Serum and Plasma Levels of Vascular Endothelial Growth Factors in Relation to Quality of Glucose Control, Biomarkers of Inflammation, and Diabetic Nephropathy.

Levels of vascular endothelial growth factors (VEGF) are regulated in a complex network of adipokines, glucose control, and low grade inflammation together with activated platelets, leucocytes, and endothelial dysfunction. Increased levels of VEGF are associated with enhanced angiogenesis and impaired repair mechanisms of vascular lesions in endorgans. Little is known about the interaction of systemic VEGF levels with quality of diabetes control, biomarkers of inflammation, and diabetic nephropathy. Moreover, it is unclear, whether serum and plasma VEGF levels are similarly suited to reflect risk associated with VEGF.In this case control study, we analyzed these parameters in serum and plasma of age and sex matched controls without diabetes (n=99) and type 2 diabetes (n=302). Serum VEGF-A was significantly increased in patients with T2DM while plasma levels were in the same range as for controls. Individual levels varied in a wide range. Serum levels were 4.9 times higher in controls and 7.3 times higher in T2DM as compared to plasma levels. T2DM was associated with significantly higher levels of hsCRP, ALAT, and albumin/creatinine ratio. When calculated for tertiles of HbA1c, we observed a highly significant increase from tertile one to the upper tertile for serum VEGF-A but not for plasma VEGF-A. Correlation analysis revealed a significant relationship between VEGF-A, HbA1c, inflammation, and diabetic nephropathy. Our results indicate that increased VEGF-A levels in T2DM significantly depend on quality of HbA1c control. Serum levels of VEGF-A, with a strong contribution of platelet derived VEGF, better reflect the glycemic burden than plasma levels of VEGF-A. Mechanistic studies are needed to explore links to inflammation and diabetic nephropathy.

Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION).

AIMS: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. METHODS: In this multinational, randomized, double-blind, phase IIIb/IV study (GENERATION; NCT01006603), patients aged ≥65 years were randomized (1 : 1) to receive saxagliptin 5 mg/day or glimepiride ≤6 mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of glycated haemoglobin (HbA1c) <7.0% at week 52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. RESULTS: Of 720 patients randomized (360 in each treatment group; mean age 72.6 years; mean T2D duration 7.6 years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9 vs 38.2%; odds ratio 0.99, 95% confidence interval 0.73, 1.34; p = 0.9415); however, a significant treatment-by-age interaction effect was detected (p = 0.0389): saxagliptin was numerically (but not significantly) superior to glimepiride for patients aged <75 years (39.2 vs 33.3%) and numerically inferior for patients aged ≥75 years (35.9 vs 45.5%). The incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1 vs 15.3%; nominal p < 0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events compared with glimepiride. CONCLUSION: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged ≥65 years.

Use of insulin in type 2 diabetes: what we learned from recent clinical trials on the benefits of early insulin initiation.

The majority of people with type 2 diabetes mellitus (T2DM) require insulin therapy to maintain HbA(1c) levels < 7% during the first decade of diagnosis. Large prospective trials investigating the cardiovascular (CV) benefits of intensive glycaemic control have produced inconsistent results; however, meta-analyses have suggested that intensive glycaemic control provides both micro- and macrovascular benefits. The ORIGIN study investigated the impact of basal insulin glargine therapy targeting ≤ 5.3 mmol/L for fasting plasma glucose compared with standard care on CV outcomes in people with pre- or early diabetes, and demonstrated a neutral effect on CV outcomes with long-term use of insulin glargine early in the course of diabetes, with a low rate of severe hypoglycaemia and modest weight gain. The EARLY, GLORY and EASIE studies also demonstrated that insulin use earlier in the treatment pathway led to improved glycaemic control, reduced weight gain and fewer hypoglycaemic episodes than when insulin was added later in the course of disease. The beneficial effect of early transient intensive insulin therapy (TIIT) at diagnosis has been demonstrated in a number of trials; it rapidly limits the damage caused by gluco- and lipotoxicity, improving residual ß-cell function and potentially slowing disease progression. The evidence suggests that people newly diagnosed with T2DM and HbA(1c) > 9% should be given early TIIT to achieve normoglycaemia within weeks, after which standard care should then be adopted. Insulin use earlier in the treatment pathway should be considered, as it reduces the risk of hypoglycaemia as well as allows ß-cell rest, which can help preserve ß-cell function.

[Hypoglycemia and cardiac arrhythmia in patients with diabetes mellitus type 2]. / Hypoglykämie und Herzrhythmusstörungen bei Patienten mit Diabetes Typ 2.

Hypoglycemia is a common and potentially life-threatening adverse effect of inappropriate diabetes treatment. Typical cardiac complications are ischemia with angina pectoris, myocardial infarction, stroke and arrhythmias, such as atrial fibrillation (AF), ventricular tachycardia and heart failure. Elderly multimorbid patients with type 2 diabetes and polypharmacy and/or cardiac autonomous neuropathy represent a very high risk group for cardiovascular complications associated with hypoglycemia. Targets for glycemic control have to be adapted to the risk of hypoglycemia with a priority of stable glucose homeostasis without rapid fluctuations. Elderly patients with diabetes have a >20% risk of AF. At blood glucose levels of <3 mmol/l with a duration of >30 min, prolongation of QTc time and ventricular tachycardia occur with an increased risk of ventricular fibrillation and sudden death. Ventricular arrhythmias and AF significantly increase mortality in patients with heart failure. Rapid fluctuations with a mean amplitude of glucose excursion (MAGE) >5 mmol/l promote vulnerability of electrical stability of the heart, particularly in frail patients with preexisting coronary heart disease and autonomic neuropathy. Antihyperglycemic agents, such as metformin, acarbose and sodium glucose cotransporter 2 (SGLT2) inhibitors have only a low risk of severe hypoglycemia. Dipeptidyl peptase 4 (DPP-IV) inhibitors and glucagon-like peptide 1 (GLP1) analogues as insulin secretagogues have a lower risk for hypoglycemia than sulfonylurea and insulin. Early basal insulin treatment in patients insufficiently controlled with metformin is efficient, safe and convenient. Targets for glucose control and HbA1c have to be individualized and the choice of drugs must be risk-adjusted. Risk of hypoglycemia should be used as guide in decision-making for safe treatment of diabetes.

Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1).

AIMS: To assess the efficacy and safety of one- and two-step dose-increase regimens of lixisenatide once daily in participants with Type 2 diabetes mellitus insufficiently controlled with metformin. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre study enrolling participants with Type 2 diabetes (n = 484) treated with metformin. Participants were randomized to receive either lixisenatide in a one-step dose increase or a two-step dose increase vs. placebo for 24 weeks, followed by a ≥ 52-week variable double blind period. Primary outcome was HbA1c reduction at week 24. RESULTS: Lixisenatide one-/two-step once daily significantly improved HbA1c at week 24 compared with placebo (P < 0.0001) and allowed more participants to achieve HbA1c < 53 mmol/mol (< 7.0%) (P ≤ 0.0005). Improvements were observed in fasting plasma glucose (-0.5/-0.6 vs. +0.1 mmol/l; P < 0.001) and body weight (-2.6/-2.7 vs. -1.6 kg; P < 0.005). At week 24, adverse events were reported by 67.7/70.8/65.6% of participants treated with lixisenatide one-/two-step/placebo, respectively--nausea and vomiting being reported most frequently. Symptomatic hypoglycaemia occurred in 1.9/2.5% of participants on one-/two-step lixisenatide and 0.6% with placebo, with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable double-blind extension period of at least 52 weeks. CONCLUSIONS: Lixisenatide one- or two-step dose-increase regimens significantly improved glycaemic control and decreased body weight over 24 weeks and during a long-term extension period without increasing hypoglycaemia. The study confirmed that tolerability in the one-step group was at least similar to the two-step dose increase, with nausea/vomiting and hypoglycaemia frequency being lower in the one-step regimen.

Insulin and atherosclerosis: how are they related?

The relationship between insulin and atherosclerosis is complex. People with type 2 diabetes are affected by three main glycaemic disorders: chronic hyperglycaemia; glycaemic variability; and iatrogenic hypoglycaemia. In addition to this triumvirate, the diabetic condition is characterized by lipid disorders, chronic low-grade inflammation and activation of oxidative stress. All these associated disorders reflect the insulin-resistant nature of type 2 diabetes and contribute to the development and progression of cardiovascular (CV) diseases. By both lowering plasma glucose and improving the lipid profile, insulin exerts beneficial effects on CV outcomes. In addition, insulin has several pleiotropic effects such as anti-inflammatory, antithrombotic and antioxidant properties. Insulin per se exerts an inhibitory effect on the activation of oxidative stress and seems able to counteract the pro-oxidant effects of ambient hyperglycaemia and glycaemic variability. However, insulin actions remain a subject of debate with respect to the risk of adverse CV events, which can increase in individuals exposed to high insulin doses. Evidence from the large-scale, long-term ORIGIN trial suggests that early implementation of insulin supplementation therapy in the course of glycaemic disorders, including type 2 diabetes, has a neutral impact on CV outcomes compared with standard management. Thus, the answer to the question "What impact does insulin have on atherosclerosis?" remains unclear, even though it is logical to deduce that insulin should be initiated as soon as possible and that small doses of insulin early on are better than higher doses later in the disease process.

Effects of insulin glargine versus metformin on glycemic variability, microvascular and beta-cell function in early type 2 diabetes.

We investigated whether basal insulin as first-line treatment in recently diagnosed type 2 diabetes (T2D) can improve glucose control, microvascular function and preserve insulin secretion in comparison with metformin (MET). In this open-label, randomized, prospective 36-week study, 75 patients (44 m, 31 f, mean age 60.7 ± 9.2 year) were allocated to treatment with either MET 1,000 mg b.i.d. (n = 36) or insulin glargine (GLA) at bedtime (n = 39). At baseline and study end, we performed a continuous glucose monitoring for assessment of interstitial glucose (IG) and measured microvascular function using Laser-Doppler fluxmetry. GLA versus MET treatment resulted in a more pronounced reduction in FPG (Δ: 3.1 ± 2.5 vs. 1.4 ± 1.5 mmol/l; p < 0.001) and overall IG (Δ AUC. 671 ± 507 vs. 416 ± 537 mmol/l min; p = 0.04). Postprandial PG and IG differences after a standardized test meal did not reach significance. Proinsulin/C-peptide and HOMA B as marker of endogenous insulin secretion were significantly more improved by GLA. Microvascular blood flow improved only in MET-treated patients. Early basal insulin treatment with GLA in T2D patients provided a better control of FPG, overall IG load and biomarker of beta-cell function compared to the standard treatment with MET. MET treatment resulted in an improvement of microvascular function. Studies of longer duration are needed to evaluate the durability of glucose control and ß cell protection with early GLA treatment.

[Diabetes and heart failure: a practically oriented critical appraisal]. / Diabetes und Herzinsuffizienz: eine praxisorientierte, kritische Bestandsaufnahme.

Patients with type 2 diabetes have an increased risk for developing symptoms of heart failure. These can be accompanied by a reduction of left ventricular ejection fraction (HFREF, systolic heart failure) or by a preserved function (HFPEF, diastolic heart failure). The pathophysiology of both entities is distinct and involves impairment of myocardial metabolism and coronary circulation alike. Although diabetes and heart failure often coincide, the management of these patients particularly with respect to the specific benefits or possible hazards of antidiabetic treatment is vague. Therefore, from a pathophysiological as well as clinical viewpoint, 1) diabetic patients with symptoms of heart failure have to be differentiated regarding systolic as well as diastolic left ventricular function by echocardiography and tissue doppler imaging. 2) Heart failure in diabetic patients needs similar attention due to a prognosis and interactions. 3) Optimized blood glucose lowering in combination with improvement of other cardiovascular risk factors is evident for HFREF and is assumed to be beneficial for HFPEF. 4) Antidiabetic medication has to be specifically adapted for both entities. As prospective, controlled studies are scarce, future interventional studies should specifically focus on clinical outcome in diabetic patients with different entities of heart failure.

Effects of pioglitazone versus simvastatin on biomarkers of inflammation in patients on high cardiovascular risk.

High levels of fetuin-A has been linked to cardiovascular disease, possibly via modulating low-grade systemic inflammation. We performed a subanalysis from the PIOSTAT study to investigate a possible link between fetuin-A and the inflammatory biomarker hs-CRP. 66 nondiabetic individuals at cardiovascular risk were randomized to either pioglitazone, simvastatin, or the combination of both, and followed for 12 weeks. At study endpoint, correlations between serum fetuin-A, hs-CRP, blood lipids, PAI-1, MMP-9, HOMA-IR, and liver transaminases were investigated by Spearman rank correlation. Changes in fetuin-A concentration did not correlate to changes in hs-CRP (r=0.19, p=0.16). A positive correlation was found for change of HOMA-IR value (r=0.33, p=0.01) and for the AST/ALT ratio (p<0.05). Our data suggest that the previously observed correlation between elevated circulating fetuin-A and hs-CRP in epidemiological studies may not reflect a causal relationship in nondiabetic patients on high cardiovascular risk.

Relationship between HbA1c on target, risk of silent hypoglycemia and glycemic variability in patients with type 2 diabetes mellitus.

OBJECTIVE: We aimed to compare time spent at low glucose level (silent hypoglycemia, glucose <3.0 mmol/l) and glycemic variability in patients who reached HbA1c <7.0% with those who did not. RESEARCH DESIGN AND METHODS: In 108 type 2 diabetic patients the interstitial glucose concentration was measured with CGMS (Continuous Glucose Monitoring System) over 72 h. Patients were divided in group 1 with an HbA1c <7.0% (n=63) and group 2 with an HbA1c≥7.0% (n=45). RESULTS: 24% in group 1 experienced silent hypoglycemia vs. 11% in group 2 (n. s.), duration of silent hypoglycemia over 48 h was 27±71 min vs. 7±36 min (n. s.). This was also valid for the subgroups treated with insulin. Patients in group 2 had a significantly higher standard deviation of average glucose (2.3±0.8 vs. 1.3±0.6; p<0.001) and MAGE (mean amplitude of glycemic excursions) (4.8±2.1 vs. 2.6±1.1; p<0.001). CONCLUSION: Silent hypoglycemia tended to occur more often and to last longer in patients with HbA1c <7%. However, patients with HbA1c >7% had a higher glycemic variability. HbA1c >7% wasn't a reliable indicator of lower risk of hypoglycemia.

Comparative efficacy and safety of aliskiren and irbesartan in patients with hypertension and metabolic syndrome.

Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/7.1 mm Hg after 12 weeks, significantly greater (P≤0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to <135/85 mm Hg (29.2 vs 16.7% with irbesartan; P=0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both P<0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.

Effect of targeting normal fasting glucose levels with basal insulin glargine on glycaemic variability and risk of hypoglycaemia: a randomized, controlled study in patients with early Type 2 diabetes.

AIMS: The purpose of this sub-study of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial was to determine efficacy and safety of targeting normal fasting plasma glucose (FPG) levels in patients with early Type 2 diabetes treated with insulin glargine in comparison with standard care. METHODS: Participants were randomly allocated to insulin or standard care. Insulin was titrated to reach FPG

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis.

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options.

[Glycemic control and cardiovascular benefit: What do we know today?]. / Blutzucker-Senkung und kardiovaskulärer Vorteil: Was wissen wir heute?

It is still a much debated question whether antidiabetic therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with advanced type 2 diabetes. New findings result from ACCORD, ADVANCE and VADT. These trials reveal that microvascular and macrovascular effects of intensive glucose lowering have to be considered separately: Glycemic control convincingly demonstrated to have a protective impact on microvascular complications, especially nephropathy. However, macrovascular benefits remain doubtful in these megatrials and have to be considered in connection with the individual global risk. On the other hand, the Diabetes Intervention Study (DIS) and UKPDS 10-year follow-up results yielded better cardiovascular outcomes for those patients who received intensive glucose-lowering therapy very early after diabetes diagnosis, but the favourable influences did not manifest until a time period of 1 - 2 decades. For the first time, the cardiovascular benefit of an antidiabetic substance (pioglitazone) could be verified in the large-scale outcome-trial PROactive for patients with advanced diabetes and multiple manifestations of macroangiopathy. The results provide strong support for a beneficial influence on macrovascular complications just under 3 years of treatment. Nevertheless, the positive findings did not result from better glycemic control, but from the complexity of effects of PPARgamma agonist pioglitazone on insulin resistance, lipoprotein spectrum, blood pressure, endothelial function and biomarkers of subclinical inflammation. It is obvious that we need to integrate such pleiotropic effects on metabolic syndrome and cardiovascular disease to improve the quality of drug-therapy decisions. This, in turn, requires a growing body of evidence from large, long-term outcome trials - but appropriate data are still unavailable for the vast majority of antidiabetic drugs.

The role of pioglitazone in modifying the atherogenic lipoprotein profile.

Pioglitazone, a thiazolidinedione, has established efficacy in improving glycaemic control in patients with type 2 diabetes. Pioglitazone also improves components of the mixed dyslipidaemia profile common in these patients, as typified by raised levels of plasma triglycerides, low levels of HDL cholesterol (HDL-C) and a raised proportion of LDL cholesterol (LDL-C) occurring as the small dense subfraction. In head-to-head trials, pioglitazone has consistently shown superior benefits on LDL-C and HDL-C as well as triglycerides compared with rosiglitazone and sulphonylureas. Pioglitazone used as monotherapy or combination therapy reduces levels of small dense LDL3 particles while raising levels of larger and less atherogenic LDL fractions. In addition, pioglitazone reduces cholesterol load and particle numbers of LDL3. Importantly, the differential effects of pioglitazone on LDL subfractions are complimentary and additive to those of simvastatin. Pioglitazone increases total HDL-C levels by 10-20%, mainly because of an increase in the larger HDL2 subfraction. Pioglitazone also significantly reduces plasma triglyceride levels by 10-25%. In recent studies, pioglitazone significantly reduced carotid and coronary atherosclerosis compared with the sulphonylurea glimepiride. The antidyslipidaemic effects of pioglitazone--in particular, improvements in HDL-C and reduction of small dense LDL3--may have contributed to these effects.

[Challenge in diabetes therapy: effects of glitazones beyond blood glucose control]. / Herausforderung Diabetestherapie: Effekte der Glitazone jenseits der Blutzuckerkontrolle.

Not just since the results of ACCORD, ADVANCE and VADT were published, it is clear that lowering blood glucose alone does not reduce the cardiovascular risk of patients with type 2 diabetes. In fact, many studies also indicate that some treatment strategies may even have adverse effects. To treat type 2 diabetes appropriately, the co-morbidities such as diabetic dyslipidaemia, hypertension or nephropathy must also be taken into account. Thiazolidinediones reduce insulin resistance thus allowing to direct the treatment of type 2 diabetes towards its pathophysiologic origin. Due to their mechanism of action, thiazolidinediones not only lower blood glucose but have also beneficial effects on inflammatory and atherogenic parameters, blood pressure and microalbuminuria. Furthermore pioglitazone improves dyslipidaemia and reduces mortality, myocardial infarction and stroke in high risk patients. Effects of rosiglitazone on the cardiovascular risk are yet unclear. Numerous studies document the efficacy and safety of thiazolidinediones and provide a basis for an evidence-based therapeutic approach beyond blood glucose control.

Effect of acarbose on postmeal mononuclear blood cell response in patients with early type 2 diabetes: the AI(I)DA study.

So far little is known about how the antidiabetic drugs acting at the level of gastrointestinal mucosa may affect immune and cellular response to food intake. The following study investigated the association between acarbose treatment and postprandial metabolism, immune- and inflammatory activity in patients with early type 2 diabetes: The Acarbose action on low grade Inflammation and Immune response in type 2 Diabetes on Atherosclerosis risk (AIIDA) study. Middle-aged patients (n=87) with early type 2 diabetes (2 h-plasma-glucose >or=11.1 mmol/l and/or HbA1c >or=6.5%) and sub-clinical inflammation (leucocytes >or=6.2 GPt/l and/or hsCRP >or=1.0 mg/l) underwent a mixed meal load (527 kcal). Metabolic parameters and markers of subclinical inflammation were measured at fasting (0'), 2 h-postprandial (2-hpp) and 4-hpp before and after 20 weeks of treatment with acarbose or placebo. Leukocytes and lymphocytes excursion after 20 weeks of treatment was significantly reduced with acarbose 4 h after testmeal [GPt/l] (7.5 vs. 7; p<0.05; and 2.29 vs. 2.14; p<0.05, respectively). Acarbose had only marginal effects on pp glucose, FFA, triglycerides, and insulin excursion. Biomarkers of inflammation (hsCRP, MBL, and PAI1) were not affected by acarbose. Multivariate analysis reveals only baseline leukocytes and of acarbose as independent determinant of 4-h leucocytes excursion. Postprandial metabolic and inflammatory parameters were strongly interrelated. These results suggest pleiotropic effects of acarbose, which may contribute to its vasoprotective potentials.