treatment, however, not in comparison to treatment with other blood glucose lowering drugs. German registry data also did not show an increased risk for heart failure for the latter comparison. Potential interactions of DPP-4 inhibitors with other drugs, e.g. ACE inhibitors, have been discussed in relation to the increased heart failure risk, as well as interactions with peptides regulating cardiovascular functions that are also split by DPP-4 enzymes such as BNP, substance P, and NPY. Results from ongoing large multicenter trials with the DPP-4 inhibitors sitagliptin and linagliptin are expected to clarify the potential heart failure issue related to treatment with DPP-4 inhibitors.

Impact of a reduced error range of SMBG in insulin-treated patients in Germany.

Modeling approaches demonstrate that improvement in the accuracy of blood glucose (BG) meters may lead to cost savings. An improvement of accuracy of BG meters on the basis of a reduction in error range from 20% to 5% has been reported to be associated with substantial cost savings in Germany. The aim of this study is to analyze potential cost savings related to a reduction in error range from 20% to 15% and 10% of glucose meters in Germany. The health economic analysis included the number of type 1 diabetic and the number of insulin-treated patients in Germany, the costs for glucose monitoring, a model on the effects of the improvement of accuracy on the impact of severe hypoglycemic episodes, HbA1c, and subsequently myocardial infarctions and the costs of diabetes-related complications in Germany. In the model, a reduction of 1% and 3.5% reduction in severe hypoglycemic episodes, and a 0.14% and 0.28% reduction in HbA1c was included. In type 1 diabetes the savings could be equal to a reduction in health care expenditures of more than €1.0 million (20% vs 15% error range) and €3.4 million (20% vs 10% error range). Respectively, potential savings of more than €6.0 million and €20.1 million were calculated for the group of insulin-treated patients. The model demonstrates that a reduction of error range of BG meters from 20% to 15% and 10% may translate into substantial savings for the German health care system.

On the potential of acarbose to reduce cardiovascular disease.

In the emerging landscape of cardiovascular (CV) outcome trials evaluating the effects of blood glucose lowering drugs in individuals with type 2 diabetes, it is becoming increasingly apparent that since the promising signals coming from the United Kingdom Prospective Diabetes Study (UKPDS) no unequivocal benefits have been established for any single therapy thus far. There is an unmet need for introducing an effective pharmacological agent which could target both correlates of glycaemic regulation and CV risk factors, to ameliorate the enormous burden of fatal and non-fatal CV events in diabetic patients. Acarbose, like other alpha-glucosidase inhibitors (AGIs), has been proven to be an effective antidiabetic treatment for decades, but the overall significant impact of this class of drugs on modulating CV risk has only recently been appreciated. Accumulating evidence has shown that apart from its multiple effects on primarily postprandial glucose dysmetabolism, a key component of mechanisms linked to increased incidence of CV events, acarbose therapy also associates with a favorable impact on an array of surrogate markers of CV disease. Data stemming from in vitro testing of human cell lines as well as from preliminary trials in diabetic populations, like the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial, have highlighted - though not undisputed - the potential beneficial effects of the drug on CV morbidity. Large scale trials, like the ongoing Acarbose Cardiovascular Evaluation (ACE) trial, aim at conclusively establishing such a positive effect in patients with coronary heart disease and impaired glucose tolerance. In view of its usually acceptable level of side effects that are, if they occur, mostly limited to transient gastrointestinal symptoms, acarbose could well be a strong future player in CV disease secondary prevention. Current discouraging results from many trials of antidiabetic medications to significantly lower CV event rates in diabetic patients, should only draw further attention on alternative glucose lowering agents, among which acarbose is indeed promising.

Assessing the analytical performance of systems for self-monitoring of blood glucose: concepts of performance evaluation and definition of metrological key terms.

Reliability of blood glucose (BG) measurements is a prerequisite for successful diabetes management. Publications on the evaluation of self-monitored glucose values, however, are frequently characterized by a confusion in terminology. We provide an inventory of key terms such as accuracy, trueness, precision, traceability, calibration, and matrix effect to avoid future misunderstanding. Definitions are taken from the metrological literature and international norms and explained in a language intended for nonspecialists in metrology. The terms are presented in light of the need to apply generally accepted definitions. In addition, a description of requirements and components for a sound evaluation of BG measurement systems is presented. These factors will also enable improvement in future comparisons of study results.

Higher accuracy of self-monitoring of blood glucose in insulin-treated patients in Germany: clinical and economical aspects.

BACKGROUND: Accuracy standards of blood glucose (BG) meters are currently under review. Revised standards are expected to tighten accuracy requirements. Regarding clinical and financial impact of BG meter accuracy, very little data are available. The aim of this study was to analyze potential cost savings related to higher accuracy of glucose meters in Germany. METHODS: As a model for calculation, a reduction of meter error from 20% to 5% was applied. The health economic analysis was based on four main pillars: (1) number of insulin-treated patients; (2) costs for glucose monitoring in Germany; (3) data of a modeling analysis on the impact on hypoglycemic episodes, glycosylated hemoglobin (HbA1c), and, subsequently, myocardial infarctions; and (4) costs of diabetes-related complications in Germany. A reduction of meter error from 20% to 5% was identified to be associated with a 10% reduction in severe hypoglycemic episodes and a 0.39% reduction in HbA1c, which translates into a 0.5% reduction of myocardial infarctions. RESULTS: According to the health economic analysis, the reduction in severe hypoglycemic episodes and myocardial infarctions led to cost savings of €24.14 per patient per year. Considering 390,000 type 1 diabetes patients or 2.3 million insulin-treated patients in Germany, these savings could be equal to a reduction in health care expenditures of more than €9.4 million and €55.5 million, respectively. CONCLUSIONS: Potential cost savings and clinical effects due to higher accuracy of BG meters should provide an impetus to implementation of tighter accuracy standards and development of glucose meters that provide highest possible accuracy.

Glycemic control: a combination of lifestyle management and the use of drugs.

Some 30% of contemporary cardiology patients have coexisting known diabetes, and another 40% have either undiagnosed diabetes or prediabetes. There is still no final conclusive evidence of cardiovascular benefit by good glycemic control in type 2 diabetes, although studies like the United Kingdom Prospective Diabetes Study (UKPDS) and the Prospective Pioglitazone Clinical Trial in Macrovascular Events, and meta-analyses based on these and other randomized controlled trials of blood glucose-lowering therapies have been encouraging. On the other hand, microvascular disease is clearly reduced by good glycemic control. Structured education has remained a mandatory prerequisite of any successful treatment. Not only is appropriate weight management by diet and exercise able to revert new onset diabetes to normal, but it is also the foundation of any successful pharmacotherapy of diabetes. Aiming at normal fasting plasma glucose concentrations of 5.3 mmol/L or 95 mg/dL appears to be safe since publication of the long-term outcome results of the Outcome Reduction with an Initial Glargine INtervention trial. Individualized target glycosylated hemoglobin levels as near to normal as safely possible (i.e., <7% and avoiding hypoglycaemia) are the goal for glycemic control. Hypoglycemia seems to emerge as a real concern in cardiology patients. Based on the findings of UKPDS, including the "legacy" study, metformin is the most widely recommended first-line drug therapy in type 2 diabetes, also in terms of preventing cardiovascular complications. An alternate first-line option in some parts of the world, especially Asian countries, is the class of alpha-glucosidase inhibitors. In most patients, combination therapies with two or three classes of drugs are warranted. Early combination are the golden strategy as type 2 diabetes is a multi-causal disease; the various classes of drugs have distinct and synergistic modes of action, and the blood glucose-lowering efficacy of these drugs is more or less fully maintained in combination. The recent joint American Diabetes Association/European Association for the Study of Diabetes position statement mentions five options as step two of the treatment algorithm for combination with metformin: sulfonylureas, pioglitazone, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, and basal insulin.

Primary and secondary prevention of cardiovascular disease in diabetes with aspirin.

Diabetes is associated with an increased cardiovascular risk. The role for aspirin in diabetes is of high clinical interest. Guidelines recommend that primary prevention of cardiovascular disease (CVD) in diabetes with aspirin should be based on the individual risk for CVD. New mechanistic studies suggest that enhanced platelet turnover may partly contribute to the fact the primary prevention studies found unequivocal results in diabetes. There is initial evidence that a potential future modification of dosages in diabetes may counteract the enhancement in platelet turnover in diabetes. The use of aspirin in diabetic patients for secondary prevention of CVD is supported by key evidence. The aim of the review is to present recent studies on aspirin for prevention of CVD in diabetes and to highlight its role also in view of new mechanistic and clinical studies with aspirin. Novel aspects of aspirin, e.g. its potential role for the prevention of cancer, are also presented.

Diabetes and the risk for colorectal cancer.

Diabetes mellitus has been reported to be associated with an increased risk for colorectal cancer. The review analyzes current epidemiological data on the association of diabetes and the risk for colorectal cancer. Hyperinsulinemia, hyperglycemia, and inflammation are suggested to play a key role in the pathophysiology of cancer in diabetes. Data regarding potential treatment-related risks, particularly in conjunction with the use of insulin and insulin analogues, are also presented. Furthermore, the impact of glycemic control and cardiorespiratory fitness on cancer prognosis is considered. Finally, the preventive potential of aspirin and other nonsteroidal anti-inflammatory drugs, and the recommendations concerning colonoscopy-screening are presented.

What should be the antihypertensive drug of choice in diabetic patients and should we avoid drugs that increase glucose levels? Pro and Cons.

It has long been known that antihypertensive drugs may affect blood glucose in a differential manner. In particular new onset diabetes is significantly increased in association with the use of thiazides or beta-blockers, respectively, compared to placebo, whereas treatment with angiotensin-conversion-enzyme-inhibitors or angiotensin-receptor-blockers is associated with a lower than expected frequency, as also assessed in several meta-analyses. In line with these notions, the NAVIGATOR Trial was the first to report a significant preventive effect of an angiotensin-receptor-blocker on new onset diabetes evaluated as a primary outcome in a prospective randomized study. Hence, and in view of the fact that comparable blood pressure lowering with any of the five major classes of antihypertensive drugs, including calcium-channel-blockers, give comparable benefits in reducing cardiovascular complications, unless there are specific indications or contraindications for an individual drug, caution should be exercised, therefore, to use beta-blockers or thiazides as first-line drugs for blood pressure lowering indications in subjects at high risk to develop diabetes, especially in patients with so called metabolic syndrome. The potential of glycemic worsening in overt diabetic patients with thiazides or beta-blockers has less well been studied systematically, yet paradigmatically in UKPDS evaluating a randomized comparison of a beta-blocker with an angiotensin-conversion-enzyme(ACE)-inhibitor. Not only was there HbA1c worsening with beta-blocker use which required additional blood glucose lowering therapy, but also significantly more weight gain which still was detectable at the 20 year follow-up. On the other hand, the overall cardiovascular outcomes were comparable in the two treatment groups irrespective whether therapy was based on the beta blocker atenolol or the ACE-inhibitor captopril. Awareness of these facts and highly individualized therapy seem to be the way forward.