[Why is a combination of basal insulin with a GLP-1 receptor agonist useful in many patients with type 2 diabetes?] / Warum ist eine Kombination von Basalinsulin mit einem GLP-1-Rezeptoragonisten bei vielen Patienten mit Typ-2-Diabetes sinnvoll?

BACKGROUND: In 2015, the combination of basal insulin and GLP-1 receptor agonist (RA) was incorporated into the guideline recommendations for type 2 diabetes as an option for the last escalation step. The two antidiabetics to be injected subcutaneously are complementary regarding their respective main effects and limitations. Basal insulin is predominantly active between meals and in the fasting state, whereas the main action of GLP-1 RA consists in preventing an excessive postprandial blood glucose increase. Moreover, GLP-1 RA is characterised by a low intrinsic risk of hypoglycaemia, body weight reduction and a positive impact on cardiovascular risk factors. Unlike GLP-1 RA, no upper dose limits are defined for basal insulin. However, initiation of insulin therapy is associated with disadvantages in terms of hypoglycaemia and weight increase. Therefore, patients achieving their treatment goals with GLP-1 RA alone are better treated without insulin. METHOD: In a review, study results on combinations of basal insulin and GLP-1-RA versus comparative therapies are presented. RESULTS: Most of the studies were carried out in patients pre-treated with basal insulin. The add-on of GLP-1 RA was commonly associated with significant reductions of body weight and also resulted in additional HbA1c reductions compared with an increase of the basal insulin dose. The add-on of a short acting insulin to an existing basal insulin therapy enabled similar HbA1c reductions to the add-on of a GLP-1 RA, but simultaneously increased the number of episodes of hypoglycaemia and might lead to more unfavourable body weight developments. A fixed combination of insulin degludec and liraglutide (IDegLira) showed an effective and rather steady blood glucose reduction in a 24-hour interval vs. basal insulin or GLP-1 RA alone. CONCLUSIONS: Combinations of basal insulin and a GLP-1 RA improve glycaemic control in many patients with type 2 diabetes without any significant increase of the risk of hypoglycaemia and without weight gain, especially compared to a dose increase of the basal insulin or add-on of a short-acting insulin.

Investigation of the vascular and pleiotropic effects of atorvastatin and pioglitazone in a population at high cardiovascular risk.

We investigated the effect of atorvastatin monotherapy and combined treatment with atorvastatin and pioglitazone on intima-media thickness, vascular function and the cardiovascular risk profile. In all, 148 patients (76 male, 72 female; aged 61.4+/-6.5 years; body mass index [BMI] 29.2+/-4.1 kg/m2; mean +/- SD) with increased cardiovascular (CV) risk factors were randomised. Intima-media thickness (IMT), the augmentation index (Aix@75), the microvascular response to acetylcholine (LDF), lipid status, and plasma levels of intact proinsulin, adiponectin, interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), sCD40L, P-selectin, tissue plasminogen activator (t-PA) and blood lipids were monitored over six months. Atorvastatin treatment, alone and in combination with pioglitazone, revealed a significant regression in IMT (0.923+/-0.013 to 0.874+/-0.012 mm and 0.921+/-0.015 to 0.882+/-0.015 mm; mean +/- SEM; p<0.05 respectively) and Aix@75 (27.3+/-1.2 to 25.9+/-1.4; and 25.6+/-1.4 to 24.8+/-1.7%; p<0.05). The endothelial response to acetylcholine as measured by laser Doppler fluximetry (LDF) improved during combined treatment (373+/-57 to 576+/-153 AU; p<0.05). Addition of pioglitazone to atorva-statin resulted in significant further effects on high-sensitivity C-reactive protein (hsCRP), t-PA, P-selectin, adiponectin, triglycerides and high-density lipoprotein (HDL) cholesterol (p<0.05 respectively). Atorvastatin significantly improved IMT and vascular elasticity. Co-administration of pioglitazone provided additional effects on endothelial function, lipid profile and laboratory markers of inflammation.

Rosiglitazone and glimeperide: review of clinical results supporting a fixed dose combination.

Type 2 diabetes has become a major burden to the health care systems worldwide. Among the drugs approved for this indication, glimepiride and rosiglitazone have gained substantial importance in routine use. While glimepiride stimulates beta-cell secretion and leads to reduction of blood glucose values, rosiglitazone activates PPARgamma and improves insulin resistance, at the vascular and metabolically active cells. Therefore, the combination of the two drugs may be an interesting approach to improve glycemic control and lower cardiovascular risk. A fixed combination of both drugs has been approved for clinical use in the US and EU. The combination of glimepiride and rosiglitazone is generally well tolerated and the use of a fixed combination may lead to improved adherence of the patients to their therapy. The purpose of this review is to evaluate the clinical data that have been published on this combination, appearing to represent a convenient way to obtain therapeutic targets in patients with type 2 diabetes mellitus.

Evaluation of CGMS during rapid blood glucose changes in patients with type 1 diabetes.

BACKGROUND: CGMS (Medtronic Minimed, Duesseldorf, Germany) allows continuous glucose monitoring. Recent studies with invasive monitoring techniques revealed discrepancies in blood glucose measurements obtained from different anatomical sites compared with those from the fingertip. The aim of this study was to investigate the CGMS and a device for alternative site testing (AST) during dynamic blood glucose changes and to compare these results with fingertip measurements. METHODS: Twelve patients with type 1 diabetes (seven women, five men; age, 33.3 +/- 8.7 years) received a 75-g oral glucose load. Insulin was applied intravenously (rapid glucose decline) or subcutaneously (moderate glucose decline) in a dosage between 3 to 18 units 2 h later in a randomized sequence on two different days. For continuous glucose measurements the CGMS standard sensor was inserted into the lower abdominal subcutis. Glucose measurements were obtained from the forearm using a minimally invasive technique (AST). CGMS and AST measurements were compared with glucose measurements obtained from the fingertip using a standard glucose oxidase method. RESULTS: No significant difference could be observed among all three methods during increasing glucose levels. Insulin-induced blood glucose decline resulted in a significant time lag in the time course of blood glucose measurements obtained by AST compared with those obtained from the fingertip (P < 0.05, respectively). No significant difference could be observed between CGMS and fingertip measurements. Error grid analysis revealed 100% during rapid glucose fall and 98.5% during modest glucose fall of CGMS measurements within the clinically acceptable zones A and B. CONCLUSIONS: Continuous glucose measurements using CGMS provide reliable glucose measurements even in the case of dynamic blood glucose changes.

[Long-term effects of 7-year growth hormone substitution on bone metabolism, bone density, and bone quality in growth hormone-deficient adults]. / Wachstumshormon und Knochen. Einfluss einer 7-jährigen Wachstumshormonsubstitution auf Knochenstoffwechsel, Knochendichte und Knochenqualität bei Erwachsenen mit einem Wachstumshormonmangel.

BACKGROUND AND PURPOSE: Subnormal bone mineral density (BMD) and increased fracture risk are described in patients with growth hormone deficiency (GHD). Growth hormone (GH) has been reported to have beneficial effects on bone in GHD. The aim of this study was to investigate the long-term effects of GH replacement therapy on bone metabolism, BMD, and bone quality in patients with GHD. PATIENTS AND METHODS: 20 adult patients with GHD (eleven male, nine female, mean age 42.5 years) were included in the study and randomized to either GH or placebo in a dose of 0.25 U/kg body weight/week. After 6 months all patients received GH. After a 1-year double-blind, placebo-controlled study the patients were followed for another 72 months in an open study. The patients were compared to 20 age- und sex-matched healthy controls. Bone turnover was determined by ICTP (type I collagen carboxyterminal cross-linked telopeptide) as parameter of bone resorption and PICP (carboxyterminal propeptide of type I procollagen) as marker of bone formation. BMD was measured at the lumbar spine by dual-photon absorptiometry (DPA) and at the forearm by single-photon absorptiometry (SPA). Apparent phalangeal ultrasound transmission velocity (APU) was assessed as parameter of bone quality independent of BMD. RESULTS: At the beginning of the study BMD at both measuring sites was lower in patients with GHD than in healthy controls. During the 1st year of GH replacement therapy BMD decreased, followed by a continuous increase in BMD (about 12%) up to 60 months which remained unchanged thereafter, building up a plateau. After 72 months no significant difference between the patients and the healthy controls could be detected. Concerning parameters of bone turnover, first ICTP as marker of bone resorption showed a significant increase, later on the marker of bone formation increased as well. APU decreased during the first 6 months of treatment, but had returned to its baseline value after 24 months and remained unchanged throughout the rest of the study. CONCLUSION: BMD is subnormal in adults with GHD. GH replacement therapy stimulates bone turnover in patients with GHD and in the long term such stimulation results in an increased BMD. Thereby, GH shows a triphasic action on BMD: an initial decrease in BMD during the 1st year, followed by a continuous increase in BMD with buildup of a stable plateau after 60 months. The newly formed bone seems to have normal bone elasticity.

Determination of nitrotyrosine concentrations in plasma samples of diabetes mellitus patients by four different immunoassays leads to contradictive results and disqualifies the majority of the tests.

BACKGROUND: In the course of type 2 diabetes mellitus, insulin resistance has a severe impact on endothelial function leading to decreased synthesis of nitric oxide (NO). Postprandial hyperglycemia leads to the generation of reactive oxygen species, which counteracts the beneficial NO effects. NO and superoxide combine very fast in solution to form peroxynitrite, which is a potent protein-oxidizing agent. The peroxynitrite concentrations can be indirectly monitored by the detection of nitrotyrosine residues in proteins, reflecting the extent of damage caused by oxidative stress. METHODS: Four commercially available nitrotyrosine-specific immunoassays were evaluated by parallel measurement of nitrotyrosine in 224 serum samples derived from 16 patients with type 2 diabetes and 12 healthy controls (13 male and 15 female, age: 33+/-11 years) following a standardized meal. RESULTS: The available ELISA tests were not applicable for nitrotyrosine determination in human plasma samples due to technical issues and implausible results. However, a competitive luminescence assay was able to provide sufficient sensitivity and lead to clinically meaningful results in our test samples. CONCLUSIONS: All three ELISA methods were disqualified and conclusions previously derived from clinical experiments using these tests should be carefully reconsidered or reconfirmed. In the absence of a liquid tandem chromatography-mass spectrometry reference method, the luminescence test appears to be the method of choice for determination of nitrotyrosine in human plasma.

Endothelial function and arterial stiffness in uncomplicated type 1 diabetes and healthy controls and the impact of insulin on these parameters during an euglycemic clamp.

BACKGROUND: In addition to its role in glucose metabolism, insulin has shown to exert numerous vascular effects, and an impaired vascular function of insulin is assumed to be a major contributor in the development of vascular complications. Arterial augmentation (AP) and the augmentation index (Aix) are surrogate parameters of arterial stiffness and are commonly used as predictors for cardiovascular risk. The aim of this study is to investigate the effect of insulin on arterial stiffness and parameters of endothelial function in patients with type 1 diabetes and healthy control subjects. METHODS: Fourteen patients with type 1 diabetes (six male, eight female) with a mean age of 36.6 +/- 11.8 years and 14 healthy subjects (seven male, seven female) with a mean age of 27.3 +/- 5.5 years were randomized to an euglygemic clamp with either a low (0.25 mU/kg/min) or a high (1.0 mU/kg/min) insulin dose on two different days. The mean HbA1c in the diabetic subjects was 7.3 +/- 0.7%. In these subjects, arterial stiffness was measured by pulse wave analysis (SphygmoCor, AtCor Medical, Australia). AP was calculated as the difference between the second and the first systolic shoulders of the central pressure wave curve, and the Aix was expressed as the percentage of AP from total pulse pressure. As parameters of endothelial function, cyclic guanosine monophosphate, nitrotyrosine, and asymmetric dimethylarginine were determined at baseline and after 120 minutes. RESULTS: Patients with type 1 diabetes showed increased values for AP with 3.5 +/- 3.1 mm Hg and Aix with 12.5 +/- 12.5% compared to healthy controls with -0.7 +/- 2.6 mm Hg for AP and -4.2 +/- 10.6% for Aix. This difference was statistically significant (p < 0.01). During the euglycemic clamp, insulin improved, but did not normalize the increased values for AP and Aix in patients with type 1 diabetes. Concerning parameters of endothelial function, patients with type 1 diabetes showed statistically significant increased values for nitrotyrosine compared to healthy controls at baseline [low insulin: diabetes mellitus (DM) 1993.12 +/- 1330.85 nmol/liter vs healthy controls 803.7 +/- 726.91; high insulin DM: 2208.02 +/- 1736.57 nmol/liter vs healthy controls: 750.83 +/- 426.03 nmol/liter] (p < 0.05). CONCLUSION: Patients with type 1 diabetes mellitus revealed an increased arterial stiffness measured as augmentation and augmentation index and increased nitrotyrosine levels as a marker of oxidative stress compared to healthy control subjects at baseline. Application of insulin improves the arterial elastic properties, but was not able to normalize the vascular function in patients with type 1 diabetes.

Increased arterial augmentation and augmentation index as surrogate parameters for arteriosclerosis in subjects with diabetes mellitus and nondiabetic subjects with cardiovascular disease.

BACKGROUND: Arterial augmentation (AP) and the augmentation index (Aix) are surrogate parameters of arterial stiffness and are commonly used as predictors for cardiovascular risk. The aim of this study is to compare these parameters in diabetic subjects and nondiabetic cardiovascular risk subjects with healthy control subjects. METHODS: One hundred sixty-six nonsmoking subjects aged between 35 and 70 years were included in the study, which included 100 subjects with cardiovascular disease but not diabetes (mean age 62.73+/-8.75 years), 33 subjects with type 2 diabetes (66.58+/-2.69 years), and 33 healthy controls (51.89+/-8.91 years). In these subjects, arterial stiffness was measured by the difference between the second and the first systolic peak of the central pressure waveform, and the Aix was calculated as the percentage of Aix from pulse pressure. RESULTS: Arterial augmentation was increased in subjects with diabetes (DM) with 10.21+/-6.97 mm Hg and in subjects with cardiovascular disease but not diabetes (CV) with 10.74+/-5.29 mm Hg in comparison to healthy controls (C) with 6.59+/-3.97 mm Hg (p < 0.0005 DM vs C; p < 0.00005 CV vs C). Moreover, Aix was increased with 26.00+/-9.91% in CV subjects compared to healthy controls with 19.84+/-9.37% (p < 0.02 CV vs C). The augmentation index was increased with 21.12+/-11.21% in subjects with type 2 diabetes mellitus compared to controls, but failed to be statistically significant. There was no statistical significance in arterial augmentation or the augmentation index between CV and diabetic subjects. CONCLUSION: The results of our study revealed a comparable increased augmentation index as a surrogate measure of arterial stiffness and arteriosclerosis in subjects with diabetes mellitus and in nondiabetic subjects with cardiovascular disease.